Linearization of carbohydrate derived polycyclic frameworks

Article abstract of DOI:10.1039/c4ra04845h

We report easy access to carbohydrate derived diverse tricyclic skeletons which could be beneficial for exploring polyfunctionalized chiral alicycles. The key reaction to assemble a sugar fused tricyclic core is intermolecular tandem esterification and 1,3-dipolar cycloaddition. The framework was elaborated using amide forming reactions, opening of isoxazolidine rings followed by N and O-acylations. The sequences provide distinct, spatially separated and encoded chemical entities that may pave the way to investigate cell functions.

Full text of DOI:10.1039/c4ra04845h

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Linearization of carbohydrate derived polycyclic
frameworks†
Cite this: RSC Adv., 2014, 4, 31892
*
Priyanka Singh and Gautam Panda
We report easy access to carbohydrate derived diverse tricyclic skeletons which could be beneficial for
exploring polyfunctionalized chiral alicycles. The key reaction to assemble a sugar fused tricyclic core is
intermolecular tandem esterification and 1,3-dipolar cycloaddition. The framework was elaborated using
amide forming reactions, opening of isoxazolidine rings followed by N and O-acylations. The sequences
provide distinct, spatially separated and encoded chemical entities that may pave the way to investigate
cell functions.
Received 22nd May 2014
Accepted 7th July 2014
DOI: 10.1039/c4ra04845h
www.rsc.org/advances
one of the cells or organisms entire collection of macromole-
cules in phenotypic screening of small molecules. In this
Introduction
context, new methodologies have to be designed for stereo-
selective synthesis of small molecule with distinct skeletal
frameworks having structural features reminiscent of natural
products.
Following our interest in the eld of synthesis of structurally
complex small molecules, we employed carbohydrates as chiral
pool that would provide an access to a large array of molecules
since it display a high density of functional groups, are available
as single enantiomers and contain multiple sites for attachment
of recognition groups.
Decrease in the conformational freedom of small molecules
can facilitate protein binding and specicity by dropping the
entropic cost of binding. In natural products, macrocyclic,
polycyclic, or highly substituted linear structures result
restriction in conformational freedom (Fig. 1). Proper combi-
nation of hydrogen bonding and hydrophobic functional
groups offer the enthalpic driving force for protein binding.
Herein, we report a strategy for highly efficient access to simi-
larly constructed molecules from carbohydrate derived tricyclic
rigid framework. We have also described our efforts towards
generation of an acyclic series of highly functionalized
compounds with dened chirality aer disintegrating sugar
based skeleton.
The powerful effects of structurally complex small molecules
having stereochemical and skeletal diversity and functionalities
have been manifested to exhibit highly specic biological
responses. In this area, complexity of small molecules is
essential since many biological processes are signicantly
dependent upon protein–protein interactions, and most of the
small molecules known to interrupt these interactions are
structurally complex natural products and natural product like
molecules (Fig. 1). The natural products; Taxol and Dis-
codermolide bind and activate, the protein tubulin,1 which
itself was discovered as the protein target of colchicines.2–4
Diversity is also important since in these screens, there is no
particular target and whereas an eventual target could be any
Result and discussion
Fig. 1 Structures of representative bioactive natural products used in
Initially, we focused our attention to synthesize tricyclic
compounds by coupling of glucal derived allylic alcohol 4 (ref. 6)
with nitrone ester 5 by using a reaction catalyzed by lewis acid
followed by intramolecular 1,3-dipolar cycloaddition.5 Synthesis
of 4 was commenced from commercially available tri-O-acetyl-
glucal 1. Treatment of 1 with dry methanol in presence of
catalytic amount of iodine furnished 2 (ref. 6) via ferrier rear-
rangement.7 Deacetylation of 2 using K2CO3 in methanol
chemical genetic studies.
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute,
Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, UP, India. E-mail:
gautam.panda@gmail.com; gautam_panda@cdri.res.in; Fax: +91-522-2623405; Tel:
+91-522-2612411-18, ext. 4661, 4662
† Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
for all the new compounds. See DOI: 10.1039/c4ra04845h
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furnished diol 3 (ref. 8) which on selective protection of primary
alcohol as TBDMS ether yielded allylic alcohol 4 (Scheme 1).
1,3-dipolar cycloaddition9,10 was attempted between nitrone
ester 5 and allyl alcohol 4. Unfortunately, instead of tricyclic
product 6, complex mixture of products was observed
(Scheme 2). This might be due to the presence of acid labile
TBDMS group.
However, it has been reported that reaction of lewis acid on a
molecule having template similar to 4 gave rearranged product
2-substituted furan.11 Since Lewis acid catalyzed reaction was
not successful with our substrates, we decided to follow
Schreiber's methodology12 in order to get tricyclic framework.
Towards this goal, nitrone carboxylic acid 11 was synthesized.13
Synthesis of 11 was started with oxime 9 which was synthesized
through condensation of 4-methoxy benzaldehyde 7 with
hydroxylamine hydrochloride 8. Reduction of 9 using NaBH3CN
under acidic condition gave N-alkyl hydroxyl amine 10.14
Condensation of N-alkyl hydroxyl amine 10 with glyoxylic acid
mono hydrate furnished 11 (Scheme 3).
Unfortunately 1,3 dipolar cycloaddition of 4 with nitrone
corboxylic acid 11 did not yield any tricyclic product (Scheme 4).
Disappointing with these results, we decided to design some
new sugar derived allylic alcohol. In this context, galactose
derived allylic alcohol 18 was undertaken.
Synthesis of 18 was started with commercially available
methyl a-methyl-D-galactopyranoside 12 as shown in Scheme 4.
Compound 13 was obtained by acetonation of 12 with
2,2-dimethoxypropane (DMP) and catalytic amount of camphor
sulfonic acid (CSA) in acetone. Acetylation of diol 13 (ref. 15)
provided protected 14 (ref. 16) which on acidic hydrolysis with
80% AcOH furnished diol 15.17 Removal of vicinal diol by
treatment with PPh3, CHI3, imidazole in toluene under
Scheme 3 Reagent and conditions: (a) 10% KOH:H2O, 0 ꢀC, 2 h, 74%
(b) NaBH3CN, MeOH, 2N HCl, 3 h, 72% (c) CHO–COOH, DCM, over-
night, 75%.
Scheme 4 Reagents and conditions: (a) PyBroP, DIPEA, DMAP, DCM,
0 ꢀC-rt, overnight.
reuxing condition provided olen 16,18 which on subsequent
deacetylation and TBDMS protection of primary alcohol 17
(ref. 19) furnished allylic alcohol 18 (ref. 20) (Scheme 5).
Treatment of the allylic alcohol 18, with 11, under esteri-
cation conditions yielded tricyclic compound 19 with complete
regio- and stereoselectivity, presumably via tandem acylation
and 1,3-dipolar cycloaddition.9 No intermediate nitrone ester or
carboxy isoxazolidine structures was observed (Scheme 6).
Scheme 5 Reagents and conditions: (a) DMP, CSA, acetone, 12 h, 60%
(b) Ac2O, pyridine, 12 h, 91% (c) 80% AcOH:H2O, 80 ꢀC, 2 h, 94% (d)
PPh3, CHI3, imidazole, toluene, reflux, 2.5 h, 94% (e) NaOMe, MeOH,
30 min, 95% (f) TBDMSCl, imidazole, DCM, 30 min, 95%.
Scheme 1 Reagents and condition: (a) methanol, I2, THF, 1.5 h, 85% (b)
K2CO3, MeOH, 30 min; 90% (c) TBDMS-Cl, imidazole, dry DCM, 30
min, 95%.
Scheme
overnight.
2
Reagents and conditions: (a) TiCl4, 4AoMS, DCE, rt, Scheme 6 Reagents and conditions: (a) PyBroP, DIPEA, DMAP, DCM,
0 ꢀC-rt, overnight, 95%.
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The stereochemistry of 19 was conrmed on the basis of 1H Unfortunately, we did not get any deprotected product but
and 2D NMR spectrum. The appearance of two doublet of complex mixture of products was observed. However, treatment
doublet at 4.62 d (J ¼ 4.4, 3.2) and 4.17, and two doublet at 5.03 d of 19 by 1(N) aq. HCl in THF furnished alcohol 20. Next plan was
(J ¼ 2.9) and 4.36 d (J ¼ 5.8) in 1H NMR data of 19 clearly to convert alcohol 20 into iodo compound 21.
indicated the cis relationship between H1, H2, H3, H30 and H4.
Treatment of 20 with PPh3, I2 and imidazole in dry toluene
The small coupling constant conrmed the stereochemistry of under reuxing condition provided iodo compound 21
19. In addition to this, signicant NOESY correlations are (Scheme 7).21 Purication of 21 was problematic due to the
shown in Fig. 2 whereas H-30 showed the NOESY correlation to much similar Rf value of side product triphenyl phosphine oxide
H-3 and H-2. H-3 showed NOESY correalation to H30, H-4 and H- and 21. So we decided rst to open the lactone ring of 19 before
2. All these correlations conrmed the stereochemistry of opening of sugar ring, thinking that it may change the polarity
tricyclic 19.
of products making purication of iodo compound easier.
With tricyclic framework in hand, we tried to access a series Reduction of lactone of 19 with reducing agents like NaBH4 and
of linear molecule having structural features reminiscent of LAH gave hemiacetal 22. However, reaction of 19 with LAH
natural products from tandem ring opening on carbohydrate under reuxing condition for 3 days gave diol 23 in trace
derived rigid tricyclic skeleton 19. The nucleophile can react amount leaving the unreacted hemiacetal 22. The reason for the
with electrophilic lactone of 19 while simultaneously unmask- inertia to reduction may presumably be due to an initial
ing alcohols for successive reactions. Furthermore, reductive formation of a highly stable complex.22 Failure of reduction of
N–O bond cleavage would offer two additional appendages for lactone of 19 prompted us to investigate other reactions on it.
functionalization. In this endeavor, we rst selected to open the Gratifyingly, aminolysis of 19 with DIBALH-NH2R complex in
sugar ring. The reaction sequence involved was opening of silyl dry THF furnished amide 24.23 Protection of secondary alcohol
group by tetrabutyl ammonium uoride (TBAF) in dry THF. did not work under standard condition like benzylation, acet-
ylation and coupling reactions. So we thought to proceed
further with 24. Towards our aim of opening the sugar ring,
treatment of 24 with 1(N) aq. HCl for deprotection of silyl ether
unfortunately furnished the recovery of compound 20
(Scheme 7). Above mentioned unsuccessful attempts to get
diverse acyclic molecules from tricyclic 19 prompted us to
synthesize a new tricyclic compound containing iodo func-
tionality. Thus, we synthesized an allylic alcohol 29.
Synthesis of 29 was commenced with 13 as shown in
Scheme 8. Selective replacement of primary alcohol by iodo
group using I2, triphenylphosphine, imidazole in toluene at
60 ꢀC furnished alcohol 25.24 Acetylation of 25 provided pro-
Fig. 2 NOESY correlation of 19.
tected compound 26 (ref. 25) which on acidic hydrolysis with
80% AcOH furnished diol 27. Removal of vicinal diol by treat-
ment with PPh3, CHI3, imidazole in toluene under reuxing
condition provided olen 28, which on subsequent deacetyla-
tion furnished allylic alcohol 29 (Scheme 8). Treatment of 29
with nitrone carboxylic acid 18 under above mentioned esteri-
cation condition yielded tricyclic compound 21 (Scheme 9). In
this case also, intermediate nitrone ester or carboxy iso-
xazolidine structures were not observed.
To synthesize highly functionalized diverse acyclic
compounds, we initiated reactions to functionalize tricyclic 21.
Scheme 7 Reagents and conditions: (a) TBAF, dry THF, 30 min.; (b) Scheme 8 Reagent and conditions: (a) I2, PPh3, Imidazole, toluene, 60
PPh3, I2, imidazole, dry toluene, reflux, 3 h; (c) 1 N aq. HCl, THF, 30 min, ꢀC, 2.5 h, 75% (b) Ac2O, pyridine, 12 h, 95% (c) 80%AcOH:H2O, 80 ꢀC,
95% (d) LAH, dry THF, 0 ꢀC, 1 h, 95% (e) LAH, dry THF, reflux, 3 days; (f) 1.5 h, 85% (d) PPh3, CHI3, imidazole, toluene, reflux, 2.5 h, 68% (e)
DIBAL-H, amine, dry THF, 0 ꢀC to rt, 2.5 h, 85%.
K2CO3, MeOH, 30 min, 78%.
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Scheme 9 Reagent and conditions: (a) PyBroP, DIPEA, DMAP, DCM,
0 ꢀC-rt, overnight, 72%.
In this endeavour, lactone ring was rst undertaken. Aminolysis
of lactone of 21 under above mentioned condition furnished
amides 30a–c. This reaction proceeded very well with number of
aliphatic, cyclic and aromatic amines as shown in Scheme 10.
With compounds 30a–c in hand, we aimed to open iso-
xazolidine ring. Treatment of 30 with Zn dust, NH4Cl and THF
at 65 ꢀC furnished complex mixture of products. However,
hydrogenolysis with Pd(OH)2 under H2 atmosphere gave
hydrogenated product 31. Gratifyingly, treatment with Mo(CO)6
in acetonitrile and water mixture (15 : 1) under reuxing
condition provided amino alcohol which was further protected
by acetyl group to give 32. (Scheme 11).
Scheme 11 Reagents and condition: (a) Pd(OH)2, H2, overnight; (b) Zn,
NH4Cl, THF, 65 ꢀC, 1.5 h; (c) (i) Mo(CO)6, ACN:H2O, reflux, 5 h; (ii) Ac2O,
pyridine, overnight.
The successful functionalization of lactone and iso-
xazolidine ring encouraged us to further derivatize the sugar
ring. Treatment of tricyclic compound 21 with Mo(CO)6 in
acetonitrile and water mixture under reuxing condition gave
amino alcohol 33. On purication, amino alcohol 33 was not
stable on column forcing us to proceed without purication.
Treatment of 33 with acetic anhydride in pyridine yielded 34
which on treatment with zinc, ammonium chloride in THF and
water mixture provided aldehyde 35. Wittig olenation of crude
aldehyde 35 with (carbethoxymethylene)triphenylphosphorane
in dry CH2Cl2 at room temperature furnished a,b-unsaturated
ester 36 (Scheme 12).
The successful synthesis and functionalization of tricyclic
compound 21 derived from a-D-galactopyranoside inspired us to
initiate further application of this strategy for the synthesis of
another structurally related tricyclic derivatives using D-ribose
derived homoallylic alcohol 42 and a-D-glucopyranoside derived
allylic alcohol 52. The synthesis of 42 was achieved from
D-ribose. Methylation of anomeric hydroxyl group of 37 using
acetyl chloride in methanol followed by acetonation with 2,2-
dimethoxypropane (DMP) and catalytic amount of camphor
Scheme 12 Reagents and condition: (a) Mo(CO)6, ACN:H2O, reflux (b)
Ac2O, pyridine, overnight, 72% over 2 steps (c) Zn, THF:H2O, 65 ꢀC (d)
Ph3PCH2COOEt, DCM, rt, overnight, 65%.
sulfonic acid (CSA) in acetone gave major isomer 38 (ref. 26)
with trace amount of other isomer. Acetylation of 38
provided protected compound 39 (ref. 27) which on acidic
hydrolysis with 80% AcOH furnished diol 40.28 Removal of
vicinal diol by treatment with PPh3, CHI3, imidazole in toluene
under reuxing condition provided olen 41, which on
subsequent deacetylation furnished homoallylic alcohol 42
(Scheme 13).
Synthesis of tricyclic compound 43 was achieved from
coupling of homoallylic alcohol 42 with nitrone 12 by following
the same reaction sequence as that described for 21
(Scheme 14). Stereochemistry of tricyclic 43 was conrmed by
2-D NMR spectrum.
Next, we turned our attention to synthesize a,D-glucopyr-
anoside derived alcohol 52. Benzylidine protection of 44 using
benzylidine dimethyl acetal and catalytic amount of camphor
sulphonic acid (CSA) in acetone furnished diol 45.29 Protection
Scheme 10 Reagents and conditions: (a) DIBAL-H, Amine, Dry THF,
4 h.
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Scheme 16 Reagent and conditions: (a) PyBroP, DIPEA, DMAP, DCM,
0
ꢀC-rt, 62%.
Scheme 13 Reagent and conditions: (a) (i) CH3COCl, methanol, reflux,
12 h, (ii) DMP, CSA, acetone, 12 h, 78% (b) Ac2O, pyridine, 12 h, 95% (c)
80%AcOH:H2O, 80 ꢀC, 1.5 h, 81% (d) PPh3, CHI3, imidazole, toluene,
reflux, 4 h, 62% (e) NaOMe, MeOH, 30 min, 78%.
Conclusion
In summary, we have synthesized four carbohydrate derived
tricyclic skeletons which could be useful for accessing poly-
functionalized chiral alicycles having structural features remi-
niscent of natural products. These tricyclic compounds were
synthesized by using intermolecular coupling reaction followed
by 1,3-dipolar cycloaddition among nitrone carboxylic acid and
galactose, glucose derived allylic and ribose derived homoallylic
alcohol. Among them, galactose derived tricyclic framework
furnished densely functionalized molecules. These four step
reaction sequences resulted in a collection of compounds con-
taining number of distinct, spatially separated, and encoded
chemical entities that may pave the way for exploring chemical
genetic approach. Efforts in this direction are currently
underway.
Scheme 14 Reagent and conditions: (a) PyBroP, DIPEA, DMAP, DCM,
0 ꢀC-rt, 62%.
of diol 45 as benzyl ether using BnBr, NaH in DMF yielded 46.30
Benzylidine deprotection of 46 using I2 in methanol under
reuxing condition for followed by TBDMS protection of
primary alcohol 47 (ref. 31) and mesyl protection of secondary
alcohol 48 (ref. 32) gave 49.33 Deprotection of TBDMS group of
49 using TBAF followed by swern oxidation of primary alcohol
50 (ref. 34) and subsequent reduction of aldehyde 51 (ref. 35) by
sodium borohydride in methanol produced allylic alcohol 52
(ref. 36) in good yield (Scheme 15).
Tricyclic compound 53 by using a-D-glucopyranoside derived
allylic alcohol 52 was also easily synthesized following the same
procedure as described for 21 but 53 was not diastereomericaly
pure but it was racemic (Scheme 16).
Experimental section
General
Organic solvents were dried by standard methods. All the
products were characterized by 1H, 13C, two-dimensional
homonuclear COSY (correlation spectroscopy), heteronuclear
single quantum coherence (HSQC), Nuclear Overhauser effect
spectroscopy (NOESY), IR, ESI-MS. Analytical TLC was per-
formed using 2.5 ꢁ 5 cm plates coated with a 0.25 mm thick-
ness of silica gel (60F-254) using UV light as visualizing agent
and an acidic solution of ninhydrin, and heat as developing
agents. Column chromatography was performed using silica gel
(60–120 and 100–200 mesh). NMR spectra were recorded on 300
MHz (1H) and 50, 75 MHz (13C). Experiments were recorded in
CDCl3, (CD3)2CO and CD3OD at 25 ꢀC. Chemical shis are given
on the d scale and are referenced to the TMS at 0.00 ppm for
proton and 0.00 ppm for carbon. For 13C NMR reference CDCl3
appeared at 77.00 ppm. IR spectra were recorded on FT-IR
spectrophotometers. Optical rotations were determined by
ꢀ
using a 1 dm cell at 28 C in chloroform and methanol as the
solvents; concentrations mentioned are in g 100 mLꢂ1
.
Experimental procedures and characterization data
((2R,3S,6S)-3-acetoxy-6-methoxy-3,6-dihydro-2H-pyran-2-yl)-
methyl acetate 2. To a solution of 1 (5 g, 0.18 mol), methanol
(1.5 mL) in THF (75 mL) was added iodine (0.90 g, 3.00 mmol).
Aer being stirred on room temperature for 1.5 h under N2
atmosphere, the mixture was diluted with ether. The resulting
dark red coloured mixture was washed with 50 mL of a 10%
aq.Na2S2O3 under stirring until the solution becomes colorless.
Scheme 15 Reagent and conditions: (a) benzylidine dimethyl acetal,
CSA, acetone, overnight; (b) BnBr, NaH, DMF; (c) I2, methanol, reflux;
(d) TBDMSCl, imidazole, DMF, 97% (e) MsCl, Et3N, DCM, 0 ꢀC to rt, 80%
(f) TBAF, THF, 30 min, 95% (g) (COCl)2, DMSO, DCM, DMAP, ꢂ78 ꢀC; (h)
NaBH4, methanol, 94%.
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The aqueous phase was extracted with ether. The combined as white solid. Rf 0.5 (1.5/3.5 EtOAc/hexane); IR (Neat): 3416,
1
organic layer was dried over Na2SO4 and the solvent was evap- 2920, 2367, 1608, 1508, 1246, 1034 cmꢂ1. H NMR (300 MHz,
orated under vacuo and residue was puried by column chro- (CD3)2CO): d 8.06 (s, 1H), 7.50 (t, 2H, J ¼ 6.8), 6.95 (t, 2H, J ¼ 1.9),
matography to give 2 (3.84 g, 85%) as white gum. [a]2D8 ¼ +140.1 3.82 (s, 3H); MS (ESI): m/z 152 (M+ + H). Anal. calcd for
(c 1.1, CHCl3); eluent column chromatography: EtOAc/hexane C8H9NO2:C, 63.56; H, 6.00; N, 9.27. Found: C, 63.62; H, 6.09; N,
(5/45, v/v); Rf 0.30 (2/3 EtOAc/hexane); IR (Neat): 3416, 2920, 9.34.
2367, 1608, 1508, 1246, 1034 cmꢂ1. 1H NMR (300 MHz, CDCl3): d
N-(4-methoxybenzyl)hydroxylamine 10. To a solution of
5.87–5.77 (m, 2H), 5.29–5.25 (m, 1H), 4.88 (br s, 1H), 4.25–4.12 oxime 9 (1.78 g, 0.01 mol) and NaBH3CN (1.11 g, 0.02 mmol) in
(m, 2H), 4.05–3.99 (m, 1H), 3.43 (s, 3H), 2.08 (s, 3H), 2.07 (s, 3H). 17 mL of methanol was added a trace of bromocresol green. A
13CNMR (75 MHz, CDCl3): d 170.1, 169.7, 129.2, 127.7, 95.4, solution of 2 N HCl methanol was then added drop wise with
66.9, 65.3, 62.8, 55.7, 20.8, 20.6; MS (ESI): m/z 245 (M+ + H). Anal. stirring to maintain the yellow color. Aer ca. 15 min, the color
calcd for C11H16O6:C, 54.09; H, 6.60. Found: C, 54.15; H, 6.65.
changed very slowly. The solution was stirred for 3 h, and the
(2R,3S,6S)-2-((tert-butyldimethylsilyloxy)methyl)-6-methoxy- methanol was removed at reduced pressure. The residue was
3,6-dihydro-2H-pyran-3-ol 4. To the stirred solution of 3 (0.90 g, dissolved in 10 mL of water, raised to pH > 9 with 6 N KOH,
5.61 mmol) in dry DCM (15 mL), TBDMSCl (0.93 g, 6.18 mmol) saturated with sodium chloride, and extracted with four 15 mL
and imidazole (0.57 g, 8.42 mmol) were added at 0 ꢀC and portions of chloroform. The combined extracts were dried over
allowed to stir for 30 min. Aer completion of reaction, it was Na2SO4 and evaporated in vucuo to give (1.35 g, 72%) of 10 as
diluted with water and extracted with dichlomethane (15 mL ꢁ white solid. Rf 0.5 (1.5/3.5 EtOAc/hexane); IR (Neat): 3416, 2920,
3). The combined organic extracts were washed with brine, and 2367, 1608, 1508, 1246, 1034 cmꢂ1 1H NMR (300 MHz,
.
dried over Na2SO4. The organic fraction was concentrated in (CD3)2CO): d 7.40 (d, 2H, J ¼ 8.7), 6.91–6.88 (m, 2H), 4.97 (s, 2H),
vacuo to give 4 (1.46 g, 95%) as colorless gum. [a]D28 ¼ + 69.2 3.79 (s, 3H); 13C NMR (75 MHz, (CD3)2CO): d 160.1, 130.0, 127.7,
(c 0.03, MeOH). Rf 0.80 (1/1 EtOAc/hexane). Eluent for column 114.3, 63.4, 55.3; MS (ESI): m/z 152 (M+ + H). Anal. calcd for
chromatography: EtOAc/hexane (7.5/22.5, v/v); IR (Neat): 3416, C8H11NO2:C, 62.73; H, 7.24; N, 9.14; Found: C, 62.82; H, 7.31;
1
2920, 2367, 1608, 1508, 1246, 1034 cmꢂ1. H NMR (300 MHz, N, 9.21.
CDCl3): d 5.93–5.87 (m, 1H), 5.72–5.64 (m, 1H), 4.79 (d, 1H, J ¼
N-(carboxymethylene)-1-(4-methoxyphenyl)methanamine
1.3), 4.14–4.06 (m, 1H), 3.93–3.81 (m, 2H), 3.79–3.59 (m, 1H), oxide 11. To the solution of 10 (0.30 g, 1.95 mmol) in dry DCM
3.40 (s, 3H), 2.82 (s, 1H), 0.92 (s, 9H), 0.11 (s, 6H). 13C NMR (75 (10 mL), glyoxalic acid (0.19 g, 2.05 mmol) was added and
MHz, CDCl3): d 133.2, 125.7, 95.2, 70.6, 66.5, 65.1, 55.5, 25.9, allowed to stir for overnight. Aer completion of reaction, it was
18.4, ꢂ5.36, ꢂ5.38; MS (ESI): m/z 275 (M+ + H). Anal. calcd for diluted with water and extracted with dichloromethane (10 mL
C
13H26O4Si:C, 56.90; H, 9.55. Found: C, 56.99; H, 9.63.
ꢁ 3). The combined organic extracts were washed with brine,
N-(2-ethoxy-2-oxoethylidene)-N-(4-methoxybenzyl)hydroxyl- and dried over Na2SO4. The organic fraction was concentrated
ammonium 5. To the solution of diethyl-D-tartrate (1.20 g, 6.00 in vacuo to give 11 (0.30 g, 75%) as white semi solid. Rf 0.2
1
mmol) in dry ether (20 mL) cooled in a cold water bath was (EtOAc); IR (Neat): 3450, 2926, 2366, 1718, 1253, 772 cmꢂ1. H
added paraperiodic acid (1.33 g, 6.00 mmol) in portion over 1 h NMR (300 MHz, CDCl3): d 14.6 (brs, 1H), 7.33 (d, 2H, J ¼ 8.6),
under nitrogen with stirring. The milky reaction mixture was 6.97 (d, 2H, J ¼ 8.6), 4.99 (s, 2H), 3.84 (s, 3H); MS (ESI): m/z 210
then stirred for a few minutes until the ether solution had (M+ + H). Anal. calcd for C10H11NO4:C, 57.41; H, 5.30; N, 6.70.
become almost clear and a white solid separated. The ether Found: C, 57.49; H, 5.40; N, 6.61.
phase was decanted, dried with molecular sieves, evaporated,
(3aS,4R,6S,7R,7aR)-4-(hydroxymethyl)-6-methoxy-2,2-dime-
and distilled through a column to give clear ethyl glyoxylate thyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-7-ol 13. To the
(1.02 g, 82%). To an ice cooled mixture of 10 (1.60 g, 11.00 solution of 12 (8.0 g, 0.04 mol) in acetone (250 mL) was added
mmol) and calcium chloride (0.29 g, 2.00 mmol) in 29 mL of 2,2-dimethoxypropane (6.07 mL, 0.05 mol) followed by catalytic
ether, ethyl glyoxylate (1.02 g, 7.00 mmol) was added drop wise, amount of camphorsulfonic acid. Aer 12 h of stirring, the
ꢀ
aer which the whole residue was stirred at 0 C for 1 h. The reaction mixture was concentrated under reduced pressure to a
solids were removed by ltration through an anhydrous Na2SO4, colorless oil which on column chromatographic purication
and the ltrate was evaporated to give 5 (1.64 g, 88%). Mp 84.0– gave the pure compound 13 (5.78 g, 60%) as a white semi solid.
86.5 ꢀC; IR (KBr): 1720, 1560, 1200, 1045, 965, 825, 700 cmꢂ1; 1H [a]D28 ¼ +17.5 (c 9.8, MeOH); Rf 0.4 (EtOAc). Eluent for column
NMR (300 MHz, CDCl3): d 7.40 (m, 5H), 7.17 and 7.09 (s, 1H), chromatography: EtOAc/hexane (30/20, v/v); IR (Neat): 3452,
5.69 and 4.96 (s, 2H), 4.25 and 4.22 (q, 2H, J ¼ 7.0), 1.30 and 1.27 3018, 2363, 1379, 1217 cmꢂ1. 1H NMR (300 MHz, CDCl3): d 4.69
(t, 3H, J ¼ 7.0); MS (ESI): m/z 238 (M+ + H). Anal. calcd for (d, 1H, J ¼ 2.1), 4.19–4.16 (m, 2H), 4.08–3.96 (m, 1H), 3.87–3.70
C12H15NO4:C, 60.75; H, 6.37; N, 5.90. Found: C, 60.82; H, 6.31; (m, 3H), 3.38 (s, 3H), 3.10 (d, 1H, J ¼ 6.3), 2.82 (d, 1H, J ¼ 3.5);
N, 5.96.
4-methoxybenzaldehyde oxime 9. To the solution of hydroxyl 62.2, 55.3, 27.6, 25.8; MS (ESI): m/z 235 (M+ + H). Anal. calcd for
13C NMR (75 MHz, CDCl3): 109.5, 98.6, 76.1, 73.6, 69.5, 67.9,
amine hydrochloride 8 (7.65 g, 0.11 mol) in saturated solution
of KOH, was added p-methoxy benzaldehyde 7 (10 g, 0.07 mol)
C
10H18O6:C, 51.27; H, 7.75; Found: C, 51.34; H, 7.82.
((3aS,4R,6S,7R,7aS)-7-acetoxy-6-methoxy-2,2-dimethylte-
and allowed to stir for 2 hour at 0 ꢀC. Aer completion of trahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yl)methyl acetate 14.
reaction, reaction mixture was ltered and residue was washed To the solution of 13 (2.03 g, 0.008 mol) in pyridine (10 mL) was
with cold water (200 mL) and dried in air to give 9 (10.2 g, 92%) added acetic anhydride (3.27 mL, 0.03 mol). Aer 12 h of
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stirring, the reaction mixture was concentrated under reduced dried over Na2SO4. The organic fraction was concentrated in
pressure to a colorless oil which on column chromatographic vacuo to give 17 (1.12 g, 95%) as white gum. [a]2D8 ¼ +93.2 (c 0.9,
purication gave the pure compound 14 (2.50 g, 91%) as a CHCl3); Rf 0.2 (1/1 EtOAc:hexane). Eluent for column chroma-
colorless gum. [a]2D8 ¼ +17.0 (c 11.8, MeOH); Rf 0.8 (1/1 EtOA- tography: EtOAc/hexane (40/10, v/v); IR (Neat): 3469, 2928, 1742,
c:hexane). Eluent for column chromatography: EtOAc/hexane 1372, 1245, 1047 cmꢂ1. 1H NMR (300 MHz, CDCl3): d 5.80 (d, 1H, J
(10/40, v/v); IR (Neat): 3433, 2995, 2364, 1735, 1377, 1236, ¼ 10.6), 5.69 (d, 1H, J ¼ 10.6), 4.91 (d, 1H, J ¼ 4.1), 4.21–4.20 (m,
1036 cmꢂ1. 1H NMR (300 MHz, CDCl3): d 4.92–4.90 (m, 1H), 4.85 2H), 3.74–3.57 (m, 2H), 3.53 (s, 3H), 2.38 (d, 1H, J ¼ 11), 2.19 (bs,
(d, 1H, J ¼ 3.5), 4.42–4.28 (m, 3H), 4.24–4.15 (m, 2H), 3.39 (s, 1H); MS (ESI): m/z 161 (M+ + H). Anal. calcd for C7H12O4:C, 52.49;
3H), 2.14 (s, 3H), 2.10 (s, 3H), 1.52 (s, 3H), 1.34 (s, 3H); 13C NMR H, 7.55; Found: C, 52.56; H, 7.64.
(75 MHz, CDCl3): 170.6, 170.3, 109.9, 96.9, 73.34, 73.31, 71.6,
(2S,3R,6S)-6-((tert-butyldimethylsilyloxy)methyl)-2-methoxy-
65.4, 63.5, 55.3, 27.7, 26.2, 20.8, 20.7; MS (ESI): m/z 319 (M+ + H). 3,6-dihydro-2H-pyran-3-ol 18. To the stirred solution of 17 (0.19
Anal. calcd for C14H22O8:C, 52.82; H, 6.97; Found: C, 52.90; H, g, 1.23 mmol) in dry DCM (5 mL), TBDMSCl (0.20 g, 1.35 mmol)
6.88.
and imidazole (0.13 g, 1.85 mmol) were added at 0 ꢀC and
((2R,3R,4S,5R,6S)-5-acetoxy-3,4-dihydroxy-6-methoxytetrahy- allowed to stir for 30 minutes. Aer completion of reaction, it
dro-2H-pyran-2-yl)methyl acetate 15. To compound 14 (2.20 g, was diluted with water and extracted with dichloromethane (10
0.007 mꢀol), 80% acetic acid (25 mL) was added and stirred for 2 mL ꢁ 3). The combined organic extracts were washed with
h at 80 C. Aer completion of reaction (TLC), the acidic solu- brine, and dried over Na2SO4. The organic fraction was
tion was concentrated under reduced pressure to give a crude concentrated in vacuo to give 18 (0.30 g, 95%) as colorless gum.
product which was puried by column chromatography to yield [a]2D8 ¼ ꢂ9.1 (c 1.5, CHCl3); Rf 0.80 (1/4 EtOAc/hexane). Eluent
compound 15 (1.80 g, 94%) as a colorless gum. Rf 0.2 (1/1 for column chromatography: EtOAc/hexane (2.5/47.5, v/v); IR
1
EtOAc:hexane). [a]D28 ¼ +99.5 (c 1.6, CHCl3); Eluent for column (Neat): 3447, 3021, 2359, 1216, 1056, 768 cmꢂ1. H NMR (300
chromatography: EtOAc/hexane (25/25, v/v); IR (Neat): 3461, MHz, CDCl3): d 5.82 (d, 1H, J ¼ 10.6), 5.73 (d, 1H, J ¼ 10.6), 4.87
3021, 1735, 1238, 1053, 756 cmꢂ1. 1H NMR (300 MHz, CDCl3): d (d, 1H, J ¼ 4.3), 4.20–4.09 (m, 2H), 3.72–3.56 (m, 2H), 3.51
4.98–4.94 (m, 1H), 4.82 (d, 1H, J ¼ 3.6), 4.32–4.26 (m, 1H), 4.21– (s, 3H), 2.24 (d, 1H, J ¼ 11.1), 0.89 (s, 9H), 0.07 (s, 6H); 13C NMR
4.15 (m, 1H), 3.92–3.91 (m, 3H), 3.55 (bs, 1H), 3.31 (s, 3H), 2.07 (CDCl3, 75 MHz): d 127.6, 127.3, 97.9, 77.6, 76.9, 76.3, 69.0, 65.4,
(s, 3H), 2.02 (s, 3H); MS (ESI): m/z 279 (M+ + H). Anal. calcd for 64.3, 55.9, 25.8, 18.3, ꢂ5.33, ꢂ5.37; MS (ESI): m/z 275 (M+ + H).
C
11H18O8:C, 47.48; H, 6.52; Found: C, 47.54; H, 6.61.
((2S,5R,6S)-5-acetoxy-6-methoxy-5,6-dihydro-2H-pyran-2-yl)- 9.63.
methyl acetate 16. Compound 15 (1.37 g, 0.005 mol) was dis- Compound 19. To the solution of 18 (0.20 g, 0.73 mmol), 11
Anal. calcd for C13H26O4Si:C, 56.90; H, 9.55 Found: C, 56.99; H,
solved in dry toluene (200 mL) under nitrogen atmosphere and (0.31 g, 1.45 mmol) and PyBroP (0.68 g, 1.45 mmol) in DCM was
stirred for 30 min. at room temperature. Then triphenyl phos- DIPEA (0.51 mL, 2.91 mmol), DMAP (0.09 g, 0.80 mmol) were
phine (5.28 g, 0.02 mol), iodoform (3.96 g, 0.01 mol) and added at 0 ꢀC under argon atmosphere. Aer overnight stirring,
imidazole (0.68 g, 0.01 mol) were successively added and the it was diluted with water and extracted with dichloromethane
reaction mixture was heated to reux for 2.5 h with vigorous (10 mL ꢁ 3). The combined organic extracts were washed with
heating. Aer cooling to room temperature, methanol and brine, and dried over Na2SO4. The organic fraction was
saturated solution of sodium bicarbonate were added. The concentrated in vacuo and puried by column chromatography
organic layer was separated and aqueous layer was extracted to give 19 (0.30 g, 95%) as yellowish gum. [a]2D8 ¼ + 123.2 (c 0.23,
with ether. The combined organic portion were dried over CHCl3), Rf 0.3 (EtOAc). Eluent for column chromatography:
Na2SO4 and concentrated under vacuo to give a crude product EtOAc/hexane (30/20, v/v); IR (Neat): 3426, 2931, 1664, 1249, 765
which was puried by column chromatography to yield cmꢂ1. 1H NMR (300 MHz, CDCl3): d 7.33 (d, 1H, J ¼ 8.5), 6.80 (d,
compound 16 (1.80 g, 94%) as a colorless. Rf 0.8 (1/1 EtOA- 1H, J ¼ 8.5), 5.03 (d, 1H, J ¼ 2.9), 4.62 (dd, 1H, J ¼ 4.4, 3.2), 4.36
c:hexane). [a]2D8 ¼ +112 (c 1.6, CHCl3); Eluent for column chro- (d, 1H, J ¼ 5.8), 4.23 (d, 1H, J ¼ 10.1), 4.17 (brs, 1H), 3.95–3.91
matography: EtOAc/hexane (7.5/42.5, v/v); IR (Neat): 3416, 2920, (m, 2H), 3.84–3.80 (m, 5H), 3.50 (s, 3H), 3.47–3.42 (m, 1H), 0.90
2367, 1608, 1508, 1246, 1034 cmꢂ1. 1H NMR (300 MHz, CDCl3): d (s, 9H), 0.08 (s, 6H); 13C NMR (CDCl3, 75 MHz): d 172.5, 159.3,
5.82 (d, 1H, J ¼ 11), 5.79 (d, 1H, J ¼ 11), 5.32–5.31 (m, 1H), 5.10 130.4, 127.7, 113.9, 95.4, 72.3, 72.1, 67.2, 65.0, 56.4, 55.2, 43.0,
(d, 1H, J ¼ 4.1), 4.39 (d, 1H, J ¼ 2.1), 4.18 (d, 1H, J ¼ 5.0), 3.50 (s, 31.4, 25.8, ꢂ5.5; MS (ESI): m/z 466 (M+ + H). Anal. calcd for
3H), 2.12 (s, 3H), 2.09 (s, 3H); 13C NMR (75 MHz, CDCl3): 170.5,
C23H35NO7Si:C, 59.33; H, 7.58; N, 3.01. Found: C, 59.41; H, 7.67;
127.8, 124.3, 95.9, 66.7, 66.5, 65.3, 56.1, 20.9, 20.8; MS (ESI): m/z N, 3.10.
245 (M+ + H). Anal. calcd for C11H16O6:C, 54.09; H, 6.60; Found:
C, 54.17; H, 6.69.
Compound 20. To the solution of 19 (0.05 g, 0.11 mmol) in
THF, 1 N HCl was added and stirred for 30 min. at room
(2S,3R,6S)-6-(hydroxymethyl)-2-methoxy-3,6-dihydro-2H- temperature. Aer completion of reaction, it was diluted with
pyran-3-ol 17. To the stirred solution of 16 (1.80 g, 0.007 mol) in water. Aqueous layer was extracted with ethyl acetate (10 mL ꢁ
methanol, anhydrous K2CO3 (2.54 g, 0.2 mol) was added and 3). The combined organic extracts were washed with brine, and
allowed to stir for 30 min. Aer completion of reaction, meth- dried over Na2SO4. The organic fraction was concentrated in
anol was evaporated in vacuo and residue was diluted with vacuo to give 20 (0.30 g, 95%) as white semi solid. [a]2D8 ¼ +53.2 (c
water. Aqueous layer was extracted with ethyl acetate (20 mL ꢁ 3). 0.35, MeOH). Rf 0.3 (0.2/9.8 MeOH/Chloroform); IR (Neat): 3416,
1
The combined organic extracts were washed with brine, and 2920, 2367, 1608, 1508, 1246, 1034 cmꢂ1. H NMR (300 MHz,
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CDCl3): d 7.21 (d, 1H, J ¼ 8.5), 6.83 (d, 1H, J ¼ 8.5), 4.94 (d, 1H, J 2363, 1657, 1518, 1251 cmꢂ1. 1H NMR (300 MHz, CDCl3): d 7.64
¼ 3.9), 4.59–4.38 (m, 4H), 3.91–3.87 (m, 2H), 3.86–3.77 (m, 4H), (t, 1H, J ¼ 5.2), 7.32–7.22 (m, 3H), 7.17–7.13 (m, 4H), 6.78 (d, 1H,
3.55–3.50 (m, 1H), 3.33 (s, 3H), 2.02 (s, 1H); 13C NMR (CDCl3, 75 J ¼ 8.5), 4.62 (d, 1H, J ¼ 3.6), 4.53–4.46 (m, 1H), 4.32 (t, 1H, J ¼
MHz): d 170.3, 158.6, 129.8, 128.9, 113.8, 97.3, 75.2, 72.7, 68.1, 7.4), 4.24–4.10 (m, 3H), 3.94–3.83 (m, 4H), 3.78–3.74 (s, 4H),
62.1, 555.4, 55.2, 48.3; MS (ESI): m/z 352 (M+ + H). Anal. calcd for 3.71–3.68 (m, 1H), 3.42 (s, 3H), 3.23–3.21 (m, 1H), 0.90 (s, 9H),
C
17H21NO7:C, 58.11; H, 6.02; N, 3.99. Found: C, 58.20; H, 6.10; 0.07 (s, 6H); 13C NMR (75 MHz, CDCl3): d 170.4, 159.3, 137.7,
N, 3.90.
130.8, 128.5, 127.6, 127.3, 114.0, 98.0, 74.4, 70.2, 68.1, 65.9, 64.2,
Compound 22. To a solution of 19 (0.05 g, 0.11 mmol) in dry 62.4, 55.4, 55.2, 47.6, 43.3, 25.9, ꢂ5.34; MS (ESI): m/z 569 (M+ +
THF, LAH (0.005 g, 0.15 mmol) was added at 0 ꢀC and stirred for H). Anal. calcd for C30H44N2O7Si:C, 62.91; H, 7.74; N, 4.89;
1 h at room temperature. Aer completion of reaction, it was Found: C, 62.90; H, 7.81; N, 4.96.
quenched by water and extracted by ethyl acetate (5 mL ꢁ 3).
(3aR,4S,6S,7R,7aR)-4-(iodomethyl)-6-methoxy-2,2-dimethyl-
The combined organic portion were washed with brine, dried tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-7-ol 25. To the solution
over Na2SO4 and concentrated under vacuo. Crude was puried of 12 (0.10 g, 0.43 mmol) in dry toluene (10 mL), triphenyl
by column chromatography to give 22 (0.04 g, 95%) as colour- phosphine (0.15 g, 0.59 mmol), iodine (0.16 g, 0.64 mol) and
less oil. [a]2D8 ¼ + 93.5 (c 0.43, CHCl3). Rf 0.4 (3/2EtOAc:hexane). imidazole (0.08 g, 1.28 mmol) were successively added and the
Eluent for column chromatography: EtOAc/hexane (20/30, v/v); reaction mixture was heated at 60 ꢀC for 2.5 h with vigorous
1
IR (Neat): 3416, 2920, 2367, 1608, 1508, 1246, 1034 cmꢂ1. H heating. Aer cooling to room temperature, organic layer was
NMR (300 MHz, CDCl3): d 7.26 (d, 2H, J ¼ 8.5), 6.85 (d, 2H, J ¼ separated and aqueous layer was extracted with ether. The
8.5), 5.26 (s, 1H), 4.90 (d, 1H, J ¼ 4.3), 4.63 (t, 1H, J ¼ 4.7), 4.26 (t, combined organic portion were dried over Na2SO4 and
1H, J ¼ 7.8), 3.99–3.94 (m, 2H), 3.89–3.88 (m, 2H), 3.81 (s, 3H), concentrated under vacuo to give a crude product which was
3.77–3.68 (m, 2H), 3.31 (s, 3H), 3.29–3.22 (m, 2H), 0.90 (s, 9H), puried by column chromatography to yield compound 25
0.07 (s, 6H); MS (ESI): m/z 467 (M+ + H). Anal. calcd for (0.11 g, 75%) as a colorless oil. [a]2D8 ¼ +119 (c 1.0, CHCl3); Rf 0.8
C
23H37NO7Si:C, 59.07; H, 7.98; N, 3.00; Found: C, 59.13; H, 7.70; (1/1EtOAc:hexane). Eluent for column chromatography: EtOAc/
N, 3.10.
hexane (5/45, v/v); IR (Neat): 3445, 2918, 1638, 1216, 1066, 761
Compound 23. To a solution of 22 (0.05 g, 0.11 mmol) in dry cmꢂ1. 1H NMR (300 MHz, CDCl3): d 4.69 (d, 1H, J ¼ 3.8), 4.26–
THF, LAH (0.012 g, 0.33 mmol) was added at 0 ꢀC and reuxed 4.19 (m, 2H), 4.08–4.04 (m, 1H), 3.79–3.76 (m, 1H), 3.44 (s, 3H),
for 3 days. Aer that, it was quenched by water and extracted by 3.28–3.24 (m, 2H), 2.69 (br s, 1H), 1.42 (s, 3H), 1.28 (s, 3H); 13
C
ethyl acetate (5 mL ꢁ 3). The combined organic portion were NMR (75 MHz, CDCl3): 109.5, 98.2, 75.6, 73.4, 69.1, 55.4, 27.3,
washed with brine, dried over Na2SO4 and concentrated under 25.6, 2.7; MS (ESI): m/z 345 (M+ + H). Anal. calcd for
vacuo. Crude was puried by column chromatography to give 23
(0.005 g, 10%) as colourless oil. [a]2D8 ¼ + 110.2 (c 0.52, CHCl3). Rf
C
10H17IO5:C, 34.90; H, 4.98; Found: C, 34.98; H, 4.90.
(3aR,4S,6S,7R,7aS)-4-(iodomethyl)-6-methoxy-2,2-dimethyl-
0.3 (EtOAc). Eluent for column chromatography: EtOAc/hexane tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-7-yl acetate 26. As
(40/10, v/v); IR (Neat): 3420, 2920, 2361, 1612, 1504, 1246, 1031 described for 13, compound 26 was prepared from compound
cmꢂ1. 1H NMR (300 MHz, CDCl3): d 7.26 (d, 2H, J ¼ 8.5), 6.84 (d, 25 (0.10 g, 0.29 mmol), dry pyridine (2 mL) and acetic anhydride
2H, J ¼ 8.5), 4.62 (s, 1H), 4.61–4.24 (m, 1H), 4.18 (t, 1H, J ¼ 4.2), (0.05 mL, 0.58 mmol). Crude product was puried by column
4.02–4.00 (m, 3H), 3.99–3.90 (m, 3H), 3.89–3.84 (m, 1H), 3.83 (s, chromatography to yield compound 26 (0.10g, 95%) as a
3H), 3.69–3.64 (m, 1H), 3.49 (s, 3H), 3.41–3.34 (m, 1H), 2.92–2.30 colorless. [a]2D8 ¼ +19.1 (c 1.5, CHCl3); Rf 0.6 (1/4 EtOAc:hexane).
(m, 1H), 0.90 (s, 9H), 0.06 (s, 6H); 13C NMR (75 MHz, CDCl3): d Eluent for column chromatography: EtOAc/hexane (5/45, v/v); IR
159.1, 130.5, 128.3, 113.8, 98.1, 73.1, 71.6, 67.3, 65.9, 64.3, 61.3, (Neat): 3416, 2920, 2367, 1608, 1508, 1246, 1034 cmꢂ1. 1H NMR
55.5, 55.2, 45.6, 31.9, 25.9, 22.7, -5.3; MS (ESI): m/z 470 (M+ + H). (300 MHz, CDCl3): d 4.91(dd, 1H, J ¼ 10.3, 6.6), 4.84 (d, 1H, J ¼
Anal. calcd for C23H39NO7Si:C, 58.82; H, 8.37; N, 2.98; Found: C, 3.4), 4.37–4.30 (m, 2H), 4.11 (d, 1H, J ¼ 7.5), 3.43 (s, 3H), 3.36–
58.91; H, 8.43; N, 2.90.
3.33 (m, 2H), 2.13 (s, 3H), 1.52 (s, 3H), 1.35 (s, 3H); 13C NMR (75
Compound 24. A solution of DIBAL–H (1.0 M in toluene, 0.62 MHz, CDCl3): 170.4, 109.7, 97.3, 73.8, 73.4, 71.5, 68.2, 55.6, 27.8,
mL, 0.62 mmol) was added to a cooled (0–5 ꢀC) solution of 26.3, 20.9, 2.1; MS (ESI): m/z 387 (M+ + H). Anal. calcd for
benzylamine (0.07 mL, 0.63 mmol) in THF (0.27 mL) under
nitrogen. The mixture was allowed to warm up and stirred at RT
C
12H19IO6:C, 37.32; H, 4.96; Found: C, 37.40; H, 4.90.
(2S,3R,4S,5R)-4,5-dihydroxy-6-(iodomethyl)-2-methoxytetra-
for 2 h. To a solution of 19 (0.05 g, 0.11 mmol) in THF (0.40 mL) hydro-2H-pyran-3-yl acetate 27. As described for 14, compound
was added, under nitrogen at rt, the DIBAL–H–amine 27 was prepared from compound 26 (0.01 g, 0.25 mmol), 80%
complexes (0.27 mL). Aer stirring at rt for 2 h, the reaction was acetic acid. Crude product was puried by column chromatog-
cooled to 0 ꢀC, and then quenched with H2O (1.5 mL) and a 1 M raphy to yield compound 27 (0.07 g, 85%) as a colorless. Rf 0.2
aqueous solution of KHSO4 (4 mL). The resulting mixture was (1/1 EtOAc:hexane). [a]2D8 ¼ +87.5 (c 1.1, CHCl3); Eluent for
extracted with CH2Cl2 (3 ꢁ 10 mL). The combined organic column chromatography: EtOAc/hexane (25/25, v/v); IR (Neat):
1
layers were washed with brine, dried over Na2SO4 and concen- 3416, 2920, 2367, 1608, 1508, 1246, 1034 cmꢂ1. H NMR (300
trated under vacuo. The residue was puried by column chro- MHz, CDCl3): d 5.01 (dd, 1H, J ¼ 10.3, 6.6), 4.88 (d, 1H, J ¼ 3.4),
matography to give 24 (0.05 g, 85%). [a]2D8 ¼ + 106.3 (c 0.85, 4.15 (d, 1H, J ¼ 2.5), 4.02–3.94 (m, 2H), 3.45 (s, 3H), 3.36 (d, 2H, J
CHCl3). Rf 0.5 (1.5/3.5 EtOAc:hexane). Eluent for column chro- ¼ 6.9), 3.26 (bs, 2H), 2.16 (s, 3H); 13C NMR (75 MHz, CDCl3):
matography: EtOAc/hexane (25/25, v/v); IR (Neat): 3370, 2925, 171.8, 97.3, 71.0, 70.5, 70.3, 68.3, 55.6, 21.1, 2.7; MS (ESI): m/z
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346 (M+ + H). Anal. calcd for C9H15IO6:C, 31.23; H, 4.37; Found: 7.20–7.17 (m, 3H), 7.13–7.10 (m, 2H), 7.01 (d, 2H, J ¼ 6.2), 6.70
C, 31.31; H, 4.30.
(d, 2H, J ¼ 8.5), 4.47 (d, 1H, J ¼ 3.5), 4.45–4.17 (m, 1H), 4.25–4.15
(2S,3R,6S)-6-(iodomethyl)-2-methoxy-3,6-dihydro-2H-pyran- (m, 1H), 4.15–4.05 (m, 1H), 4.00–3.95 (m, 1H), 3.95–3.75 (m,
3-yl acetate 28. As described for 15, compound 28 was prepared 3H), 3.68 (s, 3H), 3.41–3.32 (m, 4H), 3.24–3.13 (m, 1H), 3.10 (t,
from compound 27 (1.8 g, 0.005 mol), PPh3 (7.56 g, 0.02 mol), 2H, J ¼ 8.1); 13C NMR (75 MHz, CDCl3): d 170.1, 159.5, 128.6,
iodoform (4.24 g, 0.01 mol) and imidazole (1.41 g, 0.003 mol). 127.8, 127.7, 127.5, 127.3, 114.3, 97.2, 74.9, 67.6, 67.5, 58.4, 56.0,
Crude product was puried by column chromatography to yield 55.3, 53.5, 37.1, 4.7; MS (ESI): m/z 569 (M+ + H). Anal. calcd for
compound 28 (1.22 g, 68%) as a colorless oil. [a]2D8 ¼ +103.5
C24H29IN2O6:C, 50.71; H, 5.14; N, 4.93; Found: C, 50.70; H, 5.20;
(c 1.8, CHCl3); Rf 0.8 (1/1 EtOAc:hexane). Eluent for column N, 4.90.
chromatography: EtOAc/hexane (7.5/42.5, v/v); IR (Neat): 3416,
Compound 30b. As described for 24, compound 30b was
1
2920, 2367, 1608, 1508, 1246, 1034 cmꢂ1. H NMR (300 MHz, prepared from compound 21 (0.05 g, 0.11 mmol), cyclohexyl-
CDCl3): d 5.88–5.73 (m, 2H), 5.30–5.27 (m, 1H), 5.11 (d, 1H, J ¼ amine (0.07 mL, 0.63 mmol) in THF (0.27 mL), DIBAL-H (0.62
3.9), 4.22–4.21 (m, 1H), 3.49 (s, 3H), 3.33–3.20 (m, 2H), 2.12 mL, 0.62 mmol). Crude product was puried by column chro-
(s, 3H); 13C NMR (75 MHz, CDCl3): 170.4, 129.9, 124.2, 96.2, matography to yield compound 30b (0.05 g, 85%) as a light
67.0, 66.4, 56.0, 20.9, 8.5; MS (ESI): m/z 312 (M+ + H). Anal. calcd yellow semi solid. [a]2D8 ¼ 52.8 (c 0.03, CHCl3); Rf 0.5 (3/
for C9H13IO4:C, 34.63; H, 4.20; Found: C, 34.70; H, 4.28.
2EtOAc:hexane). Eluent for column chromatography: EtOAc/
(2S,3R,6S)-6-(iodomethyl)-2-methoxy-3,6-dihydro-2H-pyran- hexane (25/25, v/v); IR (Neat): 3416, 2920, 2367, 1608, 1508,
3-ol: 29. To the stirred solution of 28 (0.85 g, 2.71 mmol) in 1246, 1034 cmꢂ1. 1H NMR (300 MHz, CDCl3+ CD3OD): d 7.16 (d,
methanol, anhydrous K2CO3 (0.56 g, 4.06 mmol) was added and 1H, J ¼ 8.5), 6.78 (d, 1H, J ¼ 8.5), 4.49 (s, 1H), 4.15–4.01 (m, 3H),
allowed to stir for 30 min. Aer completion of reaction, meth- 3.83–3.74 (m, 3H), 3.50 (s, 3H), 3.44–3.25 (m, 2H), 3.09–3.06 (m,
anol was evaporated in vacuo and residue was diluted with 2H), 1.77–1.73 (m,1H), 1.59–1.49 (m, 5H), 1.30–1.09 (m, 4H); 13
C
water. Aqueous layer was extracted with ethyl acetate (20 mL ꢁ NMR (75 MHz, CDCl3+MeOH): d 169.1, 158.9, 130.3, 126.8,
3). The combined organic extracts were washed with brine, and 113.5, 97.7, 78.1, 69.2, 67.4, 65.0, 61.7, 55.1, 54.5, 49.2, 48.8,
dried over Na2SO4. The organic fraction was concentrated in 48.3, 47.9, 47.5, 47.0, 46.6, 31.7, 31.5, 24.8, 24.0, 5.8; MS (ESI): m/
vacuo and crude product was puried by column chromatog- z 561 (M+ + H). Anal. calcd for C23H33IN2O6:C, 49.29; H, 5.94; N,
raphy to yield compound 29 (0.57 g, 78%) as a colorless gum. 5.00; Found: C, 49.37; H, 5.88; N, 5.09.
[a]2D8 ¼ 59.3 (c 0.32, MeOH). Rf 0.5 (1.5/8.5 EtOAc:hexane). Eluent
Compound 30c. As described for 24, compound 30c was
for column chromatography: EtOAc/hexane (6/44, v/v); IR prepared from compound 19 (0.5 g, 0.11 mmol), phenethyl
(Neat): 3416, 2920, 2367, 1608, 1508, 1246, 1034 cmꢂ1. 1H NMR amine (0.08 mL, 0.64 mmol) in THF (0.27 mL) and DIBAL-H
(300 MHz, CDCl3): d 5.85–5.72 (m, 2H), 5.72–5.68 (m, 1H), 4.91 (0.62 mL, 0.62 mmol). Crude product was puried by column
(d, 1H, J ¼ 4.2), 4.21–4.20 (m, 2H), 3.53 (s, 3H), 3.32–3.18 (m, chromatography to yield compound 30c (0.05 g, 85%) as a white
2H); 13C NMR (75 MHz, CDCl3): 128.8, 127.9, 98.4, 67.0, 64.0, semi solid. [a]2D8 ¼ +181.4 (c 0.03, CHCl3) Rf 0.5 (3/2 EtOA-
56.1, 9.0; MS (ESI): m/z 270 (M+ + H). Anal. calcd for C7H11IO3:C, c:hexane). Eluent for column chromatography: EtOAc/hexane
31.13; H, 4.11; Found: C, 31.21; H, 4.20.
(25/25, v/v); IR (Neat): 3416, 2920, 2367, 1608, 1508, 1246,
Compound 21. As described for 19, compound 21 was 1034 cmꢂ1. 1H NMR (300 MHz, CDCl3+ CD3OD): d 7.33–7.19 (m,
prepared from compound 29 (0.10 g, 0.37 mmol), 11 (0.09 g, 5H), 7.12 (d, 2H, J ¼ 8.5), 6.83 (d, 2H, J ¼ 8.5), 4.55 (d, 1H, J ¼
0.44 mmol), PyBroP (0.34 g, 0.74 mmol), DIPEA (0.25 mL, 1.48 3.6), 4.20–4.01 (m, 3H), 3.89–3.84 (m, 2H), 3.83–3.79 (m, 4H),
mmol) and DMAP (0.05 g, 0.40 mmol). Crude product was 3.51–3.50 (m, 4H), 3.45–3.35 (m, 3H), 3.23–3.12 (m, 2H), 2.65–
puried by column chromatography to yield compound 21 (1.22 2.89 (m, 2H); 13C NMR (75 MHz, CDCl3+MeOH): d 170.4, 159.3,
g, 72%) as a white solid. [a]2D8 ¼ 49.3 (c 0.02, MeOH); Rf 0.5 138.6, 130.6, 128.6, 127.2, 126.5, 113.9, 98.4, 78.2, 67.6, 66.2,
(EtOAc). Eluent for column chromatography: EtOAc/hexane (30/ 62.0, 55.8, 55.2, 47.5, 40.3, 35.2, 7.1; MS (ESI): m/z 582 (M+ + H).
20, v/v); IR (Neat): 3345, 2926, 2365, 1750, 1247, 1033 cmꢂ1. 1H Anal. calcd for C25H31IN2O6:C, 51.55; H, 5.36; N, 4.81; Found: C,
NMR (300 MHz, CDCl3): d 7.20 (d, 2H, J ¼ 8.5), 6.85 (d, 2H, J ¼ 51.62; H, 5.43; N, 4.90.
8.5), 4.99 (d, 1H, J ¼ 4.1), 4.65–4.63 (m, 1H), 4.43 (s, 2H), 4.32 (d,
Compound 32a. To a stirred solution of 30a (0.05 g, 0.08
1H, J ¼ 7.1), 3.79 (s, 3H), 3.57–3.47 (m, 2H), 3.41 (s, 3H), 3.39– mmol) in acetonitrile–water (1.30 mL, 15 : 1) was added
3.27 (m, 3H); 13C NMR (75 MHz, CDCl3) d 170.3, 158.8, 131.7, Mo(CO)6 (0.03 g, 0.11 mmol) and the mixture was heated at
129.8, 128.9, 124.9, 114.0, 97.3, 75.5, 72.3, 71.6, 55.7, 55.3, 48.8, reux under nitrogen atmosphere for 5 h. It was concentrated
5.9; MS (ESI): m/z 462 (M+ + H). Anal. calcd for C17H20INO6:C, under vacuum and the residue was used in next reaction
44.27; H, 4.37; N, 3.04; Found: C, 44.33; H, 4.43; N, 3.11.
without further purication. The crude was taken in pyridine (1
Compound 30a. As described for 24, compound 30a was mL) and DMAP (cat.) and 3 drops of acetic anhydride were
prepared from compound 21 (0.05 g, 0.11 mmol), benzylamine added at 0 ꢀC, and the mixture was kept at room temperature for
(0.07 mL, 0.63 mmol) in THF (0.27 mL), DIBAL-H (0.62 mL, 0.62 12 h. Aer completion of reaction, pyridine was evaporated
mmol). Crude product was puried by column chromatography under vacuo to yield the crude which was puried by column
to give 30a (0.05 g, 85%) as gum. [a]2D8 ¼ + 63.2 (c 0.03, CHCl3) Rf chromatography to give compound 32a (0.04 g, 75%) as a white
0.5 (1.5/3.5 EtOAc:hexane). Eluent for column chromatography: semi solid. [a]2D8 ¼ +55.8 (c 0.9, CHCl3); Rf 0.5 (1/4 EtOAc:hex-
EtOAc/hexane (25/25, v/v); IR (Neat): 3416, 2920, 2367, 1608, ane). Eluent for column chromatography: EtOAc/hexane (6/44,
1
1508, 1246, 1034 cmꢂ1. H NMR (300 MHz, CDCl3+ CD3OD): d v/v); IR (Neat): 3416, 2920, 2368, 1610, 1503, 1240, 1032 cmꢂ1
.
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1H NMR (300 MHz, CDCl3): d 7.30 (d, 2H, J ¼ 6.4), 7.24–7.20 (m, Na2SO4 and concentrated under vacuo to give crude as oil. The
4H), 7.05–6.95 (m, 1H), 6.86 (d, 2H, J ¼ 6.4), 6.75 (m, 1H), 4.93– oil without further purication was taken in DCM (10 mL) and
4.86 (m, 2H), 4.68 (d, 1H, J ¼ 12.1), 4.44 (d, 1H, J ¼ 12.1), 4.38– (carbethoxymethylene)triphenylphosphorane (0.04 g, 0.13
ꢀ
4.32 (m, 2H), 3.74 (s, 3H), 3.72–3.69 (m, 1H), 3.59–3.58 (m, 1H), mmol) was added at 0 C. Aer overnight stirring, solvent was
3.42–3.38 (m, 2H), 3.35–3.31 (m, 4H), 3.14–3.11 (m, 1H), 2.12 (s, evaporated under vacuo to give crude which on column puri-
3H), 2.07 (s, 3H); 13C NMR (75 MHz, CDCl3): d 171.4, 170.1, cation yielded 36 (0.04 g, 65%) as a colorless oil. Rf 0.8 (1/
169.2, 159.5, 128.6, 128.5, 127.8, 127.7, 127.5, 127.3, 114.4, 97.2, 1EtOAc:hexane). Eluent for column chromatography: EtOAc/
74.9, 67.6, 67.5, 58.4, 56.0, 55.3, 53.5, 37.1, 21.7, 20.9, 4.7; MS hexane (6/44, v/v); IR (Neat): 3416, 2920, 2367, 1608, 1508,
(ESI): m/z 655 (M+ + H). Anal. calcd for C28H35IN2O8:C, 51.38; H, 1246, 1034 cmꢂ1. 1H NMR (300 MHz, CDCl3): d 7.23 (d, 1H, J ¼
5.39; N, 4.28; Found: C, 51.45; H, 5.47; N, 4.35.
6.3), 6.84 (d, 2H, J ¼ 6.3), 6.70–6.66 (m, 1H), 5.88–5.76 (m, 1H),
Compound 32b. As described for 32a, compound 32b was 5.75–5.70 (m, 1H), 5.32–5.27 (m, 3H), 5.24–5.06 (m, 1H), 4.64 (d,
prepared from compound 30b (0.05 g, 0.09 mmol), Mo(CO)6 1H, J ¼ 12.4), 4.22–4.19 (m, 3H), 3.74 (s, 3H), 2.09 (s, 3H), 1.98 (s,
(0.04 g, 0.13 mmol), acetonitrile: water (1.5 mL, 15 : 1) and 3H), 1.23 (t, 3H, J ¼ 5.4); 13C NMR (75 MHz, CDCl3): 171.6, 171.4,
acetic anhydride (0.1 mL). Crude product was puried by 169.2, 165.2, 159.5, 141.6, 131.6, 128.4, 127.2, 124.7, 119.9,
column chromatography to yield compound 32b (0.04 g, 78%) 114.5, 78.7, 70.3, 60.9, 55.3, 45.5, 29.6, 21.9, 20.8, 14.2; MS (ESI):
as a white semisolid. Rf 0.5 (1 : 4 EtOAc : hexane). [a]2D8 ¼ +65.3 m/z 460 (M+ + H). Anal. calcd for C24H29NO8:C, 62.73; H, 6.36; N,
(c 0.7, CHCl3); Eluent for column chromatography: EtOAc/ 3.05; Found: C, 62.81; H, 6.43; N, 3.13.
hexane (10/40, v/v); IR (Neat): 3420, 2925, 2351, 1615, 1512,
((3aR,4R,6S,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-
1246, 1038 cmꢂ1. 1H NMR (300 MHz, CDCl3): d 7.29 (d, 2H, J ¼ d][1,3]dioxol-4-yl)methanol 38. As described for 12, compound
6.5), 6.85 (d, 2H, J ¼ 6.5), 4.93–4.90 (m, 1H), 4.86 (d, 1H, J ¼ 2.9), 38 was prepared from compound 37 (0.52 g, 3.16 mmol), 2,2-
4.68 (d, 1H, J ¼ 12.1), 4.56 (d, 1H, J ¼ 12.1), 4.38–4.32 (m, 2H), DMP (0.39 g, 3.80 mmol) and acetone (40 mL). Crude product
3.74 (s, 3H), 3.71–3.69 (m, 1H), 3.58–3.57 (m, 2H), 3.42 (t, 1H, J ¼ was puried by column chromatography to yield compound 38
1.8), 3.40 (s, 3H), 3.39–3.30 (m, 1H), 3.14–3.09 (m, 1H), 2.23 (m, (0.05 g, 78%) as a colorless. Rf 0.5 (1/1 EtOAc:hexane). [a]D28
¼
1H), 2.23 (s, 3H), 2.11 (s, 3H). 1.26–1.18 (m, 10H); 13C NMR (75 ꢂ72.5 (c 0.8, MeOH); Eluent for column chromatography:
MHz, CDCl3): 171.4, 170.1, 169.2, 159.4, 128.5, 127.3, 114.2, EtOAc/hexane (13/37, v/v); IR (Neat): 3416, 2920, 2367, 1608,
1
97.1, 74.8, 67.6, 67.4, 58.3, 55.9, 55.2, 53.4, 37.0, 29.2, 29.0, 27.1, 1508, 1246, 1034 cmꢂ1. H NMR (300 MHz, CDCl3): d 4.62 (d,
24.7, 22.6, 21.6, 20.9, 4.7; MS (ESI): m/z 647 (M+ + H). Anal. calcd 1H, J ¼ 5.7), 4.51–4.47 (m, 1H), 4.29–4.25 (m, 1H), 3.82–3.76 (m,
for C27H39IN2O8:C, 50.16; H, 6.08; N, 4.33; Found: C, 50.22; H, 1H), 3.71–3.66 (m, 2H), 3.46 (s, 3H), 2.71 (d, 1H, J ¼ 5.5), 1.54 (s,
6.15; N, 4.41.
3H), 1.37 (s, 3H); 13C NMR (75 MHz, CDCl3): 109.8, 101.3, 73.0,
Compound 34. To a stirred solution of 21 (0.05 g, 0.11 mmol) 72.8, 68.4, 61.8, 55.8, 26.5, 25.2; MS (ESI): m/z 205 (M+ + H). Anal.
in acetonitrile–water (1.80 mL, 15 : 1) was added Mo(CO)6 (0.04 calcd for C9H16O5:C, 52.93; H, 7.90; Found: C, 52.83; H, 7.98.
g, 0.16 mmol) and the mixture was heated at reux under
((3aR,4R,6S,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-
nitrogen atmosphere for 5 h. It was concentrated under vacuum d][1,3]dioxol-4-yl)methyl acetate 39. As described for 13,
and the residue was used in next reaction without further compound 39 was prepared from compound 38 (0.11 g, 0.55
purication. The crude was taken in pyridine (1 mL) and DMAP mmol), acetic anhydride (0.10 mL, 1.11 mmol). Crude product
ꢀ
(cat.) and 3 drops of acetic anhydride were added at 0 C, and was puried by column chromatography to yield compound 39
the mixture was kept at room temperature for 12 h. Aer (0.12 g, 95%) as a colorless gum. [a]2D8 ¼ ꢂ13.52 (c 7.5, MeOH); Rf
completion of reaction, pyridine was evaporated under vacuo to 0.6 (1/4EtOAc:hexane). Eluent for column chromatography:
yield the crude which was puried by column chromatography EtOAc/hexane (4/46, v/v); IR (Neat): 3416, 2920, 2367, 1608,
to give compound 34 (0.04 g, 72%) as a white semi solid. [a]D28
¼
1508, 1246, 1034 cmꢂ1. 1H NMR (300 MHz, CDCl3): d 4.91–4.88
28.7 (c 0.8, CHCl3); Rf 0.7 (1/1EtOAc:hexane). Eluent for column (m, 1H), 4.74 (d, 1H, J ¼ 6.1), 4.57–4.54 (m, 1H), 4.31 (d, 1H, J ¼
chromatography: EtOAc/hexane (6/44, v/v); IR (Neat): 3416, 7.1), 3.81 (d, 1H, J ¼ 2.2), 3.77 (d, 1H, J ¼ 2.25), 3.41 (s, 3H), 2.16
1
2920, 2367, 1608, 1508, 1246, 1034 cmꢂ1. H NMR (300 MHz, (s, 3H), 1.54 (s, 3H), 1.33 (s, 3H); 13C NMR (75 MHz, CDCl3):
CDCl3): d 7.29 (d, 2H, J ¼ 6.5), 6,86 (d, 2H, J ¼ 6.5), 4.92–4.85 (m, 170.1, 110.1, 98.5, 73.4, 71.5, 69.9, 62.1, 55.4, 26.2, 25.1, 21.0; MS
2H), 4.65 (d, 1H, J ¼ 12.1), 4.46–4.40 (m, 1H), 4.38–4.32 (m, 2H), (ESI): m/z 247 (M+ + H). Anal. calcd for C11H18O6:C, 53.65; H,
3.74 (s, 3H), 3.62–3.51 (m, 1H), 3.46–3.38 (m, 1H), 3.33 (s, 3H), 7.37; Found: C, 53.71; H, 7.45.
3.15–3.05 (m 1H), 2.11 (s, 3H), 2.07 (s, 3H); 13C NMR (75 MHz,
((2R,3S,4R,5S)-3,4-dihydroxy-5-methoxytetrahydrofuran-2-yl)-
CDCl3): d 171.4, 170.1, 169.1, 159.4, 128.5, 127.3, 114.2, 97.1, methyl acetate 40. As described for 14, compound 40 was
74.8, 67.5, 67.4, 58.3, 55.9, 55.2, 53.4, 36.9, 22.5, 21.6, 20.8, 4.6; prepared from compound 39 (0.5 g, 2.03 mmol) and 80% acetic
MS (ESI): m/z 548 (M+ + H). Anal. calcd for C21H26INO8:C, 46.08; acid (10 mL). Crude product was puried by column chroma-
H, 4.79; N, 2.56; Found: C, 46.15; H, 4.86; N, 2.63.
tography to yield compound 40 (0.3 g, 81%) as a colorless gum.
Compound 36. To a stirred suspension of zinc dust (0.08 g, [a]2D8 ¼ ꢂ5.16 (c 18.5, MeOH); Rf 0.5 (EtOAc). Eluent for column
0.15 mmol) and NH4Cl (1.9 mL) in THF (1.9 mL) was added chromatography: EtOAc/hexane (25/25, v/v); IR (Neat): 3422,
compound 34 (0.08 g, 0.15 mmol) and reuxed for 1.5 h. Aer 2930, 1733, 1244, 1069 cmꢂ1. 1H NMR (300 MHz, CDCl3): d 4.96
completion of reaction, it was diluted with water. The resulting (t, 1H, J ¼ 2.5), 4.70 (d, 1H, J ¼ 2.2), 4.00–3.97 (m, 1H), 3.91–3.87
mixture was extracted with ethyl acetate (5 ꢁ 10 mL). The (m, 1H), 3.81–3.80 (m, 2H), 3.40 (s, 3H), 2.91 (d, 1H, J ¼ 8.1), 2.63
combined organic layers were washed with brine, dried over (d, 1H, J ¼ 10.2), 2.15 (s, 3H); 13C NMR (75 MHz, CDCl3): 169.9,
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98.8, 71.7, 68.6, 64.7, 63.1, 55.5. 21.0; MS (ESI): m/z 207 (M+ + H). 1055, 767 cmꢂ1
.
1H NMR (300 MHz, CDCl3): d 7.40–7.29 (m,
Anal. calcd for C8H14O6:C, 46.60; H, 6.84; Found: C, 46.69; H, 10H), 5.02 (d, 1H, J ¼ 11.4), 4.80 (dd, 1H, J ¼ 11.4, 3.5), 4.71–4.65
6.92. (m, 2H), 3.87–3.81 (m, 3H), 3.66–3.50 (m, 3H), 3.41 (s, 3H), 2.64
((2S,5S)-5-methoxy-2,5-dihydrofuran-2-yl)methyl acetate 41. (s, 1H), 0.93 (s, 9H), 0.11 (s, 6H); 13C NMR (75 MHz, CDCl3): d
As described for 15, compound 41 was prepared from 138.9, 138.1, 128.4, 128.3, 128.0, 127.9, 127.8, 127.7, 97.9, 81.4,
compound 40 (0.52 g, 2.54 mmol), PPh3, (2.66 g, 10.16 mmol), 79.6, 75.4, 73.0, 71.5, 70.7, 63.6, 54.9, 25.8, 18.3, ꢂ5.5; MS (ESI):
iodoform (2.00 g, 5.08 mmol) and imidazole (0.34 g, 5.08 mmol). m/z 489 (M+ + H). Anal. calcd for C27H40O6Si:C, 66.36; H, 8.25;
Crude product was puried by column chromatography to yield Found: C, 66.41; H, 8.31.
compound 41 (0.26 g, 62%) as a colorless. Rf 0.8 (1/1 EtOA-
(2R,3R,4R,5R,6S)-4,5-bis(benzyloxy)-2-((tert-butyldimethylsi-
c:hexane). [a]2D8 ¼ ꢂ 41.5 (c 0.4, MeOH); Eluent for column lyloxy)methyl)-6-methoxytetrahydro-2H-pyran-3-yl methanesul-
chromatography: EtOAc/hexane (7.5/42.5, v/v); IR (Neat): 3416, fonate 49. To the stirred solution of 48 (1.0 g, 2.10 mmol) in dry
1
2920, 2367, 1608, 1508, 1246, 1034 cmꢂ1. H NMR (300 MHz, DCM (25 mL), MsCl (0.19 mL, 2.50 mmol) and Et3N (0.52 mL,
CDCl3): d 6.10–6.00 (m, 2H), 4.94 (t, 1H, J ¼ 3.1), 4.89 (d, 1H, J ¼ 0.38 mmol) were added at 0 ꢀC and allowed to stir for 1 h. Aer
2.3), 4.13 (dd, 1H, J ¼ 13.0, 2.7), 3.83 (d,1H, J ¼ 13.3), 3.43 (s, completion of reaction, it was diluted with water and extracted
3H), 2.09 (s, 3H); 13C NMR (75 MHz, CDCl3): 170.6, 130.7, 125.0, with dichloromethane (10 mL ꢁ 3). The combined organic
94.0, 63.3, 61.2, 55.7, 21.1; MS (ESI): m/z 173 (M+ + H). Anal. extracts were washed with brine, and dried over Na2SO4. The
calcd for C8H12O4:C, 55.81; H, 7.02; Found: C, 55.90; H, 7.10.
organic fraction was concentrated in vacuo to give 49 (0.95 g,
((2S,5S)-5-methoxy-2,5-dihydrofuran-2-yl)methanol 42. As 80%) as colourless gum. [a]2D8 ¼ +90.2 (c 0.45, MeOH); Rf 0.5 (1/4
described for 16, compound 42 was prepared from compound EtOAc:hexane). Eluent for column chromatography: EtOAc/
41 (0.5 g, 2.89 mmol) and anhy. K2CO3 (0.59 g, 4.33 mmol). hexane (5/45, v/v); IR (Neat): 3021, 2927, 2858, 2365, 1360,
Crude product was puried by column chromatography to yield 1176, 767 cmꢂ1 1H NMR (300 MHz, CDCl3): d 7.36–7.34 (m,
.
compound 42 (0.29 g, 78%) as a colorless gum. Rf 0.5 10H), 5.06 (d, 1H, J ¼ 10.9), 4.98–4.72 (m, 2H), 4.67–4.63 (m,
(1/1EtOAc:hexane). [a]D28 ¼ ꢂ6.24 (c 18.5, CHCl3) Eluent for 2H), 4.47 (t, 1H, J ¼ 9.5), 4.06–3.94 (m, 2H), 3.82–3.72 (m, 1H),
column chromatography: EtOAc/hexane (12.5/47.5, v/v); IR 3.42 (s, 3H), 2.86 (s, 3H), 0.92 (s, 9H), 0.09 (s, 6H). 13C NMR (75
1
(Neat): 3408, 2924, 2357, 1598, 1218, 770 cmꢂ1. H NMR (300 MHz, CDCl3): d 137.9, 137.6, 128.5, 128.4, 128.1, 127.7, 97.2,
MHz, CDCl3): d 6.16–6.10 (m, 1H), 5.88 (dd, 1H, J ¼ 10.0, 3.6), 80.3, 78.8, 78.1, 75.4, 73.3, 70.2, 62.1, 55.1, 38.5, 25.8, 18.2, -5.4;
4.82 (d,1H, J ¼ 2.7), 4.11–4.06 (m, 1H), 3.81–3.77 (m, 2H), 3.43 MS (ESI): m/z 589 (M++Na). Anal. calcd for C28H42O8SSi:C, 59.34;
(s, 3H), 2.35 (d, 1H, J ¼ 6.5); 13C NMR (75 MHz, CDCl3): 129.2, H, 7.47; Found: C, 59.39; H, 7.51.
128.2, 94.2, 64.2, 61.4, 55.6; MS (ESI): m/z 131 (M+ + H). Anal.
calcd for C6H10O3:C, 55.37; H, 7.74; Found: C, 55.45; H, 7.82.
(2R,3R,4R,5R,6S)-4,5-bis(benzyloxy)-2-(hydroxymethyl)-6-
methoxytetrahydro-2H-pyran-3-yl methanesulfonate 50. To a
Compound 43. As described for 19, compound 43 was cooled solution of 49 (0.86 g, 1.52 mmol) in dry THF (25 mL),
prepared from compound 42 (0.05 g, 3.84 mmol), 11 (1.21 g, solution of TBAF (1.0 M in THF, 0.56 mL) was added, and
5.76 mmol), PyBroP (3.58 g, 7.68 mmol), DIPEA (2.66 mL, 15.36 allowed to stir for 30 min. Aer completion of the reaction,
mmol) and DMAP (0.52 g, 4.22 mmol). Crude product was mixture was concentrated in vacuo; the residue was diluted with
puried by column chromatography to yield compound 43 (0.07 ethyl acetate. The combined organic layer was washed with
g, 62%) as a white gum. [a]2D8 ¼ ꢂ53.85 (c 0.13, CHCl3). Rf 0.4 water followed by brine. The organic layer was dried over
(EtOAc). Eluent for column chromatography: EtOAc/hexane (25/ anhydrous Na2SO4 and concentrated under vacuum to colour-
25, v/v); IR (Neat): 3294, 2932, 2370, 1604, 1248, 1027, 836 cmꢂ1
.
less oil, which on column chromatographic purication gave
1H NMR (300 MHz, (CD3)2CO): d 7.38 (d, 2H, J ¼ 8.5), 6.92 the pure compound 50 as white gum (0.64 g, 95%). [a]D28 ¼ +77.5
(d, 2H, J ¼ 8.5), 4.68 (s, 1H), 4.61 (d, 1H, J ¼ 7.4), 4.47 (d, 1H, J ¼ (c 0.6, MeOH); Rf 0.3 (1.5 : 3.5 EtOAc : hexane). Eluent for
8.4), 4.12–4.08 (m, 2H), 3.96–3.90 (m, 2H), 3.81–3.78 (m, 5H), column chromatography: EtOAc/hexane (15/35, v/v); IR (Neat):
3.41 (s, 3H); 13C NMR (75 MHz, (CD3)2CO): d 159.3, 130.3, 128.7, 3488, 2921, 2365, 1458, 1354, 1172, 1099, 1039, 954, 758 cmꢂ1
.
113.6, 95.8, 72.0, 70.3, 56.4, 54.6, 54.4, 38.3; MS (ESI): m/z 322 1H NMR (300 MHz, CDCl3): d 7.32 (m, 10H), 5.08 (d, 1H,
(M+ + H). Anal. calcd for C16H19NO6:C, 59.81; H, 5.96; N, 4.36; J ¼ 16.7), 4.78–4.61 (m, 4H), 4.47 (t, 1H, J ¼ 14.3), 4.04 (t, 1H, J ¼
Found: C, 59.90; H, 5.90; N, 4.45.
14.3), 3.95–3.88 (m, 1H), 3.79–3.68 (m, 2H), 3.59 (dd, 1H, J ¼
(2R,3R,4S,5R,6S)-4,5-bis(benzyloxy)-2-((tert-butyldimethyl- 14.2, 5.3), 3.37 (s, 3H), 2.79 (s, 3H), 2.52 (br s, 1H); 13C NMR
silyloxy)methyl)-6-methoxytetrahydro-2H-pyran-3-ol 48. To the (75 MHz, CDCl3): d 137.8, 137.4, 128.5, 128.4, 128.2, 127.8,
stirred solution of 47 (0.79 g, 2.11 mmol) in dry DCM (15 mL), 127.7, 97.6, 80.1, 78.4, 77.6, 75.6, 73.2, 69.5, 60.3, 55.4, 38.2. MS
TBDMSCl (0.35 g, 2.32 mmol) and imidazole (0.29 g, 4.22 mmol) (ESI): m/z 475 (M++Na). Anal. calcd for C22H28O8S:C, 58.39; H,
were added at 0 ꢀC and allowed to stir for 30 minutes. Aer 6.24; Found: C, 58.45; H, 6.30.
completion of reaction, it was diluted with water and extracted
((2S,3R,4S)-3,4-bis(benzyloxy)-2-methoxy-3,4-dihydro-2H-
with dichloromethane (10 mL ꢁ 3). The combined organic pyran-6-yl)methanol 52. To the solution of 51 (0.58 g, 1.63
ꢀ
extracts were washed with brine, and dried over Na2SO4. The mmol) in methanol (15 mL) at 0 C was added NaBH4 (0.09 g,
organic fraction was concentrated in vacuo to give 48 (1.0 g, 2.29 mmol) and stirred at room temperature. Aer completion
97%) as colourless gum. [a]2D8 ¼ +58.8 (c 0.45, MeOH); Rf 0.5 of reaction (TLC control, 30 min.), 5 mL of acetone was added to
(1 : 1 EtOAc : hexane). Eluent for column chromatography: neutralize excess NaBH4. The solvent was then concentrated to
EtOAc/hexane (6/44, v/v); IR (Neat): 3453, 2927, 2365, 1218, dryness to give the residue that was dissolved in ethyl acetate
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(15 mL) and was washed with water and brine. The organic layer 10 K. V. Gothelf and K. A. Jørgensen, Chem. Rev., 1998, 98, 863–
was dried over Na2SO4 and evaporated under reduced pressure
to obtain clear oil. Crude product was puried by column
chromatography to yield compound 52 (0.54 g, 94%) as a white
gum. [a]2D8 ¼ +21.5 (c 1.5, CHCl3); Rf 0.5 (1 : 1, EtOAc : hexane).
Eluent for column chromatography: EtOAc/hexane (12.5/37.5,
909; J. Marco-Contelles and E. de Opazo, Tetrahedron Lett.,
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v/v); IR (Neat): 3428, 2920, 2366, 1682, 1454, 1094, 745, 699 11 M. Saquib, I. Husain, B. Kumar and A. K. Shaw, Chem.–Eur.
1
cmꢂ1. H NMR (300 MHz, CDCl3): d 7.38–7.21 (m, 10H), 4.99
(d, 1H, J ¼ 2.9), 4.82 (d, 1H, J ¼ 2.2), 4.75 (d, 1H, J ¼ 1.5), 4.59 12 S. T. Derek, A. F. Michael, D. S. Matthew and S. L. Schreiber,
(s, 2H), 4.17–4.15 (m, 1H), 3.99 (s, 2H), 3.76–3.73 (m, 1H), 3.48 J. Am. Chem. Soc., 1998, 120, 8565–8566.
(s, 3H), 2.12 (s, 1H); MS (ESI): m/z 379 (M++Na). Anal. calcd for 13 D. Keirs and K. Overton, Heterocycles, 1989, 28, 841–848.
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C
21H24O5:C, 70.77; H, 6.79; Found: C, 70.82; H, 6.85.
(2S,3R,4R)-3,4-bis(benzyloxy)-2-methoxy-6-(4-methoxybenzyl)-
14 A. V. Prosyanic, D. V. Fedoseenko and V. I. Markov, Zh. Org.
Kim, 1985, 21, 1637; Chem. Abstr., 1986, 105, 42309z.
hexahydrofuro[3,4-c]pyrano[2,3-d]isoxazol-7(9H)-one 53. As 15 R. Abdul, Can. J. Chem., 1990, 68(7), 1122–7.
described for 19, compound 53 was prepared from compound 52 16 S. Riku and K. T. Liisa, Eur. J. Org. Chem., 2013, 22, 4971–
(0.35 g, 0.98 mmol), 11 (0.41 g, 1.97 mmol), PyBroP (0.92 g, 1.97
mmol), DIPEA (0.68 mL, 3.95 mmol) and DMAP (0.13 g, 1.08 17 J. T. Vazquez, W. T. Wiesler and K. Nakanishi, Carbohydr.
mmol). Crude product was puried by column chromatography Res., 1988, 176(2), 175–194.
to yield compound 53 (0.07 g, 62%) as a white solid. Rf 0.4 (4 : 1, 18 L. V. Dunkerton, K. T. Brady, F. Mohamed and
EtOAc : hexane). Eluent for column chromatography: EtOAc/ B. P. McKillican, J. Carbohydr. Chem., 1988, 7(1), 49–65.
hexane (32/18, v/v); IR (Neat): 3010, 2930, 1754, 1678, 1603, 19 A. M. Jordan, H. M. I. Osborn, P. M. Stafford, G. Tzortzis and
1510, 1452, 1256, 1031, 756 cmꢂ1. 1H NMR (300 MHz, CDCl3): d
R. A. Rastall, J. Carbohydr. Chem., 2003, 22(7 & 8), 705–717.
8.23–8.18 (m, 2H), 7.32–7.31 (m, 10H), 6.92–6.88 (m, 2H), 5.08 (d, 20 V. Seran, B. Manuel, G. M. Ana and P. Pilar, J. Org. Chem.,
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4978.
4.60–4.59 (m, 1H), 4.35 (d, 1H, J ¼ 8.8), 4.20–4.15 (m, 1H), 3.81 21 B. Bernet and A. Vasella, Helv. Chim. Acta, 1979, 62, 1990;
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161.5, 160.9, 159.0, 145.9, 138.1, 137.9, 136.9, 130.8, 129.7, 129.1,
128.4, 128.3, 128.2, 128.0, 127.8, 127.7, 127.6, 122.8, 114.2, 114.0,
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1885.
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Acknowledgements
The authors P.S. cordially thank CSIR for providing fellowships
(NET-SRFs). Financial support from BSC 0120 is acknowledged.
This has CDRI communication no. 8742.
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