Total synthesis of nhatrangin a

Article abstract of DOI:10.1021/jo401248n

A concise and stereoselective approach for the synthesis of key intermediates for aplysiatoxins, oscillatoxins, and nhatrangins and their utility for the total synthesis of nhatrangin A has been demonstrated. The advanced intermediates aromatic aldehyde 11 and dihydroxy acid 12 were synthesized in eight steps (44% overall yield) and three steps (55% overall yield), respectively. An asymmetric Michael addition, CBS reduction, and proline-catalyzed crossed-aldol reactions were utilized as key steps for the generation of all the chirality of main chain hydroxyaldehyde, while the appended side-chain-protected 3,4-dihydroxypentanoic acid was achieved in a shortest route, using Sharpless dihydroxylation, diol protection, and RuO ₄-catalyzed aromatic over-oxidation reactions. Synthesis of nhatrangin A was accomplished by coupling of dihydroxy acid 12 with β-hydroxyallyl ester (obtained from 11) under Yamaguchi reaction conditions followed by a one-pot deprotection of all protecting groups.

Full text of DOI:10.1021/jo401248n

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Article
Total Synthesis of Nhatrangin A
J. S. Yadav, Goreti Rajendar, Ramisetti Srinivasa Rao, and Srihari Pabbaraja
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo401248n • Publication Date (Web): 08 Aug 2013
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Total Synthesis of Nhatrangin A
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Jhillu Singh Yadav,* Goreti Rajendar, Ramisetti Srinivasa Rao and Srihari Pabbaraja
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Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology,
Hyderabad 500007, India.
yadavpub@iict.res.in
TOC/Abstract Graphic
ABSTRACT: A concise and stereoselective approach for the synthesis of key
intermediates for aplysiatoxins, oscillatoxins and nhatrangins and their utility for
the total synthesis of nhatrangin A has been demonstrated. The advanced
intermediates aromatic aldehyde 11 and dihydroxy acid 12 were synthesized in 8
steps (44% overall yield) and 3 steps (55% overall yield) respectively. An
asymmetric Michael addition, CBS reduction and proline catalyzed crossed aldol
reactions were utilized as key steps for the generation of all the chirality of main
chain hydroxyaldehyde. While the appended side chain protected 3,4-
dihydroxypentanoic acid was achieved in a shortest route, using Sharpless
dihydroxylation, diol protection and RuO4 catalyzed aromatic over oxidation
reactions. Synthesis of nhatrangin A was accomplished by coupling of dihydroxy
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acid 12 with β-hydroxyallylester (obtained from 11) under Yamaguchi reaction
condition followed by a one pot deprotection of all protecting groups.
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INTRODUCTION
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Secondary metabolites produced by cyanobacteria display variety of biological
activities like cytotoxic, antitumor, antiviral, antibiotic, antimalarial, antimycotics, multi-
drug resistance reversers, antifeedant, herbicides and immunosuppressive activities.1,2
Two polyketide secondary metabolites nhatrangin A (1) and B (2) were isolated by
Orjala3 et.al.in 2010 from Lyngbya majuscula and they were named after the collection
site of Nha Trang Bay, Vietnam. These nhatrangins are the simplest analogues of
aplysiatoxins (3-5) and oscillatoxins (6-10), which were previously isolated from marine
blue-green algae Lyngbya majuscula and Schizothrix calcicola/Oscillatoria nigrouiridis
respectively (Figure 1).4 The nhatrangins A and B possess a simple architecture and are
less lipophilic in nature compared to aplysiatoxins. The structures of nhatrangins were
elucidated using 900 MHz cryoprobe 2D NMR spectroscopy and mass spectrometry. And
the absolute configuration was determined by circular dichroism which was compared
with the CD spectrum of debromoaplysiatoxin.
Aplysiatoxins, which are derivatives of nhatrangins are widely recognized as
tumor promoting agents and protein kinase C activators.5,6 However, the recently isolated
nhatrangins have not been investigated for their biological properties owing to their
limited availability from the nature. In continuation of our on-going research programme
towards the synthesis of complex biologically active natural products,7 we became
interested in the synthesis of nhatrangin A.
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HO
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O
OH
O OMe X
OMe X1
O
OH
O
O
O
R
O
O
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HO
X2
O
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OH
OH
R
X1 X2
X= H, Nhatrangin A (1)
X= Br, Nhatrangin B (2)
OH
Aplysiatoxin (3)
: CH3 Br
: CH3
: CH3 Br Br
H
Debromoaplysiatoxin (4)
19-Bromoaplysiatoxin (5)
Oscillatoxin A (6)
17-Bromo oscillatoxin (7)
17,19-Dibromo oscillatoxin (8) : H
H
H
O
: H
: H
H
Br
H
H
O
O
OMe
Br Br
R
O
O
O
OH
: R = H
30-Methyloscillatoxin (10) : R = CH3
Oscillatoxin D (9)
Figure 1. The structures of nhatrangins (1-2), aplysiatoxins (3-5) and oscillatoxins (6-
10).
As depicted in Figure 1, nhatrangins A (1) and B (2) possess two acid fragments that
are coupled by an ester linkage at C3 carbon of the main chain. The main chain aromatic
acid fragment contains a benzylic oxygen protected as methyl ether, and an 2,3-anti-3,4-
syn-stereotriad at C2 to C4 positions. This fragment can also serve as a common and
advanced intermediate for C9-C21 portion of all aplysiatoxins 3-5 and oscillatoxins 6-
10.8,9 Recently Piva9f et.al reported an approach towards the total synthesis of nhatrangin
A, while Kamal9g et.al reported a first total synthesis of nhatrangin A. By considering
these aspects, we have developed a concise and stereoselective strategy for the synthesis
of the aromatic fragment 11, and the side chain 12, and these fragments have been
successfully utilized to accomplish the total synthesis of nhatrangin A 1 (Scheme 1).
RETROSYNTHETIC ANALYSIS
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Retrosynthetic analysis in scheme 1 reveals advanced intermediates 11 and 12,
which are crucial for the series of aplysiatoxins, oscillatoxins and nhatrangins. In addition
nhatrangin A 1 could be extended to nhatrangin B 2 by aromatic bromination. As of
current interest, we further envisaged that synthesis of nhatrangin A could be
accomplished by the coupling of acid fragment 12 with β-hydroxyallylester, which in
turn can be obtained from 11 in two steps involving oxidation and allylprotection. The
crucial aromatic aldehyde fragment 11 would be accomplished from compound 13
followed by a sequence of reactions involving methyl ether formation, reduction,
oxidation, and an asymmetric aldol reaction. The compound 13 could be obtained starting
from aldehyde 14 through a vinyl Grignard reaction, oxidation of resulting alcohol,
asymmetric Michael addition reaction and CBS reduction reactions. On the other hand
acid fragment 12 would be attained from 2-butenylbenzene 15 in three steps using
asymmetric dihydroxylation and TBS protection followed by an aromatic oxidation
reaction.
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Scheme 1. Retrosynthetic analysis of nhatrangin A (1).
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O
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O
OMe
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OMe
OH
X
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O
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O
O
OH
OH
O
Oscillatoxins
OH
Aplysiatoxins
HO
R = CH3
X = Br or H
OH
O OMe X
O
O
O
OH
OMe
OTBS
HO
COOH
+
11
X = H, Nhatrangin A
X = Br, Nhatrangin B
OTBS
12
OH
OTBS
OTBS
O
OH
O
OHC
N
O
15
OTBS
14
13
Ph
RESULTS AND DISCUSSION
Our strategy for the synthesis of key intermediate 11 in stereoselective manner
commenced with the generation of first methyl stereogenic centre at C4 position via an
auxiliary based asymmetric Michael addition reaction.10 Accordingly, the silyl protected
3-hydroxy benzaldehyde 14 on treatment with vinyl magnesium bromide in THF
afforded allyl alcohol, which was further oxidized to aryl vinyl ketone 16 in 93% yield
using 2-iodoxy benzoic acid. Titanium enolate resulted from (R)-4-benzyl-3-
propionyloxazolidin-2-one 17 upon treatment with (i-PrO)TiCl3 and N,N’-
diisopropylethylamine, underwent conjugate addition on phenyl vinyl ketone 16 to afford
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ketone 18 exclusively as a single diastereomer in 89% yield.10 Keto functionality of
compound 18 was selectively reduced with borane in the presence of proline based R-
CBS catalyst to provide alcohol 13 as a major diastereomer in 93% isolated yield.11
Selectivity (varies from 9:1 to 98:2) mainly depends on amount of catalyst used and rate
of addition of compound to the reagent. Methyl protection of alcohol 13 using
iodomethane in the presence of strong bases (like NaH and NaHMDS) leads to the
formation of unwanted products and decomposition of starting material. To avoid this,
compound 13 was treated with methyltriflate in the presence of a mild organic base 2,6-
ditertiarybutylpyridine in DMF to produce corresponding methyl ether 19 in 87%
yield.12Auxiliary of compound 19 was reductively removed using NaBH4 in aqueous
THF to afford corresponding alcohol, which on subsequent oxidation with IBX resulted
in aldehyde 20 with 80% yield over two steps. Achievement of anti, syn-triod was
realized in single step using proline catalyzed asymmetric crossed aldol strategy.13 Thus,
aldehyde 20 on reaction with propionaldehyde in DMF at 2 oC for 48 h in the presence of
D-proline as catalyst afforded β-hydroxyaldehyde 11 with excellent diastereoselectivity
(> 99% by NMR analysis)14 in 80% yield (brsm). Thus one of the key motif 11 for the
synthesis of nhatrangin A, which also becomes a crucial intermediate for the synthesis of
aplysiatoxins and oscillatoxins was achieved in 8 steps with 40% overall yield (Scheme
2).
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Scheme 2. Synthesis of key aromatic aldehyde 11.
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O
MgBr
O
17, TiCl3(OiPr),
5
6
i. THF, 0 oC 1 h, 95%
DIPEA, CH2Cl2
ii. IBX, DMSO:DCM,
(1:3), rt, 3 h, 93%
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-5 oC , 30 min,
OTBS
14
89%, >99% de
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OTBS
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O
N
O
O
O
OH
O
R-CBS, Me2S:BH3
N
O
O
-5 oC, 4 h, 93%
Bn
Bn
18
OTBS
13
OTBS
O
OMe
O
i. NaBH4, THF/H2O,
rt, 14 h
MeOTf,
2,6-ditert.butylpyridine
DCM, 0 oC to rt,
N
O
ii. IBX, DMSO:DCM
(1:3), 0 oC to rt, 3 h,
80% two steps
Bn
18 h, 94%
19
OTBS
OMe
D-Proline
(20 mol%),
propanal
DMF, 2 oC, 48 h,
O
OMe
O
OH
O
H
Ph
Ph
O
N
O
N
O
80% brsm, >99% de
B
11
20
Bn
OTBS
OTBS
17
(R)-CBS
In our next attempt we have focused on the synthesis of chiral β,γ-dihydroxy carboxylic
acid motif 12, which is also a subunit of nhatrangins, aplysiatoxins and few oscillatoxins.
Synthesis of this appended acid with completely masked vicinal diol was achieved in
good yields and optical purity when compared to previous routes. For this 2-
butenylbenzene15 15 was employed as the starting material, which underwent an
asymmetric dihydroxylation with OsO4 in the presence of catalytic (DHQD)2PHAL to
produce vicinal diol 21 in 91% yield with 92% ee.16 The diol 21 on treatment with
TBDMS-Cl and DMAP in DMF afforded bis-silylether 22 in 91% yield. The phenyl
group in compound 22 was subjected to oxidation without effecting the vicinal diol using
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RuO4 (generated in situ from RuCl3 and NaIO4) in a solvent system CH3CN/CCl4/pH 7
buffer (1:2:1) to furnish the corresponding carboxylic acid 12 in 66 % yield (Scheme 3).17
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Scheme 3. Synthesis of key side chain acid 12.
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OH
(DHQD)2PHAL, OsO4,
CH3SO2NH2, K3FeCN6,
TBDMSCl, DMAP
DMF, 70 oC, 6 h,
91%
K2CO3, t-BuOH/H2O,
0 oC, 91% and 92 ee
OH
15
21
OTBS
OTBS
O
RuCl3, NaIO4
CH3CN+CCl4+pH 7 buffer
(1:2:1), 6 h, rt, 66%
OTBS
OH OTBS
12
22
With two fragments in hand, we moved to final steps to accomplish the total
synthesis of nhatrangin A. Consequently one of the key fragment 11 was subjected to a
chemoselective Pinnick oxidation18 with NaOCl in the presence of 2-methyl-2-butene in
t-BuOH to afford β-hydroxyacid 23 in 98% yield. The main chain hydroxy allyl ester 24
was finally achieved by treatment of acid 23 with ally bromide and K2CO3 in DMF at
room temperature in 96% yield. Formation of internal ester at C3-position was realized
by coupling of hydroxy ester 24 with acid 12 under Yamaguchi mixed anhydride
protocol.19 The other reaction conditions for the formation of ester remained
unsuccessful.20 Thus acid 12 was treated with 2,4,6-trichlorobenzoyl chloride in the
presence of DMAP in toluene for 2 h to furnish the corresponding mixed anhydride,
which was subsequently treated with alcohol 24 for 4 h to provide ester 25 in 40% yield.
Unfortunately, higher reaction temperatures or longer reaction time to improve the yield
lead to epimerization of C2-methyl carbon. The compound 25 was subjected to allyl
deprotection using palladium tetrakis-triphenylphosphine and morpholine21 in dry THF
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and later was followed by treatment with 3N HCl to afford natural product nhatrangin A
1 in 67% yield. The structural integrity of synthetic nhatrangin A 1 was confirmed by
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comparison of its spectral (1H and 13C NMR) data and specific rotation (synthetic. [α]D
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= +0.8, (c 0.3 in MeOH), Lit. [α]D 25 = +0.2, (c 0.05 in MeOH)9g, which were in good
agreement with the reported values for natural product (Scheme 4).3
Scheme 4. Synthesis of nhatrangin A.
O
OH
OMe
NaOCl, NaH2PO4,
2-methyl-2-butene
allyl bromide,
K2CO3, DMF
HO
11
tBuOH:H2O,
rt, 1 h, 98%
rt, 48 h, 96%
23
OTBS
TBSO
O
OTBS
OMe
12, 2,4,6-trichlorobenzoyl
chloride, DMAP, toluene,
0 oC to rt, 2 h
O
OH
OMe
O
O
O
O
then, 24, 4 h, rt, 40%
25
24
OTBS
OTBS
HO
OH
OMe
O
Pd(PPh3)4, morpholine,
THF, rt, 12 h
O
O
HO
3N HCl, 12 h, 67%
Nhatrangin A (1)
OH
CONCLUSIONS
In conclusion a concise and stereoselective approach for the synthesis of key
intermediates for aplysiatoxins, oscillatoxins and nhatrangins and their application to the
total synthesis of nhatrangin A has been demonstrated. Evans auxiliary based asymmetric
Michael addition reaction, CBS reduction, proline catalysed crossed aldol reaction
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provided aromatic aldehyde 11 in 8 steps with 44% overall yield. Asymmetric
dihydroxylation, silyl protection of vicinal diol and ruthenium catalysed aromatic over
oxidation provided appended acid chain 12 in three steps with 55% overall yield. This
strategy can be used for the preparation of other β,γ-dihydroxycarboxilic acids and β-
hydroxy-γ-lactones, which are main constitutes in many natural product molecules. Final
total synthesis of nhatrangin A 1 was achieved by successful coupling of fragments 24
and 12 under Yamaguchi reaction conditions followed by a deprotection step to remove
all the protecting groups.
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Experimental Section
General Methods. NMR spectra were recorded in CDCl3 or DMSO-d6 solvent on 300
1
and 500 MHz spectrometers. Chemical shifts are reported in parts per million (ppm). H
NMR spectra were recorded at 300MHz, and chemical shifts are referenced to TMS (δ=
0.0) as internal standard. 13C NMR spectra were recorded at 75 MHz, and chemical shifts
are referenced to CDCl3 (δ = 77.0). FTIR spectra were recorded on KBr thin films.
Optical rotations were measured on digital polarimeter by using a 1-mL cell with a path
length of 1 dm. HRMS were recorded on an LC-ESI-QTOF-mass spectrometer. All
reagents and solvents were of reagent grade and used without further purification unless
otherwise stated. Technical-grade EtOAc, hexanes, CHCl3, and MeOH used for column
chromatography were distilled before use. THF when used as a solvent for reactions was
freshly distilled from sodium benzophenone ketyl. Column chromatography was carried
on silica gel (60−120 mesh) packed in glass columns. All of the reactions were performed
under N2 in flame or oven-dried glassware with magnetic stirring.
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1-(3-(tert-Butyldimethylsilyloxy)phenyl)prop-2-en-1-ol (16). To a stirred solution of
aldehyde 14 (4.2 g, 17.7 mmol) in dry THF (100 mL) under nitrogen atmosphere at –10
oC was added vinylmagnesium bromide (22.0 mL 1 M solution in THF, 22.0 mmol)
drop-wise over 5 min. After stirring for 1 h at the same temperature, the reaction was
quenched with saturated aq. NH4Cl (10 mL). Organic layer was separated and the
aqueous layer was extracted with ethyl acetate (2 X 40 mL). The combined organic layers
were washed with water and brine, dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The crude product was purified by silica gel chromatography ((eluting
with hexane/ethyl acetate, 9:1) as an eluent to obtain alcohol (4.46 g, 95%) as clear
liquid: IR (neat) ʋmax 3380, 2956, 2859, 1601, 1484, 1274, 1220, 841 cm-1; 1H NMR (300
MHz, CDCl3): δ 0.20 (s, 6H), 0.99 (s, 9H), 2.24 (bs, 1H), 5.12 (d, J = 5.8 Hz, 1H), 5.17,
(d, J = 10.4 Hz, 1H), 5.31 (d, J = 17.2 Hz, 1H), 5.95–6.08 (m, 1H), 6.76 (dd, J = 1.5, 8.1
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Hz, 1H), 6.86 (s, 1H), 6.94 (d, J = 7.7 Hz, 1H), 7.21 (t, J = 7.7, 7.9 Hz, 1H); C NMR
(75 MHz, CDCl3): δ –4.4, 18.1, 25.6, 75.0, 115.0, 118.0, 119.1, 119.2, 129.4, 140.1,
144.2, 155.8; MS (ESI) m/z 265 (M+H)+, 287 (M + Na)+.
To a stirred solution of IBX (6.97 g, 24.9 mmol) in DMSO (20 mL) was added a
solution of alcohol (4.40 g, 16.6 mmol) in dry CH2Cl2 (40 mL) under nitrogen
atmosphere at 0 oC. After 5 min, reaction was allowed to room temperature and continued
to stir for 3 h. Water (30 mL) was added to the reaction mixture and filtered over celite
pad. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2
X 30 mL). The combined organic layers were washed with water and brine, dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was
purified by silica gel chromatography ((eluting with hexane/ethyl acetate, 9.5:0.5) to
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obtain compound 16 (4.06 g, 93%) as clear liquid: IR (neat)ʋmax 2956, 2932, 2859, 1675,
5
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1596, 1484, 1278, 927, 837 cm-1; H NMR (300 MHz, CDCl3): δ 0.22 (s, 6H), 0.99 (s,
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9H), 5.91 (dd, J = 1.5, 10.4 Hz, 1H), 6.42 (dd, J = 1.5, 17.0 Hz, 1H), 7.05 (m, 1H), 7.11
(dd, J = 10.7, 10.5 Hz, 1H), 7.33 (t, J = 7.7, 7.9 Hz, 1H), 7.41 (t, J = 1.7, 1.8 Hz, 1H),
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7.53 (d, J = 7.7 Hz, 1H); C NMR (75 MHz, CDCl3): δ –4.5, 18.1, 25.6, 119.9, 121.7,
124.8, 129.5, 129.9, 138.7, 155.9, 190.5; HRMS (ESI) calcd. for C15H23O2Si 263.1483,
found 263.1467.
(S)-1-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-5-(3-(tert-butyldimethyl-silyloxy)phenyl)-
2-methylpentane-1,5-dione (18). To a stirred solution of TiCl4 (2.0 mL, 18.6 mmol) in
dry CH2Cl2 (20 mL) under nitrogen atmosphere at r.t. was added Ti(OiPr)4 (1.84 mL,
6.20 mmol) and continued to stir for 2 h. Then solution was cooled to 0 oC and was added
(R)-4-benzyl-3-propionyloxazolidin-2-one 17 (5.31g, 22.9 mmol) in CH2Cl2 (40 mL) in
drop wise manner. After 5 min., DIPEA (4.4 mL, 24.8 mmol) was added and stirred for
additional 30 min. Then vinyl ketone 16 (5.0 g, 19.1 mmol) in dry CH2Cl2 (40 mL) was
added over 5 min. at –5 oC and stirring was continued for 30 min. Reaction was quenched
by the addition of saturated aq. NH4Cl (10 mL). Organic layer was separated and aqueous
layer was extracted with CH2Cl2 (2 X 40 mL). The combined organic layers were washed
with water and brine, dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The crude product was purified by silica gel chromatography (eluting with
hexane/ethyl acetate, 8:2) to obtain compound 18 (8.4 g, 89%, >99% de) as a clear thick
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liquid: [α]D –8.5 (c 1.5, CHCl3); IR (neat)ʋmax 2955, 2931, 2858, 1780, 1692, 1387,
1279, 1252, 835, 780 cm-1; H NMR (300 MHz, CDCl3): δ 0.21 (s, 6H), 0.98 (s, 9H),
1
1.25 (d, J = 6.7 Hz, 3H), 1.86–2.0 (m, 1H), 2.14–2.27 (m, 1H), 2.76 (dd, J = 9.6, 9.8 Hz,
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1H), 2.92–3.13 (m, 2H), 3.32 (dd, J = 3.4, 13.4 Hz, 1H), 3.82 (m, 1H), 4.13–4.24 (m,
2H), 4.62–4.74 (m, 1H), 7.03 (m, 1H), 7.18–7.37 (m, 6H), 7.42 (t, J = 1.7, 3.7 Hz, 1H),
7.55 (m, 1H); 13C NMR (75 MHz, CDCl3): δ –4.5, 16.9, 18.1, 25.6, 28.0, 36.1, 37.0, 37.9,
55.3, 66.0, 119.2, 121.1, 124.8, 127.2, 128.9, 129.3, 129.5, 135.2, 138.2, 153.0, 155.9,
176.5, 199.1; HRMS (ESI) calcd. for C28H37NO5SiNa (M + Na)+ 496.2513, found
496.2522.
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(R)-4-Benzyl-3-((2S,5S)-5-(3-(tert-butyldimethylsilyloxy)phenyl)-5-hydroxy-2-
methylpentanoyl)oxazolidin-2-one (13). To a stirred solution of borane dimethyl sulfide
o
(0.138 mL, 1.45 mmol) in dry CH2Cl2 (4 mL) –5 C under nitrogen atmosphere was
added
(R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo(1,2-c)(1,3,2)-
oxazaborolidine (0.24 mL, 1 M solution in toluene, 20 mol%) and the resulting mixture
was continued to stir for 30 min. To this reaction mixture was added a solution of
compound 18 (0.60 g, 1.21 mmol) in CH2Cl2 (6 mL) over a period of 4 h and maintained
the reaction temperature between –5 oC to 0 oC. Stirring was continued for 1 h until TLC
showed complete conversion of reaction. Then reaction was quenched by adding CH3OH
(1 mL) slowly at 0 oC, followed by the addition of saturated aq. NH4Cl and continued to
stir for 15 min. Organic layer was separated and the aqueous layer was extracted with
CH2Cl2 (3 X 5 mL). The combined organic layers were washed with water and brine,
dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude
product was purified by silica gel chromatography (eluting with hexane/ethyl acetate,
7:3) to afford compound 13 (0.56 g, 93%) as a clear thick liquid along with the minor
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isomer (0.011 g, 1.8%). Compound 13: [α]D –40 (c 1.0, CHCl3); IR (neat)ʋmax 3525,
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2930, 2858, 1780, 1698, 1483, 1387, 1276, 839, 780 cm-1; 1H NMR (300 MHz, CDCl3):
δ 0.18 (s, 6H), 0.97 (s, 9H), 1.16 (d, J = 6.7 Hz, 3H), 1.52–1.64 (m, 1H), 1.69–1.90 (m,
3H), 2.5 (bs, 1H), 2.70 (dd, J = 9.8, 9.6 Hz, 1H), 3.26 (dd, J = 3.2, 13.4 Hz, 1H), 3.68–
3.80, (m, 1H), 4.09–4.19 (m, 2H), 4.60–4.70 (m, 2H), 6.73 (m, 1H), 6.84 (t, J = 1.8, 3.5
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Hz, 1H), 6.93 (d, J = 7.7 Hz, 1H), 7.14–7.22 (m, 3H), 7.23–7.34 (m, 3H); C NMR (75
MHz, CDCl3): δ –4.5, 16.4, 18.1, 25.6, 29.6, 36.1, 37.0, 37.9, 55.3, 66.0, 73.2, 117.4,
118.6, 118.9, 127.2, 128.8, 129.3, 135.2, 146.2, 153.1, 155.6, 176.9; HRMS (ESI) calcd.
for C28H39NO5SiNa (M + Na)+ 520.2489, found 520.2486.
(R)-4-Benzyl-3-((2S,5S)-5-(3-(tert-butyldimethylsilyloxy)phenyl)-5-methoxy-2-
methylpentanoyl)oxazolidin-2-one (19). To a stirred solution of alcohol 13 (500 mg,
o
1.06 mmol) in dry CH2Cl2 (10 mL) under nitrogen atmosphere at 0 C was added 2,6-
ditertiarybutyl pyridine (0.7 mL, 3.18 mmol) followed by methyl triflate (0.35 mL, 3.18
mmol) and continued to stir for 5 minutes. Then reaction mixture was stirred for 18 h at
room temperature. After completion of the reaction, saturated aq. NH4Cl. was added. The
organic layer was separated and aqueous layer was extracted with CH2Cl2 (2 X 5 mL).
The combined organic layers were washed with water and brine, dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The crude product was purified by
silica gel chromatography (eluting with hexane/ethyl acetate, 9:1) to afford methylether
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19 (0.483 g, 94%) as a colorless liquid:[α]D : –25.6 (c 1.1, CHCl3); IR (neat)ʋmax 2930,
2857, 1781, 1698, 1482, 1386, 1276, 1215, 1103, 839, 773 cm-1; H NMR (300 MHz,
1
CDCl3): δ 0.17 (s, 6H), 0.96 (s, 9H), 1.15 (d, J = 6.8 Hz, 3H), 1.56–1.68 (m, 2H), 1.69–
1.82 (m, 2H), 2.66 (m, 1H), 3.18 (s, 3H), 3.30 (dd, J = 3.7, 13.5 Hz, 1H), 3.73 (m, 1H),
4.01 (d, J = 6.0 Hz, 1H), 4.09–4.19 (m, 2H), 4.61 (m, 1H), 6.66–6.75 (m, 2H), 6.82 (d, J
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= 7.5 Hz, 1H), 7.11–7.34 (m, 6H); 13C NMR (75 MHz, CDCl3): δ –4.5, 16.8, 18.1, 25.6,
30.0, 35.4, 37.2, 38.0, 55.3, 56.5, 65.9, 83.5, 118.1, 119.2, 119.7, 127.2, 128.8, 129.3,
125.3, 143.8, 153.0, 155.7, 176.9; HRMS (ESI) calcd. for C29H41NO5SiNa (M + Na)+
534.2646, found 534.2641.
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(2S,5S)-5-(3-(tert-Butyldimethylsilyloxy)phenyl)-5-methoxy-2-methylpentanal (20).
To a stirred solution of compound 19 (1.2 g, 2.34 mmol) in mixture of THF (10 mL) and
H2O (5 mL) at room temperature was added NaBH4 (0.177 g, 4.68 mmol). The reaction
mixture was continued to stir for overnight. After completion of the reaction additional
water (5 mL) was added. The organic layer was separated and aqueous layer was
extracted with EtOAc (3 X 5 mL). The combined organic layers were washed with water
and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The
crude product was purified by silica gel chromatography (eluting with hexane/ethyl
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acetate, 8:2) to furnish alcohol (0.682 g, 86%) as a clear liquid: [α]D –39.1 (c 1.2,
CHCl3); IR (neat)ʋmax 3399, 2932, 2860, 1602, 1587, 1483, 1276, 1098, 838, 783 cm-1;
1H NMR (300 MHz, CDCl3): δ 0.19 (s, 6H), 0.89 (d, J = 6.8 Hz, 3H), 0.98 (s, 9H), 1.23–
1.42 (m, 2H), 1.53–1.71 (m, 2H), 1.77–1.90 (m, 1H), 3.19 (s, 3H), 3.35–3.51 (m, 2H),
4.02 (dd, J = 5.2, 7.5 Hz, 1H), 6.73–6.79 (m, 2H), 6.86 (d, J = 7.5 Hz, 1H), 7.19 (t, J =
8.3, 15.8 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ –4.5, 16.5, 18.2, 25.6, 29.1, 35.4, 35.5,
56.5, 67.9, 84.0, 118.1, 119.2, 119.7, 129.2, 143.9, 155.7; HRMS(ESI) calcd. for
C19H34O3SiNa (M + Na)+ 361.2169, found 361.2171.
To a stirred solution of IBX (0.697 g, 2.49 mmol) in DMSO (4 mL) was added a
o
solution of alcohol (0.560 g, 1.66 mmol) in dry CH2Cl2 (10 mL) at 0 C. Stirring after 5
min at 0 oC, reaction was allowed to stir at room temperature for 3 h. Water (5 mL) was
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added to the reaction mixture and filtered over celite pad. Organic layer was separated
then aqueous layer was extracted with CH2Cl2 (2 X 5 mL). The combined organic layers
were washed with water and brine, dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The crude compound was purified by silica gel chromatography
(eluting with hexane/ethyl acetate, 95:5) to afford aldehyde 20 (0.517 g, 93%) as a clear
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liquid. [α]D –27.4 (c 1.4, CHCl3); H NMR (300 MHz, CDCl3): δ 0.13 (s, 6H), 0.92 (s,
9H), 1.01 (d, J = 6.8 Hz, 3H), 1.40–1.46 (m, 1H), 1.50–1.71 (m, 3H), 2.16–2.25 (m, 1H),
3.10 (s, 3H), 3.91 (dd, J = 5.1, 6.8 Hz, 1H), 6.60–6.64 (m, 2H), 6.72 (d, J = 7.7 Hz, 1H),
13
7.07 (t, J = 7.7 Hz, 1H), 9.48 (d, J = 1.7 Hz, 1H); C NMR (75 MHz, CDCl3): δ –4.4,
13.3, 18.2, 25.7, 26.6, 35.4, 46.1, 56.5, 83.5, 118.1, 119.3, 119.7, 129.3, 143.5, 155.8,
205.0; MS (ESI) m/z 359 (M + Na)+.
(2R,3R,4S,7S)-7-(3-(tert-Butyldimethylsilyloxy)phenyl)-3-hydroxy-7-methoxy-2,4-
dimethylheptanal (11). To a stirred solution of aldehyde 20 (500 mg, 1.49 mmol) in dry
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DMF (5mL) under nitrogen atmosphere at 2 C was added D-proline (0.034 g, 0.297
mmol, 20 mol%). Then propionaldehyde (0.54 mL, 7.44 mmol) in dry DMF (5 mL) was
added over a period of 16 h using a syringe pump at 2 oC, and reaction was continued to
stir at same temperature for additional 32 h. After completion of the reaction water (8
mL) was added. The organic layer was separated and the aqueous layer was extracted
with Et2O (2 X 10 mL). The combined organic layers were washed with water and brine,
dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude
product was purified by silica gel chromatography (eluting with hexane/ethyl acetate,
95:5) to afford desired β-hydroxyaldehyde 11 (0.280 g, 48%) along with starting
aldehyde 20 (0.20 g, 40%) (Note: most of the times, the mixture of 11 and
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propionaldehyde self aldol adduct was directly used in next step. The propionaldeyde self
aldol adduct was removed in the next step by converting it into its corresponding 3-
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hydroxy acid). [α]D –22.6 (c 1.4, CHCl3); H NMR (300 MHz, CDCl3): δ 0.19 (s, 6H),
0.87 (d, J = 6.0 Hz, 3H), 0.99 (s, 9H), 1.04 (d, J = 7.7 Hz, 3H), 1.37–1.46 (m, 1H), 1.50–
1.64 (m, 3H), 1.69–1.79 (m, 1H), 2.47 (q, J = 7.6 Hz, 1H), 3.17 (s, 3H), 3.62 (dd, J = 2.5,
8.5 Hz, 1H), 3.93–3.97 (m, 1H), 5.32 (s, 1H), 6.65–6.70 (m, 2H), 6.79 (d, J = 6.8 Hz,
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1H), 7.13 (t, J = 7.7 Hz, 1H), 9.71 (s, 1H); C NMR (75 MHz, CDCl3): δ –4.1, 10.9,
12.8, 14.4, 18.5, 26.0, 34.9, 36.1, 53.2, 56.6, 74.4, 84.0, 118.1, 119.2, 119.8, 129.4, 144.2,
155.9, 204.7; MS (ESI) m/z 417 (M + Na)+. HRMS(ESI) calcd. for C22H38O4SiNa [M +
Na]+ 417.2437, found 417.2442.
(2R,3R)-1-Phenylbutane-2,3-diol (21). To a stirred solution of H2O (40 mL) and t-
BuOH (40 mL) under nitrogen atmosphere at room temperature were sequentially added
K2CO3 (7.87 g, 57.0 mmol), K3Fe(CN)6 (18.75 g, 57.0 mmol), CH3SO2NH2 (181.0 g,
19.0 mmol) and (DHQD)2-PHAL (0.296 g, 0.379 mmol) and a solution OsO4 (9.6 mL,
o
0.5% in toluene). The reaction mixture was stirred for 15 min and cooled to 0 C then
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olefin 15 (2.5 g, 19.0 mmol) was added directly. Stirring was continued for 24 h at 0 C,
then quenched with saturated aq. Na2SO3 (50 mL) and continued to stir for an additional
30 min. After extracting aqueous layer with EtOAc (3 X 20 mL), the combined organic
layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The crude product was purified by silica gel chromatography
(eluting with hexane/ethyl acetate, 3:1) to furnish the diol 21 (2.86 g, 91%) as a black
thick liquid: [α]D30 +27.3 (c 1.2, CHCl3); IR (neat) ʋmax 3459, 2983, 2929, 2865, 1725,
1
1376, 1242, 1087, 772, 700 cm-1; H NMR (300 MHz, CDCl3): δ 1.21 (d, J = 6.2 Hz,
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3H), 2.41 (bs, 2H), 2.63 (dd, J = 8.6, 8.6 Hz, 1H), 2.83 (dd, J = 4.0, 4.0 Hz, 1H), 3.47–
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3.55 (m, 1H), 3.60 (q, J = 6.0, 12.8 Hz, 1H), 7.13–7.22 (m, 3H), 7.23–7.31 (m, 2H); C
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NMR (75 MHz, CDCl3): δ 19.4, 39.9, 69.9, 76.6, 126.4, 128.5, 129.3, 138.1; MS (EI) m/z
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189 (M + Na)+.
(5R,6R)-5-Benzyl-2,2,3,3,6,8,8,9,9-nonamethyl-4,7-dioxa-3,8-disiladecane (22). To a
stirred solution of compound 21 (1.2 g, 7.2 mmol) in dry DMF (15 mL) under nitrogen
atmosphere at room temperature was added 4-(dimethylamino)pyridine (DMAP) (2.63 g,
21.6 mmol) and TBSCl (3.30 g, 21.6 mmol) sequentially. Then resulting mixture was
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heated at 70 C and continued to stir for 6 h. After completion of the reaction, the
reaction mixture was cooled to room temperature and diluted with water (10 mL) and
extracted with Et2O (2 X 30 mL). The combined organic layers were washed with water,
brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure.
Purification by silica gel chromatography (hexane/ethyl acetate, 0.2:9.8 as an eluent)
furnished product 22 (2.86 g, 91%) as a pale yellow oil: [α]D30 + 12.6 (c 0.9, CHCl3); IR
(neat) ʋmax 2955, 2930, 2857, 1472, 1255, 1219, 1104, 834, 772 cm-1; H NMR (300
1
MHz, CDCl3): δ –0.45 (s, 3H), –0.06 (s, 3H), 0.22 (d, J = 3.0 Hz, 6H), 0.91 (s, 9H), 1.07
(s, 9H), 1.29 (d, J = 6.8 Hz, 3H), 2.53 (dd, J = 10.5, 9.8 Hz, 1H), 3.11 (dd, J = 1.5, 12.8
Hz, 1H), 3.74–3.81 (m, 1H), 3.90–3.99 (m, 1H), 7.21–7.30 (m, 3H), 7.31–7.38 (m, 2H);
13C NMR (75 MHz, CDCl3): δ –6.10, –5.3, –5.1, –4.9, 16.0, 17.5, 17.6, 25.3, 25.4, 35.9,
70.3, 76.1, 125.3, 127.6, 129.4, 140.4; MS (ESI) m/z 417 (M + Na)+.
(3R,4R)-3,4-bis(tert-Butyldimethylsilyloxy)pentanoic acid (12). To a stirred solution
of compound 22 (0.730 g, 1.85 mmol) in CCl4 (6 mL), CH3CN (6 mL) and pH 7 buffer
(10 mL) at room temperature was added NaIO4 (5.90 g, 27.70 mmol). After stirring for 5
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min., RuCl3 (0.038 g, 0.18 mmol) was added and continued to stir for 6 h at the same
temperature. After completion of the reaction, reaction was diluted with CH2Cl2 (10 mL).
The organic layer was separated and aqueous layer was extracted with CH2Cl2 (3 X 10
mL). The combined organic layers were washed with water and brine, dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was
purified by silica gel chromatography (eluting with hexane/ethyl acetate, 9.5:0.5) to
afford 12 (0.440 g, 66%) as a colorless liquid. [α]D30 +23.1 (c 1.0, CHCl3); IR (neat) ʋmax
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3420, 2931, 2858, 1707, 1595, 1482, 1276, 1101, 841, 784 cm-1; H NMR (300 MHz,
CDCl3): δ 0.04 (s, 3H), 0.06 (s, 6H), 0.08 (s, 3H), 0.86 (s, 9H), 0.88 (s, 9H), 1.08 (d, J =
6.0 Hz, 3H), 2.31 (dd, J = 9.0, 9.8 Hz, 1H), 2.66 (dd, J = 2.3, 3.0 Hz, 1H), 3.75–3.84 (m,
1H), 4.04–4.13 (m, 1H); 13C NMR (75 MHz, CDCl3): δ –4.9, –4.8, –4.7, 16.2, 17.8, 17.9,
25.6, 25.7, 35.8, 69.9, 72.1; MS (ESI) m/z 385 (M + Na)+.
(2R,3R,4S,7S)-7-(3-(tert-butyldimethylsilyloxy)phenyl)-3-hydroxy-7-methoxy-2,4-
dimethylheptanoic acid (23). To a stirred solution of β-hydroxyaldehyde 11 (0.380 g,
0.926 mmol) in t-BuOH (6 mL) was added 2-methyl-2-butene (1.0 mL, 9.5 mmol), H2O
(1.5 mL), NaClO2 (0.350 g, 3.85 mmol) and NaH2PO4 (0.752 g, 4.80 mmol) sequentially
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at 0 C. Stirring was continued for 1 h at the same temperature. After completion of the
reaction, Et2O (5 mL) followed by 0.5 M aqueous citric acid solution (3 mL) was added.
The organic layer was separated and aqueous layer was extracted with Et2O (2 X 5 mL).
The combined organic layers were washed with water and brine, dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The crude product was purified by
silica gel chromatography (eluting with hexane/ethyl acetate, 1:1) to furnish β-
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hydroxyacid 23 (0.387 g, 98%) as a colorless oil: [α]D –16.5 (c 2.0, CHCl3); IR
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(neat)ʋmax 3420, 2959, 2931, 2858, 1708, 1602, 1483, 1277, 1101, 840, 783 cm-1; H
NMR (300 MHz, CDCl3): δ 0.19 (s, 6H), 0.87 (d, J = 6.0 Hz, 3H), 0.98 (s, 9H), 1.16 (d, J
= 6.7 Hz, 3H), 1.37–1.46 (m, 1H), 1.51–1.67 (m, 3H), 1.69–1.83 (m, 1H), 2.59 (q, J = 7.5
Hz, 1H), 3.18 (s, 3H), 3.56 (dd, J = 3.7, 8.3 Hz, 1H), 3.93–4.01 (dd, J = 5.2, 6.7 Hz, 1H),
6.66–6.73 (m, 2H), 6.80 (d, J = 7.5 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H); 13C NMR (75 MHz,
CDCl3): δ –4.4, 12.5, 14.2, 18.2, 25.7, 29.9, 34.7, 35.6, 43.1, 56.6, 75.6, 83.9, 118.9,
119.2, 119.8, 129.3, 143.8, 155.7, 180.9; HRMS (ESI) calcd. for C22H38O5 SiNa (M +
Na)+ 433.2380, found 433.2378.
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(2R,3R,4S,7S)-Allyl-7-(3-(tert-butyldimethylsilyloxy)phenyl)-3-hydroxy-7-
methoxy-2,4-dimethylheptanoate (24). To a stirred solution of β-hydroxy acid 23 (0.20
o
g, 0.487 mmol) in dry DMF (4 mL) under nitrogen atmosphere at 0 C was added
anhydrous K2CO3 (0.134 g, 0.974 mmol) and freshly distilled allyl bromide (0.584 mmol)
sequentially. The reaction mixture was allowed to stir at room temperature for 48 h and
then quenched by the addition of saturated aq. NH4Cl (5 mL). After extracting aqueous
layer with Et2O (3 X 5 mL), the combined organic layers were washed with water and
brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude
product was purified by silica gel chromatography (eluting with hexane/ethyl acetate,
7.5:2.5) to afford allyl ester 24 (0.210 g, 96%) as a clear liquid: [α]D30 –26 (c 0.9, CHCl3);
IR (neat) ʋmax 2931, 2858, 1727, 1711, 1596, 1463, 1275, 1102, 838, 779 cm-1; 1H NMR
(300 MHz, CDCl3): δ 0.20 (s, 6H), 0.87 (d, J = 6.8 Hz, 3H), 0.99 (s, 9H), 1.16 (d, J = 6.8
Hz, 3H), 1.44–1.66 (m, 3H), 1.66-1.87 (m, 2H), 2.60 (q, J = 7.5 Hz, 1H), 3.18 (s, 3H),
3.49–3.57 (m, 1H), 3.93–4.01 (dd, J = 5.2, 7.5 Hz, 1H), 4.58 (d, J = 6.0 Hz, 2H), 5.20–
5.27 (dd, J = 1.5, 10.5 Hz, 1H), 5.28–5.36 (dd, J = 1.5, 16.5 Hz, 1H), 5.83–5.87 (m, 1H),
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6.67–6.73 (m, 2H), 6.82 (d, J = 7.5 Hz, 1H), 7.12–7.20 (m, 1H); 13C NMR (75 MHz,
CDCl3): δ –4.4, 12.6, 14.3, 25.6, 29.6, 27.0, 34.9, 35.9, 43.1, 56.6, 65.2, 75.6, 83.9, 118.1,
118.4, 119.2, 119.7, 129.2, 131.9, 143.9, 155.7, 184.7; HRMS (ESI) calcd. for
C25H42O5SiNa (M + Na)+ 473.2693, found 473.2699.
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(2R,3R,4S,7S)-Allyl-3-((3R,4R)-3,4-bis(tert-butyldimethylsilyloxy)pentan-oyloxy)-
7-(3-(tert-butyldimethylsilyloxy)phenyl)-7-methoxy-2,4-dimethylheptanoate (25). To
a stirred solution of 2,4,6-trichlorobenzoyl chloride (0.023 mL, 0.150 mmol) in dry
o
toluene (2 mL) under nitrogen atmosphere at 0 C was added acid 12 (0.056 g, 0.155
mmol), followed by DMAP (0.038 g, 0.311 mmol). The resulting mixture was allowed to
stir at room temperature for 2 h, then hydroxy-allyl ester 24 (0.035 g, 0.077 mmol) in
toluene (0.5 mL). The reaction mixture was allowed to stir at room temperature for
additional 4 h. Then reaction was quenched by the addition of saturated aq. NH4Cl (2
mL). The organic layer was separated and aqueous layer was extracted with EtOAc (3 X
2 mL). The combined organic layers were washed with water and brine, dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was
purified by silica gel chromatography eluting with (ethyl acetate/hexane, 9.5:0.5) to
furnish 25 (0.0247 g, 40%) as a pale yellow oil along with recovery of hydroxy-allylester
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24 (0.020 g, 58%): [α]D +1.8 (c 0.8, CHCl3); IR (neat) ʋmax 2929, 2857, 2318, 1743,
1462, 1255, 1219, 1099, 837, 774 cm-1; 1H NMR (300 MHz, CDCl3): δ 0.05 (s, 6H), 0.07
(s, 6H), 0.20 (s, 6H), 0.86 (s, 9H), 0.88 (s, 9H), 0.91 (d, J = 5.8 Hz, 3H), 0.99 (s, 9H),
1.06 (d, J = 6.0 Hz, 3H), 1.11 (d, J = 8.0 Hz, 3H), 1.33–1.42 (m, 2H), 1.59–1.65 (m, 1H),
1.66–1.76 (m, 2H), 2.20–2.32 (m, 1H), 2.59 (dd, J = 2.0, 17.0, 1H), 2.76 (dd, J = 7.0, 9.0,
1H), 3.16 (s, 3H), 3.77 (t, J = 5.0, 6.0, 1H), 3.93 (dd, J = 4.1, 5.0 Hz, 1H), 4.05–4.12 (m,
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1H), 4.49 (d, J = 5.0 Hz, 2H), 5.03 (dd, J = 4.0, 4.0 Hz, 1H), 5.21 (d, J = 10.1 Hz, 1H),
5.29 (d, J = 16.0 Hz, 1H), 5.82–5.91 (m, 1H), 6.69 (s, 1H), 6.71 (d, J = 7.0 Hz, 1H), 6.81
(d, J = 8.0 Hz, 1H), 7.14 (t, J = 8.0, 1H); 13C NMR (75 MHz, CDCl3): δ –4.7, –4.7, –4.6,
–4.4, 13.7, 13.9, 16.5, 17.9, 18.0, 18.2, 25.7, 25.8, 25.8, 29.9, 34.0, 35.2, 36.2, 42.1, 56.6,
65.2, 69.9, 71.4, 71.6, 83.8, 118.0, 118.3, 119.2, 119.7, 129.3, 132.1, 144.2, 155.8, 171.9,
173.5; HRMS (ESI) calcd. for C42H78O8Si3Na (M + Na)+ 817.4896, found 817.4893.
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Nhatrangin A (1). To a stirred solution of allyl ester 25 (0.010 g, 0.0125 mmol) in dry
THF (3 mL) under nitrogen atmosphere at room temperature was added Pd(PPh3)4
(0.0018 g, 0.0015 mmol) in a dark hood, followed by the drop-wise addition of redistilled
morpholine (0.011 mL, 0.125 mmol). The reaction mixture was continued to stir at room
temperature for 12 h. Then reaction mixture was concentrated and diluted with Et2O (2
mL). The organic layer was separated and aqueous layer was extracted with Et2O (2 X 2
mL). The combined organic layers were washed with 1N HCl (2 mL), water and brine,
dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude
residue was dissolved in THF (5 mL) and added 3N HCl (1mL) at room temperature. The
resulting mixture was continued to stir at the same temperature for 12 h. After completion
of the reaction, solvents were evaporated under reduced pressure. The crude compound
was purified by silica gel eluting with (MeOH/CHCl3, 1:9) to afford nhatrangin A 1
(0.0035 g, 67%) as yellow oil: [α]D30 = +0.8 (c 0.3, MeOH), Lit. [α]D25 = +0.2 (c 0.05,
MeOH)10g; IR (neat) ʋmax 3284, 2929, 2857, 1722, 1452, 1255, 1219, 1097, 837, 774 cm-
1
1; H NMR (500 MHz, DMSO-d6): δ 0.72 (d, J = 6.8 Hz, 3H), 0.83 (d, J = 7.3 Hz, 3H),
0.94 (d, J = 6.2 Hz, 3H), 1.22–1.30 (m, 2H) 1.51–1.67 (m, 2H), 1.68–174 (m, 1H), 2.19
(dd, J = 15.4, 5.4 Hz, 1H), 2.25 (d, J = 7.7 Hz, 1H), 2.38 (dd, J =15.4, 4.3 Hz, 1H), 3.08
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(s, 3H), 3.49–3.56 (m, 1H), 3.68–3.74 (m, 1H), 3.95 (dd, J = 5.4, 4.3 Hz, 1H), 4.94 (dd, J
= 4.3, 4.4 Hz, 1H), 6.63–6.71 (m, 3H), 7.11 (t, J = 7.7 Hz, 1H), 9.29 (s, 1H);13CNMR (75
MHz, DMSO-d6): δ 13.9, 15.3, 18.0, 29.9, 33.5, 35.3, 38.5, 40.5, 55.9, 68.4, 70.9, 78.6,
83.2, 112.9, 114.1, 116.9, 129.1, 144.0, 157.2, 171.0, 176.1; HRMS (ESI) calcd. for
C21H31O8Na (M + Na)+435.1995, found 435.1988.
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ACKNOWLEDGMENTS
G.R. thanks CSIR-New Delhi for the award of a research fellowship, and R.S.R.
thanks DIICT for financial assistance. J. S. Y thanks CSIR-New Delhi for CSIR-
Bhatnagar fellowship.
SUPPORTING INFORMATION
1
Copies of H and 13C NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
NOTES
The authors declare no competing financial interests.
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(20) The other reagents like DCC, EDCI, EDCI/HOBT and MNBA when used for
the esterification reaction in various reaction conditions did not succeed to our
expectations.
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