Diastereoselective one-pot Wittig olefination-Michael addition and olefin cross metathesis strategy for total synthesis of cytotoxic natural product (+)-varitriol and its higher analogues

Article abstract of DOI:10.1039/c1ob06039b

A stereoselective route for the total synthesis of anticancer marine natural product (+)-varitriol (1) is detailed herein. The impressive biological activity and interesting structural features of natural (+)-varitriol fuelled us to undertake the synthesi

Full text of DOI:10.1039/c1ob06039b

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PAPER
Diastereoselective one-pot Wittig olefination–Michael addition and olefin
cross metathesis strategy for total synthesis of cytotoxic natural product
(+)-varitriol and its higher analogues†
Partha Ghosal,a Deepty Sharma,b Brijesh Kumar,b Sanjeev Meena,c Sudhir Sinhac and Arun K. Shaw*a
Received 28th June 2011, Accepted 29th July 2011
DOI: 10.1039/c1ob06039b
A stereoselective route for the total synthesis of anticancer marine natural product (+)-varitriol (1) is
detailed herein. The impressive biological activity and interesting structural features of natural
(+)-varitriol fuelled us to undertake the synthesis of some higher analogues (1a–j) of this molecule. The
key features of the synthetic strategy include one-pot Wittig olefination followed by a highly
diastereoselective oxa-Michael addition to assemble stereochemically pure tetrasubstituted THF
moiety of the natural varitriol and olefin cross metathesis to couple the aromatic part with
tetrasubstituted THF moiety. The total synthesis of title natural product is efficient with 21.8% overall
yield for 9 linear steps from D-ribose and thus facilitates the more scaled-up practical route for the
synthesis of 1 and its analogues as well. The synthetic (+)-varitriol (1) and its analogues were screened
for their cytotoxicity. The present synthetic approach paves the way for preparation of numerous
analogues of the title natural product for drug development.
Recent decades have seen cancer as the number one killer among
all the deadly diseases both in the developed and developing
countries.1 Therefore, development of novel and more selective
therapeutics for the treatment of cancer by chemical synthesis as
well as chemical modification of known structural classes have
become an important research area as it can lead to the discovery
of several promising classes of small molecules with improved
anticancer activity and also provide useful information about
the biochemistry of the cancer cell and their structure–activity
Fig. 1 Structure of natural (+)-varitriol (1) and its analogues (1a–q).
relationship.2
Natural products have since long been recognized as an invalu-
able source of lead structures in the anticancer drug discovery
Venezuelan waters ofthe Caribbean Seain2002andshowed potent
cytotoxicity toward a variety of cancer cell lines.5
field.2 A very large percentage, about 75% of anticancer agents in
clinical trials for cancer treatment are either natural products or
pharmacophores derived from natural products.3 In the recent
decades, natural products, especially marine natural products
having anticancer activity received more attention from chemists
and motivated them to develop more practical and scalable total
syntheses of these natural products as well as their novel analogues
for improved activity.2 (+)-Varitriol4 (1, Fig. 1) is such a marine
natural product isolated by Barrero et al. from a marine strain
(named M75-2) of the fungus Emericella variecolor, collected in
The potent anticancer activity of natural (+)-varitriol (1), a more
than 100-fold increased potency (over the mean toxicity) toward
the RXF 393 (renal cancer, GI50 = 1.63 ¥ 10-7 M), SNB-75 (CNS
cancer, GI50 = 2.44 ¥ 10-7 M) and T-47D (breast cancer, GI50
=
2.10 ¥ 10-7 M) cell lines has attracted an immense synthetic interest
from synthetic community. As a result several elegant approaches
toward the total synthesis of (+) and (-)-varitriol as well as its
analogues have been reported to date.
In 2006 Clemens et al.6 disclosed the total synthesis of unnatural
(-)-varitriol from D-(-)-ribose by utilizing olefin cross metathesis
as the key step. Subsequently in that year the Taylor group7
reported the total synthesis of unnatural (-)-varitriol and (-)-
3¢-epi-varitriol via a Ramberg–Ba¨cklund route from D(-)-ribose.
The first total synthesis of natural (+)-varitriol was achieved by
our group involving a highly diastereoselective iodocyclization
reaction for the construction of tetrasubstituted THF part of
aDivision of Medicinal and Process Chemistry, Central Drug Research
Institute (CDRI), CSIR, Lucknow, 226 001, India
bSophisticated Analytical Instrument Faculty, Central Drug Research Insti-
tute (CDRI), CSIR, Lucknow, 226 001, India
cDrug Target Discovery and Development, Central Drug Research Institute
(CDRI), CSIR, Lucknow, 226 001, India
† Electronic supplementary information (ESI) available: 1H (1D and 2D),
13C NMR spectra and GC chromatograms. See DOI: 10.1039/c1ob06039b
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the natural product which was later coupled with the required
aromatic moiety by olefin cross- metathesis.8 Gracza et al. reported
the synthesis of (+)-1 by applying Kocien´ski-Julia olefination of
sulfonyl furan derivative with corresponding aromatic aldehyde.9
Ghosh and coworkers disclosed the synthesis of both (+) and (-)-
1 and their epimers by using Heck coupling between the olefinic
sugar moiety and the aromatic triflate.10
Brichacek et al. furnished a report on synthesis of (+)-varitriol
by copper catalyzed vinyl oxirane ring expansion reaction and
Julia olefination.11 Latter Srinivas et al. reported two synthetic
strategies toward (+)-1 by using olefin cross metathesis strategy
starting from D(-)-ribose and ethyl (S)- lactate respectively.12
Recently Zeng et al. described an efficient total synthesis of (+)-1
in which the THF part was constructed by BF3·Et2O promoted
coupling of ethynyltrifluoroborate with glycosyl fluoride, derived
from D(-)-ribose and later it was linked with the corresponding
aromatic triflate by utilizing Sonogashira cross-coupling.13 Very
recently Gracza et al. reported a total synthesis of natural varitriol
from D-ribonolactone by utilizing Julia-Kocien´ski olefination.14
Furthermore, synthetic analogues of (+)-1 were also reported by
various approaches.15
In spite of promising biological activity of (+)-varitriol, its
mode of action is still unknown. To the best of our knowledge,
the synthesis and screening of unprotected analogues of natural
varitriol have not yet been reported. Therefore, the impressive
biological activity, interesting structural features, natural scarcity,
lack of literature report on cytotoxicity of unprotected (+)-
varitriol analogues and also as a result of our interest toward the
utilization of carbohydrate-based chiral building blocks (CBBs)16
for the synthesis of natural product or biologically important
molecules8,17 motivated us to synthesize natural (+)-varitriol and
its higher analogues for anticancer drug development through
high efficiency chemical synthesis. Herein, we wish to disclose a
short and efficient route for second generation synthesis of (+)-
varitriol from D-ribose in which the construction of the THF part
was achieved by an efficient one-pot Wittig olefination and highly
diastereoselective intramolecular oxa-Michael addition followed
by coupling with the aromatic part by olefin cross metathesis
reaction. Synthesis of some analogues of this natural product was
also completed by the similar strategy.
furanoside 4 involving the olefin cross metathesis strategy. The
latter, which have all the four streocentres identical to that of
natural (+)-varitriol could be obtained from tosytate 5 by reductive
elimination of the tosyl group. Tosylate 5 could be derived from
the methyl ester 7 by LiAlH4 reduction followed by tosylation
of the resulting alcohol 6. The ester 7 whose synthesis could be
possible from lactol 8 by its Wittig olefination followed by oxa-
Michael addition and lactol 8 which in turn could be prepared
easily from 2,3-O-isopropylidine-D-ribose 10 by methyl Grignard
addition followed by NaIO4 mediated oxidative cleavage.
Thus, as per the retrosynthesis shown above, the stereochem-
ically pure tetrasubstituted THF subunit 4 was synthesized
from 2,3-O-isopropylidine-D-ribose18 10 which could be easily
prepared from commercially available inexpensive D-ribose. The
treatment of 2,3-O-isopropylidine-D-ribose with an excess methyl
◦
magnesium bromide in diethyl ether at -50 C to rt afforded the
triol 9 which on oxidative cleavage with NaIO4 without further
purification furnished the known lactol 812,19 in 64% yield over
two steps (Scheme 2). A solution of lactol 8 in CH3CN was then
subjected to undergo Wittig olefination on reflux with methyl
(triphenyl-phosphoranylidene)acetate at 110 ◦C for 2 h. Presuming
that open chain intermediates (8a) could have been formed,
refluxing of the same reaction mixture was continued overnight
to facilitate the intramolecular oxa-Michael addition to obtain
THF derivative 7.20 However, the cyclization was not completed
even after overnight refluxing.
Scheme 2 One-pot Wittig and oxa-Michael addition reaction. Reagent
and conditions: (a) 2,2-dimethoxypropane, acetone, PTSA, 0 ◦C, 2h, 90%;
(b) MeMgBr, -50 ◦C to rt, 12 h; (c) NaIO4, THF–H2O, 4 h, rt, 64% over
two steps; (d) Ph3P CHCO2Me, acetonitrile, 110 ◦C, 2 h then K2CO3, rt,
4 h, 91%.
The retrosynthetic strategy for (+)-varitriol (1) is depicted
in Scheme 1. We envisaged that 1 could be elaborated from
protected varitriol 2 by acetonide deprotection which could in
turn be prepared by coupling the aromatic part 3 with the vinylic
We, then, decided to use a weak base like NaHCO3 or K2CO3
to complete the cyclization of the Wittig intermediate. Among
these two weak bases used, K2CO3 was found to be the best in
terms of yield of 7. Thus, after completion of Wittig olefination
(2h, TLC control) K2CO3 was added to the stirred solution of the
reaction mixture in CH3CN. The stirring was continued for 4 h
to obtain the cyclized Wittig product 7 in 91% yield with high
diasteroselectivity (>99%, determined by GC) (Scheme 2). The
stereochemistry of the newly created chiral centre was established
on the basis of its NOE spectrum (Fig. 2) that led to confirm the
presence of same stereochemistry as required for the synthesis
of natural (+)-varitriol. Thus, we have developed an efficient
one-pot Wittig olefination/oxa-Michael addition procedure to
obtain the stereochemically pure tetrasubstituted THF core 7
and the reaction was very efficient even in multigram scale. The
Scheme 1 Retrosynthetic analysis of (+)-varitriol (1).
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with methyl iodide and potassium carbonate in acetone afforded
3, the methylation of the diol 13 with MeI in the presence of
sodium hydride in DMF furnished the corresponding dimethoxy
derivative 14 which was used later (Scheme 4).
Having two types of building blocks, 3 and 4 in our hand,
coupling of the styrene 3 with the vinylic furanoside 4 was carried
out by olefin cross metathesis reaction and the beneficial result
was obtained when 4 was treated with 2-fold excess of 3 in the
presence of Grubbs’ second generation catalyst (6 mol %) in dry
DCM under refluxing condition to furnish exclusively E isomer
of the cross coupled product 2 in 62.4% yield.
Finally, the natural (+)-varitriol (1) was obtained in 90% yield by
exposing the cross coupled product 2 to aqueous HCl. The spectral
and analytical data were in close agreement with the reported
values.4
Fig. 2 Conformationl analysis and NOE correlations for compound 7.
high diastereoselective cyclization of the intermediate 8a may be
attributed to the isopropylidene protection in 8. Our argument
can be rationalized on the basis of the fact that the favorable
conformation (A) of 8a with Z-geometry20b was involved in this
process leading to the formation of 2,5 cis fused adduct 7 through
Re- face attack. The severe A1,3 strain in the conformer (B) makes
it unfavorable and therefore cannot take part in the cyclization to
give trans fused adduct 7a(Fig. 2).20c
To complete the synthesis of compound 4, LiAlH4 reduction of
the ester 7 furnished alcohol 6 in 91% yield (Scheme 3). Tosylation
of the alcohol 6 with tosyl chloride in the presence of triethylamine
afforded tosylate 5 in 96% yield and its subsequent treatment with
tBuOK afforded the vinylic furanoside 4 in good yield.17g It is worth
mentioning that the vinylic furanoside 4 was slightly volatile and
therefore the work-up and purification process were done below
30 ◦C.
The unique biological activity of (+)-varitriol with still unde-
fined mode of action has produced diverse interests in this natural
product, which deserve more comprehensive studies pertaining
to anticancer drug development on this molecule. Lack of
literature report about the cytotoxicity of unprotected (+)-varitriol
analogues and also as a result of our interest toward the synthesis
of natural products or natural product like molecules8,17 inspired
us to synthesize some higher analogues of natural (+)-varitriol
(1). Therefore, after completion of the total synthesis of (+)-
varitriol (1), we focused our attention toward the synthesis of
some higher analogues and their biological screening. First, we
thought to replace the methyl group in natural varitriol by an
ethyl group keeping the aromatic part same and in our subsequent
strategy we thought to change aromatic part to monitor the effect
of these changes on cytotoxicity of the new varitriol analogues.
Thus, we followed the same synthetic strategy as discussed above
to complete the synthesis of (+)-varitriol (1) that involved one-pot
Wittig olefination followed by oxa-Michael addition sequence to
obtain ethyl containing vinylic furanoside part and afterwards its
coupling with the styrenes by olefin cross metathesis reaction.
The general retrosynthetic strategy for varitriol analogues is
shown in Scheme 6. We envisaged that 1a–n could be elaborated
from protected varitriol analogues 15 by their acetonide deprotec-
tion which could in turn be prepared by coupling between aromatic
and carbohydrate portions 17 and 16 respectively, involving
the olefin cross metathesis strategy. The carbohydrate fragment
16, having all the four stereocentres similar to that of natural
(+)-varitriol could be obtained from alcohol 19 by oxidation
followed by Wittig methylination. Synthesis of alcohol 19 could
be possible from the ester 23 that could be obtained from 2,3-
O-isopropylidine-5-O-tetr-butyldimethyl silyl-D-ribose 24 which
in turn could be easily prepared from commercially available
inexpensive D-ribose.
Scheme 3 Synthesis of vinylic furanoside 4. Reagent and conditions: (a)
LiAlH4, Dry THF, 0 ◦C to rt, 2 h, 91%; (b) TsCl, Et3N, dry DCM, 0 ◦C to
rt, 4 h, 96%; (c) tBuOK, Dry THF, -20 ◦C to rt, 12 h, 85%.
With the furanoside part 4 in hand, our next attempt was
focused toward the construction of substituted styrene 3.8 Its
synthesis was initiated from commercially available phenolic acid
11. The Stille cross-coupling reaction21 of the intermediate triflate
1222,23 with tributylvinyl tin (TBVT) in the presence of tetrakis
(triphenyl- phosphine)palladium(0) and lithium chloride followed
by LiAlH4 reduction24 furnished the diol 13 (Scheme 4). While
the selective methylation of the phenolic alcohol 13 by treating it
Scheme 4 Synthesis of styrene 3 and 14. Reagent and conditions: (a) & (b)
Ref. 22, 23; (c) Ref. 8, MeI, K2CO3, dry acetone, rt, 88%; (d) MeI, NaH,
dry DMF, 0 ◦C to rt, 85%.
Scheme 5 Synthesis of (+)-varitriol (1). Reagent and conditions: (a)
Grubbs’ second generation catalyst (6 mol%), dry DCM, 50 ◦C, 32 h,
62.4%; (b) 1 N HCl, THF, rt, 6 h, 90%.
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subsequent treatment with LiAlH4 afforded the furanoside 20 in
72% yield (Scheme 8).17b Its TBS deprotection with TBAF in
THF furnished the alcohol 19 in 90% yield. Its oxidation with
IBX in acetonitrile under refluxing condition yielded the aldehyde
18 which was directly used for the next step without further
purification. Wittig olefination of the aldehyde 18 furnished the
desired vinylic furanoside 16, which was structurally very closely
related to the THF portion of (+)-varitriol (1).
Scheme 6 General retrosynthetic analysis of (+)-varitriol analogues.
The primary hydroxyl group of 2,3-O-isopropylidine-D-ribose
was protected as silyl ether by using TBDMSCl and imidazole
to give the known hemiacetal 2418 in 90% yield. A solution
of hemiacetal 24 in CH3CN was subjected to undergo Wittig
olefination with methyl (triphenyl-phosphoranylidene)acetate at
110 ◦C and in this case also cyclization of the open chain
intermediate 23a was not completed even after overnight refluxing
(Scheme 7).
Scheme 8 Synthesis of vinylic furanoside, 16 for varitriol analogues.
Reagent and conditions: (a) LiAlH4, dry THF, 0 ◦C to rt, 2 h; (b) TsCl,
Et3N, dry DCM, 0 ◦C to rt, 4 h; (c) LiAlH4, Dry THF, -20 ◦C to rt, 2
h; (d) TBAF, THF, 0 ◦C to rt, 2 h; (e) IBX, Acetonitrile, 100 ◦C, 1 h; (f)
Ph3P CH2, dry THF, -20 ◦C to 0 ◦C, 2 h.
It should be noted here that the vinylic furanoside 16 was slightly
volatile and therefore the work-up and purification process were
done below 30 ◦C. With the furanoside part in hand, our next
attempt was focused toward the coupling of two types of building
blocks, vinylic furanoside 16 and styrenes (3, 14, 17a–i) (Fig. 4).
Scheme 7 One-pot Wittig and oxa-Michael addition reaction of 24.
Reagent and conditions: (a) 1) 2,2-dimethoxypropane, acetone, PTSA,
0
◦C, 2 h, 90%; 2) TBDMSCl, imidazole, dry DCM, 0 ◦C, 2 h, 90%;
(b) Ph3P CHCO2Me, CH3CN, 110 ◦C, 2 h then dry K2CO3, rt, 4 h, 87%.
We then decided to go through our standardized procedure
as discussed above. Thus, after completion of Wittig olefination
(2 h, TLC control), the reaction mixture was cooled to room
temperature and then K2CO3 was added to the stirred solution
of the reaction mixture in CH3CN. The stirring was continued
for 6 h to obtain the cyclized Wittig product 23 in a very good
yield and with high diastereoselectivity (>99%, determined by
GC) (Scheme 7). The stereochemistry of the newly created chiral
centre was established on the basis of its NOE spectrum (Fig. 3).
Fig. 4 Structures of various styrenes used for cross metathesis reaction.
Now, the coupling of vinylic furanoside 16 with styrenes (3, 14,
17a–i), should furnish the desired protected varitriol analogues.
Thus, when the cross metathesis of 16 with the above styrenes was
carried out in the presence of Grubbs’ second generation catalyst
(5 mol %) in dry DCM under refluxing condition, the acetonide
protected varitriol analogues 15a–i were obtained. In this study
the styrenes 17a and 17b did not undergo cross metathesis
reaction (Scheme 9). Since the metathesis reaction proceeds under
thermodynamic control,25 the yield and stereoselectivity of a cross
metathesis reaction can be improved by increasing the equivalent
of one alkene and the reaction time. Thus, from our previous
experiences,17a,b,c,f the best results were obtained when the ratios
3 : 16 = 2 : 1, 14 : 16 = 2 : 1 and 17c–i : 16 = 4 : 1 were maintained to
obtain exclusively E isomer in all the cases (Table 1).
Fig. 3 NOE correlations for compound 23.
Some interesting cytotoxic natural products with long hydro-
carbon chain in nature26 inspired us to synthesize one varitriol
analogue by replacing aromatic portion with a long hydrocar-
bon chain. Therefore, the cross-coupling reaction of the vinylic
To complete the synthesis of compound 16, the ester 23 was
reduced with LiAlH4 to furnish alcohol 22 in 87% yield. Its
tosylation furnished the tosylate 21 in 87% yield (Scheme 3) whose
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Table 1 Optimization of cross metathesis reaction of 16 with styrenes (3, 14, 17c–j) in DCM under refluxing condition in presence of Grubbs’ second
generation catalyst (5 mol%)
Entry
Equiv. of 16
Styrene
Equiv. of styrene
Time/h
Product
Yield (%)
1
2
3
4
5
6
7
8
1.5
1.5
1
1
1
1
1
1
1
3
1
1
4
4
4
4
4
4
4
6
12
12
18
18
18
24
24
24
24
6
15a
15b
15c
15d
15e
15f
15g
15ha
15i
70
14
NCb
74
17c
17d
17e
17f
17g
17h
17i
17j
64.4
NCb
90
NCb
81
9
10
NCb
81
1
15j
a Compound 15h was not so stable and it was used immediately for the next step after it’s purification; b NC = In case of 15b, 15e, 15g and 15i the desired
cross metathesis products were formed along with the aromatic dimers which were not separated by silica gel column chromatography and so the yields
are not calculated for this step.
The deprotection of acetonide derivatives 15a–j should now
furnish the target molecules 1a–j, structurally closely related to
natural (+)-varitriol (1) (Fig. 5). Thus, the unprotected analogues
1a–j (Fig. 5) were obtained by exposing their respective precursors
15a–j to aqueous HCl (Scheme 10). As shown in the Table 1, the
cross metathesis products 15b, 15e, 15g and 15i were obtained as
inseparable mixture with some unidentified side products on silica
gel column chromatography. However, the desired products were
separated and purified after the treatment of each of the mixtures
with aqueous HCl. The conditions and yields for acetonide
deprotection are given in Table 2.
Scheme 9 Synthesis of protected varitriol analogues 15a–j via olefin cross
metathesis reaction.
Fig. 5 Varitriol analogues (1a–i and 1q) after acetonide deprotection.
furanoside 16 with 1-pentadecene (17j) in presence of Grubbs’
second generation catalyst (5 mol %) furnished 15j (17j : 16 = 6 : 1)
(Scheme 9).
The natural (+)-varitriol was tested in the National Cancer
Institute (NCI) 60-cell-line in vitro panel and showed activity
Table 2 Reaction conditions and yield for acetonide deprotection reaction of compounds 16a–i and 16q
Entry
CM product
Time/h
Temp./◦
C
HCl strength
Product
Yield (%)
1
2
3
4
5
6
7
8
15a
15b
15c
15d
15e
15f
15g
15h
15i
8
8
30
30
30
30
30
30
30
0–10
30
60
2 N
2 N
2 N
2 N
2 N
2 N
2 N
1 N
2 N
6 N
1a
1b
1c
1d
1e
1f
82
43a
89
12
12
12
12
12
4
71
40a
73
1g
1h
1i
44a
69
9
10
8
12
44a
64
15j
1j
a Yield over two steps, i.e. cross metathesis and acetonide deprotection.
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project on biological activity and drug discovery under CDRI drug
development programme which will be presented in due course.
Experimental
General
Scheme 10 Acetonide deprotection of varitriol analogues 15a–i and 15q.
Organic solvents were dried by standard methods. NMR spectra of
the synthesized compounds were recorded on Bruker Avance DPX
200FT, Bruker Robotics, and Bruker DRX 300 Spectrometers at
200, 300 MHz (1H) and 50, 75 MHz (13C) respectively. Experiments
were recorded in CDCl3 and CD3OD at 25 ◦C. Chemical shifts are
given on the d scale and are referenced to the TMS at 0.00 ppm
for proton and 0.00 ppm for carbon. Reference CDCl3 for 13C
NMR appeared at 77.4 ppm. Using DART and ESI mode mass
spectra were recorded on a JEOL ACCUTOF DARTMS and 6520
Accurate Mass Q-TOF LC/MS high resolution spectrometer and
IR spectra on Perkin–Elmer 881 and FTIR-8210 PC Shimadzu
Spectrophotometers. Optical rotations were determined on an
Autopol III polarimeter using a 1 dm cell at 28 ◦C in chloroform
as the solvents; concentrations mentioned are in g/100 mL. The
Auto System XL GC spectrum was recorded on Parkin Elmer
Instrument on OB-1 column (10 feet) within temperature range
50 ◦C to 200 ◦C with a temperature rising rate 4 ◦C/min and
hold time 3 min. Analytical TLC was performed using 2.5 ¥ 5 cm
plates coated with a 0.25 mm thickness of silica gel (60F-254), and
visualization was accomplished with CeSO4 (1% in 2 N H2SO4)
followed by charring over hot plate. Silica gel (100–200 and 230–
400 mesh) was used for column chromatography. All the products
against RXF 393 (renal cancer), T-47D (breast cancer), SNB-75
(CNS cancer), DU-145 (prostate cancer), HL-60 (TB) (leukemia),
CCRFCEM (leukemia), OVCAR-5 (ovarian cancer), SNB-19
(CNS cancer), and COLO 205 (colon cancer) cell lines and was
inactive against the remaining cell lines at a concentration of 10-4
M.4 The synthetic natural varitriol (1) and its newly synthesized
higher analogues (1a–j) described herein were screened for their
cytotoxicity against KB (Oral squamous cell carcinoma), C-33A
(Cervical cancer), MCF-7 (Breast cancer), A-549 (Lung carci-
noma), NIH/3T3 (Mouse embryo fibroblast) cell lines according
to the reported screening protocol (see ESI†) but they did not
show any significant cytotoxicity (IC50 > 20 mM) against any of
these cell lines.
Conclusion
Our laboratory had previously succeeded in first total synthesis
of natural (+)-varitriol (1)8 and now we have achieved a greatly
improved short and efficient second generation route for the total
synthesis of natural (+)-varitriol from D-ribose. Here we have
accomplished the construction of the tetrasubstituted furanoside
part 4 of the title natural product by one-pot Wittig olefination
followed by diastereoselective oxa-Michael addition of lactol 8
with 21.8% overall yield for 9 linear steps from D-ribose. Our
synthetic protocol that involved one-pot Wittig/oxa-Michael ad-
dition reactions to obtain stereochemically pure densely function-
alized tetrahydrofurans (7 and 23) with four/five point diversity
(Fig. 6) did not require dry condition and was very efficient, even
on multigram scale, with high diasteroselectivity (>99%). The
coupling between THF subunit 4 with aromatic counterpart 3
has been successfully achieved by utilizing olefin cross metathesis
strategy and in every case the E isomer was formed exclusively.
1
were characterized by H, 13C, IR, ESI-MS spectroscopy. Low-
temperature reactions were performed by using immersion cooler
with ethanol as the cooling agent. Grubbs’ second generation
catalyst was purchased from Sigma–Aldrich Co.
General procedure for preparation of compound 10
D-Ribose (10 g, 66.2 mmol) and 2,2-dimethoxypropane (12.2 mL,
99.3 mmol) were taken in dry acetone (50 mL) and the mixture was
cooled to 0 ◦C. A catalytic amount of p-toluenesulfonic acid (1.5 g)
was added to the mixture and it was stirred for 2 h at 0 ◦C. After
completion of the reaction, the reaction mixture was quenched
with Et3N and the mixture was evaporated under reduced pressure
to give an oily residue. Water (80 ml) was added to it and
extracted with EtOAc (3 ¥ 60 mL). The combined organic layer was
washed once with water, dried over Na2SO4 and evaporated under
reduced pressure to obtain a residue. Column chromatographic
purification of the residue yielded compound 2,3-O-isopropylidine
D-ribose, 1017 as an oil (11.31 g, 59.60 mmol, 90%).
Fig. 6 Sites of diversification in the synthesized THF core.
By applying this convergent strategy we also synthesized some
higher analogues (1a–j) of cytotoxic marine natural product (+)-
varitriol and screened them for their cytotoxicity against KB
(oral squamous cell carcinoma), C-33A (cervical cancer), MCF-7
(breast cancer), A-549 (lung carcinoma) and NIH/3T3 (mouse
embryo fibroblast) cell lines. The synthetic varitriol (1) and its
analogues reported in this publication were found to be inactive
against the above mentioned cell lines. The flexibility of this syn-
thetic strategy gives us the opportunity to rapid library generation
of numerous varitriol analogues, keeping the furanoside part struc-
turally same as present in natural (+)-varitriol, for our ongoing
General procedure for preparation of lactol 8
To a stirred solution of MeMgI (82.1 mL, 246.3 mmol)], 2,3-
O-isopropylidene-D-ribofuranose 10 (5.2 g, 27.37 mmol) in ether
(15 mL) was added at -50 ◦C and the stirring was continued for 6 h
at this temperature. The reaction mixture was then slowly warmed
to rt and stirred for another 12 h. Afterward it was quenched with
saturated aqueous NH4Cl (25 mL) and extracted with EtOAc (5 ¥
50 mL). The combined organic layer was dried over Na2SO4 and
concentrated under reduced pressure. The crude triol 9 was used
for the next step without further purification.
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To the above obtained crude triol 9 dissolved in THF/H2O
(10 : 1, 50 mL) was added NaIO4 (7.72 g, 36 mmol) at 0 C and
(1.23 g, 6.4 mmol) was added to the reaction mixture portion wise
and stirring was continued for one hour at the same temperature
and afterwards for 3 h without cooling. After completion of
the reaction, a saturated aqueous solution of NH4Cl (15 mL)
was added and the resulting solution was extracted with CH2Cl2
(4 ¥ 20 mL). The combined organic phase was dried over Na2SO4
and the solvent was removed under reduced pressure. Column
chromatographic purification of the residue furnished 5 as an oil
(1.1 g, 3.09 mmol, 96%).
◦
stirred for 5 h without further cooling. The reaction mixture was
quenched with saturated Na2S2O3 (30 mL) and extracted with
EtOAc (2 ¥ 50 mL). The combined organic layer was dried over
Na2SO4, and concentrated under reduced pressure to give a residue
which after column chromatographic purification afforded lactol
8
12,19 (3.05 g, 17.52 mmol, 64% over two steps) as pale yellow liquid.
Eluent for column chromatography: EtOAc/hexane (1 : 9, v/v);
[a]2D8 +6.4 (c 1.00, CHCl3); Rf 0.44 (1 : 4, EtOAc/hexane); IR
(neat, cm-1): 2982, 2931, 2369, 2339, 1599, 1458, 1363; 1H NMR
(300 MHz, CDCl3) d 1.19(d, J = 6.4, 3H), 1.27 (s, 3H), 1.47 (s, 3H),
1.80–1.87 (m, 1H), 1.98–2.05 (m, 1H), 2.42 (s, 3H), 3.71–3.80 (m,
2H), 4.08–4.19 (m, 3H), 4.26–4.30 (m, 1H), 7.31 (d, J = 8.0 Hz,
2H), 7.77 (d, J = 8.3 Hz, 2H); 13C NMR (75 MHz, CDCl3) d
19.1 (CH3), 21.9 (CH3), 25.8 (CH3), 27.6 (CH3), 33.2 (CH2), 67.5
(CH2), 80.40 (CH), 80.43 (CH), 85.3 (CH), 86.4 (CH), 115.4 (qC),
128.3 (2 ¥ Ar-CH), 130.1 (2 ¥ Ar-CH), 133.4 (Ar-qC), 145.0 (Ar-
qC); DART-HRMS: m/z [M+H]+ Calcd for C17H25O6S 357.1372,
found 357.1378.
Compound 7
To a solution of lactol 8 (304 mg, 1 mmol) in acetonitrile (5 mL),
Ph3P CHCO2Me (500 mg, 1.5 mmol) was added and the reaction
mixture was allowed to stir under reflux (110 C) for 2 h. After
◦
completion of the Wittig olefination (TLC control), the reaction
mixture was cooled to room temp., K2CO3 (276 mg, 2 mmol)
was added to it and left for stirring at this temperature. After
4 h, water (10 ml) was added to the reaction mixture and was
extracted with EtOAc (3 ¥ 15 mL). The combined organic layer
was evaporated under reduced pressure to get an oily residue which
after column chromatographic purification afforded compound 7
(327 mg, 0.91 mmol, 91% from 8) as a colorless oil.
Eluent for column chromatography: EtOAc/hexane (1 : 11,
Compound 4
v/v); [a]2D8 +2.5 (c 1.76, CHCl3); Rf 0.75 (1 : 4, EtOAc/hexane);
1
IR (neat, cm-1): 2982, 2932, 2364, 1740, 1375, 1244; H NMR
The tosylate 5 (500 mg, 1.4 mmol) was dissolved in dry THF
(30 mL) and cooled to -30 ◦C. To the cooled solution was
(300 MHz, CDCl3) d 1.19(d, J = 6.4, 3H), 1.24 (s, 3H), 1.44 (s,
3H), 2.47–2.63 (m, 2H), 3.60 (s, 3H), 3.81–3.90 (m, 1H), 4.07–
4.13 (m, 1H), 4.17–4.21 (m, 1H), 4.41 (dd, J = 4.7, 6.9 Hz, 1H);
13C NMR (75 MHz, CDCl3) d 19.1 (CH3), 25.7 (CH3), 27.5 (CH3),
38.4(CH2), 51.8 (CH), 80.3 (CH), 80.5 (CH), 84.8(CH), 86.3 (CH),
115.0 (qC), 170.9 (C O); DART-HRMS: m/z [M+H]+ Calcd for
C11H19O5 231.1232, found 231.1230.
t
added BuOK (400 mg, 3.6 mmol) portion wise over a period
of about 2 h. The resulting reaction mixture was allowed to
stir at this temperature for another 4 h and then left stirring
overnight without cooling. After completion of the reaction, the
reaction mixture was quenched by addition of aqueous NH4Cl
solution (20 ml) and was extracted with DCM (3 ¥ 20 mL). The
combined organic phase was evaporated under reduced pressure
and purified by column chromatography to afford compound 4
(219 mg, 1.19 mmol, 85%). Here all the workup, purification and
evaporation of column fractions were done below 30 ◦C.
Compound 6
The ester 7 (500 mg, 2.17 mmol) was dissolved in dry THF (10 mL)
and cooled to 0 ◦C. To this cooled solution was added LiAlH4
(124 mg, 3.26 mmol) in 3 portions over a period of about 5 min. The
resulting reaction mixture was allowed to stir at 0 ◦C for 1 h and
then left stirring for another 1 h without cooling. After completion
of the reaction, excess LiAlH4 was quenched by addition of EtOAc.
The reaction mixture was then passed through a short silica gel bed
and washed with EtOAc (3 ¥ 10 mL). The combined organic layer
was evaporated under reduced pressure and purified by column
chromatography to afford compound 6 (400 mg, 1.97 mmol, 91%).
Eluent for column chromatography: EtOAc/hexane (1 : 6, v/v);
[a]2D8 +7.0 (c 0. 896, CHCl3); Rf 0.33 (1 : 4, EtOAc/hexane);
Eluent for column chromatography: EtOAc/hexane (1 : 13,
v/v); [a]2D8 +5.1 (c 0.345, CHCl3); Rf 0.45(1 : 4, EtOAc/hexane); IR
(neat, cm-1): 2981, 2931, 2365, 1376, 1218; H NMR (300 MHz,
1
CDCl3) d 1.29–1.31(m, 6H), 1.52 (s, 3H), 3.93–4.01(m, 1H), 4.22–
4.29 (m, 2H), 4.42 (dd, J = 5.1, 6.8 Hz, 1H), 5.19 (d, J = 10.4 Hz,
1H), 5.35 (d, J = 17.2 Hz, 1H), 5.82–5.94 (m, 1H); 13C NMR
(75 MHz, CDCl3) d 19.3 (CH3), 25.8 (CH3), 27.7 (CH3), 80.5 (CH),
85.3 (CH), 85.7 (CH), 86.5 (CH), 115.2 (qC), 117.5 (CH2), 136.4
(CH); DART-HRMS: m/z [M+H]+ Calcd for C10H17O3 185.1178,
found 185.1160.
1
IR (neat, cm-1): 3423, 2980, 2931, 2361, 1378, 1214; H NMR
(300 MHz, CDCl3) d 1.26(d, J = 6.4, 3H), 1.28 (s, 3H), 1.48 (s,
3H), 1.75–1.91 (m, 2H), 2.61 (br m, 1H), 3.71–3.75 (m, 2H),
3.86–3.91 (m, 2H), 4.21 (dd, J = 5.0, 7.0, 1H), 4.33–4.37 (m,
1H); 13C NMR (75 MHz, CDCl3) d 19.3 (CH3), 25.8 (CH3), 27.6
(CH3), 36.1 (CH2), 60.7 (CH2), 80.6 (CH), 83.5 (CH), 85.4 (CH),
86.3 (CH), 115.4 (qC); DART-HRMS: m/z [M+H]+ Calcd for
C10H19O4 203.1283, found 203.1281.
Compound 2
Under argon atmosphere Grubbs’ second generation catalyst
(28 mg, 0.0335 mmol) was added to a 50 mL oven dried two necked
round bottomed flask fitted with a reflux condenser and septum.
Dry CH2Cl2 (2 mL) was added to the flask through a syringe and
the solution was kept for stirring. Vinylic furanoside 4 (100 mg,
0.54 mmol) and the alkene 3 (180 mg, 1.1 mmol) in DCM (2 mL
each) were added in succession through a syringe to the reaction
mixture. The septum was replaced with a glass stopper while the
stirring was continued. The solution was refluxed for 32h. After
completion of the reaction, the organic solvent was evaporated
Compound 5
To a stirred solution of alcohol 6 (650 mg, 3.21 mmol) in dry
DCM (10 mL) at 0 ◦C Et3N (1.3 mL, 9.3 mmol) was added. TsCl
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under reduced pressure to give a black residue which was purified
by column chromatography to give compound 2 as an oil (108 mg,
0.337 mmol, 62.4% from alkene 4).
mixture was cooled to room temp., K2CO3 (276 mg, 2 mmol) was
added to it and left for stirring at this temperature. After 4 h,
water (10 ml) was added to the reaction mixture which was then
extracted with EtOAc (3 ¥ 15 mL). The combined organic layer
was evaporated under reduced pressure to get an oily residue which
after column chromatographic purification afforded compound 23
(312 mg, 0.87 mmol, 87% from 24) as a colorless oil.
Eluent for column chromatography: EtOAc/hexane (1 : 3, v/v);
[a]2D8 +17.1 (c 0.375, CHCl3); Rf 0.42 (1 : 3, EtOAc/hexane); IR
1
(neat, cm-1): 3457, 2931, 2371, 1580, 1219; H NMR (300 MHz,
CDCl3) d 1.36–1.38 (m, 6H), 1.59 (s, 3H), 2.30 (brm, 1H, OH),
3.87 (s, 3H), 4.02–4.10 (m, 1H), 4.35 (dd, J = 4.7, 6.9 Hz, 1H),
4.44–4.48 (m, 1H), 4.54–4.58 (m, 1H), 4.80 (s, 2H), 6.17 (dd, J =
6.6, 15.8 Hz,1H), 6.83 (d, J = 8.0 Hz, 1H), 7.05–7.11 (m, 2H),
7.22–7.28 (m, 1H); 13C NMR (75 MHz, CDCl3) d 19.4 (CH3),
25.9 (CH3), 27.7 (CH3), 56.0 (CH), 57.1 (CH2), 80.7 (CH), 85.2
(CH), 85.9 (CH), 86.6 (CH), 110.1 (CH), 115.4 (qC), 119.7 (CH),
126.8 (Ar-qC), 129.2 (Ar-CH), 129.8 (Ar-CH), 131.1 (Ar-CH),
137.7 (Ar-qC), 158.4 (Ar-qC); DART-HRMS: m/z [M]+ Calcd for
C18H24O5 320.1624, found 320.1609.
Eluent for column chromatography: EtOAc/hexane (1 : 15,
v/v); [a]2D5 -17.9 (c 1.135, CHCl3); Rf 0.64 (1 : 4, EtOAc/hexane);
1
IR (neat, cm-1): 2936, 2365, 1740, 1465, 1378, 1218; H NMR
(300 MHz, CDCl3) d 0.05 (s, 6H), 0.89 (brs, 9H), 1.33 (s, 3H), 1.52
(s, 3H), 2.61–2.64 (m, 2H), 3.68–3.69 (m, 5H), 4.06 (dd, J = 3.25,
6.51 Hz, 1H), 4.28–4.34 (m, 1H), 4.41 (dd, J = 4.50, 6.24 Hz, 1H),
4.65 (dd, J = 3.05, 6.37 Hz, 1H); 13C (75 MHz, CDCl3) d -5.1
(CH3), -5.0 (CH3), 18.7 (qC), 25.9 (CH3), 26.3 (3 ¥ CH3), 27.8
(CH3), 39.0 (CH2), 52.1 (CH3), 64.2 (CH2), 81.6 (CH), 82.4 (CH),
85.0 (CH), 85.3 (CH), 114.2 (qC), 171.5 (C O); IR (neat, cm-1):
3021, 2936, 2365, 1740, 1650, 1218; ESI-HRMS: m/z [M+H]+
Calcd for C17H33O6Si 361.2046, found 361.2028.
Compound 1
A solution of compound 2 (80 mg, 0.25 mmol) in THF (5 mL)
was stirred with 1 N HCl (5 mL) for 4 h at room temperature.
After completion of the reaction, EtOAc (10 ml) was added to it
and the resulting mixture was extracted with EtOAc (3 ¥ 10 mL).
The combined organic layer was then washed with water, dried
over Na2SO4 and concentrated under reduced pressure to give a
residue which was purified by column chromatography to obtain
(+)-varitriol (1) as a semisolid (63 mg, 0.225 mmol, 90%).
Compound 22
The ester 23 (500 mg, 1.39 mmol) was dissolved in dry THF
(10 mL) and cooled to 0 ◦C. To the cooled solution was added
LiAlH4 (80 mg, 2.1 mmol) in 3 portions over a period of about
5 min. The resulting reaction mixture was allowed to stir at 0 ◦C
for 1 h and then left stirring for another 1 h without cooling.
After completion of the reaction, excess LiAlH4 was quenched by
addition of EtOAc. The reaction mixture was then passed through
a short silica gel bed and washed with EtOAc (3 ¥ 10 mL). The
combined organic layer was evaporated under reduced pressure
and purified by column chromatography to afford compound 22
(400 mg, 1.20 mmol, 87%).
Eluent for column chromatography: EtOAc/hexane (1 : 4, v/v);
[a]2D8 -15.9 (c 0.71, CHCl3); Rf 0.33 (1 : 3, EtOAc/hexane); IR
(neat, cm-1): 3452, 2935, 2862, 2360, 1518, 1464, 1217; 1H NMR
(300 MHz, CDCl3) d 0.05 (s, 6H), 0.88 (brs, 9H), 1.32 (s, 3H), 1.51
(s, 3H), 1.75–1.94 (m, 2H), 2.50 (brm, 1H, OH), 3.71 (d, J = 3.67,
2H), 3.75 (t, J = 5.5 Hz, 2H), 3.98–4.04 (m, 2H), 4.32–4.36(m,1H),
4.61 (dd, J = 3.5, 6.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) d -5.1
(CH3), -5.0 (CH3), 18.7 (qC), 25.9 (CH3), 26.2 (3 ¥ CH3), 27.8
(CH3), 35.8 (CH2), 60.9 (CH2), 63.7 (CH2), 81.9 (CH), 84.4 (CH),
84.8(CH), 85.1 (CH), 114.5 (qC); ESI-HRMS: m/z [M+H]+ Calcd
for C16H33O5Si 333.2097, found 333.2106.
Eluent for column chromatography: EtOAc/hexane (3 : 1, v/v);
[a]2D8 +13.9 (c 0.52, CH3OH) {Ref. 4 [a]D28 +18.5 (c 2.30, CH3OH)};
Rf 0.52 (EtOAc); IR (KBr, cm-1): 3366, 2926, 2366, 1583, 1356,
1
1219; H NMR (300 MHz, CDCl3 + CD3OD) d 1.31 (d, J =
6.3 Hz, 3H), 2.34 (brm, 3H, 3OH), 3.67 (t, J = 5.54, 1H), 3.84–
3.91 (m, 5H), 4.29 (t, J = 6.44, 1H), 4.76 (dd, J = 11.8, 32.0 Hz,
2H), 6.09 (dd, J = 7.0, 15.7 Hz,1H), 6.81 (d, J = 8.1 Hz, 1H), 6.99–
7.10 (m, 2H), 7.20–7.28 (m, 1H); 13C NMR (75 MHz, CDCl3 +
CD3OD) d 19.4 (CH3), 56.0 (CH), 56.2 (CH2), 75.5 (CH), 76.3
(CH), 80.2 (CH), 84.4 (CH), 110.2 (CH), 119.5 (CH), 126.3 (Ar-
qC), 129.4 (CH), 129.8 (CH), 131.5 (CH), 138.0 (Ar-qC), 158.3
(Ar-qC); DART-HRMS: m/z [M]+ Calcd for C15H20O5 280.1311,
found 280.1297.
General procedure for preparation of compound 24
To a precooled (0 ◦C) solution of 2,3-O-isopropylidine -D-ribose 10
(10.31 g, 54.28 mmol) in dry DCM (40 mL) was added imidazole
(5.54 g, 81.4 mmol). TBDMSCl (9.00 g, 59.71 mmol) was then
added to the reaction mixture and stirring was continued for 2 h.
After completion of the reaction, a saturated aqueous solution of
NH4Cl (15 mL) was added and the resulting solution was extracted
with dichloromethane (4 ¥ 20 mL). The combined organic phase
was dried over Na2SO4 and the solvent was removed under reduced
pressure. The residue was purified by column chromatography to
furnish 2418 (14.87 g, 48.85 mmol, 90%) as a colorless oil.
Compound 21
To a stirred solution of alcohol 22 (500 mg, 1.5 mmol) in dry
DCM (20 mL) at 0 ◦C Et3N (0.6 mL, 4.3 mmol) was added. TsCl
(575 mg, 3 mmol) was then added to the reaction mixture portion
wise and stirring was continued first for one hour at the same
temperature and then for 3 h without cooling. After completion
of the reaction, a saturated aqueous solution of NH4Cl (15 mL)
was added and the resulting solution was extracted with CH2Cl2
(4 ¥ 20 mL). The combined organic phase was dried over Na2SO4
and the solvent was removed under reduced pressure. Column
chromatographic purification of the residue furnished 21 as an oil
(635 mg, 1.3 mmol, 87%).
Compound 23
To a solution of the hemiacetal 24 (305 mg, 1 mmol) in acetonitrile
(5 mL), Ph3P CHCO2Me (500 mg, 1.5 mmol) was added and
the reaction mixture was allowed to stir under reflux (110 ◦C)
for 2 h. After completion of the wittig olefination, the reaction
Eluent for column chromatography: EtOAc/hexane (1 : 5, v/v);
[a]2D8 -27.8 (c 0.83, CHCl3); Rf 0.42(1 : 3, EtOAc/hexane); IR
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1
(neat, cm-1): 2933, 2362, 1643, 1365, 1217; H NMR (300 MHz,
84.9 (CH), 86.0 (CH), 114.8 (qC); ESI-HRMS: m/z [M+Na]+
CDCl3) d 0.02 (s, 3H), 0.03 (s, 3H), 0.87 (brs, 9H), 1.31 (s, 3H),
1.49 (s, 3H), 1.86–1.91 (m, 1H), 1.98–2.03 (m, 1H), 2.44 (s, 3H),
3.65 (d, J = 2.7, 2H), 3.83–3.89 (m, 1H), 3.93 (dd, J = 3.3, 6.7 Hz,
1H), 4.11–4.17 (m, 2H), 4.24–4.27 (m, 1H), 4.60 (dd, J = 3.4,
Calcd for C10H18O4Na 225.1103, found 225.1108.
Compound 16
6.5 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.2 Hz, 2H); 13
C
A solution of CH3CN (10 mL) containing alcohol 19 (500 mg,
2.47 mmol) and IBX (2.77 g, 9.9 mmol) in a 100 mL round bottom
flask was refluxed for 1 h with cold water circulation. The reaction
NMR (75 MHz, CDCl3) d -5.1 (CH3), -5.0 (CH3), 18.6 (qC), 21.9
(CH3), 25.8 (CH3), 26.2 (3 ¥ CH3), 27.8 (CH3), 33.4 (CH2), 63.8
(CH2), 67.8 (CH2), 81.0 (CH), 82.1 (CH), 84.9 (CH), 85.2 (CH),
114.3 (qC), 128.3 (2 ¥ Ar-CH), 130.1 (2 ¥ Ar-CH), 133.4 (Ar-qC),
145.0 (Ar-qC); ESI-HRMS: m/z [M+H]+ Calcd for C23H39O7Si
487.2186, found 487.2168.
◦
mixture was then cooled to 0 C and diluted with ether. After 1
h, the reaction mixture was filtered through a celite bed and the
filtrate was concentrated under reduced pressure to obtain an oil
18 (485 mg) which was immediately used for the next step without
further purification.
Methyl triphenylphosphonium bromide (3.03 g, 8.3 mmol) and
tBuOK (683 mg, 6.1 mmol) were taken in a◦flame dried two necked
round bottomed flask and cooled to -20 C. Dry THF (25 mL)
was added to the reaction mixture under nitrogen atmosphere and
it was stirred for 1 h without further cooling. The reaction mixture
was then again cooled to -20 ◦C and the aldehyde 18 in THF
(3 mL) was added to the mixture drop wise. The reaction mixture
Compound 20
The tosylate 21 (500 mg, 1.03 mmol) was dissolved in dry THF
(10 mL) and cooled to -20 ◦C. To this cooled solution was added
LiAlH4 (78 mg, 2.06 mmol) in 3 portions over a time period of
about 15 min. The resulting reaction mixture was stirred at -20 ◦C
for about 1 h then the reaction mixture was allowed to stir for
another one hour without further cooling. After completion of
the reaction, excess LiAlH4 was quenched with EtOAc at 0 ◦C.
The reaction mixture was then passed through a short silica gel
bed and washed with EtOAc (3 ¥ 15 mL). The combined organic
layer was evaporated under reduced pressure to obtain an oily
residue which on column chromatographic purification yielded
compound 20 (235 mg, 0.74 mmol, 72%).
◦
was allowed to warm to 0 C and the stirring was continued for
another 2 h. After completion of the reaction, saturated aqueous
NH4Cl was added to the reaction mixture and was extracted with
EtOAc (3 ¥ 20 mL). The combined organic layer was washed twice
with brine, dried over Na2SO4 and concentrated in vacuo to give
a residue. Column chromatographic purification of the residue
yielded compound 16 as an oil (310 mg, 1.56 mmol, 63% for two
steps). Here the work-up, purification and evaporation of column
fractions were done below 30 ◦C.
Eluent for column chromatography: EtOAc/hexane (1 : 49,
v/v); [a]2D8 +10.0 (c 0.23, CHCl3); Rf 0.9 (1 : 40, EtOAc/hexane); IR
(neat, cm-1): 2983, 2933, 2877, 2364, 1460, 1378, 1216; 1H NMR
(300 MHz, CDCl3) d 0.99 (t, J = 7.4 Hz, 3H), 1.33 (s, 3H), 1.54
(s, 3H), 1.60–1.66 (m, 2H), 3.78–3.82 (m, 1H), 4.25 (dd, J = 5.00,
6.1, 1H), 4.31–4.42 (m, 2H), 5.18–5.22 (m, 1H), 5.37 (dt, J = 1.3,
17.3 Hz, 1H), 5.83–5.94 (m, 1H); 13C NMR (75 MHz, CDCl3) d
10.2 (CH3), 25.8 (CH3), 26.9 (CH2), 27.7 (CH3), 85.1 (CH), 85.2
(CH), 85.5 (CH), 85.8 (CH), 115.1 (qC), 117.6 (CH2), 136.4 (CH);
ESI-HRMS: m/z [M+H]+ Calcd for C11H19O3 199.1334, found
199.1327.
Eluent for column chromatography: EtOAc/hexane (1 : 9, v/v);
[a]2D8 -5.8 (c 1.18, CHCl3); Rf 0.54 (1 : 4, EtOAc/hexane); IR (neat,
cm-1): 2935, 2864, 2366, 1465, 1378, 1218; H NMR (300 MHz,
1
CDCl3) d 0.02 (s, 3H), 0.03 (s, 3H), 0.86 (brs, 9H), 0.93 (t, J =
7.4, 3H), 1.30 (s, 3H), 1.49 (s, 3H), 1.51–1.61 (m, 2H), 3.67 (d, J =
2.7, 2H), 3.72–3.78 (m, 1H), 3.93 (dd, J = 3.8, 7.6 Hz, 1H), 4.23
(dd, J = 4.9, 6.7 Hz, 1H), 4.57 (dd, J = 3.7, 6.7 Hz, 1H); 13C NMR
(50 MHz, CDCl3) d -5.1 (CH3), -5.0 (CH3), 10.1 (CH3), 18.7 (qC),
25.9 (CH3), 26.2 (3 ¥ CH3), 27.1 (CH2), 27.8 (CH3), 64.0 (CH2),
82.2 (CH), 84.6 (CH), 85.2 (CH), 86.1 (CH), 114.1 (qC); ESI-
HRMS: m/z [M+Na]+ Calcd for C16H32O4SiNa 339.1968, found
339.1957.
Compound 19
Compound 14
To a stirred solution of silyl ether 20 (500 mg, 1.58 mmol)
in THF (10 mL) was added TBAF (1.8 mL, 1 M solution in
THF) at 0 ◦C and left for stirring at room temperature. After
2 h, saturated aqueous solution of NH4Cl (15 mL) was added
to the reaction mixture and it was extracted with EtOAc (3 ¥
15 mL). The combined organic layer was dried over Na2SO4 and
concentrated under reduced pressure to give a residue which on
column purification afforded compound 19 (287 mg, 1.42 mmol,
90%) as a colorless oil.
To a precooled solution of 13 (100 mg, 0.67 mmol) in DMF
(5 mL) was added anhydrous NaH (48 mg, 2 mmol), methyl
iodide (0.16 mL, 2.68 mmol) and the resulting mixture was
allowed to stir for 2 h at 0 ◦C and then at rt. After 2 h the
reaction mixture was quenched by adding MeOH and the resulting
solution was concentrated under reduced pressure to a residue
that was dissolved in ethyl acetate (15 mL) and washed with
water. The organic layer was dried over Na2SO4 and concentrated
under reduced pressure to an oil which was purified by column
chromatography to give 14 (105 mg, 0.58 mmol, 88%) as a colorless
oil.
Eluent for column chromatography: EtOAc/hexane (1 : 5, v/v);
[a]2D8 +7.2 (c 1.12, CHCl3); Rf 0.4 (1 : 4, EtOAc/hexane); IR (neat,
1
cm-1): 3460, 2973, 2935, 2879, 2366, 1460, 1379, 1216; H NMR
(300 MHz, CDCl3) d 0.93 (t, J = 7.4 Hz, 3H), 1.27 (s, 3H), 1.47
(s, 3H), 1.54–1.59 (m, 2H), 2.64 (brs, 1h, OH), 3.58–3.61 (m, 1H),
3.70–3.74 (m, 2H), 3.87–3.89 (m, 1H), 4.21–4.24 (m, 1H), 4.49–
4.53 (m, 1H); 13C NMR (75 MHz, CDCl3) d 10.0 (CH3), 25.7
(CH3), 26.7 (CH2), 27.6 (CH3), 62.9 (CH2), 81.7 (CH), 84.4 (CH),
Eluent for column chromatography: EtOAc/hexane (1 : 10,
v/v); Rf 0.5 (2 : 7, EtOAc/hexane); IR (neat, cm-1): 3011, 2929,
2368, 1646, 1577, 1467, 1262; 1H NMR (300 MHz, CDCl3) d 3.38
(s, 3H), 3.81 (s, 3H), 4.58 (s, 2H), 5.33 (dd, J = 1.2, 11.0 Hz, 1H),
5.68 (dd, J = 1.2, 17.4 Hz, 1H), 6.80 (d, J = 7.9, 2H), 7.03–7.27 (m,
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3H); 13C NMR (75 MHz, CDCl3) d 56.2 (CH3), 58.4 (CH3), 65.0
(CH), 110.3 (CH), 116.9 (CH2), 118.6 (CH), 123.7 (Ar-qC), 129.5
(CH), 134.8 (CH), 140.2 (Ar-qC), 158.5 (Ar-qC); DART-HRMS:
m/z [M]+ Calcd for C11H14O2 178.0994, found 178.0982.
(m, 4H), 4.37–4.41 (m, 1H), 4.47–4.51 (m, 2H), 6.23 (dd, J = 6.4,
16.1 Hz, 1H), 6.78 (dd, J = 1.1, 8.0 Hz, 1H), 6.92–6.98 (m, 1H),
7.02–7.08 (m, 2H); 13C NMR (75 MHz, CDCl3) d 10.2 (CH3),
15.3 (CH3), 16.0 (CH3), 25.9 (CH3), 27.1 (CH2), 27.8 (CH3), 64.6
(CH2), 69.4 (CH2), 85.3 (CH), 85.4 (CH), 85.9 (CH), 85.94 (CH),
113.3 (CH), 115.0 (qC), 118.6 (CH), 124.0 (CH), 127.6 (CH), 128.5
(CH), 131.3 (Ar-qC), 146.7 (Ar-qC), 152.7 (Ar-qC); ESI-HRMS:
m/z [M+H]+ Calcd for C21H31O5 363.2171, found 363.2156.
Compound 15a
Under argon atmosphere Grubbs’ second generation catalyst
(28 mg, 0.0335 mmol) was added to a 50 mL oven dried two
necked round bottomed flask fitted with a reflux condenser and
septum. Dry CH2Cl2 (2 mL) was then added to the flask through
a syringe and the solution was kept for stirring. Vinylic furanoside
16 (100 mg, 0.5 mmol) and the alkene 3 (164 mg, 1 mmol) in
DCM (2 mL each) were added in succession through a syringe
to the reaction mixture. The septum was replaced with a glass
stopper and the stirring was continued. The solution was refluxed
for 12h. After completion of the reaction, the organic solvent was
evaporated under reduced pressure to give a black residue which
was purified by column chromatography to give compound 15a as
a semi-solid (117 mg, 0.35 mmol, 70%).
Compound 15f
Eluent for column chromatography: EtOAc/hexane (1 : 12, v/v);
[a]2D8 +51.2 (c 1.06, CHCl3); Rf 0.74 (1 : 9, EtOAc/hexane); IR
(neat, cm-1): 2975, 2934, 2367, 1459, 1377, 1217; 1H NMR
(300 MHz, CDCl3) d 1.05 (t, J = 7.4 Hz, 3H), 1.37 (s, 3H), 1.60
(s, 3H), 1.64–1.76 (m, 2H), 3.91 (dd, J = 6.5, 10.9 Hz, 1H), 4.40–
4.43 (m, 1H), 4.48–4.54 (m, 2H), 6.24 (dd, J = 5.8, 15.8 Hz, 1H),
7.08–7.17 (m, 2H), 7.39 (dd, J = 7.8, 21.4 Hz, 2H); 13C NMR
(75 MHz, CDCl3) d 10.2 (CH3), 25.8 (CH3), 27.0 (CH2), 27.7
(CH3), 30.0 (Grease), 84.7 (CH), 85.2 (CH), 85.6 (CH), 86.0 (CH),
115.2 (qC), 125.5 (CH), 127.4 (CH), 128.6 (CH), 129.7 (CH), 131.8
(CH), 133.7 (Ar-qC), 137.4 (2 ¥ Ar-qC); ESI-HRMS: m/z [M+H]+
Calcd for C17H21Cl2O3 343.0868, found 343.0861.
Eluent for column chromatography: EtOAc/hexane (1 : 10,
v/v); [a]2D8 +36.9 (c 0.13, CHCl3); Rf 0.52 (1 : 9, EtOAc/hexane);
1
IR (neat, cm-1): 3452, 3009, 2930, 2367, 1579, 1466, 1218; H
NMR (300 MHz, CDCl3) d 1.03 (t, J = 7.4 Hz, 3H), 1.36 (s, 3H),
1.58 (s, 3H), 1.62–1.74 (m, 3H), 3.84–3.91 (m, 4H), 4.37–4.53 (m,
3H), 4.79 (s, 3H), 6.14 (dd, J = 6.4, 15.8 Hz, 1H), 6.82 (d, J =
8.1 Hz, 1H), 7.03–7.09 (m, 2H), 7.20–7.26 (m, 1H); 13C NMR
(75 MHz, CDCl3) d 10.2 (CH3), 25.9 (CH3), 27.0 (CH2), 27.8
(CH3), 56.0 (CH), 57.2 (CH2), 85.1 (CH), 85.2 (CH), 85.8 (CH),
85.9 (CH), 110.1 (CH), 115.3 (qC), 119.7 (CH), 126.8 (Ar-qC),
129.2 (CH), 129.7 (CH), 131.2 (CH), 137.7 (Ar-qC), 158.5 (Ar-
qC); ESI-HRMS: m/z [M+Na]+ Calcd for C19H26O5Na 357.1678,
found 357.1670.
Compound 15h
Eluent for column chromatography: EtOAc/hexane (1 : 15, v/v);
[a]2D8 +42.8 (c 0.97, CHCl3); Rf 0.62 (1 : 12, EtOAc/hexane); IR
(neat, cm-1): 2932, 2362, 1377, 1218; 1H NMR (300 MHz, CDCl3)
d 1.06 (t, J = 7.4 Hz, 3H), 1.38 (s, 3H), 1.61 (s, 3H), 1.66–1.78 (m,
2H), 3.92 (dd, J = 6.7, 11.1 Hz, 1H), 4.41–4.45 (m, 1H), 4.56–4.58
(m, 2H), 6.24–6.31 (m, 1H), 7.40–7.53 (m, 4H), 7.60 (dd, J = 6.9,
1H), 7.76–7.85 (m, 2H), 8.10–8.13 (m, 1H); 13C NMR (75 MHz,
CDCl3) d 10.2 (CH3), 25.9 (CH3), 27.0 (CH2), 27.8 (CH3), 85.2
(CH), 85.3 (CH), 85.85 (CH), 85.9 (CH), 115.2 (qC), 124.2 (CH),
124.3 (CH), 125.9 (CH), 126.1 (CH), 126.4 (CH), 128.5 (CH),
128.8 (CH), 129.8 (CH), 130.9 (CH), 131.5 (Ar-qC), 133.9 (Ar-
qC), 134.6 (Ar-qC); ESI-HRMS: m/z [M+H]+ Calcd for C21H25O3
325.1804, found 325.1784.
Compounds 15b–j were synthesized by following the same pro-
cedure as adopted for compound 15a. The respective equivalents
of alkenes and time are given in Table 1.
Compound 15c
Eluent for column chromatography: EtOAc/hexane (1 : 10, v/v);
[a]2D8 +46.4 (c 0.79, CHCl3); Rf 0.50 (1 : 8, EtOAc/hexane); IR
Compound 15j
1
(neat, cm-1): 3022, 2934, 2365, 1469, 1218; H NMR (300 MHz,
Eluent for column chromatography: EtOAc/hexane (1 : 11, v/v);
CDCl3) d 1.02 (t, J = 7.4 Hz, 3H), 1.35 (s, 3H), 1.43 (t, J = 6.9 Hz,
3H), 1.57 (s, 3H), 1.61–1.71 (m, 2H), 3.81 (s, 3H), 3.84–3.89 (m,
1H), 4.05 (dd, J = 6.9, 13.9 Hz, 2H), 4.37–4.41 (m, 1H), 4.45–4.53
(m, 2H), 6.23 (dd, J = 6.6, 16.1 Hz, 1H), 6.79 (d, J = 7.2 Hz,1H),
6.93–7.07 (m, 3H); 13C NMR (50 MHz, CDCl3) d 10.2 (CH3),
15.2 (CH3), 25.8 (CH3), 27.0 (CH2), 27.7 (CH3), 61.1 (CH), 64.5
(CH2), 85.2 (CH), 85.4 (CH), 85.8 (CH), 85.9 (CH), 113.2 (CH),
115.0 (qC), 118.6 (CH), 124.1 (CH), 127.3 (CH), 128.7 (CH), 130.9
(Ar-qC), 147.5 (Ar-qC), 152.6 (Ar-qC); ESI-HRMS: m/z [M+H]+
Calcd for C20H29O5 349.2015, found 349.1999.
[a]2D8 +17.1 (c 0.34, CHCl3); Rf 0.44 (1 : 9, EtOAc/hexane); IR
1
(neat, cm-1): 2926, 2856, 2368, 1462, 1216; H NMR (300 MHz,
CDCl3) d 0.85–0.90 (m, 3H), 0.99 (t, J = 7.4 Hz, 3H), 1.25 (m,
22H), 1.33 (s, 3H), 1.54 (s, 3H), 1.60–1.67 (m, 2H), 2.04 (dd, J =
6.5, 13.3 Hz, 2H), 3.73–3.79 (m, 1H), 4.19 (dd, J = 5.2, 7.0 Hz,
1H), 4.30–4.39 (m, 2H), 5.47 (dd, J = 7.5, 15.6 Hz, 1H), 5.77–5.85
(m, 1H); 13C NMR (75 MHz, CDCl3) d 10.2 (CH3), 14.5 (CH3),
23.1 (CH2), 25.9 (CH3), 26.9 (CH2), 27.8 (CH3), 29.3 (CH2), 29.6
(CH2), 29.7 (CH2), 29.9 (CH2), 29.96 (CH2), 30.0 (CH2), 30.0–30.1
(3 ¥ CH2), 32.3 (CH2), 32.7 (CH2), 85.3 (2 ¥ CH), 85.6 (CH),
85.8 (CH), 115.2 (qC), 127.9 (CH), 135.7 (CH); ESI-HRMS: m/z
[M+H]+ Calcd for C21H45O3 381.0974, found 381.0992.
Compound 15d
Eluent for column chromatography: EtOAc/hexane (1 : 10, v/v);
[a]2D8 +39.4 (c 0.49, CHCl3); Rf 0.54 (1 : 8, EtOAc/hexane); IR
Compound 1a
1
(neat, cm-1): 2973, 2927, 2358, 2334, 1577, 1463, 1265, 1213; H
NMR (300 MHz, CDCl3) d 1.03 (t, J = 7.4 Hz, 3H), 1.35–1.45 (m,
9H), 1.58 (s, 3H), 1.64–1.71 (m, 2H), 3.87–3.88 (m, 1H), 3.99–4.08
A solution of compound 15a (100 mg, 0.3 mmol) in THF (5 mL)
was stirred with 2 M HCl (10 mL) for 8 h at room temperature.
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After completion of the reaction, EtOAc (10 ml) was added to it
and the resulting mixture was extracted with EtOAc (3 ¥ 10 mL).
The combined organic layer was then washed with water, dried
over Na2SO4 and concentrated under reduced pressure to give a
residue which was purified by column chromatography to obtain
varitriol analogue (1a) as a colorless oil (70 mg, 0.238 mmol, 79%).
Eluent for column chromatography: EtOAc/hexane (1 : 2, v/v);
[a]2D8 -7.2 (c 0.77, CHCl3); Rf 0.34 (1 : 3, EtOAc/hexane); IR (neat,
(300 MHz, CDCl3) d 1.00 (t, J = 7.4 Hz, 3H), 1.34–1.45 (m,
6H), 1.61–1.67 (m, 2H), 3.20 (m, 2H, 2OH), 3.74–3.84 (m, 3H),
3.98–4.07 (m, 4H), 4.30 (t, J = 5.9 Hz, 1H), 6.17 (dd, J = 7.0,
16.0 Hz, 1H), 6.78(d, J = 7.4 Hz, 1H), 6.92-7.07 (m, 3H); 13C
NMR (75 MHz, CDCl3) d 10.3 (CH3), 15.3 (CH3), 16.0 (CH3), 27.1
(CH2), 64.6 (CH2), 69.5 (CH2), 74.9 (CH), 76.1 (CH), 84.2 (CH),
85.5 (CH), 113.2 (CH), 118.5 (CH), 124.1 (CH), 127.5 (CH), 128.9
(CH), 131.2 (Ar-qC), 146.3 (Ar-qC), 152.7 (Ar-qC); ESI-HRMS:
m/z [M+H]+ Calcd for C18H27O5 323.1858, found 323.1857.
1
cm-1): 3347, 2923, 2364, 1571, 1461, 1253; H NMR (300 MHz,
CDCl3) d 0.87 (t, J = 7.4 Hz, 3H), 1.43–1.50 (m, 2H), 3.59–3.63
(m, 4H), 3.72 (s, 3H), 4.16 (t, J = 6.5 Hz, 1H), 4.59 (d, J = 11.8 Hz,
1H), 4.71 (d, J = 11.8 Hz, 1H), 5.96 (dd, J = 7.0, 15.6 Hz,1H), 6.70
(d, J = 8.0 Hz, 1H), 6.91 (d, J = 15.7 Hz, 1H), 7.00 (d, J = 7.7 Hz,
1H), 7.12 (t, J = 7.9 Hz, 1H); 13C NMR (50 MHz, CDCl3) d 10.2
(CH3), 27.1 (CH2), 55.9 (CH2), 56.0 (CH), 74.7 (CH), 75.8 (CH),
83.5 (CH), 85.7 (CH), 110.2 (CH), 119.3 (CH), 126.2 (Ar-qC),
129.3 (CH), 129.8 (CH), 131.4 (CH), 138.0 (Ar-qC), 158.2 (Ar-
qC); ESI-HRMS: m/z [M+Na]+ Calcd for C16H22O5Na 317.1365,
found 317.1345.
Compound 1e
Eluent for column chromatography: EtOAc/hexane (1 : 2, v/v);
[a]2D8 +15.7 (c 0.75, CHCl3); Rf 0.40 (1 : 2, EtOAc/hexane); IR
(neat, cm-1): 3395, 2930, 2368, 1462, 1220; H NMR (300 MHz,
1
CDCl3) d 1.00 (t, J = 7.4 Hz, 3H), 1.61–1.66 (m, 2H), 3.04 (m, 2H,
2 OH), 3.71–3.76 (m, 1H), 3.84 (brm, 11H), 4.25–4.29 (m, 1H),
6.09 (dd, J = 7.2, 15.9 Hz, 1H), 6.62 (d, J = 8.7 Hz, 1H), 6.85–
6.90 (m, 1H), 7.13–7.17 (m, 1H); 13C NMR (75 MHz, CDCl3) d
10.3 (CH3), 27.1 (CH2), 56.4 (CH), 61.2 (CH), 61.5 (CH), 74.9
(CH), 76.1 (CH), 84.4(CH), 85.5 (CH), 108.1(CH), 121.6 (CH),
123.9 (Ar-qC), 127.1 (CH), 127.4 (CH), 142.6 (Ar-qC), 151.9 (Ar-
qC), 153.7 (Ar-qC); ESI-HRMS: m/z [M+H]+ Calcd for C17H25O6
325.1651, found 325.1642.
The other analogues 1b–j were synthesized by following the
same procedure as described above for 1a. The respective strength
of the HCl solution and time are given in Table 2.
Compound 1b
Eluent for column chromatography: EtOAc/hexane (1 : 3, v/v);
Compound 1f
[a]2D8 +2.4 (c 0.65, CHCl3); Rf 0.44 (1 : 3, EtOAc/hexane); IR (neat,
1
cm-1): 3391, 2927, 2365, 1578, 1464, 1259; H NMR (300 MHz,
Eluent for column chromatography: EtOAc/hexane (1 : 3, v/v);
[a]2D8 +29.0 (c 0.24, CHCl3); Rf 0.42 (1 : 3, EtOAc/hexane); IR
(neat, cm-1): 3448, 3022, 2927, 2361, 1568, 1419, 1218; 1H NMR
(300 MHz, CDCl3) d 1.03 (t, J = 7.4 Hz, 3H), 1.65–1.73 (m, 2H),
3.03 (brm, 2H, 2 OH), 3.77–3.82 (m, 1H), 3.86–3.93 (m, 2H), 4.35
(t, J = 5.7 Hz, 1H), 6.20 (dd, J = 6.5, 15.8 Hz, 1H), 7.07–7.16 (m,
2H), 7.33–7.44 (m,2H); 13C NMR (75 MHz, CDCl3) d 10.3 (CH3),
27.1 (CH2), 74.9 (CH), 76.1 (CH), 83.5 (CH), 85.8 (CH), 125.5
(CH), 127.5 (CH), 128.9 (CH), 129.8 (CH), 131.7 (Ar-qC), 131.9
(CH), 133.8 (Ar-qC), 137.3 (Ar-qC); ESI-HRMS: m/z [M+H]+
Calcd for C14H17Cl2O3 303.0555, found 303.0535.
CDCl3) d 1.00 (t, J = 7.4 Hz, 3H), 1.60–1.64 (m, 2H), 3.21 (m,
1H, OH), 3.37 (s, 3H), 3.57 (m, 1H, OH), 3.74 (brm, 3H), 3.82 (s,
3H), 4.29 (t, J = 5.7 Hz, 1H), 4.59 (dd, J = 10.6, 17.4 Hz, 2H),
6.10 (dd, J = 6.9, 15.6 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 7.01 (d,
J = 15.8 Hz,1H), 7.11–7.14 (m, 1H), 7.21–7.26 (m, 1H); 13C NMR
(75 MHz, CDCl3) d 10.3 (CH3), 27.1 (CH2), 56.2 (CH), 58.3 (CH),
65.0 (CH2), 74.8 (CH), 76.0 (CH), 83.9 (CH), 85.6 (CH), 110.3
(CH), 119.0 (CH), 123.5 (Ar-qC), 129.7 (CH), 129.9 (CH), 130.9
(CH), 139.0 (Ar-qC), 158.6 (Ar-qC); ESI-HRMS: m/z [M+H]+
Calcd for C17H25O5 309.1702, found 309.1687.
Compound 1g
Compound 1c
Eluent for column chromatography: EtOAc/hexane (1 : 2, v/v);
[a]2D8 +20.1 (c 0.39, CHCl3); Rf 0.46 (1 : 2, EtOAc/hexane); IR
(neat, cm-1): 3387, 2926, 2362, 1579, 1453, 1220; 1H NMR
(300 MHz, CDCl3) d 1.00 (t, J = 7.4 Hz, 3H), 1.59–1.69 (m, 2H),
3.13–3.25 (m, 2H, 2 OH), 3.71–3.77 (m, 1H), 3.81–3.89 (m, 2H),
4.24–4.28 (m, 1H), 5.96 (m, 2H), 6.39 (dd, J = 6.8, 16.0 Hz, 1H),
6.60–6.81 (m, 4H); 13C NMR (75 MHz, CDCl3) d 10.3 (CH3), 27.0
(CH2), 53.8 (solvent peak, DCM), 74.9 (CH), 76.0 (CH), 84.1(CH),
85.6 (CH), 101.2 (CH2), 108.0 (CH), 119.5 (Ar-qC), 121.4 (CH),
121.9(CH), 127.2(CH), 130.7(CH), 145.2(Ar-qC), 147.9(Ar-qC);
ESI-HRMS: m/z [M+H]+ Calcd for C15H19O5 279.1232, found
279.1221.
Eluent for column chromatography: EtOAc/hexane (2 : 5, v/v);
[a]2D8 +18.8 (c 0.47, CHCl3); Rf 0.33 (1 : 3, EtOAc/hexane); IR
(neat, cm-1): 3435, 2928, 2358, 1602, 1466, 1263; 1H NMR
(300 MHz, CDCl3) d 1.00 (t, J = 7.4 Hz, 3H), 1.46 (t, J = 6.9 Hz,
3H), 1.59–1.67 (m, 2H), 3.19–3.34 (brm, 2H, 2 OH), 3.72–3.87
(m, 6H), 4.05 (dd, J = 6.9, 13.9 Hz, 2H), 4.28–4.32 (m, 1H), 6.18
(dd, J = 7.2, 16.0 Hz, 1H), 6.79 (d, J = 8.0 Hz,1H), 6.93–7.07 (m,
3H); 13C NMR (50 MHz, CDCl3) d 10.2 (CH3), 15.3 (CH3), 27.1
(CH2), 30.0 (Grease), 61.2 (CH), 64.6 (CH2), 74.9 (CH), 76.0 (CH),
84.3 (CH), 85.6 (CH), 113.2 (CH), 118.7 (CH), 124.3 (CH), 127.3
(CH), 129.2 (CH), 130.9 (Ar-qC), 147.3 (Ar-qC), 152.6 (Ar-qC);
ESI-HRMS: m/z [M+H]+ Calcd for C17H25O5 309.1702, found
309.1722.
Compound 1h
Compound 1d
Eluent for column chromatography: EtOAc/hexane (1 : 3, v/v);
Eluent for column chromatography: EtOAc/hexane (2 : 5, v/v);
[a]2D8 +15.1 (c 0.87, CHCl3); Rf 0.40 (1 : 2, EtOAc/hexane); IR
(neat, cm-1): 3426, 2925, 2858, 2362, 1580, 1463, 1217; 1H NMR
[a]2D8 +20.6 (c 0.80, CHCl3); Rf 0.50 (1 : 4, EtOAc/hexane); IR
1
(neat, cm-1): 3407, 2362, 1646, 1458, 1218; H NMR (300 MHz,
CDCl3) d 1.06 (t, J = 7.4 Hz, 3H), 1.67–1.72 (m, 2H), 3.29 (brm,
7382 | Org. Biomol. Chem., 2011, 9, 7372–7383
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2H, 2 OH), 3.82–3.99 (m, 3H), 4.46 (t, J = 6.3 Hz, 1H), 6.25
(dd, J = 6.8, 15.6 Hz, 1H), 7.40–7.53 (m, 4H), 7.60–7.63 (m,1H),
7.78–7.87 (m, 2H), 8.11–8.14 (m, 1H); 13C NMR (75 MHz, CDCl3)
d 10.3 (CH3), 27.1 (CH2), 75.0 (CH), 76.2 (CH), 84.1 (CH), 85.6
(CH), 124.0 (CH), 124.3 (CH), 125.9 (CH), 126.1 (CH), 126.5
(CH), 128.5 (CH), 128.9 (CH), 130.0 (CH), 130.9 (CH), 131.5
(Ar-qC), 134.0 (Ar-qC), 134.4 (Ar-qC); ESI-HRMS: m/z [M+H]+
Calcd for C18H21O3 285.1491, found 285.1492.
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Compound 1i
Eluent for column chromatography: EtOAc/hexane (1 : 2, v/v);
[a]2D8 +13.7 (c 0.79, CHCl3); Rf 0.34 (1 : 3, EtOAc/hexane); IR
(neat, cm-1): 3415, 3020, 2929, 2365, 1470, 1217; 1H NMR
(300 MHz, CDCl3) d 1.00 (t, J = 7.4 Hz, 3H), 1.59–1.70 (m, 2H),
3.06–3.21 (brm, 2H, 2OH), 3.74–3.88 (m, 9H), 4.28–4.32 (m, 1H),
6.19 (dd, J = 7.0, 16.1 Hz, 1H), 6.79–6.82 (m, 1H), 6.97–7.10 (m,
3H); 13C NMR (75 MHz, CDCl3) d 10.2 (CH3), 27.1 (CH2), 56.1
(CH), 61.3 (CH), 74.9 (CH), 76.0 (CH), 84.3 (CH), 85.6 (CH),
112.0 (CH), 118.7 (CH), 124.4 (CH), 127.2 (CH), 129.3 (CH),
130.9 (Ar-qC), 147.0 (Ar-qC), 153.0 (Ar-qC); ESI-HRMS: m/z
[M+H]+ Calcd for C16H23O5 295.1545, found 295.1543.
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Compound 1j
Eluent for column chromatography: EtOAc/hexane (1 : 3, v/v);
[a]2D8 +8.7 (c 0.39, CHCl3); Rf 0.46 (1 : 3, EtOAc/hexane); IR (neat,
cm-1): 3399, 2924, 2363, 1644, 1219; 1H NMR (300 MHz, CDCl3)
d 0.85–0.90 (m, 3H), 1.00 (t, J = 7.4 Hz, 3H), 1.25–1.38 (m, 22H),
1.58–1.67 (m, 2H), 2.01–2.08 (m, 2H), 2.74 (brm, 2H, 2OH), 3.67
(dd, J = 6.1, 10.7 Hz, 1H), 3.74–3.80 (m, 2H), 4.02–4.07 (m, 1H),
5.44 (dd, J = 7.4, 15.3 Hz, 1H), 5.77–5.85 (m, 1H); 13C NMR
(75 MHz, CDCl3) d 10.3 (CH3), 14.5 (CH3), 23.1 (CH2), 27.1
(CH2), 29.4 (CH2), 29.6 (CH2), 29.7 (CH2), 29.9 (CH2), 30.0 (CH2),
30.1 (4 ¥ CH2), 32.3 (CH2), 32.8 (CH2), 74.9 (CH), 75.9 (CH),
84.2 (CH), 85.5 (CH), 128.0 (CH), 136.0 (CH); ESI-HRMS: m/z
[M+H]+ Calcd for C21H41O3 341.3056, found 341.3057.
Acknowledgements
We are thankful to Sophisticated Analytical Instrument Facility,
CDRI for providing spectral data, DST (project SR/SI/OC-
17/2010) for financial support and Mr. A.K. Pandey for technical
assistance. P. G. thanks CSIR, New Delhi, for financial support.
CDRI communication no. 8103.
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26 Examples of some naturally occuring cytotoxic natural products with
long alifatic chain: (+)-Jaspine B or Pachastrissamine, (-)-Muricatacin,
(+)-Spisulosine etc.
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The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 7372–7383 | 7383
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