Synthesis of maradolipid

Article abstract of DOI:10.1021/jo200979n

The first synthesis of maradolipid, a unique dissymmetrically 6,6′-di-O-acylated trehalose glycolipid isolated from C. elegans, is accomplished in five steps starting from trehalose in 45% overall yield. The short synthesis relies on dissymmetrization of trehalose core via regioselective acylation of a 2,3,4,2′,3′,4′-hexa-O-TMS trehalose 6,6′-diol derivative as a key step.

Full text of DOI:10.1021/jo200979n

NOTE
pubs.acs.org/joc
Synthesis of Maradolipid
Vikram A. Sarpe and Suvarn S. Kulkarni*
Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400076, India
S Supporting Information
b
ABSTRACT: The first synthesis of maradolipid, a unique
dissymmetrically 6,60-di-O-acylated trehalose glycolipid isolated
from C. elegans, is accomplished in five steps starting from
trehalose in 45% overall yield. The short synthesis relies on
dissymmetrization of trehalose core via regioselective acylation
of a 2,3,4,20,30,40-hexa-O-TMS trehalose 6,60-diol derivative as a
key step.
ematode Caenorhabditis elegans responds to extreme envir-
onmental stress by arresting its reproductive cycle and
N
forming a highly stress resistant dauer larva. Very recently, it
was discovered that during the transition from the reproductive
larval stage to dauer larval stage, the worm synthesizes a novel
class of 6,60-di-O-acyltrehaloses, termed maradolipids.1 The
structure of the major component of maradolipids was assigned
by using advanced 2D NMR spectroscopy as 6-O-(13-
methylmyristoyl)-60-O-oleoyltrehalose 1 (Figure 1).
Figure 1. Structure of maradolipid 1 from C. elegans.
Maradolipids are the first diacyltrehaloses found to be pro-
duced in animal kingdom. Intriguingly, they show striking structural
resemblance with the glycolipid from Mycobacterium tuberculosis
named cord factor (trehalose-6,60-dimycolate, TDM), which is
known to confer desiccation resistance to the bacteria by
imparting stability to the lipid layer of the cell wall, and shows
diverse immune activities.2 In fact, such desiccation protection to
membranes has also been observed for synthetic TDM analogues
with symmetrical trehalose core linked to two simpler 15ꢀ18
carbon chains at 6,60.3 The structural similarity of maradolipids
with TDM and their abundance (∼6% of the total dauer phos-
pholipids) in dauer larvae are indicative of their putative biolo-
gical functions. Although the dauer larvae formation pathway is
well studied from biological perspectives, not much is known
about the chemical changes that help the dauer larvae to resist
and adapt the unfavorable environmental changes. The discovery
of maradolipids is regarded as an important breakthrough, which
may provide further clues in the pursuit of finding possible pathways
of the stress associated chemical remodeling of cell. Toward
understanding the molecular level details of the dauer resistance
strategies and delineate the chemical pathway, structurally well-
defined and chemically pure glycolipids are essential. However,
the purified fractions of natural maradolipids show highly hetero-
geneous lipid composition. Thus, a short and efficient chemical
synthesis of maradolipids is pivotal for obtaining pure glycolipids
and their analogues in good purity and amounts for the struc-
tureꢀactivity relationship studies. In this paper, we report the
first total synthesis and structure confirmation of maradolipid 1.
Maradolipid 1, being a first example of a 6,60-dissymmetrically
substituted trehalose-based glycolipids, presents a challenge to
synthetic chemists. Any route starting with commercially avail-
able R,R-trehalose 2 would essentially entail a differentiation of
two primary alcohols as a key step. Regioselective protection of
trehalose polyol has been the subject of intense research.4ꢀ30
Synthesis of TDM analogues received immense attention, and
procedures affording diesters4ꢀ16 or monoesters7ꢀ13 have been
developed, both by nucleophilic displacement of 6,60-dideoxy
derivatives bearing sulfonates5,13,15,16 or halides4 at 6,60positions
and by acylations of 6,60-diol of trehalose,7ꢀ12,14 with its second-
ary hydroxyl groups protected as TMS4ꢀ10 or benzyl11ꢀ16 groups.
Direct diacylations of unprotected trehalose using transesterification,17
Mitsunobu conditions,18,19 and tributylstannylation20 are also
reported. In addition, several protocols have been devised for
selective protection of various hydroxyl groups to access more
complex molecules containing dissymmetrically functionalized
trehalose core.21ꢀ30 Some of the routes, however, involve lengthy
protectionꢀdeprotection steps affording mixtures of isomers,
necessitating column chromatographic purification of the inter-
mediates and resulting in poor overall efficiency.
In recent years, the trimethylsilyl group (TMS) has gained
importance in carbohydrate synthesis, as evidenced by increasing
number of publications involving this protection.4ꢀ10,29ꢀ46
Hindsgaul first explored the use of TMS ethers in glycosylation
reaction.31,32 The unique reactivity of TMS protecting group is
further endorsed by two seminal studies, Hung’s TMSOTf
Received: May 15, 2011
Published: July 08, 2011
r
2011 American Chemical Society
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|

The Journal of Organic Chemistry
NOTE
Scheme 1. Synthesis of Maradolipid 1
catalyzed one-pot protection of carbohydrate polyols33ꢀ37 and
Gervay-Hague’s glycosyl iodide mediated one-pot stereoselec-
tive glycosylation protocols,38ꢀ41 both involving per-O-silylated
monosaccharides. Along with this, subsequent studies by Beau
and co-workers first employing cat. Cu(OTf)2 for one-pot
protection of per-O-TMS monosaccharides42 and recently ex-
oleic acid. However, in our hands, the reaction proceeded
sluggishly to afford the desired product in very low yields
(12%). Use of EDCI9,11 (3 equiv), as a coupling reagent, showed
only marginal improvement as judged from the TLC analysis.
With these preliminary results, we decided to carry out a
systematic study for selective acylation of 6,60-diol 4. The
detailed reaction conditions including reagent equivalents, tem-
perature, time, concentration, and product yields are presented in
Table 1. First, toluene was added to an equimolar mixture of diol 4,
oleic acid, DCC, and catalytic amount of DMAP in the presence
of 3 Å molecular sieves at 0 °C, and the reaction mixture was
stirred at rt for 6 h and further heated to 60 °C for 12 h10 to afford
mono-oleate 5 (12%) along with the corresponding dioleate 6
(3%) and unreacted 4 (entry 1). The scenario could be improved
(entry 2) by adding a premixed solution of oleic acid (1.15
equiv), DCC (3 equiv), and cat. DMAP to a solution of diol 4 and
3 Å MS in toluene at 0 °C, stirring the mixture at rt, and then
heating it to 60 °C. This reaction offered mono-oleate 5 in a
modest 34% yield along with the dioleate 6 (14%). Conducting
the same reaction without molecular sieves did not show any
significant effect on the yield (compare entries 2 and 3).
Encouraged by these results, we changed the solvent to CH2Cl2
and conducted a series of reactions (entries 4ꢀ8) with increasing
equivalents of reagents in CH2Cl2 at 0 °C to rt with overnight
stirring. Among these, the best results were obtained when a
combination of oleic acid (1.7 equiv), DCC (4 equiv), and
DMAP (1 equiv) was used to furnish 5 (46%) as a major product
along with minor 6 (16%) (entry 7). Prolonged stirring (∼2 d,
entry 9) under these conditions offered marked improvements in
yields of 5 (54%) and 6 (27%). In all cases, unused starting
material 4 was recovered back. A characteristic feature of this
reaction was its tendency to stall after a few hours. The observa-
tion that even after using 2 equiv of oleic acid only 23% of
dioleate was formed (entry 8) encouraged us to try a reverse
addition, wherein the diol solution was added to a premixed, well-
stirred solution of oleic acid, DCC, and DMAP at 0 °C, and the
stirring was continued for 5 h (entry 10). Gratifyingly, under the
conditions, compound 5 was obtained in a satisfactory yield of
60% along with 17% of di and 14% recovered starting material.
These conditions emerged as optimized conditions from our
tended to per-O-TMS trehalose using FeCl3 6H2O,30 speaks
3
volumes about the stability of TMS groups under varied reaction
conditions. We decided to use per-O-silylated trehalose 3 as a
starting point for several reasons. TMS groups are easy to
introduce; they improve the solubility of parent sugar in organic
solvents and are fairly stable. More importantly, the primary
TMS ethers could be hydrolyzed4ꢀ10,43ꢀ45 or acetylated46
selectively in the presence of secondary TMS ethers. Finally,
global deprotection could be achieved instantly and cleanly
under mild conditions without disturbing the double bonds.
It was envisaged that the known 2,3,4,20,30,40-hexa-O-TMS
trehalose 6,60-diol4,7 could be regioselectively monoacylated with
oleic acid via a DCC-mediated coupling.10 Sequential acylation
using 13-methylmyristic acid followed by treatment with acidic
resin would afford maradolipid 1.
A short and efficient synthesis of maradolipid 1 is outlined in
Scheme 1. Treatment of a suspension of anhydrous trehalose 2 in
dichloromethane (CH2Cl2) with triethylamine (Et3N) and
trimethylsilyl chloride (TMSCl) afforded per-O-trimethylsilyl
trehalose 3. Employment of Et3N as a base in place of
pyridine4,7,30 expedited the workup and evaporation. The crude
compound 3, which was free of any detectable impurities, was
subjected to controlled alkaline hydrolysis using catalytic amount
of potassium carbonate (K2CO3) in methanol/dichloromethane
(3:1) solvent mixture to furnish the trehalose 6,60-diol 4 in
excellent yield (92% over two steps).4 It should be noted that the
use of dichloromethane as a cosolvent improved the solubility
that allowed us to carry out the reaction with much lesser amount
of methanol (∼1/10 volume) as compared to the original
procedure, a feature which turned out to be useful for scale up
operation. Regioselective acylation of the 6,60-diol 4, although
reported in literature with a different set of carboxylic acids,10
turned out to be notoriously difficult. Following the reported
procedure, 4 was subjected to a DCC-mediated coupling with
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NOTE
Table 1. Regioselective Acylation of 6,60-Diol 4 with Oleic Acid
Yield
entry
acid (equiv)
DCC (equiv)
DMAP (equiv)
time (h)
solvent (mL/0.1 g)
T (°C)
5 (%)
6 (%)
1a
2a
3
1
1
0.02
0.16
0.16
0.01
0.5
0.5
1
18
36
28
18
16
18
18
18
43
5
toluene (0.4)
toluene (0.4)
toluene (1.2)
CH2Cl2 (1.2)
CH2Cl2 (1.7)
CH2Cl2 (1.7)
CH2Cl2 (3.0)
CH2Cl2 (3.0)
CH2Cl2 (3.0)
CH2Cl2 (2.0)
CH2Cl2 (2.3)
0 to rt then 60
0 to rt then 60
0 to rt then 60
0 to rt
12
34
35
33
33
28
46
42
54
60
46
3
14
12
10
13
14
16
23
27
17
23
1.15
1.15
1
3
3
4a
2.5
3.5
3.5
4
5
1.3
1.5
1.7
2
0 to rt
6
0 to rt
7
0 to rt
8
2
1
0 to rt
9
1.7
1
4
1
0 to rt
10
2
0.5
0.5
0 to rt
11
1
2
18
0 to rt
a 3 Å molecular sieves were used.
study. Running the same reaction for prolonged time (18 h, entry
11) resulted in an increase in the formation of di 6 (23%) and
consequent decrease in the yield of 5 (46%). Compounds 4, 5,
and 6 were well separated on TLC and easily purified by flash
column chromatography. The secondary TMS ethers in 4, 5, and
6 are found to be stable to chromatographic purification condi-
tions, and no special care is required.
With the mono-oleate 5 in hand, we proceeded further to
complete the synthesis of 1 (Scheme 1). DCC-mediated cou-
pling of alcohol 5 with readily accessible 13-methylmyristic acid47
(13-methyltetradecanoic acid) furnished the requisite myristoyl
derivative 7 (89%), which upon removal of TMS protecting
groups using a brief treatment with Dowex 50WX8-200 ion-
exchange resin in methanol cleanly afforded maradolipid 1
(93%). The spectral data of synthetic maradolipid 1 corroborated
well with the reported one confirming its identity and structure
(see the Supporting Information).1
In conclusion, we have completed first synthesis of marado-
lipid 1 starting from trehalose 2 in five steps and 45% overall
yield. As per our knowledge, this is the first example of a
dissymmetrically 6,60-di-O-acylated trehalose derivative. Our
synthesis capitalizes on the unique reactivity of TMS protecting
groups. Regioselective acylation avoids lengthy protection-de-
protection sequences improving the overall efficacy. All of the
reactions are done either at rt or in ice bath and do not need any
special apparatus. The short sequence may be executed in 3 d.
The first synthesis of maradolipid has opened up a doorway to
access pure maradolipids and related analogues to study their
biological role in dauer larvae resistance as well as their immu-
nological properties.
polarity correlated with TLC mobility. NMR experiments were conducted
on 400 MHz instrument using CDCl3 (D, 99.8%) or CD3OD (D,
99.9%) as solvents. Chemical shifts are relative to the deuterated solvent
peaks and are in parts per million (ppm). Hꢀ H COSY was used to
confirm proton assignments. Mass spectra were acquired in the ESI
mode. Melting points were determined by capillary apparatus. Specific
rotation experiments were measured at 589 nm (Na) and 25 °C unless
otherwise mentioned. IR spectra were recorded on an FT-IR spectro-
meter using CsCl plates.
1
1
2,3,4,20,30,40-Hexakis-O-(trimethylsilyl)-R,R-trehalose
(4). Triethylamine (18.3 mL, 130.9 mmol) was added to a stirred
suspension of trehalose (1.12 g, 3.27 mmol) in CH2Cl2 (15 mL).
Reaction mixture was cooled to 0 °C, and trimethylsilyl chloride
(4.87 mL, 39.26 mmol) was added to it. The solution was stirred at rt
for 12 h. An additional 1.6 mL of trimethylsilyl chloride (13.08 mmol)
was added at 0 °C, and the reaction was stirred for 4 h at rt. Solvents
were evaporated on rotor, and the crude product was extracted in pet
ether (50 mL ꢁ 5). The combined organic layer was dried on
anhydrous sodium sulfate and concentrated in vacuo to obtain
2,3,4,6,20,30,4060-octakis-O-(trimethylsilyl)-R,R-trehalose
3 as a
cream-colored solid (3.04 g). Compound 3 showed no impurity
1
peaks in H and 13C NMR spectrum: [R]20 +111.0 (c 1, CHCl3)
D
[lit.4 [R]20 +95.0 (c 1, CHCl3)]; IR (CHCl3) ν 2957, 1251, 1159,
D
1086, 1013, 906, 651 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 4.91 (d,
J = 3.1 Hz, 2H), 3.88 (t, J = 8.8 Hz, 2H), 3.80ꢀ3.77 (m, 2H),
3.71ꢀ3.64 (m, 4H), 3.42 (t, J = 9.3 Hz, 2H), 3.39 (dd, J = 3.1, 9.3 Hz, 2H),
0.14 (s, 18H), 0.13 (s, 18H), 0.11 (s, 18H), 0.09 (s, 18H); 13C NMR (100
MHz, CDCl3) δ 94.5, 73.8, 73.4, 73.0, 71.9, 62.3, 1.3, 1.1, 0.3, ꢀ0.1; HRMS
calcd for C36H86O11Si8 [M + Na]+ 941.4222, found 941.4218.
To a cooled solution of compound 3 (3.04 g, 3.31 mmol) in
MeOH and CH2Cl2 (19 mL, 3:1) at 0 °C was added K2CO3 (54 mg,
0.40 mmol), and the reaction was stirred for 15 min at 0 °C and then
at rt for 1 h. Reaction was quenched by addition of acetic acid
(0.7 mL). Solvents were evaporated in vacuo, and crude product was
separated by column chromatography on silica gel (2:8 ethyl
acetate/petroleum ether) to afford compound 4 (2.38 g, 92%) as a
white solid: [R]20 +120.4 (c 1, CHCl3) [lit.4 [R]20 +100 (c 1,
’ EXPERIMENTAL SECTION
General Methods. All reactions were conducted under a dry
nitrogen atmosphere. Solvents (CH2Cl2 >99%, toluene >99%) were
purchased in capped bottles and dried under CaH2 or sodium. All other
solvents and reagents were used without further purification. All
glassware used was oven-dried before use. TLC was performed on
precoated aluminum plates of silica gel 60 F254 (0.25 mm, E. Merck).
Developed TLC plates were visualized under a short-wave 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 (100ꢀ200 and 230ꢀ400 mesh) and employed a solvent
D
D
CHCl3)]; mp 114ꢀ115 °C [lit4 115ꢀ118 °C]; IR ν 3595, 3019,
2957, 1388, 1252, 1216, 1168, 1110, 1077, 1005, 965, 873, 845,
760 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 5.05 (d, J = 3.1 Hz, 2H,
H-1, H-10), 4.04 (t, J = 9.0 Hz, 2H, H-3, H-30), 4.01 (dt, J = 3.1, 9.0
Hz, 2H, H-5, H-50), 3.88ꢀ3.80 (m, 4H, H-6ab, H-6ab0), 3.63 (t,
J = 9.0 Hz, 2H, H-4, H-40), 3.57 (dd, J = 3.1, 9.0 Hz, 2H, H-2, H-20),
1.97 (bt, 2H), 0.31 (s, 18H), 0.29 (s, 18H), 0.27 (s, 18H); 13C NMR
6868
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The Journal of Organic Chemistry
NOTE
(100 MHz, CDCl3): δ 94.8, 73.5, 73.2, 72.9, 71.5, 61.8, 1.2, 1.0, 0.3, 0.2;
HRMS calcd for C30H70O11Si6 [M + Na]+ 797.3432, found 797.3394.
6-O-Oleoyl-2,3,4,20,30,40-hexakis-O-(trimethylsilyl)-R,R-
trehalose (5). To a premixed, well-stirred solution of DCC (58 mg,
0.28 mmol), DMAP (9 mg, 0.07 mmol), and oleic acid (45 μL,
0.14 mmol) in CH2Cl2 (1 mL) was added a solution of 4 (105 mg,
0.14 mmol) in CH2Cl2 (1 mL) at 0 °C in a slow, dropwise manner. The
reaction mixture was gradually allowed to come to rt and stirred for 5 h.
The reaction mixture was concentrated, and the crude product was
purified by silica gel (230ꢀ400 mesh) column chromatography (1:9
ethyl acetate/petroleum ether, Rf = 0.3) of the residue to give pure
compound 5 (84 mg, 60%) as a pale yellow liquid along with colorless
CHCl3); IR ν 3021, 2927, 2855, 1737, 1461, 1252, 1216, 1167, 1078,
1007, 965, 872, 846, 759 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
δ 5.36ꢀ5.33 (m, 2H, CHdCH), 4.92 (d, J = 3.1 Hz, 2H, H-1, H-10),
4.28 (dd, J = 11.8, 1.8 Hz, 2H, H-6a, H-6a0), 4.06 (dd, J = 11.8, 4.4 Hz,
2H, H-6b, H-6b0), 4.02ꢀ3.98 (m, 2H, H-5, H-50), 3.91 (t, J = 9.0 Hz, 2H,
H-3, H-30), 3.48 (t, J = 9.0 Hz, 2H, H-4, H-40), 3.44 (dd, J = 3.2, 9.0 Hz,
2H, H-2, H-20), 2.34 (dt, J = 3.6, 7.5 Hz, 4H), 2.02ꢀ1.98 (m, 4H),
1.68ꢀ1.61 (m, 4H), 1.51 (h, J = 6.5 Hz, 1H), 1.30ꢀ1.26 (m, 36H),
1.18ꢀ1.12 (m, 2H), 0.90ꢀ0.85 (m, 9H), 0.15 (s, 18H), 0.13 (s, 18H),
0.12 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 173.87, 173.84, 130.1,
129.9, 94.5, 73.7, 72.8, 72.1, 70.9, 63.5, 39.2, 34.3, 32.1, 30.1, 29.94,
29.88, 29.82, 29.79, 29.70, 29.6, 29.5, 29.4, 29.32, 29.30, 28.1, 27.6, 27.4,
27.3, 24.9, 22.8, 14.3, 1.2, 1.1, 0.3; HRMS calcd for C63H130O13Si6 [M +
Na]+ 1285.8025, found 1285.8010.
liquid 6 (30 mg, 17%). 5: [R]25 +81.5 (c 1, CHCl3); IR (CHCl3) ν
D
3443, 2926, 2855, 1742, 1457, 1251, 1166, 1111, 1077, 1044, 1009, 965,
6-O-(13-Methyltetradecanoyl)-60-O-oleoyl-R,R-trehalose/
Maradolipid (1).1. Dowex-50WX8-200 ion-exchange resin (350 mg)
was added to the solution of 7 (84 mg, 0.07 mmol) in methanol (20 mL)
at rt and stirred for 15 min. Dowex was filtered using a sintered funnel
and washed several times with methanol and concentrated to get a white
crude product which was separated by column chromatography (1:19
1
843, 750 cmꢀ1; H NMR (400 MHz, CDCl3) δ 5.38ꢀ5.29 (m, 2H,
CHdCH), 4.91 (t, J = 2.8 Hz, 1H, H-1), 4.90 (t, J = 2.8 Hz, 1H, H-10),
4.29 (dd, J = 11.8, 1.2 Hz, 1H, H-6a), 4.06 (dd, J = 11.8, 4.5 Hz, 1H,
H-6b), 4.02ꢀ3.99 (m, 1H, H-5), 3.91 (t, J = 9.0 Hz, 1H, H-3), 3.90 (t, J =
9.0 Hz, 1H, H-30), 3.83 (td, J = 3.5, 6.6 Hz, 1H, H-50), 3.69 (m, 2H,
H-6a0, H-6b0), 3.48 (dd, J = 9.0, 2.4 Hz, 2H, H-4, H-40), 3.45ꢀ3.41 (m,
2H, H-2, H-20), 2.34 (dt, J = 7.5, 5.0 Hz, 2H), 2.05ꢀ1.98 (m, 4H), 1.76
(m, 1H, OH), 1.62 (m, 2H), 1.30ꢀ1.25 (m, 20H), 0.89ꢀ0.86 (m, 3H),
0.16 (s, 9H), 0.15 (s, 9H), 0.14 (s, 9H), 0.13 (s, 18H), 0.12 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 173.9, 130.2, 129.9, 94.7, 94.5, 73.7, 73.5,
73.1, 72.9, 72.8, 72.1, 71.6, 70.9, 63.5, 61.8, 34.3, 32.1, 29.95, 29.90,
29.83, 29.80, 29.7, 29.5, 29.4, 29.3, 27.39, 27.35, 24.9, 22.9, 14.3, 1.2,
1.18, 1.1, 1.0, 0.3; HRMS calcd for C48H102O12Si6 [M + Na]+ 1061.5885
found, 1061.5908.
ethyl acetate/methanol) to obtain a white solid (51 mg, 93%): [R]25
D
+70.7 (c 0.45, CH3OH); IR ν 3399, 2926, 2854, 1739, 1459, 1033,
757 cmꢀ1
;
1H NMR (400 MHz, CD3OD) δ 5.36ꢀ5.34 (m, 2H,
CHdCH), 5.05 (d, J = 3.7 Hz, 2H, H-1, H-10), 4.36 (dd, J = 11.9, 2.1
Hz, 2H, H-6a, H-6a0), 4.20 (dd, J = 11.9, 5.4 Hz, 2H, H-6b, H-6b0),
4.03ꢀ3.99 (m, 2H, H-5, H-50), 3.78 (t, J = 9.5 Hz, 2H, H-3, H-30), 3.47
(dd, J = 3.8, 9.5 Hz, 2H, H-2, H-20), 3.35ꢀ3.30 (m, 2H, H-4, H-40), 2.34
(t, J = 7.4 Hz, 4H), 2.04ꢀ2.01 (m, 4H), 1.64ꢀ1.60 (m, 4H), 1.53 (h, J =
6.6 Hz, 1H), 1.33ꢀ1.20 (m, 36H), 1.18ꢀ1.12 (m, 2H), 0.90ꢀ0.85 (m,
9H); 13C NMR (100 MHz, CD3OD) δ 175.6, 131.0, 130.9, 95.3, 74.6,
73.2, 72.0, 71.6, 64.5, 64.4, 40.4, 35.2, 33.2, 31.2, 30.96, 30.90, 30.87,
30.7, 30.6, 30.5, 30.4, 30.3, 29.3, 28.7, 28.3, 26.2, 23.8, 23.2, 14.6; HRMS
calcd for C45H82O13 [M + Na]+ 853.5653, found 853.5674.
6,60-Di-O-oleoyl-2,3,4,20,30,40-hexakis-O-(trimethylsilyl)-
R,R-trehalose (6): [R]25D +71.4 (c 1, CHCl3); IR (CHCl3) ν 3020,
2856, 1733, 1252, 1215, 1168, 1111, 1078, 1044, 1008, 929, 897, 872,
1
847, 763, 669 cmꢀ1; H NMR (400 MHz, CDCl3) δ 5.40ꢀ5.30 (m,
4H), 4.92 (d, J = 3.1 Hz, 2H), 4.28 (dd, J = 11.8, 1.8 Hz, 2H), 4.06 (dd,
J = 11.8, 4.4 Hz, 2H), 4.02ꢀ3.98 (m, 2H), 3.91 (t, J = 9.0 Hz, 2H), 3.48
(t, J = 9.0 Hz, 2H), 3.44 (dd, J = 9.0, 3.1 Hz, 2H), 2.34 (dt, J = 7.5, 3.7 Hz,
4H), 2.08ꢀ1.98 (m, 8H), 1.70ꢀ1.59 (m, 4H), 1.30ꢀ1.26 (m, 40H),
0.89ꢀ0.86 (m, 6H), 0.15 (s, 18H), 0.14 (s, 18H), 0.13 (s, 18H); 13C
NMR (100 MHz, CDCl3) δ 173.9, 130.2, 129.9, 94.6, 73.7, 72.8, 72.1,
70.9, 63.5, 34.3, 32.1, 29.95, 29.90, 29.84, 29.80, 29.7, 29.6, 29.5, 29.4,
29.3, 27.39, 27.35, 24.9, 22.9, 14.3, 1.2, 1.1, 0.4; HRMS calcd for
C66H134O13Si6 [M + H]+ 1303.8518, found 1303.8485.
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra for
S
b
all compounds and 1Hꢀ H COSY spectra for compounds 4, 5, 7,
1
and 1. This material is available free of charge via the Internet at
http://pubs.acs.org.
13-Methyltetradecanoic Acid. 13-Methyltetradecanoic acid
(13-methylmyristic acid) was prepared following a procedure reported
by Foglia and Vail.47 A Wittig olefination of isobuteraldehyde with a
triphenylphosphonium iodide salt of 11-bromoundecanoate, followed
by catalytic hydrogenation of the so-formed olefin and its concomitant
hydrolysis afforded 13-methylmyristic acid in 47% overall yield: mp
51ꢀ51.7 °C (lit.47 51.5ꢀ52 °C); IR (CHCl3) ν 3300 (br), 2925, 2854,
2254, 1965, 1708, 1466, 1412, 1384, 1288, 1096, 908, 733, 651, 544,
473 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 2.34 (t, J = 7.5 Hz, 2H), 1.63
(quin, J = 7.5 Hz, 2H), 1.51 (h, J = 6.6 Hz, 1H), 1.32ꢀ1.25 (m, 16H),
1.17ꢀ1.12 (m, 2H), 0.86 (d, J = 6.6 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 180.5, 39.2, 34.3, 30.1, 29.9, 29.84, 29.79, 29.6, 29.4, 29.3,
28.2, 27.6, 24.9, 22.8; HRMS calcd for C15H30O2 [M + H]+ 243.2324,
found 243.2319.
6-O-(13-Methyltetradecanoyl)-60-O-oleoyl-2,3,4,20,30,40-
hexakis-O-(trimethylsilyl)-R,R-trehalose (7). A solution of com-
pound 5 (105 mg, 0.10 mmol) in CH2Cl2 (2.5 mL) was added to a
premixed, well-stirred solution of 13-methyltetradecanoic acid (49 mg,
0.20 mmol), DMAP (15 mg, 0.12 mmol), and DCC (90 mg, 0.41 mmol)
in CH2Cl2 (1 mL) at rt. The reaction was allowed to stir for 8 h at rt.
Solvents were evaporated in vacuo, and the crude product was purified
by silica gel column chromatography (1:19 ethyl acetate/petroleum
ether) to afford 7 as a colorless liquid (112 mg, 89%): [R]25D +72.9 (c 2,
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: suvarn@chem.iitb.ac.in.
’ ACKNOWLEDGMENT
This work was supported by the Department of Science and
Technology (Grant No. SR/S1/OC-40/2009). V.A.S. thanks
CSIR-New Delhi for a fellowship. We thank SAIF IIT-Bombay
for spectral facility.
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