Scalable synthesis of the unusual amino acid segment (ADMOA unit) of marine anti-inflammatory peptide: Solomonamide A

Article abstract of DOI:10.1039/c5ob00481k

The most abundantly available hexose sugar, d-glucose has been converted to protected 4-amino(2′amino-4′-hydroxy phenyl)-3,5-dihydroxy-2-methyl-6-oxo hexanoic acid (protected ADMOA, 3), the unusual amino acid present in marine natural product solomonamide

Full text of DOI:10.1039/c5ob00481k

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Scalable synthesis of the unusual amino
acid segment (ADMOA unit) of marine
Cite this: DOI: 10.1039/c5ob00481k
anti-inflammatory peptide: solomonamide A†
Nerella Kavitha and Srivari Chandrasekhar*
Received 11th March 2015,
Accepted 23rd April 2015
The most abundantly available hexose sugar, D-glucose has been converted to protected 4-amino-
(2’amino-4’-hydroxy phenyl)-3,5-dihydroxy-2-methyl-6-oxo hexanoic acid (protected ADMOA, 3), the
unusual amino acid present in marine natural product solomonamide A in gram quantities involving easy
to operate chemical transformations.
DOI: 10.1039/c5ob00481k
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Introduction
The cyclic peptide natural products originating from marine
sources have tremendous potential as drug leads.1 Also,
some of these natural peptides incorporate non-proteinogenic
(uncommon) amino acids which add new properties to these
natural products.2 These uncommon amino acids provide
additional stability to enzyme degradation and provide three
dimensional shapes for better biological activities.3 A good
number of marine peptides have been taken into chemical
development viz. dolastatin,4 didemnins,5 auristatin,6 ectein-
ascidin 743.7
Zampella’s group has isolated two cyclic peptides, namely
solomonamides A and B (Fig. 1, 1 and 1a),8 from the marine
sponge Theonella swinhoei and have characterized and
assigned structures based on extensive spectral studies. Solo-
monamide A has one unusual amino acid, 4-amino(2′-amino-
4′-hydroxy phenyl)-3,5-dihydroxy-2-methyl-6-oxo hexanoic acid
(ADMOA, 2) and solomonamide B has a similar amino acid
except that it lacks one hydroxy group at the 5′-position and is
named as AHMOA, 2a. Solomonamide A was the minor com-
ponent of several molecules isolated from Theonella species
and the biological targets are not validated owing to scarcity of
the natural product, except that some in vivo studies indicated
anti-inflammatory properties (100 µg per kg weight). Thus, the
synthesis of the natural product and its analogues would be of
utmost desire to explore further potential of this natural
product. Besides, the very uncommon γ-amino acid (ADMOA, 2)
Fig. 1 Structure of solomonamide A, B and their unusual amino acid
units.
poses a synthetic challenge owing to the presence of multiple
and adjacent chiral centers.
The synthetic efforts from our own research group9 and the
group of Reddy10 are far from accomplishing the total syn-
thesis. It is thought that the accomplishment of a scalable syn-
thesis of the most functionalized part of solomonamide A,
namely protected ADMOA 3, will pave the way for the total
synthesis of solomonamide and related peptides along with
simplified analogues rather efficiently.
Results and discussion
Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical
In this regard, a general and scalable synthetic route involving
readily accessible chemicals is conceived. D-Glucose, undoubt-
edly the cheapest chiral precursor,11 which already has most of
the necessary chiral centers built in, was chosen as the starting
Technology, Tarnaka, Hyderabad 500 007, India. E-mail: srivaric@iict.res.in;
Fax: +91-40-27160152; Tel: +91-40-27193210, 27193434
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5ob00481k
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The desired furanose derivative 6 was prepared from
D-glucose following a literature procedure.12,13 Pyridinium
chlorochromate (PCC) mediated oxidation of alcohol 6 to
methyl ketone 7 was achieved in 83% yield. One carbon
homologation using methylenetriphenylphosphorane (in situ
generated from methyltriphenylphosphonium bromide and
n-BuLi) provided 5-deoxy sugar 8 in 78% yield.14 Substrate
controlled diastereoselective hydroboration of the olefin in
the presence of 9-BBN furnished furano alcohol 9, with 20 : 1
de in favour of the required isomer, and the major isomer
was separated by silica gel column chromatography in pure
form (85% yield).12 Similar hydroboration on 3′-O-benzyl pro-
tected substrate provided low diastereoselectivity, which com-
pelled us to switch to tosyl protection at the 3′-position. The
tosyl group at the 3′ position in 9 was removed using Na-
naphthalenide15 to give the diol 10 (87%), and the selective
protection of the primary alcohol as TBDPS ether gave 11 in
98% yield. The double inversion technique was employed to
install the azido group at the 3′ position wherein the treat-
ment of 11 with triphenylphosphine, triiodoimidazole16 furn-
ished iodo with allo-configuration which upon treatment
with NaN3 furnished azido furanose with xylo-configuration
to provide 12 in 65% yield over two steps. Classical ring
opening of 1,2-O-isopropylidene furan in 12 with EtSH and
BF3·OEt2 as catalyst provided the acyclic dithiane 13 in 74%
yield.17 For operational simplicity the diol functionality was
Scheme 1 Retrosynthetic analysis of protected ADMOA 3.
material to make intermediate 5, based on the retrosynthesis silylated to provide trisilyl derivative 14 in 92% yield. Metal
shown in Scheme 1. Grignard reaction on the unmasked thio- catalyzed reduction (Zn/NH4Cl) of azide to amine followed by
acetal 5 with nitro aryl iodide 4 would provide the aromatic part treatment with Cbz–Cl gave the carbamate 5 in 79% yield
to realize the uncommon and protected ADMOA fragment 3.
(Scheme 2).
Scheme 2 Synthesis of compound 5.
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Infrared (IR) spectra were obtained using either thin films (for
oils) or a KBr matrix (for solids). Commercially available
reagents were used, unless otherwise indicated. Tetrahydro-
furan was distilled under nitrogen from Na-benzophenone
prior to use. CH2Cl2 was dried over 4 Å molecular sieves. Tech-
nical grade ethyl acetate and hexanes used for column chrom-
atography were distilled prior to use. Column chromatography
was carried out with silica gel (60–120 mesh) packed in glass
columns. All the reactions were performed under nitrogen in
oven-dried glassware with magnetic stirring.
(3aR,5S,6R,6aR)-5-Acetyl-2,2-dimethyltetrahydrofuro[2,3-d]-
[1,3]dioxol-6-yl 4-methylbenzenesulfonate (7). To a suspen-
sion of pyridinium chlorochromate (PCC, 9.0 g, 41.8 mmol)
and finely powdered 4 Å molecular sieves (2.0 g) in anhydrous
CH2Cl2 (80 mL) was added a solution of 6 (7.5 g, 20.9 mmol)
in anhydrous CH2Cl2 (25 mL). The mixture was stirred at room
temperature for 4 h. After consumption of starting material (by
TLC profile), the mixture was diluted with ether (100 mL). The
precipitates were filtered off through Celite, washed with ether
(50 mL) and the ether layer was evaporated in vacuo. The
residue was purified by column chromatography with EtOAc–
pet. ether (1 : 5) as an eluant to give 7 (6.1 g, 83%) as a color-
less syrup.
[α]2D5 = −88.51 (c = 2.39, CHCl3); {lit. [α]2D0 = −47.88 (c = 1.4,
MeOH)};12 IR (neat): νmax 2989, 1726, 1371, 1217, 1028, 849,
717 cm−1 1H NMR (CDCl3, 300 MHz): δ 7.70 (d, J = 8.3 Hz,
;
Scheme 3 Synthesis of compound 3.
2H), 7.36 (d, J = 8.1 Hz, 2H), 6.07 (d, J = 3.5 Hz, 1H), 4.94 (d, J =
3.2 Hz, 1H), 4.83 (d, J = 3.5 Hz, 1H), 4.56 (d, J = 3.3 Hz, 1H),
2.45 (s, 3H), 2.13 (s, 3H), 1.44 (s, 3H), 1.30 (s, 3H); 13C NMR
(CDCl3, 75 MHz): δ 203.9, 145.6, 131.8, 129.9, 128.0, 112.8,
105.3, 83.4, 82.6, 27.8, 26.5, 26.1, 21.6; HRMS (ESI): m/z calcu-
lated for C16H20NaO7S: [M + Na]+ 379.0822, found 379.0860.
(3aR,5R,6S,6aR)-2,2-Dimethyl-5-(prop-1-en-2-yl)tetrahydrofuro-
[2,3-d][1,3]dioxol-6-yl4-methylbenzenesulfonate (8). A stirred
solution of methylenetriphenylphosphorane {prepared from
n-BuLi (13.4 mL, 2.5 M in hexane, 33.7 mmol) and methyl-
triphenylphosphonium bromide (15.0 g, 42.1 mmol) in THF
(50 mL)} was added dropwise to a solution of the ketone 7
(6.0 g, 16.8 mmol) in THF (30 mL) at room temperature. After
1 h, the reaction mixture was poured into ice-water (50 mL)
and extracted with EtOAc (2 × 75 mL). The extracts were
washed with water, dried, and evaporated under reduced
pressure, and the crude residue was chromatographed on a
silica gel column with pet. ether–EtOAc (10 : 1) as eluant to
afford the product 8 as oil (4.6 g, 78%).
The masked aldehyde functionality in 5 was released to free
aldehyde 5a using iodine in the presence of sodium bicarbon-
ate,18 which underwent Grignard reaction with nitro aryl
iodide 4 in the presence of PhMgCl (metal–halogen exchange)
to furnish the diastereomeric alcohol 15 in 58% yield.19 Oxi-
dation of 15 using Dess–Martin periodinane (DMP) gave enan-
tiopure keto derivative 16 in 92% yield. Selective deprotection
of the TBDPS group at the primary end with NH4F in methanol
gave the alcohol 17 which upon one-pot oxidation using (diace-
toxyiodo)benzene (BAIB)/2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO)20 provided free carboxylic acid 3 in 78% yield
(Scheme 3).21,22 The acid 3 has built in all the required chiral
centers of ADMOA and also is differentially protected for
utility of this in a total synthesis.
[α]2D5 = −13.36 (c = 1.09, CHCl3); IR (neat): νmax 2930, 2857,
1675, 1043, 699 cm−1; 1H NMR (CDCl3, 300 MHz): δ 7.74 (d, J =
8.3 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 5.91 (d, J = 3.6 Hz, 1H),
Experimental
General information
1H NMR and 13C NMR spectra were recorded in CDCl3 using 5.03 (s, 1H), 4.87 (d, J = 1.1 Hz, 1H), 4.75 (d, J = 2.6 Hz, 1H),
300, 400 or 500 MHz spectrometers at ambient temperature. 4.65 (d, J = 3.7 Hz, 1H), 4.53 (s, 1H), 2.46 (s, 3H), 1.51 (s, 3H),
Chemical shifts were measured in ppm and coupling con- 1.47 (s, 3H), 1.29 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 145.2,
stants in hertz (Hz). The shifts were measured relative to the 136.6, 132.8, 129.8, 127.9, 113.5, 112.2, 104.2, 83.1, 81.9,
signals for residual CHCl3 (7.26 ppm), CDCl3 (77.0 ppm). All 80.9, 26.5, 26.1, 21.6, 19.2; HRMS (ESI): m/z calculated for
13C NMR spectra were proton decoupled. Optical rotations C17H23O6S: [M + H]+ 355.1209, found 355.1227.
were measured on a digital polarimeter operating on the
(3aR,5R,6S,6aR)-5-((R)-1-Hydroxypropan-2-yl)-2,2-dimethyl-
sodium D line with a 1 mL cell with a 1 dm path length. tetrahydrofuro[2,3-d][1,3]dioxol-6-yl4-methyl benzenesulfonate
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(9). To a stirred solution of olefin 8 (4.5 g, 12.7 mmol) in THF concentrated under vacuum. Purification by silica gel column
(30 mL) was added a 1 M solution of 9-BBN in THF (13.9 mL, chromatography using hexanes–EtOAc (4 : 1) afforded com-
13.9 mmol) at 0 °C. After 5 h, aqueous 15% NaOH (112.5 mL) pound 11 (4.0 g, 98%) as colorless oil.
and 30% H2O2 (67.5 mL) were added slowly, and the mixture
[α]2D5 = −21.42 (c = 1.12, CHCl3); IR (neat): νmax 3429, 2933,
was stirred vigorously for 6 h. The aqueous layer was extracted 2860, 1379, 1215, 1074, 702 cm−1; H NMR (CDCl3, 300 MHz):
with EtOAc (3 × 50 mL). The organic extracts were washed with δ 7.75–7.65 (m, 4H), 7.47–7.34 (m, 6H), 5.92 (d, J = 3.7 Hz, 1H),
water, dried (Na2SO4), evaporated under reduced pressure, and 4.53 (d, J = 3.8 Hz, 1H), 4.20–4.11 (m, 2H), 3.81–3.74 (dd, J =
purified by silica gel chromatography with pet. ether–EtOAc 4.5, 9.9 Hz, 1H), 3.73–3.67 (dd, J = 4.5, 9.9 Hz, 1H), 2.65 (d, J =
1
(1 : 2) as eluant to afford 9 (4.0 g, 85%).
5.8 Hz, 1H), 2.09–1.97 (m, 1H), 1.47 (s, 3H), 1.32 (s, 3H), 1.07
[α]2D5 = −31.18 (c = 3.17, CHCl3); {lit. [α]D20 = −35.0 (c = 1.27, (d, J = 7.5 Hz, 3H), 1.05 (s, 9H); 13C NMR (CDCl3, 75 MHz):
CHCl3)};12 IR (neat): νmax 3429, 2979, 2936, 1372, 1216, δ 135.6, 135.5, 133.3, 133.1, 129.5, 127.6, 111.3, 104.3, 85.1,
1
1019 cm−1; H NMR (CDCl3, 300 MHz): δ 7.82 (d, J = 8.3 Hz, 81.3, 75.1, 65.2, 34.7, 26.7, 26.5, 26.2, 19.2, 14.3; HRMS (ESI):
2H), 7.38 (d, J = 8.1 Hz, 2H), 5.89 (d, J = 3.7 Hz, 1H), 4.84 (d, J = m/z calculated for C26H36NaO5Si: [M + Na]+ 479.2224, found
2.4 Hz, 1H), 4.68 (d, J = 3.7 Hz, 1H), 4.03–3.96 (dd, J = 2.4, 479.2268.
10.1 Hz, 1H), 3.60 (d, J = 5.0 Hz, 2 H), 2.46 (s, 3H), 2.04–1.91
((R)-2-((3aR,5R,6S,6aR)-6-Azido-2,2-dimethyl tetrahydrofuro-
(m, 1H), 1.48 (s, 3H), 1.28 (s, 3H), 0.62 (d, J = 6.7 Hz, 3H); [2,3-d][1,3]dioxol-5-yl)propoxy)(tert-butyl) diphenylsilane
13C NMR (CDCl3, 125 MHz): δ 145.4, 132.8, 129.9, 127.7, 112.1, (12). A mixture of 11 (3.7 g, 8.1 mmol), triphenylphosphine
104.2, 82.4, 81.8, 66.0, 33.6, 26.3, 26.0, 21.6, 12.3; HRMS (ESI): (4.2 g, 16.2 mmol), and tri-iodoimidazole (3.6 g, 8.1 mmol) in
m/z calculated for C17H24NaO7S: [M + Na]+ 395.1135, found toluene (50 mL) was stirred under reflux at a bath temperature
395.1167.
of 120 °C for 4 h, after which additional triphenylphosphine
(3aR,5R,6S,6aR)-5-((R)-1-Hydroxypropan-2-yl)-2,2-dimethyl- (4.2 g, 16.2 mmol) and tri-iodoimidazole (3.6 g, 8.1 mmol)
tetrahydrofuro[2,3-d][1,3]dioxol-6-ol (10). Finely chopped were added. After 24 h, the reaction mixture was cooled to rt,
sodium metal (2.3 g, 103.0 mmol) and naphthalene (4.4 g, quenched with water (20 mL) and extracted with EtOAc
34.3 mmol) were dissolved in anhydrous THF (100 mL) and (2 × 30 mL). The combined organic layers were washed with
the mixture was subjected to ultrasonic irradiation for 30 min water, dried (Na2SO4), and evaporated under reduced pressure
to provide a dark green solution (stock solution, stored at to provide a viscous oil which was directly used for the next
−20 °C). The desired O-tosyl compound 9 (4.0 g, 10.7 mmol) step without further purification.
in THF (40 mL) was cooled to −60 °C and the Na-naphthale-
To a solution of the iodide (prepared above) in DMF
nide solution was added dropwise to the reaction via syringe, (40 mL) was added sodium azide (1.5 g, 24.3 mmol) and the
until a dark green color persisted for 5 min. The reaction was mixture was heated at 110 °C for 24 h. After cooling to room
quenched with aqueous NH4Cl (to discharge the green color) temperature, water (3 mL) was added to the solution, and the
and the reaction was diluted with ether (50 mL). The ether mixture was extracted with chloroform (3 × 25 mL). The com-
layer was separated and the aqueous layer was extracted with bined organic layers were dried over Na2SO4, filtered, and con-
ether (2 × 25 mL). The combined organic layers were dried centrated under reduced pressure. The residue was purified by
(Na2SO4), filtered and concentrated. Purification by silica flash column chromatography (EtOAc/pet. ether 1 : 10) to give
gel chromatography using hexanes–EtOAc (1 : 1) as eluant azide 12 (2.53 g, 65% for two steps).
provided the diol product 10 (2.0 g, 87% yield).
[α]2D5 = −34.84 (c = 0.6, CHCl3); IR (neat): νmax 2929, 2859,
1
[α]2D5 = −26.87 (c = 2.94, CHCl3); IR (neat): νmax 3384, 2936, 1729, 1463, 1085, 1027, 702 cm−1; H NMR (CDCl3, 300 MHz):
2880, 1214, 1071, 1009, 782, 654 cm−1 1H NMR (CDCl3, δ 7.73–7.65 (m, 4H), 7.42–7.35 (m, 6H), 5.88 (d, J = 3.7 Hz, 1H),
;
300 MHz): δ 5.85 (d, J = 3.7 Hz, 1H), 4.44 (d, J = 3.7 Hz, 1H), 4.69 (d, J = 3.7 Hz, 1H), 4.33–4.26 (dd, J = 3.0, 10.5 Hz, 1H),
4.03 (d, J = 2.2 Hz, 1H), 3.89–3.83 (dd, J = 2.2, 9.0 Hz, 1H), 3.93–3.87 (dd, J = 3.7, 9.8 Hz, 1H), 3.79 (d, J = 3.0 Hz, 1H),
3.72–3.64 (dd, J = 6.7, 10.5 Hz, 1H), 3.63–3.50 (m, 3H), 3.68–3.61 (dd, J = 2.2, 9.8 Hz, 1H), 2.05–1.91 (m, 1H), 1.48
2.16–2.02 (m, 1H), 1.46 (s, 3H), 1.28 (s, 3H), 0.92 (d, J = 6.7 Hz, (s, 3H), 1.35 (s, 3H), 1.12 (d, J = 6.7 Hz, 3H), 1.07 (s, 9H);
3H); 13C NMR (CDCl3, 125 MHz): δ 111.4, 104.3, 84.6, 84.2, 13C NMR (CDCl3, 75 MHz): δ 135.7, 135.6, 133.7, 133.4, 129.5,
74.5, 66.1, 33.9, 26.4, 25.9, 13.3; HRMS (ESI): m/z calculated for 129.4, 127.8, 127.5, 125.7, 111.7, 104.3, 83.4, 79.9, 66.2, 65.2,
C10H18NaO5: [M + Na]+ 241.1046, found 241.1064.
(3aR,5R,6S,6aR)-5-((R)-1-(tert-Butyldiphenylsilyloxy)propan- C26H35N3NaO4Si: [M + Na]+ 504.2289, found 504.2327.
2-yl)-2,2-dimethyl tetrahydrofuro[2,3-d][1,3]dioxol-6-ol (11). To (2R,3S,4R,5R)-3-Azido-6-(tert-butyldiphenylsilyloxy)-1,1-bis-
35.4, 26.8, 26.3, 26.2, 19.3, 13.5; HRMS (ESI): m/z calculated for
a stirred solution of compound 10 (2.0 g, 9.1 mmol) in anhy- (ethylthio)-5-methylhexane-2,4-diol (13). To a solution of azide
drous CH2Cl2 (20 mL) at 0 °C under nitrogen atmosphere was 12 (2.5 g, 5.2 mmol) and ethanethiol (0.96 g, 15.6 mmol) in
added imidazole (1.5 g, 22.9 mmol). After stirring for 5 min, anhydrous dichloromethane (25 mL) was added BF3·OEt2
TBDPS-Cl (2.7 g, 10.0 mmol) and DMAP (0.1 g, 0.9 mmol) were (2.2 g, 15.6 mmol) at 0 °C under nitrogen atmosphere. After
added to the reaction mixture. After 1 h, the reaction mixture stirring the mixture at room temperature for 1 h, the reaction
was quenched with aqueous NH4Cl (10 mL) and the product was quenched with saturated NaHCO3 (10 mL) and the
was extracted with CHCl3 (2 × 20 mL). The combined organic mixture was extracted with dichloromethane (3 × 25 mL). The
layers were washed with brine (50 mL), dried (Na2SO4), and extracts were combined, dried (Na2SO4), filtered, and the
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filtrate evaporated in vacuo. The residue obtained was purified 4.2 mmol) followed by Cbz–Cl (50% in toluene, 0.8 mL,
by flash chromatography on silica gel using pet. ether–EtOAc 2.5 mmol) at 0 °C. The reaction was warmed to rt and stirred
(2 : 1) gave diol 13 (2.1 g, 74%).
[α]2D5 = −26.13 (c = 0.45, CHCl3); IR (neat): νmax 3495, 2983, (20 mL) and the product was extracted with EtOAc (2 × 25 mL).
2820, 2197, 1097, 665 cm−1 1H NMR (CDCl3, 300 MHz): The combined organic layer was dried over Na2SO4, filtered,
for 1 h, quenched the reaction by the addition of water
;
δ 7.70–7.62 (m, 4H), 7.47–7.34 (m, 6H), 4.10–4.05 (m, 2H), concentrated and purified through silica gel chromatography
4.00–3.94 (m, 1H), 3.91–3.81 (m, 2H), 3.71–3.60 (m, 2H), 3.52 (pet. ether) gave Cbz–amine 5 (1.6 g, 79% for two steps).
(d, J = 1.5 Hz, 1H), 2.80–2.66 (m, 4H), 2.19–2.05 (m, 1H),
[α]2D5 = +9.1 (c = 0.4, CHCl3); IR (neat): νmax 3451, 2926, 2856,
1.36–1.25 (m, 6H), 1.07 (s, 9H), 0.93 (d, J = 6.8 Hz, 3H); 1742, 1459, 1257, 1109, 1072, 699 cm−1 1H NMR (CDCl3,
;
13C NMR (CDCl3, 75 MHz): δ 135.5, 132.7, 129.9, 127.8, 127.5, 500 MHz): δ 7.68–7.61 (m, 4H), 7.43–7.30 (m, 10H), 7.29–7.18
78.0, 75.2, 68.4, 62.9, 55.0, 37.4, 29.6, 26.8, 25.7, 24.8, 19.1, (m, 1H), 5.12–4.99 (m, 3H), 4.39–4.33 (m, 1H), 3.95–3.92 (dd,
14.5, 13.3; HRMS (ESI): m/z calculated for C27H41N3O3NaS2Si: J = 2.4, 6.8 Hz, 1H), 3.88–3.81 (m, 2H), 3.51–3.46 (dd, J = 6.8,
[M + Na]+ 570.2250, found 570.2240.
10.7 Hz, 1H), 2.76–2.53 (m, 4H), 1.95–1.87 (m, 1H), 1.27–1.15
(5R,6S,7R,8R)-6-Azido-5-(bis(ethylthio)methyl)-7-(tert-butyl- (m, 6H), 1.06 (s, 9H), 1.05 (d, J = 7.3 Hz, 3H), 0.90–0.81 (m,
dimethylsilyloxy)-2,2,3,3,8,12,12-heptamethyl-11,11-diphenyl- 18H), 0.16 (s, 3H), 0.08–0.04 (m, 6H), −0.02 (s, 3H); 13C NMR
4,10-dioxa-3,11-disilatridecane (14). To a stirred solution of (CDCl3, 125 MHz): δ 160.5, 135.67, 135.62, 133.8, 131.9, 129.5,
compound 13 (1.5 g, 2.74 mmol) in CH2Cl2 (20 mL) were 128.3, 128.0, 127.8, 127.6, 75.3, 71.9, 66.3, 65.7, 56.1, 53.7,
added DIPEA (2.4 mL, 13.7 mmol) and TBSOTf (1.8 g, 41.4, 29.7, 27.05, 27.00, 26.3, 26.03, 26.01, 19.1, 18.2, 14.46,
6.8 mmol) sequentially at 0 °C under N2 atmosphere. After 14.41, −5.9, −3.7, −3.9; HRMS (ESI): m/z calculated for
5 min, the reaction mixture was warmed to rt and stirred for C47H78NO5S2Si3: [M + H]+ 884.4623, found 884.4656.
1 h. Then the reaction was quenched with saturated NH4Cl
Benzyl (5R,6S,7R,8R)-7-(tert-butyldimethylsilyloxy)-5-(4-
solution and extracted with CH2Cl2 (2 × 25 mL). The combined methoxy-2-nitrobenzoyl)-2,2,3,3,8,12,12-heptamethyl-11,11-
organic extracts were washed successively with water (10 mL), diphenyl-4,10-dioxa-3,11-disilatridecan-6-ylcarbamate (16). A
brine (10 mL), dried over Na2SO4 and concentrated under solution of 5 (1.2 g, 1.3 mmol) in a mixture of acetone/water
vacuum. The residue was purified by silica gel column chrom- (20 mL, 9 : 1) was treated with NaHCO3 (0.45 g, 5.4 mmol) and
atography (5% EtOAc/pet. ether) to afford 14 (1.9 g, 92%) as a iodine (0.75 g, 3.0 mmol). After stirring at rt for 1 h, the sus-
colorless liquid.
pension was diluted with an aqueous solution of Na2S2O3
[α]2D5 = +18.51 (c = 0.55, CHCl3); IR (neat): νmax 2930, 2858, (20 mL). The aqueous phase was extracted with ethyl acetate
2107, 1466, 1255, 1107, 833, 701, 614 cm−1; H NMR (CDCl3, (2 × 25 mL) and the combined organic phases were dried
1
500 MHz): δ 7.68–7.63 (m, 4H), 7.44–7.34 (m, 6H), 4.15–4.12 (Na2SO4), filtered, concentrated and used directly for the next
(dd, J = 3.0, 6.4 Hz, 1H), 3.90 (t, J = 4.2 Hz, 1H), 3.85 (d, J = 2.9 step.
Hz, 1H), 3.80–3.76 (dd, J = 5.2, 10.2 Hz, 1H), 3.74–3.71 (dd, J =
To a stirred solution of 4-iodo 3-nitro anisole 4 (0.3 g,
4.2, 6.4 Hz, 1H), 3.60–3.55 (dd, J = 7.0, 10.2 Hz, 1H), 2.71–2.58 1.1 mmol) in anhydrous ether (10 mL) at −40 °C was added
(m, 4H), 2.05–1.95 (m, 1H), 1.24 (t, J = 7.3 Hz, 3H), 1.18 (t, J = PhMgCl (2 M in THF, 0.58 mL, 1.1 mmol) in dropwise. After
7.4 Hz, 3H), 1.08 (d, J = 7.0 Hz, 3H), 1.06 (s, 9H), 0.95 (s, 9H), 10 min, aldehyde (1.0 g, 1.2 mmol) in dry ether (10 mL) was
0.82 (s, 9H), 0.22 (s, 3H), 0.18 (s, 3H), 0.09 (s, 3H), 0.02 (s, 3H); added to the reaction mixture at −40 °C and stirred for
13C NMR (CDCl3, 125 MHz): δ 135.6, 133.7, 133.6, 129.5, 127.6, another 1 h. The reaction mixture was quenched with satu-
75.7, 74.1, 66.5, 65.1, 55.9, 40.4, 29.7, 26.9, 26.3, 26.1, 26.0, rated NH4Cl (5 mL) and poured into water (20 mL). The
25.0, 19.2, 18.5, 18.3, 14.4, 14.3, 13.9, −3.7, −3.8, −4.1, −4.4; aqueous phase was extracted with ethyl acetate (2 × 25 mL)
HRMS (ESI): m/z calculated for C39H69N3O3NaS2Si3: [M + Na]+ and the organic fractions were washed with brine (20 mL),
798.3980, found 798.3995.
dried (Na2SO4) and concentrated in vacuo. Flash chromato-
Benzyl (5R,6S,7R,8R)-5-(bis(ethylthio)methyl)-7-(tert-butyldi- graphy on silica gel furnished the product 15 (0.73 g, 58% for
methylsilyloxy)-2,2,3,3,8,12,12-heptamethyl-11,11-diphenyl- two steps) as colorless oil.
4,10-dioxa-3,11-disilatridecan-6-ylcarbamate (5). To a stirred
Dess–Martin periodinane (0.37 g, 0.89 mmol) was added at
solution of azide 14 (1.8 g, 2.3 mmol) and ammonium chloride 0 °C under nitrogen to a solution of alcohol 15 (0.69 g,
(0.3 g, 5.8 mmol) in ethyl alcohol (18 mL) and water (6 mL), 0.74 mmol) in CH2Cl2 (15 mL) and the resulting mixture was
zinc powder (0.2 g, 3.0 mmol) was added and the mixture was stirred at rt for 3 h. After completion of the reaction (TLC ana-
stirred vigorously at room temperature. After 1 h (monitored lysis), saturated NaHCO3/Na2S2O3 solution (1 : 1, 20 mL) was
by TLC), the mixture was diluted with ethyl acetate (25 mL). added, the aqueous phase was separated and extracted with
The reaction mixture was filtered through a pad of Celite, and CH2Cl2 (2 × 20 mL). The combined organic extracts were dried
washed with ethyl acetate (20 mL). The filtrate was washed over Na2SO4, filtered and concentrated. Purification of the
with brine, dried over Na2SO4, and concentrated to give the residue by flash chromatography gave ketone 16 (0.63 g, 92%)
amine product which was used without further purification for as colorless oil.
the subsequent reaction.
[α]2D5 = +89.81 (c = 2.16, CHCl3); IR (neat): νmax 2931, 2857,
1
To a stirred solution of the above crude amine (1.6 g, 1723, 1608, 1539, 1464, 1253, 1076, 834, 700.6, 613 cm−1; H
2.1 mmol) in CH2Cl2 (50 mL) was added DIPEA (0.7 mL, NMR (CDCl3, 300 MHz): δ 8.23 (d, J = 8.8 Hz, 1H), 7.65–7.54
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(m, 4H), 7.47–7.31 (m, 11H), 7.19 (d, J = 2.4 Hz, 1H), 7.11–7.06 132.1, 128.4, 128.2, 128.1, 124.4, 118.0, 109.8, 72.2, 67.0, 56.0,
(dd, J = 2.4, 8.7 Hz, 1H), 7.03–6.92 (m, 1H), 5.28–5.20 (m, 2H), 55.1, 43.6, 25.8, 25.7, 18.1, 18.0, 13.5, −4.0, −4.5, −4.6, −5.0;
5.12 (t, J = 11.1 Hz, 1H), 4.43–4.28 (m, 1H), 4.08–4.03 (m, 1H), HRMS (ESI): m/z calculated for C34H52O10N2NaSi2: [M + Na]+
3.89 (s, 3H), 3.62–3.53 (dd, J = 6.4, 10.2 Hz, 1H), 3.37–3.28 (dd, 727.3052, found 727.3054.
J = 7.7, 8.1 Hz, 1H), 2.12–1.94 (m, 1H), 1.00 (s, 9H), 0.95–0.88
(m, 12H), 0.86 (s, 9H), 0.16 (s, 3H), 0.13 (s, 3H), 0.06 (s, 3H),
0.03 (s, 3H); 13C NMR (CDCl3, 125 MHz): δ 198.0, 161.8, 156.1,
150.7, 136.4, 135.4, 133.6, 132.6, 130.2, 129.46, 129.42, 128.5,
Conclusions
128.4, 128.0, 127.8, 127.5, 127.2, 123.5, 116.6, 110.0, 78.2, 70.3, In conclusion, this sequence of chemical transformations
66.8, 65.7, 55.9, 53.9, 41.0, 26.6, 25.9, 25.5, 19.0, 18.0, 17.9, starting from D-glucose in a linear high yielding process with
12.3, −4.1, −4.5, −5.0; HRMS (ESI): m/z calculated for affordable chemicals provided differentially protected unusual
C50H73N2O9Si3: [M + H]+ 929.4618, found 929.4628.
amino acid (ADMOA, 3) present in solomonamide A in multi-
Benzyl (5R,6S,7R)-5-((R)-1-hydroxypropan-2-yl)-7-(4-methoxy- gram quantities in very efficient manner.
2-nitrobenzoyl)-2,2,3,3, 9,9,10,10-octamethyl-4,8-dioxa-3,9-di-
silaundecan-6-ylcarbamate (17). To a stirred solution of 16
(0.55 g, 0.59 mmol) in MeOH (5 mL) was added NH4F
(43.0 mg, 1.18 mmol) at 0 °C. After complete consumption of
Acknowledgements
starting material (∼4 h, by TLC analysis), methanol was evap- NK thanks CSIR, New Delhi, for a research fellowship. SC
orated and EtOAc (20 mL) was added. The organic layer was thanks CSIR, New Delhi, for funding under XII five year plan
washed with aqueous NaHCO3 solution (2 × 20 mL), water and (CSC-0108). The authors thank Dr Vemula Praveen Kumar and
brine sequentially, dried over Na2SO4 and concentrated under Dr P. S. Mainkar for useful suggestions.
reduced pressure. The obtained residue was purified by silica
gel column chromatography (pet. ether–EtOAc (3 : 1)) to give
alcohol 17 (335 mg, 82%) as viscous oil.
Notes and references
[α]2D5 = +53.8 (c = 0.06, CHCl3); IR (neat): νmax 3435, 2930,
1
2861, 1696, 1639, 1524, 683 cm−1; H NMR (CDCl3, 300 MHz):
δ 7.48–7.30 (m, 7H), 7.00–6.96 (dd, J = 2.5, 8.4 Hz, 1H),
5.16–4.98 (m, 3H), 4.70 (d, J = 4.2 Hz, 1H), 4.30–4.23 (m, 1H),
3.91–3.84 (m, 4H), 3.64–3.57 (dd, J = 7.5, 10.9 Hz, 1H),
3.38–3.32 (dd, J = 4.2, 10.9 Hz, 1H), 1.87–1.79 (m, 1H),
0.93–0.81 (m, 21H), 0.12–0.04 (m, 12H); 13C NMR (CDCl3,
75 MHz): δ 199.8, 161.5, 156.1, 148.4, 136.5, 131.6, 131.3,
128.4, 128.2, 128.0, 125.4, 118.9, 109.4, 76.9, 73.3, 66.8, 64.0,
56.0, 54.6, 38.6, 25.9, 25.8, 18.0, 14.5, −4.0, −4.3, −4.6, −5.0;
HRMS (ESI): m/z calculated for C34H54O9N2NaSi2: [M + Na]+
713.3260, found 713.3268.
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[α]2D5 = +82.4 (c = 0.94, CHCl3); IR (neat): νmax 3440, 2934,
2858, 1715, 1535, 1251, 1125, 837, 694 cm−1; H NMR (CDCl3,
1
300 MHz): δ 7.68 (d, J = 8.4 Hz, 1H), 7.41–7.31 (m, 6H),
7.08–7.02 (dd, J = 2.4, 8.6 Hz, 1H), 5.12 (d, J = 9.8 Hz, 1H), 5.07
(s, 2H), 4.72 (d, J = 4.9 Hz, 1H), 4.27–4.18 (m, 1H), 4.03 (t, J =
4.7 Hz, 1H), 3.89 (s, 3H), 2.75–2.65 (m, 1H), 1.13 (d, J = 7.1 Hz,
3H), 0.87 (s, 9H), 0.84 (s, 9H), 0.11–0.02 (m, 12H); 13C NMR
(CDCl3, 75 MHz): δ 198.4, 177.8, 161.8, 155.9, 149.4, 136.4,
Org. Biomol. Chem.
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Paper
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21 The present route has an advantage of using the cheaply
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our earlier method using expensive (R)-Roche ester as the
starting material (ref. 9). Even though, the numbers of syn-
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prepared.
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