γ-Aminoalcohol rearrangement applied to pentahydroxylated azepanes provides pyrrolidines epimeric to homoDMDP

Article abstract of DOI:10.1039/c5ob00050e

A series of pentahydroxylated pyrrolidines, displaying five contiguous stereogenic centres and epimeric to α-glucosidase inhibitor homoDMDP, have been synthesized. The key step involves a γ-aminoalcohol rearrangement applied to polyhydroxylated azepanes. These five-membered iminosugars demonstrate micromolar inhibition of glycosidases. This journal is

Full text of DOI:10.1039/c5ob00050e

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γ-Aminoalcohol rearrangement applied to
pentahydroxylated azepanes provides pyrrolidines
epimeric to homoDMDP†
Cite this: Org. Biomol. Chem., 2015,
13, 3446
Y. Jagadeesh,a A. T. Tran,b B. Luo,b N. Auberger,a J. Désiré,a S. Nakagawa,c A. Kato,c
Y. Zhang,b M. Sollogoubb and Y. Blériot*a
Received 9th January 2015,
Accepted 28th January 2015
A series of pentahydroxylated pyrrolidines, displaying five contiguous stereogenic centres and epimeric to
α-glucosidase inhibitor homoDMDP, have been synthesized. The key step involves a γ-aminoalcohol
rearrangement applied to polyhydroxylated azepanes. These five-membered iminosugars demonstrate
micromolar inhibition of glycosidases.
DOI: 10.1039/c5ob00050e
www.rsc.org/obc
Introduction
A vast array of iminosugars based on a polyhydroxylated pyrro-
lidine1 scaffold have been isolated from natural sources,
including the potent glycosidase inhibitors 1,4-dideoxy-1,4-
imino-D-arabinitol (DAB),2 1,4-dideoxy-1,4-imino-D-mannitol
(DIM),3 2,5-dideoxy-2,5-imino-D-mannitol (DMDP)4 and 2,5-
Fig. 1 Structures of DAB, DIM, DMDP, and homoDMDP.
dideoxy-2,5-imino-glycero-D-manno-heptitol
(homoDMDP)5
(Fig. 1). The structural basis for the glycosidase inhibition of
five-membered iminosugars has been elucidated.6
The high inhibitory potential of this family of molecules
has prompted the discovery of powerful approaches that
exploit nitrone chemistry,7 Petasis-type aminocyclization,8
RCM,9 green10 as well as chemo-enzymatic11 routes being
among the most recent ones. In addition, many analogs have
been synthesized, some of them demonstrating therapeutic
potential.12 Designing new routes to this type of iminosugar
that allow access to both configurational and structural diver-
sity is of current interest to increase the number of
compounds available for biological testing. Amongst poly-
hydroxylated pyrrolidines, homoDMDP, found to strongly
inhibit β-glucosidase and β-galactosidase, represents the most
complex representative as it exhibits five contiguous stereo-
genic centres. Several synthetic strategies toward this molecule,
as well as epimers and analogs have been reported.13 Exploit-
Fig. 2 Structure of homoDMDP epimers 1–4.
ing a γ-aminoalcohol rearrangement applied to pentasubsti-
tuted azepanes, we report herein a new synthetic route to
homoDMDP epimers including the 2,5-diepi- 1, the 2,6-diepi-
2, the patented 6-epi- 314 and the 5-epi- 4 derivatives that were
further evaluated as glycosidase inhibitors (Fig. 2).
In the last decade, our group15 and colleagues16 have dis-
closed a new class of glycosidase inhibitors, the pentasubsti-
tuted azepanes, which proved to be interesting molecules
notably as hexosaminidase conformational probes17 and/or
inhibitors.18 In addition to their biochemical usefulness, poly-
hydroxylated azepanes19 also hold synthetic potential as their
ring isomerisation can efficiently lead to highly substituted
piperidines with complete stereocontrol. According to this
methodology, Le Merrer20 developed new access to deoxynojiri-
mycin and Davies21 reported a de novo preparation of piper-
idine iminosugars. Starting from pentahydroxylated azepanes,
we have described a new route to iminosugar C-glycosides22
and homoiminosugars,23 some of them displaying potent glyco-
sidase inhibition.24 This transformation goes through a tran-
aGlycochemistry Group of “Organic Synthesis” Team, Université de Poitiers,
UMR-CNRS 7285 IC2MP, 4 rue Michel Brunet, 86073 Poitiers Cedex 9, France.
E-mail: yves.bleriot@univ-poitiers.fr; Tel: +33 5 49453966
bSorbonne Universités, UPMC Univ Paris 06, Institut Universitaire de France,
UMR-CNRS 8232, IPCM, LabEx MiChem, F-75005 Paris, France
cDepartment of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama
930-0194, Japan
†This article is dedicated to Pr. Max Malacria on the occasion of his 65th
birthday.
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Scheme 1 Skeletal rearrangement strategy used to access homoDMDP
congeners.
sient fused piperidine–aziridinium ion that is displaced at the
methylene position by the released nucleophile to furnish the
corresponding piperidine (Scheme 1). We would like now to
apply this methodology to γ-aminoalcohols, starting from
pentahydroxylated azepanes, which should provide the corres-
ponding pyrrolidines. To the best of our knowledge there is
only one example of such transformation applied to a tetra-
hydroxylated azepane25 (Scheme 1).
Results and discussion
To selectively obtain the target pyrrolidines from the corres-
ponding azepanes, regioselective activation of the hydroxyl
group γ to the nitrogen in the starting β,γ-dihydroxyazepane
requires regioselective protection of the hydroxyl group β to
the nitrogen. Silylation of this hydroxyl group proved unsatis-
factory because of silyl group migration. Its protection as
benzyl ether was investigated as hydrogenolysis in the final
step could directly provide the target pyrrolidine. Regioselec-
tive benzylation of β,γ-dihydroxy azepanes 5–8 (easily available
from D-arabinose)15a under various conditions (low tempera-
ture, stannylene activation, phase transfer conditions) failed to
provide the γ-hydroxy derivatives in good yield. Alternatively,
protection of the β,γ-diol as its benzylidene acetal followed by
regioselective reductive ring opening was examined. Diols 5–8
were acetalized in good yield (76–100%) under standard con-
ditions (benzylidene dimethyl acetal, CSA, acetonitrile) to
furnish the corresponding azepanes 9–12 respectively as mix-
tures of epimeric acetals that were usually not separated
and directly engaged in the next step. The γ-aminoalcohol
rearrangement requires an electron-donating group on the
endocyclic nitrogen. Removal of the benzyl carbamate (Lindlar
catalyst, Et3N, EtOH) followed by N-benzylation (BnBr, K2CO3,
DMF) was achieved to yield the fully protected N-benzyl
azepanes 13–16 in 58–98% yield over two steps (Scheme 2).
Regioselective reductive opening of the 1,2-O-benzylidene
acetals was then studied. Benzylidene acetals are generally
reduced at the less sterically hindered oxygen26 but electronic
effects of the adjacent substituents have also to be con-
Scheme 2 Synthesis of N-benzyl azepanes 13–16. Reagents and con-
ditions: (a) benzylidene dimethyl acetal, CSA, CH3CN; (b) H2, Pd Lindlar,
Et3N, EtOH then BnBr, K2CO3, DMF.
sidered.27 Several classical conditions (NaBH3CN/TFA, LiAlH4/
AlCl3, BH3·THF/TMSOTf, Et3SiH/TFA) were applied to azepanes
13–16 but failed to give the desired γ-hydroxyazepanes as the
major product in good yield. Alternatively, DIBAL, known to
achieve the reductive ring opening of 1,2-O-benzylidenes,28
was used and afforded the desired alcohols 17–20 in moderate
to excellent yield. Use of dichloromethane as the solvent is
crucial to achieve a good regioselectivity, toluene giving a
1 : 1 mixture of the two secondary alcohols (Scheme 3). In the
case of D-azepanes 15 and 16, regioselectivity in the benzyli-
dene ring opening with DIBAL was less pronounced and
needed separation of the γ-hydroxyazepanes from the
unwanted β-hydroxyazepanes. These regioisomers were not
separable at this stage. Acetylation of the free OH group in
these molecules followed by subsequent deacetylation afforded
the pure γ-hydroxyazepanes 19 and 20. With the azepane pre-
cursors in hand, several alcohol activation conditions were
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Experimental
Materials and methods
All commercial reagents were used as supplied. Solvents (DMF,
THF) were distilled under anhydrous conditions. TLC plates
(Macherey-Nagel, ALUGRAM® SIL G/UV254, 0.2 mm silica gel
60 Å) were visualized under 254 nm UV light and/or by dipping
the TLC plate into a solution of 3 g of phosphomolybdic acid
in 100 mL of ethanol followed by heating with a heat gun.
Flash column chromatography was performed using
Macherey-Nagel silica gel 60 (15–40 μm). NMR experiments
were recorded on a Bruker Avance 400 spectrometer at
400 MHz for 1H nuclei and at 100 MHz for 13C nuclei. The
chemical shifts are expressed in parts per million (ppm) rela-
tive to TMS (δ = 0 ppm) and the coupling constant J in hertz
(Hz). NMR multiplicities are reported using the following
abbreviations: b = broad, s = singlet, d = doublet, t = triplet,
q = quadruplet, m = multiplet. HRMS were obtained from the
Mass Spectrometry Service, ICOA, at the University of Orléans,
France, using a Bruker Maxis Q-TOF Maxis spectrometer.
(2S,3R,4S,5R,6R)-Benzyl-3,4-bis(benzyloxy)-2-((benzyloxy)-
methyl)-5,6-O-(benzylidene)azepane-1-carboxylate 9. A mixture
of diol 5 (117 mg, 0.195 mmol), camphorsulfonic acid (cat.,
10 mg) and benzaldehyde dimethyl acetal (88 μL, 0.588 mmol)
in CH3CN (10 mL) was stirred at 50 °C under an atmosphere of
nitrogen overnight and quenched with triethylamine (0.2 mL).
Scheme 3 Synthesis of homoDMDP epimers 1–4. Reagents and con-
ditions: (a) DIBAL, CH2Cl2, −78 °C to RT; (b) Ac2O, pyridine then NaOH,
MeOH; (c) TFAA, Et3N, toluene then 10 % aq. NaOH; (d) H2, 10% Pd/C,
1 M HCl, CH3OH.
tested to efficiently generate the pyrrolidine ring. Mitsunobu After concentration, the resulting residue was purified by flash
conditions (PPh3, DEAD, p-nitrobenzoic acid) produced the column chromatography (Cy–EtOAc, 8 : 1) to give compound 9
expected pyrrolidines albeit in low 22–44% yield. Use of less as an oil (101 mg, 76%). Due to the mixture of rotational
hindered phosphine (PPhMe2) did not significantly improve isomers, NMR was not resolved clearly and this compound was
the yield of this transformation. Finally, switching to the con- used directly in the next step. Rf 0.33, Cy–EtOAc, 4 : 1;
ditions developed by Cossy29 using TFAA and Et3N for the skel- ESI-HRMS calcd for C43H43NO7Na [M + Na]+: 708.2931, found
etal rearrangement of β-aminoalcohols provided the protected 708.2926.
pyrrolidines 21–24 in good (62%) to excellent yield (92%) after
(2S,3R,4S,5R,6R)-1-Benzyl-3,4-bis(benzyloxy)-2-((benzyloxy)-
trifluoroacetyl ester hydrolysis. HMBC NMR experiments were methyl)-5,6-O-(benzylidene)azepane
13. Compound
9
necessary to confirm the size of the azacycle. Final hydrogeno- (101 mg, 0.145 mmol) was dissolved in EtOH (20 mL) and a
lysis of pyrrolidines 21–24 under mild acidic conditions catalytic amount of Et3N (15 μL) was introduced, followed by
furnished the target pyrrolidines 1, 2, 3 and 4 as their hydro- addition of Lindlar’s catalyst (100 mg). The reaction flask was
chloride salts (Scheme 3). The structure of iminosugar 2 was purged of air and filled with H2. The suspension was stirred
firmly established in comparison with its enantiomer, homo- under H2 for 4 h by the end of which TLC (Cy–EtOAc, 4 : 1)
D-galactitol,30 a UDP-Gal mutase and mycobacterial galactan showed a complete reaction. The reaction mixture was filtered
biosynthesis inhibitor. A good agreement between the spectro- through a pad of Celite, eluted with MeOH and concentrated
scopic data and an opposite value for the optical rotation was under reduced pressure to afford the crude N-deprotected
observed. Similarly, the structure of iminosugar 3 was con- azepane. This oil was dissolved in DMF (5 mL) and K2CO3
firmed by comparing its spectroscopic data with its (61 mg, 0.435 mmol) was added, followed by benzyl bromide
L-enantiomer.13a
(35 μL, 0.292 mmol). The mixture was stirred at 50 °C under
an atmosphere of nitrogen overnight. After concentration, the
resulting residue was partitioned between water (20 mL) and
Glycosidase inhibition
The four pentahydroxylated pyrrolidines 1–4 were assayed as DCM (20 mL). The organic phase was dried over MgSO4 and
inhibitors of a collection of glycosidases, including glucosi- concentrated under reduced pressure. The resulting residue
dases, galactosidases and mannosidases (Table 1). While 2,5- was purified by flash column chromatography (Cy–EtOAc, 4 : 1)
and 2,6-diepi-homoDMDP 1 and 2 showed weak glycosidase to give compound 13 as an oil (91 mg, 98%) and as an insepar-
inhibition, 6-epi-homoDMDP 3 was a good but rather unselec- able mixture of two epimers in a 3/7 ratio according to 1H
tive α-glucosidase inhibitor (IC50 14.4 μM for rice α-glucosi- NMR. Rf 0.57, Cy–EtOAc, 4 : 1; 1H NMR (CDCl3, 400 MHz):
dase). The 5-epi-homoDMDP 4 proved to be a weak (IC50 7.56–7.25 (m, 40H, 8 × Ph), 6.31 (s, 1H, H-8′), 5.78 (s, 1H, H-8),
167 μM) albeit selective α-glucosidase inhibitor.
5.22 (d, 1H, J = 12.0 Hz, CHPh), 5.00 (dd, 1H, J = 7.4, 2.4 Hz,
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Table 1 Glycosidase inhibition profile of pyrrolidines 1–4
Concentration of iminosugars giving 50% inhibition of various glycosidases IC50 (μM)
2,5-Diepi-homoDMDP
1
2,6-Diepi-homoDMDP
2
6-epi-homoDMDP
3
5-epi-homoDMDP
4
Enzyme
α-Glucosidase
Rice
Yeast
Rat intestinal maltase
Aspergillus niger
β-Glucosidase
Almond
465
254
NI (26.4%)
NI (4.0%)
NIa (26.2%)b
NI (40.7%)
NI (21.3%)
NI (1.9%)
14.4
221
32.3
817
167
NI (45.4%)
366
NI (9.7%)
148
NI (40.4%)
NI (17.3%)
283
318
NI (8.7%)
118
765
NI (32.4%)
NI (34.1%)
NI (23.0%)
NI (14.2%)
Bovine liver
Aspergillus niger
α-Galactosidase
Coffee beans
β-Galactosidase
Bovine liver
α-Mannosidase
Jack beans
320
NI (28.4%)
198
660
NI (11.5%)
NI (32.2%)
NI (0.82%)
NI (15.7%)
NI (0%)
NI (28.4%)
287
464
NI (49.0%)
NI (32.2%)
NI (2.4%)
173
NI (41.0%)
705
β-Mannosidase
Snail
240
α-L-Rhamnosidase
Penicillium decumbens
α-L-Fucosidase
Bovine kidney
β-Glucuronidase
E.coli
NI (17.8%)
110
NI (8.5%)
127
NI (16.1%)
79.6
198
424
780
255
389
NI (0%)
NI (0%)
Bovine liver
α,α-Trehalase
Porcine kidney
Amyloglucosidase
Aspergillus niger
Rhizopus Sp.
NI (12.1%)
NI (4.17%)
NI (21.8%)
NI (14.7%)
NI (1.14%)
NI (0%)
NI (0%)
NI (0%)
NI (21.6%)
NI (23.4%)
NI (0%)
NI (1.94%)
a NI: no inhibition (less than 50% inhibition at 1000 mM); ND: not determined. b ( ): inhibition % at 1000 mM.
H-5′), 4.87–4.83 (m, 2H, H-5, CHPh), 4.78–4.60 (dd, 2H, J = was consumed completely. Aqueous HCl (1.5 mL, 1 M solu-
11.8 Hz, H-6, H-6′), 4.65–4.40 (m, 12H, 12 × CHPh), 4.35 (dd, tion) was added at −30 °C to quench the reaction. The result-
1H, J = 6.5, 2.6 Hz, H-4′), 4.23 (dd, 1H, J = 6.5, 2.6 Hz, H-4), ing solution was warmed to r.t., then partitioned between
4.04–3.96 (m, 4H, H-3, H-3′, 2NCHPh), 3.89–3.70 (m, 10H, water (20 mL) and DCM (20 mL). The organic phase was dried
H-2′, H-2, H-9′a, H-9a, H-9′b, H-9b, 2NCHPh, 2CHPh), over MgSO4 and concentrated under reduced pressure. The
3.40–3.30 (m, 4H, H-7′a, H-7a, H-7′b, H-7b); 13C NMR (CDCl3, resulting residue was purified by flash column chromato-
100 MHz): 139.28, 139.24, 138.41, 137.68, 137.53, 137.46, graphy (Cy–EtOAc, 4 : 1) to give compound 17 as a clear oil
137.43, 137.37, 137.30, 136.14 (10 × Cipso), 128.77–123.10 (50 (109 mg, 95%). Rf 0.26, Cy–EtOAc, 4 : 1; [α]D −7 (c = 1.05,
aromatic C), 104.03 (C-8′), 103.57 (C-8), 79.66 (C-4′), 78.38 CHCl3); 1H NMR (CDCl3, 400 MHz): 7.27–7.04 (m, 25H, 5 ×
(C-4), 78.21 (C-3′), 78.10 (C-3), 77.93 (C-5′), 77.93 (C-5), 77.16 Ph), 4.54–4.49 (t, 3H, J = 11.8, 10.0 Hz, 3 × CHPh), 4.36–4.20
(C-6′), 76.85 (C-6), 74.45, 74.45, 74.27, 73.30, 73.19, 73.11, (m, 5H, 5 × CHPh), 4.11 (s, 1H, H-5), 3.85 (d, 1H, J = 13.6,
73.07, 73.07 (8CHPh), 69.66 (C-9′), 69.60 (C-9), 61.42 (C-2′), NCHPh), 3.70 (dd, 1H, J = 8.3, 5.4 Hz, H-3), 3.66–3.60 (m, 2H,
61.34 (C-2), 51.27 (NCH2Ph), 51.27 (NCH2Ph), 50.61 (C-7′), H-8a, NCHPh), 3.52–3.46 (m, 2H, H-8b, H-6), 3.40 (m, 1H,
50.61 (C-7); ESI-HRMS calcd for C42H44NO5 [M + H]+: 642.3214, H-2), 3.35 (dd, 1H, J = 8.5, 1.0 Hz, H-4), 3.08 (dd, 1H, J = 13.3,
found 642.3299.
(2S,3R,4R,5R,6R)-1-Benzyl-3,4,6-tris(benzyloxy)-2-((benzyloxy)- (CDCl3, 100 MHz): 139.34, 138.86, 138.57, 138.36, 138.14 (5 ×
methyl) azepan-5-ol 17. To solution of compound 13 Cipso), 128.60–127.01 (25 aromatic C), 83.53 (C-4), 82.05 (C-3),
6.8 Hz, H-7a), 2.70 (dd, 1H, J = 13.3, 8.7 Hz, H-7b); 13C NMR
a
(114 mg, 0.178 mmol) in dry DCM (3 mL) was added quickly 76.13 (C-6), 74.16, 73.22, 73.00, 71.13 (4 × CH2Ph), 73.13 (C-5),
DIBAL (1.77 mL, 1.5 M in toluene, 2.664 mmol) at −78 °C 67.50 (C-8), 59.23 (C-2), 59.22 (N-CH2Ph), 51.84 (C-7);
under an atmosphere of nitrogen with stirring. After 15 min at ESI-HRMS calcd for C42H46NO5 [M + H]+: 644.3370, found
−78 °C, TLC (Cy–EtOAc, 4 : 1) showed that the starting material 644.3354.
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2-[(S)-1-Benzyloxy-2-hydroxyethyl]-(2S,3R,4R,5S)-1-benzyl-3,4-
Compound 10a. Rf 0.33, Cy–EtOAc, 4 : 1; [α]D + 17 (c = 1.01,
bis(benzyloxy)-5-((benzyloxy)methyl)pyrrolidine 21. To a solu- CHCl3); 1H NMR (CDCl3, 400 MHz): 7.23–7.08 (m, 50H, 10 ×
tion of 17 (50 mg, 0.078 mmol) in dry toluene (2 mL) were Ph), 5.74 (s, 1H, H-8), 5.69 (s, 1H, H-8′), 5.11–5.01 (m, 3H, 3 ×
added trifluoroacetic anhydride (17 μL, 0.117 mmol) and Et3N NCOOCHPh), 4.93 (d, 1H, J = 12.4 Hz, NCOOCHPh), 4.78–4.70
(17 μL, 0.156 mmol) at 0 °C. The reaction mixture was then (m, 2H, H-2, CHPh), 4.66 (dd, 2H, J = 12.4, 1.7 Hz, 2 × CHPh),
refluxed for 5 hours before being cooled to room temperature. 4.58–4.30 (m, 16H, 9 × CHPh, H-6, H-6′, H-5, H-5′, H-4, H-4′,
A solution of NaOH (10%, 2 mL) was added and the resulting H-2′), 3.99 (t, 2H, J = 5.9, 5.4 Hz, H-3, H-3′), 3.85 (dd, 1H, J =
mixture was stirred for 1 h. The reaction mixture was diluted 13.8, 5.4 Hz, H-7a), 3.77–3.48 (m, 7H, H-7a′, H-9a, H-9a′, H-9b,
with EtOAc and the organic and aqueous layers were separated. H-9b′, H-7b, H-7b′); 13C NMR (CDCl3, 100 MHz): 155.94,
The aqueous layer was extracted twice with EtOAc and the com- 155.67 (2 × CvO), 138.19, 138.08, 138.04, 138.04, 138.02,
bined organic layers were dried over MgSO4, filtered and con- 138.02, 137.96, 137.96, 136.78, 136.66 (10
×
Cipso),
centrated under reduced pressure. The residue was then 128.44–126.48 (50 aromatic C), 102.16 (C-8), 102.12 (C-8′),
purified by column chromatography (P.E.–EtOAc, 8.5/1.5) to 79.74 (C-5), 79.12 (C-5′), 76.83 (C-3), 76.44 (C-3′), 75.04 (C-6),
give 21 (38 mg, 76%) as colorless oil. Rf 0.28, Cy–EtOAc, 4 : 1; 74.89 (C-6′), 74.89 (C-4), 74.34 (C-4′), 73.99, 73.80, 73.76, 73.62,
[α]D −5.6 (c
=
0.05, CHCl3); 1H NMR (CDCl3, 73.25, 73.21, (6 × CH2Ph), 67.51, 67.38 (2 × NCOOCH2Ph),
400 MHz):7.39–7.15 (m, 25H, 5 × Ph), 4.78, 4.68 (2d, 2H, J = 67.28 (C-9), 67.10 (C-9′), 54.61 (C-2), 54.42 (C-2′), 42.99 (C-7),
11.4 Hz, CH2Ph), 4.63–4.40 (m, 9H, 4 × CH2Ph, H-4), 4.24 (t, 42.74 (C-7′); ESI-HRMS calcd for C43H43NO7Na [M + Na]+:
1H, J = 13.6 Hz, H-3), 3.98 (m, 2H, H-1′), 3.92–3.87 (m, 2H, 708.2931, found 708.2937.
Compound 10b. Rf 0.31, Cy–EtOAc, 4 : 1; [α]D + 43 (c = 1.00,
CHCl3); 1H NMR (CDCl3, 400 MHz): 7.44–7.19 (m, 50H, 10 ×
Ph), 5.79 (s, 1H, H-8), 5.75 (s, 1H, H-8′), 5.22 (s, 2H, 2 ×
NCOOCHPh), 5.18 (dd, 2H, J = 12.4 Hz, 2 × NCOOCHPh), 4.90
(m, 1H, H-2), 4.82–4.69 (m, 7H, H-2′, 6 × CHPh), 4.60–4.39 (m,
12H, 6 × CHPh, H-6, H-6′, H-5, H-5′, H-4, H-4′), 4.05 (t, 2H, J =
6.3, 5.4 Hz, H-3, H-3′), 3.97 (dd, 1H, J = 13.4, 4.4 Hz, H-7a),
3.90–3.78 (m, 4H, H-7a′, H-9a, H-9a′, H-9b), 3.69–3.55 (m, 3H,
H-9b′, H-7b, H-7b′); 13C NMR (CDCl3, 100 MHz): 155.77,
155.67 (2 × CvO), 138.31, 138.19, 138.12, 137.98, 137.98,
NCH2Ph), 3.69 (dd, 1H, J = 8.9, 4.4 Hz, H-2′), 3.67 (dd, 1H, J =
8.1, 4.8 Hz, H-5), 3.58 (dd, 1H, J = 10.2, 3.7 Hz, H-6a), 3.45 (dd,
1H, J = 10.2, 1.7 Hz, H-6b), 3.32 (m, 1H, H-2); 13C NMR (CDCl3,
100 MHz): 139.43, 138.67, 138.51, 138.47, 138.41 (5 × Cipso),
128.29–126.82 (25 aromatic C), 83.57 (C-4), 83.19 (C-3), 79.20
(C-2′), 73.68, 73.26, 72.64, 72.13 (4 × CH2Ph), 66.03 (C-6),
63.89 (C-5), 61.28 (C-1′), 58.31 (C-2), 53.71 (NCH2Ph);
ESI-HRMS calcd for C42H46NO5 [M + H]+: 644.3370, found
644.3357.
(2S,3R,4R,5S)-2-((S)-1,2-Dihydroxyethyl)-5-(hydroxymethyl)-
pyrrolidine-3,4-diol 1. To a solution of pyrrolidine 21 (20 mg,
0.031 mmol) in MeOH (3 mL) and 1 M aq. HCl (50 μL) was
added 10% Pd/C (20 mg). The suspension was stirred under a
H2 atmosphere for 4 h at r.t., filtered through a Celite plug
eluted with MeOH. The solvent was removed under reduced
pressure to afford pyrrolidine 1 in quantitative yield as its
137.89, 136.90, 136.72, 136.72, 136.56 (10
×
Cipso),
129.44–126.90 (50 aromatic C), 103.36, 103.36 (C-8, C-8′), 81.16
(C-5), 80.66 (C-5′), 77.36 (C-3), 77.26 (C-3′), 75.30 (C-6), 75.11
(C-6′), 74.19, 74.02, 74.02, 73.84, 73.13, 73.09 (6 × CH2Ph),
73.40 (C-4), 73.40 (C-4′), 67.40, 67.26 (2 × NCOOCH2Ph), 67.26
(C-9), 66.97 (C-9′), 54.55 (C-2), 54.17 (C-2′), 43.90 (C-7), 43.66
(C-7′); ESI-HRMS calcd for C43H43NO7Na [M + Na]+: 708.2931,
found 708.2944.
1
hydrochloride salt. [α]D + 54 (c = 0.1, CH3OH); H NMR (D2O,
400 MHz): 4.37 (dd, 1H, J = 3.3, 1.5 Hz, H-3), 4.31 (dd, 1H, J =
3.6, 1.5 Hz, H-4), 4.12 (ddd, 1H, J = 8.7, 5.0, 3.3 Hz, H-2′),
4.04–3.86 (m, 4H, H-5, H-2, H-6), 3.78 (dd, 1H, J = 12.2, 3.3 Hz,
H-1a′), 3.66 (dd, 1H, J = 12.2, 5.1 Hz, H-1b′); 13C NMR (D2O,
100 MHz): 77.96 (C-3), 75.33 (C-4), 68.16 (C-2′), 63.16 (C-5),
62.83 (C-1′), 62.52 (C-2), 57.37 (C-6); ESI-HRMS calcd for
C7H16O5N [M + H]+: 194.1023, found 194.1018.
(2S,3R,4S,5S,6S,8R)-Benzyl-3,4-bis(benzyloxy)-2-((benzyloxy)-
methyl)-5,6-O-(benzylidene)azepane-1-carboxylate 10a and
(2S,3R,4S,5S,6S,8S)-benzyl-3,4-bis(benzyloxy)-2-((benzyloxy)-
(2S,3R,4S,5S,6S,8R)-1-Benzyl-3,4-bis(benzyloxy)-2-((benzyloxy)-
methyl)-5,6-O-(benzylidene)azepane
14a. Compound
10a
(400 mg, 0.58 mmol) was dissolved in EtOH (40 mL) and a
catalytic amount of Et3N (50 μL) was introduced, followed by
addition of Lindlar’s catalyst (400 mg). The reaction flask was
purged of air and filled with H2. The suspension was stirred
under H2 for 4 h by the end of which TLC (Cy–EtOAc, 4 : 1)
showed a complete reaction. The reaction mixture was filtered
through a pad of Celite, eluted with MeOH and concentrated
under reduced pressure to afford the N-deprotected azepane as
an oil. This oil was dissolved in DMF (15 mL), K2CO3 (244 mg,
1.74 mmol) was introduced, followed by addition of benzyl
bromide (86 μL, 0.73 mmol). The mixture was stirred at 50 °C
under an atmosphere of nitrogen overnight. After concen-
tration, the resulting residue was partitioned between water
(100 mL) and DCM (100 mL). The organic phase was dried
over MgSO4 and concentrated under reduced pressure. The
resulting residue was purified by flash column chromato-
graphy (Cy–EtOAc, 4 : 1) to give compound 14a as an oil
(289 mg, 78%). Rf 0.58, Cy–EtOAc, 4 : 1; [α]D −26 (c = 1.10,
methyl)-5,6-O-(benzylidene)azepane-1-carboxylate
10b. A
mixture of diol 6 (340 mg, 0.57 mmol), camphorsulfonic acid
(cat., 12 mg) and benzaldehyde dimethyl acetal (256 μL,
1.71 mmol) in CH3CN (20 mL) was stirred at 50 °C under an
atmosphere of nitrogen overnight. TLC (Cy–EtOAc, 4 : 1)
showed a complete conversion. The reaction was quenched
with triethylamine (0.6 mL). After concentration, the resulting
residue was purified by flash column chromatography
(Cy–EtOAc, 15 : 1) to give compound 10a as an oil (98 mg, 25%)
and further elution afforded compound 10b as an oil (282 mg,
70%).
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CHCl3); 1H NMR (CDCl3, 400 MHz): 7.31–7.18 (m, 25H, 5 × flash column chromatography (Cy–EtOAc, 20 : 1) to give com-
Ph), 5.89 (s, 1H, H-8), 4.80–4.70 (m, 3H, 3 × CHPh), 4.48–4.42 pound 18 as an oil (152 mg, 80%). Rf 0.35, Cy–EtOAc, 4 : 1;
(m, 3H, 3 × CHPh), 4.34 (t, 1H, J = 7.4, 6.5 Hz, H-5), 4.26–4.24 [α]D + 6 (c = 1.07, CHCl3); 1H NMR (CDCl3, 400 MHz):
(m, 1H, H-6), 3.98 (t, 1H, J = 7.9, 5.9 Hz, H-4), 3.93–3.64 (m, 7.38–7.28 (m, 25H, 5 × Ph), 4.82 (d, 1H, J = 11.2 Hz, CHPh),
5H, NCH2Ph, H-9a, H-9b, H-3), 3.19 (s, 1H, H-2), 3.04 (t, 1H, J = 4.69–4.48 (m, 7H, 7 × CHPh), 4.14 (d, 1H, J = 6.1 Hz, H-5),
11.2 Hz, H-7a), 2.81 (t, 1H, J = 13.8 Hz, H-7b); 13C NMR (CDCl3, 4.04–3.88 (m, 6H, H-4, H-8a, H-6, NCH2Ph, H-3), 3.82 (dd, 1H,
100 MHz): 139.87, 138.65, 138.65, 138.40, 138.40 (5 × Cipso), J = 9.6, 5.9 Hz, H-8b), 3.57 (b, 1H, OH), 3.33 (dd, 1H, J = 10.5,
128.50–126.10 (25 aromatic C), 101.96 (C-8), 80.88 (C-5), 80.26 6.1 Hz, H-2), 3.24 (dd, 1H, J = 14.4, 4.8 Hz, H-7a), 2.88 (dd,1H,
(C-3), 79.37 (C-4), 74.57, 73.95, 73.22 (3 × CH2Ph), 74.45 (C-6), J = 14.4, 5.4 Hz, H-7b); 13C NMR (CDCl3, 100 MHz): 140.22,
67.83 (C-9), 61.28 (C-2), 59.56 (N-CH2Ph), 48.67 (C-7); ESI-HRMS 138.79, 138.55, 138.25, 138.22 (5 × Cipso), 128.52–127.00 (25
calcd for C42H44NO5 [M + H]+: 642.3214, found 642.3214.
aromatic C), 82.56 (C-3), 79.83 (C-4), 76.96 (C-6), 74.34, 73.71,
(2S,3R,4S,5S,6S,8S)-1-Benzyl-3,4-bis(benzyloxy)-2-((benzyloxy)- 73.71, 72.12 (4 × CH2Ph), 72.62 (C-5), 68.34 (C-8), 60.24 (C-2),
methyl)-5,6-O-(benzylidene)azepane 14b. Compound 10b 59.44 (N-CH2Ph), 50.97 (C-7); ESI-HRMS calcd for C42H46NO5
(660 mg, 0.963 mmol) was dissolved in EtOH (60 mL) and a [M + H]+: 644.3370, found 644.3374.
catalytic amount of Et3N (60 μL) was introduced, followed by
2-[(R)-1-Benzyloxy-2-hydroxyethyl]-(2R,3R,4R,5S)-1-benzyl-3,4-
addition of Lindlar’s catalyst (660 mg). The reaction flask was bis(benzyloxy)-5-((benzyloxy)methyl)pyrrolidine 22. To a solu-
purged of air and filled with H2. The suspension was stirred tion of 18 (50 mg, 0.078 mmol) in dry toluene (2 mL) were
under H2 for 4 h by the end of which TLC (Cy–EtOAc, 4 : 1) added trifluoroacetic anhydride (17 μL, 0.117 mmol) and Et3N
showed a complete reaction. The reaction mixture was filtered (17 μL, 0.156 mmol) at 0 °C. Then the solution was refluxed
through a pad of Celite, eluted with MeOH and concentrated for 5 hours before being cooled to room temperature. A solu-
under reduced pressure to afford the N-deprotected azepane as tion of NaOH (10%, 2 mL) was added and the resulting
an oil. This oil was dissolved in DMF (20 mL), K2CO3 (462 mg, mixture was stirred for another 1 h. EtOAc was added and the
3.30 mmol) was introduced, followed by addition of benzyl layers were separated. The aqueous layer was extracted twice
bromide (164 μL, 1.38 mmol). The mixture was stirred at 50 °C with EtOAc and the combined organic layers were dried on
under an atmosphere of nitrogen overnight. After concen- MgSO4, filtered and concentrated under reduced pressure. The
tration, the resulting residue was partitioned between water residue was then purified by column chromatography (P.E.–
(100 mL) and DCM (100 mL). The organic phase was dried EtOAc, 8.5/1.5) to give 22 (45 mg, 90%) as colorless oil. Rf 0.33,
over MgSO4 and concentrated under reduced pressure. The Cy–EtOAc, 4 : 1; [α]D + 20 (c = 1.12, CHCl3); 1H NMR (CDCl3,
resulting residue was purified by flash column chromato- 400 MHz): 7.38–7.18 (m, 25H, 5 × Ph), 4.62–4.39 (m, 8H, 4 ×
graphy (Cy–EtOAc, 15 : 1) to give compound 14b as an oil CH2Ph), 4.13 (s, 1H, H-3), 3.95 (s, 1H, H-4), 3.94 (d, 1H, J =
(450 mg, 87%). Rf 0.52, Cy–EtOAc, 4 : 1; [α]D + 8 (c = 1.01, 13.6 Hz, NCHPh), 3.75 (d, 1H, J = 13.8 Hz, NCHPh), 3.71–3.68
CHCl3); 1H NMR (CDCl3, 400 MHz): 7.34–7.09 (m, 25H, 5 × (m, 2H, H-6a, H-1′b), 3.62 (dd, 1H, J = 8.5, 3.7 Hz, H-1′a), 3.52
Ph), 5.63 (s, 1H, H-8), 4.74–4.66 (m, 3H, 3 × CHPh), 4.49 (d, (dd,1H, J = 9.2, 5.0 Hz, H-6b), 3.33–3.26 (m, 3H, H-2, H-5,
1H, J = 11.6 Hz, CHPh), 4.41 (s, 2H, 2 × CHPh), 4.29 (t, 1H, J = H-2′); 13C NMR (CDCl3, 100 MHz): 136.68, 136.51, 136.51,
7.6 Hz, H-5), 4.23–4.20 (m, 1H, H-6), 3.95–3.89 (m, 2H, H-4, 136.08, 135.95 (5 × Cipso), 129.98–127.39 (25 aromatic C), 81.92
NCHPh), 3.81 (dd, 1H, J = 9.6, 6.8 Hz, H-9a), 3.76–3.66 (m, 3H, (C-4), 80.48 (C-3), 75.42 (C-2′), 72.86 (C-2), 73.39, 71.48, 71.77,
H-9b, NCHPh, H-3), 3.23 (b, 1H, H-2), 2.95 (dd, 1H, J = 13.8, 70.92 (4 × CH2Ph), 69.08 (C-6), 66.07 (C-5), 62.34 (C-1′), 59.08
10.9 Hz, H-7a), 2.78 (dd, 1H, J = 13.8, 3.7 Hz, H-7b); 13C NMR (NCH2Ph); ESI-HRMS calcd for C42H46NO5 [M + H]+: 644.3370,
(CDCl3, 100 MHz): 139.95, 138.74, 138.74, 138.46, 136.93 (5 × found 644.3361.
Cipso), 129.41–126.80 (25 aromatic C), 103.00 (C-8), 81.86 (C-5),
(2R,3R,4R,5S)-2-((R)-1,2-Dihydroxyethyl)-5-(hydroxymethyl)-
80.47 (C-4), 80.26 (C-3), 74.98 (C-6), 74.83, 74.10, 73.30 (3 × pyrrolidine-3,4-diol 2. To a solution of pyrrolidine 22 (41 mg,
CH2Ph), 67.77 (C-9), 61.79 (C-2), 59.85 (N-CH2Ph), 49.22 (C-7); 0.064 mmol) in MeOH (3 mL) and conc. HCl (20 μL) was
ESI-HRMS calcd for C42H44NO5 [M + H]+: 642.3214, found added 10% Pd/C (40 mg). The suspension was stirred under a
642.3219.
H2 atmosphere for 24 h at r.t., filtered through a Celite plug
(2S,3R,4R,6S,5S)-1-Benzyl-3,4,6-tris(benzyloxy)-2-((benzyloxy)- eluted with MeOH. The solvent was removed under reduced
methyl) azepan-5-ol 18. To a solution of dry compound 14b pressure to afford pyrrolidine 2 in quantitative yield as its
(190 mg, 0.296 mmol) in dry DCM (7 mL) was added quickly hydrochloride salt. [α]D +20 (c = 1.21, CH3OH); 1H NMR
DIBAL (2.96 mL, 1.5 M in toluene, 4.44 mmol) at −78 °C under (CD3OD, 400 MHz): 4.13 (dd, 2H, J = 5.9, 2.8 Hz, H-3, H-4),
an atmosphere of nitrogen with stirring. After 15 min at 3.98–3.91 (m, 3H, H-6a, H-6b, H-2′), 3.76 (dd, 2H, J = 11.7, 4.0
−78 °C, additional DIBAL (1 mL) was added. After another Hz, H-2, H-1′a), 3.68 (dd, 1H, J = 11.6, 4.6 Hz, H-1′b), 3.48 (dd,
1.5 h, TLC showed that the starting material was consumed 1H, J = 7.7, 2.9 Hz, H-5); 13C NMR (CD3OD, 100 MHz): 78.30
completely. 1.5 mL of 1 M aq. HCl was added at −30 °C to (C-4), 76.52 (C-3), 70.96 (C-2′), 69.70 (C-5), 64.78 (C-1′), 64.68
quench the reaction. The resulting solution was warmed to (C-2), 58.37 (C-6); ESI-HRMS: Calcd for C7H16O5N [M + H]+:
r.t., then partitioned between water (50 mL) and DCM (50 mL). 194.1023, found 194.1022.
The organic phase was dried over MgSO4 and concentrated
(2R,3R,4S,5S,6S,8R)-Benzyl-3,4-bis(benzyloxy)-2-((benzyloxy)-
under reduced pressure. The resulting residue was purified by methyl)-5,6-O-(benzylidene)azepane-1-carboxylate 11a and
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(2R,3R,4S,5S,6-S,8S)-benzyl-3,4-bis(benzyloxy)-2-((benzyloxy)- tion. The reaction mixture was filtered through a Celite plug
methyl)-5,6-O-(benzylidene)azepane-1-carboxylate 11b. To eluted with MeOH and concentrated under reduced pressure
a
solution of diol 7 (50 mg, 0.083 mmol) in CH3CN (2 mL) were to afford the N-deprotected azepane as an oil. This crude com-
added benzaldehyde dimethyl acetal (38 μL, 0.25 mmol) and pound was dissolved in DMF (30 mL), then K2CO3 (403 mg,
camphorsulfonic acid (3 mg). The mixture was stirred for 1.5 h 2.88 mmol) and benzyl bromide (143 μL, 1.20 mmol) were
at 50 °C. The reaction mixture was then cooled to r.t., neutral- added successively. The mixture was stirred at 50 °C under an
ized with Et3N, and concentrated under reduced pressure. atmosphere of nitrogen overnight. After concentration, the
Purification by flash column chromatography (Cy–EtOAc, resulting residue was partitioned between water (100 mL) and
10 : 1) afforded acetal 11a as an oil (17 mg, 30%). Further DCM (100 mL). The organic phase was dried over MgSO4 and
elution (Cy–EtOAc, 5 : 1) afforded acetal 11b as an oil (40 mg, concentrated under reduced pressure. The resulting residue
70%).
Compound 11a. Rf 0.68, Cy–EtOAc, 2 : 1; [α]D +33 (c = 1.70,
was purified by flash column chromatography (Cy–EtOAc, 8 : 1)
to give acetal 15 as a clear oil (360 mg, 58%). Rf 0.27,
Cy–EtOAc, 4 : 1; [α]D +94 (c = 1.77, CHCl3); 1H NMR (CDCl3,
400 MHz): 7.43–7.03 (m, 25H, 5 × Ph), 5.77 (s, 1H, H-8), 4.86
(d, 1H, J = 10.7 Hz, CHPh), 4.72 (d, 1H, J = 11.3 Hz, CHPh),
4.61 (d, 1H, J = 11.3 Hz, CHPh), 4.40–4.31 (m, 3H, 3 × CHPh),
4.19 (dd, 1H, J = 8.4, 1.1 Hz, H-5), 4.05–4.02 (m, 1H, H-6),
3.98–3.94 (dd, 2H, J = 12.6, 8.6 Hz, H-4, NCHPh), 3.77 (d, 1H,
J = 13.5 Hz, NCHPh), 3.71–3.67 (dd, 1H, J = 10.0, 9.9, 2.4 Hz,
H-9a), 3.65–3.62 (dd, 1H, J = 10.0, 9.9, 3.5 Hz, H-9b), 3.52 (t,
1H, J = 9.4 Hz, H-3), 3.62–3.57 (dd, 1H, J = 15.9, 2.6 Hz, H-7a),
3.04–3.00 (dd, 1H, J = 15.9, 3.5 Hz, H-7b), 2.67–2.63 (dd, 1H,
J = 9.4, 2.6 Hz, H-2); 13C NMR (CDCl3, 100 MHz): 138.51,
138.02, 137.44, 137.40, 136.25 (5 × Cipso), 127.69–125.82 (25
aromatic C), 101.97 (C-8), 82.41 (C-4), 80.01 (C-5), 77.35 (C-6),
76.03 (C-3), 74.27, 74.27, 72.34 (3 × CH2Ph), 66.91 (C-9), 61.26
(C-2), 58.19 (N-CH2Ph), 47.98 (C-7); ESI-HRMS calcd for
C42H44NO5 [M + H]+: 642.3214, found 642.3204.
CHCl3); 1H NMR (CDCl3, 400 MHz): 7.59–7.15 (m, 50H, 10 ×
Ph), 5.89 (s, 1H, H-8), 5.83 (s, 1H, H-8′), 5.34 (d, 1H, J = 12.5
Hz, NCOOCHPh), 5.19 (dd, 2H, J = 12.4, 12.2 Hz 2 ×
NCOOCHPh), 5.09–4.95 (m, 5H, 4 × CHPh, NCOOCHPh), 4.84
(dd, 2H, J = 11.4, 9.2 Hz, 2 × CHPh), 4.63–4.29 (m, 13H, 6 ×
CHPh, H-7a, H-7′a, H-5, H-5′, H-3, H-3′, H-2), 4.15–4.10 (m, 3H,
H-4, H-4′, H-2′), 3.91–3.50 (m, 8H, H-9a, H-9′a, H-9b, H-9′b,
H-7b, H-7′b, H-6, H-6′); 13C NMR (CDCl3, 100 MHz): 156.74,
156.74 (2 × CvO), 139.28, 138.51, 138.51, 138.20, 138.20,
138.10, 137.93, 137.93, 136.84, 136.56 (10
×
Cipso),
128.82–126.09 (50 aromatic C), 102.25 (C-8), 102.06 (C-8′),
81.34 (C-3), 81.10 (C-3′), 79.39 (C-6), 79.39 (C-6′), 74.97 (C-4),
74.89 (C-4′), 74.80 (C-5), 74.78 (C-5′), 75.64, 75.43, 75.39, 73.36,
73.31, 73.31 (6 × CH2Ph), 70.17 (C-9), 69.90 (C-9′), 67.66, 67.32
(2 × NCOOCH2Ph), 58.27 (C-2), 57.92 (C-2′), 41.35 (C-7), 41.35
(C-7′); ESI-HRMS calcd for C43H43NO7Na [M + Na]+: 708.2931,
found 708.2929.
(2R,3R,4R,5S,6S)-1-Benzyl-3,4,6-tris(benzyloxy)-2-((benzyloxy)-
methyl) azepan-5-ol 19. To a solution of acetal 15 (300 mg,
0.47 mmol) in dry DCM (7 mL) was quickly added DIBAL
(4.6 mL, 1.5 M in toluene, 7.01 mmol) at −78 °C under an
atmosphere of nitrogen with stirring. After 1.5 h at −78 °C,
TLC indicated a complete reaction. A solution of 1 M aq. HCl
(1.5 mL) was added at −30 °C to quench the reaction. The
resulting solution was then warmed to r.t., partitioned
between DCM (50 mL) and water (50 mL). The organic phase
was dried over MgSO4 and concentrated under reduced
pressure to afford a mixture of alcohols (Rf 0.24, Cy–EtOAc,
4 : 1), which were difficult to separate by flash column
chromatography. The mixture of crude alcohols was dissolved
in pyridine (4 mL), and Ac2O (2 mL) was added. The reaction
mixture was stirred under an atmosphere of nitrogen at r.t.
overnight and concentrated under reduced pressure. Purifi-
cation by flash column chromatography (Cy–EtOAc, 15 : 1)
afforded a minor acetylated compound as an oil (58 mg, 18%).
Further elution afforded major acetylated compound as an oil
(258 mg, 80%).
Compound 11b. Rf 0.56, Cy–EtOAc, 2 : 1; [α]D +26 (c = 1.00,
CHCl3); 1H NMR (CDCl3, 400 MHz): 7.35–7.06 (m, 50H, 10 ×
Ph), 5.89 (s, 1H, H-8), 5.83 (s, 1H, H-8′), 5.16 (d, 1H, J = 12.2
Hz, NCOOCHPh), 5.08 (d, 1H, J = 12.2 Hz, NCOOCHPh), 5.00
(s, 2H, 2 × NCOOCHPh), 4.88 (d, 1H, J = 10.9 Hz, CHPh), 4.83
(d, 1H, J = 10.7 Hz, CHPh), 4.70 (d, 1H, J = 11.2 Hz, CHPh),
4.61 (dd, 1H, J = 13.8, 2.2 Hz, H-7a), 4.56 (d, 1H, J = 11.1 Hz,
CHPh), 4.46–4.10 (m, 14H, H-7′a, 8 × CHPh, H-5, H-5′, H-4,
H-4′, H-2), 3.95 (d, 1H, J = 9.6 Hz, H-2′), 3.78 (dd, 1H, J =
3.0 Hz, H-9a), 3.72 (dd, 1H, J = 3.0 Hz, H-9′a), 3.68–3.46
(m, 8H, H-9b, H-9′b, H-7b, H-7′b, H-6, H-6′, H-3, H-3′); 13C
NMR (CDCl3, 100 MHz): 156.87, 156.64 (2 × CvO), 138.89,
138.89, 138.70, 138.38, 138.38, 138.22, 138.22, 138.08, 137.93,
136.58 (10 × Cipso), 129.27–126.41 (50 aromatic C), 103.36 (C-8),
103.11 (C-8′), 83.51 (C-6), 83.20 (C-6′), 80.25 (C-5), 80.19 (C-5′),
77.37 (C-4), 77.29 (C-4′), 76.05, 75.87, 75.64, 75.44 (4 × CH2Ph),
74.77 (C-3), 74.63 (C-3′), 73.56, 73.47 (2 × CH2Ph), 70.46 (C-9),
70.08 (C-9′), 67.70, 67.70 (2 × NCOOCH2Ph), 58.32 (C-2), 58.04
(C-2′), 41.43 (C-7), 41.36 (C-7′); ESI-HRMS calcd for
C43H43NO7Na [M + Na]+: 708.2931, found 708.2926.
Minor acetylated compound. Rf 0.39, Cy–EtOAc, 4 : 1; [α]D +37
(c = 1.14, CHCl3); 1H NMR (CDCl3, 400 MHz): 7.29–7.11 (m,
25H, 5 × Ph), 5.40 (d, 1H, J = 6.5 Hz, H-6), 4.62–4.49 (m, 5H,
5 × CHPh), 4.37 (s, 2H, 2 × CHPh), 4.32 (d, 1H, J = 11.3 Hz,
CHPh), 4.02–3.93 (m, 3H, NCHPh, H-4, H-5), 3.79 (d, 1H, J =
14.6 Hz, NCHPh), 3.71 (dd, 1H, J = 8.5, 3.1 Hz, H-3), 3.65 (d,
2H, J = 4.5 Hz, H-8a, H-8b), 3.43 (dd, 1H, J = 9.1, 4.5 Hz, H-2),
2.99 (t, 1H, J = 13.2, 10.8 Hz, H-7a), 2.75 (dd, 1H, J = 13.2, 4.7
(2R,3R,4S,5S,6S,8S)-1-Benzyl-3,4-bis(benzyloxy)-2-((benzyloxy)-
methyl)-5,6-O-(benzylidene)azepane 15. To a solution of acetal
11b (538 mg, 0.790 mmol) in EtOH (60 mL) was added a cataly-
tic amount of Et3N (60 μL), followed by addition of Lindlar’s
catalyst (538 mg). The reaction flask was purged of air and
filled with H2. The suspension was stirred under a H2 atmos-
phere for 4 h. TLC (Cy–EtOAc, 4 : 1) showed a complete reac-
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Paper
Hz, H-7b), 1.87 (s, 3H, CH3); 13C NMR (CDCl3, 100 MHz): Rf 0.25, Cy–EtOAc, 4 : 1; [α]D −20 (c = 1.00, CHCl3); 1H
170.44 (CvO), 140.95, 138.73, 138.66, 138.66, 138.44 (5 × NMR (CDCl3, 400 MHz): 7.27–7.16 (m, 25H, 5 × Ph), 4.65–4.33
Cipso), 128.62–126.75 (25 aromatic C), 81.78 (C-3), 80.36 (C-5), (m, 9H, 4 × CH2Ph, H-4), 4.07 (s, 1H, H-3), 3.97 (d, 1H, J = 13.6
79.86 (C-4), 73.41, 73.26, 73.16, 72.90 (4 × CH2Ph), 70.84 (C-8), Hz, NCHPh), 3.88–3.71 (m, 5H, H-6a, H-1′a, H-6b, H-2′,
69.36 (C-6), 63.96 (C-2), 53.39 (NCH2Ph), 49.70 (C-7), 21.39 NCHPh), 3.61 (m, 1H, H-1′b), 3.46 (m, 2H, H-5, H-2); 13C NMR
(CH3); ESI-HRMS: calcd for C44H48NO6 [M + H]+: 686.3476, (CDCl3, 100 MHz): 138.50, 138.50, 138.41, 138.41, 138.02 (5 ×
found 686.3481.
Cipso), 128.59–127.25 (25 aromatic C), 84.07 (C-4), 83.18 (C-3),
76.35 (C-2′), 73.29, 71.87, 71.62, 71.29 (4 × CH2Ph), 70.17 (C-2),
65.76 (C-1′), 63.16 (C-5), 62.10 (C-6), 52.82 (NCH2Ph);
ESI-HRMS calcd for C42H46NO5 [M + H]+: 644.3370, found
644.3379.
Major acetylated compound. Rf 0.33, Cy–EtOAc, 4 : 1; [α]D +30
(c = 0.68, CHCl3); 1H NMR (CDCl3, 400 MHz): 7.39–7.24 (m,
25H, 5 × Ph), 5.61 (dd, 1H, J = 5.2, 1.9 Hz, H-5), 4.75–4.67 (m,
3H, 3 × CHPh), 4.57 (d, 1H, J = 11.8 Hz, CHPh), 4.44 (d, 1H, J =
11.8 Hz, CHPh), 4.37–4.30 (m, 4H, 3 × CHPh, H-4), 4.05–40.1
(m, 1H, H-6), 3.96 (d, 1H, J = 14.2 Hz, NCHPh), 3.78–3.68 (m,
3H, NCHPh, H-3, H-8a), 3.59 (d, 1H, H-8b), 3.25–3.21 (m, 1H,
H-2), 2.89 (dd, 1H, J = 12.4, 5.6 Hz, H-7a), 2.76 (t, 1H, J = 12.4,
10.0 Hz, H-7b), 1.95 (s, 3H, Me); 13C NMR (CDCl3, 100 MHz):
170.69 (CvO), 140.31, 140.31, 138.28, 138.28, 138.11 (5 ×
Cipso), 128.43–126.76 (25 aromatic C), 80.23 (C-4), 79.77 (C-3),
74.09 (C-5), 73.04 (C-6), 73.82, 73.31, 73.22, 71.26 (4 × CH2Ph),
68.70 (C-8), 65.54 (C-2), 56.41 (N-CH2Ph), 50.24 (C-7), 21.17
(CH3); ESI-HRMS: calcd for C44H48NO6 [M + H]+: 686.3476,
found 686.3472.
(2R,3R,4R,5R)-2-((R)-1,2-Dihydroxyethyl)-5-(hydroxymethyl)-
pyrrolidine-3,4-diol 3. To a solution of pyrrolidine 23 (40 mg,
0.062 mmol) in MeOH (3 mL) and conc. HCl (20 μL) was
added 10% Pd/C (40 mg). The suspension was stirred under a
H2 atmosphere for 24 h at r.t., filtered through a Celite plug
eluted with MeOH. The solvent was removed under reduced
pressure to afford pyrrolidine 3 in quantitative yield as its
hydrochloride salt. [α]D +29 (c = 0.31, CH3OH); 1H NMR
(CD3OD, 400 MHz): 4.07 (t, 1H, J = 7.5, 6.8 Hz, H-4), 3.99 (t,
1H, J = 7.9, 6.8 Hz, H-3), 3.92 (dd, 1H, J = 9.0, 4.9 Hz, H-2′),
3.88–3.75 (m, 2H, H-6), 3.66 (d, 2H, J = 5.0, H-1′), 3.44 (dd, 1H,
J = 7.6, 4.0 Hz, H-2), 3.37 (m, 1H, H-5); 13C NMR (CD3OD,
100 MHz): 77.29 (C-4), 75.85 (C-3), 69.27 (C-2′), 65.14 (C-2),
65.07 (C-5), 64.90 (C-2′), 59.06 (C-6); ESI-HRMS calcd for
C7H16O5N [M + H]+: 194.1023, found 194.1025.
A
mixture of major acetylated compound (100 mg,
0.140 mmol), NaOH (17 mg, 0.440 mmol) in MeOH (3 mL)
and water (0.5 mL) was refluxed for 1 h. The reaction mixture
was neutralized with 1 M HCl (0.15 mL) and concentrated
under reduced pressure. The resulting residue was partitioned
between DCM (20 mL) and water (20 mL). The organic phase
was dried over MgSO4 and concentrated under reduced
pressure to afford compound 19 as an oil (98 mg, quant.).
Rf 0.32, Cy–EtOAc, 4 : 1; [α]D −5 (c = 1.05, CHCl3); 1H NMR
(CDCl3, 400 MHz): 7.34–7.17 (m, 25H, 5 × Ph), 4.65–4.51 (m,
4H, J = 3.0 Hz, J = 13.1 Hz, 4 × CHPh), 4.43–4.29 (m, 4H, 4 ×
CHPh), 4.13 (s, 1H, H-5), 3.95–3.91 (m, 2H, H-6, H-4), 3.87 (d,
1H, J = 12.9 Hz, NCHPh), 3.76 (d, 1H, J = 13.1 Hz, NCHPh),
3.66–3.61 (m, 3H, H-3, H-8a, H-8b), 3.19 (dd, 2H, J = 12.0, 6.8
Hz, H-2, H-7a), 2.81 (dd, 1H, J = 12.0, 8.5 Hz, H-7b); 13C NMR
(CDCl3, 100 MHz): 139.14, 138.58, 138.53, 138.46, 138.33 (5 ×
Cipso), 129.17–127.45 (25 aromatic C), 83.61 (C-4), 79.10 (C-3),
75.52 (C-6), 74.66 (C-5), 73.29, 73.29, 72.85, 71.43 (4 × CH2Ph),
67.15 (C-8), 63.16 (C-2), 60.69 (NCH2Ph), 51.34 (C-7);
ESI-HRMS calcd for C42H46NO5 [M + H]+: 644.3370, found
644.3373.
(2R,3R,4S,5R,6R)-Benzyl-3,4-bis(benzyloxy)-2-((benzyloxy)-
methyl)-5,6-O-(benzylidene)azepane-1-carboxylate
mixture of diol 8 (115 mg, 0.193 mmol), camphorsulfonic acid
(cat., mg) and benzaldehyde dimethyl acetal (87 μL,
12. A
2
0.579 mmol) in CH3CN (4 mL) was stirred at 50 °C under an
atmosphere of nitrogen overnight and quenched with triethyl-
amine (0.1 mL). After concentration, the resulting residue was
purified by flash column chromatography (Cy–EtOAc, 5 : 1) to
yield compound 12 as an oil (120 mg, 91%). Due to the
mixture of rotational isomers, NMR was not resolved clearly
and this compound was used directly in the next step. Rf 0.51,
Cy–EtOAc, 4 : 1; ESI-HRMS calcd for C43H43NO7Na [M + Na]+:
708.2931, found 708.2928.
(2R,3R,4S,5R,6R)-1-Benzyl-3,4-bis(benzyloxy)-2-((benzyloxy)-
methyl)-5,6-O-(benzylidene)azepane 16. Compound 12 (56 mg,
0.081 mmol) was dissolved in EtOH (5 mL) and a catalytic
amount of Et3N (5 μL) was introduced, followed by the
addition of Lindlar’s catalyst (56 mg). The reaction flask was
purged of air and filled with H2. The suspension was stirred
under H2 for 4 h by the end of which TLC (Cy–EtOAc, 4 : 1)
showed a complete reaction. The reaction mixture was filtered
through a pad of Celite, eluted with MeOH and concentrated
under reduced pressure to afford the N-deprotected azepane as
an oil. This oil was dissolved in DMF (3 mL), K2CO3 (34 mg,
0.243 mmol) was introduced, followed by addition of benzyl
bromide (20 μL, 0.163 mmol). The mixture was stirred at 50 °C
under an atmosphere of nitrogen overnight. After concen-
tration, the resulting residue was partitioned between water
(20 mL) and DCM (20 mL). The organic phase was dried over
MgSO4 and concentrated under reduced pressure. The result-
2-[(R)-1-Benzyloxy-2-hydroxyethyl]-(2R,3R,4R,5R)-1-benzyl-
3,4-bis(benzyloxy)-5-((benzyloxy)methyl)pyrrolidine 23. To
a
solution of 19 (50 mg, 0.078 mmol) in dry toluene (2 mL) were
added trifluoroacetic anhydride (17 μL, 0.117 mmol) and Et3N
(17 μL, 0.156 mmol) at 0 °C. Then the solution was refluxed
for 5 hours before being cooled to room temperature. To this
solution, NaOH (10%, 2 mL) was added and the resulting
mixture was stirred for another 1 h. EtOAc was added and the
layers were separated. The aqueous layer was extracted twice
with EtOAc and the combined organic layers were dried on
MgSO4, filtered and concentrated under reduced pressure.
The residue was then purified by column chromatography
(P.E.–EtOAc, 8.5/1.5) to give 23 (46 mg, 92%) as colorless oil.
This journal is © The Royal Society of Chemistry 2015
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ing residue was purified by flash column chromatography H-2), 2.53 (d, 1H, J = 10.2 Hz, H-7b), 2.13 (s, 3H, CH3); 13C
(Cy–EtOAc, 8 : 1) to give compound 16 as an oil (36 mg, 70%), NMR (CDCl3, 100 MHz): 170.44 (CvO), 140.03, 138.75, 138.68,
which was an inseparable mixture of two epimers. Rf 0.55, 138.52, 138.21 (5 × Cipso), 128.98–127.24 (25 aromatic C), 80.32
Cy–EtOAc, 4 : 1; 1H NMR (CDCl3, 400 MHz): 7.44–7.12 (m, 50H, (C-6), 77.94 (C-4), 76.57 (C-3), 74.28, 73.21, 73.21, 71.11 (4 ×
10 × Ph), 6.16 (s, 1H, H-8′), 5.74 (s, 1H, H-8), 4.90–4.25 (m, CH2Ph), 71.02 (C-5), 69.02 (C-8), 65.17 (C-2), 61.06 (NCH2Ph),
14H, 6 × CHPh, H-5, H-5′), 4.25–4.11 (m, 3H, H-6, H-6′, H-4), 47.05 (C-7), 21.38 (CH3); ESI-HRMS: calcd for C44H48NO6
4.05–3.65 (m, 11H, H-4′, H-3, H-3′, NCH2Ph, NCH2Ph′, H-9, [M + H]+: 686.3476, found 686.3481.
H-9′), 3.50–3.20, (m, 2H, H-7a, H-7a′), 3.25–2.99, (m, 2H,
A mixture of major acetylated compound (150 mg,
H-2, H-2′), 2.87–2.65 (m, 2H, H-7b, H-7b′; 13C NMR (CDCl3, 0.218 mmol), NaOH (26 mg, 0.654 mmol) in MeOH (3 mL)
100 MHz): 140.18, 140.15, 139.50, 138.66, 136.61, 138.51, and water (0.5 mL) was refluxed for 1 h. The reaction mixture
138.45, 138.42, 138.38 (10 × Cipso), 129.29–126.28 (50 aro- was neutralized with 1 M HCl (0.3 mL) and concentrated
matic C), 104.14, 103.73 (C-8, C-8′), 81.70, 80.93 (C-4, C-4′), under reduced pressure. The resulting residue was partitioned
80.31, 79.45 (C-5, C-5′), 78.55, 76.34 (C-6, C-6′), 75.70, 75.17 between DCM (20 mL) and water (20 mL). The organic phase
(C-3, C-3′), 74.75, 74.44, 74.03, 73.29, 73.14, 72.62 (10 × was dried over MgSO4 and concentrated under reduced
CH2Ph), 68.68, 66.59 (C-9, C-9′), 63.80, 63.27 (C-2, C-2′), pressure to afford compound 20 as a syrup (120 mg, 86%). Rf
60.67, 60.40 (N-CH2Ph, N-CH2Ph′), 48.68, 48.05 (C-7, C-7′); 0.28, Cy–EtOAc, 4 : 1; [α]D +13 (c = 2.8, CHCl3); 1H NMR (CDCl3,
ESI-HRMS calcd for C42H44NO5 [M + H]+: 642.3214, found 400 MHz): 7.38–7.09 (m, 25H, 5 × Ph), 4.87 (dd, 2H, J = 11.8,
642.3206.
(2R,3R,4R,5R,6R)-1-Benzyl-3,4,6-tris(benzyloxy)-2-((benzyloxy)- (m, 3H, 3 × CHPh), 4.24 (d, 1H, J = 12.0 Hz, CHPh), 4.22 (ddd,
methyl) azepan-5-ol 20. To solution of compound 16 1H, J = 2.9, 1.5, 1.3 Hz, H-6), 4.14 (d, 1H, J = 12.0 Hz, CHPh),
11.2 Hz, 2 × CHPh), 4.69 (d, 1H, J = 11.6 Hz, CHPh), 4.51–4.43
a
(349 mg, 0.544 mmol) in dry DCM (5 mL) was added quickly 4.07 (t, 1H, J = 8.8, 7.6 Hz, H-4), 3.96 (dd, 1H, J = 8.8, 1.3 Hz,
DIBAL (7.3 mL, 1.5 M in toluene, 2.664 mmol) at −78 °C under H-5), 3.90 (d, 1H, J = 13.2 Hz, NCHPh), 3.81 (d, 1H, J = 13.2 Hz,
an atmosphere of nitrogen with stirring. After 30 min at NCHPh), 3.75 (dd, 1H, J = 10.1, 5.6 Hz, H-8a), 3.65 (dd, 1H, J =
−78 °C, TLC (Cy–EtOAc, 4 : 1) showed that the starting material 10.1, 3.5 Hz, H-8b), 3.13–3.06 (m, 2H, H-7a, H-3), 3.02 (tt, 1H,
was consumed completely. A solution of 1 M aq. HCl (3 mL) J = 10.8, 3.52 Hz, H-2), 2.48 (dd, 1H, J = 13.6, 3.5 Hz, H-7b); 13
C
was added at −30 °C to quench the reaction. The resulting NMR (CDCl3, 100 MHz): 140.25, 138.95, 138.87, 138.72, 138.18
solution was warmed to r.t., and then extracted with DCM/ (5 × Cipso), 129.13–127.19 (25 aromatic C), 81.17 (C-5), 77.89
water, dried over MgSO4, concentrated under reduced (C-3), 76.32 (C-4), 74.61, 74.02, 73.19, 71.06 (4 × CH2Ph), 71.98
pressure, to provide an inseparable mixture of diols. This (C-6), 69.18 (C-8), 65.75 (C-2), 60.84 (N-CH2Ph), 45.29 (C-7);
mixture of crude diols was dissolved in pyridine (4 mL) and ESI-HRMS calcd for C42H46NO5 [M + H]+: 644.3370, found
Ac2O (2 mL), then stirred under an atmosphere of nitrogen at 644.3364.
r.t. overnight. After evaporation, the resulting residue was puri-
2-[(S)-1-Benzyloxy-2-hydroxyethyl]-(2S,3R,4R,5R)-1-benzyl-3,4-
fied by flash column chromatography (Cy–EtOAc, 15 : 1) to give bis(benzyloxy)-5-((benzyloxy)methyl)pyrrolidine 24. To a solu-
minor acetylated compound as a clear oil (66 mg, 18%), and tion of 20 (70 mg, 0.109 mmol) in dry toluene (3 mL) were
further elution afforded major acetylated compound as a clear added trifluoroacetic anhydride (23 μL, 0.163 mmol) and Et3N
oil (173 mg, 46%).
(30 μL, 0.218 mmol) at 0 °C. Then the solution was refluxed
for 5 hours before being cooled to room temperature. A solu-
tion of NaOH (10%, 2 mL) was added and the resulting
mixture was stirred for another 1 h. EtOAc was added and the
layers were separated. The aqueous layer was extracted twice
with EtOAc and the combined organic layers were dried on
MgSO4, filtered and concentrated under reduced pressure. The
residue was then purified by column chromatography (P.E.–
EtOAc, 8.5/1.5) to give 24 (43 mg, 62%) as a colorless oil. Rf
Minor acetylated compound. Rf 0.52, Cy–EtOAc, 4 : 1; [α]D +7
(c = 0.98, CHCl3); 1H NMR (CDCl3, 400 MHz): 7.43–7.20 (m,
25H, 5 × Ph), 4.90–4.69 (m, 5H, 4 × CHPh, H-6), 4.52–4.38 (m,
4H, 4 × CHPh), 4.25 (d, 1H, J = 2.6 Hz, H-5), 4.09–3.94 (m, 4H,
NCH2Ph, H-4, H-3), 3.79 (dd, 1H, J = 9.5, 6.0 Hz, H-8a), 3.70
(dd, 1H, J = 9.5, 5.8 Hz, H-8b), 3.31–3.22 (m, 2H, H-2, H-7a),
2.61 (dd, 1H, J = 14.0, 4.6 Hz, H-7b), 1.99 (s, 3H, CH3); 13C
NMR (CDCl3, 100 MHz): 170.35 (CvO), 140.05, 138.97, 138.90,
138.86, 138.75 (5 × Cipso), 128.68–127.11 (25 aromatic C), 82.97
(C-3), 79.56 (C-4), 78.81 (C-5), 74.23, 73.78, 73.39, 73.05 (4 ×
CH2Ph), 72.30 (C-6), 69.25 (C-8), 64.26 (C-2), 61.23 (NCH2Ph),
46.39 (C-7), 21.24 (CH3); ESI-HRMS: calcd for C44H48NO6
[M + H]+: 686.3476, found 686.3482.
Major acetylated compound. Rf 0.47, Cy–EtOAc, 4 : 1; [α]D +19
(c = 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz): 7.37–7.10 (m,
25H, 5 × Ph), 5.83 (s, 1H, H-5), 4.78–4.66 (ddd, 3H, J = 11.4,
11.2, 10.8 Hz, 3 × CHPh), 4.78–4.66 (4d, 4H, J = 12.3, 11.8, 10.9
Hz, 4 × CHPh), 4.19 (d, 1H, J = 12.0 Hz, CHPh), 4.01 (dd, 1H,
J = 8.8, 1.1 Hz, H-6), 3.92–3.80 (m, 3H, NCH2Ph, H-4),
3.75–3.65 (m, 2H, H-8a, H-8b), 3.13–3.11 (m, 3H, H-7a, H-3,
1
0.25, Cy–EtOAc, 4 : 1; [α]D +3 (c = 0.5, CHCl3); H NMR (CDCl3,
400 MHz): 7.40–7.10 (m, 25H, 5 × Ph), 4.68–4.37 (m, 7H,
CH2Ph), 4.29 (d, 1H, J = 12.1 Hz, CH2Ph), 4.15–4.04 (m, 4H,
H-3, H-4, NCH2Ph), 3.96 (dd, 1H, J = 11.4, 5.4 Hz, H-1′a), 3.78
(dd, 1H, J = 9.4, 5.5 Hz, H-2′), 3.70 (d, 1H, OH), 3.63 (dd, 1H,
J = 11.3, 3.7 Hz, H-1′b), 3.46 (t, 1H, J = 5.8 Hz, H-5), 3.39 (t, 1H,
J = 9.1 Hz, H-6′a) 3.14 (ddd, 1H, J = 7.5, 5.3, 1.8 Hz, H-2), 3.05
(dd, 1H,
J =
9.1, 5.4 Hz, H-6′b); 13C NMR (CDCl3,
100 MHz): 138.97, 138.52, 138.52, 138.44, 137.81 (5 × Cipso),
129.62–127.34 (25 aromatic C), 83.30 (C-4), 82.46 (C-3), 78.60
(C-2′), 72.84, 72.25, 72.16, 71.84 (4 × CH2Ph), 71.21 (C-6), 68.17
(C-2), 66.87 (C-5), 62.40 (C-1′), 61.53 (NCH2Ph); ESI-MS (m/z):
3454 | Org. Biomol. Chem., 2015, 13, 3446–3456
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644 (M+ + H). ESI-HRMS calcd for C42H46NO5 [M + H]+:
644.3370, found 644.3369.
S. G. Withers and N. C. J. Strynadka, Angew. Chem., Int. Ed.,
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(2S,3R,4R,5R)-2-((S)-1,2-Dihydroxyethyl)-5-(hydroxymethyl)-
pyrrolidine-3,4-diol 4. To a solution of pyrrolidine 24 (21 mg,
0.033 mmol) in MeOH (2 mL) and 1 M aq. HCl (50 μL) was
added 10% Pd/C (20 mg). The suspension was stirred under a
H2 atmosphere for 4 h at r.t., filtered through a Celite plug
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400 MHz): 4.09–4.13 (m, 2H), 4.04–3.99 (m, 1H), 3.91 (dd, 1H,
J = 11.7, 5.5 Hz), 3.85 (dd, 2H, J = 11.4, 8.9 Hz), 3.78 (dd, 1H,
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4.2 Hz), 3.49 (m, 1H); 13C NMR (CD3OD, 100 MHz): 78.23,
76.24, 69.62, 69.20, 65.94, 64.69, 61.35; ESI-MS (m/z): 194
(M+ + H). ESI-HRMS: calcd for C7H16O5N [M + H]+: 194.1023,
found 194.1024.
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Conclusions
We have demonstrated that, starting from easily available di-
hydroxyazepane precursors, a regioselective protection of the
hydroxyl group β to the nitrogen allows the orientation of the
ring isomerization of the seven-membered azacycle towards
highly substituted polyhydroxylated pyrrolidines developed as
homoDMDP epimers. Amongst them, the 6-epi-homoDMDP
proved to be a fairly good α-glucosidase inhibitor.
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Acknowledgements
Y. Jagadeesh, A. T. Tran and N. Auberger thank respectively
Dorphan and Sanfilippo foundation Switzerland for post-
doctoral fellowships.
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Notes and references
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