Total synthesis of (?)-tirandamycin c utilizing a desymmetrization protocol

Article abstract of DOI:10.1021/jo3016709

A highly stereoselective total synthesis of (?)-tirandamycin C has been achieved following a desymmetrization protocol developed in our group, Horner-Wadsworth-Emmons olefination, acid-catalyzed ketalization, Still-Gennari (Z)-selective olefination, and D

Full text of DOI:10.1021/jo3016709

Article
pubs.acs.org/joc
Total Synthesis of (−)-Tirandamycin C Utilizing a Desymmetrization
Protocol
J. S. Yadav,*,† Santu Dhara,† Sk. Samad Hossain,† and Debendra K. Mohapatra*,†
†Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
S
* Supporting Information
ABSTRACT: A highly stereoselective total synthesis of (−)-tirandamycin
C has been achieved following a desymmetrization protocol developed in
our group, Horner−Wadsworth−Emmons olefination, acid-catalyzed
ketalization, Still−Gennari (Z)-selective olefination, and Dieckmann
cyclization as key reactions.
INTRODUCTION
■
Marine organisms have been found to be a rich source of
bioactive secondary metabolites, which are often used as lead
structures in the development of novel pharmaceuticals.1
Among them, some members of the tetramic acid family,
belonging to an emerging class of potent antibiotics, have
unique chemical structures composed of a 2,6-dioxabicyclono-
nane skeleton and the characteristic dienoyl tetramic acid
moiety formed from the condensation of an amino acid to a
polyketide derived acyl chain.2 They exhibit a wide breadth of
biological activities such as HIV-1 integrase inhibition, bacterial
DNA-directed RNA polymerase inhibition, and potent
antimicrobial activity.3 These compounds continue to attract
significant interest due to their broad structural diversity and
potent biological activities. Recently, during a screen to
discover new natural products from marine derived actino-
mycetes with activity against vancomycin-resistant Enterococcus
faecalis (VRE), tirandamycin C and tirandamycin D were
isolated from the marine environmental isolate Streptomyces sp.
307−9,4 which also produced previously identified products
Figure 1. Structures of tirandamycins A, B, C, and D.
tirandamycins A5 and B.6 Spectral analysis of tirandamycins C
and D indicated structural similarity to A and B, with
differences only in the pattern of pendant oxygenation on the
bicyclic ketal system. They exhibited antibacterial activity
against Gram-positive bacteria and in vitro activity against
bacterial RNA polymerase.
report herein a new flexible synthetic protocol for tirandamycin
C (1). We designed the synthetic strategy as shown in Figure 2.
This strategy involves a late stage tetramic acid unit formation
via Dieckmann cyclization. The key precursor 5 could be
obtained via Horner−Wadsworth−Emmons olefination of
aldehyde 7 with phosphonate 8. Aldehyde 7 in turn could be
accessible from intermediate 9 via acid catalyzed ketalization.
The α,β-unsaturated ketone intermediate 9 could be obtained
via Still−Gennari (Z)-selective coupling of phosphonate 10 and
aldehyde 11 which in turn could be achieved from a known
bicyclic intermediate 12.
The distinct structural features and potent pharmacological
properties render this family of antibiotics worthy targets for
synthetic exploration.7 The only synthesis of tirandamycin C
(1) has been recently reported by Roush et al.8 The most
significant synthetically challenging feature of the tirandamycins
is the anti,anti-dipropionate stereotriad unit. We recently
disclosed the synthesis of saliniketals A and B employing our
desymmetrization technique to create contiguous chiral centers
from a single bicyclic precursor 12.9 To demonstrate the
potential of this protocol in the synthesis of stereochemically
complex natural products and, equally to gain further insight
into the structure−activity relationship of tirandamycins, we
Received: August 9, 2012
© XXXX American Chemical Society
A
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was removed by hydrogenation to obtain diol 19 followed by
acetonide protection of the two secondary hydroxyl groups,
which produced compound 20 in 92% yield. The silyl ether was
removed by using TBAF to obtain 21 in 93% yield, which on
treatment with IBX,12 furnished aldehyde 11 in 95% yield.
Aldehyde 11 on subsequent Still−Gennari (Z)-selective
olefination13 with 10 resulted in formation of alkene 9 in 80%
yield (20:1 ratio). Acid catalyzed intramolecular cyclization of
the α,β-unsaturated ketone 9 yielded a dioxabicyclo inter-
mediate 22 in 86% yield. The pivaloyl protecting group of 22
was reduced with DIBAL-H to afford a primary alcohol which
on subsequent oxidation with the Dess-Martin periodinane,14
followed by Wittig olefination, afforded alkene 24 in 73% over
three steps. The ester group was reduced with DIBAL-H to
provide an allylic alcohol which, on subsequent oxidation with
TEMPO and BAIB, afforded aldehyde 7 in 95% yield (Scheme
2).15
Scheme 2. Synthesis of Aldehyde 7
Figure 2. Retrosynthetic analysis.
RESULTS AND DISCUSSION
Our first objective focused on the stereoselective synthesis of
the 2,6-dioxabicyclic skeleton 7. As outlined in Scheme 1, the
■
Scheme 1. Synthesis of Aldehyde 11
Our next objective was to introduce the tetramic acid unit
conjugated with two olefinic double bonds. Treatment of
phosphonate 816 with NaH in anhydrous THF followed by
addition of aldehyde 7 furnished the triene 5 in 93% yield.17
The intermediate 5 and N-dimethoxybenzyl protected glycine
ester (6)18 were heated under reflux in toluene to produce
coupling product 25 in 99% yield.19
Dieckmann cyclization of the diketo ester 25 by using TBAF
as a mild base in THF afforded N-dimethoxybenzyl protected
tirandamycin C (26) in 86% yield.20 To get the desired final
product, deprotection of the DMB group was needed and, thus,
intermediate 26 upon treatment with TFA in CH2Cl2 yielded 1
in 75% yield (Scheme 3).21 The spectral (1H and 13C NMR)
29
and analytical data {[α]D −56.7 (c = 0.55, EtOH; 96.1%ee);
25
lit.8 [α]D −59 (c = 0.11, EtOH)) were in good agreement
with the values reported for natural product.
key fragment 11, which contains all of the required stereo-
centers of target molecule 1 was prepared starting from a
known precursor 12.9−11 The diastereomeric purity of
compound 12 was ≥98% as per the HPLC analysis. Lithium
aluminum hydride mediated reduction of 12 followed by
acetonide protection afforded 16 in 95% yield. The primary
hydroxyl group was protected with PivCl and subsequent
deprotection of the acetonide group followed by chemo-
selective primary hydroxyl group protection with TBDMSCl
yielded 18 (76% over three steps). The benzyl protecting group
CONCLUSIONS
■
We have achieved a highly stereoselective total synthesis of
tirandamycin C in 20 steps with 12% overall yield starting from
a known bicyclic intermediate 12 followed by Horner−
Wadsworth−Emmons olefination, acid catalyzed ketalization,
Still-Gennari (Z)-selective olefination, and Dieckmann cycliza-
tion as key reactions. Following the same protocol, synthesis of
related natural products is in progress and will be reported in
due course.
B
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gel column chromatography using ethyl acetate and hexane (1:9) as
the mobile phase to afford compound 16 (8.7 g, 95%) as a white solid.
Mp 116.5 °C; [α]D29 −29.6 (c = 1.0, CHCl3); IR (neat): ν 3471, 2983,
2959, 2898, 2833, 2071, 1602, 1456, 1383 cm−1; 1H NMR (300 MHz,
CDCl3): δ 7.36−7.24 (m, 5H), 4.63 (dd, J = 12.8, 11.3 Hz, 2H), 4.26
(dt, J = 12.1, 2.2 Hz, 1H), 3.93 (td, J = 12.1, 3.0 Hz, 1H), 3.87−3.77
(m, 2H), 3.54 (m, 1H), 3.44 (dd, J = 9.1, 3.0 Hz, 1H), 2.60 (br s, 1H),
1.96−1.71 (m, 3H), 1.39 (s, 3H), 1.35 (s, 3H), 1.24 (m, 1H), 1.18 (d,
J = 6.7 Hz, 3H), 0.92 (d, J = 7.5 Hz, 3H) ppm; 13C NMR (75 MHz,
CDCl3): δ 138.2, 128.5, 127.7, 127.2, 98.1, 85.6, 77.0, 75.2, 67.4, 64.5,
60.0, 41.4, 36.2, 30.0, 28.6, 19.5, 16.2, 10.5 ppm; HRMS (ESI) m/z
calcd. for C19H30O4Na [M + Na]+: 345.2041, found: 345.2027.
(2R,3R,4S)-3-(Benzyloxy)-4-((R)-2,2-dimethyl-1,3-dioxan-4-
yl)-2-methylpentyl Pivalate (17). To a stirred solution of alcohol
16 (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 wes extracted with CH2Cl2 (2 × 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 pivalate ester 17 (5.7 g, 91%) as a colorless
liquid. [α]D29 −7.8 (c = 1.55, CHCl3); IR (neat): ν 3441, 2972, 1727,
1462, 1377, 1282, 1158 cm−1; 1H NMR (300 MHz, CDCl3): δ 7.33−
7.22 (m, 5H), 4.60 (s, 2H), 4.32−4.21 (m, 2H), 3.96−3.85 (m, 2H),
3.79 (dd, J = 10.9, 5.5 Hz, 1H), 3.36 (dd, J = 9.4, 2.2 Hz, 1H), 2.16 (m,
1H), 1.85 (qd, J = 12.2, 5.5 Hz, 1H), 1.70 (m, 1H), 1.37 (s, 3H), 1.34
(s, 3H), 1.25 (m, 1H), 1.19 (s, 9H), 1.09 (d, J = 6.9 Hz, 3H), 0.95 (d, J
= 7.0 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ 178.5, 138.8,
128.3, 127.3, 126.9, 98.0, 82.8, 74.8, 67.2, 65.7, 60.0, 40.9, 38.7, 35.0,
30.0, 28.4, 27.1, 19.5, 16.0, 10.4 ppm; HRMS (ESI) m/z calcd. for
C24H38O5Na [M + Na]+: 429.2616, found: 429.2597.
Scheme 3. Accomplishment of the Total Synthesis of
(−)-Tirandamycin C
EXPERIMENTAL SECTION
■
General Method. Air and/or moisture sensitive reactions were
carried out in anhydrous solvents under an atmosphere of argon in an
oven or flame-dried glassware. All anhydrous solvents were distilled
prior to use: THF, benzene, toluene, diethyl ether from Na and
benzophenone; CH2Cl2, DMSO, DMF, hexane from CaH2; MeOH,
EtOH from Mg cake. Commercial reagents were used without
purification. Column chromatography was carried out by using silica
gel (60−120 mesh). Specific optical rotations [α]D are given in 10−1
degcm2g−1. Infrared spectra were recorded in CHCl3/neat (as
mentioned) and reported in wavenumber (cm−1). TOF analyzer
type was used for the HRMS measurement. 1H and 13C NMR
chemical shifts are reported in ppm downfield from tetramethylsilane
and coupling constants (J) are reported in hertz (Hz). The following
abbreviations are used to designate signal multiplicity: s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, and br = broad.
(3R,4S,5R,6R)-5-(Benzyloxy)-4,6-dimethylheptane-1,3,7-triol
(15). To an ice-cooled suspension of LAH (3.43 g, 90.5 mmol) in
THF (150 mL) was added a solution of lactone 12 (10.0 g, 36.2
mmol) in THF (50 mL) under nitrogen atmosphere. The reaction
mixture was stirred for 6 h at room temperature. After complete
consumption of starting material (monitored by TLC), it was
quenched with saturated ammonium chloride solution (100 mL)
and the formed precipitate was filtered off on a pad of diatomaceous
earth using ethyl acetate. The filtrate was concentrated under reduced
pressure to get crude triol which was purified by column
chromatography over silica gel (ethyl acetate: hexane = 3:2) to
afforded triol 15 (9.08 g, 89%) as a viscous liquid. [α]D29 +9.7 (c = 1.5,
CHCl3); IR (neat): ν 3412, 2964, 2881, 1716, 1648, 1457, 1051 cm−1;
1H NMR (300 MHz, CDCl3): δ 7.35−7.27 (m, 5H), 4.66 (s, 2H),
(2R,3R,4S,5R)-3-(Benzyloxy)-5,7-dihydroxy-2,4-dimethylhep-
tyl Pivalate. To a solution of compound 17 (5.0 g, 12.3 mmol) in
MeOH (50 mL), camphoresulphonic acid (0.43 g, 1.84 mmol) was
added at room temperature and stirred for 2 h. After completion of the
reaction (monitored by TLC), it was quenched with Et3N (10 mL).
The reaction mass was concentrate under reduced pressure to afford
the crude product, which on purification by silica gel column
chromatography using ethyl acetate and hexane (2:3) as the mobile
phase afforded the diol (4.01 g, 89%) as a white solid. Mp 89.0 °C;
29
[α]D +24.3 (c = 0.9, CHCl3); IR (neat): ν 3305, 2958, 2925, 2855,
1
1726, 1459, 1400, 1290, 1055 cm−1; H NMR (300 MHz CDCl3): δ
7.36−7.26 (m, 5H), 4.58 (dd, J = 15.1, 10.5 Hz, 2H), 4.25 (dd, J =
10.5, 3.7 Hz, 1H), 4.20 (m, 1H), 4.10 (dd, J = 11.3, 6.0 Hz, 1H),
3.81−3.74 (m, 2H), 3.40 (dd, J = 8.3, 3.0 Hz, 1H), 3.35 (s, 1H), 2.54
(brs, 1H), 2.24 (m, 1H), 1.86 (m, 1H), 1.73 (m, 1H), 1.37 (m, 1H),
1.22 (s, 9H), 1.13 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H) ppm;
13C NMR (75 MHz, CDCl3): δ 178.4, 137.4, 128.6, 128.1, 127.8, 86.8,
76.0, 70.5, 66.0, 61.9, 38.9, 38.5, 36.4, 35.7, 27.2, 14.7, 12.0 ppm;
HRMS (ESI) m/z calcd. for C21H34O5Na [M + Na]+: 389.2303,
found: 389.2308.
4.22 (dd, J = 12.1, 2.2 Hz, 1H), 3.82−3.70 (m, 3H), 3.63 (m, 1H),
3.48 (dd, J = 7.5, 3.7 Hz, 1H), 3.39 (br s, 1H), 2.73 (brs, 1H), 2.01 (m,
1H), 1.85 (m, 1H) 1.69 (m, 1H), 1.39 (m, 1H), 1.09 (d, J = 7.5 Hz,
3H), 0.99 (d, J = 6.7 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ
137.5, 128.5, 128.0, 127.8, 87.9, 76.0 70.3, 64.8, 61.5, 39.1, 37.7, 36.5,
14.9, 11.7 ppm; HRMS (ESI) m/z calcd. for C16H26O4Na [M + Na]+:
305.1728, found: 305.1735.
(2R,3R,4S)-3-(Benzyloxy)-4-((R)-2,2-dimethyl-1,3-dioxan-4-
yl)-2-methylpentan-1-ol (16). To a stirred solution of triol 15 (8.0
g, 28.3 mmol) in anhydrous dichloromethane (75 mL) was added 2,2-
dimethoxypropane (20.85 mL, 170.2 mmol) followed by a catalytic
amount of CSA (750 mg) at 0 °C. The reaction mixture was stirred for
12 h at room temperature. After completion of reaction (monitored by
TLC), it was quenched with H2O (20 mL). Organic layer was
separated and aqueous layer extracted with dichloromethane (2 × 50
mL). The combined organic layer was dried over anhydrous Na2SO4,
concentrate to dryness under reduced pressure and purified by silica
(2R,3R,4S,5R)-3-(Benzyloxy)-7-(tert-butyldimethylsilyloxy)-5-
hydroxy-2,4-dimethylheptyl Pivalate (18). To an ice cooled
solution of diol (4.0 g, 10.92 mmol) and imidazole (1.86 g, 27.32
mmol) was added TBDMSCl (2.47 g, 16.39 mmol) in CH2Cl2 (50
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 × 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
(1:20) as mobile phase to afford silyl ether 18 (4.93 g, 94%) as a
29
colorless liquid. [α]D +11.8 (c = 1.55, CHCl3); IR (neat): ν 3521,
3031, 2957, 2930, 2883, 2858, 1729, 1462, 1397, 1248, 1157 cm−1; 1H
NMR (300 MHz, CDCl3): δ 7.32- 7.26 (m, 5H), 4.62 (ABq, δA 4.68,
δB 4.57 J = 10.9 Hz, 2H), 4.26 (dd, J = 10.9, 4.3 Hz, 1H), 4.16 (m,
C
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1H), 4.02 (dd, J = 10.9, 6.8 Hz, 1H), 3.82−3.69 (m, 2H), 3.41 (t, J =
6.0 Hz, 1H), 3.19 (s, 1H), 2.19 (m, 1H), 1.84−1.66 (m, 2H), 1.40 (m,
1H), 1.29 (s, 9H), 1.04 (d, J = 2.4 Hz, 3H), 1.02 (d, J = 2.4 Hz, 3H),
0.89 (s, 9H), 0.05 (s, 6H) ppm; 13C NMR (75 MHz, CDCl3): δ 178.5,
138.0, 128.4, 127.8, 127.7, 85.8, 75.9, 68.5, 65.9, 61.6, 39.2, 38.8, 37.4,
35.5, 27.2, 25.8, 18.1, 15.1, 11.1, −5.5 ppm; HRMS (ESI) m/z calcd.
for C27H49O5Si [M + H]+: 481.3349, found: 481.3352.
(1.4 g, 4.75 mmol) was taken in anhydrous DMSO (4.5 mL) and
stirred for 30 min. Alcohol 21 (1.0 g, 3.16 mmol) in anhydrous THF
(10 mL) was added to the reaction mixture at room temperature and
allowed to stir for 2 h. After completion of the reaction (monitored by
TLC), the reaction mixture was diluted with Et2O (20 mL), stirred for
15 min. The solid precipitate was filtered off and washed with Et2O (2
× 10 mL). The organic layer was washed with H2O (30 mL), dried
over anhydrous Na2SO4, concentrated under reduced pressure and
filtered through a small pad of silica gel to give aldehyde 11 (944 mg,
95%) as a colorless liquid which was used for the next step without
further purification.
(2R,3R,4S,5R)-7-(tert-Butyldimethylsilyloxy)-3,5-dihydroxy-
2,4-dimethylheptyl Pivalate (19). To a solution of compound 18
(2.0 g, 4.16 mmol) in anhydrous hexane (15 mL) was added catalytic
amount of Pd−C (150 mg, 10%) under hydrogen ballon pressure and
stirred at room temperature for 12 h. After complete consumption of
starting material (monitored by TLC), it was filtered through a small
pad of diatomaceous earth and concentrated to dryness under reduced
pressure. The residue was purified by silica gel column schromatog-
raphy utilizing ethyl acetate and hexane (1:9) as mobile phase to
To a solution of bis(2,2,2-trifluoroethyl)3-oxobutan-2-ylphospho-
nate 10 (2.4 g, 80% purity, 6.01 mmol) and 18-crown-6 (1.41 g, 6.01
mmol) in 30 mL anhydrous THF at −78 °C was added KHMDS (10.2
mL, 0.5 M in toluene, 5.11 mmol) dropwise under argon. After stirring
for 30 min at −78 °C, a solution of aldehyde 11 (944 mg, 3.0 mmol)
in anhydrous THF (20 mL) was added at −78 °C dropwise and the
resulting mixture stirred for another 1 h at −78 °C. The reaction
mixture was gradually warmed to room temperature in 4 h. Saturated
NH4Cl solution (20 mL) was added and the reaction mixture was
extracted with ethyl acetate (3 × 25 mL). The combined organic
extracts were washed with brine (50 mL), dried over Na2SO4, and
concentrated under reduced pressure. The crude product was purified
by silica gel column chromatography using ethyl acetate and hexane
(1:19) as mobile phase to obtain enone 9 (885 mg, 80%) as a 20:1
29
obtain alcohol 19 (1.56 g, 96%) as a colorless oil. [α]D +4.7 (c =
1.08, CHCl3); IR (neat): ν 3445, 2959, 1726, 1468, 1286, 1163, 1093
cm−1; 1H NMR (500 MHz, CDCl3): δ 4.27 (dd, J = 10.8, 4.3 Hz, 1H),
4.15 (d, J = 9.8, 1H), 4.11 (dd, J = 10.8, 6.5 Hz, 1H), 3.89 (m, 1H),
3.83−3.77 (m, 2H), 3.38 (br s, 1H), 2.03 (m, 1H), 1.89−1.76 (m,
2H), 1.45 (m, 1H), 1.20 (s, 9H), 0.99 (d, J = 6.5 Hz, 3H), 0.96 (d, J =
7.6 Hz, 3H), 0.89 (s, 9H), 0.08 (s, 6H); ppm; 13C NMR (75 MHz,
CDCl3): δ 178.8, 77.4, 73.6, 66.3, 63.1, 38.8, 38.1, 36.0, 34.8, 27.2,
25.7, 18.0, 14.7, 12.0, −5.6 ppm; HRMS (ESI) m/z calcd. for
C20H42O5Si [M + H]+: 391.2879, found: 391.2879.
29
ratio of Z/E isomers. [α]D +9.27 (c = 1.0, CHCl3); IR (neat): ν
3639, 2973, 2937, 1728, 1462, 1380, 1284, 1225, 1161, 1021 cm−1; 1H
NMR (500 MHz, CDCl3): δ 5.75 (t, J = 5.9 Hz, 1H), 4.16 (dd, J =
10.9, 4.9 Hz, 1H), 3.99 (dd, J = 9.9, 6.9 Hz, 1H), 3.81 (m, 1H), 3.22
(dd, J = 6.9, 5.9 Hz, 1H), 2.47−2.36 (m, 2H), 2.25 (s, 3H), 1.96 (s,
3H), 1.95 (m, 1H), 1.84 (m, 1H), 1.31 (s, 3H), 1.30 (s, 3H), 1.20 (s,
9H), 1.01 (d, J = 6.9 Hz, 3H), 0.88 (d, J = 6.9 Hz, 3H) ppm; 13C NMR
(75 MHz, CDCl3): δ 202.5, 178.5, 136.1, 136.0, 100.4, 76.1, 69.4, 65.9,
38.8, 37.0, 30.9, 29.9, 27.2, 25.3, 23.3, 21.1, 13.9, 12.7 ppm; HRMS
(ESI) m/z calcd. for C21H36O5 Na [M + Na]+: 391.2455, found:
391.2478.
(R)-2-((4R,5S,6R)-6-(2-(tert-Butyldimethylsilyloxy)ethyl)-
2,2,5-trimethyl-1,3-dioxan-4-yl)propyl Pivalate (20). To a stirred
solution of diol 19 (2.0 g, 5.12 mmol) in anhydrous dichloromethane
(40 mL) was added 2,2-dimethoxypropane (6.1 mL, 51.28 mmol)
followed by a catalytic amount of CSA (150 mg) at 0 °C. The reaction
mixture was stirred for 1 h at room temperature. After completion of
the reaction (monitored by TLC), it was quenched with H2O (20
mL). The organic layer was separated and the aqueous layer was
extracted with CH2Cl2 (2 × 30 mL). The combine organic layer was
dried over anhydrous Na2SO4, concentrated to dryness under reduced
pressure and purified by silica gel column chromatography using ethyl
acetate and hexane (1:19) as mobile phase to afford compound 20
(R)-2-((1R,3R,4S,5R)-1,4,8-Trimethyl-2,9-dioxabicyclo[3.3.1]-
non-7-en-3-yl)propyl Pivalate (22). To a stirred solution of enone
9 (0.8 g, 2.17 mmol) in MeOH (10 mL), was added catalytic amount
CSA (50 mg) at 0 °C and stirred at room temperature for 2 h. After
completion of the reaction (monitored by TLC), MeOH was removed
under reduced pressure and the residue was dissolve in ethyl acetate
(20 mL) and washed with sodium bicarbonate solution (10 mL). The
extract was dried over anhydrous Na2SO4, concentrated under reduced
pressure and purified by silica gel column chromatography using ethyl
acetate and hexane (1:24) as mobile phase to afford bicyclic
29
(2.03 g, 92%) as light yellow oil. [α]D +8.5 (c = 1.0, CHCl3); IR
(neat): ν 2958, 2933, 2882, 2859, 1732, 1463, 1255, 1221, 1158 cm−1;
1H NMR (300 MHz, CDCl3): δ 4.15 (dd, J = 10.9, 4.5 Hz, 1H), 4.0−
3.93 (m, 2H), 3.66−3.60 (m, 2H), 3.17 (dd, J = 7.2, 6.9 Hz, 1H), 1.92
(m, 1H), 1.79 (m, 1H), 1.63−1.45 (m, 2H), 1.27 (s, 6H), 1.20 (s, 9H),
1.01 (d, J = 6.8 Hz, 3H), 0.89 (s, 9H), 0.86 (d, J = 6.8 Hz, 3H), 0.04
(s, 6H); 13C NMR (75 MHz, CDCl3): δ 178.5, 100.3, 76.1, 66.0, 65.5,
59.6, 38.8, 37.2, 37.1, 33.8, 27.2, 25.9, 25.3, 23.4, 18.2, 13.9, 12.8, −5.4
ppm; HRMS (ESI) m/z calcd. for C23H46O5SiNa [M + Na]+:
453.3019, found: 453.3002.
29
compound 22 (580 mg, 86%) as a light yellow oil. [α]D −26.75 (c
= 1.0, CHCl3); IR (neat): ν 3451, 2926, 1727, 1638, 1458, 1374, 1286,
1158 cm−1 ; 1H NMR (500 MHz, CDCl3): δ 5.67 (br s, 1H), 4.33 (dd,
J = 10.8, 5.8 Hz, 1H), 3.96 (dd, J = 6.8, 5.8 Hz, 1H), 3.88 (dd, J = 10.8,
7.8 Hz, 1H), 3.46 (dd, J = 10.8, 1.9 Hz, 1H), 2.38 (m, 1H), 2.23 (m,
1H), 2.04 (m, 1H), 1.95 (dd, J = 18.6, 3.9 Hz, 1H), 1.59 (s, 3H), 1.36
(s, 3H), 1.20 (s, 9H), 0.98 (d, J = 6.8 Hz, 3H), 0.78 (d, J = 6.8 Hz,
3H) ppm; 13C NMR (75 MHz, CDCl3): δ 178.6, 132.4, 123.3, 95.4,
75.8, 71.2, 65.438.7, 34.2, 33.2, 27.2, 24.2, 24.0, 18.3, 15.3, 13.4 ppm;
HRMS (ESI) m/z calcd. for C18H30O4Na [M + Na]+: 333.2041,
found: 333.2028.
(R)-2-((4R,5S,6R)-6-(2-Hydroxyethyl)-2,2,5-trimethyl-1,3-di-
oxan-4-yl)propyl Pivalate (21). To an ice cooled solution of silyl
ether 20 (2.0 g, 4.65 mmol) in anhydrous THF (15 mL) was added
TBAF (9.3 mL, 1 M solution in THF, 9.3 mmol). The reaction
mixture was stirred for 2 h at room temperature. After completion of
the reaction (monitored by TLC), it was quenched with aqueous
ammonium chloride solution (20 mL). The reaction mixture was
extracted with ethyl acetate (3 × 50 mL), dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography utilizing ethyl acetate
and hexane (1:6) as mobile phase to afford alcohol 21 (1.36 g, 93%) as
(R)-2-((1R,3R,4S,5R)-1,4,8-Trimethyl-2,9-dioxabicyclo[3.3.1]-
non-7-en-3-yl)propan-1-ol. A stirred solution of Piv-protected
bicyclic compound 22 (550 mg, 1.77 mmol) in anhydrous CH2Cl2 (20
mL) was treated with DIBAL-H (2.8 mL, 3.89 mmol, 20% solution in
toluene) at 0 °C and stirred for 1 h. The reaction was quenched with
MeOH (1 mL) and saturated aqueous sodium potassium tartrate
solution (10 mL). The mixture was warmed to room temperature and
stirred for 2 h. Organic layer was separated and the aqueous layer
extracted with CH2Cl2 (2 × 20 mL). Combined organic layer was
dried over Na2SO4, concentrated under reduced pressures. The crude
product was purified by silica gel column chromatography using ethyl
acetate and hexane (1:9) as mobile phase to afford alcohol (357 mg,
89%) as a colorless liquid. [α]D29 −51.1 (c = 1.0, CHCl3); IR (neat): ν
29
a colorless liquid. [α]D −3.54 (c = 1.0, CHCl3); IR (neat): ν 3446,
2972, 1727, 1462, 1379, 1226, 1164, 1025 cm−1; 1H NMR (300 MHz,
CDCl3): δ 4.16 (dd, J = 10.7, 3.4 Hz, 1H), 4.03 (m, 1H), 3.96 (dd, J =
10.9, 6.9 Hz, 1H), 3.76−3.71 (m, 2H), 3.21 (dd, J = 7.1, 5.6 Hz, 1H),
1.98−1.70 (m, 3H), 1.48 (m, 1H), 1.34 (s, 3H), 1.29 (s, 3H), 1.19 (s,
9H), 1.01 (d, J = 6.9 Hz, 3H), 0.89 (d, J = 6.7, 3H) ppm; 13C NMR
(75 MHz, CDCl3): δ 178.5, 100.4, 76.1, 69.2, 65.8, 61.6, 38.7, 37.2,
37.0, 32.6, 27.1, 25.4, 23.3, 14.0, 12.8 ppm; HRMS (ESI) m/z calcd.
for C17H32O5Na [M + Na]+: 339.2147, found: 339.2148.
(R)-2-((4R,5S,6R)-2,2,5-Trimethyl-6-((Z)-3-methyl-4-oxopent-
2-enyl)-1,3-dioxan-4-yl)propyl Pivalate (9). Iodoxybenzoic acid
D
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3451, 2963, 2926, 1455, 1375, 1222, 1178, 1116, 1041 cm−1; 1H NMR
(300 MHz, CDCl3): δ 5.70 (br s, 1H), 4.02−3.91 (m, 2H), 3.56 (dd, J
= 11.3, 2.3 Hz, 1H), 3.47 (dd, J = 11.3, 3.7 Hz, 1H), 2.40 (m, 1H),
2.29 (m, 1H), 1.95 (m, 1H), 1.76 (m, 1H), 1.62−1.59 (m, 3H), 1.39
(s, 3H), 1.07 (d, J = 7.5 Hz, 3H), 0.74 (d, J = 7.5 Hz, 3H) ppm; 13C
NMR (75 MHz, CDCl3): δ 131.6, 123.8, 95.8, 78.5, 71.0, 63.3, 34.6,
34.2, 24.4, 24.0, 18.2, 15.1, 13.3 ppm; HRMS (ESI) m/z calcd. for
C13H22O3Na [M + Na]+: 249.1466, found: 249.1472.
(R,E)-Ethyl-2-methyl-4-((1R,3R,4S,5R)-1,4,8-trimethyl-2,9-
dioxabicyclo[3.3.1]non-7-en-3-yl)pent-2 (24). To a stirred
solution of primary alcohol (320 mg, 1.41 mmol) and solid anhydrous
NaHCO3 (356 mg) in CH2Cl2 (30 mL) at 0 °C was added Dess−
Martin periodinane (900 mg, 2.11 mmol). The resulting reaction
mixture was stirred at 0 °C to room temperature for 1 h. After
completion of the reaction (monitored by TLC), the mixture was
filtered through filter paper. The filtrate was washed with saturated
NaHCO3 solution (20 mL) and CH2Cl2 (30 mL). The organic layer
was separated and the aqueous layer extracted with CH2Cl2 (3 × 30
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 23 (286 mg, 90%) as a colorless oil which
was used for the next step without further purification.
anhydrous Na2SO4 and concentrated under reduced pressure. The
crude product was purified by silica gel column chromatography using
ethyl acetate and hexane (1:9) as mobile phase to afford aldehyde 7
29
(189 mg, 95%) as a pale yellow viscous liquid. [α]D −40.2 (c = 0.7,
CHCl3); IR (neat): ν 3332, 2962, 2927, 1679, 1459, 1379, 1338, 1265,
1193, 1159, 1118 cm−1; 1H NMR (300 MHz, CDCl3): δ 9.46 (s, 1H),
6.75 (m, 1H), 5.71 (br s, 1H), 3.95 (t, J = 6.3 Hz, 1H), 3.53 (dd, J =
10.5, 2.2 Hz, 1H), 2.91 (m, 1H), 2.40 (m, 1H), 1.96 (m, 1H), 1.85 (m,
1H), 1.76 (d, J = 1.5 Hz, 3H), 1.64−1.62 (m, 3H), 1.43 (s, 3H), 1.09
(d, J = 6.8 Hz, 3H), 0.70 (d, J = 6.8, Hz, 3H) ppm; 13C NMR (75
MHz, CDCl3): δ 195.5, 155.1, 139.1, 132.3, 123.2, 95.4, 76.1, 70.8,
35.1, 34.3, 24.1, 24.0, 18.2, 16.4, 13.1, 9.1 ppm; HRMS (ESI) m/z
calcd. for C16H25O3 [M + H]+: 265.1804, found: 265.1801.
2,2-Dimethyl-6-((R,1E,3E)-3-methyl-5-((1R,3R,4S,5R)-1,4,8-
trimethyl-2,9-dioxabicyclo [3.3.1]non-7-en-3-yl)hexa-1,3-dien-
yl)-4H-1,3-dioxin-4-one (5). In a flame-dried, two-necked RB flask,
charged with NaH (39 mg, 60% suspension in mineral oil, 0.99 mmol)
under argon atmosphere, anhydrous THF (5 mL) was added and cool
to 0 °C. To this stirred solution phosphonate 8 (316 mg, 1.1 mmol) in
anhydrous THF (20 mL) was added dropwise at 0 °C and was allowed
to stir for 30 min. Then aldehyde 7 (150 mg, 0.568 mmol) in THF (10
mL) was added at 0 °C. The resulting mixture was allowed to stir for
12 h at room temperature. The reaction was quenched with saturated
aqueous solution of NH4Cl (5 mL), extracted with ethyl acetate (3 ×
10 mL). Combined extracts were dried over Na2SO4 and concentrated
under reduced pressure. The crude product was purified by silica gel
column chromatography to afford compound 5 (216 mg, 93%) as a
The resulting aldehyde 23 (286 mg, 1.27 mmol) and
(carbethoxyethylidene)triphenyl phosphorane (2.3 g, 6.39 mmol)
were dissolved in toluene (30 mL), heated at 110 °C for 12 h. Toluene
was removed under reduced pressure and the residue was purified by
silica gel column chromatography using ethyl acetate and hexane (1:9)
as mobile phase to afford ester 24 (342 mg, 87%) as a10:1 E/Z
29
colorless liquid. [α]D +4.32 (c = 1.08, CHCl3); IR (neat): ν 3448,
2925, 1724, 1624, 1380, 1269, 1203, 1118, 1015 cm−1; 1H NMR (300
MHz, CDCl3): δ 7.02 (d, J = 15.8 Hz, 1H), 6.11 (d, J = 9.8 Hz, 1H),
5.87 (d, J = 15.8 Hz, 1H), 5.69 (br s, 1H), 5.28 (s, 1H), 3.93 (m, 1H),
3.46 (dd, J = 10.5, 2.2 Hz, 1H), 2.75 (m, 1H), 2.39 (m, 1H), 1.99−
1.87 (m, 2H), 1.81 (d, J = 1.5 Hz, 3H), 1.75 (s, 3H), 1.74 (s, 3H),
1.63−1.60 (m, 3H), 1.42 (s, 3H), 1.02 (d, J = 6.7 Hz, 3H), 0.67 (d, J =
6.8 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ 164.0, 162.1,143.4,
142.4, 132.8, 132.4, 123.2, 117.0, 106.1, 95.4, 93.7, 76.5, 71.0, 34.9,
34.1, 25.1, 24.8, 24.3, 24.1, 18.3, 17.1, 13.1, 12.0 ppm; HRMS (ESI)
m/z calcd. for C23H32O5Na [M + Na]+: 411.2147, found: 411.2145.
Ethyl-2-((R,4E,6E)-N-(2,4-dimethoxybenzyl)-6-methyl-3-oxo-
8-((1R,3R,4S,5R)-1,4,8-tri-methyl-2,9-dioxabicyclo[3.3.1]non-7-
en-3-yl)nona-4,6-dienamido)acetate (25). Compound 5 (80 mg,
0.21 mmol) and DMB-glycine ester 6 (62.5 mg, 0.25 mmol) were
dissolved in anhydrous toluene (5 mL) in a flame dry RB flask
equipped with a condenser under argon atmosphere. The solution was
heated to reflux at 110 °C for 6 h. The reaction mixture was cooled to
room temperature and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography using ethyl
acetate and hexane (2:3) as mobile phase to afford compound 25 (119
mg, 99%) as pale yellow oil. [α]D29 −5.2 (c = 1.35, CHCl3); IR (neat):
ν 3449, 2925, 2854, 1744, 1615, 1585, 1507, 1462, 1206, 1120 cm−1;
1H NMR (ketone and enol forms, 300 MHz, CDCl3): δ 14.0 (s, 0.5H),
29
isomers. [α]D −23.1 (c = 0.7, CHCl3); IR (neat): ν 3635, 2963,
2929, 2876, 1710, 1650, 1447, 1375, 1243 cm−1; 1H NMR (500 MHz,
CDCl3): δ 6.86 (dd, J = 10.5, 0.9 Hz, 1H), 5.66 (br s, 1H), 4.22−4.16
(m, 2H), 3.90 (m, 1H), 3.43 (dd, J = 10.5, 1.9 Hz, 1H), 2.68 (m, 1H),
2.37 (m, 1H), 1.95−1.84 (m, 2H), 1.83 (d, J = 0.95 Hz, 3H), 1.62−
1.60 (m, 3H), 1.40 (s, 3H), 1.33 (t, J = 7.6 Hz, 3H), 1.02 (d, J = 6.6
Hz, 3H), 0.67 (d, J = 6.6 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3):
δ 168.2, 142.6, 132.5, 127.8, 123.2, 95.4, 76.2, 71.0, 60.4, 34.9, 34.3,
24.2, 24.1, 18.3, 16.5, 14.3, 13.2, 12.4 ppm; HRMS (ESI) m/z calcd.
for C18H28O4Na [M + Na]+: 331.1880, found: 331.1885.
(R,E)-2-Methyl-4-((1R,3R,4S,5R)-1,4,8-trimethyl-2,9-
dioxabicyclo[3.3.1]non-7-en-3-yl)pent-2-en-1-ol. A stirred sol-
ution of ester 24 (350 mg, 1.13 mmol) in anhydrous CH2Cl2 (10 mL)
was treated with DIBAL-H (2.55 mL of 1 M solution in toluene, 2.55
mmol) at 0 °C and stirred for 3 h. The reaction was quenched with
MeOH (1 mL) and saturated aqueous sodium potassium tartrate
solution (10 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 × 10 mL). Combined
organic layers were dried over Na2SO4, 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 afford alcohol (266 mg, 88%) as a colorless liquid. [α]D29 −44.36 (c
= 1.0, CHCl3); IR (neat): ν 3455, 2960, 2925, 1456, 1370, 1222, 1175,
7.32 (d, J = 15.8 Hz, 0.5H), 7.13 (d, J = 15.8 Hz, 1H), 7.02 (m, 1H),
6.44−6.39 (m, 2H), 6.22 (m, 1H), 6.01 (d, J = 9.8 Hz, 1H), 5.75 (d, J
= 15.8 Hz 1H), 5.66 (br s, 1H), 5.26 (s, 0.5H), 4.50 (s, 2H), 4.21−
4.09 (m, 2H), 4.07−4.04 (m, 2H), 3.97 (s, 1H), 3.90 (m, 1H), 3.83−
3.78 (m, 6H), 3.43 (m, 1H), 2.71 (m, 1H), 2.35 (m, 1H), 1.91 (m,
2H), 1.79 (m, 3H), 1.60 (s, 3H), 1.30−1.23 (m, 3H), 1.04−0.97 (m,
3H), 0.69−0.63 (m, 3H) ppm; 13C NMR (ketone and enol forms, 75
MHz, CDCl3): δ 193.9, 172.9, 170.2, 169.5, 169.3, 169.0, 168.1, 160.9,
160.5, 158.6, 158.1, 149.8, 145.5, 145.0, 141.2, 140.0, 133.1, 132.7,
132.6, 132.5, 131.4, 130.0, 128.5, 123.5, 123.1, 123.0, 120.4, 116.4,
115.8, 104.2, 103.9, 98.6, 98.5, 98.2, 95.4, 95.3, 88.6, 76.6, 71.0, 61.1.
60.0, 55.3, 55.2, 48.3, 47.2, 47.0, 46.8, 46.6, 34.9, 34.8, 34.3, 34.0, 24.2,
24.1, 18.3, 17.2, 17.0, 14.1, 13.2, 12.1 ppm; HRMS (ESI) m/z calcd.
for C33H45NO8Na [M + Na]+: 606.3042, found: 606.3049.
1
1114, 1041 cm−1; H NMR (300 MHz, CDCl3): δ 5.65 (br s, 1H),
5.57 (d, J = 9.8 Hz, 1H), 4.02 (s, 2H), 3.90 (t, J = 6.8 Hz, 1H), 3.38
(dd, J = 10.5, 2.2 Hz, 1H), 2.56 (m, 1H), 2.36 (m, 1H), 1.68 (s, 3H),
1.62−1.58 (m, 3H), 1.37 (s, 3H), 0.96 (d, J = 6.8 Hz, 3H), 0.67 (d, J =
6.8 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ 135.2, 132.8, 127.3,
123.3, 95.6, 77.6, 71.3, 69.4, 34.7, 33.1, 24.5, 24.4, 18.5, 17.8, 13.9, 13.6
ppm; HRMS (ESI) m/z calcd. for C16H26O3Na [M + Na]+: 289.1779,
found: 289.1766.
(R,E)-2-Methyl-4-((1R,3R,4S,5R)-1,4,8-trimethyl-2,9-
dioxabicyclo[3.3.1]non-7-en-3-yl)pent-2-ena (7). To a stirred
solution of alcohol (200 mg, 0.75 mmol) and iodobenzene diacetate
(362 mg, 1.12 mmol) in anhydrous CH2Cl2 (10 mL) was added
TEMPO (11.7 mg, 0.075 mmol) at room temperature and stirred for 1
h. After completion of reaction (monitored by TLC), it was quenched
with saturated aqueous solution of NaHCO3 (5 mL) followed by
saturated aqueous solution of Na2S2O3 (5 mL) and stirred for 1 h. The
organic layer was separated and the aqueous layer extracted with
CH2Cl2 (2 × 10 mL). Combined organic layer was dried over
Dimethoxybenzyl (DMB) Protected Tirandamycin C (26). A
stirred solution of diketo compound 25 (50 mg, 0.09 mmol) in
anhydrous THF (2 mL) under argon atmosphere was treated with
TBAF (0.214 mL, 1 M solution in THF, 0.22 mmol) and the resulting
yellow solution stirred for 15 min at room temperature. After
E
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completion of the reaction (monitored by TLC), it was quenched with
10% HCl solution (2 mL) and extracted with ethyl acetate (3 × 10
mL). Combined organic extracts were dried over anhydrous Na2SO4,
concentrated 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 DMB protected tirandmycin C 26
(39.7 mg, 86%) as a pale yellow oil. [α]D29 −49.7 (c = 0.7, CHCl3); IR
(neat): ν 3414, 2959, 2870, 1710, 1616, 1470, 1380, 1291, 1206, 1159,
1118, 1033, 882, 787 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.57 (d, J
= 15.6 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 7.09 (d, J = 15.6 Hz, 1H),
6.48−6.44 (m, 2H), 6.29 (d, J = 10.4 Hz, 1H), 5.69 (br s, 1H), 4.57 (s,
2H), 3.94 (t, J = 6.2 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.64 (s, 2H),
3.48 (dd, J = 10.4, 2.0 Hz, 1H), 2.80 (m, 1H), 2.38 (m, 1H), 1.98−
1.84 (m, 2H), 1.89 (s, 3H), 1.62−1.59 (m, 3H), 1.42 (s, 3H), 1.04 (d,
J = 6.3 Hz, 3H), 0.68 (d, J = 6.3 Hz, 3H) ppm; 13C NMR (75 MHz,
CDCl3): δ 192.1, 174.0, 173.5, 160.9, 158.6, 149.6, 146.2, 134.0, 132.5,
131.2, 123.2, 116.1, 116.0, 104.3, 100.7, 98.5, 95.4, 76.6, 71.0, 55.6,
55.4, 40.0, 35.0, 34.5, 24.3, 24.1, 18.3, 17.0, 13.2, 12.2 ppm; HRMS
(ESI) m/z calcd. for C31H40NO7 [M + H]+: 538.2782, found:
538.2789.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
S.D. and S.S.H. thank the CSIR for financial assistance in the
form of a research fellowship.
■
REFERENCES
■
(1) (a) Review: Capon, R. J. Eur. J. Org. Chem. 2001, 633−645. (b)
Review: Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.;
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Tirandamycin C (1). To a stirred solution of dimethoxybenzyl
(DMB) protected tirandamycin C 26 (25 mg, 0.05 mmol) in
anhydrous CH2Cl2 (2 mL), was added CF3CO2H (1 mL). The
resulting wine red solution was stirred at room temperature for 30 min
and then quenched with ice pieces. The light yellow solution was
extracted with CH2Cl2 (3 × 10 mL), combined extracts were dried
over anhydrous Na2SO4 and concentrated under reduced pressure.
The crude product was purified by reversed-phase HPLC to give
tirandamycin C 1 (13.5 mg, 75%) as yellow oil. [α]D29 −56.7 (c = 0.55,
EtOH); IR (neat): ν 3422, 2950, 2924, 2853, 1617, 1570, 1460, 1378,
(4) Carlson, J. C.; Li, S.; Burr, D. A.; Sherman, D. H. J. Nat. Prod.
2009, 72, 2076−2079.
(5) Meyer, C. E. J. Antibiot. 1971, 24, 558−560.
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Arch. Microbiol. 1976, 109, 65−76.
(7) (a) Schlessinger, R. H.; Bebernitz, G. R.; Lin, P.; Poss, A. J. Am.
Chem. Soc. 1985, 107, 1777−1778. (b) DeShong, P.; Ramesh, S.;
Elango, V.; Perez, J. J. Am. Chem. Soc. 1985, 107, 5219−5224.
(c) Boeckman, R. K.; Starrett, J. E.; Nickell, D. G.; Sum, P. E. J. Am.
Chem. Soc. 1986, 108, 5549−5559. (d) Neukom, C.; Richardson, D.
P.; Myerson, J. H.; Bartlett, P. A. J. Am. Chem. Soc. 1986, 108, 5559−
5568. (e) Shimshock, S. J.; Waltermire, R. E.; DeShong, P. J. Am.
Chem. Soc. 1991, 113, 8791−8796. (f) Shiratani, T.; Kimura, K.;
Yoshihara, K.; Hatakeyama, S.; Irie, H.; Miyashita, M. Chem. Commun.
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1
1292, 1237, 1119, 1041 cm−1; H NMR (500 MHz, CD2Cl2): δ 7.62
(d, J = 15.6 Hz, 1H), 7.12 (d, J = 15.6 Hz, 1H), 6.32 (d, J = 10.3 Hz,
1H), 5.70 (br s, 1H), 3.90 (t, J = 6.2 Hz, 1H), 3.78 (s, 2H), 3.49 (dd, J
= 10.7, 1.5 Hz, 1H), 2.83 (m, 1H), 2.33 (m, 1H), 1.93 (m, 1H), 1.91
(d, J = 0.7 Hz, 3H), 1.84 (m, 1H), 1.61 (m, 3H), 1.38 (s, 3H), 1.05 (d,
J = 6.9 Hz, 3H), 0.68 (d, J = 6.9 Hz, 3H) ppm; 13C NMR (75 MHz,
CD2Cl2): δ 192.9, 177.0, 174.8, 150.5, 147.5, 134.5, 132.9, 123.6,
116.0, 100.2, 95.8, 77.0, 71.3, 52.0, 35.5, 35.0, 24.5, 24.5, 18.4, 17.2,
13.3, 12.3 ppm; HRMS (ESI) m/z calc. for C22H30NO5 [M + H]+:
388.2123, found: 388.2129.
Ethyl 2-(2,4-dimethoxybenzylamino)acetate (6). Ethyl bro-
moacetate (0.8 mL, 7.18 mmol) was added dropwise to a solution of
(2,4-dimethoxybenzyl)amine (1.0 g, 5.98 mmol) and triethyl amine
(2.5 mL, 17.94 mmol) in anhydrous THF (10 mL) at 0 °C under
argon. The reaction mixture was warmed to room temperature and
stirred overnight. Brine (20 mL) was added, and the reaction mixture
was extracted with ethyl acetate (3 × 40 mL). The combined organic
layers were dried over Na2SO4, concentrated under reduced pressure.
The residue was purified by silica gel column chromatography using
ethyl acetate and hexane (1:1) as mobile phase to afford compound 6
(1.19 g, 79%). IR (neat): ν 3342, 2939, 2837, 1738, 1613, 1507, 1461,
1290, 1263, 1207, 1157, 1130, 1035 cm−1; 1H NMR (300 MHz,
CDCl3): δ 7.12 (d, J = 7.9 Hz, 1H), 6.46−6.44 (m, 2H), 4.16 (q, J =
7.1 Hz, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.74 (s, 2H), 3.37 (s, 2H),
1.95 (br s, 1H), 1.26 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (75 MHz,
CDCl3): δ 172.2, 160.0, 158.5, 130.4, 119.7, 103.5, 98.2, 60.3, 55.0,
49.8, 47.8,13.9 ppm; HRMS (ESI) m/z calcd. for C13H19NO4Na [M +
Na]+: 276.1211, found: 276.1211.
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ASSOCIATED CONTENT
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S
* 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.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yadavpub@iict.res.in; mohapatra@iict.res.in
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dx.doi.org/10.1021/jo3016709 | J. Org. Chem. XXXX, XXX, XXX−XXX