Expeditious Synthesis of Ieodoglucomides A and B from the Marine-Derived Bacterium Bacillus licheniformis

Article abstract of DOI:10.1002/ejoc.201800209

We report the total synthesis of ieodoglucomides A and B. The key steps of the synthesis are a glycosyl-iodide-mediated β-stereoselective glycosylation without neighbouring-group participation, a regioselective acylation, and a Grubbs cross-metathesis reaction. The short and efficient synthesis involves 11 steps, with 38–40 % overall yield.

Full text of DOI:10.1002/ejoc.201800209

A Journal of
Accepted Article
Title: Expeditious Synthesis of Ieodoglucomides A and B from Marine-
Derived Bacterium Bacillus licheniformis
Authors: Suvarn S. Kulkarni, Ananda Rao Podilapu, and Madhu
Emmadi
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800209
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Supported by

10.1002/ejoc.201800209
European Journal of Organic Chemistry
Expeditious Synthesis of Ieodoglucomides A and B from
Marine-Derived Bacterium Bacillus licheniformis
Ananda Rao Podilapu, Madhu Emmadi and Suvarn S. Kulkarni*
Department of Chemistry, Indian Institute of Technology Bombay, Mumbai, India.
*E-mail: suvarn@chem.iitb.ac.in.
http://ether.chem.iitb.ac.in/~suvarn/
.
Abstract: Herein we report the total synthesis of ieodoglucomides A and B via glycosyl
iodide mediated β-stereoselective glycosylation without neighboring group participation,
regioselective acylation and Grubbs’ cross metathesis reaction, as key steps. The short and
efficient synthesis involves 11 steps, with 38-40% overall yields.
1
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10.1002/ejoc.201800209
European Journal of Organic Chemistry
Introduction:
In 2012, Shin et al. isolated and characterized two structurally unique glycopeptides,
ieodoglucomide A (1a) and B (1b) from a marine-derived Gram-positive bacterium Bacillus
licheniformis (strain 09IDYM23).1 In their initial biological investigations, ieodoglucomide
A and B displayed moderate antimicrobial activity against Gram-positive as well as Gram-
negative bacteria and fungi. Moreover, the cytotoxicity of ieodoglucomide A and B was
evaluated against six human cancer cell lines in which ieodoglucomide B exhibited cancer
cell growth inhibition against lung cancer (NCI-H23) and stomach cancer (NUGC-3) cell
lines, with GI50 values of 25.18 and 17.78 µg/mL, respectively.1 The structurally related
glycopeptides ieodoglucomides 1a and 1b (Figure 1) consist of a C30 and C29 skeleton,
respectively, and comprise an amino acid (L-alanine for 1a and L-glycine for 1b), a new fatty
acid (14-hydroxy-15-methylhexadecanoic acid), a succinic acid, and a β-linked sugar (D-
glucose). Due to their biological potential and unique architecture, ieodoglucomides are
attractive synthetic targets. In continuation of our ongoing project on the synthesis of
bacterial glycoconjugates,2 we embarked on the total synthesis of ieodoglucomides. While
our work was in progress, Raji Reddy and co-workers reported the first synthesis of the
proposed structures of ieodoglucomides A and B as well as their C14 epimers.3 However due
to the discrepancy in the sign of optical rotation and some NMR chemical shifts, they were
not able to unambiguously confirm the stereochemistry of the C14 center in the proposed
1
structure. Based on the H NMR data, they concluded that the absolute stereochemistry of
C14 in the natural product is most likely ‘S’ as proposed in the original paper, although the
sign of optical rotation is opposite. Subsequently, Shin et al. corrected the sign of their
optical rotations from plus to minus and also corrected the structures, specifically the
stereochemistry of C14 to be ‘R’.4 Herein, we report the synthesis of the corrected structures
2
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10.1002/ejoc.201800209
European Journal of Organic Chemistry
of ieodoglucomides A and B through an expeditious and high yielding route and thereby
confirm its structure.
O
OH
O
O
O
H
O
HO
HO
1
N
O
OH
14
8
12
HO
O
R
H3C
CH3
1a; R = CH3; Ieodoglucomide A
1b; R = H; Ieodoglucomide B
Figure 1. Structure of the Ieodoglucomides 1a and 1b
The main challenges encountered in the synthesis of ieodoglucomides A (1a) and B
(1b) are the β-stereoselective glycosylation, regioselective 6-O-acylation and carbon chain
extension. Typically, as employed in the first total synthesis, the β-selectivity in
glycosylation is achieved by placing a participating ester group at C2 position of the glycosyl
donor and the 6-O-acylation can be achieved by first masking the 6-OH group by an
orthogonal protecting group. Such a process involves a number of steps for protecting group
manipulations and one has to carry out related work ups and purifications, which mars the
overall efficiency. We envisioned that an SN2 type glycosylation in lieu of the O2
participating group and a direct regioselective functionalization of the more reactive primary
6-OH of the sugar tetraol would obviate all the unnecessary protection/deprotection steps and
improve the efficiency as well as elegance.
Results and discussion:
Retrosynthetically, as shown in Scheme 1, the target molecule 1a and 1b could be
synthesized by Grubbs’ cross metathesis reaction of olefin 2 with compounds 3a and 3b,
respectively, followed by global deprotection. Amide 3a or 3b could in turn be obtained
3
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10.1002/ejoc.201800209
European Journal of Organic Chemistry
using a literature procedure from respective amino acids L-alanine and L-glycine,5 whereas
the key intermediate 2 could be synthesized by carrying out regioselective O6 acylation6 of 4
with acid 5 followed by TMS protection. It was envisaged that compound 4 can be
synthesized via β-selective glycosylation of glycosyl iodide7b donor 6 and acceptor 7.
Acceptor 7 can be obtained from the known epoxide 88 via Mitsunobu Reaction. Compound
6 and 8 could be easily prepared from cheaply available D-glucose and L-valine, respectively.
O
OH
O
O
H
O
O
HO
HO
N
O
OH
8
OH
O
R
H3C
CH3
1a; R = CH3; Ieodoglucomide A
1b; R = H; Ieodoglucomide B
Grubbs cross metathesis
O
OBn
O
O
O
H
O
TMSO
TMSO
O
N
8
OBn
TMSO
O
R
H3C
CH3
2
3a; R = CH3
3b; R = H
Regioselective acylation
OH
O
O
HO
HO
O
OBn
HO
HO
O
5
4
H3C
CH3
-stereoselective glycosylation
OTMS
O
HO
O
TMSO
TMSO
TMSO
H3C
CH3
I
H3C
CH3
6
7
8
Scheme 1. Retrosynthetic analysis
4
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10.1002/ejoc.201800209
European Journal of Organic Chemistry
Our synthesis started with procurement of the alcohol 7 (Scheme 2) starting from
easily accessible epoxide 8.8 Regioselective ring opening of 1,2-epoxide 8 using 2.0 M
o
o
solution of allylmagnesium bromide in diethyl ether and copper iodide9 at -20 C to 0 C
25
cleanly afforded alcohol 9 {[α]D = -22.36 (c = 1.0, CHCl3)} in 92% yield as a single
isomer. Compound 9 was treated with PPh3, DIAD and PhCOOH to give the benzoyl ester
10 in 88% yield with inversion of stereochemistry. Debenzoylation of 10 using NaOMe and
MeOH afforded desired acceptor 7 {[α]D25 = +22.4 (c = 1.0, CHCl3)} in 94% yield.
PPh3 (2 equiv)
AllMgBr (2.5 equiv)
DIAD (2 equiv)
O
CuI (0.1 equiv), Et2O
-20 oC to 0 oC, 1 h
PhCOOH (2 equiv)
CH2Cl2, 1.5 h
HO
H3C
CH3
CH3
H3C
92%
88%
8
9
NaOMe (1.2 equiv), MeOH
CH2Cl2, 0.5 h
O
O
HO
H3C
CH3
94%
H3C
CH3
10
7
Scheme 2. Synthesis of acceptor 7
Preparation of amides 3a and 3b is outlined in Scheme 3. Commercially available 10-
undecanoic acid 11 was coupled with amine 12 and 1310 using DCC and DIPEA to afford
amides 3a and 3b in 92 and 94% yields respectively.
5
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European Journal of Organic Chemistry
CH3
OBn
H2N
12
O
CH3
O
O
OBn
OBn
N
8
H
O
3a, 92%
DCC (1.5 equiv),
DIPEA (0.5 equiv)
DMF, 2 h
OH
8
11
O
N
8
H
OBn
H2N
O
3b, 94%
O
13
Scheme 3. Preparation of amides 3a and 3b
With acceptor 7 in our hand, the stage was now set for the glycosylation. For this purpose,
we resorted to per-O-TMS glycosyl iodide donors which is pioneered by Gervay-Hague
group.7 Kulkarni and Gervay-Hague have previously employed D-galactosyl per-O-TMS
o
iodide for coupling with cholesterol in the presence of Ag2CO3 at 110 C in 1:9 α/β
selectivity.7b Accordingly, the persilylated D-glucose 14 was converted to the corresponding
o
glucosyl iodide 6 using TMSI at 0 C and the so formed glucosyl iodide was coupled with
acceptor 7 using Ag2CO3 as a promoter at RT in dichloromethane as a solvent. Subsequent
desilylation using K2CO3 and methanol cleanly afforded β-linked glycoside 4 in 84% yield
over two steps. The corresponding α-isomer was not encountered. It should be noted that
this is the first example of completely β-stereoseletive glycosylation using per-O-TMS
glucosyl iodides and Ag2CO3. The reaction conditions are mild and the conversion takes
place at ambient temperature.
6
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10.1002/ejoc.201800209
European Journal of Organic Chemistry
Scheme 4. Synthesis of ieodoglucomides 1a & 1b
Earlier, Grindley and co-workers carried out regioselective O6 acylation of trehalose.5 Under
similar conditions, regioselective acylation of D-glucosyl tetraols 4 with acid 511 in the
presence of TBTU, DIPEA and pyridine6 generated the 6-O-acylated product 15 in 89% yield
as a single isomer. The regioselectivity of the acylation was further confirmed by HMBC
correlation of CH2 with the O6 ester carbonyl group (see Supporting Information).
Attempted cross metathesis reaction of 15 with 3a using Grubbs-II catalysts failed to give the
desired product and generated the dimer corresponding to 3a. Therefore, the free hydroxyl
groups of 15 were capped with silyl group by a brief treatment with TMSCl and Et3N to
obtain 2 in 94% yield. Grubbs’ cross metathesis reaction of compound 2 and olefin 3a and
3b using Grubbs-II generation catalyst cleanly furnished fully protected compound 16a and
16b in 82% and 80% yields, respectively. Global deprotection of 16a and 16b was done in
7
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10.1002/ejoc.201800209
European Journal of Organic Chemistry
two steps. Removal of TMS groups using TBAF in THF and acetic acid followed by
cleavage of benzyl groups and double bond reduction under hydrogenation conditions
afforded ieodoglucomides 1a (obtained; [α]D25= -23.34 (c = 0.1, CH3OH), reported4; [α]D
=
23
-24.0 (c = 0.2, CH3OH)) and 1b [α]D25= -14.72 (c = 0.1, CH3OH), reported4; [α]D23= -16.0 (c
= 0.3, CH3OH)) in 92% and 90% yields using reversed-phase HPLC purification on a C18
1
13
column using MeOH and H2O as eluents. The H and C NMR data of 1a and 1b matched
perfectly well with the reported spectral data confirming their structures.
Conclusion:
In conclusion, the total synthesis of ieodoglucomides A and B is accomplished using
per-O-TMS glucosyl iodide. The key features of the synthesis include a β-stereoselective
glycosylation of per-O-TMS D-glucosyl iodide in lieu of neighbouring group participation
(NGP), regioselective O6-acylation, and Grubbs’ cross metathesis reaction. Our total
synthesis involves 11 steps from known epoxide 8, and can be completed in two weeks with
38-40% overall yield. This is a remarkable improvement over the first generation synthesis
which reports an overall yield of 9-10% in 13 steps. The synthesis is particularly useful for
rapidly synthesizing various analogues of ieodoglucomides for SAR studies.
Experimental:
General:
All reactions were conducted under a dry nitrogen atmosphere. Solvents (CH2Cl2 >99%, THF
99.5%, Acetonitrile 99.8%, DMF 99.5%) were purchased in capped bottles and dried under
sodium or CaH2. All other solvents and reagents were used without further purification. All
glasswares used were oven dried before use. TLC was performed on pre-coated Aluminium
plates of Silica Gel 60 F254 (0.25 mm, E. Merck). Developed TLC plates were visualized
8
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10.1002/ejoc.201800209
European Journal of Organic Chemistry
under a shortwave UV lamp and by heating plates that were dipped in ammonium
molybdate/cerium (IV) sulfate solution. Silica gel column chromatography was performed
using Silica Gel (100-200 mesh) and employed a solvent polarity correlated with TLC
mobility. NMR experiments were conducted on 500 and 400 MHz instrument using CDCl3
(D, 99.8%), MeOD (D, 99.9%) as solvents. Chemical shifts are relative to the deuterated
solvent peaks and are in parts per million (ppm). 1H-1H COSY, HSQC and HMBC were used
to confirm proton assignments. Mass spectra were acquired in the ESI mode. Specific
rotation experiments were measured at 589 nm (Na) and 25 °C.
Synthesis of (S)-2-methylhept-6-en-3-ol (9):
A solution of AllMgBr in THF (2.0 M, 62.4 mL, 124.8 mmol) was added dropwise to a
o
stirred solution of CuI (0.95 g, 4.9 mmol) in Et2O (85 mL) at -20 C. To this cold solution
((S)-2-isopropyloxirane 8 (4.3 g, 49.9 mmol) in Et2O (13 mL) was added dropwise over a
period of 15 min. After complete consumption of starting material (monitored by TLC), the
reaction was quenched with saturated NH4Cl solution and the mixture was extracted with
Et2O (3 × 20 mL). The combined organic layers were dried over Na2SO4, concentrated and
purified by silica gel column chromatography (15% ethyl acetate: pet ether) to give 9 (5.87 g,
92%) as a colorless liquid; [α]D = -22.36 (c = 1.0, CHCl3); IR (cm-1, CHCl3) 3542, 2952,
25
1
1621, 1287, 1005, 669, 514, 473; H NMR (400 MHz, CDCl3): δ 5.90-5.80 (m, 1H, =CH),
5.01 (dd, J = 14.2, 1.9 Hz, 1H, =CH2), 3.38-3.34 (m, 1H, -CH), 2.31-2.19 (m, 1H), 2.18-2.04
(m, 1H), 1.71-1.42 (m, 4H, -CH2, -CH, -OH), 1.01 (d, J = 6.8 Hz, 3H, -CH3), 1.00 (d, J = 6.7
13
Hz, 3H, -CH3); C NMR (100 MHz, CDCl3): δ 139.0, 114.9, 76.3, 33.7, 33.4, 30.6, 18.9,
17.3; HR-ESI-MS (m/z): [M + Na]+ calcd. for C8H16ONa, 151.1093; found, 151.1067.
9
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Synthesis of (R)-2-methylhept-6-en-3-yl benzoate (10):
PhCOOH (0.72 g, 5.96 mmol) and PPh3 (1.95 g, 7.45 mmol) were added sequentially to a
stirred solution of 9 (0.61 g, 4.76 mmol) in CH2Cl2 (7 mL). To this well stirred solution
DIAD (1.46 mL, 7.45 mmol) in CH2Cl2 (3 mL) was added dropwise at rt. After complete
consumption of starting material (monitored by TLC), solvent was removed under reduced
pressure and the obtained crude product was purified by silica gel column chromatography
(10% ethyl acetate: pet ether) to give 10 (1.0 g, 88%) as a colorless liquid; [α]D25 = +6.6 (c
1
= 0.2, CHCl3); IR (cm-1, CHCl3) 2968, 1728, 1625, 1245, 996, 680, 551; H NMR (500
MHz, CDCl3): δ 8.11-8.08 (m, 2H, ArH), 7.59-7.55 (m, 1H, ArH), 7.47-7.44 (m, 2H, ArH),
5.88-5.81 (m, 1H), 5.10-4.96 (m, 3H), 2.18-2.11 (m, 2H), 2.09-1.98 (m, 1H), 1.84-1.74 (m,
13
2H), 1.03-1.00 (m, 6H); C NMR (125 MHz, CDCl3): δ 166.4, 138.1, 132.8, 129.9, 129.7,
128.4, 115.0, 78.5, 66.8, 59.6, 31.7, 30.6, 30.0, 18.7, 17.7; HR-ESI-MS (m/z): [M + H]+
calcd. for C15H21O2, 233.1536; found, 233.1565.
Synthesis of (R)-2-methylhept-6-en-3-ol (7):
NaOMe (50 mg) was added to a stirred solution of 10 (0.5 g, 2.15 mmol) in MeOH (5 mL)
and CH2Cl2 (1 mL). After complete consumption of starting material (monitored by TLC)
reaction was quenched with Amberlite IR120 H+ and filtered through Celite. The collected
solution was concentrated and the obtained crude product was purified by silica gel column
chromatography (15% ethyl acetate: pet ether) to obtain 7 (0.26 g, 94%) as a colorless liquid;
[α]D = +22.4 (c = 1.0, CHCl3); IR (cm-1, CHCl3) 3551, 2964, 1623, 1284, 1011, 671, 519,
25
478; 1H NMR (400 MHz, CDCl3): δ 5.92-5.83 (m, 1H, =CH), 5.03 (dd, J =14.2, 1.90 Hz, 1H,
=CH2), 3.39-3.34 (m, 1H, -CH), 2.32-2.21 (m, 1H), 2.19-2.06 (m, 1H), 1.72-1.41 (m, 4H),
1.02 (d, J = 6.8 Hz, 3H, -CH3), 1.01 (d, J = 6.7 Hz, 3H, -CH3); 13C NMR (100 MHz, CDCl3):
10
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European Journal of Organic Chemistry
δ 138.9, 114.8, 76.3, 33.7, 33.4, 30.6, 18.9, 17.3; HR-ESI-MS (m/z): [M + K]+ calcd. for
C8H16OK, 167.0833; found, 167.0804.
Compound (3a):
To a solution of 10-undecenoic acid 11 (3.1 mL, 14.95 mmol) in dry DMF (20 mL), DCC
(7.71 g, 37.37 mmol) and DMAP (0.91 g, 7.4 mmol) were added. After 10 min, to this stirred
solution (S)-benzyl-2-aminopropanoate 12 (3.9 g, 22.45 mmol) in dry DMF (10 mL) was
added dropwise. After 2 h, the reaction mixture was filtered through Celite and washed with
brine solution. The separated organic layers were dried over Na2SO4, concentrated and the
crude compound was purified by silica gel column chromatography to afford 3a (4.74 g,
25
92%) as a white solid; [α]D = +27.7 (c = 1.0, CHCl3); IR (cm-1, CHCl3) 2958, 1648, 1252,
1
1015, 791, 681, 523, 491; H NMR (400 MHz, CDCl3) δ 7.41-7.29 (m, 5H, ArH), 6.21 (s,
1H, NH), 5.86-5.75 (m, 1H, =CH), 5.25-5.12 (m, 2H, -CH2Ph), 5.15 (dd, J = 18.0, 12.4 Hz,
2H, =CH2) 4.72-4.64 (m, 1H, -CHOH), 2.18 (t, J = 7.6 Hz, 2H), 2.01 (q, J = 6.8 Hz, 2H),
1.63-1.55 (m, 2H), 1.38 (d, J = 7.2 Hz, 3H), 1.29-1.42 (m, 10H); 13C NMR (100 MHz,
CDCl3): δ 173.2, 172.8, 139.2, 135.4, 128.7, 128.5, 128.2, 114.2, 67.2, 48.1, 36.6, 33.9, 29.4,
29.3, 29.1, 29.0, 25.6, 18.6; HR-ESI-MS (m/z): [M + K]+ calcd. for C21H31NO3K, 384.1936;
found, 384.1934.
Compound (3b):
25
Compound 3b was prepared using same procedure as described for compound 3a; [α]D
=
1
+8.4 (c = 0.5, CHCl3); IR (cm-1, CHCl3) 2958, 1652, 1261, 1021, 797, 692, 528; H NMR
(400 MHz, CDCl3) δ 7.40-7.31 (m, 5H, ArH), 5.95 (s, 1H, NH), 5.86-5.74 (m, 1H), 5.01 (s,
2H), 5.02-4.91 (m, 2H), 4.49 (d, J = 5.20 Hz, 2H), 2.23 (t, J = 7.62 Hz, 2H), 2.09-1.95 (m,
13
2H), 1.35-1.19 (m, 12H); C NMR (100 MHz, CDCl3): δ 173.4, 170.2, 139.3, 128.8, 128.7,
11
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European Journal of Organic Chemistry
128.5, 114.3, 67.4, 41.5, 36.6, 33.9, 29.45, 29.44, 29.4, 29.2, 29.1, 26.0, 25.7, 23.0; HR-ESI-
MS (m/z): [M + Na]+ calcd. for C20H29NO3Na, 354.2040; found, 354.2013.
Synthesis of (R)-2-methylhept-6-en-3-oyl-β-D-glucopyranoside (4):
TMSI (95 µL, 0.66 mmol) was added to a stirred solution of 2,3,4,6-penta-O-trimethylsilyl D-
glucopyranoside 14 (0.3 g, 0.55 mmol) in CH2Cl2 (3.0 mL) at 0 oC. The reaction was stirred
under nitrogen for 25 min. After completion of the reaction (observed by TLC) reaction was
stopped by adding anhydrous benzene (2 mL) and the crude product was azeotroped two
times (dry benzene) on a rotary evaporator under high vacuum to obtain the crude glycosyl
iodide 6. This crude product 6 was dissolved in CH2Cl2 (3 mL) and cannulated dropwise into
a stirred solution of acceptor 7 (17 mg, 0.13 mmol), Ag2CO3 (0.62 g, 2.21 mmol), and 3 Å
MS (0.7 g) in CH2Cl2 (1.5 mL) at room temperature. After 0.5 h the reaction mixture was
filtered through Celite, concentrated and kept under vacuum for 15 min.
The above crude product which was removed from the vacuum was dissolved in
MeOH (1 mL) and CH2Cl2 (0.5 mL). To this stirred solution, K2CO3 (0.9 g, 7.2 mmol) was
added at room temperature. After 10 min the reaction was quenched with a few drops of
acetic acid. The reaction solvent was removed under reduced pressure and the obtained crude
product was purified by silica gel column chromatography (5% methanol: ethyl acetate) to
afford 4 (32 mg, 84%) as a yellow sticky liquid; [α]D = -7.41 (c = 1.5, MeOH); IR (cm-1,
25
1
CHCl3) 3651, 3448, 2964, 1632, 1219, 1016, 992, 778, 682, 525, 431; H NMR (400 MHz,
CD3OD): δ 5.85-5.79 (m, 1H, =CH), 5.01-4.96 (m, 2H, =CH2), 4.30 (d, J = 7.6 Hz , 1H, H-
1β), 3.83 (dd, J = 11.6, 2.0 Hz, 1H), 3.68 (dd, J = 11.6, 5.6 Hz, 1H), 3.53-3.48 (m, 1H), 3.38-
3.28 (m, 3H), 3.28-3.25 (m, 1H), 3.23-3.21 (m, 1H), 2.24-2.05 (m, 2H), 1.99-1.85 (m, 1H),
1.61-1.52 (m, 2H), 0.94 (d, J = 4.0 Hz, 3H, -CH3), 0.93 (d, J = 3.6 Hz, 3H, -CH3); 13C NMR
(100 MHz, CD3OD): δ 139.0, 113.2, 102.4, 83.0, 76.8, 76.3, 74.0, 70.4, 61.5, 30.5, 29.8,
12
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European Journal of Organic Chemistry
29.5, 17.1, 16.4; HR-ESI-MS (m/z): [M + Na]+ calcd. for C14H26O6Na, 313.1622; found,
313.1627.
Compound (15):
TBTU (0.18 mg, 0.57 mmol) and DIPEA (0.14 mL, 1.10 mmol) were added sequentially to a
stirred solution of compound 4 (0.15 g, 0.52 mmol) in dry pyridine (2.9 mL). After 0.5 h, to
this stirred solution, compound 5 (0.12 g, 0.57 mmol) in pyridine (4.6 mL) was added
dropwise. After complete consumption of starting material (monitored by TLC) the solvent
was evaporated under reduced pressure and the obtained crude residue was dissolved in
EtOAc and washed with aq. NaHCO3 solution. The organic layer was dried over Na2SO4,
concentrated and purified by silica gel column chromatography (70% ethyl acetate: pet ether)
25
to obtain 15 (0.22 g, 89%) as a sticky yellow liquid; [α]D = +4.79 (c = 2.0, CHCl3);
1
IR (cm-1, CHCl3) 3665, 3558, 2978, 1731, 1726, 1600, 1280, 1014, 681, 522, 491; H NMR
(500 MHz, CDCl3): δ 7.40-7.33 (m, 5H, ArH), 5.86-5.78 (m, 1H), 5.17-5.12 (m, 2H), 5.01
(dd, J = 13.8, 2.2 Hz, 2H, =CH2), 4.43-4.35 (m, 2H, H-6, 6’), 4.31 (d, J = 7.7 Hz, 1H, H-1),
3.95 (s, 1H, -OH), 3.81 (s, 1H, -OH), 3.58-3.55 (m, 1H, H-3), 3.47-3.44 (m, 2H, H-4 & H-5),
3.40 (t, J = 8.5 Hz, 1H, H-2), 2.75 (s, 4H, 2×CH2), 2.24-2.16 (m, 1H), 2.14-2.08 (m, 1H),
2.07-2.05 (m, 2H), 1.92-1.86 (m, 1H), 1.63-1.50 (m, 2H), 0.93 (d, J = 7.4 Hz, 3H, -CH3),
13
0.92 (d, J = 7.5 Hz, 3H, -CH3); C NMR (125 MHz, CDCl3): δ 172.9, 172.5, 139.1, 135.8,
128.8, 128.5, 128.4, 114.7, 102.4, 84.2, 76.3, 74.2, 73.7, 70.3, 66.9, 63.9, 31.2, 30.2, 29.8,
29.3, 29.2, 18.3, 17.9; HR-ESI-MS (m/z): [M + Na]+ calcd. for C25H36O9Na, 503.2252; found,
503.2252.
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European Journal of Organic Chemistry
Compound (2):
Et3N (0.47 mL, 3.37 mmol) and TMSCl (0.42 mL, 3.37 mmol) were added sequentially to a
o
stirred solution of 15 (0.27 g, 0.56 mmol) in CH2Cl2 (3 mL) at 0 C. After 1 h, reaction
mixture was diluted with CH2Cl2 and transferred into a separating funnel and washed with
H2O. Collected organic layer was dried over Na2SO4, concentrated and purified by silica gel
column chromatography (10% ethyl acetate: pet ether) to afford 2 (0.36 g, 94%) as a sticky
25
yellow liquid; [α]D = -1.63 (c = 0.5, CHCl3); IR (cm-1, CHCl3) 2895, 1721, 1711, 1602,
1278, 1016, 664, 531, 495; 1H NMR (400 MHz, CDCl3): δ 7.38-7.25 (m, 5H, ArH), 5.87-5.76
(m, 1H, =CH), 5.13 (s, 2H, CH2Ph), 5.10 (dd, J = 12.8, 4.5 Hz, 2H, =CH2), 4.46 (dd, J =
11.6, 2.3 Hz, 1H, H-6), 4.24 (d, J = 7.4 Hz, 1H, H-1), 4.10 (dd, J = 11.4, 2.3 Hz, 1H, H-6’),
3.48-3.36 (m, 4H, H-3, H-4, H-5, -CH), 3.28 (t, J = 4.3 Hz, 1H, H-2), 2.56 (s, 4H, 2×CH2),
2.22-2.19 (m, 1H), 2.18-2.01 (m, 1H), 1.98-1.85 (m, 1H), 1.62-1.54 (m, 2H), 0.98 (d, J = 7.2
Hz, 3H), 0.96 (d, J = 7.3 Hz, 3H), 0.20-0.10 (m, 27H); 13C NMR (100 MHz, CDCl3): δ 172.2,
172.1, 139.6, 135.9, 128.7, 128.4, 128.3, 114.2, 114.1, 101.9, 82.2, 77.7, 75.0, 74.0, 72.3,
66.7, 64.1, 32.1, 30.7, 30.4, 29.9, 29.8, 29.3, 29.2, 29.1, 22.8, 19.1, 17.7, 14.3, 1.4, 1.2, 1.1.
HR-ESI-MS (m/z): [M + Na]+ calcd. for C34H60O9Si3Na, 719.3437; found, 719.3439.
Compound (16a):
Azeotroped mixture of compound 2 (60.0 mg, 0.08 mmol) and 3a (60.0 mg, 0.17 mmol) was
dissolved in CH2Cl2 (1 mL). To this stirred solution, Grubbs-II generation catalyst (3.4 mg,
5.01 µmol) was added and the reaction mixture was refluxed at 40 oC for 8 h. After complete
consumption of starting material (monitored by TLC), reaction solvent was removed under
reduced pressure and the obtained crude product was purified by silica gel column
chromatography (15% ethyl acetate: pet ether) to afford 16a (66.5 mg, 82%) as a yellow
25
liquid; [α]D = +4.56 (c = 2.0, CHCl3); IR (cm-1, CHCl3) 2986, 2885, 1719, 1710, 1658,
1604, 1281, 1021, 998, 894, 762, 668, 541, 498; 1H NMR (400 MHz, CDCl3) δ 7.38-7.30 (m,
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10.1002/ejoc.201800209
European Journal of Organic Chemistry
10H, ArH), 6.02 (d, J = 7.0 Hz, 1H, NH), 5.38-5.42 (m, 2H), 5.23-5.11 (m, 4H), 4.65 (q, J =
7.2 Hz, 1H), 4.44 (dd, J = 8.2, 2.4 Hz, 1H), 4.23 (d, J = 7.3 Hz, 1H), 4.01 (dd, J = 9.6, 3.2 Hz,
1H), 3.45-3.31 (m, 3H), 3.23 (d, J = 7.8 Hz, 1H), 2.68 (s, 4H), 2.18 (t, J = 6.1 Hz, 2H), 2.02-
1.82 (m, 4H), 1.61 (bs, 3H), 1.48-1.43 (m, 1H), 1.40 (d, J = 7.16 Hz, 3H), 1.39-1.21 (m,
12H), 0.90 (d, J = 6.9 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H), 0.12-0.17 (m, 27H); 13C NMR (100
MHz, CDCl3): δ 173.1, 172.8, 172.0, 136.1, 128.6, 128.5, 128.4, 128.3, 128.1, 101.7, 74.9,
73.7, 72.4, 67.2, 66.5, 48.0, 36.6, 29.2, 25.5, 18.9, 18.6, 1.3, 1.0, 0.9; HR-ESI-MS (m/z): [M
+ Na]+ calcd. for C53H87NO12Si3Na, 1036.5428; found, 1036.5422.
Compound (16b):
Compound 16b was synthesized using same procedure as described for compound 16a;
25
[α]D = +11.54 (c = 5.0, CHCl3); IR (cm-1, CHCl3) 2975, 2864, 1720, 1713, 1648, 1610,
1289, 1031, 996, 896, 766, 664, 545, 499; 1H NMR (500 MHz, CDCl3) δ 7.45-7.28 (m, 10H,
ArH), 6.04 (bs, 1H, NH), 5.49-5.31 (m, 2H), 5.45 (s, 2H), 5.41 (s, 2H), 4.52-4.49 (m, 1H),
4.34-4.29 (m, 2H), 4.11 (s, 2H), 3.57 (bs, 1H), 3.51-3.36 (m, 4H), 2.71 (s, 4H), 2.25 (t,
J = 7.5 Hz, 2H), 2.13 (t, J = 7.6 Hz, 2H), 2.01-1.95 (m, 3H), 1.93-1.85 (m, 2H), 1.39-1.24
(m, 12H), 0.92-0.98 (m, 6H), 0.09 (s, 5H), 0.02 (s, 6H); 13C NMR (125 MHz, CDCl3): δ
173.4, 172.3, 170.1, 135.7, 130.4, 128.7, 128.6, 128.4, 128.3, 128.2, 102.4, 76.3, 74.2, 73.5,
70.6, 67.3, 41.4, 36.5, 32.6, 30.1, 29.7, 29.6, 29.2, 29.1, 26.1, 25.5, 22.8, 1.9, 0.01; HR-ESI-
MS (m/z): [M + Na]+ calcd. for C52H85NO12Si3Na, 1022.5272; found, 1022.5256.
Ieodoglucomide (1a):
TBAF in THF (0.28 mL, 0.28 mmol) and AcOH (19 µL, 0.28 mmol) was added dropwise to
a stirred solution of compound 16a (45 mg, 0.04 mmol) in THF (0.8 mL). After complete
consumption of starting material (monitored by TLC) the reaction mixture was diluted with
EtOAc and concentrated under reduced pressure.
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10.1002/ejoc.201800209
European Journal of Organic Chemistry
The residue was dissolved in EtOH (5 mL). To this well stirred solution 10% Pd/C
(50 mg) was added and stirring was continued at rt under H2 atmosphere. After 1 h, reaction
mixture was filtered through Celite. The crude product obtained after the removal of the
solvent was purified by HPLC using a C18 column to afford ieodoglucomide 1a (22.5 mg,
92%) as a yellow sticky liquid; [α]D25 = -23.34 (c = 0.1, CH3OH); IR (cm-1, MeOH); 3690,
1
3358, 2926, 2862, 1654, 1371, 1219, 1054, 1033, 772, 554; H NMR (500 MHz, CD3OD) δ
4.46 (dd, J = 11.7, 1.9 Hz, 1H, H-6), 4.38 (q, J = 7.1 Hz, 1H), 4.31 (d, J = 7.7 Hz, 1H, H-1),
4.19 (dd, J = 11.7, 6.3 Hz, 1H, H-6’), 3.56-3.41 (m, 1H, H-5), 3.18-3.12 (m, 2H, H-3 & H-4),
3.20 (t, J = 8.4 Hz, 1H), 2.63-2.61 (m, 4H, 2×CH3), 2.24 (t, J = 7.4 Hz, 2H), 1.92-1.86 (m,
1H), 1.67-1.54 (m, 2H), 1.52-1.45 (m, 3H), 1.39 (d, J = 7.2 Hz, 3H), 1.38-1.28 (m, 17H),
13
0.95 (s, 3H), 0.94 (s, 3H); C NMR (125 MHz, CD3OD) δ 174.7, 174.4, 172.5, 102.6, 84.2,
76.7, 74.0, 73.6, 70.5, 63.7, 35.4, 30.8, 30.7, 29.4, 29.38, 29.33, 29.2, 29.0, 28.8, 28.7, 28.4,
25.4, 25.1, 17.1, 16.8, 16.3; HRMS (m/z) calcd for C30H53NO12Na [M + Na]+ 642.3460,
found 642.3476.
Ieodoglucomide (1b):
TBAF in THF (0.13 mL, 0.13 mmol) and AcOH (6 µL, 0.13 mmol) was added
dropwise to a stirred solution of compound 16b (20 mg, 0.02 mmol) in THF (0.5 mL). After
complete consumption of starting material (monitored by TLC) reaction mixture was diluted
with EtOAc and concentrated under reduced pressure.
The residue was dissolved in EtOH (2.0 mL). To this stirred solution Pd/C (20 mg)
was added and the stirring was continued at rt under H2 atmosphere. After 1 h, reaction
mixture was filtered through Celite, concentrated and purified by HPLC using a C18 column
to afford ieodoglucomide 1b (10.6 mg, 90%) as a yellow sticky liquid; [α]D25 = -14.72 (c =
0.1, CH3OH); IR (cm-1, MeOH) 3668, 3386, 2940, 2866, 1657, 1371, 1219, 1054, 1032, 772;
1H NMR (500 MHz, CD3OD) δ 4.45 (dd, J = 11.6, 1.8 Hz, 1H, H-6), 4.30 (d, J = 7.7 Hz, 1H,
16
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10.1002/ejoc.201800209
European Journal of Organic Chemistry
H-1), 4.19 (dd, J = 11.7, 6.3 Hz, 1H, H-6’), 3.90 (s, 2H), 3.49-3.41 (m, 2H), 3.39-3.25 (m,
2H), 3.24-3.19 (m, 1H), 2.63 (s, 4H), 2.26 (t, J = 7.4 Hz, 2H), 1.92-1.86 (m, 1H), 1.68-1.59
(m, 3H), 1.51-1.43 (m, 2H), 1.39-1.23 (m, 17H), 0.96 (d, J = 1.0 Hz, 3H), 0.94 (d, J = 0.9 Hz,
13
3H); C NMR (125 MHz, CD3OD) δ 102.7, 84.1, 77.0, 74.0, 73.6, 70.6, 63.7, 35.5, 30.8,
30.7, 29.4, 29.2, 29.1, 28.9, 25.5, 25.1, 17.1, 16.7; HRMS (m/z) calcd for C29H49NO12Na
[M + Na]+ 626.3147, found 626.3141.
Acknowledgment:
We thank the Department of Science and Technology (Grant No. EMR/2014/000235), ISF-
UGC joint research program framework (Grant No. 2253) and A.R.P. thanks CSIR-New
Delhi and IRCC-IIT Bombay for a fellowship.
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European Journal of Organic Chemistry
Entry for the Table of Contents
Expeditious Synthesis of Ieodoglucomides A and B from Marine-Derived Bacterium
Bacillus licheniformis
Ananda Rao Podilapu, Madhu Emmadi and Suvarn S. Kulkarni*
FULL PAPER
Key Topic: Bacterial Glycoconjugate Synthesis
Total synthesis of marine derived bacterial glycopeptides ieodoglucomides A and B is
accomplished and its revised structure is confirmed. The key features of the synthesis
include a β-stereoselective glycosylation of per-O-TMS D-glucosyl iodide in lieu of
neighbouring group participation (NGP), regioselective O6-acylation, and Grubbs’
cross metathesis reaction. The total synthesis involves 11 steps, and can be completed
in two weeks with 38-40% overall yield.
19
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