Highly stereoselective directed reactions and an efficient synthesis of azafuranoses from a chiral aziridine

Article abstract of DOI:10.1039/c3ob27390c

Polyhydroxylated pyrrolidines, such as biologically important azafuranoses represented by the natural product (+)-2,5-imino-2,5,6-trideoxy-gulo-heptitol and its C(3)-epimer, were elaborated from a commercially available enantiomerically pure (2R)-hydroxymethylaziridine by highly stereoselective directed reactions in more than 61% overall yield. At first, the nucleophile 2-trimethylsilyloxyfuran was directed to (2R)-aziridine-2-carboxaldehyde by ZnBr₂ to yield the unusual anti-addition product as a single isomer via the chelation-controlled transition. The ring opening of aziridine was followed by conjugate addition to give a cis-fused bicycle, which was converted to the target molecule after the required reductive operations. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob27390c

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ARTICLE TYPE
Highly Stereoselective Directed Reactions and an Efficient Synthesis of
Azafuranose from a Chiral Aziridine
Hogyu Lee,a Jun Hee Kim,a Won Koo Lee,*a Jaeheung Cho,b Wonwoo Nam,c Jaedeok Lee,d and
Hyun-Joon Ha*d
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Polyhydroxylated pyrrolidines, as biologically important azafuranose represented by the natural product
(+)-2,5-imino-2,5,6-trideoxy-gulo-heptitol and its C(3)-epimer, were elaborated from a commercially
available enantiomerically pure (2R)-hydroxymethylaziridine by highly stereoselective directed reactions
10 in more than 61% overall yield. At first, the nucleophile trimethylsilyloxyfuran was directed to (2R)-
aziridine-2-carboxaldehyde by ZnBr2 to yield the unusual anti-addition product as a single isomer rose
from the chelation-controlled transition. The ring-opening of aziridine was followed by conjugate
addition to give a cis-fused bicycle, which was converted to the target molecule after required reductive
operations.
15 Introduction
Syntheses and structural evaluations of azasugars have
attracted great attention due to their biological activities, such as
glycosidase and glycosyltransferase inhibitors in the sugar
metabolism.1
Recently,
(+)-2,5-imino-2,5,6-trideoxy-gulo-
20 heptitol (1) and its stereoisomers were isolated from Hyacinthus
orientalis, and they were found to show specific glycosidase-
inhibiting properties.2 An efficient and stereoselective synthesis
of aza-sugars3 is still needed to overcome the drawbacks of most
reported methods4 including the difficulties of obtaining starting
25 materials and the formation of unwanted diastereoisomers. Most
synthetic pathways required to introduce an hydroxyethyl side
chain or its equivalent whose stereoselectivity was poor.4 As part
of our chiral aziridine program, we succeeded in the asymmetric
synthesis of azapyranose sugar.5 This time, we would like to
30 develop highly efficient and stereoselective synthesis of
azafuranose, specifically, (+)-2,5-imino-2,5,6-trideoxy-gulo-
Scheme 1 Retrosynthetic analysis of (+)-2,5-imino-2,5,6-trideoxy-gulo-
heptitol
50
The target azafuranose, (+)-2,5-imino-2,5,6-trideoxy-gulo-
heptitol (1), includes a pyrrolidine ring, which could be
elaborated by the intramolecular conjugated addition of the amine
liberated from the aziridine ring-opening reaction of the synthetic
heptitol (1) and its C(3)epimer
2 through the highly
stereoselective directed reactions.
35 aDepartment of Chemistry, Sogang University, Seoul 121-742, Korea.
E-mail: wonkoo@sogang.ac.kr
55 intermediate 4 (Scheme 1). The compound 3, bearing all
necessary carbons, should be derived from the addition reaction
of 2-trimethylsilyloxyfuran to aziridine-2-carboxaldehyde. Other
than the stereochemistry at C5 of the pyrrolidine ring, all
stereocenters, including C2, C3, and C4, should be generated
60 from the reactions, including the addition of 2-
trimethylsilyloxyfuran to the aziridne-2-carboxaldehyde (3) and
the subsequent intramolecular conjugate addition of the amine to
the 2,5-didhydrofuran-2-one in the compound 4. Our previous
study6 encouraged us to apply the highly stereoselective directed
65 reactions. The stereochemistry of alcohol in the compound 4 will
[journal], [year], [vol], 00–00 | 1
bDepartment of Emerging Materials Science, DGIST, Daegu 711-873,
Korea
E-mail: jaeheung @dgist.ac.kr
40 cDepartment of Chemistry and Nano Science, Department of Bioinspired
Science, Ewha Womans University, Seoul 120-750, Korea
E-mail: wwnam@mm.ewha.ac.kr
dDepartment of Chemistry and Protein Research Center for Bio-Industry,
Hankuk University of Foreign Studies, Yongin 449-719, Korea
45 E-mail: hjha@hufs.ac.kr
† Electronic supplementary information (ESI) available. See DOI:
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be generated from the chelation-controlled addition of the 45 This stereochemical outcome clearly indicates that the
nucleophile whose alignment will guide the facial selectivity of
2-trimethylsilyloxyfuran to establish the configuration of a
lactone ring. The aziridine ring opening by an oxygen nucleophile
and the subsequent conjugate addition of the released amine to
,-unsaturated lactone ring yield the bicyclic adduct 5, with the
final C-N bond formation for the pyrrolidine ring. All necessary
carbons with proper stereochemistry in the compound 5 will
afford the targets after necessary reductive operations.
configurations of the secondary alcohol and its adjacent lactone
ring in the compound 4 are S and R, respectively.
5
10 Results and discussion
The starting material
(1S)-phenylethylaziridine-(2R)-
carboxaldehyde (3) was prepared from the commercially
available corresponding alcohol in 95% yield.7 The addition of 2-
trimethylsilyloxyfuran to the aldehyde 3 in the presence of ZnBr2
15 (1.5 eq) in THF at 0 oC provided the coupled product 4 as a single
isomer in 87% yield. The absolute configurations of the
secondary alcohol in 4 can be predicted based on our previously
known metal-catalyzed addition reaction of 2-acyl- and 2-
iminoaziridines with chelation-controlled transition states.8
20 However, the absolute configuration of the lactone site was not
clear at this stage. Therefore, we proceeded with regioselective
aziridine ring-opening reaction using trifluoroacetic acid in
H2O:THF (4:1) to obtain the bicyclic compound 5 in 95% yield.9
The product 5 bearing the [5,5’]-fused ring system was generated
25 from the intramolecular cyclization of the amine derived from the
aziridine ring-opening reaction to the ,-unsaturated lactone
ring. The stereochemistry of the newly formed C-N bond for the
ring was controlled only by the configuration of the lactone to
lead to [5,5’]-bicyclic compound (Scheme 2). Obtaining a good
30 crystalline derivative of this bicycle for X-ray analysis the two
hydroxyl groups were reacted with p-nitrobenzoyl chloride and
Et3N in CH2Cl2 to yield the corresponding ester 6 as a solid in 90%
yield.
Fig 1 ORTEP Drawing of the bicyclic compound 6
50
The addition of the nucleophile 2-trimethylsilyloxyfuran to the
aziridine-2-carboxaldehyde was directed by the chelation-
controlled transition state as expected. However, the
stereochemistry of the alcohol and the lactone ring had an
55 unusual anti-relationship. Most cases of vinylogous aldol
reactions10 with silyloxyfuran yield the syn-adduct with “Diels-
Alder-like” orientation of the two reactants in the s-trans
conformation.11 This unusual anti-relationship can possibly be
explained by the formation of the pre-associated chelation-
60 controlled transition state between aziridine and aldehyde
(Scheme 3). Once this was generated the transition state A
leading to the unusual anti-adduct 4 is more favourable to avoid
the non-bonding interaction between the 2-phenylethyl group and
the silicon substituent rather than the “Diels-Alder-like”
65 transition state B.
35 Scheme 2 Synthesis of the C(3) epimer of the natural product (+)-2,5-
imino-2,5,6-trideoxy-gulo-heptitol. Reagents and conditions: (i) ZnBr2
(1.5 eq.), THF (0.1 M; (ii) TFA (5 eq.), H2O:THF (4:1); (iii) BH3·SMe2 (4 eq.)
THF; (iv) H2 (1 atm), Pd(OH)2, MeOH (0.1 M).
40 The compound 6 was purified by recrystallization and we
obtained X-ray crystalline structure (Figure 1) to confirm the
absolute configurations of the consecutive four carbon centres.
The crystalline structure clearly shows cis-fused [5,5’]-bicycle
with the configuration at carbon centres as 2R, 3S, 4R and 5S.
Scheme 3 Possible transition structures of the addition of 2-
trimethylsilyloxyfuran to aziridine-2-carboxaldehyde
70
2
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The next operation was the aziridine ring opening12 by the
addition of the amine released from the ring-opening reaction of
aziridine.
oxygen nucleophile to release the amine which is ready to react
with the -position of the ,-unsaturated lactone via conjugate
addition.13 The stereochemical pathway of this conjugate addition
was pre-determined by the configuration of the lactone to lead
cis-fused [5,5’]-bicyclic compound 5 without any other choice.
The whole sequence of the reactions was directed as one by one,
i.e. the first chelation-controlled transition of the nucleophilic
addition in aziridine-2-carboxaldehyde directed the facial
Experimental
5
55 General experimental procedures
All reactions were carried out under an atmosphere of nitrogen in
oven-dried glassware with magnetic stirring. Air sensitive
reagents and solutions were transferred via syringe and were
introduced to the apparatus through rubber septa. Tetrahydrofuran
10 selectivity of the silyloxyfuran ring and then this adduct lead the
stereochemical pathway of the conjugate addition.14 After 60 (THF)
was
distilled
from
sodium/benzophenone.
establishment of the absolute configuration, the lactone moiety of
5 was reduced with BH3·SMe2 in THF to the corresponding
tetraol 7 in 79% yield and the following hydrgenolytic cleavage
15 of the N-benzyl group provided the C(3)-epimer 2 of the natural
Dichloromethane was distilled from calcium hydride. MeOH was
commercial grade reagents (99.9 % assay) and used without
further purification. Reactions were monitored by thin layer
chromatography (TLC) with 0.25 mm E. Merck pre-coated silica
product 1 in quantitative yield (Scheme 2). We also synthesized 65 gel plates (60 F254). Visualization was accomplished with either
the enantiomer of 2 (ent-2) starting from the enantiomer of
starting material, (1R)-phenylethylaziridine-(2S)-carboxaldehyde.
The target natural product, (+)-2,5-imino-2,5,6-trideoxy-gulo-
20 heptitol (1), has 3R configuration of the hydroxide which is
UV light, or by immersion in solutions of ninhydrin, p-
anisaldehyde, or phosphomolybdic acid (PMA) followed by
heating on a hot plate for about 10 sec. Purification of reaction
products was carried out by flash chromatography using
1
opposite stereochemistry in the initial adduct 4. We succeeded the 70 Kieselgel 60 Art 9385 (230-400 mesh). H-NMR and 13C-NMR
synthesis of the natural product involving the inversion of the
hydroxy configuration by the Mitsunobu reaction (Scheme 4).
spectra were obtained using a Varian Vnmr-400 (400 MHz for 1H,
1
and 100 MHz for 13C), or a Varian Inova-500 (500 MHz for H,
and 125 MHz for 13C) spectrometer. Chemical shifts are reported
1
relative to chloroform (δ = 7.26) for H NMR and chloroform (δ
75 = 77.2) for 13C NMR. Data are reported as (br = broad, s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet.) Coupling
constants are given in Hz. Ambiguous assignments were resolved
on the basis of standard one dimensional proton decoupling
experiments. Optical rotations were determined at 589 nm at
25 Scheme 4 Synthesis of the natural product (+)-2,5-imino-2,5,6-trideoxy-
gulo-heptitol. Reagents and conditions: (i) AcOH (5 eq.), CH2Cl2; (ii) 1)
PPh3 (2 eq.) PNBA (2 eq.) DIAD (2 eq.), Toluene, RT to 100 °C, (iii) BH3·
SMe2 (15 eq.), THF; (iv) H2 (1 atm), Pd(OH)2, MeOH (0.1M).
80 26C. Data are reported as follows: , concentration (c in
g/100 mL), and solvent. Elemental analyses were performed
using a Carlo Erba EA 1180 elemental analyzer. High resolution
mass spectra were recorded on a 4.7 Tesla IonSpec ESI-FOFMS
and JEOL (JMS-700). All commercially available compounds
85 were used as received unless stated otherwise.
30 For the convenience of the Mitsunobu reaction to invert the
configuration of C3 of the bicycle we performed regioselective
aziridine ring-opening reaction12 of 4 with AcOH (5 eq.) in
CH2Cl2 instead of H2O to provide the fused lactone 8 in
quantitative yield.15 The reaction of 8 with Ph3P (2 eq.) and p-
35 nitrobenzoic acid (PNBA, 2 eq.) in the presence of DIAD (2 eq.)
in toluene at 100 oC provided an inversion product16 as the
benzoate which was reduced in the aforementioned method with
BH3·SMe2 in THF (15 eq.) at 50 oC to result in the tetraol 9 in 78%
yield. The reductive cleavage of the N-benzyl group by catalytic
40 hydrogenation with Pd(OH)2 ·C in MeOH produced the target
molecule 1 as a free base in 99% yield. The enantiomer of the
target molecule (ent-1) was also prepared from the (1R)-
phenylethylaziridine-(2S)-carboxaldehyde.
(R)-5-((S)-hydroxy((R)-1-((S)-1-phenylethyl)aziridin-2-
yl)methyl)furan-2(5H)-one (4)
To a solution of zinc bromide (1427 mg, 6.34 mmol) in 35.0 mL
in THF of under nitrogen atmosphere at 0 °C was added 2-
90 (trimethylsilyloxy)furan (0.93 mL, 5.50 mmol). The mixture was
stirred for 10 min and then treated with (R)-1-((S)-1-
phenylethyl)aziridine-2-carbaldehyde 3 (740 mg, 4.23 mmol) in
7.0 mL of THF via cannula at 0 °C. The mixture was stirred for 1
h 30 min at 0 °C and then treated with sat’d sodium bicarbonate
95 solution. The organic layer was separated, and the aqueous layer
was extracted with EtOAc (40.0 mL 4). The combined extracts
were dried over anhydrous magnesium sulfate and filtered. The
solvent was removed and purification by silica gel flash
chromatography (EtOAc:hexane, 50:50) gave 4 in 952 mg (87 %)
Conclusions
100 yield as yellow solid: (4) = -17.6 (c = 1.00, in CHCl3), (ent-
o
1
4) = +19.4 (c = 1.20, in CHCl3); mp 115-117 C; H NMR
45
In conclusion we successfully synthesized the natural product
(400 MHz, CDCl3): δ 7.36-7.26 (m, 5H, arom. H), 7.30-7.24 (m,
1H, C5), 6.01 (m, 1H, C6), 3.87 (dd, J1 = 8.4 Hz, J2 = 1.6 Hz, 1H,
C3), 3.23 (t, J = 7.6 Hz, 1H, C4), 2.87 (d, J = 7.2, 1H, C2), 2.68
105 (q, 1H, -CHCH3), 2.08 (m, 1H, C2), 1.97 (dd, J1 = 6.4 Hz, J2 =
0.8 Hz, 1H, C1), 1.65 (dd, J1 = 6.4 Hz, J2 = 0.4 Hz, 1H, C1), 1.48
(dd, J1 = 6.4 Hz, J2 = 0.8 Hz, 3H, -CHCH3). 13C NMR (100 MHz,
(+)-2,5-imino-2,5,6-trideoxy-gulo-heptitol and its C(3)-epimer
from
an
enantiomerically
pure
commercial
(2R)-
hydroxymethylaziridine by the highly stereoselective directed
reactions in more than 61% overall yield. The key steps include
50 the nucleophilic anti-addition of 2-trimethylsilyloxyfuran to (2R)-
aziridine-2-carboxaldehyde with ZnBr2, and the conjugate
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CDCl3): δ 182.9, 155.7, 143.6, 128.7, 127.9, 127.1, 121.7, 84.8,
mixture was stirred for 4 h at room temperature, and then treated
69.4, 68.6, 38.3, 30.5, 21.9; Anal. Calcd for C15H17NO3: C, 69.48; 60 with MeOH slowly. The solvent was removed and purification by
H, 6.61; N, 5.40. Found: C, 69.42; H, 6.68; N, 5.35.
silica gel flash chromatography (MeOH:EtOAc, 20:80) gave 7 in
(3aS,5R,6S,6aR)-6-hydroxy-5-(hydroxymethyl)-4-((S)-1-
phenylethyl)hexahydro-2H-furo[3,2-b]pyrrol-2-one (5).
To a solution of 4 (276 mg, 1.07 mmol) in 2.10 mL of H2O and
34 mg (79 %) yield as yellow liquid: (7) = +28.4 (c = 2.00,
1
5
in CHCl3), (ent-7) = -27.1 (c = 4.81, in CHCl3); H NMR
(400 MHz, CDCl3): δ 7.36-7.18 (m, 5H, arom. H), 4.21 (m, 1H),
8.50 mL of THF was added trifluoroacetic acid (0.41 mL, 1.13 65 4.12 (q, 1H), 4.03 (m, 1H), 3.82 (m, 2H, C1 or C7), 3.39 (d, J =
mmol). The mixture was stirred for 15 h, and then treated with
NaHCO3 saturated solution. The organic layer was separated, and
10 the aqueous layer was extracted with EtOAc (5.0 mL 4). The
10.8 Hz, 1H), 3.25 (m, 2H, C1 or C7), 2.45 (dd, J1 = 9.6 Hz, J2 =
4.0 Hz, 1H), 2.01 (m, 2H, C6), 1.41 (d, J = 7.2 Hz). 13C NMR
(100 MHz, CDCl3): δ 143.1, 128.4, 127.7, 127.3, 72.4, 72.3, 61.1,
60.0, 59.4, 58.8, 56.0, 32.0, 11.4; HRMS m/z calcd for
combined extracts were dried over anhydrous magnesium sulfate
and filtered. The solvent was concentrated and purification by 70 C15H23NO4: [M+Na]+304.1519 Found 304.1530.
silica gel flash chromatography (EtOAc:hexane, 70:30) gave 5 in
(2S,3R,4S,5R)-2-(2-hydroxyethyl)-5-
(hydroxymethyl)pyrrolidine-3,4-diol (2).
To a solution of 7 (27 mg, 0.096 mmol) in 1.40 mL of MeOH
was added palladium hydroxide on carbon (2.7 mg, 10 wt %).
278 mg (95 %) yield as yellow liquid: (5) = -4.0 (c = 1.56,
1
15 in CHCl3), (ent-5) = +3.7 (c = 1.13, in CHCl3); H NMR
(400 MHz, CDCl3): δ 7.40-7.34 (m, 2H, arom. H), 7.33-7.29 (m,
1H, arom. H), 7.28-7.24 (m, 3H, arom. H), 4.70 (dd, J1 = 6.8 Hz, 75 The resultant mixture was stirred for 7 h under at atmospheric
J2 = 5.2 Hz, 1H, C4), 4.37 (q, J = 6.4 Hz, 1H, C3), 4.00 (q, J =
6.8 Hz, 1H, -CHCH3), 3.88 (td, J1 = 7.2 Hz, J2 = 4.0 Hz, 1H, C5),
20 3.54-3.52 (m, 2H, C1), 3.22 (m, 1H, C2), 3.04 (d, J = 7.2 Hz, 1H,
-OH), 2.69 (dd, J1 = 17.6 Hz, J2 = 6.8 Hz, 1H, C6), 2.60 (dd, J1 =
pressure of H2. The mixture was filtered and the filtrate was
concentrated under vacuo to provide 2 in 17 mg (99 %) yield as
yellow liquid: (2) = +17.2 (c = 0.50, in MeOH), (ent-2)
1
= -18.4 (c = 0.63, in MeOH); H NMR (400 MHz, D2O): δ
17.6 Hz, J2 = 4.0 Hz, 1H, C6), 2.34 (dd, J1 = 7.6 Hz, J2 = 4.8 Hz, 80 4.38 (dd, J1 = 7.2 Hz, J2 = 4.8 Hz, 1H, C3), 4.11 (t, 1H, C4), 3.75
1H, -OH), 1.49 (d, J = 7.2 Hz, 3H, -CHCH3). 13C NMR (100
MHz, CDCl3): δ 176.9, 141.0, 128.6, 127.8, 127.7, 82.1, 73.0,
25 62.7, 60.8, 57.9, 57.6, 38.7, 18.8; HRMS m/z calcd for
C15H19NO4: [M+Na]+300.1206 Found 300.1210.
((3aS,5R,6S,6aR)-6-((4-nitrobenzoyl)oxy)-2-oxo-4-((S)-1-
phenylethyl)hexahydro-2H-furo[3,2-b]pyrrol-5-yl)methyl 4-
nitrobenzoate (6).
(dd, J1 = 11.6 Hz, J2 = 4.8 Hz, 1H, C1 or C7), 3.70-3.62 (m, 3H,
C1 and C7), 3.33 (q, J = 6.4 Hz, 1H, C2), 3.17 (dd, J1 = 11.6 Hz,
J2 = 7.2 Hz, 1H, C5), 1.95-1.85 (m, 1H, C6), 1.76 (m, J = 6.8 Hz,
1H, C6). 13C NMR (100 MHz, D2O): δ 71.83, 71.79, 71.67, 59.77,
85 59.04, 56.47, 30.61; HRMS m/z calcd for C7H15NO4:
[M+Na]+200.0899 Found 200.0893.
((3aS,5R,6S,6aR)-6-hydroxy-2-oxo-4-((S)-1-
30 To a solution of 5 (66 mg, 0.238 mmol) in 2.40 mL of
dichloromethane under nitrogen atmosphere at 0 °C was added p-
phenylethyl)hexahydro-2H-furo[3,2-b]pyrrol-5-yl)methyl
acetate (8).
nitrobenzoyl chloride (132 mg, 0.714 mmol), and triethylamine 90 To a solution of 4 (762 mg, 2.94 mmol) in 29.0 mL of
(0.10 mL, 0.729 mmol). The mixture was warmed to room
temperature and stirred for 4 h, and then treated with ammonium
35 chloride saturated solution. The organic layer was separated, and
the aqueous layer was extracted with dichloromethane (5.0 mL
dichloromethane under nitrogen atmosphere at room temperature
was added acetic acid (14.7 mmol, 0.28 mL). The mixture was
stirred for 15 h at room temperature, and then treated with sat’d
sodium bicarbonate solution. The organic layer was separated,
4). The combined extracts were dried over anhydrous magnesium 95 and the aqueous layer was extracted with dichloromethane (5.0
sulfate and filtered. The solvent was concentrated and
purification by silica gel flash chromatography
mL 4). The combined extracts were dried over anhydrous
magnesium sulfate and filtered. The solvent was removed and
40 (dichloromethane:EtOAc, 50:1) gave 6 in 124 mg (90 %) yield as
purification by silica gel flash chromatography (EtOAc:hexane,
yellow solid: (6) = -140.1 (c = 2.15, in CHCl3), (ent-6)
50:50) gave 8 in 938 mg (100 %) yield as yellow solid: (8)
o
1
= +135.4 (c = 1.13, in CHCl3); mp 79-80 C; H NMR (400 100 = -22.0 (c = 6.63, in CHCl3), (ent-8) = +22.8 (c = 2.44, in
1
MHz, CDCl3): δ 8.26-8.12 (m, 6H, arom. H), 8.04-7.98 (m, 2H,
CHCl3); mp 112-114 °C; H NMR (400 MHz, CDCl3): δ 7.38-
7.25 (m, 5H, arom. H), 4.64 (dd, J1 = 7.6 Hz, J2 = 5.2 Hz, 1H,
C4), 4.25 (m, 3H, C1 and C3), 4.01 (q, J = 3.4 Hz, 1H, -CHCH3),
3.85 (dt, J1 = 12 Hz, J2 = 7.2 Hz, 1H, C5), 3.28 (dd, J1 = 10.8 Hz,
arom. H), 7.42-7.28 (m, 5H, arom. H), 5.56 (dd, J1 = 6.8 Hz, J2 =
45 5.2 Hz, 1H, C4), 4.97 (dd, J1 = 6.4 Hz, J2 = 5.2 Hz, 1H, C3),
4.52-4.38 (m, 2H, C1), 4.11 (q, 1H, -CHCH3), 4.01 (td, J1 = 6.8
Hz, J2 = 7.2 Hz, 1H, C5), 3.89 (m, 1H, C2), 2.70 (dd, J1 = 18.4 105 J2 = 6.0 Hz, 1H, C2), 2.59 (m, 2H, C6), 2.08 (s, 3H, -OCOCH3),
Hz, J2 = 7.2 Hz, 1H, C6), 2.60 (dd, J1 = 18.0 Hz, J2 = 2.8 Hz, 1H,
C6), 1.57 (d, J = 6.8 Hz, 3H, -CHCH3). 13C NMR (100 MHz,
50 CDCl3): δ 175.5, 164.1, 163.7, 150.8, 150.5, 140.5, 134.8, 134.1,
130.9, 130.6, 128.8, 128.2, 127.7, 123.7, 123.5, 80.7, 73.0, 59.7,
1.47 (d, J = 7.2 Hz, 3H, -CHCH3). 13C NMR (100 MHz, CDCl3):
δ 176.7, 171.322, 140.6, 128.5, 127.8, 127.7, 81.6, 71.3, 62.7,
61.8, 58.414, 57.139, 38.8, 21.0, 19.5; Anal. Calcd for
C17H21NO5: C, 63.94; H, 6.63; N, 4.39. Found: C, 63.97; H, 6.60;
58.1, 38.8, 19.4, 14.2; Anal. Calcd for C29H25N3O10: C, 60.52; H, 110 N, 4.40.
4.38; N, 7.30. Found: C, 60.56; H, 4.51; N, 7.44.
(2S,3R,4S,5R)-2-(2-hydroxyethyl)-5-(hydroxymethyl)-1-((S)-1-
55 phenylethyl)pyrrolidine-3,4-diol (7).
(2S,3R,4R,5R)-2-(2-hydroxyethyl)-5-(hydroxymethyl)-1-((S)-
1-phenylethyl)pyrrolidine-3,4-diol (9).
To a solution of 8 (92 mg, 0.288 mmol) in 2.90 mL of toluene
under nitrogen atmosphere at room temperature was added
To a solution of 5 (42 mg, 0.152 mmol) in 0.51 mL of THF under
nitrogen atmosphere at room temperature was added borane 115 triphenylphosphine (151 mg, 0.576 mmol), diisopropyl
dimethyl sulfide complex (0.30 mL, 2.00 M) in THF. The
azodicarboxylate (DIAD) (0.11 mL, 0.576 mmol), and p-
4
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Organic & Biomolecular Chemistry
Kizu, Y. Kameda, A. A. Watson, R. J. Nash, G. W. J. Fleet
and N. Asano, J. Nat. Prod., 2002, 65, 1875. (d) N. Asano, R.
J. Nash, R. J. Molyneux and G. W. Fleet, Tetrahedron:
Asymmetry, 2000, 11, 1645.
nitrobenzoic acid (96 mg, 0.576 mmol). The mixture was stirred
60
65
for 5 h at 100 °C and cooled to room temperature, and then
treated with water. The organic layer was separated, and the
aqueous layer was extracted with EtOAc (5.0 mL 4). The
combined extracts were dried over anhydrous magnesium sulfate
and filtered. The solvent was concentrated and purification by
silica gel flash chromatography (EtOAc:hexane, 30:70) gave the
corresponding p-nitrobenzoate product. To the benzoate was
added borane dimethyl sulfide complex in THF (2.20 mL, 2.00 M)
3
4
(a) N. Asano, R. J. Nash, R. J. Molyneux and G. W. Fleet,
Tetrahedron: Asymmetry, 2000, 11, 1645. (b) J.-B. Behr and
G. Guillerm, Tetrahedron: Asymmetry, 2002, 13, 111.
(a) J.-B. Behr, M. S. M. Pearson, C. Bello, P. Vogel and R.
Plantier-Royon, Tetrahedron: Asymmetry, 2008, 19, 1829. (b)
M. Kummeter and U. Kazmaier, Eur. J. Org. Chem., 2003, 17,
3330. (c) Y. Chikawa, Y. Igarashi, M. Ichikawa and Y.
Suhara, J. Am. Chem. Soc., 1998, 120, 3007. (d) A. Guaragna,
S. D’Errico, D. D’Alonzo, S. Pedatella and G. Palumbo, Org.
Lett., 2007, 9, 3473.
A. Singh, B. C. Kim, W. K. Lee and H.-J. Ha, Org. Biomol.
Chem., 2011, 9, 1372.
(a) H. J. Yoon, Y.-W. Kim, B. K. Lee, W. K. Lee, Y. Kim and
H.-J. Ha, Chem. Commun., 2007, 1, 79. (b) H. G. Choi, J. H.
Kwon, J. C. Kim, W. K. Lee, H. Eum and H.-J. Ha,
Tetrahedron Lett., 2010, 51, 3284.
5
70
10 under nitrogen atmosphere at room temperature. The mixture was
stirred for 4 h at 50 °C, and then treated with MeOH slowly. The
organic layer was concentrated and purification by silica gel flash
5
6
chromatography (MeOH:EtOAc, 20:80) gave 9 in 63 mg (78 %)
yield as yellow liquid: (9) = +11.0 (c = 3.67, in CHCl3),
75
1
15 (ent-9) = -11.6 (c = 1.03, in CHCl3); H NMR (400 MHz,
CDCl3): δ 7.36-7.28 (m, 4H), 7.28-7.24 (m, 1H), 4.50 (s, 4H),
4.02 (q, J = 6.4 Hz, 1H), 3.97 (m, 1H), 3.81 (t, J = 6.0, 1H), 3.72
(m, 1H), 3.63 (m, 1H), 3.33 (m, 2H), 2.95 (m, 2H), 1.84 (m, 1H),
1.70 (m, 1H), 1.44 (d, J = 6.4, 3H). 13C NMR (100 MHz, CDCl3):
20 δ 142.6, 128.5, 127.8, 127.5, 77.6, 76.1, 64.1, 61.3, 60.0, 58.2,
32.4, 14.8; HRMS m/z calcd for C15H23NO4: [M+H]+ 282.1700,
Found 282.1700.
7
8
W. K. Lee and H.-J. Ha, Aldrichimica Acta, 2003, 36, 57.
(a) J. M. Yun, T. B. Sim, H. S. Hahm, W. K. Lee and H.-J. Ha,
J. Org. Chem., 2003, 68, 7675. (b) M.-J. Suh, S. W. Kim, S. I.
Beak, H.-J. Ha and W.-K. Lee, Synlett., 2004, 3, 489.
F. A. Davis and G. V. Reddy, Tetrahedron Lett., 1996, 37,
4349.
80
9
85
10 For reviews, see. (a) G. Casiraghi, L. Battistini, C. Curti, G.
Rassu, and F. Zanardi, Chem. Rev., 2011, 111, 3076. (b) G.
Casiraghi, F. Zanardi, G. Appendino and G. Rassu, Chem.
Rev., 2000, 100, 1929.
11 (a) R. K. Boeckman Jr., J. E. Pero and D. J. Boehmler, J. Am.
Chem. Soc., 2006, 128, 11032. (b) M. Frings, I. Atodiresei, J.
Runsink, G. Raabe and C. Bolm, Chem. Eur. J., 2009, 15,
1566. (c) D. A. Evans, C. S. Burgey, M. C. Kozlowski and S.
W. Tregay, J. Am. Chem. Soc., 1999, 121, 686. (d) M. De
Rosa, L. Citro and A. Soriente, Tetrahedron Lett., 2006, 47,
8507.
12 S. Stankovic, M. D’hooghe, S. Catak, H. Eum, M. Waroquier,
V. Van Speybroeck, N. De Kimpe, and H.-J. Ha, Chem. Soc.
Rev., 2012, 41, 643.
13 D.-H. Yoon, H.-J. Ha, B. C. Kim and W. K. Lee, Tetrahedron
Lett., 2010, 51, 2181.
14 The term “directed reaction” generally is used to explain that
a certain major product favors among a number of possible
products by certain functional groups in the starting material
through the transient interaction of a substrate functional
group with the incoming reagent. For reviews, see. (a) A. H.
Hoveyda, D. A. Evans and G. C. Fu, Chem. Rev., 1993, 93,
1307. (b) B. Breit and Y. Schmidt, Chem. Rev., 2008, 108,
2928.
15 (a) C. S. Park, H. G. Choi, H. Lee, W. K. Lee and H.-J. Ha,
Tetrahedron: Asymmetry, 2000, 11, 3283. (b) H.-J. Ha, M. C.
Hong, S. W. Ko, Y. W. Kim, W. K. Lee and J. Park, Bioorg.
Med. Chem. Lett., 2006, 16, 1880.
2,5-Imino-2,5,6-trideoxy-L-gulo-heptitol (1).
To a solution of 9 (23 mg, 0.082 mmol) in 1.20 mL of MeOH
25 was added palladium hydroxide on carbon (2.3 mg, 10 wt %).
The mixture was stirred for 7 h under at atmospheric pressure of
90
H2. The mixture was filtered and concentrated under vacuo to
give 1 in 14 mg (99 %) yield as yellow liquid: (1) = +20.8
(c = 0.19, in MeOH), (ent-1) = -21.5 (c = 0.69, in MeOH);
30 1H NMR (400 MHz, D2O): δ 3.95 (m, 1H), 3.85 (m, 1H), 3.74-
3.60 (m, 4H), 3.20 (q, J = 7.6 Hz, 1H), 2.93 (q, J = 6.0 Hz, 1H),
1.89-1.76 (m, 1H), 1.75-1.65 (m, 1H). 13C NMR (100 MHz, D2O):
δ 76.0, 75.5, 67.4, 60.2, 59.7, 58.3, 27.7; HRMS m/z calcd for
C7H15NO4: [M+H]+178.1074, Found 178.1082.
95
100
105
110
115
35 Acknowledgements
The authors are grateful for the financial support from the
National Research Foundation of Korea (NRF-2010-0005538 and
NRF-2009-0081956 for W.K.L. and NRF-2010-0008424 and
KRF-2011-0012379 for H.J.H).
40
Notes and references
1
(a) G. Legler, in Iminosugars as Glycosidase Inhibitors, eds.
A. E. Stütz, Wiley-VCH, Inc., New York, 1998, ch. 3, pp. 31-
67. (b) N. Asano, in Iminosugars, eds. P. Compain and O. R.
Martin, John Wiley and Sons, Inc., New York, 2007, Chap 1,
pp. 7-24. (c) N. Asano, in Modern Alkaloids, eds. E.
Fattorusso and O. Taglialatela-Scafati, Wiley-VCH, inc.,
Weinheim, 2008, ch. 5, pp. 111-138. (d) I. Robina, A. J.
Moreno-Vargas, A.-T. Carmona abd P. Vogel, Curr. Drug
Metabol., 2004, 5, 329. (e) M. S. M. Pearson, M. Mathĕ-
Allainment, V. Fargeas and J. Lebreton, Eur. J. Org. Chem.,
2005, 11, 2159.
16 K. Hagiya, N. Muramoto, T. Misaki and T. Sugimura,
Tetrahedron, 2009, 65, 6109.
45
50
55
2
(a) N. Asano, K. Yasuda, H. Kizu, A. Kato, J.-Q. Fan, R. J.
Nash, G. W. J. Fleet and R. J. Molyneux, Eur. J. Biochem.,
2001, 268, 35. (b) X. Kato, I. Adachi, M. Miyauchi, K. Ikeda,
T. Komae, H. Kizu, Y. Kameda, A. A. Watson, R. J. Nash, M.
R. Wormald, G. W. J. Fleet and N. Asano, Carbohydrate
Research, 1999, 316, 95. (c) T. Yamashita, K. Yasuda, H.
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