An easy route to synthetic analogues of radicamine B, codonopsine and codonopsinine from d-mannitol

Article abstract of DOI:10.1039/c4ob00503a

A general strategy for the synthesis of analogues of radicamine B has been carried out from d-mannitol. This method has been further extended to the synthesis of analogues of codonopsine and codonopsinine using appropriate Grignard reagents. The hence obtained molecules have been tested against various commercially available glycosidases and found to act as moderate to good inhibitors. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00503a

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PAPER
An easy route to synthetic analogues
of radicamine B, codonopsine and
codonopsinine from D-mannitol†
Cite this: Org. Biomol. Chem., 2014,
12, 4983
Suresh Dharuman, Ashok Kumar Palanivel and Yashwant D. Vankar*
Received 6th March 2014,
Accepted 17th April 2014
A general strategy for the synthesis of analogues of radicamine B has been carried out from D-mannitol.
This method has been further extended to the synthesis of analogues of codonopsine and codonopsinine
using appropriate Grignard reagents. The hence obtained molecules have been tested against various
commercially available glycosidases and found to act as moderate to good inhibitors.
DOI: 10.1039/c4ob00503a
www.rsc.org/obc
Introduction
Synthesis of naturally occurring polyhydroxylated pyrrolidines,
a class of 1,4-iminocyclitols and their analogues has gained
importance1 in recent years due to their promising biological
activities. The naturally occurring polyhydroxylated pyrroli-
dines are found in plants and microorganisms2 and behave as
sugars mimics as the ring oxygen of the natural sugar could be
thought of as having been replaced by nitrogen. Many imino-
cyclitols including 5-membered, 6-membered and bicyclic mole-
cules strongly bind to glycosidases and glycosyl transferases
and consequently act as antiviral,3 antidiabetic,4 anticancer5
and anti-lysosomal storage disorders.6 Further, polyhydroxy-
lated pyrrolidines are also structural parts of biologically
important bicyclic iminocyclitols such as casuarine, hyacintha-
cine, swainsonine, uniflorine A, steviamine, etc.7 More
recently,8 a polyhydroxylated pyrrolidine analogue α-1-C-butyl-
L-arabinitol has been developed as an α-glucosidase inhibitor
with high promise as an antidiabetic agent, whereas many
other derivatives of polyhydroxylated pyrrolidines are excellent
α-L-fucosidase inhibitors.9
Fig. 1 Structure of polyhydroxylated pyrrolidines.
(Campanulaceae) which also exhibit potent α-glucosidase
inhibitory activity (Fig. 1).12
In view of this, many syntheses of both radicamine and
codonopsinine and their analogues have been reported in the
literature over the past few years.13
Further, very recently, a synthesis of 4-epi-(+)-codonopsinine
was reported by Behr et al.14 which was found to show micro-
molar (Ki = 0.8 μm) inhibition of α-L-fucosidase from bovine
kidney. Due to the interesting glycosidase inhibitory activity of
these iminosugars as well as our continued research interest
in the synthesis of glycosidase inhibitors15 and amino acids16
from D-mannitol, we were motivated to design an easy route
towards analogues of radicamine B, codonopsine and codo-
nopsinine and evaluate their glycosidase inhibitory activity.
We herein report the synthesis of these analogues from com-
mercially available D-mannitol and their inhibitory activity
against a few commercially available glycosidases.
Apart from this, a new class of pyrrolidine alkaloids has
been isolated from Codonopsis clematidea,10 in which an aryl
moiety is present at the C-2 position. (−)-Codonopsinine 1 and
(−)-codonopsine 2 are examples of this rare class of alkaloids
which show hypotensive pharmacological activity without
causing any effect on the central nervous system in animals.11
In addition, two more alkaloids radicamine A 3 and radica-
Results and discussion
mine B 4 have been isolated from Lobelia chinensis LOUR The retrosynthetic analysis shown in Scheme 1 indicates that
the target compounds F and G can be synthesized from the
cyclic molecule E using appropriate synthetic manipulations.
The cyclised derivative E could be obtained from D via mesyla-
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India.
tion of the free hydroxyl group followed by intramolecular
E-mail: vankar@iitk.ac.in
†Electronic supplementary information (ESI) available: Copies of 1H and 13C
cyclisation with the amino group. Compound D, in turn, could
be obtained from compound B via C with deprotection of the
NMR spectra for all new compounds. See DOI: 10.1039/c4ob00503a
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ing secondary hydroxyl group was converted to the corres-
ponding mesylate using mesyl chloride and triethylamine
in the presence of
a catalytic amount of DMAP. The
diastereomeric mesylates were purified through a short silica
gel column and each of them underwent intramolecular
cyclisation upon treatment with t-BuOK in THF to give the
cyclised products 12a and 12b in 40% and 31%, respectively
(Scheme 2).
1
The structures of the products were confirmed by their H
NMR and mass spectral data (see Experimental section). These
two diastereomers could only be separated after 6 steps from
the Grignard reaction step.
Scheme 1 Retrosynthetic analysis of 14a and 14b.
The stereochemistry of the newly generated stereocenter
was established from the NOE studies of the N-methyl deriva-
tives 13a and 13b which were obtained by the LiAlH4 reduction
of 12a and 12b (Scheme 3), respectively. In compound 13a, the
coupling constant of H-2 proton with H-3 (J2,3 = 2.7 Hz) indi-
cates that H-2 proton is oriented pseudo equatorially. In NOE
analysis (Fig. 2), irradiation of the signal at δ 4.15 corres-
ponding to H-2 of compound 13a led to the enhancement
(7.1%) of the signal at δ 4.44 corresponding to H-3 and
enhancement (0.4%) of one of the H-6 protons at δ 3.35 but
not the signal at δ 3.46 corresponding to H-5 and vice versa.
This suggested that protons H-2 and H-5 are trans oriented
with respect to each other. For 13b, irradiation of the signal at
δ 2.96 corresponding to H-5 led to the enhancement (4.9%) of
the signal at δ 3.18 corresponding to H-2 proton and vice versa.
Further, it also showed an enhancement (10.5%) of the signal
at δ 4.06 corresponding to H-4 proton. This indicated that the
H-2, H-4 and H-5 protons are cis oriented with respect to each
acetonide group followed by selective protection of the primary
alcohol as its trityl ether. Compound B could be synthesised
from alcohol A which could be derived from aldehyde 5 via
aryl Grignard addition reaction.
In this regard, syntheses of radicamine B analogues began
from the chiral aldehyde 5 which, in turn, was synthesized
from D-mannitol using a literature procedure.17 Addition of
4-benzyloxyphenyl magnesium bromide 6a18 on chiral aldehyde
5
gave alcohol 7 as a 1.2 : 1 mixture of diastereomers
(Scheme 2) that was converted to the corresponding mesylates
using mesyl chloride and triethylamine in the presence of a
catalytic amount of DMAP. Unfortunately, the diastereomeric
mesylates were not stable during purification by column
chromatography and hence the crude diastereomeric mixture
was then subjected to azidation using NaN3 in DMF to give
azido compound 8a in 70% (over 2 steps) yield as a mixture of
diastereomers. In addition to this, a minor product was iso-
lated in 18% yield which was found to be an eliminated
product 8b (Scheme 2). The stereochemistry of the double
bond was proved from the NOE analysis and was confirmed as
the Z isomer (see ESI†). Furthermore, the azide group in 8a
was subjected to the Staudinger reduction followed by amine
protection to give the corresponding Cbz protected amine 9.
The acetonide group was deprotected using AcOH–H2O (8 : 2)
to give diol 10 in 92% yield. The primary hydroxyl group of
diol 10 was selectively protected as trityl ether using trityl
chloride and triethylamine to form compound 11. The remain-
Scheme 3 Synthesis of 13a and 13b.
Scheme 2 Synthesis of cyclised products 12a and 12b.
4984 | Org. Biomol. Chem., 2014, 12, 4983–4998
Fig. 2 NOE analyses of 13a and 13b.
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Scheme 4 Global deprotections of 12a and 12b.
Scheme 6 Synthesis of acetates 33a and 34a.
Scheme 7 Synthesis of acetates 33b and 34b.
to hydrogenolysis with Pd(OH)2/H2 in the presence of 5% HCl
in MeOH to give the fully deprotected product. On completion
of the reaction, the catalyst was filtered off and the filtrate was
passed through a Dowex basic resin to give a crude product.
The N-methylation of this crude product was carried out under
hydrogenation conditions using 30% HCHO solution in the
presence of Pd(OH)2/H2 and the product was characterised as
Scheme 5 Synthesis of cyclised products 25a, 25b, 26a and 26b.
other. Also, the coupling constant of H-2 proton with H-3 its acetate 33a. Similarly, compound 26a was converted to 34a
(J2,3 = 6.1 Hz) confirmed the stereochemistry of H-2 proton.
following the same sequence of reactions.
Initially, we attempted one pot deprotection of all the pro-
Similarly, the acetates of codonopsinine and codonopsine
tecting groups viz. benzyl, trityl and carbamate groups under analogues 33b and 34b were synthesized using the same
hydrogenation conditions but that failed to give the required sequence of steps as shown in Scheme 7.
products. However, global deprotection using 1 M solution of
BBr3
The absolute configuration of the newly formed stereocen-
in CH2Cl2 gave the desired products 14a and 14b tres of the hence obtained codonopsinine analogues 33a and
19
(Scheme 4).
33b was established from NOE analysis. Thus, for 33a,
After successfully synthesizing radicamine analogues 14a irradiation of the signal at δ 3.99 corresponding to H-2 led to
and 14b, we turned our attention to synthesize codonopsinine the enhancement (11.0%) of the signal at δ 0.93 corresponding
and codonopsine analogues using appropriate aryl Grignard to H-6 protons and it did not give any enhancement of the
reagents 4-methoxyphenyl magnesium bromide 6b and 3,4- signal at δ 3.72 corresponding to the H-5 proton. This
dimethoxyphenyl magnesium bromide 6c respectively.
suggested that the protons H-2 and H-6 of the CH3 protons are
The cyclised products 25a, 25b, 26a and 26b were syn- cis to each other and hence H-2 and H-5 are trans to each
thesised using the same sequence of reactions as used in syn- other. This was again confirmed by irradiation of the signal at
thesis of radicamine analogues (Scheme 5).
δ 3.72 corresponding to the H-5 proton which did not show
After procuring the cyclised products 25a, 25b, 26a and 26b any enhancement of the H-2 proton at δ 3.99. For 33b,
their conversion to analogues of codonopsinine and codonop- irradiation of the signal at δ 3.11 corresponding to H-2 led to
sine was then separately carried out. Thus, cyclised product the enhancement (12.0%) of the signal at δ 2.70 which corres-
25a was treated with TFA in dry CH2Cl2 (Scheme 6) to furnish ponds to the H-5 proton and vice versa. It also gave an
the free hydroxyl compound 27a which was then converted to enhancement (2.4%) of the signal δ 5.18 corresponding to the
the corresponding iodo derivative 29a using PPh3, imidazole H-4 proton. This indicates the H-2, H-4, H-5 protons are
and iodine.20 The deiodination of 29a was carried out by its oriented cis to each other (Fig. 3).
treatment with Et3N and RANEY® Ni catalyst under a H2
Likewise, the stereochemistry of the codonopsine analogues
atmosphere20 to furnish 31a in 68% yield which was subjected 34a and 34b was established from 1H, COSY and NOE analysis.
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Fig. 3 NOE analysis of 33a, 33b.
Scheme 8 Synthesis of analogues of codonopsinine and codonopsine.
β-glucosidase with IC50 of 114 μM (Table 1). This observation
reveals that inversion of the hydroxymethyl stereochemistry at
C-5 position of radicamine B (IC50 = 9.3 μM, α-glucosidases
from Lobelia chinensis LOUR) changes the inhibition affinity
towards β-glucosidases.
Fig. 4 NOE analysis of 34a, 34b.
For compound 34a, irradiation of the signal at δ 3.97 corres-
ponding to H-2 led to the enhancement (0.9%) of the signal at
δ 0.94 corresponding to H-6 and did not give any enhancement
of the signal at δ 3.73 corresponding to the H-5 proton. This
suggests that proton H-2 and the H-6 protons of the CH3 group
are cis to each other and hence H-2 and H-5 are trans to each
other. For 34b, irradiation of the signal at δ 3.12 corresponding
to H-2 led to enhancement (4.4%) of the signal at δ 2.75 corres-
ponding to the H-5 proton and vice versa. It also gave an
enhancement (0.8%) of the signal at δ 5.18 corresponding to
the H-4 proton. This indicates that the protons H-2, H-4, H-5
are cis to each other (Fig. 4).
Finally, acetate groups of the compounds 33a, 33b, 34a and
34b were deprotected under K2CO3–MeOH to give codonopsi-
nine analogues 35a, 35b and codonopsine analogues 36a, 36b
which were characterized by spectral means (cf. see Experi-
mental section) (Scheme 8).
Codonopsinine analogue 35a displayed moderate but non-
selective inhibition against α-mannosidase, α-galactosidase
with somewhat better inhibition against β-mannosidase at the
94 μM concentration. Compounds 35b and 36a showed very
good inhibition against α-L-fucosidase at a concentration of
84 μM and 75 μM respectively. In addition, compound 35b
showed weak inhibition against β-glucosidase and β-galactosi-
dase. Likewise, compound 36a also showed weak inhibition
against α-glucosidase and β-glucosidase. On the other hand,
compound 36b showed good inhibition against various glyco-
sidases. Further, compound 36a showed more affinity towards
α-L-fucosidase (IC50 = 75μM) as compared to glucosidases,
while its isomer 36b did not inhibit α-L-fucosidase, rather it
inhibited most of the other glycosidases tested. It is the first
time that the glycosidase inhibition activity of codonopsine
and codonopsinine analogues, except for the 4-epi codonopsi-
nine analogue which is reported to act as an α-L-fucosidase
inhibitor at micromolar concentrations,14 has been tested with
Enzyme inhibition study
The above described synthesised analogues were tested as gly- various commercially available glycosidases. Thus, as expected,
cosidase inhibitors against various enzymes (Table 1). The compounds 35b and 36a were found to be good inhibitors of
radicamine B analogue 14a showed good inhibition against α-L-fucosidase. In contrast, compounds 35a and 36b showed
β-glucosidase at a concentration of 150 μM and it also showed good inhibition against β-D-mannosidase and did not show
excellent inhibition against α-mannosidase at a 34 μM concen- any inhibition against α-L-fucosidase. These studies clearly
tration. However, it was less specific as compared to com- indicate that the absence or presence of a methoxy group has
pound 14b which showed very specific inhibition against a profound influence on the inhibition outcome.21,22
Table 1 IC50 (μM) values for compounds 14a, 14b, 35a, 35b, 36a and 36ba
Entry
Enzymes
14a
14b
35a
35b
36a
36b
1
2
3
4
5
6
7
α-D-Glucosidase from Baker’s yeast
β-D-Glucosidase from almonds
α-D-Mannosidase from jack beans
β-D-Mannosidase from Helix pomatia crude extract
α-D-Galactosidase from coffee beans
β-D-Galactosidase from bovine lever
α-L-Fucosidase from bovine kidney
NI
NI
114 μM
NI
NI
NI
NI
NI
NI
NI
184 μM
94 μM
180 μM
NI
NI
200 μM
NI
NI
NI
289 μM
84 μM
242 μM
652 μM
NI
NI
NI
NI
75 μM
56 μM
185 μM
NI
49 μM
87 μM
279 μM
NI
150 μM
34 μM
NI
NI
NI
NI
NI
a Inhibition studies were carried out at micromolar concentration, optimal pH of the enzymes, and 37 °C.
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2.16 mmol) and a catalytic amount of DMAP (12 mg,
0.18 mmol). The reaction mixture was stirred for 1 h at 0 °C,
Conclusions
In conclusion, a new concise route for the synthesis of ana- quenched by the addition of H2O (10 mL) and extracted with
logues of radicamine B, codonopsine and codonopsinine has CH2Cl2 (3 × 10 mL). The combined organic layer was washed
been described from D-mannitol. These synthetic analogues with water (1 × 10 mL), brine (1 × 10 mL), and dried over anhy-
14a, 14b, 35a, 35b, 36a and 36b were tested against various gly- drous Na2SO4. Concentration of the organic layer on a rotary
cosidases among which compound 14a inhibits α-mannosi- evaporator gave a crude product which was dissolved in dry
dase and 14b exhibits selective and strong inhibition against DMF (15 mL) and treated with NaN3 (0.586 g, 9.0 mmol) and
β-glucosidase and compounds 35b and 36a show very good tetrabutylammonium iodide (64 mg, 0.18 mmol). The reaction
inhibition against α-L-fucosidase, very much like their parent mixture was heated at 110 °C for 8 h. After completion of
compounds.
the reaction, the product was extracted with diethyl ether
(2 × 25 mL). The combined organic layer was washed with cold
water (1 × 20 mL), brine (1 × 20 mL), and dried over anhydrous
Na2SO4. Solvent was evaporated under a vacuum to give a
crude product which was purified by silica-gel column
chromatography.
Experimental
General
All experiments were performed in oven dried glass apparatus
under a nitrogen atmosphere. All solvents and common General procedure (C): reduction of azide followed by Cbz
reagents were purified by established procedures. Thin layer protection of amine
chromatography was performed on prepared thin layers of
To a solution of azide (1.72 mmol) in THF (8 mL) was added
silica gel on microscopic slides. The visualization of spots on
PPh3 (0.542 g, 2.07 mmol) followed by H2O (0.046 mL,
TLC plates was effected by exposure to iodine or by spraying
2.58 mmol) and the mixture was stirred for 12 h at room temp-
erature. Once the starting material was completely consumed
(TLC monitoring), 5 mL of H2O was added and cooled it to
0 °C. To this, CbzCl (50% soln in toluene) (0.738 mL,
with 10% H2SO4 and charring. Column chromatography was
performed over Acme Silica gel (100–200 mesh) using relevant
eluents. 1H (500 MHz or 400 MHz), 13C (125 MHz or 100 MHz),
COSY and nOe spectra were recorded on a JEOL JNM-LA 500
2.58 mmol) was added followed by the addition of solid
FT NMR spectrometer in a solution of CDCl3 and D2O. Chemi-
NaHCO3 (0.291 g, 3.44 mmol), and the reaction mixture was
cal shifts are reported in ppm downfield to tetramethylsilane.
slowly brought to room temperature and stirred for 1 h. The
Coupling constants are reported and expressed in Hertz, split-
reaction mixture was extracted with EtOAc (2 × 20 mL), washed
with water (1 × 10 mL), brine (1 × 10 mL) and dried over
Na2SO4. Solvent evaporation followed by purification through
ting patterns are designated as br (broad), s (singlet), d
(doublet), dd (double doublet), q (quartet), m (multiplet).
Infrared spectra were recorded on a Bruker Vector 22 FT-IR
column chromatography using silica-gel gave the protected
spectrometer and the absorption bands are reported in reci-
amine as a mixture of diastereomers.
procal centimeters (cm−1). The mass spectra were recorded on
high-resolution ESI mass spectrometer using a Q-TOF analy-
zer. Rotation values were recorded on an Autopol II automatic
polarimeter at the wavelength of the sodium D-line (589 nm)
at 28 °C.
General procedure (A): aryl Grignard addition on aldehyde
5. To a solution of mannitol aldehyde 5 (1.0 g, 2.70 mmol) in
General procedure (D): deprotection of primary acetonide
group
An amino compound (1.4 mmol) was dissolved in AcOH–H2O
(16 : 4 (v/v), 20 mL) and stirred for 24 h at room temperature.
After completion of the reaction (TLC monitoring), the reac-
tion mixture was slowly quenched with saturated NaHCO3
THF (10 mL), arylmagnesium bromide 6a (1.12 mL,
solution. The product was extracted with EtOAc (3 × 20 mL)
4.05 mmol), prepared following literature procedures17,18
and the organic phase washed with H2O (1 × 20 mL), brine
(6b was used for 15 and 6c was used for 16), was added drop-
(1 × 20 mL) and dried over Na2SO4. The combined organic
wise at about 0 °C. The reaction mixture was stirred for 15 min
layer was evaporated under vacuum. The crude product was
at the same temperature. Once the starting material was con-
further purified by column chromatography using silica-gel to
give pure diol as a mixture of diastereomers.
sumed (TLC monitoring), the reaction mixture was quenched
with saturated aqueous NH4Cl solution (5 mL), extracted with
EtOAc (3 × 20 mL) and washed with brine solution (1 × 15 mL).
The combined extracts were dried and solvents were removed
General procedure (E): tritylation of primary alcohol
under vacuum. The residue was purified by column chromato- To a stirred solution of a diol (1.54 mmol) in CH2Cl2 (10 mL)
graphy using silica-gel (hexane–EtOAc) to give alcohol 7 or 15 were added Et3N (0.430 mL, 3.0 mmol), TrCl (0.517 g,
or 16 as a colorless oil.
1.85 mmol) and a catalytic amount of DMAP (12 mg,
General procedure (B): azidation of alcohols 7, 15 and 0.15 mmol). The reaction mixture was stirred for 5 h at room
16. To a stirred solution of alcohol (1.80 mmol) in CH2Cl2 temperature and the usual work-up with CH2Cl2 gave a crude
(10 mL) at 0 °C was added Et3N (0.276 mL, 1.98 mmol), fol- product which was purified by column chromatography using
lowed by slow addition of methanesulfonyl chloride (0.167 mL, silica-gel to yield pure trityl protected compound.
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General procedure (F): mesylation followed by
1065 cm−1
;
1H NMR (500 MHz, CDCl3, 1.3 : 1 mixture of dia-
intramolecular cyclisation
stereomers) δ 7.38–7.12 (m, 10H, both isomers), 6.89–6.85 (m,
4H, both isomers), 4.90 (d, J = 4.9 Hz, 1H, major isomer), 4.87
(d, J = 7.0 Hz, 1H, minor isomer), 4.79 (d, J = 11.6 Hz, 1H,
minor isomer), 4.72 (d, J = 11.6 Hz, 1H, major isomer),
4.61–4.56 (m, 3H: 1H for major isomer, 2H for minor isomer),
4.43 (d, J = 11.3 Hz, 1H, major isomer), 4.29–4.15 (m, 2H, both
isomers), 4.05–3.92 (m, 2H, both isomers), 3.81 (s, 3H, minor
isomer) 3.80 (s, 3H, major isomer), 3.80–3.78 (m, 1H, minor
isomer), 3.74 (t, J = 4.5 Hz, 1H, major isomer), 3.65 (t, J = 4.3
Hz, 1H, major isomer), 3.60 (dd, J = 2.7, 7.0 Hz, 1H, minor
isomer), 2.98 (br s, 1H, both isomers), 1.39 (s, 3H, minor
isomer), 1.37 (s, 3H, major isomer), 1.31 (s, 3H, major isomer),
1.29 (s, 3H, minor isomer); 13C NMR (125 MHz, CDCl3,
1.3 : 1 mixture of diastereomers) δ 159.2, 138.2–127.8 (Ar–C),
113.9, 113.8, 108.6, 108.2, 84.0, 82.2, 79.7, 78.6, 75.0, 74.4,
73.2, 72.4, 66.3, 66.2, 53.3, 26.5, 25.0; HRMS calcd for
C29H34NaO6 [M + Na]+ 501.2253, found 501.2257.
(2R,3R)-2,3-Bis(benzyloxy)-1-(3,4-dimethoxyphenyl)-3-((R)-
2,2-dimethyl-1,3-dioxolan-4-yl)propan-1-ol (16). Following
general procedure A, compound 16 was obtained as a colorless
oil (3,4-dimethoxyphenyl magnesium bromide 6c was used):
Yield 1.19 g (87%); Rf 0.40 (hexane–EtOAc = 2 : 1); IR (neat)
νmax 3464, 3062, 3030, 2985, 2934, 1593, 1515, 1454, 1419,
1380, 1262, 1138, 1066, 1028 cm−1; 1H NMR (500 MHz, CDCl3,
1.1 : 1 mixture of diastereomers) δ 7.38–7.10 (m, 10H, both
isomers), 6.94–6.82 (m, 3H, both isomers), 4.91 (t, J = 4.3 Hz,
1H, minor isomer), 4.84–4.80 (m, 2H, major isomer), 4.75 (d,
J = 11.0 Hz, 1H, minor isomer), 4.64–4.57 (m, 3H: 1H for major
isomer, 2H for minor isomer), 4.37 (d, J = 11.0 Hz, 1H, minor
isomer), 4.30–4.21 (m, 3H: 2H for major isomer, 1H for minor
isomer), 4.09–3.96 (m, 3H, both isomers), 3.88 (s, 3H, major
isomer), 3.87 (s, 3H, minor isomer), 3.79 (s, 3H, major
isomer), 3.76 (s, 3H, minor isomer), 3.76–3.74 (m, 1H, major
isomer), 3.72–3.70 (m, 1H, minor isomer), 3.59 (dd, J = 2.7,
7.3 Hz, 1H, major isomer), 3.07 (d, J = 4.5 Hz, 1H, minor
isomer), 2.87 (d, J = 4.3 Hz, 1H, major isomer), 1.41 (s, 3H,
major isomer), 1.39 (s, 3H, minor isomer), 1.34 (s, 3H, minor
isomer), 1.32 (s, 3H, major isomer); 13C NMR (125 MHz,
CDCl3, 1.1 : 1 mixture of diastereomers) δ 149.0, 148.9, 148.5,
138.1–127.7 (Ar–C), 118.7, 111.0, 110.9, 109.9, 109.6, 108.7,
108.2, 84.0, 82.3, 80.0, 78.6, 76.8, 76.6, 75.0, 74.4, 73.3, 72.5,
66.4, 66.2, 56.0, 55.9, 55.8, 26.6, 25.0; HRMS calcd for
C30H36NaO7 [M + Na]+ 531.2359, found 531.2356.
To a stirred solution of an alcohol (1.1 mmol) in CH2Cl2
(10 mL) at 0 °C was added Et3N (0.172 mL, 1.2 mmol), followed
by slow addition of methanesulfonyl chloride (0.104 mL,
1.3 mmol) and
a catalytic amount of DMAP (13 mg,
0.1 mmol). The reaction mixture was stirred for 3 h at room
temperature. On completion of the reaction (TLC monitoring),
it was quenched by the addition of H2O (10 mL) and the
mixture was extracted with CH2Cl2 (2 × 20 mL). The combined
organic layer was washed with water (1 × 10 mL), brine
(1 × 10 mL) and dried over anhydrous Na2SO4. Solvent evapor-
ation followed by purification through short silica gel column
chromatography gave a mixture of diastereomers which was
dissolved in dry THF (8 mL). To it was added t-BuOK
(0.388 mg, 3.3 mmol) portion-wise at 0 °C and the reaction
mixture was brought to room temperature gradually and
stirred for 3 h. After completion of reaction (TLC monitoring),
the reaction mixture was quenched with a saturated solution
of NH4Cl (10 mL). It was extracted with EtOAc (2 × 20 mL),
washed with brine (1 × 10 mL) and dried over Na2SO4. The
combined extracts were evaporated under vacuum to give a
crude product. The diastereomeric mixture was separated at
this stage using column chromatography to obtain the pure
products.
(2R,3R)-2,3-Bis(benzyloxy)-1-(4-(benzyloxy)phenyl)-3-((R)-2,2-
dimethyl-1,3-dioxolan-4-yl)propan-1-ol (7). Following general
procedure A, compound 7 was obtained as a colorless oil
(4-benzyloxy phenyl magnesium bromide 6a was used): Yield
1.25 g (84%); Rf 0.40 hexane–EtOAc = 3 : 1); IR (neat) νmax 3452,
3063, 2985, 2931, 1609, 1585, 1510, 1454, 1380, 1345, 1242,
1172, 1066, 1027 cm−1
;
1H NMR (500 MHz, CDCl3,
1.2 : 1 mixture of diastereomers) δ 7.44–7.24 (m, 15H, both
isomers), 7.21–7.11 (m, 2H, both isomers), 6.96–6.93 (m, 2H,
both isomers), 5.07–5.06 (m, 2H, both isomers), 4.90 (t, J =
4.6 Hz, 1H, major isomer), 4.88–4.85 (m, 1H, minor isomer),
4.79 (d, J = 11.4 Hz, 1H, major isomer), 4.72 (d, J = 11.4 Hz,
1H, minor isomer), 4.61–4.56 (m, 3H: 2H for major isomer, 1H
for minor isomer), 4.42 (d, J = 10.9 Hz, 1H, minor isomer),
4.30–4.26 (m, 1H, both isomers), 4.20–4.14 (m, 1H, both
isomers), 4.06–3.94 (m, 5H: 4H for major isomer, 1H for
minor isomer), 3.74 (t, J = 4.5 Hz, 1H, minor isomer),
3.67–3.66 (m, 1H, minor isomer), 3.60 (dd, J = 2.5, 6.8 Hz,
1H, minor isomer), 2.98–2.97 (m, 1H, both isomers), 1.40
(s, 3H, major isomer), 1.38 (s, 3H, minor isomer), 1.32 (s, 3H,
minor isomer), 1.30 (s, 3H, major isomer); 13C NMR (125 MHz,
CDCl3, 1.2 : 1 mixture of diastereomers) δ 158.4, 138.0–127.5
(Ar–C), 114.8, 108.6, 108.2, 83.9, 82.1, 79.7, 78.6, 76.7, 75.1,
74.4, 73.2, 73.1, 72.3, 70.1, 66.3, 66.2, 26.6, 25.0; HRMS calcd
for C35H38NaO6 [M + Na]+ 577.2566, found 577.2564.
(R)-4-((1S,2R)-3-Azido-1,2-bis(benzyloxy)-3-(4-(benzyloxy)-
phenyl)propyl)-2,2-dimethyl-1,3-dioxolane (8a). Following
general procedure B, compound 8a was obtained as a colorless
oil: Yield 0.731 g (70%); Rf 0.60 (hexane–EtOAc = 4 : 1); IR
(neat) νmax 3064, 3031, 2985, 2929, 2102, 1607, 1510, 1454,
1380, 1245, 1175, 1070, 1026 cm−1; 1H NMR (500 MHz, CDCl3,
(2R,3R)-2,3-Bis(benzyloxy)-3-((R)-2,2-dimethyl-1,3-dioxolan- 1.2 : 1 mixture of diastereomers) δ 7.44–7.16 (m, 15H, both
4-yl)-1-(4-methoxyphenyl)propan-1-ol (15). Following general isomers), 7.00–6.91 (m, 4H, both isomer), 5.08–5.06 (m, 2H,
procedure A, compound 15 was obtained as a colorless oil both isomers), 4.87–4.82 (m, 1H, both isomers), 4.75 (d, J =
(4-methoxyphenyl magnesium bromide 6b was used): Yield 11.6 Hz, 1H, major isomer), 4.72–4.65 (m, 3H: 1H for major
1.0 g (77%); Rf 0.30 hexane–EtOAc = 4 : 1); IR (neat) νmax 3450, isomer, 2H for minor isomer), 4.25 (d, J = 11.6 Hz, 1H, major
3063, 2985, 2929, 1611, 1585, 1512, 1454, 1345, 1248, 1159, isomer), 4.20–4.14 (m, 3H: 1H for major isomer, 2H for minor
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isomer), 3.96–3.90 (m, 2H, both isomers), 3.84 (d, J = 7.0 Hz, 12.0 Hz, 1H), 4.11–4.03 (m, 2H), 3.97 (d, J = 6.3 Hz, 1H), 3.79
1H, major isomer), 3.82–3.79 (m, 2H, minor isomer), 3.76 (d, (s, 3H), 1.41 (s, 3H), 1.34 (s, 3H); 13C NMR (125 MHz, CDCl3)
J = 10.4 Hz, 1H, major isomer), 3.66 (dd, J = 2.4, 4.1 Hz, 1H, δ 158.6, 151.0, 138.0–127.7 (Ar–C), 115.1, 113.8, 109.5, 81.2,
minor isomer), 3.40 (dd, J = 3.0, 4.6 Hz, 1H, major isomer), 76.6, 72.2, 71.1, 66.5, 55.3, 26.7, 25.5; HRMS calcd for
1.42 (s, 3H, major isomer), 1.34 (s, 3H, major isomer), 1.31 (s, C29H32NaO5 [M + Na]+ 483.2147, found 483.2141.
3H, minor isomer), 1.27 (s, 3H, minor isomer); 13C NMR
Compound 18
(125 MHz, CDCl3, 1.2 : 1 mixture of diastereomers) δ 162.1,
159.0, 138.3–127.6 (Ar–C), 115.2, 115.1, 114.4, 108.6, 108.4, Following general procedure B, compound 18 was obtained as
83.9, 83.2, 82.5, 79.0, 76.2, 75.5, 74.9, 74.8, 73.9, 70.1, 67.5, a colorless oil: Yield 0.850 g (81%); Rf 0.50 (hexane–EtOAc =
67.0, 66.2, 64.8, 26.7, 26.5, 25.3, 24.8; HRMS calcd for 4 : 1); IR (neat) νmax 3031, 2986, 2931, 2102, 1601, 1514, 1454,
1
C35H37N3NaO5 [M + Na]+ 602.2631, found 602.2630.
1380, 1370, 1266, 1238, 1072, 1042 cm−1; H NMR (500 MHz,
(R)-4-((R,Z)-1,2-Bis(benzyloxy)-3-(4-(benzyloxy)phenyl)allyl)- CDCl3, 1.2 : 1 mixture of diastereomers) δ 7.37–7.20 (m, 10H,
2,2-dimethyl-1,3-dioxolane (8b). Following general procedure both isomers), 6.92–6.78 (m, 3H, both isomers), 4.85–4.82 (m,
B, compound 8b was obtained as a colorless oil (minor 1H, major isomer), 4.80–4.78 (m, 1H, minor isomer), 4.76–4.67
product): Yield 0.173 g (18%); Rf 0.65 (hexane–EtOAc = 4 : 1); (2H, both isomers), 4.32–4.30 (m, 1H, minor isomer),
[α]2D8 = +29.1 (c 1.20, CH2Cl2); IR (neat) νmax 3031, 2985, 2872, 4.23–4.16 (m, 5H: 3H for major isomer, 2H for minor isomer),
1605, 1508, 1454, 1380, 1244, 1175, 1155, 1073, 1026 cm−1
;
3.99–3.92 (m, 2H, both isomers), 3.90 (s, 3H, major isomer),
1H NMR (500 MHz, CDCl3) δ 7.58–7.56 (m, 2H, Ar–H), 3.88 (s, 3H, minor isomer), 3.90–3.85 (m, 1H, minor isomer),
7.47–7.18 (m, 15H, Ar–H), 6.93–6.91 (m, 2H, Ar–H), 5.97 (s, 1H, 3.83 (s, 3H, major isomer), 3.78–3.76 (m, 1H, major isomer),
vinylic-H), 5.10–5.07 (m, 2H, –OCH2Ph), 4.90 (d, J = 11.3 Hz, 3.71 (s, 3H, minor isomer), 3.64 (dd, J = 2.7, 9.2 Hz, 1H, major
1H, –OCH2Ph), 4.87 (d, J = 11.3 Hz, 1H, –OCHPh), 4.70 (d, J = isomer), 3.46–3.44 (m, 1H, minor isomer), 1.44 (s, 3H, major
11.6 Hz, 1H, –OCHPh), 4.47 (d, J = 11.6 Hz, 1H, –OCHPh), 4.41 isomer), 1.36 (s, 3H, minor isomer), 1.32 (s, 3H, major
(dd, J = 6.1, 12.2 Hz, 1H, H-2), 4.11–4.04 (m, 2H, H-1, H-1′), isomer), 1.29 (s, 3H, minor isomer); Eliminated product:
3.98 (d, J = 6.4 Hz, 1H, H-3), 1.46 (s, 3H, –CCH3), 1.36 (s, 3H, δ 7.37–7.20 (m, 10H), 7.02–6.81 (m, 3H), 5.94 (s, 1H), 4.95–4.89
–CCH3); 13C NMR (125 MHz, CDCl3)
δ 157.8, 151.1, (m, 2H), 4.76–4.74 (m, 1H), 4.50 (d, J = 11.6 Hz, 1H), 4.43 (dd,
138.0–127.5 (Ar–C), 115.1, 114.7, 109.5, 81.2, 76.5, 72.3, 71.1, J = 6.1, 12.2 Hz, 1H), 4.13–4.06 (m, 2H), 4.00–4.98 (m, 1H),
70.0, 66.6, 26.7, 25.5; HRMS calcd for C35H40NO5 [M + NH4]+ 3.87 (s, 3H), 3.58 (s, 3H), 1.44 (s, 3H), 1.34 (s, 3H); 13C NMR
554.2906, found 554.2906.
(125 MHz, CDCl3, 1.2 : 1 mixture of diastereomers + eliminated
(R)-4-((1S,2R)-3-Azido-1,2-bis(benzyloxy)-3-(4-methoxyphenyl)- product) δ 151.0, 149.2, 149.0, 148.6, 148.1, 138.4–120.3 (Ar–C),
propyl)-2,2-dimethyl-1,3-dioxolane (17a). Following general 115.4, 111.6, 111.1, 111.0, 110.7, 110.6, 109.5, 108.6, 108.5,
procedure B, compound 17a was obtained as a colorless oil: 83.4, 82.5, 81.1, 79.4, 78.9, 76.7, 76.6, 76.3, 75.5, 74.8, 73.9,
Yield 0.715 g (68%); Rf 0.70 (hexane–EtOAc = 4 : 1); IR (neat) 72.4, 71.7, 67.7, 66.9, 66.3, 65.1, 56.0, 55.9, 55.5, 26.7, 26.6,
νmax 3064, 2986, 2928, 2102, 1611, 1585, 1513, 1380, 1304, 25.5, 25.3, 24.9; HRMS calcd for C30H35N3NaO6 [M + Na]+
1251, 1068, 1030 cm−1
1 : 1 mixture of diastereomers) δ 7.37–7.25 (m, 16H), 7.21–7.17
;
1H NMR (500 MHz, CDCl3, 556.2424, Found: 556.2426.
Benzyl (2R,3S)-2,3-bis(benzyloxy)-1-(4-(benzyloxy)phenyl)-3-
(m, 6H), 6.98–6.86 (m, 6H), 4.86–4.82 (m, 2H), 4.75 (d, J = ((R)-2,2-dimethyl-1,3-dioxolan-4-yl)propylcarbamate (9). Fol-
11.4 Hz, 1H, one isomer), 4.72–4.64 (m, 4H), 4.26 (d, J = lowing general procedure C, compound 9 was obtained as a
11.4 Hz, 1H, one isomer), 4.21–4.15 (m, 3H), 3.96–3.91 (m, colorless oil: Yield 0.853 g (72% over 2 steps); Rf 0.30 (hexane–
4H), 3.85–3.77 (m, 3H), 3.82 (s, 3H, one isomer), 3.81 (s, 3H, EtOAc = 3 : 1); IR (neat) νmax 3416, 3315, 3088, 2985, 2933,
1
one isomer), 3.67 (dd, J = 2.5, 9.1 Hz, 1H, one isomer), 3.40 1720, 1610, 1585, 1509, 1454, 1289, 1221, 1062, 1026 cm−1; H
(dd, J = 3.1, 4.8 Hz, 1H, one isomer), 1.42 (s, 3H, one isomer), NMR (500 MHz, CDCl3, 1.2 : 1 mixture of diastereomers)
1.34 (s, 3H, one isomer), 1.31 (s, 3H, one isomer), 1.27 (s, 3H, δ 7.45–7.20 (m, 20H, both isomers), 7.08–7.05 (m, 2H, both
one isomer); 13C NMR (125 MHz, CDCl3, 1 : 1 mixture of isomers), 6.94–6.90 (m, 2H, both isomers), 6.60 (d, J = 7.9 Hz,
diastereomers) δ 159.8, 138.3–127.6 (Ar–C), 114.3, 114.1, 108.6, 1H, major isomer), 5.86 (d, J = 7.3 Hz, 1H, minor isomer),
108.4, 83.1, 82.5, 79.0, 76.2, 75.5, 74.8, 73.9, 67.5, 66.9, 66.2, 5.30–5.28 (m, 1H, minor isomer), 5.11–4.99 (m, 9H, 5H major
64.8, 55.4, 26.7, 26.5, 25.3, 24.8; HRMS calcd for C29H37N4O5 isomer, 4H minor isomer), 4.83 (d, J = 11.0 Hz, 1H, minor
[M + NH4]+ 521.2764, found 521.2769.
isomer), 4.73 (d, J = 11.6 Hz, 1H, major isomer), 4.71–4.66 (m,
(R)-4-((R,Z)-1,2-Bis(benzyloxy)-3-(4-methoxyphenyl)allyl)-2,2- 1H, both isomers), 4.56 (d, J = 10.6 Hz, 1H, major isomer),
dimethyl-1,3-dioxolane (17b). Following general procedure B, 4.50 (d, J = 11.3 Hz, 1H, minor isomer), 4.32–4.29 (m, 1H, both
compound 17b was obtained as a colorless oil (minor isomers), 4.13–4.00 (m, 5H, 2H major isomer, 3H minor
product): Yield 0.202 g (21%); Rf 0.75 (hexane–EtOAc = 4 : 1); isomer), 3.92 (t, J = 6.9 Hz, 1H, major isomer), 3.72–3.66 (m,
[α]2D8 = +25.0 (c 0.12, CH2Cl2); IR (neat) νmax 3063, 2986, 2853, 2H, both isomers), 1.44 (s, 3H, minor isomer), 1.37 (s, 3H,
1
1607, 1510, 1454, 1380, 1176, 1155, 1073, 1037 cm−1; H NMR major isomer), 1.33 (s, 3H, minor isomer), 1.27 (s, 3H, major
(500 MHz, CDCl3) δ 7.57–7.55 (m, 2H), 7.35–7.25 (m, 10H), isomer); 13C NMR (125 MHz, CDCl3, 1.2 : 1 mixture of diaster-
6.87–6.85 (m, 2H), 5.96 (s, 1H), 4.88–4.87 (m, 2H), 4.69 (d, J = eomers) δ 158.1, 156.4, 155.8, 138.2–127.4 (Ar–C), 115.1, 114.9,
12.0 Hz, 1H), 4.47 (d, J = 12.0 Hz, 1H), 4.40 (dd, J = 6.1, 109.2, 107.9, 83.4, 80.1, 79.9, 78.5, 78.3, 76.5, 75.1, 74.8, 74.1,
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71.6, 70.1, 66.9, 66.5, 66.4, 65.5, 54.9, 53.8, 26.5, 26.4, 25.2, CH2Cl2); IR (neat) νmax 2986, 2932, 1650, 1513, 1454, 1370,
1
24.5; HRMS calcd for C43H46NO7 [M + H]+ 688.3274, found 1267, 1161, 1155, 1072, 1027 cm−1; H NMR (400 MHz, CDCl3)
688.3276.
δ 7.37–7.26 (m, 11H), 7.01 (d, J = 8.7 Hz, 1H), 6.80 (d, J =
Benzyl (2R,3S)-2,3-bis(benzyloxy)-3-((R)-2,2-dimethyl-1,3- 8.2 Hz, 1H), 5.94 (s, 1H), 4.93 (d, J = 11.0 Hz, 1H), 4.89 (d, J =
dioxolan-4-yl)-1-(4-methoxyphenyl)propylcarbamate (19). Fol- 11.0 Hz, 1H), 4.72 (d, J = 11.9 Hz, 1H), 4.49 (d, J = 11.9 Hz, 1H),
lowing general procedure C, compound 19 was obtained as a 4.42 (dd, J = 6.4, 12.6 Hz, 1H), 4.12–4.03 (m, 2H), 3.99 (d, J =
colorless oil: Yield 0.922 g (76% over 2 steps); Rf 0.30 (hexane– 6.4 Hz, 1H), 3.86 (s, 3H), 3.57 (s, 3H), 1.43 (s, 3H), 1.35 (s, 3H);
EtOAc = 3 : 1); IR (neat) νmax 3411, 3410, 3063, 2985, 2930, 13C NMR (125 MHz, CDCl3) δ 151.0, 148.7, 148.1, 138.0–127.7
1
1722, 1611, 1586, 1511, 1455, 1342, 1248, 1157, 1062 cm−1; H (Ar–C), 122.0, 115.3, 111.7, 110.8, 109.5, 81.2, 76.6, 72.4,
NMR (500 MHz, CDCl3, 1.1 : 1 mixture of diastereomers) 71.2, 66.6, 55.9, 55.5, 26.7, 25.5; HRMS calcd for C30H38NO6
δ 7.35–7.20 (m, 15H, both isomers), 7.09–7.05 (m, 2H, both [M + NH4]+ 508.2699, Found: 508.2698.
isomers), 6.86–6.82 (m, 2H, both isomers), 6.60 (d, J = 8.0 Hz,
Benzyl (2R,3R,4R)-2,3-bis(benzyloxy)-1-(4-(benzyloxy)-phenyl)-
1H, major isomer), 5.86 (d, J = 8.0 Hz, 1H, minor isomer), 5.28 4,5-dihydroxypentylcarbamate (10). Following general pro-
(dd, J = 5.1, 8.0 Hz, 1H, minor isomer), 5.08–4.97 (m, 5H: 3H cedure D, compound 10 was obtained as a colorless oil: Yield
for major isomer, 2H for minor isomer), 4.82 (d, J = 11.1 Hz, 0.867 g (92%); Rf 0.40 (hexane–EtOAc = 1 : 2); IR (neat)
1H, minor isomer), 4.72 (d, J = 11.1 Hz, 1H, major isomer), νmax 3413, 3088, 3031, 2927, 1701, 1609, 1585, 1509, 1454,
4.67–4.65 (m, 2H, minor isomer), 4.55–4.49 (m, 1H, both 1342, 1240, 1056, 1026 cm−1 1H NMR (500 MHz, CDCl3,
;
isomer) 4.32–4.30 (m, 1H, both isomer), 4.13–3.99 (m, 5H: 4H 1.2 : 1 mixture of diastereomers) δ 7.44–7.25 (m, 20H, both
for major isomer, 1H for minor isomer), 3.91 (t, J = 7.1 Hz, 1H, isomers), 7.20–7.04 (m, 2H, both isomers), 6.94–6.90 (m, 2H,
minor isomer), 3.80 (s, 3H, minor isomer), 3.79 (s, 3H, major both isomers), 6.42 (d, J = 7.6 Hz, 1H, major isomer), 5.89 (d,
isomer), 3.71–3.64 (m, 2H, both isomers), 1.43 (s, 3H, minor J = 9.1 Hz, 1H, minor isomer), 5.23–5.21 (m, 1H, minor
isomer), 1.36 (s, 3H, major isomer), 1.34 (s, 3H, minor isomer), 5.09–5.04 (m, 9H: 5H for major isomer, 4H for minor
isomer), 1.25 (s, 3H, major isomer); 13C NMR (125 MHz, isomer), 4.70 (d, J = 11.0 Hz, 1H, major isomer), 4.65–4.58
CDCl3, 1.1 : 1 mixture of diastereomers) δ 158.9, 156.4, 155.8, (m, 3H: 1H for major isomer, 2H for minor isomer), 4.51–4.46
138.2–127.4 (Ar–C), 114.1, 114.0, 109.2, 107.9, 83.4, 80.1, 79.9, (m, 1H, both isomers), 4.35 (d, J = 11.0 Hz, 1H, minor isomer),
78.5, 78.3, 76.5, 75.0, 74.8, 74.1, 71.6, 66.9, 66.5, 66.4, 65.5, 4.08 (d, J = 10.7 Hz, 1H, major isomer), 3.90–3.54 (m, 9H: 5H
55.4, 54.9, 53.8, 26.5, 26.4, 25.2, 24.5; HRMS calcd for for major isomer, 4H for minor isomer), 3.41 (br s, 1H, minor
C37H41NNaO7 [M + Na]+ 634.2781, found 634.2789.
isomer), 3.08 (d, J = 5.8 Hz, 1H, major isomer), 2.99 (d, J =
Benzyl (2R,3S)-2,3-bis(benzyloxy)-1-(3,4-dimethoxyphenyl)-3- 4.9 Hz, 1H, minor isomer), 2.22 (br s, 1H, minor isomer),
((R)-2,2-dimethyl-1,3-dioxolan-4-yl)propylcarbamate (20a). Fol- 2.03 (br s, 1H, major isomer); 13C NMR (125 MHz, CDCl3,
lowing general procedure C, compound 20a was obtained as a 1.2 : 1 mixture of diastereomers) δ 158.2, 158.1, 156.2, 156.0,
colorless oil: Yield 0.938 g (78% over 2 steps); Rf 0.40 (hexane– 137.9–127.4 (Ar–C), 115.1, 115.0, 83.5, 79.9, 79.8, 77.9, 75.3,
EtOAc = 2 : 1); IR (neat) νmax 3349, 3031, 2986, 2934, 1720, 74.8, 72.9, 72.4, 71.9, 71.3, 70.1, 67.1, 66.6, 63.6, 63.5, 54.4;
1592, 1514, 1380, 1261, 1235, 1141, 1027 cm−1
(500 MHz, CDCl3, 1 : 1 mixture of diastereomers) δ 7.33–7.08 648.2961.
(m, 30H), 6.83–6.60 (m, 6H), 6.60 (d, J = 7.9 Hz, 1H, one Benzyl (2R,3R,4R)-2,3-bis(benzyloxy)-4,5-dihydroxy-1-
; C40H42NO7 [M +
1H NMR HRMS calcd for H]+ 648.2961, found
isomer), 5.87 (d, J = 7.6 Hz, 1H, one isomer), 5.25 (d, J = (4-methoxyphenyl)pentylcarbamate (21). Following general
12.9 Hz, 1H, one isomer), 5.10 (d, J = 12.2 Hz, 1H, one isomer), procedure D, compound 21 was obtained as a colorless oil:
5.05–5.03 (m, 3H), 5.02 (d, J = 12.3 Hz, 1H, one isomer), 4.96 Yield 0.802 g (86%); Rf 0.50 (hexane–EtOAc = 1 : 3); IR (neat)
(d, J = 7.9 Hz, 1H, one isomer), 4.82 (d, J = 11.0 Hz, 1H, one νmax 3413, 3063, 3031, 2930, 1700, 1611, 1585, 1512, 1454,
isomer) 4.71 (d, J = 11.3 Hz, 1H, one isomer), 4.70–4.68 (m, 1401, 1292, 1248, 1056 cm−1 1H NMR (500 MHz, CDCl3,
;
3H), 4.57 (d, J = 10.3 Hz, 1H, one isomer), 4.52 (d, J = 11.3 Hz, 1.2 : 1 mixture of diastereomers) δ 7.33–7.06 (m, 17H, both
1H, one isomer), 4.34–4.29 (m, 2H), 4.12–4.01 (m, 5H), isomers), 6.86–6.83 (m, 2H, both isomers), 6.43 (d, J = 7.3 Hz,
3.92–3.87 (m, 1H), 3.85 (s, 6H), 3.72 (s, 6H), 3.70–3.66 (m, 2H), 1H, minor isomer), 5.91 (d, J = 9.1 Hz, 1H, major isomer), 5.21
1.43 (s, 3H, one isomer), 1.35 (s, 3H, one isomer), 1.34 (s, 3H, (t, J = 6.4 Hz, 1H, minor isomer), 5.09–5.04 (m, 5H: 3H for
one isomer), 1.26 (s, 3H, one isomer); 13C NMR (125 MHz, major isomer, 2H for minor isomer), 4.70 (d, J = 11.0 Hz, 1H,
CDCl3, 1 : 1 mixture of diastereomers) δ 156.4, 155.8, 149.2, major isomer), 4.65–4.58 (m, 3H: 1H for major isomer, 2H for
149.0, 148.3, 138.2–127.5 (Ar–C), 118.5, 118.4, 111.4, 111.1, minor isomer), 4.51–4.47 (m, 1H, both isomers), 4.35 (d, J =
109.6, 109.2, 107.9, 83.4, 80.1, 79.9, 78.6, 78.4, 76.5, 75.0, 74.8, 11.0 Hz, 1H, minor isomer), 4.09 (d, J = 10.3 Hz, 1H, major
74.2, 71.8, 67.0, 66.6, 66.5, 65.5, 56.0, 55.8, 55.7, 55.2, 54.1, isomer), 3.90–3.80 (m, 2H, both isomers), 3.80 (s, 3H, major
27.1, 26.5, 25.2, 24.6; HRMS calcd for C38H44NO8 [M + H]+ isomer), 3.79 (s, 3H, minor isomer), 3.74–3.68 (m, 3H: 2H for
642.3067, found 642.3063.
major isomer, 1H for minor isomer), 3.62 (dd, J = 3.6, 11.3 Hz,
(R)-4-((R,Z)-1,2-Bis(benzyloxy)-3-(3,4-dimethoxyphenyl)allyl)- 1H, minor isomer), 3.53 (dd, J = 5.2, 11.3 Hz, 1H, major
2,2-dimethyl-1,3-dioxolane (20b). The unreacted minor isomer), 3.41 (br s, 1H, minor isomer), 3.12–3.05 (m, 1H,
product 20b was obtained as a colorless oil: Yield 0.115 g both isomer); 13C NMR (125 MHz, CDCl3, 1.2 : 1 mixture of
(12%); Rf 0.50 (hexane–EtOAc = 4 : 1); [α]2D8 = +36.3 (c 1.65, diastereomers) δ 159.0, 158.9, 156.1, 137.3–127.4 (Ar–C), 114.1,
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114.0, 83.5, 79.9, 79.8, 78.0, 75.3, 74.8, 72.9, 72.4, 72.0, 71.4, isomers), 6.70 (d, J = 8.2 Hz, 1H, major isomer), 5.88 (d, J =
67.1, 66.6, 63.6, 63.5, 55.4, 55.3, 54.4; HRMS calcd for 7.6 Hz, 1H, minor isomer), 5.26–5.23 (m, 1H, major isomer),
C34H38NO7 [M + H]+ 572.2648, found 572.2647.
5.04–4.96 (m, 5H: 2H for major isomer, 3H for minor isomer),
Benzyl (2R,3R,4R)-2,3-bis(benzyloxy)-1-(3,4-dimethoxy-phenyl)- 4.60–4.52 (m, 3H: 1H for major isomer, 2H for minor isomer),
4,5-dihydroxypentylcarbamate (22). Following general pro- 4.43–4.38 (m, 1H, both isomers), 4.22–4.20 (m, 1H, major
cedure D, compound 22 was obtained as a colorless oil: Yield isomer), 4.15 (br s, 1H, minor isomer), 4.04 (d, J = 10.6 Hz, 1H,
0.824 g (88%); Rf 0.4 (hexane–EtOAc = 2 : 3); IR (neat) νmax minor isomer), 3.99 (br s, 1H, major isomer), 3.90 (d, J =
3417, 3063, 3031, 2926, 1701, 1592, 1514, 1454, 1420, 1345, 10.6 Hz, 1H, minor isomer), 3.79–3.78 (m, 1H, major isomer),
1261, 1236, 1140, 1057, 1027 cm−1; 1H NMR (500 MHz, CDCl3, 3.78 (s, 3H, both isomer), 3.77 (br s, 1H, both isomer), 3.72
2 : 1 mixture of diastereomers) δ 7.33–7.06 (m, 15H, both (br s, 1H, both isomers), 3.60 (br s, 1H major isomer),
isomers), 6.85–6.75 (m, 3H, both isomers), 6.43 (d, J = 7.0 Hz, 3.45–3.43 (m, 1H, both isomers), 3.32 (d, J = 8.8 Hz, 1H, major
1H, minor isomer), 5.95 (d, J = 9.2 Hz, 1H, major isomer), isomer), 3.24 (d, J = 7.6 Hz, 1H, minor isomer), 2.95 (t, J =
5.20–5.07 (m, 3H, both isomer), 4.71 (d, J = 11.3 Hz, 1H, major 8.5 Hz, 1H, major isomer); 13C NMR (125 MHz, CDCl3,
isomer), 4.62–4.50 (m, 2H, both isomer), 4.38 (d, J = 10.9 Hz, 1.2 : 1 mixture of diastereomers) δ 158.8, 158.7, 156.5, 156.0,
1H, minor isomer), 4.10 (d, J = 10.4 Hz, 1H, major isomer), 143.7–127.2 (Ar–C), 114.1, 113.9, 113.6, 109.7, 86.9, 86.7, 83.2,
3.93–3.86 (m, 3H: 2H for major isomer, 1H for minor isomer), 80.0, 79.6, 75.2, 74.5, 71.6, 71.5, 71.3, 68.9, 66.8, 66.5, 64.4,
3.90 (s, 6H, major isomer), 3.77–3.64 (m, 7H: 4H for major 55.3, 53.7; HRMS calcd for C53H51NNaO7 [M + Na]+ 836.3563,
isomer, 3H for minor isomer), 3.69 (s, 6H, minor isomer), 3.57 found 836.3568.
(dd, J = 5.2, 11.0 Hz, 1H, minor isomer), 3.46 (br s, 1H, minor
Benzyl (2R,3R,4R)-2,3-bis(benzyloxy)-1-(3,4-dimethoxy-phenyl)-
isomer); 13C NMR (125 MHz, CDCl3, 2 : 1 mixture of diastereo- 4-hydroxy-5-(trityloxy)pentylcarbamate (24). Following general
mers) δ 156.2, 156.1, 149.0, 148.4, 148.3, 137.9–128.0 (Ar–C), procedure E, compound 24 was isolated as a colorless oil:
119.0, 118.4, 111.3, 111.1, 110.0, 109.5, 83.5, 80.1, 79.7, 78.2, Yield 1.28 g (92%); Rf 0.50 (hexane–EtOAc = 4 : 1); IR (neat)
75.2, 74.8, 73.1, 72.6, 72.1, 71.4, 67.2, 66.7, 63.5, 56.0, 55.9, νmax 3415, 3060, 3031, 2926, 1718, 1594, 1513, 1450, 1419,
55.8, 54.7; HRMS calcd for C35H40NO8 [M + H]+ 602.2754, 1342, 1261, 1140, 1065, 1027 cm−1; 1H NMR (500 MHz, CDCl3,
found 602.2750.
1.2 : 1 mixture of diastereomers) δ 7.46–7.05 (m, 30H, both
Benzyl (2R,3R,4R)-2,3-bis(benzyloxy)-1-(4-(benzyloxy)-phenyl)- isomers), 6.80–6.67 (m, 7H: 4H for major isomer, 3H for
4-hydroxy-5-(trityloxy)pentylcarbamate (11). Following general minor isomer), 5.96 (d, J = 7.6 Hz, 1H, minor isomer),
procedure E, compound 11 was isolated as a colorless oil: 5.28–5.26 (m, 1H, major isomer), 5.12–5.02 (m, 5H: 2H for
Yield 1.34 g (quantitative); Rf 0.40 (hexane–EtOAc = 4 : 1); IR major isomer, 3H for minor isomer), 4.63 (d, J = 11.0 Hz, 1H,
(neat) νmax 3421, 3087, 3031, 2929, 1719, 1610, 1585, 1509, minor isomer), 4.57–4.55 (m, 2H, major isomer), 4.49 (d, J =
1451, 1382, 1290, 1222, 1177, 1068, 1027 cm−1 1H NMR 11.0 Hz, 1H, minor isomer), 4.40 (d, J = 11.0 Hz, 1H, minor
;
(500 MHz, CDCl3, 1.2 : 1 mixture of diastereomers) δ 7.46–7.06 isomer), 4.26 (d, J = 11.0 Hz, 1H, major isomer), 4.18–4.01 (m,
(m, 35H, both isomers), 7.05–6.83 (m, 4H, both isomers), 6.70 3H: 1H for major isomer, 2H for minor isomer), 3.96 (d, J =
(d, J = 8.2 Hz, 1H, major isomer), 5.87 (d, J = 7.6 Hz, 1H, minor 10.6 Hz, 1H, major isomer), 3.88 (s, 3H, both isomers),
isomer), 5.26 (dd, J = 5.5, 8.2 Hz, 1H, minor isomer), 5.07–4.96 3.87–3.75 (m, 2H, both isomers), 3.67 (s, 3H, minor isomer),
(m, 9H: 5H for major isomer, 4H for minor isomer), 4.60–4.54 3.63 (s, 3H, major isomer), 3.48–3.45 (m, 1H, both isomers),
(m, 1H, both isomer), 4.43–4.39 (m, 1H, both isomers), 4.20 3.34 (dd, J = 5.8, 9.4 Hz, 1H, minor isomer), 3.22 (d, J = 7.9 Hz,
(d, J = 10.7 Hz, 1H, minor isomer), 4.15–4.13 (m, 1H, major 1H, major isomer), 3.03 (t, J = 8.2 Hz, 1H, major isomer), 2.84
isomer), 4.04–4.01 (m, 2H, major isomer), 3.93 (d, J = 10.7 Hz, (br s, 1H, minor isomer); 13C NMR (125 MHz, CDCl3,
1H, minor isomer), 3.76–3.69 (m, 4H: 1H for major isomer, 3H 1.2 : 1 mixture of diastereomers) δ 156.5, 156.0, 149.1, 149.0,
for minor isomer), 3.61 (br s, 1H, major isomer), 3.46–3.44 (m, 148.2, 143.7–127.2 (Ar–C), 118.5, 111.4, 111.1, 109.7, 109.4,
1H, both isomers), 3.23 (dd, J = 5.5, 9.4 Hz, 1H, major isomer), 86.9, 86.8, 83.2, 79.9, 79.8, 75.2, 74.4, 71.7, 71.6, 71.5, 69.1,
3.23 (d, J = 7.9 Hz, 1H, minor isomer), 2.97 (t, J = 8.5 Hz, 1H, 66.9, 66.5, 64.5, 56.0, 55.9, 55.7, 54.1; HRMS calcd for
major isomer), 2.80 (br s, 1H, minor isomer); 13C NMR C54H53NNaO8 [M + Na]+ 866.3669, found 866.3662.
(125 MHz, CDCl3, 1.2 : 1 mixture of diastereomers) δ 158.0,
(2S,3R,4R,5S)-Benzyl 3,4-bis(benzyloxy)-2-(4-(benzyloxy)-phenyl)-
156.5, 156.0, 143.7–127.2 (Ar–C), 115.0, 114.9, 86.7, 79.6, 75.2, 5-(trityloxymethyl)pyrrolidine-1-carboxylate (12a). Following
74.5, 71.5, 71.3, 70.0, 69.0, 66.5, 64.4, 53.8; HRMS calcd for general procedure F, compound 12a was isolated as a colorless
C59H55NNaO7 [M + Na]+ 912.3876, found 912.3872.
oil: Yield 0.391 g (40%); Rf 0.55 (hexane–EtOAc = 4 : 1); [α]D28
=
Benzyl (2R,3R,4R)-2,3-bis(benzyloxy)-4-hydroxy-1-(4-methoxy- −41.1 (c 0.85, CH2Cl2); IR (neat) νmax 3061, 3031, 2930, 1703,
phenyl)-5-(trityloxy)pentylcarbamate (23). Following general 1610, 1510, 1494, 1450, 1404, 1350, 1313, 1240, 1176, 1106,
1
procedure E, compound 23 was isolated as a colorless oil: 1041, 1027 cm−1; H NMR (500 MHz, CDCl3, 1.2 : 1 mixture of
Yield 1.34 g (95%); Rf 0.50 (hexane–EtOAc = 3 : 1); IR (neat) rotamers) δ 7.48–7.06 (m, 35H, both rotamers), 6.96–6.72 (m,
νmax 3419, 3060, 3031, 2932, 1718, 1611, 1512, 1449, 1247, 4H, both rotamers), 5.26 (d, J = 8.5 Hz, 1H, minor rotamer),
1178, 1066, 1030 cm−1; 1H NMR (500 MHz, CDCl3, 1.2 : 1 mixture 5.15 (d, J = 8.2 Hz, 1H, major rotamer), 5.08–4.95 (m, 4H, both
of diastereomers)
δ 7.42–7.22 (m, 30H, both isomers), rotamers), 4.76 (d, J = 12.5 Hz, 1H, minor rotamer), 4.70–4.66
7.12–6.99 (m, 2H, both isomers), 6.81–6.74 (m, 2H, both (m, 3H: 2H for major rotamer, 1H for minor rotamer),
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4.56–4.48 (m, 3H, both rotamers), 4.40 (t, J = 8.2 Hz, 1H, minor 30H, Ar–H), 6.92–6.82 (m, 4H, Ar–H), 5.04 (s, 2H, –OCH2Ph),
rotamer), 4.34 (t, J = 8.2 Hz, 1H, major rotamer), 4.30–4.28 4.51 (d, J = 11.9 Hz, 1H, –OCHPh), 4.45 (d, J = 11.9 Hz, 1H,
(m, 1H, major rotamer), 4.22–4.20 (m, 1H, minor rotamer), –OCHPh), 4.31 (d, J = 11.6 Hz, 1H, –OCHPh), 4.28 (d, J = 11.6
3.63 (dd, J = 3.3, 9.7 Hz, 1H, major rotamer), 3.50–3.42 (m, 1H, Hz, 1H, –OCHPh), 4.06 (d, J = 6.1 Hz, 1H, H-4), 3.80 (d, J =
both rotamers), 3.34 (d, J = 8.8 Hz, 1H, minor rotamer); 5.1 Hz, 1H, H-3), 3.50–3.39 (m, 2H, H-6, H-6′), 3.18 (d, J = 6.1
13C NMR (125 MHz, CDCl3, 1.2 : 1 mixture of rotamers) Hz, 1H, H-2), 2.98–2.94 (m, 1H, H-5), 2.10 (s, 3H, N–CH3);
δ 158.1, 154.3, 144.1, 144.0, 138.3–126.9 (Ar–C), 114.5, 87.5, 13C NMR (125 MHz, CDCl3) δ 144.4, 138.4–126.9 (Ar–C), 114.7,
82.5, 81.9, 81.2, 80.6, 73.5, 72.5, 70.1, 66.8, 66.7, 61.5, 61.3, 90.1, 87.1, 82.5, 76.2, 72.0, 70.0, 68.1, 62.8, 39.9, 29.7; HRMS
61.0, 59.3, 56.8, 56.7; HRMS calcd for C59H53NNaO6 [M + Na]+ calcd for C52H50NO4 [M + H]+ 752.3740, found 752.3741.
894.3771, found 894.3770.
(2S,3R,4R,5S)-2-(Hydroxymethyl)-5-(4-hydroxyphenyl)-pyrro-
(2R,3R,4R,5S)-Benzyl 3,4-bis(benzyloxy)-2-(4-(benzyloxy)- lidine-3,4-diol (14a). To a stirred solution of 12a (0.1 g,
phenyl)-5-(trityloxymethyl)pyrrolidine-1-carboxylate (12b). Fol- 0.114 mmol) in dry CH2Cl2 (4 mL) was added BBr3 (1 M solu-
lowing general procedure F, compound 12b was isolated as a tion in CH2Cl2, 0.534 mL, 0.672 mmol) dropwise carefully. The
colorless oil: Yield 0.303 g (31%); Rf 0.50 (hexane–EtOAc = reaction mixture was warmed to room temperature and stirred
4 : 1); [α]2D8 = +20.0 (c 0.35, CH2Cl2); IR (neat) νmax 3086, 3031, for 5 h. Excess of BBr3 was quenched by addition of 2–3 drops
2926, 1704, 1510, 1495, 1450, 1403, 1345, 1299, 1239, 1222, of MeOH. The reaction mixture was concentrated under
1
1176, 1101, 1026 cm−1; H NMR (500 MHz, CDCl3) δ 7.43–7.09 vacuum to give a crude product. The pure product 14a was
(m, 37H), 6.70–6.68 (m, 2H), 5.08 (d, J = 2.1 Hz, 1H), 5.06–4.97 obtained as a semi-solid after washing the residue with
(m, 2H), 4.83 (br s, 1H), 4.64 (br s, 1H), 4.59–4.47 (m, 5H), 4.27 hexane, EtOAc and CHCl3 solvents: Yield 0.024 g (96%); Rf 0.3
(br s, 1H), 4.20 (t, J = 7.0 Hz, 1H), 3.53–3.46 (m, 2H); 13C NMR (EtOAc–MeOH = 4 : 1); [α]2D8 = +24.0 (c 0.25, MeOH); IR (neat)
(125 MHz, CDCl3) δ 157.9, 155.7, 143.9, 138.1–126.9 (Ar–C), νmax 3403, 2957, 1616, 1585, 1520, 1342, 1258, 1216, 1077,
114.5, 87.7, 72.9, 72.8, 70.0, 62.0, 58.6; HRMS calcd for 1033 cm−1
;
1H NMR (500 MHz, D2O) δ 7.28–7.26 (m, 2H),
6.84–6.82 (m, 2H), 4.79 (br s, 1H), 4.39 (d, J = 3.9 Hz, 1H), 4.24
C59H53NNaO6 [M + Na]+ 894.3771, found 894.3773.
(2S,3R,4R,5S)-3,4-Bis(benzyloxy)-2-(4-(benzyloxy)phenyl)- (br s, 1H), 4.03 (d, J = 7.6 Hz, 1H), 3.91 (dd, J = 4.5, 12.2 Hz,
1-methyl-5-(trityloxymethyl)pyrrolidine (13a). To a stirred sus- 1H), 3.85–3.81 (m, 1H); 13C NMR (125 MHz, D2O) δ 156.3,
pension of LiAlH4 (0.042 g, 1.14 mmol) in THF (2 mL) was 130.1, 122.1, 115.7, 76.8, 74.6, 64.0, 63.0, 57.5; HRMS calcd for
added pyrrolidine derivative 12a (0.1 g, 0.114 mmol) in THF C11H16NO4 [M + H]+ 226.1079, found 226.1070.
(1 mL) at 0 °C. After addition was completed, the reaction
(2S,3R,4R,5R)-2-(Hydroxymethyl)-5-(4-hydroxyphenyl)-pyrro-
mixture was heated to reflux for 1 h. The reaction mixture was lidine-3,4-diol (14b). Compound 14b was obtained as a semi-
cooled to 0 °C, quenched with EtOAc (0.1 mL), followed by solid using the same procedure as followed for compound 14a:
addition of 15% NaOH (0.20 mL) and water (0.20 mL) succes- Yield 0.022 g (88%); Rf 0.3 (EtOAc–MeOH = 4 : 1); [α]2D8 = +20.0
sively. After 15 min of stirring at room temperature, the reac- (c 0.35, MeOH); IR (neat) νmax 3253, 2925, 1613, 1582,
1
tion mixture was filtered through a Celite pad, washed with 1519, 1445, 1195, 1106, 1057 cm−1; H NMR (500 MHz, D2O)
ethyl acetate (3 × 10 mL) and the filtrate evaporated under δ 7.29–7.28 (m, 2H), 6.82–6.80 (m, 2H), 4.38 (t, J = 2.7 Hz, 1H),
vacuum. The residue was purified by silica-gel column chrom- 4.28–4.22 (m, 2H), 3.86–3.83 (m, 3H); 13C NMR (125 MHz,
atography to afford the N-methyl derivative 13a in 79% D2O) δ 156.9, 130.4, 123.8, 116.0, 79.7, 74.4, 66.9, 62.5,
(0.068 g) yield as a colorless oil: Rf 0.60 (hexane–EtOAc = 4 : 1); 56.9; HRMS calcd for C11H16NO4 [M + H]+ 226.1079, found
[α]2D8 = −11.4 (c 0.35, CH2Cl2); IR (neat) νmax 3060, 3031, 2925, 226.1078.
1
1608, 1493, 1509, 1449, 1239, 1104, 1027, 697 cm−1; H NMR
(2S,3R,4R,5S)-Benzyl 3,4-bis(benzyloxy)-2-(4-methoxyphenyl)-
(500 MHz, CDCl3) δ 7.51–7.18 (m, 30H, Ar–H), 6.98–6.95 (m, 5-(trityloxymethyl)pyrrolidine-1-carboxylate (25a). Compound
4H, Ar–H), 5.08 (s, 2H, –OCH2Ph), 4.62 (d, J = 11.6 Hz, 1H, 25a was obtained as a colorless oil following general procedure
–OCHPh), 4.56 (d, J = 11.6 Hz, 1H, –OCHPh), 4.45–4.43 (m, 1H, F: Yield 0.361 g (37%); Rf 0.55 (hexane–EtOAc = 3 : 1); [α]D28
=
H-3), 4.38–4.35 (m, 1H, H-4), 4.15 (d, J = 2.7 Hz, 1H, H-2), −35.0 (c 0.40, CH2Cl2); IR (neat) νmax 3061, 3031, 2926, 1705,
1
4.15–4.13 (m, 1H, –OCHPh), 4.08 (d, J = 11.6 Hz, 1H, –OCHPh), 1612, 1513, 1449, 1345, 1247, 1221, 1101, 1029 cm−1; H NMR
3.48–3.45 (m, 1H, H-5), 3.41 (dd, J = 3.9, 10.0 Hz, 1H, H-6), (500 MHz, CDCl3, 1.2 : 1 mixture of rotamers) δ 7.41–7.06 (m,
3.35 (dd, J = 2.7, 10.0 Hz, 1H, H-6′), 2.03 (s, 3H, N–CH3); 30H, both rotamers), 6.97–6.72 (m, 4H, both rotamers), 5.25
13C NMR (125 MHz, CDCl3) δ 144.1, 138.5–126.9 (Ar–C), 114.2, (d, J = 8.2 Hz, 1H, minor rotamer), 5.15 (d, J = 8.2 Hz, 1H,
84.7, 72.7, 72.0, 70.1, 69.4, 62.7, 59.5, 57.8, 35.6, 31.0; HRMS major rotamer), 5.05–4.97 (m, 2H, both rotamers), 4.76 (d, J =
calcd for C52H50NO4 [M + H]+ 752.3740, found 752.3748.
12.5 Hz, 1H, major rotamer), 4.70–4.65 (m, 1H, both rotamers),
(2R,3R,4R,5S)-3,4-Bis(benzyloxy)-2-(4-(benzyloxy)phenyl)- 4.56–4.48 (m, 7H: 3H for major rotamer, 4H for minor
1-methyl-5-(trityloxymethyl)pyrrolidine (13b). Compound 13b rotamer), 4.39 (t, J = 8.5 Hz, 1H, minor rotamer), 4.34 (t, J =
was obtained as a colorless oil using the same procedure as 8.2 Hz, 1H, major rotamer), 4.30–4.28 (m, 1H, major rotamer),
followed for compound 13a: Yield 0.062 g (72%); Rf 0.55 4.22 (dd, J = 2.4, 7.6 Hz, 1H, minor rotamer), 3.82 (s, 3H,
(hexane–EtOAc = 4 : 1); [α]2D8 = +16.0 (c 0.25, CH2Cl2); IR (neat) major rotamer), 3.80 (s, 3H, minor rotamer), 3.63 (dd, J = 3.3,
νmax 3060, 3031, 2925, 1609, 1492, 1509, 1449, 1238, 1107, 9.4 Hz, 1H, major rotamer), 3.49 (dd, J = 3.3, 9.8 Hz, 1H, minor
1027, 697 cm−1 1H NMR (500 MHz, CDCl3) δ 7.46–7.11 (m, rotamer), 3.43 (d, J = 9.2 Hz, 1H, minor rotamer), 3.34 (d, J =
;
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9.2 Hz, 1H, major rotamer); 13C NMR (125 MHz, CDCl3, 138.0–127.0 (Ar–C), 118.7, 110.9, 109.7, 87.5, 72.9, 72.7, 66.9,
1.2 : 1 mixture of rotamers) δ 158.8, 154.2, 144.1, 144.0, 65.4, 62.0, 59.1, 55.9, 55.5; HRMS calcd for C54H51NNaO7
138.0–126.9 (Ar–C), 113.6, 87.5, 82.5, 81.9, 81.2, 80.6, 73.5, [M + Na]+ 848.3563, Found: 848.3564.
72.5, 66.8, 66.6, 61.5, 61.3, 59.3, 56.8, 56.6, 55.4, 55.3;
HRMS calcd for C53H49NNaO6 [M + Na]+ 818.3458, found 5-(4-methoxyphenyl)pyrrolidine-1-carboxylate (27a). To an ice
818.3453. cooled solution of compound 25a (0.5 g, 0.628 mmol) dis-
(2S,3R,4R,5S)-Benzyl 3,4-bis(benzyloxy)-2-(hydroxymethyl)-
(2R,3R,4R,5S)-Benzyl 3,4-bis(benzyloxy)-2-(4-methoxyphenyl)- solved in dry CH2Cl2 was added trifluoroacetic acid (0.146 mL,
5-(trityloxymethyl)pyrrolidine-1-carboxylate (25b). Compound 1.88 mmol) slowly. The reaction mixture was brought to room
25b was obtained as a colorless oil following general procedure temperature gradually and stirred for 0.5 h. Once the starting
F: Yield 0.332 g (34%); Rf 0.50 (hexane–EtOAc = 3 : 1); [α]D28
=
material was completely consumed (TLC monitoring), excess
+20.0 (c 0.30, CH2Cl2); IR (neat) νmax 3061, 3032, 2926, 1705, acid was quenched by adding a saturated solution of NaHCO3.
1513, 1494, 1449, 1403, 1358, 1302, 1247, 1102, 1028 cm−1
The reaction mixture was extracted with CH2Cl2 (3 × 25 mL).
;
1H NMR (500 MHz, CDCl3) δ 7.44–7.09 (m, 32H), 6.62–6.60 The organic extract was washed with H2O (1 × 10 mL), brine
(m, 2H), 5.07 (d, J = 11.9 Hz, 1H), 4.83 (br s, 1H), 4.63 (1 × 10 mL) and dried over Na2SO4. The combined extracts
(br s, 1H), 4.57 (d, J = 11.9 Hz, 1H), 4.56–4.53 (m, 4H), 4.27 were evaporated in a rotary evaporator to give a crude product
(br s, 1H), 4.20 (t, J = 7.3 Hz, 1H), 3.75 (s, 3H), 3.54–3.48 which was purified by silica-gel column chromatography to
(m, 2H); 13C NMR (125 MHz, CDCl3)
δ 158.6, 155.7, afford 27a in 83% (0.288 g) as a colorless oil: Rf 0.40 (hexane–
144.0–126.9 (Ar–C), 113.6, 87.7, 72.9, 72.8, 66.9, 64.8, 62.0, EtOAc = 1 : 1); [α]2D8 = −35.3 (c 1.30, CH2Cl2); IR (neat)
58.6, 55.3; HRMS calcd for C53H49NNaO6 [M + Na]+ 818.3458, νmax 3441, 3062, 2930, 1699, 1612, 1513, 1497, 1454, 1351,
found 818.3452.
1248, 1209, 1102, 1028 cm−1 1H NMR (500 MHz, CDCl3,
;
(2S,3R,4R,5S)-Benzyl 3,4-bis(benzyloxy)-2-(3,4-dimethoxy- 3.5 : 1 mixture of rotamers) δ 7.35–7.02 (m, 15H, both rota-
phenyl)-5-(trityloxymethyl)pyrrolidine-1-carboxylate (26a). Fol- mers), 6.88–6.74 (m, 4H, both rotamers), 5.15–5.04 (m, 3H: 1H
lowing general procedure F, compound 26a was obtained as a for major rotamer, 2H for minor rotamer), 5.03 (d, J = 12.8 Hz,
colorless oil: Yield 0.446 g (46%); Rf 0.40 (hexane–EtOAC = 1H, major rotamer), 4.82 (d, J = 12.8 Hz, 1H, major rotamer),
2 : 1); [α]2D8 = −30.0 (c 0.50, CH2Cl2); IR (neat) νmax 3086, 3031, 4.77 (d, J = 11.1 Hz, 1H, minor rotamer), 4.70 (d, J = 11.6 Hz,
2933, 1703, 1516, 1494, 1463, 1449, 1404, 1351, 1352, 1260, 1H, major rotamer), 4.61 (d, J = 11.1 Hz, 1H, minor rotamer),
1
1141, 1028 cm−1; H NMR (500 MHz, CDCl3, 1.4 : 1 mixture of 4.58 (d, J = 11.6 Hz, 1H, major rotamer), 4.54–4.52 (m, 1H,
rotamers) δ 7.43–7.41 (m, 7H, both rotamers), 7.29–6.97 minor rotamer), 4.47 (d, J = 11.6 Hz, 1H, major rotamer),
(m, 23H, both rotamers), 6.84–6.60 (m, 3H, both rotamers), 4.46–4.42 (m, 1H, minor rotamer), 4.42–4.29 (m, 9H: 4H for
5.24 (d, J = 8.3 Hz, 1H, minor rotamer), 5.13 (d, J = 12.0 Hz, major rotamer, 5H for minor rotamer), 4.29–4.03 (m, 1H,
1H, major rotamer) 5.06–4.97 (m, 2H, both rotamers), 4.75 major rotamer), 3.90–3.87 (m, 1H, both rotamer), 3.83 (s, 3H,
(d, J = 12.0 Hz, 1H, major rotamer), 4.69–4.63 (m, 1H, both major rotamer), 3.80 (s, 3H, minor rotamer), 3.33 (d, J =
rotamers), 4.61–4.50 (m, 7H: 3H for major rotamer, 4H for 12.5 Hz, 1H, major rotamer); 13C NMR (125 MHz, CDCl3,
minor rotamer), 4.39–4.23 (m, 2H, both rotamers), 3.90 (s, 3H, 3.5 : 1 mixture of rotamers) δ 159.0, 155.7, 137.6–127.5 (Ar–C),
major rotamer), 3.86 (s, 3H, minor rotamer), 3.79 (s, 3H, 113.8, 113.7, 81.9, 80.9, 73.7, 73.5, 72.6, 67.0, 61.9, 61.6, 59.9,
minor rotamer), 3.70 (s, 3H, major rotamer), 3.65 (dd, J = 3.1, 55.4; HRMS calcd for C34H35NNaO6 [M + Na]+ 576.2362, found
9.7 Hz, 1H, major rotamer), 3.51 (dd, J = 3.7, 9.7 Hz, 1H, minor 576.2362.
rotamer), 3.45 (d, J = 9.4 Hz, 1H, minor rotamer), 3.36 (d, J =
(2S,3R,4R,5R)-Benzyl 3,4-bis(benzyloxy)-2-(hydroxymethyl)-5-
9.4 Hz, 1H, major rotamer); 13C NMR (125 MHz, CDCl3, (4-methoxyphenyl)pyrrolidine-1-carboxylate (27b). Compound
1.4 : 1 mixture of rotamers) δ 154.3, 154.1, 148.6, 148.2, 144.1, 27b was obtained as a colorless oil using the same procedure
144.0, 138.3–126.9 (Ar–C), 119.3, 111.4, 111.3, 111.0, 87.7, 87.5, as followed for compound 27a: Yield 0.267g (77%); Rf 0.40
82.6, 81.9, 81.0, 80.5, 73.5, 72.7, 66.8, 66.7, 61.5, 60.0, 59.4, (hexane–EtOAc = 1 : 1); [α]2D8 = +18.8 (c 0.85, CH2Cl2); IR (neat)
56.8, 56.7, 56.0, 55.9; HRMS calcd for C54H51NNaO7 [M + Na]+ νmax 3422, 3063, 3031, 2926, 1698, 1513, 1497, 1454, 1408,
1
848.3563, found 848.3568.
1350, 1247, 1176, 1103, 1029 cm−1; H NMR (500 MHz, CDCl3)
(2R,3R,4R,5S)-Benzyl 3,4-bis(benzyloxy)-2-(3,4-dimethoxy- δ 7.31–7.14 (m, 15H), 6.83–6.72 (m, 4H), 5.03 (d, J = 14.6 Hz,
phenyl)-5-(trityloxymethyl)pyrrolidine-1-carboxylate (26b). Fol- 1H), 4.90 (d, J = 14.6 Hz, 1H), 4.72 (d, J = 5.1 Hz, 1H), 4.50 (br
lowing general procedure F, compound 26b was obtained as a m, 4H), 4.33 (br s, 1H), 4.18 (br s, 1H), 4.12–4.10 (m, 1H), 4.06
colorless oil: Yield 0.405 g (41%); Rf 0.45 (hexane–EtOAc = (d, J = 11.1 Hz, 1H), 3.96 (br s, 1H), 3.81 (s, 3H), 3.72 (br s, 1H);
2 : 1); [α]2D8 = +26.6 (c 0.15, CH2Cl2); IR (neat) νmax 3060, 2931, 13C NMR (125 MHz, CDCl3) δ 158.8, 137.6–127.4 (ArC), 113.8,
1703, 1515, 1494, 1450, 1345, 1304, 1264, 1235, 1075, 87.3, 82.5, 72.6, 67.3, 65.6, 63.0, 61.0, 55.3; HRMS calcd for
1
1028 cm−1; H NMR (500 MHz, CDCl3) δ 7.43–7.12 (m, 28H), C34H36NO6 [M + H]+ 554.2543, found 554.2542.
6.98–6.97 (m, 2H), 6.81 (d, J = 8.3 Hz, 1H), 6.70 (s, 1H), 6.60 (d,
(2S,3R,4R,5S)-Benzyl 3,4-bis(benzyloxy)-2-(3,4-dimethoxy-
J = 8.3 Hz, 1H), 5.08 (d, J = 12.3 Hz, 1H), 4.90 (d. J = 12.3 Hz, phenyl)-5-(hydroxymethyl)pyrrolidine-1-carboxylate (28a). Com-
1H), 4.76–4.45 (m, 6H), 4.23–4.18 (m, 2H), 3.82 (s, 3H), 3.57 pound 28a was obtained as a colorless oil using the same pro-
(dd, J = 4.6, 9.1 Hz, 1H), 3.48 (br s, 1H), 3.38 (br s, 3H); cedure as followed for compound 27a: Yield 0.286 g (81%);
13C NMR (125 MHz, CDCl3) δ 155.9, 148.7, 147.9, 144.0, Rf 0.40 (hexane–EtOAc = 1 : 1); [α]2D8 = −10.0 (c 0.20, CH2Cl2);
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IR (neat) νmax 3448, 3062, 3003, 2934, 2835, 1699, 1516, 1497, for minor rotamer), 3.81–3.78 (m, 1H, both rotamers), 3.81
1
1454, 1407, 1352, 1259, 1140, 1027 cm−1; H NMR (500 MHz, (s, 3H, both rotamers), 3.74–3.72 (m, 1H, major rotamer),
CDCl3, 3.4 : 1 mixture of rotamers) δ 7.34–7.06 (m, 15H, both 3.55 (br s, 1H, major rotamer); 13C NMR (125 MHz, CDCl3,
rotamers), 6.83–6.52 (m, 3H, both rotamers), 5.13–5.06 (m, 2H, 2.5 : 1 mixture of rotamers) δ 159.0, 157.7, 137.9–127.5 (Ar–C),
minor rotamer), 5.03–5.00 (m, 2H, major rotamer), 4.79 (d, J = 113.7, 113.6, 80.7, 80.3, 73.6, 72.7, 67.4, 66.9, 57.9, 55.3, 5.0,
12.6 Hz, 1H, major rotamer), 4.75 (d, J = 11.7 Hz, 1H, minor 4.3; HRMS calcd for C34H35INO5 [M + H]+ 664.1560, found
rotamer), 4.68 (d, J = 11.4 Hz, 1H, major rotamer), 4.61–4.55 664.1566.
(m, 3H: 1H for major rotamer, 2H for minor rotamer),
(2R,3R,4R,5R)-Benzyl 3,4-bis(benzyloxy)-2-(iodomethyl)-5-
4.50–4.39 (m, 2H, both rotamers), 4.33–4.27 (m, 3H, both rota- (4-methoxyphenyl)pyrrolidine-1-carboxylate (29b). Compound
mers), 4.04 (t, J = 12.0 Hz, 1H, major rotamer), 3.94–3.87 (m, 29b was obtained as a colorless oil using the same procedure
2H, minor rotamer), 3.89 (s, 3H, major rotamer), 3.85 (s, 3H, as followed for compound 29a: Yield 0.096 g (80%); Rf 0.50
minor rotamer), 3.74 (s, 3H, minor rotamer), 3.65 (s, 3H, (hexane–EtOAc = 4 : 1); [α]2D8 = +30.0 (c 0.70, CH2Cl2); IR (neat)
major rotamer), 3.37 (dd, J = 4.3, 8.8 Hz, 1H, major rotamer); νmax 3063, 3030, 2925, 1702, 1512, 1497, 1454, 1398, 1350,
1
13C NMR (125 MHz, CDCl3, 3.4 : 1 mixture of rotamers) 1247, 1174, 1118, 1028, 696 cm−1; H NMR (500 MHz, CDCl3)
δ 155.7, 148.7, 148.3, 137.6–127.6 (Ar–C), 119.1, 110.9, 81.9, δ 7.36–7.10 (m, 15H), 6.87–6.79 (m, 4H), 5.16–5.09 (m, 3H),
80.8, 73.4, 72.7, 67.1, 62.0, 60.2, 56.0, 55.8; HRMS calcd for 4.59 (br s, 2H), 4.53–4.51 (m, 1H), 4.44 (d, J = 11.2 Hz, 1H),
C35H38NO7 [M + H]+ 584.2648, found 584.2643.
4.29 (d, J = 11.2 Hz, 1H), 4.16 (dd, J = 2.0, 5.1 Hz, 1H),
(2R,3R,4R,5S)-Benzyl 3,4-bis(benzyloxy)-2-(3,4-dimethoxy- 4.01–3.99 (m, 2H), 3.79 (s, 3H), 3.47–3.43 (m, 1H); 13C NMR
phenyl)-5-(hydroxymethyl)pyrrolidine-1-carboxylate (28b). Com- (100 MHz, CDCl3) δ 158.6, 156.3, 137.5–127.2 (Ar–C), 113.6,
pound 28b was obtained as a colorless oil using the same pro- 84.9, 82.4, 76.8, 73.0, 71.8, 67.9, 67.1, 54.5, 1.8; HRMS calcd
cedure as followed for compound 27a: Yield 0.321 g (91%); for C34H35INO5 [M + H]+ 664.1560, Found: 664.1565.
Rf 0.40 (hexane–EtOAc = 1 : 1); [α]2D8 = −22.2 (c 0.90, CH2Cl2);
IR (neat) νmax 3421, 3063, 3030, 2930, 1697, 1515, 1497, phenyl)-5-(iodomethyl)pyrrolidine-1-carboxylate (30a). Com-
1453, 1409, 1350, 1236, 1138, 1102, 1027 cm−1 1H NMR pound 30a was obtained as a colorless oil using the same pro-
(2S,3R,4R,5R)-Benzyl 3,4-bis(benzyloxy)-2-(3,4-dimethoxy-
;
(500 MHz, CDCl3) δ 7.31–7.14 (m, 15H), 6.87–6.77 (m, 3H), cedure as followed for compound 29a: Yield 0.1 g (85%);
5.06 (d, J = 11.4 Hz, 1H), 4.91 (d, J = 8.9 Hz, 1H), 4.71 (d, J = Rf 0.60 (hexane–EtOAc = 2 : 1); [α]2D8 = −22.5 (c 0.80, CH2Cl2); IR
4.8 Hz, 1H), 4.55–4.49 (m, 3H), 4.33(br s, 1H), 4.20 (br s, (neat) νmax 3062, 3030, 2930, 1701, 1513, 1496, 1453, 1349,
1H), 4.12–4.08 (m, 2H), 3.96 (br s, 1H), 3.88 (s, 3H), 3.75–3.73 1247, 1103, 1029, 697 cm−1 1H NMR (500 MHz, CDCl3,
;
(m, 1H), 3.63 (br s, 3H); 13C NMR (125 MHz, CDCl3) δ 156.7, 3.4 : 1 mixture of rotamers) δ 7.34–7.02 (m, 15H, both rota-
149.0, 148.1, 137.6–127.7 (Ar–C), 118.7, 110.9, 109.7, 87.3, mers), 6.82–6.52 (m, 3H, both rotamers), 5.17 (d, J = 12.0 Hz,
82.1, 72.7, 72.6, 67.4, 66.1, 63.3, 61.9, 56.0, 55.7; HRMS calcd 1H, minor rotamer), 5.09 (d, J = 12.0 Hz, 1H, minor rotamer),
for C35H38NO7 [M + H]+ 584.2648, found 584.2649.
(2R,3R,4R,5S)-Benzyl
5.06–5.04 (m, 1H, major rotamer), 4.97 (d, J = 12.3 Hz, 1H,
3,4-bis(benzyloxy)-2-(iodomethyl)-5- major rotamer), 4.81 (d, J = 12.3 Hz, 1H, major rotamer),
(4-methoxyphenyl)pyrrolidine-1-carboxylate (29a). To a stirred 4.70–4.65 (m, 5H: 2H for major rotamer, 3H for minor
solution of compound 27a (0.1 g, 0.180 mmol) in dry THF rotamer), 4.57–4.31 (m, 5H, both rotamers), 3.89 (s, 3H, major
were added PPh3 (0.094 g, 0.361 mmol), imidazole (0.049 g, rotamer), 3.89–3.86 (m, 1H, minor rotamer), 3.86 (s, 3H, minor
0.722 mmol) and iodine (0.091 g, 0.361 mmol) successively. rotamer), 3.82–3.77 (m, 2H, major rotamer), 3.74 (s, 3H, minor
After the addition was complete, the reaction mixture was rotamer), 3.64 (s, 3H, major rotamer), 3.57 (br s, 1H, minor
heated to reflux for 0.5 h. On consumption of the starting rotamer); 13C NMR (125 MHz, CDCl3, 3.4 : 1 mixture of rota-
material (TLC monitoring), the solvent was evaporated in vacuo mers) δ 154.8, 148.7, 148.3, 137.8–127.7(Ar–C), 119.3, 111.0,
and washed with sodium thiosulfate solution (1 × 10 mL). The 110.8, 80.6, 73.6, 72.8, 67.0, 62.6, 62.2, 58.1, 57.2, 56.0, 55.9,
compound was extracted with CH2Cl2 (3 × 10 mL), washed 55.8, 4.1; HRMS calcd for C35H37INO6 [M + H]+ 694.1666,
with brine (1 × 10 mL) and dried over Na2SO4. The organic found 694.1661.
layer was concentrated under vacuum to give a crude product
(2R,3R,4R,5R)-Benzyl 3,4-bis(benzyloxy)-2-(3,4-dimethoxy-
which was purified through column chromatography using phenyl)-5-(iodomethyl)pyrrolidine-1-carboxylate (30b). Com-
silica gel to afford compound 29a in 84% (0.1 g) yield as a col- pound 30b was obtained as a colorless oil using the same pro-
orless oil: Rf 0.60 (hexane–EtOAc = 4 : 1); [α]2D8 = −49.0 (c 0.55, cedure as followed for compound 29a: Yield 0.107 g (91%);
CH2Cl2); IR (neat) νmax 3031, 2929, 1703, 1514, 1402, 1350, Rf 0.60 (hexane–EtOAc = 2 : 1); [α]2D8 = +34.5 (c 1.10, CH2Cl2); IR
1307, 1249, 1177, 1151, 1029, 697 cm−1
;
1H NMR (500 MHz, (neat) νmax 3062, 2932, 2863, 1703, 1516, 1497, 1454, 1399,
1H NMR
CDCl3, 2.5 : 1 mixture of rotamers) δ 7.34–7.00 (m, 17H, both 1350, 1322, 1266, 1139, 1069, 1028, 698 cm−1
;
rotamers), 6.89–6.75 (m, 2H, both rotamer), 5.18 (d, J = (500 MHz, CDCl3) δ 7.36–6.94 (m, 15H), 6.75–6.66 (m, 3H),
12.2 Hz, 1H, minor rotamer), 5.12 (d, J = 7.6 Hz, 1H, minor 5.09 (br s, 3H), 4.63–4.52 (m, 3H), 4.47 (d, J = 11.0 Hz, 1H),
rotamer), 5.08 (d, J = 17.3 Hz, 1H, major rotamer), 5.01–4.95 4.31 (d, J = 11.0 Hz, 1H), 4.17 (dd, J = 2.4, 5.5 Hz, 1H), 4.00 (br
(m, 1H, both rotamers), 4.84 (d, J = 12.5 Hz, 1H, major s, 2H), 3.86 (s, 3H), 3.57 (s, 3H), 3.46 (t, J = 9.7 Hz, 1H); 13C
rotamer), 4.70–4.56 (m, 7H: 3H for major rotamer, 4H for NMR (125 MHz, CDCl3) δ 156.8, 148.8, 147.9, 137.5–127.8
minor rotamer), 4.46–4.32 (m, 7H: 3H for major rotamer, 4H (Ar–C), 118.3, 110.8, 109.4, 84.9, 82.5, 73.2, 71.9, 68.3, 62.9,
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56.0, 55.7, 2.7; HRMS calcd for C35H37INO6 [M + H]+ 694.1666, rotamer), 4.63–4.55 (m, 8H: 3H for major rotamer, 5H for
found 694.1667. minor rotamer), 4.38 (dd, J = 6.4, 13.4 Hz, 1H, major rotamer),
(2S,3R,4R,5S)-Benzyl 3,4-bis(benzyloxy)-2-(4-methoxyphenyl)- 4.35–4.30 (m, 1H, minor rotamer), 4.28–4.18 (m, 2H, both
5-methylpyrrolidine-1-carboxylate (31a). To a solution of com- rotamer), 3.89 (s, 3H, major rotamer), 3.85 (s, 3H, minor
pound 29a (0.3 g, 0.452 mmol) in MeOH (3 mL), Et3N rotamer), 3.75 (s, 3H, minor rotamer), 3.67 (s, 3H, major
(0.125 mL, 0.904 mmol) was added. The mixture was hydro- rotamer), 1.32 (d, J = 6.7 Hz, 3H, major rotamer), 1.26 (d, J =
genated over freshly prepared RANEY® nickel (500 mg) in a H2 5.9 Hz, 3H, minor rotamer); 13C NMR (125 MHz, CDCl3,
atmosphere for 1 h. The presence of the desired compound 1.9 : 1 mixture of rotamers) δ 154.7, 148.6, 148.2, 138.0–127.5
was revealed by TLC (EtOAc–hexane, 1 : 3) with lower mobility (Ar–C), 119.1, 110.9, 110.9, 81.1, 80.7, 80.6, 80.2, 72.9, 72.8,
than the starting material. The catalyst was filtered off and 67.1, 66.7, 60.7, 56.0, 55.8, 52.8, 15.8, 14.8; HRMS calcd for
washed with MeOH (5 mL), and the combined filtrate and C35H38NO6 [M + H]+ 568.2699, found 568.2692.
washings were concentrated to give a residue which was
(2R,3R,4R,5S)-Benzyl 3,4-bis(benzyloxy)-2-(3,4-dimethoxy-
further purified by silica-gel column chromatography to give phenyl)-5-methylpyrrolidine-1-carboxylate (32b). Compound
pure 31a as a colorless oil: Yield 0.164 g (68%); Rf 0.50 32b was obtained as a colorless oil using the same procedure
(hexane–EtOAc = 4 : 1); [α]2D8 = −63.7 (c 0.95, CH2Cl2); IR (neat) as followed for compound 31a: Yield 0.198 g (81%); Rf 0.30
νmax 3062, 3031, 2933, 1701, 1612, 1513, 1454, 1401, 1348, (hexane–EtOAc = 1 : 2); [α]2D8 = +7.30 (c 0.95, CH2Cl2); IR (neat)
1
1306, 1248, 1177, 1140, 1097, 1029 cm−1; H NMR (500 MHz, νmax 3063, 2931, 1701, 1594, 1515, 1454, 1403, 1346, 1216,
CDCl3, 1.8 : 1 mixture of rotamers) δ 7.35–7.02 (m, 16H, both 1138, 1028 cm−1 1H NMR (500 MHz, CDCl3) δ 7.34–7.18 (m,
;
rotamers), 6.87–6.73 (m, 3H, both rotamers), 5.15 (d, J = 15H), 6.84–6.75 (m, 3H), 5.04–4.91 (m, 1H), 4.63–4.48 (m, 6H),
12.2 Hz, 1H, minor rotamer), 5.03–4.97 (m, 2H, both rota- 4.40–4.38 (m, 1H), 4.10–4.03 (m, 2H), 3.88 (s, 3H), 3.69 (br s,
mers), 4.81 (d, J = 12.5 Hz, 1H, major rotamer), 4.64–4.51 3H), 1.40 (d, J = 6.4 Hz, 3H); 13C NMR (125 MHz, CDCl3)
(m, 4H, both rotamers), 4.41–4.21 (m, 3H, both rotamers) δ 155.4, 148.9, 148.1, 138.0, 137.7, 128.5, 128.4, 127.9, 127.7,
3.82 (s, 3H, major rotamer), 3.79 (s, 3H, minor rotamer), 1.30 127.6, 118.2, 111.1, 109.5, 87.4, 82.1, 73.0, 72.4, 66.9, 64.8,
(d, J = 6.4 Hz, 3H, major rotamer), 1.24 (d, J = 6.4 Hz, 3H, 56.0, 55.7, 54.3, 16.0; HRMS calcd for C35H38NO6 [M + H]+
minor rotamer); 13C NMR (125 MHz, CDCl3, 1.8 : 1 mixture of 568.2699, found 568.2699.
rotamers) δ 158.9, 154.7, 138.0–127.3 (Ar–C), 113.7, 113.6, 81.0,
(2S,3R,4R,5S)-2-(4-Methoxyphenyl)-1,5-dimethylpyrrolidine-
80.9, 80.5, 80.4, 73.0, 72.9, 67.0, 66.6, 60.4, 60.3, 55.3, 52.7, 3,4-diyl diacetate (33a). To a stirred solution of compound 31a
52.4, 15.8, 14.9; HRMS calcd for C34H36NO5 [M + H]+ 538.2593, (0.1 g, 0.185 mmol) in 5% HCl in MeOH (2 mL), was added
found 538.2592.
Pd(OH)2/C (10 mg, 20 wt%) and the mixture was stirred for 4 h
(2R,3R,4R,5S)-Benzyl 3,4-bis(benzyloxy)-2-(4-methoxyphenyl)- under hydrogen atmosphere. On consumption of the starting
5-methylpyrrolidine-1-carboxylate (31b). Compound 31b was material (TLC monitoring), the catalyst was filtered off and the
obtained as a colorless oil using the same procedure as fol- solution passed through Dowex (1 × 8) basic resin. The solu-
lowed for compound 31a: Yield 0.179 g (74%); Rf 0.45 (hexane– tion was concentrated and dissolved in MeOH (2 mL). To this
EtOAc = 3 : 1); [α]D28 = +2.6 (c 0.75, CH2Cl2); IR (neat) νmax 3063, solution, 30% formalin (0.5 mL) was added and it was hydro-
3031, 2925, 1701, 1512, 1497, 1453, 1402, 1345, 1207, 1174, genated in the presence of Pd(OH)2/C under a H2 atmosphere
1097, 1038 cm−1 1H NMR (500 MHz, CDCl3) δ 7.34–7.18 for 1 h. After completion of the reaction (monitored by ESI
;
(m, 17H), 6.85–6.83 (m, 2H), 5.01–4.93 (m, 2H), 4.64–4.57 (m, mass), the catalyst was filtered through a Celite pad and the
3H), 4.53–4.48 (m, 2H), 4.39 (br s, 1H), 4.09–4.04 (m, 2H), 3.81 solution concentrated under vacuum to give a residue. The
(s, 3H), 1.40 (d, J = 6.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) residue was subjected to acetylation with an excess of pyridine
δ 158.8, 155.3, 138.1–127.4 (Ar–C), 113.9, 87.8, 82.1, 72.9, 72.3, and Ac2O (1 : 1, 2 mL) at room temperature for 10 h. Usual
66.8, 64.5, 55.3, 54.2, 16.1; HRMS calcd for C34H35NNaO5 work-up and purification by silica-gel chromatography gave
[M + Na]+ 560.2413, found 560.2410.
33a as a colorless oil: Yield 0.041 g (67% over 3 steps); Rf 0.50
(2S,3R,4R,5S)-Benzyl 3,4-bis(benzyloxy)-2-(3,4-dimethoxy- (hexane–EtOAc = 1 : 1); [α]2D8 = −13.0 (c 0.45, CH2Cl2); IR (neat)
phenyl)-5-methylpyrrolidine-1-carboxylate (32a). Compound νmax 2934, 1742, 1611, 1512, 1457, 1375, 1237, 1181,
32a was obtained as a colorless oil using the same procedure 1047 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.18–7.17 (m, 2H, Ar–
as followed for compound 31a: Yield 0.193 g (79%); Rf 0.30 H)), 6.82–6.80 (m, 2H, Ar–H), 5.39–5.31 (m, 2H, H-3, H-4), 3.99
(hexane–EtOAc = 1 : 2); [α]2D8 = −65.2 (c 0.95, CH2Cl2); IR (neat) (d, J = 7.9 Hz, 1H, H-2), 3.78 (s, 3H, OCH3), 3.73–3.70 (m, 1H,
νmax 3062, 2933, 1701, 1606, 1516, 1453, 1400, 1348, 1209, H-5), 2.14 (s, 3H, COCH3), 2.09 (s, 3H, COCH3), 1.55 (s, 3H,
1
1027 cm−1; H NMR (500 MHz, CDCl3 1.9 : 1 mixture of rota- N–CH3), 0.93 (d, J = 6.4 Hz, 3H, H-6); 13C NMR (125 MHz,
mers) δ 7.40–7.12 (m, 15H, both rotamers), 6.82–6.74 (m, 1H, CDCl3) δ 170.5, 170.2, 159.0, 130.9, 128.8, 113.1, 77.9, 76.8,
both rotamers), 6.70 (d, J = 8.2 Hz, 1H, minor rotamer), 6.66 66.9, 57.5, 55.2, 35.4, 21.0, 20.4, 7.6; HRMS calcd for
(d, J = 1.5 Hz, 1H, major rotamer), 6.64 (d, J = 1.8 Hz, 1H, C17H24NO5 [M + H]+ 322.1654, found 322.1651.
minor rotamer), 6.53 (d, J = 1.5 Hz, 1H, major rotamer), 5.14
(2R,3R,4R,5S)-2-(4-Methoxyphenyl)-1,5-dimethylpyrrolidine-
(d, J = 12.2 Hz, 1H, minor rotamer), 5.06 (d, J = 12.2 Hz, 1H, 3,4-diyl diacetate (33b). Compound 33b was obtained as a col-
minor rotamer), 5.03–5.01 (m, 2H, major rotamer), 4.95 (d, J = orless oil using the same procedure as followed for compound
7.6 Hz, 1H, major rotamer), 4.79 (d, J = 12.5 Hz, 1H, major 33a: Yield 0.036 g (63% over 3 steps); Rf 0.55 (hexane–EtOAc =
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1 : 1); [α]2D8 = +5.7 (c 0.35, CH2Cl2); IR (neat) νmax 2923, 2852, 1.12 (d, J = 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 159.5,
2781, 1742, 1612, 1586, 1512, 1460, 1369, 1289, 1239, 130.9, 127.6, 114.1, 114.0, 79.1, 78.7, 69.2, 60.6, 55.3, 35.8,
1033 cm−1 1H NMR (500 MHz, CDCl3) δ 7.29–7.27 (m, 2H, 8.5; HRMS calcd for C13H20NO3 [M + H]+ 238.1443, found
;
Ar–H)), 6.87–6.85 (m, 2H, Ar–H), 5.18 (dd, J = 2.3, 6.0 Hz, 1H, 238.1440.
H-4), 4.95 (dd, J = 2.3, 6.9 Hz, 1H, H-3), 3.79 (s, 3H, OCH3),
(2R,3R,4R,5S)-2-(4-Methoxyphenyl)-1,5-dimethylpyrrolidine-
3.11 (d, J = 6.9 Hz, 1H, H-2), 2.71–2.69 (m, 1H, H-5), 2.12 3,4-diol (35b). Compound 35b was obtained as a colorless oil
(s, 3H, COCH3), 2.06 (s, 3H, COCH3), 1.99 (s, 3H, N–CH3), 1.10 using same procedure as followed for compound 35a: Yield
(d, J = 6.5 Hz, 3H, H-6); 13C NMR (125 MHz, CDCl3) δ 170.5, 12.5 mg (86%); Rf 0.40 (MeOH–EtOAc = 1 : 4); [α]2D8 = −5.0
169.9, 159.4, 131.2, 129.2, 113.9, 83.6, 78.0, 74.8, 63.3, 38.1, (c 0.20, CH2Cl2); IR (neat) νmax 3338, 2928, 1612, 1514, 1455,
1
20.9, 12.7; HRMS calcd for C17H24NO5 [M + H]+ 322.1654, 1249, 1180, 1032 cm−1; H NMR (500 MHz, CDCl3) δ 7.27–7.25
found 322.1656.
(m, 2H), 6.87–6.85 (m, 2H), 3.93–3.91 (m, 1H), 3.87 (dd, J = 2.1,
(2S,3R,4R,5S)-2-(3,4-Dimethoxyphenyl)-1,5-dimethyl-pyrroli- 5.5 Hz, 1H), 3.79 (s, 3H), 2.97 (d, J = 5.8 Hz, 1H), 2.68–2.63 (m,
dine-3,4-diyl diacetate (34a). Compound 34a was obtained as a 1H), 2.29–2.20 (m, 2H), 2.08 (s, 3H), 1.20 (d, J = 6.7 Hz, 3H);
colorless oil using the same procedure as followed for com- 13C NMR (125 MHz, CDCl3) δ 159.3, 132.0, 129.0, 114.1, 85.4,
pound 33a: Yield 0.043 g (69% over 3 steps); Rf 0.5 (hexane– 79.1, 77.6, 63.8, 55.3, 38.0, 12.7; HRMS calcd for C13H20NO3
EtOAC = 1 : 1); [α]2D8 = −26.6 (c 0.15, CH2Cl2); IR (neat) νmax [M + H]+ 238.1443, found 238.1442.
1
2926, 2853, 1745, 1592, 1515, 1453, 1376, 1048 cm−1; H NMR
(2S,3R,4R,5S)-2-(3,4-Dimethoxyphenyl)-1,5-dimethylpyrroli-
(500 MHz, CDCl3) δ 6.85 (s, 1H, Ar–H), 6.78–6.77 (m, 2H, dine-3,4-diol (36a). Compound 36a was obtained as a colorless
Ar–H)), 5.40 (dd, J = 6.4, 7.9 Hz, 1H, H-3), 5.31 (t, J = 6.4 Hz, oil using the same procedure as followed for compound 35a:
1H, H-4), 3.97 (d, J = 7.9 Hz, 1H, H-2), 3.87 (s, 3H, OCH3), 3.85 Yield 14 mg (92%); Rf 0.10 (MeOH–EtOAc = 1 : 4); [α]2D8 = +36.0
(s, 3H, OCH3), 3.75–3.72 (m, 1H, H-5), 2.16 (s, 3H, COCH3), (c 0.50, CH2Cl2); IR (neat) νmax 3358, 2917, 2849, 1516, 1465,
1
2.09 (s, 3H, COCH3), 1.57 (s, 3H, N–CH3), 0.94 (d, J = 6.7 Hz, 1263, 1141, 1023 cm−1; H NMR (500 MHz, CDCl3) δ 6.89–6.85
3H, H-6); 13C NMR (125 MHz, CDCl3) δ 170.6, 170.2, 148.4, (m, 3H), 4.23 (t, J = 7.4 Hz, 1H), 4.13 (dd, J = 5.7, 7.4 Hz, 1H),
129.5, 122.1, 112.4, 110.2, 77.9, 67.0, 57.5, 56.0, 55.9, 35.4, 3.93 (d, J = 7.7 Hz, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.52–3.49
21.0, 20.5, 7.5; HRMS calcd for C18H26NO6 [M + H]+ 352.1760, (m, 1H), 2.21 (s, 3H), 1.04 (d, J = 6.6 Hz, 3H); 13C NMR
found 352.1760.
(125 MHz, CDCl3) δ 149.2, 148.6, 129.8, 121.2, 111.9, 111.1,
(2R,3R,4R,5S)-2-(3,4-Dimethoxyphenyl)-1,5-dimethyl-pyrroli- 79.6, 78.8, 69.4, 59.5, 56.0, 35.8, 29.9, 8.0; HRMS calcd for
dine-3,4-diyl diacetate (34b). Compound 34b was obtained as C14H22NO4 [M + H]+ 268.1549, found 268.1549.
a colorless oil using the same procedure as followed for com-
(2R,3R,4R,5S)-2-(3,4-Dimethoxyphenyl)-1,5-dimethyl-pyrroli-
pound 33a: Yield 0.045 g (72% over 3 steps); Rf 0.55 (hexane– dine-3,4-diol (36b). Compound 36b was obtained as a color-
EtOAC = 1 : 1); [α]D28 = +10.0 (c 0.40, CH2Cl2); IR (neat) νmax less oil using the same procedure as followed for compound
2923, 2851, 1739, 1592, 1513, 1461, 1369, 1233, 1026 cm−1
;
35a: Yield 14.2 mg (93%); Rf 0.10 (MeOH–EtOAc = 1 : 4); [α]D28
=
1H NMR (500 MHz, CDCl3) δ 6.92 (d, J = 2.0 Hz, 1H, Ar–H), −20.0 (c 0.15, CH2Cl2); IR (neat) νmax 3374, 2934, 2838, 1517,
6.88 (dd, J = 2.0, 8.0 Hz, 1H, Ar–H), 6.80 (d, J = 8.3 Hz, 1H, 1463, 1262, 1231, 1138, 1025 cm−1; H NMR (500 MHz, CDCl3)
1
Ar–H), 5.18 (dd, J = 2.6, 6.0 Hz, 1H, H-4), 4.94 (dd, J = 2.6, 6.8 δ 6.94 (s, 1H), 6.89 (d, J = 9.8 Hz, 1H), 6.82 (d, J = 7.9 Hz, 1H),
Hz, 1H, H-3), 3.89 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.12 (d, 4.00 (d, J = 6.4 Hz, 1H), 3.91–3.90 (m, 1H), 3.87 (s, 3H), 3.86 (s,
J = 6.8 Hz, 1H, H-2), 2.77–2.70 (m, 1H, H-5), 2.12 (s, 3H, 3H), 3.02 (d, J = 6.4 Hz, 1H), 2.74–2.72 (m, 1H), 2.32 (br s, 2H),
COCH3), 2.09 (s, 3H, COCH3), 1.99 (s, 3H, N–CH3), 1.11 (d, J = 2.15 (s, 3H), 1.23 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz,
6.8 Hz, 3H, H-6); 13C NMR (125 MHz, CDCl3) δ 170.5, 169.9, CDCl3) δ 149.5, 149.0, 120.7, 111.1, 110.5, 84.9, 78.7, 78.0, 64.7,
149.2, 148.8, 131.7, 120.6, 110.9, 110.5, 83.4, 77.9, 75.0, 56.1, 55.9, 37.8, 12.2; HRMS calcd for C14H22NO4 [M + H]+
63.3, 56.0, 55.9, 38.2, 20.9, 12.7; HRMS calcd for C18H26NO6 268.1549, found 268.1541.
[M + H]+ 352.1760, found 352.1764.
(2S,3R,4R,5S)-2-(4-Methoxyphenyl)-1,5-dimethylpyrrolidine-
General procedure for enzyme inhibition studies
3,4-diol (35a). To
a stirred solution of 33a (20 mg, All the enzymes and their corresponding substrates were pro-
0.062 mmol) in MeOH (3 mL) was added potassium carbonate cured from Sigma-Aldrich Chemical Co. The inhibition studies
(25 mg, 0.186 mmol) at room temperature. The reaction of compounds (14a, 14b, 35a, 35b, 36a, 36b) were determined
mixture was stirred for 8 h. On consumption of the starting by measuring the residual hydrolytic activities of the glycosi-
material (TLC analysis), the solvent was concentrated under dases. The substrates and enzymes were prepared as 0.025 M
reduced pressure. The residue was dissolved in CHCl3 and the solutions in the respective pH buffer solutions of the corres-
solid material was filtered off to give the title compound 35a ponding enzyme. In all cases, the substrates used were the
as a colorless oil: Yield 12 mg (85%); Rf 0.30 (MeOH–EtOAc = corresponding p-nitrophenyl glycopyranosides. The incubation
1 : 4); [α]2D8 = +48.0 (c 0.25, CH2Cl2); IR (neat) νmax 3351, 2923, mixture consisted of 100 μL of the enzyme solution, 200 μL of
2852, 1610, 1512, 1302, 1248, 1179, 1035 cm−1 1H NMR 1 mg mL−1 aqueous solution of the test compound, and
;
(500 MHz, CDCl3) δ 7.29–7.28 (m, 2H), 6.89–6.87 (m, 2H), 100 μL of the appropriate buffer solution at the optimum pH
4.24–4.22 (m, 1H), 4.19–4.17 (m, 1H), 4.12 (d, J = 6.7 Hz, 1H), for the enzyme. After incubation at 37 °C for 1 h, 100 μL of the
3.79 (s, 3H), 3.59–3.56 (m, 1H), 3.46 (br s, 2H), 2.22 (s, 3H), substrate solution was added and allowed to react for 10 min.
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The reaction mixture was quenched using 2.5 mL of 0.05 M
borate buffer (pH = 9.8). In all cases, control experiments were
run simultaneously in the absence of the test compound.
A series of blank experiments for the substrate were also carried
out in the respective buffer solutions without the enzyme or
test compounds. The absorbance of the liberated p-nitro-
phenol in each reaction (both test and control reactions) was
recorded using a spectrophotometer at 405 nm. Percentage
inhibition was calculated as the ratio of the difference in the
observed absorbances of the control and test reactions to the
observed absorbance of the control reaction. Results have thus
been reported as IC50 values, which is the concentration of the
test compound that causes 50% inhibition of the enzyme.
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Acknowledgements
We thank the Department of Science and Technology, New
Delhi, for a J. C. Bose National Fellowship (JCB/SR/S2/JCB-26/
2010) and the Council of Scientific and Industrial Research,
New Delhi, for financial support [grant no. 02(0124)/13/
EMR-II)] to Y.D.V.; S. D and A. K. P. thank the Council of
Scientific Industrial Research, New Delhi, for Senior Research
Fellowships.
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ref. 21 where a distal functional group has caused a change
in inhibition profile.
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