Efficient and Easy Access to Optically Pure Tetrasubstituted Tetrahydrofurans via Stereoselective Opening of C2-Symmetric Epoxide and Aziridine Rings

Article abstract of DOI:10.1002/ejoc.201501540

An efficient and facile protocol to functionalize position C-3 of 2,5-anhydro-D-mannitol via diastereoselective ring opening of a C₂-symmetric epoxide 2,5:3,4-dianhydro-D-allitol 3 has been developed. This method is protecting-group-free, high-

Full text of DOI:10.1002/ejoc.201501540

DOI: 10.1002/ejoc.201501540
Full Paper
Homochiral Tetrahydrofurans
Efficient and Easy Access to Optically Pure Tetrasubstituted
Tetrahydrofurans via Stereoselective Opening of C2-Symmetric
Epoxide and Aziridine Rings
Venkata Pavan Kumar Kondapi,[a][‡] Olivier-Mohamad Soueidan,[a][‡]
Seyedeh Nargess Hosseini,[a] Nauras Jabari,[a] and Frederick G. West*[a]
Abstract: An efficient and facile protocol to functionalize posi- access to C-3- and C-4-modified 2,5-anhydro-
-mannitols 19–
D
tion C-3 of 2,5-anhydro-
opening of a C2-symmetric epoxide 2,5:3,4-dianhydro-
has been developed. This method is protecting-group-free,
high-yielding, and provides access to C-3-modified 2,5-anhydro-
D
-mannitol via diastereoselective ring
-allitol 3
27 in excellent global yields and moderate to good diastereose-
lectivities. These structures and their derivatives are potentially
useful in a variety of applications, including organocatalysis of
asymmetric Michael additions as demonstrated with diamine
monosulfonamides 28a and 28b, which provide adducts with
complementary enantioselectivity.
D
D
-mannitols 5a, 11a–15a and 16–17. This method was then
extrapolated to the synthesis of a C2-symmetric aziridine, which
underwent ring opening with various nucleophiles to provide
Introduction
GLUT5, and as an asymmetric ligand in homogeneous cataly-
sis.[9,13,14]
Substituted tetrahydrofurans (THFs), often with multiple stereo-
genic centers, are commonly encountered as structural core
units in various natural products, such as annonaceous aceto-
genins,[1] macrolides,[2] and marine toxins.[3] They are also found
in various unnatural products displaying a broad spectrum of
biological activities.[4] Moreover, they have been widely used in
the synthesis of modified nucleosides, some of which are highly
effective antiviral agents.[5] The diverse and important biologi-
cal activities associated with this structural motif has inspired
considerable interest in the development of efficient methods
to synthesize optically pure, highly functionalized THFs. A num-
ber of synthetic approaches to substituted THFs have been re-
ported, along with their application to natural product targets
containing these structures.[6] However, most were concerned
with the construction of 2,5-disubstituted and 2,3,5-trisubsti-
tuted THFs,[6a,7] while relatively few focused on the synthesis
of tetrasubstituted THFs.[8] Many strategies are limited to the
formation of alkyl- or aryl-substituted THF derivatives, and are
incompatible with the presence of biologically or catalytically
useful heteroatom functionality. One conspicuous example is
the readily available tetrasubstituted THF derivative with all
Hexose sugars are transported from extracellular space to
intracellular space by hexose transporters, which are also
known as GLUTs (SLC2A family).[10] One of the
D
-fructose trans-
porters, GLUT5, was found to be overexpressed in human breast
cancer cells compared to normal breast cells.[11] 2,5-Anhydro-
mannitol 1 is a structural surrogate for ꢀ- -fructofuranose (Fig-
ure 1, 2) and inhibits -fructose transport into cells expressing
GLUT5 (ki ≈ 12–15 m
).[9] 2,5-AM derivatives are also known to
D
-
D
D
M
undergo enzymatic phosphorylation by both hexokinase and
fructokinase, which may allow development of tracers that are
metabolically trapped inside cells to provide diagnostic image
of cancer cells that overexpress GLUT5 (e.g. breast cancer and
prostate cancer).[12,13] On the other hand, 2,5-AM derivatives
that are functionalized with Lewis basic atoms or functionalities
were demonstrated as asymmetric ligands in homogeneous ca-
talysis to yield high asymmetric induction.[14,15]
substituents in a trans relationship, 2,5-anhydro-D-mannitol (2,5-
AM, 1), which can function as a substrate for the transporter
Figure 1. Representative structures of GLUT5 substrates.
Epoxides and aziridines are highly strained three membered
heterocyclic ring systems and have been extensively used as
versatile synthetic intermediates in organic synthesis.[16,17]
Upon ring opening of epoxides and aziridines, synthetically use-
ful vicinal heteroatom-alcohol and heteroatom-amine function-
alities can be accessed. The ꢀ-functionalized alcohols and
amines can undergo further functional group transformations
[a] Department of Chemistry, University of Alberta,
11227 Saskatchewan Drive, Edmonton, AB, Canada T6G 2G2, Canada
E-mail: frederick.west@ualberta.ca
http://www.chem.ualberta.ca/~fgwest/public_html/Home.html
[‡] Both authors contributed equally to this work and to manuscript
preparation.
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201501540.
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to provide access to numerous vicinal difunctionalities. Nucleo- termined by 19F NMR analysis) was obtained. These two dia-
philic ring opening of C2-symmetric epoxides 3, 6, 7 and 8 stereomers (5a and 5b) were inseparable by column chroma-
could provide quick access to C-3-modified 2,5-AM derivatives tography and an 83:17 diastereomeric ratio was judged unsuita-
(Scheme 1). However, this process produces two diastereomers; ble for in vitro evaluation of 3-FDAM 5a. Hence, we set out to
i) C-3-modified 2,5-anhydro-
produces A or B or C) ii) C-4-modified 2,5-anhydro-
D
-mannitol derivatives (C-3 attack improve the diasteromeric ratio. At this stage, we envisioned a
-iditol de- possible improvement of diastereoselectivity via protection of
D
rivatives (C-4 attack produces D or E or F). To date, there exists the hydroxymethyl groups at C-2 and C-5 positions of the epox-
only one report on ring opening of 7 (primary hydroxyl groups ide 3. To test the effect of protecting groups, we chose to use
were protected with trityl group) with adenine as a nucleophile azide rather than fluoride as the ring opening nucleophile,
to yield product B in moderate diastereoselectivity (80:20).[18] given its comparatively higher reactivity and the consequent
Further, upon nucleophilic ring opening, unprotected epoxide need for less extreme forcing conditions than are necessary
3 may provide direct access to protecting-group-free and C-3- with fluoride.
modified 2,5-AM derivatives A. However, this process also may
yield mixture of diastereomers A and D and the suppression of
formation of the 2,5-anhydro- -allitol derivative D could be a
D
potential challenge to overcome. Here we describe our results,
providing direct access to a variety of C-3-modified 2,5-AM de-
rivatives A, a tetrasubstituted THF derivative with all vicinal sub-
stituents in trans relationship to each other in excellent yields
and diastereoselectivities. This method was extrapolated to the
synthesis of C-3- and C-4-modified 2,5-AM derivatives via ring
opening of aziridine 4, a C2-symmetric compound, synthesized
from the azido-alcohol B obtained from the epoxide ring open-
ing of compound 8. To the best of our knowledge synthesis
of C-3- and C-4-modified 2,5-AM derivatives has never been
reported. We further demonstrated the potential usage of C-3-
and C-4-modified 2,5-AM derivatives by showcasing an asym-
metric Michael addition reaction, which was catalyzed by C-3-
and C-4-modified 2,5-AM derivative 28a and its diastereomer
28b to provide adduct 31 with complementary enantioselectiv-
ity.
Scheme 2. Fluorination of epoxide 3 under conventional conditions.
NH4Cl and CeCl3 are commonly used catalysts to perform
azidolysis of epoxide rings.[20] Upon ring opening of unpro-
tected epoxide 3, we obtained mixture of 3-azido-3-deoxy-2,5-
anhydro-
D
-mannitol (11a) and 3-azido-3-deoxy-2,5-anhydro-D-
iditol (11b) in 83 % yield with a diastereomer ratio of 80:20 in
favor of 11a (Table 1, entry 1). The 80:20 diastereomer ratio
obtained from the ring opening of unprotected epoxide 3 was
used as reference to study the directing ability of various pro-
tecting groups. Our investigation started with the benzyl pro-
tecting group, which is easy to install and can be removed by
simple hydrogenolysis. Epoxide 3 was treated with NaH in DMF
followed by benzyl bromide to yield 1,6-di-O-benzyl-2,5:3,4-di-
anhydro- -allitol 8 in quantitative yield. Nucleophilic ring open-
D
ing of epoxide 8 was carried out with azide to yield a mixture
of diastereomers 10a and 10b in a 70:30 ratio, (Table 1, entry
2). Having observed a reduced diastereomer ratio during the
epoxide ring opening of benzyl protected epoxide 8, we turned
our attention to the epoxide 6, in which the two primary hy-
droxyl groups of 3 are protected with bulkier pivaloyl groups.
Protection of primary hydroxyl groups of epoxide 3 was carried
out with pivaloyl chloride in pyridine to yield 1,6-di-O-pivaloyl-
2,5:3,4-dianhydro- -allitol 6 in 91 % yield. Subjection of epoxide
D
6 to the abovementioned reaction conditions resulted the cor-
responding ꢀ-azido-alcohol in high yield (Table 1, entry 3) as a
mixture of diatereomers 9a and 9b in an 83:17 ratio. The ab-
sence of any significant improvement in dr as compared with
unprotected epoxide 3 indicated that pivaloyl groups would
not be optimal for this process.
Scheme 1. Strategy for the preparation of optically pure tetrasubstituted
THFs.
We next turned our attention to the bulkier trityl group. Not
only is the trityl group larger in size compared to the pivaloyl
group, but its steric bulk also remains in closer proximity to the
Results and Discussion
We started our investigation with the ring opening of epoxide sugar core in comparison to the tert-butyl group of pivaloyl,
3 with fluoride ion, which can provide direct access to 3-fluoro- and thus it might direct the incoming nucleophile efficiently.
3-deoxy-2,5-anhydro-
D
-mannitol (3-FDAM) 5a (Scheme 2). The 1,6-Di-O-trityl-2,5:3,4-dianhydro-D-allitol 7 was obtained in
[18F] version of fluoro-sugar 5a is an attractive potential tracer moderate yields (66 %) by heating epoxide 3 with trityl chloride
for use in positron emission tomography (PET). Upon heating in pyridine with catalytic DMAP. Unfortunately, efforts to open
epoxide 3 with KHF2 in ethylene glycol at reflux, a typical proto- trityl epoxide 7 with azide were unsuccessful as it was found to
col to open an epoxide ring with fluoride ion,[19] a mixture of be unreactive below 90 °C (Table 1, entry 4). Heating 7 in the
two diastereomers in an about 83:17 diastereomeric ratio (de- presence of Lewis acids led to decomposition; however, a re-
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Table 1. Study of epoxide 3 ring opening reaction with azide.
Entry
Solvent
Pg
T [°C]
Product
dr (a:b)
Yield [%][a]
1
2
3
4
5
6
7
8
EtOH
EtOH
EtOH
EtOH
DMF
DMF
DMF
DMSO
H (3)
75
78
78
78
85
85
85
85
11
10
9
–
9
10
11
11
≈ 80:20
70:30
≈ 83:17
83[b][c]
54[d]
Bn (8)
Piv (6)
Tr (7)
Piv (6)
Bn (8)
H (3)
72[d]
no reaction[e]
≈ 83:17
70:30
95:5
81[d][f]
60[d][f]
88[b][f][g]
86[d][f]
H (3)
95:5
[a] Combined yield of both diastereomers. [b] dr was determined by 1H NMR analysis via integration of methine protons CH-OH. [c] Usage of NH4Cl as catalyst
instead CeCl3 has provided same result. [d] Ratio was determined by 1H NMR analysis via integration of methine protons CH-N3. [e] Under the defined
experimental conditions, only starting material was observed by 1H NMR analysis. [f] Amberlyst 15 (dry form) (1.1 equiv.) was used as catalyst instead CeCl3
in this reaction. [g] Low yields were observed with the usage of NH4Cl as catalyst in the place of Amberlyst 15.
cent report demonstrates epoxide ring opening of 7 with lith- sponding azido-alcohol 11 with an excellent diastereomeric ra-
ium amide under basic conditions at 120 °C, furnishing product tio of 95:5 (entry 7). Similar results were obtained when DMSO
with a moderate diastereomer ratio (80:20).[21]
The diastereoselectivity observed during ring opening of ep-
oxides 3, 6 and 8 with sodium azide in EtOH (Table 1, entries
1, 2 and 3) seemed to be independent of the size of the groups
was used (entry 8). Thus, the combination of unprotected epox-
ide, Amberlyst 15 and polar aprotic solvent is essential to obtain
high diastereomeric ratios in this process.
To explore further the scope of this protocol, we investigated
on the C-1 and C-6 hydroxyl groups. Therefore, we examined the ring opening of epoxide 3 with other nucleophiles (Table 2).
the effect of polar aprotic solvents on this process, with a focus At 75 °C, epoxide 3 reacted with sodium thiomethoxide result-
on polar aprotic solvents. This was necessarily limited to DMF ing ꢀ-hydroxy-thioether 12 in good yield and dia-
and DMSO due to low solubility in other solvents (e.g., THF, stereoselectivity (entry 1). We then examined the compatibility
dioxane or DCM). Common Lewis acid catalysts were found to of this protocol with halide ions (entries 2, 3 and 4). Ring open-
be ineffective, presumably due to Lewis base coordination by ing of epoxide 3 was successfully accomplished using chloride,
solvent. However, the convenient polystyrene resin-bound bromide and iodide ions at lower temperatures, resulting the
Brønsted acid Amberlyst 15[22a] used in dry form was able to corresponding halo alcohols 13, 14 and 15 in high yields and
promote the ring opening in DMF. The higher rate of reaction excellent diastereoselectivity (all ≥ 97:3). However, use of KF
using Amberlyst 15 may result from enhanced catalytic activity or NaF as the nucleophilic fluoride source did not afford the
due to cooperativity among several nearby sulfonic acid moie- corresponding fluoro-sugar 5. Efforts to increase the reactivity
ties on the resin backbone during Brønsted acid activation of of the fluoride ion with the assistance of cation chelating li-
the epoxide 3.[22b] However, no improvement of diastereomeric gands like [18]-crown-6 were also unsuccessful. Finally, we suc-
ratio was observed during ring opening of epoxides 6 and 8 in cessfully opened epoxide 3 with fluoride ion by heating at re-
DMF (Table 1, entries 5 and 6). Surprisingly, epoxide 3 reacted flux in DMF with KHF2 to yield 67 % of 3-fluoro-3-deoxy-2,5-AM
with azide under these conditions yielding 88 % of the corre- 5 (3-FDAM) with excellent diastereoselectivity (entry 5). Unfor-
Table 2. Diastereoselective ring opening of epoxide 3 with Nu.
Entry
Nu
T (°C)
t [h]
Product
dr (a:b)
Yield [%][a]
1
2
3
4
5
NaSMe
NaCl
NaBr
NaI
75
15
8
8
8
24
12
13
14
15
5
90:10
≥ 97:3
≥ 97:3
≥ 97:3
96:4
74[b]
84[c]
–40 to r.t.
–40 to r.t.
–40 to r.t.
153
91[c]
94[c]
KHF2
67[d][e][f]
[a] Isolated yield after purification by column chromatography. [b] Dr was determined by 1H NMR analysis via integration of methyl group protons attached
to S atom. [c] dr was determined by 1H NMR analysis via integration methine protons CH-OH. [d] 10 equiv. of KHF2 was added. [e] dr was determined by 19F
NMR analysis. [f] Amberlyst 15 was not added to the reaction mixture.
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tunately, this protocol is not applicable to radiosynthesis of Applications of Epoxide Ring-Opening Process
[18F]-3-FDAM, as the reaction requires 24 h for completion.
Observed diastereoselectivity during epoxide ring opening
of compounds 3, 6 and 8 was affected by three factors; i) substi-
tution on the oxygen functionality on C-1 and C-6, ii) the nature
of the nucleophile and iii) the nature of the solvent. Only epox-
ide 3, which contains free hydroxyl groups at C-1 and C-6
yielded high diastereomeric ratios in polar aprotic solvents. In
polar protic solvents, epoxide ring opening of 3 yielded lower
diastereomeric ratios, irrespective of the solvent. Epoxides 6
and 8, which have protecting groups on positions C-1 and C-6,
provided low diastereomeric ratios. Thus, a fine balance of sol-
vent and substrate was essential to achieve higher diastereomer
ratios. The major diastereomer in all cases arises from nucleo-
philic attack of the epoxide at C-3 via transition state A (Fig-
ure 2), which can be attributed to the greater steric hindrance
experienced by the nucleophile when approaching C-4 (TS B)
due to the adjacent cis CH2OR group. In polar aprotic solvents,
unprotected diol 3 may participate in hydrogen bonding with
solvent, exaggerating the steric bulk of the neighboring CH2OH
group at C-5 to further disfavor attack at C-4, furnishing the
enhanced selectivity observed under these conditions. Bis(ben-
zyl ether) 8 and bis(pivalate) 6 lack the capacity for hydrogen
bonding, and display a correspondingly lower diastereoselectiv-
ity. In the polar protic solvent ethanol, modest diastereoselect-
ivity was seen with 3, 6 and 8, and with relatively small differen-
ces among these substrates. This may be indicative of a similar
degree of solvent organization around the CH2OR substituents
regardless of the protecting group. Moreover, further erosion of
selectivity for attack at C-3 may arise from the possible inter-
vention of solvent assisted delivery of the nucleophile (TS C).
Having accomplished epoxide ring opening of 3 in good yields
and gained access to C-3-modified 2,5-AM derivatives with high
diastereoselectivity, we proceeded further to show the syn-
thetic applications of the products (Scheme 3). As mentioned
above, anhydromannitol 1 is an effective substrate for trans-
membrane uptake by the hexose transporter protein GLUT5.
With a goal of developing a short and efficient route to nitro-
gen-containing structural analogs of 1, we examined the use
of 11a as a convenient starting material (Scheme 3). Catalytic
hydrogenation/hydrogenolysis of the azide moiety afforded 3-
amino-3-deoxy-2,5-anhydro-D-mannitol, which could be di-
rectly acylated with the esters N-acetoxysuccinimide or ethyl
trifluoroacetate to furnish 3-acetamido-3-deoxy-2,5-anhydro-
D
-
-
mannitol 16 and 3-trifluoroacetamido-3-deoxy-2,5-anhydro-
D
mannitol 17 in moderate to good yield. It is notable that these
targets were obtained by a protecting-group-free sequence
that is potentially amenable to the preparation of a variety of
other analogs. These compounds are under current study, and
their effects on GLUT5 will be discussed elsewhere.
Scheme 3. Synthesis of amides 16 and 17.[a] [a] Reagents and conditions: (a)
Pd/C, H2 (1 atm), room temp., 2 h; (b) N-acetoxysuccinimide, NaHCO3, 40 °C,
MeOH, 24 h, 53 %; (c) ethyl trifluoroacetate, NaHCO3, 40 °C, MeOH, 8 h, 73 %.
With the epoxide ring opening approach to substituted tet-
rahydrofurans in hand, we next sought to extend the methodol-
ogy to the corresponding aziridine system (Scheme 1, products
C and/or F). With an eventual goal of surveying the suitability
of some of the aziridine opening products as organocatalysts,
we considered protection of the C-1 and C-6 primary alcohols
to be desirable, and therefore identified bis(benzyl) ether 4 as
the target substrate. The previously described diastereomeric
azido alcohols 10a and 10b could be reduced with LiAlH4 to
afford the corresponding amino alcohols (Scheme 4), which
could be selectively tosylated at nitrogen to provide hydroxy-
sulfonamides 18 in 85 % yield over two steps as a 7:3 mixture.
Subsequent treatment with Mitsunobu conditions then af-
forded 4 in good yield. Direct formation of 18 via Lewis acid-
assisted epoxide ring opening[24] employing 8 and TsNH2 was
not effective, presumably due to the relatively poor nucleophil-
icity of the neutral sulfonamide. Likewise, direct Sharpless
aziridination[25] of dihydrofuran G (available from 1 by a known
two-step procedure[26]) was unsuccessful. Nevertheless, conve-
nient access to 4 was in hand via 10 and 18, and we now
set out to examine its ring opening behavior using azide as a
representative nucleophile (Table 3).
We observed no reaction of aziridine 4 with azide at room
temperature in CH3CN, DCM or THF solvents. However, 4 re-
acted with azide in DMF at room temperature to produce good
yield of compounds 19 with a dr of 89:11 (entry 1). Effective
conversion at room temperature contrasts notably with the ele-
vated temperatures required for azide opening of epoxide 8
Figure 2. Factors affecting regioselectivity of epoxide ring opening.
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Scheme 4. Synthesis of aziridine 4.[a] [a] Reagents and conditions: (a) LiAlH4, THF, 0 °C, 1 h then room temperature, 1 h; (b) TsCl, Et3N, THF, 0 °C then room
temperature, 12 h (85 % over two steps, 70:30 mixture of 18a/18b); (c) PPh3, DIAD, DMF, 0 °C then room temperature, 12 h (88 %).
Table 3. Study of aziridine 4 ring opening reaction by azide.
chloride opened the aziridine ring of 4 at the same temperature
(entries 4 and 5), but required longer reaction times (especially
NaCl), and furnished the corresponding bromides 23a/23b and
chlorides 24a/24b in good yields with diastereomer ratios of
81:19. In contrast to the result in Table 4, treatment of 4 with
20 equiv. ethereal HCl in DMF required 4 d to reach completion
(dr = 83:17), indicating the importance of Amberlyst 15 in the
activation of 4. Under similar conditions, potassium thiocyanate
and sodium cyanide reacted effectively with 4 to afford 25a/b
and 26a/b in good yields, though somewhat longer reaction
times were required to achieve complete conversion (entries 6
and 7). Notably, while ring opening by thiocyanate occurred
with moderate diastereoselectivity (76:24), reaction with cyan-
ide was unselective. The reasons for the abnormally low stereo-
selectivity seen with cyanide remain unclear, though similar ob-
servations have been noted in SN1 trapping process.[27] Finally,
ring opening with an oxygen nucleophile, sodium acetate, was
investigated. At room temperature, no reaction was observed
and the aziridine 4 was recovered unchanged after 24 h. At
elevated temperature (60 °C), a partial conversion of 40 % was
obtained after 24 h. However, complete conversion required
Entry
T [°C]
t [h]
19a:19b[a]
Yield [%][b]
1
2
3
25
60
85
24
12
6
89:11
86:14
80:20
79[c]
92
95
[a] Ratio was determined by 1H NMR analysis via integration of sulfonamide
NH protons. [b] Combined yield of major and minor isomers after initial chro-
matographic purification. Analytically pure samples of each isomer could be
obtained by careful chromatography. [c] 10 % of aziridine 4 was recovered.
(Table 1). Higher temperatures with 4 reduced reaction time,
but resulted in a minor drop in the diastereoselectivity (entries
2 and 3). The diastereomer ratio obtained during ring opening
of aziridine 4 is comparable to the diastereomer ratio observed
during the ring opening of structurally similar epoxide 8, and
consistent with the selectivity rationale (Figure 2). One impor-
tant distinction between the azide adducts of 4 and those de-
rived from 3 or 8 is their separability. While epoxide ring open-
ing afforded inseparable mixtures of diastereomers, azide ad-
ducts 19a and 19b could be easily separated by silica gel chro-
matography.
Table 4. Ring opening reactions of aziridine 4 with nucleophiles.
Encouraged by these preliminary results, we then investi-
gated the scope of the ring opening reaction of aziridine 4 with
a variety of nucleophiles under similar conditions (Table 4).
Both sodium thiomethoxide and sodium thiophenoxide ef-
fected ring opening at room temperature in one hour to afford
the corresponding thioether sulfonamide products 20 and 21
in high yields (entries 1 and 2). As with azide adduct 19, good
diastereoselectivity was seen in favor of the all-trans isomers
(20a:20b = 90:10; 21a:21b = 93:7). The excellent conversion
obtained under mild conditions presumably arises from the rel-
atively high nucleophilicity of the thiolate anions. With this in
mind, we turned our attention to other nucleophiles. Reaction
of 4 with halides was examined next (entries 3–5). Sodium iod-
ide reacted only slowly at room temperature, but 4 could be
consumed in 30 min at 60 °C (entry 3). Unfortunately, the dia-
stereoselectivity in this case was modest (22a:22b = 70:30). Re-
action of 4 with sodium iodide under microwave heating gave
lower yields and selectivities. Sodium bromide and sodium
Entry Nu
T [°C]
t [h]
Product
dr (a:b)[a]
Yield [%][b]
1
2
3
4
5
6
7
8
NaSMe
NaSPh
NaI
NaBr
NaCl
KSCN
NaCN
NaOAc
r.t.
r.t.
60
60
60
60
60
100
1
1
0.5
1
12
24
14
20
20
21
22
23
24
25
26
27
90:10
93:7
95
94
70:30
81:19
81:19
76:24
50:50
82:18
90[c]
87
80[d]
80
85
90[e]
[a] Ratio was determined by 1H NMR analysis via integration of the sulfon-
amide NH protons. Ratios of isolated yields of separated isomers were in
close agreement with measured ratios. [b] Combined yield of both diastereo-
mers (see footnote b of Table 1). [c] Aziridine ring opening with sodium
iodide under microwave heating gave lower yields and selectivities. [d] Aziri-
dine ring opening in the presence of the ethereal solution of HCl in DMF was
completed after 4 d with a diastereomeric ratio of 83:17 in favor of 24a. [e]
40 % conversion was obtained at 60 °C.
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heating at 100 °C for 20 h to afford acetates 27 in excellent tion. These observations, along with consistent trends in vicinal
yield and moderate dr (27a:27b = 82:18; entry 8). Although coupling constants among the various adducts, allowed us to
diastereomer ratios were determined by NMR analysis of the assign the relative stereochemistry of both diastereomers of
mixtures (see Supporting Information), it was possible in most 19–21 and 23–27 by analogy to 22a and 22b.
cases to separate the diastereomers by chromatographic purifi-
cation. Thus, major isomers 19a–27a could be obtained as
stereochemically pure tetrahydrofurans, potentially useful
building blocks for further synthetic transformations. Minor iso-
mers 19b, 22b, 23b, 24b and 25b could also be isolated in
pure form.
Stereochemical Assignments
In the 1H NMR spectra of epoxide ring opening products 5a
and 11a–15a, the C-4 methine proton adjacent to the OH
group was observed as an apparent triplet with coupling con-
stant constants of 7.2–8 Hz (Figure 3). Based on these consistent
J values, we concluded that all the compounds synthesized in
this protocol have same relative stereochemistry on the tetrahy-
Figure 4. TROESY correlations of 22a and 22b.
drofuran ring; however, J values alone could not permit rigor-
ous assignment of the relative configuration. 2D-TROESY experi-
Asymmetric Michael Addition
ments were also inconclusive, as the chemical shifts of key pro-
tons overlap. Fortunately, acetamide 16 could be crystalized
and X-ray diffraction analysis showed unambiguously that the
all-trans relative configuration was present. Since 16 was de-
rived from azide 11a by simple functional group transforma-
tions with no adjustment of the stereochemical configuration,
it can be inferred that 11a (and by analogy 5a and 12a–15a)
all possess the all-trans relative configuration.
Finally, azide adducts 19a and 19b were subjected to reduction
conditions to furnish diamine monosulfonamides 28a and 28b
in quantitative yields (Scheme 5). Rigid amine-containing com-
pounds have enjoyed success as chiral ligands on transition
metal complexes or organocatalysts.[28] Moreover, the presence
an adjacent sulfonamide NH able to function as a mild Brønsted
acid further enhances the catalytic potential of such com-
pounds.[29] The utility of diamine monosulfonamides 28a and
28b as potential organocatalysts for the asymmetric Michael
addition of 2-nitropropane 29 with 4-(4-chlorophenyl)but-3-en-
2-one 30 was explored (Scheme 6). Initially, the catalytic behav-
ior of 28a in different solvents (DCM, Et2O, THF, MeCN, toluene)
Figure 3. Ortep X-ray structure of 16[35] and coupling pattern of 5a, 9a–13a.
In contrast, with adducts of aziridine 4, accessability of both
diastereomers in the pure form and appreciable difference in
the chemical shift value of the key protons permitted the as-
signment of the relative configuration via 2D-NMR with confi-
dence, as illustrated for 22a and 22b (Figure 4). For the major
product, all-trans isomer 22a, TROESY correlations indicated a
cis relationship between ring protons H-2/H-4 and a cis relation-
ship between H-3 and one of the H-1 (CH2OBn) methylene pro-
tons as well as sulfonamide proton. In the case of minor dia-
stereomer 22b, correlations between the sulfonamide proton
and the neighboring H-1 methylene and a transannular correla-
tion with H-5, as well as the absence of an H-4/H-6 correlation,
offered strong support for the cis-trans-cis relative configura-
Scheme 5. Synthesis of diamine derivatives 28a and 28b.
Scheme 6. Asymmetric Michael addition catalyzed by 28a and 28b.
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Hertz [Hz]. Standard notation was used to describe the multiplicity
of signals observed in 1H NMR spectra: broad (br), multiplet (m),
singlet (s), doublet (d), triplet (t), etc. Carbon nuclear magnetic reso-
nance spectra (13C NMR) were recorded at 100 MHz or 125 MHz
and are reporte δ (ppm) relative to the center line of the triplet
from [D]chloroform (δ = 77.0 ppm). Mass spectra were determined
on a high-resolution electrospray positive ion mode spectrometer.
using 20 mol-% of 28a at room temperature was investigated.
In most cases, the Michael adduct 31 was isolated in low yields
(10–20 %) and moderate enantioselectivities (58–69 %) after
4 d. However, the reaction in neat nitropropane provided the
desired product 31 in better enantioselectivity (77 %) but its
yield remained in the same range. Recently, a combination of
acid and base additives has been demonstrated to improve the
conversion and enantioselectivity of the amine-catalyzed asym-
metric intermolecular cross conjugate additions of nitroalkenes
to α,ꢀ-enals and enones.[30] Inspired by these observations, we
2,5-Anhydro- -mannitol (1) was synthesized by following a reported
D
procedeure.[13c]
3,4:2,5-Dianhydro-D-allitol (3): A one-neck round-bottomed flask,
maintained under Ar atmosphere was charged with 2,5-AM 1
(1.64 g, 10.0 mmol) and PPh3 (5.78 g, 22.0 mmol). DMF (18 mL) was
then added and the resulting mixture was stirred at room tempera-
ture until the solids were completely dissolved. This solution was
cooled to 10 °C and diisopropyl azodicarboxylate (DIAD) (4.4 mL,
2.2 mmol) was added dropwise but quickly. The reaction mixture
was allowed to attain room temp., before being stirred at 40 °C for
2 h. DMF was evaporated under reduced pressure to afford a vis-
cous syrup, which was partitioned between water (150 mL) and
diethyl ether (100 mL). The aqueous layer was collected and washed
again with diethyl ether (100 mL). The aqueous layer was concen-
trated under reduced pressure and the crude product was sub-
jected to silica gel column chromatography, eluting with DCM and
acetone solvent mixture (3:1 to 2:3). Fractions containing product
were combined and concentrated to yield compound 3 (1.26 g,
86 %) as a white solid that matched with previously reported char-
acterization data.[32] Rf = 0.37 (50:50, DCM/acetone). 1H NMR
(400 MHz, D2O): δ = 4.22–4.17 (m, 2 H), 4.02 (br. d, J = 3.0 Hz, 1 H),
3.91 (br. d, J = 3.0 Hz, 1 H), 3.78–3.60 (m, 4 H) ppm. 13C NMR
(100 MHz, D2O): δ = 79.7, 78.9, 62.8, 61.5, 58.3, 57.2 ppm.
explored the reaction in the presence of 20 mol-% of D-mande-
lic acid and 20 mol-% of DMAP to access the desired product
31 in 90 % yield and 70 % enantiomeric excess. The isomeric
diamine monosulfonamide 28b was examined under the same
conditions. Interestingly, this catalyst yielded better enantiose-
lectivity (76 %) and led to the formation of the opposite
enantiomer. The absolute configuration of compound 31 was
determined by comparison the obtained optical rotations with
those reported in the literature.[31] Based upon these results,
the utility of diamine adducts 28a and 28b as potential organo-
catalysts for enantioselective reactions is apparent, and merits
further study.
Conclusions
We have developed a versatile method to synthesize C-3-modi-
fied 2,5-AM derivatives by diastereoselective ring opening of
C2-symmetric epoxide 3. Epoxide opening occurred under mild
conditions in DMF using Amberlyst 15 as an additive. This
method is protecting-group-free and provides direct access to
C-3 functionalized 2,5-AM derivatives in high yields and excel-
lent diastereoselectivity. The strategy was extrapolated to the
C2-symmetric aziridine 4, which is readily available from epox-
ide 8, the dibenzylated version of 3. Compound 4 underwent
ring opening with various nucleophiles to provide access to the
C-3- and C-4-modified 2,5-AM derivatives 19a–27a in high
yields and moderate to good diastereoselectivities. Diamine
monosulfonamides 28a and 28b could be easily obtained from
azide adducts 19a and 19b, and were found to catalyze Michael
addition of nitroalkane 29 with enone 30 to provide access to
adduct 31 with complementary enantioselectivity. Study of C-
3- and/or C-4-modified 2,5-AM derivatives as GLUT5 ligands is
in progress. In addition, further applications of these readily
available homochiral tetrahydrofurans are under investigation,
and will be reported in due course.
1,6-Di-O-Pivaloyl-3,4:2,5-dianhydro-D-allitol (6): To a stirred solu-
tion of epoxide 3 (1.46 g, 10.0 mmol) in pyridine (15 mL) under Ar
atmosphere, triethylamine (3 mL) and DMAP (0.31 g, 2.5 mmol)
were added. This mixture was cooled to 0 °C and pivaloyl chloride
(2.6 mL, 22 mmol) was added dropwise. The reaction mixture was
warmed to room temp. and stirred for 5 h. Solvent was evaporated
under reduced pressure to yield a viscous syrup, which was diluted
with DCM (150 mL). The organic layer was washed with saturated
NaHCO3 solution (100 mL) and subsequently with brine solution
(100 mL). The DCM layer was dried with anhydrous Na2SO4, then
filtered and concentrated under vacuum to yield crude product,
which was subjected to column chromatography on silica gel and
eluted with hexane and ethyl acetate (80:20) to yield compound 6
as colorless oil: Rf = 0.47 (20:80, EtOAc/hexane). [α]D20 = +31.97 (c =
0.65, MeOH). IR (cast film): ν = 2974, 2937, 1734, 1481, 1461, 1398,
˜
1161, 1086, 1037, 941 cm–1. 1H NMR (400 MHz, CDCl3): δ = 4.2 (app
t, J = 4.2 Hz, 1 H), 4.24–4.04 (m, 4 H), 4.05 (dd, J = 12.0, 4.5 Hz, 1
H) 3.74 (d, J = 3.0 Hz, 1 H), 3.67 (d, J = 3.0 Hz, 1 H), 1.18 (s, 9 H),
1.17 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 177.6, 177.5, 75.7,
74.9, 63.5, 61.9, 56.7, 56.1, 38.2 (2 C), 26.63, 26.61 ppm. HRMS (ESI)
calcd. for C16H26O6 [M + Na+] 337.1629, found 337.1622.
Experimental Section
General Procedure: Reactions were carried out in flame-dried
glassware under a positive argon atmosphere unless otherwise
1,6-Ditrityl-3,4:2,5-dianhydro-D-allitol (7): A round-bottomed
stated. Transfer of anhydrous solvents and reagents was accom- flask, maintained under Ar atmosphere was charged with epoxide
plished with oven-dried syringes or cannulae. Solvents were dis- 3 (1.46 g, 10.0 mmol), triethylamine (3 mL) and pyridine (15 mL).
tilled before use: dichloromethane (CH2Cl2) and dimethylformamide
After the epoxide was completely dissolved, trityl chloride (6.4 g,
(DMF) from calcium hydride, tetrahydrofuran (THF) from sodium/
2.3 mmol) and DMAP (0.31 g, 2.5 mmol) were added. The reaction
benzophenone ketyl and pyridine from KOH. Thin layer chromatog- mixture was heated at 60 °C for 10 h, before being cooled to room
raphy was performed on glass plates precoated with 0.25 mm silica
gel. Flash chromatography columns were packed with 230–
400 mesh silica gel. Optical rotations were measured at 22 2 °C.
temperature. Pyridine was removed under reduced pressure to pro-
vide a viscous syrup, which was subjected to silica gel column chro-
matography using hexane and ethyl acetate (95:5) to yield pure
Proton nuclear magnetic resonance spectra (1H NMR) were recorded compound 7 as a white solid (3.85 g, 66 %) that matched with
at 400 MHz or 500 MHz and coupling constants (J) are reported in
previously reported characterization data.[18] Rf = 0.47 (5:95, EtOAc/
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hexane). 1H NMR (400 MHz, CDCl3): δ = 7.57–7.23 (m, 30 H), 4.35
desired product as a pale yellow oil, cotaining mixture of two insep-
(app t, J = 6.3 Hz, 1 H), 4.24 (app t, J = 4.2 Hz, 1 H), 4.02 (d, J = arable isomers (70:30) (2.7 g, 60 %): Rf = = 0.50 (95:5, DCM/acetone).
3.0 Hz, 1 H), 3.75 (d, J = 3.0 Hz, 1 H), 3.45–3.32 (m, 3 H), 3.19 (dd,
J = 10.0, 3.6, Hz, 1 H) ppm.
IR (cast film): ν = 3430, 3030, 2864, 2105, 1486, 1453, 1363 cm–1. 1H
˜
NMR (500 MHz, CDCl3): δ = 7.36–7.26 (m, 10 H), 4.64 (d, J = 11.9 Hz,
1 H), 4.57 (d, J = 3.0 Hz, 2 H), 4.56 (d, J = 11.9 Hz, 1 H), 4.12–4.10
(m, 2 H), 4.02–4.00 (m, 2 H), 3.69 (dd, J = 10.5, 3.0 Hz, 1 H), 3.63–
3.60 (m, 2 H), 3.55 (dd, J = 10.5, 5.5 Hz, 1 H), 3.15 (d, J = 7.5 Hz, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 137.5, 136.9, 128.2, 128.1,
127.7, 127.5, 127.5, 127.4, 83.1, 80.6, 77.3, 73.4, 73.2, 70.2, 69.9, 68.2
ppm. HRMS (ESI) calcd. for C20H23N3NaO4 [M + Na]+ 392.1581, found
392.1573.
1,6-Di-O-benzyl-3,4:2,5-dianhydro-D-allitol (8): Compound 3
(0.20 g, 1.4 mmol) was dissolved in dry DMF (5 mL) and NaH (60 %
dispersion; 0.12 g, 3.1 mmol) was added in a single portion at 0 °C.
After 10 min, BnCl (0.36 mL, 3.1 mmol) was added neat at 0 °C and
the reaction mixture was warmed to room temperature and stirred
for 4 h. After the reaction was judged to be complete by TLC, the
mixture was quenched by water (5 mL) and the aqueous layer was
extracted by DCM (3 × 5 mL). The combined organic layers were
1,6-Di-O-benzyl-3-azido-3-deoxy-2,5-dianhydro-D-iditol (10b):
dried with MgSO4, filtered and concentrated under reduced pres- (Partial data): Rf = 0.50 (95:5, DCM/acetone). 1H NMR (500 MHz,
sure to provide a viscous oil in quantitative yield. The crude product
CDCl3): δ = 4.48 (ddd, J = 6.0, 6.0, 4.5 Hz, 1 H), 4.45 (ddd, J = 6.7,
was used in the next step without further purification: Rf = 0.80
6.7, 2.2 Hz, 1 H), 4.20 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
(98:2, DCM/acetone). [α]D20 = –60.09 (c = 1.40, CH2Cl2). IR (cast film): 128.0 ppm.
1
ν = 3062, 3030, 2862, 1496, 1453, 1406, 1361, 1089 cm–1. H NMR
˜
General Procedure to Synthesize 11 and 12: To a stirred hetero-
(500 MHz, CDCl3): δ = 7.38–7.29 (m, 10 H), 4.62 (d, J = 12.0 Hz, 1
H), 4.58 (d, J = 12.0 Hz, 1 H), 4.56 (d, J = 12.0 Hz, 1 H), 4.52 (d, J =
12.0 Hz, 1 H), 4.24–4.26 (m, 2 H), 3.83 (d, J = 3.0 Hz, 1 H), 3.76 (d,
J = 3.0 Hz, 1 H), 3.65 (d, J = 6.5 Hz, 2 H), 3.59 (d, J = 4.5 Hz, 2 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 138.1, 138.0, 128.5, 128.4,
127.9, 127.8, 127.7, 127.5, 77.3, 76.7, 73.6, 73.5, 70.5, 69.0, 58.0, 57.2
ppm. HRMS (ESI) calcd. for C20H22NaO4 [M + Na]+ 349.1410, found
349.1409.
geneous mixture of compound 3 (1.46 g, 10.0 mmol) and NaNu
(Nu = N3 and SMe, 50.0 mmol) in DMF (30 mL), Amberlyst 15 (2.73 g,
10.0 mmol) was added. This mixture was heated (at 85 °C for Nu =
N3 and 75 °C for Nu = SMe) for 17 h. DMF was removed under
reduced pressure and to yield paste. To the crude mixture, 1:1 mix-
ture of DCM/acetone was added and stirred for 15 min. Solids were
filtered under vacuum and filtrate was concentrated to yield crude
compound. The crude compound was subjected to silica gel flash
1,6-Di-O-pivaloyl-3-azido-3-deoxy-2,5-dianhydro-D-mannitol chromatography, eluted with DCM/acetone (50:50) solvent mixture.
(9): Epoxide 6 (1.50 g, 4.78 mmol) was dissolved in a mixture of
EtOH/H2O (25 mL, 9:1). To this solution, NaN3 (3.27 g, 48.0 mmol)
and CeCl3. 7H2O (0.93 g, 2.5 mmol) were added.[33] This mixture
was stirred at 75 °C for 24 h. Solvents were evaporated under re-
duced pressure to yield crude compound, which was then sub-
jected to column chromatography on silica gel, (95:5, DCM/acet-
one). Both diastereomers were separated and pure fractions corre-
sponding to each diastereomer were combined. Removal of solvent
resulted major diastereomer (1.22 g, 67 %) and minor diastereomer
(0.24 g, 14 %). Both diastereomers were isolated as colorless oils
with combined yield of 81 % (1.47 g).
Fractions containing compound were combined and evaporated to
yield inseparable diastereomeric mixtures of 11a/11b or 12a/12b.
3-Azido-3-deoxy-2,5-dianhydro-D-mannitol (11): Pale yellow vis-
cous oil (1.66 g, 88 %), 11a/11b = 95:5. Rf = 0.37 (50:50, DCM/
acetone). [α]D20 = +26.06 (c = 0.95, MeOH). IR (cast film): ν = 3357,
˜
2930, 2883, 2106, 1376, 1258, 1043, 857, 696 cm–1
.
1H NMR
(500 MHz, D2O): δ = 4.16 (app t, J = 7.0 Hz, 1 H), 3.95 (dd, J = 8.0,
7.0 Hz, 1 H), 3.92–3.86 (m, 2 H), 3.77 (dd, J = 12.5, 3.5 Hz, 2 H), 3.70
(dd, J = 12.5, 4.9 Hz, 1 H), 3.66 (dd, J = 12.4, 5.2 Hz, 1 H) ppm. 13C
NMR (125 MHz, D2O): δ = 82.2, 80.4, 75.0, 66.3, 61.0, 60.8 ppm.
HRMS (ESI) calcd. for C6H11N3O4Na [M + Na+] 212.0642, found
Major 9a: Rf = = 0.61 (95:5, DCM/acetone). [α]D20 = +71.53 (c = 1.50, 212.0638.
MeOH). IR (cast film): ν = 3473, 2975, 2937, 2876, 2107, 1733, 1481,
˜
3-Thiomethyl-3-deoxy-2,5-dianhydro-D-mannitol (12): Pale yel-
1398, 1366, 1284, 1160, 1036, 942, 770 cm–1
.
1H NMR (500 MHz,
low viscous oil (1.43 g, 74 %), 12a/12b = 90:10. Rf = 0.37 (50:50,
CDCl3): δ = 4.32–4.19 (m, 4 H), 4.12 (ddd, J = 5.0, 5.0, 4.8 Hz, 1 H),
4.04–3.97 (m, 1 H), 3.91 (app t, J = 7.2 Hz, 1 H), 2.9 (d, J = 4.9 Hz, 1
H), 1.26 (s, 9 H), 1.24 (s, 9 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
179.0, 178.2, 80.8, 78.5, 76.8, 67.5, 63.5, 63.2, 38.95, 38.91, 27.2, 27.1
ppm. HRMS (ESI): calculated for C16H27N3NaO6 [M + Na]+ 380.1792,
found 380.1787.
DCM:acetone). [α]D20 = +44.41 (c = 0.38, MeOH). IR (cast film): ν =
˜
3359, 2922, 2876, 1429, 1387, 1320, 1239, 1184, 1041, 900, 829,
1
664 cm–1. H NMR (500 MHz, D2O): δ = 4.07 (dd, J = 7.6, 7.3 Hz, 1
H), 3.94 (ddd, J = 9.0, 4.9, 2.8 Hz, 1 H), 3.84 (ddd, J = 7.2, 5.3, 3.0 Hz,
1 H), 3.78 (dd, J = 12.4, 2.8 Hz, 1 H) 3.77 (dd, J = 11.2, 3.0 Hz, 1 H),
3.70 (dd, J = 12.5, 5.0 Hz, 1 H), 3.60 (dd, J = 12.4, 5.4 Hz, 1 H), 3.0
(dd, J = 9.0, 8.0 Hz, 1 H), 2.15 (s, 3 H) ppm. 13C NMR (125 MHz, D2O):
1,6-Di-O-pivaloyl-3-azido-3-deoxy-2,5-dianhydro-D-iditol (9b):
(Partial data): Rf = = 0.63 (95:5, DCM/acetone). [α]D20 = +7.84 (c = δ = 82.9, 81.9, 75.0, 61.5, 60.9, 50.3, 12.3 ppm. HRMS (ESI) calcd. for
1.15, MeOH). IR (cast film): ν = 3478, 2974, 2910, 2108, 1733, 1481, C7H14SO4Na [M + Na+] 217.0505; found m/z 217.050.
˜
1399, 1284, 1164, 1092, 1036, 940, 771 cm–1
.
13C NMR (125 MHz,
General Procedure to Synthesize 13, 14 and 15: Epoxide 3
(0.540 g, 3.78 mmol) was dissolved in DMF (10 mL) and cooled to
–40 °C. To this solution, Amberlyst 15 (1.1 g, 4.0 mmol) and NaX
(X = Cl, Br and I, 19 mmol) were added. Resulting heterogenious
CDCl3): δ = 179.8, 178.1, 81.8, 78.6, 75.2, 68.6, 62.4, 61.2, 38.9, 38.7,
27.2, 27.1 ppm. HRMS (ESI): calculated for C16H27N3NaO6 [M + Na]+
380.1792, found 380.1792.
1,6-Di-O-benzyl-3-azido-3-deoxy-2,5-dianhydro-
D-mannitol mixture was stirred for 4 h and slowly allowed to attain room tem-
(10): To a solution of compound 8 (4.1 g, 13 mmol) in dry DMF perature over a period of 3 h. After the reaction mixture was
(50 mL), Amberlyst 15 (1.8 g, 25 mmol) was added followed by
careful addition of NaN3 (4.1 g, 63 mmol) in several portions.[33] The
reaction mixture was stirred at 120 °C for 2 d. The Amberlyst 15
was filtered off and the crude product was purified by column chro-
matography, eluting with mixture of DCM and acetone (95:5). Evap-
warmed to room temperature, stirring was continued for an addi-
tional 1 h. DMF was removed under reduced pressure to result
paste. To the crude mixture a 1:1 mixture of DCM/acetone (50 mL)
was added and stirred for 15 min. Solids were filtered under vac-
uum and filtrate was concentrated to yield crude compound. The
oration of the organic solvent under reduced pressure yielded the crude compound was subjected to silica gel flash chromatography,
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eluted with DCM/acetone (50:50) solvent mixture. Fractions contain-
washed with excess of MeOH. Evaporation of MeOH under reduced
ing compound were combined and the solvent was evaporated to pressure yielded a viscous syrup, which was subjected to silica gel
yield 13, 14 and 15 as inseparable diastereomeric mixtures.
column chromatography using DCM/MeOH mixture (100:0 to 80:20
for 16, 100:0 to 85:15 for 17). Fractions with compound were com-
bined and concentrated under vacuum to yield clear crystals.
3-Chloro-3-deoxy-2,5-dianhydro- -mannitol (13): Colorless vis-
D
cous syrup (0.56 g, 84 %), 13a/13b ≥ 97:3. Rf = 0.37 (50:50, DCM/
acetone). [α]D20 = +38.20 (c = 3.72, MeOH). IR (cast film): ν = 3349,
3-Acetamido-3-deoxy-2,5-dianhydro-D-mannitol (16): Clear crys-
˜
2928, 1360, 1390, 1040, 901, 823 cm–1. 1H NMR (500 MHz, D2O): δ =
4.26 (app t, J = 7.2 Hz, 1 H), 4.14–4.06 (m, 2 H), 3.92–3.86 (m, 1 H),
3.84–3.77 (m, 2 H), 3.75–3.66 (m, 2 H) ppm. 13C NMR (125 MHz,
D2O): δ = 85.6, 84.7, 79.8, 63.5, 62.5, 62.3 ppm. HRMS (ESI) calcd. for
[M + Na+] C6H11ClO4Na 205.0238; found m/z 205.0239.
tals (0.142 g, 53 % over two steps). Rf = 0.2 (80:20, DCM/MeOH);
m.p. 34.2–36.1 °C. [α]D20 = +33.62 (c = 0.70, MeOH). IR (cast film): ν =
˜
1
3288, 2930, 2878, 1654, 1557, 1432, 1376, 1312, 1047, 958 cm–1. H
NMR (400 MHz, D2O): δ = 4.19 (app t, J = 7.5 Hz, 1 H), 4.06 (app t,
J = 7.5 Hz, 1 H), 3.88 (ddd, J = 7.6, 4.9, 2.6 Hz, 1 H), 3.83 (ddd, J =
8.3, 5.2, 3.0 Hz, 1 H), 3.73 (dd, J = 12.5, 3.0 Hz, 1 H), 3.68 (dd, J =
12.5, 3.0 Hz, 1 H), 3.63 (dd, J = 12.5, 5.2 Hz, 1 H), 3.58 (dd, J = 12.5,
5.2 Hz, 1 H), 1.83 (s, 3 H) ppm. 13C NMR (100 MHz, D2O): δ = 174.5,
82.4, 80.7, 74.6, 61.4, 60.9, 56.6, 21.9 ppm. HRMS (ESI) calcd. for [M
+ Na+] C8H15NO5Na 228.0842.1105; found 228.0841.
3-Bromo-3-deoxy-2,5-dianhydro-D-mannitol (14): Pale yellow
viscous syrup (0.76 g, 91 %), 14a/14b ≥ 97:3. Rf = 0.37 (50:50, DCM/
acetone). [α]D20 = +30.29 (c = 0.74, MeOH). IR (cast film): ν = 3365,
˜
2927, 2879 cm–1. 1383, 1230, 1183, 1041, 896, 776 cm–1
,
1H NMR
(500 MHz, D2O): δ = 4.33 (app t, J = 7.6 Hz, 1 H), 4.17 (ddd, J = 9.0,
2.9, 2.8 Hz, 1 H), 4.09 (dd, J = 9.0, 8.0 Hz, 1 H), 3.88–3.66 (m, 5 H)
ppm. 13C NMR (125 MHz, D2O): δ = 84.2, 83.1, 78.5, 61.8, 60.7 49.9
ppm. HRMS (ESI) calcd. for C6H11BrO4Na [M + Na+] calcd. 248.9733;
found 248.9731.
3-Trifluoroacetamido-3-deoxy-2,5-dianhydro-D-mannitol (17):
Clear crystals (0.243 g, 73 % over two steps). Rf = 0.37 (DCM/MeOH,
85:15); m.p. 58.9–60.7 °C. [α]D20 = +30.34 (c = 1.60, MeOH). IR (cast
film): ν = 3305, 3099, 2932, 2882, 1708, 1567, 1385, 1216, 1189,
˜
1
1161, 1053, 935, 898 cm–1. H NMR (500 MHz, D2O): δ = 4.37 (app
3-Iodo-3-deoxy-2,5-dianhydro-D-mannitol (15): Pale yellow vis-
t, J = 7.9 Hz, 1 H), 4.23 (app t, J = 7.5 Hz, 1 H) 4.0 (ddd, J = 8.3, 5.0,
3.0 Hz, 1 H) 3.96 (ddd, J = 7.5, 5.0, 3.0 Hz, 1 H), 3.80 (dd, J = 12.6,
3.0 Hz, 1 H), 3.75 (dd, J = 12.6, 3.0 Hz, 1 H), 3.68 (dd, J = 12.6, 4.6 Hz,
1 H), 3.65 (dd, J = 12.6, 4.8 Hz, 1 H) ppm. 13C NMR (125 MHz, D2O):
δ = 159.2 (q, JC,F = 37.9 Hz), 115.7 (q, JC,F = 285.8 Hz), 82.5, 80.0,
74.1, 61.1, 60.7, 57.0 ppm. HRMS (ESI) calcd. for C8H12NF3O5Na [M
+ Na+] 282.0560; found 282.0562.
cous syrup (0.94 g, 94 %), 15a/15b ≥ 97:3. Rf = 0.37 (50:50, DCM/
acetone). [α]D20 = +17.86 (c = 3.60, MeOH). IR (cast film): ν = 3377,
˜
2926, 2881, 1385, 1327, 1221, 1184, 1156, 1036, 896, 834, 741,
1
663 cm–1. H NMR (500 MHz, D2O): δ = 4.34 (app t, J = 8.5 Hz, 1 H),
4.22 (m, 1 H), 4.04 (dd, J = 9.9, 9.7 Hz, 1 H), 3.9–3.75 (m, 4 H), 3.68
(dd, J = 12.2, 4.7 Hz, 1 H) ppm. 13C NMR (125 MHz, D2O): δ = 84.9,
82.4, 79.3, 61.0, 59.7, 23.9 ppm. HRMS (ESI) calcd. for C6H11IO4Na [M
+ Na+] 296.9594; found 296.9590.
(2R,3S,4S,5S)-2,5-Bis[(benzyloxy)methyl]tetrahydro-4-(tosyl-
amino)furan-3-ol (18a): LiAlH4 (0.24 g, 6.3 mmol) was added in a
single portion to a solution of 4 (1.2 g, 3.1 mmol) in dry THF
(100 mL) at 0 °C. The reaction was stirred at 0 °C for one hour and
then warmed to room temperature and stirred for one extra hour.
After reaction completion, the mixture was cooled down to 0 °C
and quenched by saturated Na2SO4 (40 mL). The mixture was fil-
tered through Celite and the Celite plug was washed with Et2O.
The organic layer was separated and the aqueous layer was then
extracted with Et2O (3 × 10 mL). The combined organic layers were
dried with MgSO4 and concentrated under reduced pressure. The
crude was then treated with triethylamine (0.50 mL, 3.5 mmol) in
dry THF (11 mL) at 0 °C and stirred for 5 min. Tosyl chloride (0.60 g,
3.1 mmol) was added and the reaction mixture was stirred 10 min
at 0 °C and then warmed to room temperature and stirred for 16 h.
The reaction mixture was concentrated under reduce pressure and
purified by column chromatography on silica gel (90:10 DCM/acet-
one) to afford the yellow pale product as two inseparable isomers
3-Fluoro-3-deoxy-2,5-dianhydro-D-mannitol (5): KHF2 (3.21 g,
41.1 mmol) was added to a solution of epoxide 3 (0.60 g,
4.11 mmol) in DMF (12 mL). The heterogeneous mixture was heated
at 100 °C for 6 h, before being reflexed for 18 h. DMF was removed
under reduced pressure and acetone (30 mL) was then added. Sol-
ids were filtered and evaporation of acetone from filtrate resulted
crude compound. The crude was subjected to silica gel column
chromatography, eluted with DCM/acetone (50:50). Fractions con-
taining compound were combined and concentrated to yield a mix-
ture of diastereomers 5a/5b (dr = 96:4) as a colorless viscous syrup
(0.47 g, 67 %). Rf = 0.37 (50:50, DCM/acetone). [α]D20 = +35.99 (c =
0.50, MeOH). IR (cast film): ν = 3380, 2937, 1387, 1320, 1217, 1054,
˜
1
911, 853 cm–1. H NMR (400 MHz, D2O): δ = 4.94 (app dt, J = 53.5,
3.8 Hz, 1 H), 4.32 (ddd, J = 20.2, 5.7, 3.5 Hz, 1 H), 4.21 (ddd, J = 21.6,
9.5, 5.2 Hz, 1 H), 3.97 (ddd, J = 5.6, 5.6, 3.9 Hz, 1 H), 3.76–3.62 (m,
4 H) ppm. 19F NMR (375 MHz, D2O): δ = 189.7 (app dt, J = 53.51,
20.8 Hz) ppm. 13C NMR (100 MHz, D2O): δ = 98.2 (d, JC,F = 181.6 Hz),
83.5 (d, JC,F = 5.4 Hz), 81.8 (d, JC,F = 25.1 Hz), 75.1 (d, JC,F = 24.7 Hz),
60.8 (d, JC,F = 1.5 Hz), 60.5 (d, JC,F = 7.2 Hz) ppm. HRMS (ESI) calcd.
for C6H11FO4Na [M + Na+] 189.0534; found 189.0529.
(70:30, 1.4 g, 85 %): Rf = 0.40 (95:5, DCM/acetone). IR (cast film): ν =
˜
3453, 3266, 2916, 2865, 1598, 1495, 1453, 1330, 1184 cm–1. 1H NMR
(500 MHz, CDCl3): δ = 7.53 (d, J = 8.2 Hz, 2 H), 7.44–7.22 (m, 8 H),
7.27–7.28 (m, 2 H), 7.22–7.24 (m, 2 H), 6.00 (d, J = 9.1 Hz, 1 H), 4.65–
4.45 (m, 4 H), 4.10–4.07 (m, 2 H), 4.03 (d, J = 9.1 Hz, 1 H), 3.91 (ddd,
J = 9.1, 2.5, 2.5 Hz, 1 H), 3.74 (ddd, J = 9.1, 3.5, 2.5 Hz, 1 H), 3.65
(dd, J = 10.5, 2.5 Hz, 1 H), 3.58 (dd, J = 10.5, 2.5 Hz, 1 H), 3.56 (dd,
J = 10.0, 3.5 Hz, 1 H), 3.53 (dd, J = 10.0, 2.5 Hz, 1 H), 2.42 (s, 3 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 143.4, 137.6, 136.9, 136.8,
129.7, 128.8, 128.7, 128.3, 128.2, 128.2, 127.9, 127.0, 86.7, 84.3, 78.8,
74.1, 73.9, 71.6, 71.3, 63.6, 21.5 ppm. HRMS (ESI) calcd. for
C27H32NO6S [M + H]+ 498.1945; found 498.1943.
General Procedure to Synthesize 16 and 17: A 50 mL round-
bottomed flask was charged with azide 11 (0.25 g, 1.32 mmol) and
MeOH (25 mL). To this mixture, 10 % Pd/C (0.05 g, 20 % by weight)
was added and the resulting heterogeneous mixture was stirred at
room temperature, under H2 atmosphere (1 atm). After stirring for
2 h, solids were filtered out and washed with MeOH (10–20 mL).
Filtrate was taken into a 100 mL round-bottomed flask and MeOH
was partially evaporated to concentrate the solution (ca. 25 mL). To
this mixture, activated ester (5.0 mmol, 0.79 g of N-acetoxy succin- (2R,3R,4R,5S)-2,5-Bis[(benzyloxy)methyl]tetrahydro-4-(tosyl-
imide for 16; 10 mmol, 1.2 mL of ethyl trifluoroacetate for 17) and
excess of NaHCO3 were added. This heterogeneous mixture was
amino)furan-3-ol (18b): (Partial data): Rf = 0.40 (95:5, DCM/acet-
one). H NMR (500 MHz, CDCl3): δ = 7.65 (d, J = 8.2 Hz, 2 H), 5.95
1
heated at 40 °C (24 h for 16 and 8 h for 17). Solids were filtered and (d, J = 7.1 Hz, 1 H), 4.41 (app. q, J = 5.2 Hz, 1 H), 4.29 (ddd, J = 5.3,
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3.5, 3.5 Hz, 1 H), 4.23 (ddd, J = 6.0, 3.5, 2.3 Hz, 1 H), 3.81 (ddd, J = CDCl3): δ = 143.7, 137.9, 137.0, 136.9, 129.8, 128.8, 128.4, 128.3,
6.9, 6.9, 4.4 Hz, 1 H), 3.47 (dd, J = 11.1, 2.3 Hz, 1 H), 3.20 (d, J = 128.1, 127.8, 127.7, 127.1, 77.4, 76.6, 74.3, 73.6, 69.6, 69.3, 67.6, 60.4,
5.3 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 129.6, 128.7, 128.5,
128.1, 128.0, 127.7, 127.1, 78.1, 77.9, 76.3, 74.2, 69.7, 69.5, 62.6 ppm.
21.5 ppm. HRMS (ESI) calcd. for C27H30N4NaO5S [M + Na]+ 545.1829;
found 545.1829.
(1S,2S,4S,5R)-2,4-Bis[(benzyloxy)methyl]-6-tosyl-3-oxa-6-aza-bi-
cyclo[3.1.0]hexane (4): PPh3 (0.70 g, 2.5 mmol) was added to a
solution of compound 18 (1.2 g, 2.4 mmol) in dry THF (18 mL). The
reaction mixture was cooled down to 0 °C followed by slow addition
of diisopropyl azodicarboxylate (0.50 mL, 2.5 mmol). After stirring
for 5 min at 0 °C, the ice bath was removed and the reaction was
stirred for 16 h at room temperature. After reaction completion, the
mixture was concentrated under reduced pressure and purified by
column chromatography (95:5 DCM/acetone) on silica gel to afford
the desired product as a pale yellow oil; (1.0 g, 88 %): Rf = 0.80
(95:5, DCM/acetone). [α]D20 = –47.69 (c = 2.26, CHCl3). IR (cast film):
(2S,3R,4S,5R)-2,5-Bis[(benzyloxy)methyl]tetrahydro-4-(methyl-
thio)-N-tosylfuran-3-amine (20a): Pale yellow oil; Rf = 0.30 (99:1,
DCM/acetone). [α]D20 = +38.80 (c = 2.60, CH2Cl2). IR (cast film): ν =
˜
3266, 3061, 2921, 2863, 1453, 1331, 1305, 1265, 1161 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 7.58 (d, J = 8.0 Hz, 2 H), 7.41–7.23 (m, 10 H),
7.17 (d, J = 8.0 Hz, 2 H), 5.45 (d, J = 9.1 Hz, 1 H), 4.62 (d, J = 11.2 Hz,
1 H), 4.51 (d, J = 11.2 Hz, 1 H), 4.49 (s, 2 H), 4.02–4.00 (m, 2 H), 3.89
(ddd, J = 9.1, 4.5, 4.5 Hz, 1 H), 3.72 (dd, J = 10.5, 2.1 Hz, 1 H), 3.58
(dd, J = 10.5, 2.6 Hz, 1 H), 3.52 (d, J = 5.0 Hz, 2 H), 3.01 (dd, J = 4.5,
4.5 Hz, 1 H), 2.39 (s, 3 H), 1.91 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 142.9, 137.7, 137.4, 136.9, 129.1, 128.3, 127.9, 127.8,
127.7, 127.2, 127.1, 126.8, 84.1, 82.5, 73.6, 72.9, 71.0, 70.1, 59.6, 51.7,
21.1, 13.7 ppm. HRMS (ESI) calcd. for C28H33NNaO5S2 [M + Na]+
550.1692; found 550.1686.
ν = 3087, 2913, 2864, 1597, 1496, 1453, 1537, 1324, 1186, 1161 cm–
˜
1
1. H NMR (400 MHz, CDCl3): δ = 7.85 (d, J = 8.3 Hz, 2 H), 7.37–7.21
(m, 12 H), 4.54 (d, J = 12.0 Hz, 1 H), 4.50 (d, J = 12.0 Hz, 1 H), 4.32
(m, 1 H), 4.30 (d, J = 12.0 Hz, 1 H), 4.26 (dd, J = 4.0, 4.0 Hz, 1 H),
4.23 (d, J = 12.0 Hz, 1 H), 3.76 (d, J = 5.5 Hz, 1 H), 3.70 (dd, J = 5.5,
2.0 Hz, 1 H), 3.56 (dd, J = 4.0, 2.0 Hz, 2 H), 3.49 (dd, J = 9.1, 5.5 Hz,
1 H), 3.25 (dd, J = 9.1, 7.0 Hz, 1 H), 2.40 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 144.2, 137.5, 137.3, 134.8, 129.3, 128.1, 127.9,
127.5, 127.4, 127.2, 127.1, 127.0, 77.8, 76.6, 73.2, 72.9, 70.3, 68.8,
46.7, 46.2, 21.2 ppm. HRMS (ESI) calcd. for C27H30NO5S [M + H]+
480.1839; found 480.1839.
(2S,3S,4R,5R)-2,5-Bis[(benzyloxy)methyl]tetrahydro-4-(methyl-
thio)-N-tosylfuran-3-amine (20b) (partial data): Pale yellow oil;
1
Rf = 0.30 (99:1, DCM/acetone). H NMR (400 MHz, CDCl3): δ = 6.02
(d, J = 8.0 Hz, 1 H), 4.18 (ddd, J = 6.5, 2.6, 2.6 Hz, 1 H), 3.34 (dd, J =
11.1, 2.0 Hz, 1 H), 3.28 (t, J = 6.5, Hz, 1 H), 2.20 (s, 3 H), 2.10 (s, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 129.2, 128.2, 128.0, 127.6,
127.3, 127.2, 126.6, 76.6 ppm.
(2S,3R,4S,5R)-2,5-Bis[(benzyloxy)methyl]tetrahydro-4-(phenyl-
thio)-N-tosylfuran-3-amine (21a): Pale yellow oil; Rf = 0.50 (98:2,
General Procedure for Ring opening Reactions of Aziridine 4:
To a solution of aziridine 4 (0.50 g, 1.0 mmol) in dry DMF (10 mL)
was added desired nucleophile (5.2 mmol) and Amberlyst 15
(1.1 mmol). The reaction mixture was stirred at room temperature
(N3, SMe, SPh), 60 °C (I, Br, Cl, SCN, CN), 100 °C (OAc) and monitored
by TLC plate. After reaction completion, the reaction mixture was
concentrated under reduced pressure. The desired product was ob-
tained after purification by column chromatography. Major and mi-
nor isomer of 19, 22, 23, 13, 25 and 26 were separable by silica
gel flash column chromatography while only the major isomer of
21 and 27 was separable by the same technique. Compound 20
was isolated as a mixture of two diastereomers in favor of the all-
trans isomers.
DCM/acetone). [α]D20 = +63.86 (c = 1.3, CH2Cl2). IR (cast film): ν =
˜
3267, 3061, 3030, 2863, 1597, 1495, 1473, 1452, 1439, 1331, 1305,
1
1291, 1160 cm–1. H NMR (500 MHz, CDCl3): δ = 7.51 (d, J = 8.0 Hz,
2 H), 7.41–7.12 (m, 17 H), 5.56 (d, J = 9.5 Hz, 1 H), 4.55 (d, J =
11.5 Hz, 1 H), 4.49 (s, 2 H), 4.44 (d, J = 11.5 Hz, 1 H), 4.08 (ddd, J =
5.0, 2.5, 2.5 Hz, 1 H), 4.05 (app. q, J = 5.0 Hz, 1 H), 3.86 (ddd, J =
9.5, 4.0, 4.0 Hz, 1 H), 3.68 (dd, J = 10.6, 2.5 Hz, 1 H), 3.51 (d, J =
5.0 Hz, 2 H), 3.43 (app. q, J = 4.0 Hz, 1 H), 3.41 (dd, J = 10.6, 2.5 Hz,
1 H), 2.37 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 143.3, 138.0,
137.7, 137.1, 133.6, 131.6, 129.6, 129.1, 128.7, 128.3, 128.2, 128.1,
127.8, 127.5, 127.4, 127.2, 84.8, 83.6, 74.0, 73.3, 71.6, 70.5, 60.6, 53.1,
21.5 ppm. HRMS (ESI) calcd. for C33H35NNaO5S2 [M + Na]+ 612.1849;
found 612.1845.
(2S,3S,4S,5S)-4-Azido-2,5-bis[(benzyloxy)methyl]tetrahydro-
N-tosylfuran-3-amine (19a): Pale yellow oil; Rf = 0.50 (98:2, DCM/
acetone). [α]D20 = +66.20 (c = 1.1, CHCl3). IR (cast film): ν = 3264,
(2S,3R,4S,5R)-2,5-Bis[(benzyloxy)methyl]tetrahydro-4-iodo-N-to-
sylfuran-3-amine (22a): Pale yellow oil; Rf = 0.30 (98:2, DCM/acet-
˜
2864, 2107, 1495, 1453, 1333, 1184 cm–1. 1H NMR (500 MHz, CDCl3):
δ = 7.63 (d, J = 8.5 Hz, 2 H), 7.43–7.23 (m, 10 H), 7.24 (d, J = 8.5 Hz,
2 H), 5.63 (d, J = 9.8 Hz, 1 H), 4.62 (d, J = 11.5 Hz, 1 H), 4.52 (d, J =
11.5 Hz, 1 H), 4.51 (s, 2 H), 4.04–4.02 (m, 2 H), 3.83–3.81 (m, 2 H),
3.70 (dd, J = 10.5, 2.8 Hz, 1 H), 3.59 (dd, J = 10.5, 2.8 Hz, 1 H), 3.47
(dd, J = 10.4, 4.2 Hz, 1 H), 3.43 (dd, J = 10.4, 5.5 Hz, 1 H), 2.42 (s, 3
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 143.6, 137.9, 137.4, 136.9,
129.8, 128.8, 128.4, 128.3, 128.2, 127.7 (two overlapping carbons),
127.1, 84.6, 82.6, 74.2, 73.5, 71.3, 69.8, 68.2, 60.7, 21.6 ppm. HRMS
(ESI) calcd. for C27H30N4NaO5S [M + Na]+ 545.1829; found 545.1825.
one). [α]D20 = +16.20 (c = 1.60, CH2Cl2). IR (cast film): ν = 3263, 2919,
˜
1
2862, 1495, 1452, 1332, 1161 cm–1. H NMR (500 MHz, CDCl3): δ =
7.63 (d, J = 8.0 Hz, 2 H), 7.41–7.30 (m, 10 H), 7.22 (d, J = 8.0 Hz, 2
H), 5.47 (d, J = 9.2 Hz, 1 H), 4.60 (d, J = 11.6 Hz, 1 H), 4.54 (s, 2 H),
4.49 (d, J = 11.6 Hz, 1 H), 4.32 (ddd, J = 6.5, 2.5, 2.5 Hz, 1 H), 4.17
(ddd, J = 9.2, 6.5, 6.5 Hz, 1 H), 4.02–4.00 (m, 1 H), 3.97 (dd, J = 6.5,
6.5 Hz, 1 H), 3.55–3.67 (m, 4 H), 2.41 (s, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 143.2, 137.6, 137.0, 136.9, 129.3, 128.3, 127.9, 127.6,
127.5, 127.3, 127.2, 127.0, 86.4, 83.3, 73.4, 73.0, 69.9, 68.8, 64.2, 22.4,
21.9 ppm. HRMS (ESI) calcd. for C27H30INNaO5S [M + Na]+ 630.0782;
found 630.0772.
(2S,3R,4R,5S)-4-Azido-2,5-bis[(benzyloxy)methyl]tetrahydro-N-
tosylfuran-3-amine (19b): Pale yellow oil; Rf = 0.60 (98:2, DCM/
acetone). [α]D20 = +3.76 (c = 0.51, CHCl3). IR (cast film): ν = 3296, (2S,3S,4R,5R)-2,5-Bis[(benzyloxy)methyl]tetrahydro-4-iodo-N-to-
˜
2919, 2865, 2107, 1453, 1340, 1184 cm–1. 1H NMR (500 MHz, CDCl3): sylfuran-3-amine (22b): Pale yellow oil; Rf = 0.70 (98:2, DCM/acet-
δ = 7.61 (d, J = 8.5 Hz, 2 H), 7.44–7.34 (m, 10 H), 7.23 (d, J = 8.5 Hz,
2 H), 5.97 (d, J = 8.0 Hz, 1 H), 4.65 (d, J = 12.0 Hz, 1 H), 4.59 (d, J =
11.5 Hz, 1 H), 4.54 (d, J = 11.5 Hz, 1 H), 4.53 (d, J = 12.0 Hz, 1 H),
one). [α]D20 = +47.03 (c = 0.54, CH2Cl2). IR (cast film): ν = 3265, 2917,
˜
2862, 1453, 1341, 1206, 1163, 1092 cm–1. 1H NMR (500 MHz, CDCl3):
δ = 7.59 (d, J = 10.5 Hz, 2 H), 7.43–7.27 (m, 10 H), 7.20–7.18 (m, 2
4.36 (app. q, J = 5.5 Hz, 1 H), 4.14–4.12 (m, 2 H), 4.07–4.04 (m, 1 H), H), 6.19 (d, J = 7.2 Hz, 1 H), 4.63 (d, J = 14.5 Hz, 1 H), 4.59 (d, J =
3.64 (dd, J = 11.2, 2.3 Hz, 1 H), 3.62 (app d, J = 5.5 Hz, 2 H), 3.41
14.5 Hz, 1 H), 4.52 (d, J = 14.5 Hz, 1 H), 4.45 (d, J = 14.5 Hz, 1 H),
4.36–4.33 (m, 1 H), 4.31–4.29 (m, 2 H), 4.00 (app. q, J = 5.0 Hz, 1 H),
(dd, J = 11.2, 1.8 Hz, 1 H), 2.43 (s, 3 H) ppm. 13C NMR (125 MHz,
Eur. J. Org. Chem. 2016, 1367–1379
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3.79 (dd, J = 12.5, 6.0 Hz, 1 H), 3.69–3.62 (m, 2 H), 3.42 (dd, J = 14.5,
2.0 Hz, 1 H), 2.41 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 143.4,
2 H), 5.51 (d, J = 9.7 Hz, 1 H), 4.60 (d, J = 12.0 Hz, 1 H), 4.51 (d, J =
11.5 Hz, 1 H), 4.49 (d, J = 11.5 Hz, 1 H), 4.46 (d, J = 12.0 Hz, 1 H),
137.7, 136.9, 136.8, 129.5, 128.6, 128.3, 128.1, 128.0, 127.7, 127.6, 4.29 (ddd, J = 5.0, 2.5, 2.5 Hz, 1 H), 4.03–4.01 (m, 1 H), 3.93 (ddd,
127.1, 77.9, 76.6, 75.1, 74.3, 73.5, 69.5, 64.8, 30.7, 21.6 ppm. HRMS
J = 9.7, 5.2, 5.2 Hz, 1 H), 3.78 (dd, J = 10.9, 2.2 Hz, 1 H), 3.61 (dd,
(ESI) calcd. for C27H30INNaO5S [M + Na]+ 630.0782; found 630.0779. J = 10.9, 2.5 Hz, 1 H), 3.53–3.48 (m, 2 H), 3.37 (dd, J = 10.6, 4.1 Hz,
1 H), 2.41 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 143.6, 137.2,
136.7, 136.5, 129.4, 128.4, 128.0, 127.9, 127.7, 127.4, 127.3, 126.7,
(2S,3R,4S,5R)-2,5-Bis[(benzyloxy)methyl]-4-bromo-tetrahydro-
N-tosylfuran-3-amine (23a): Pale yellow oil; Rf = 0.40 (98:2, DCM/
110.0, 83.2, 83.0, 73.6, 73.1, 69.9, 69.1, 59.6, 51.2, 21.2 ppm. HRMS
acetone). [α]D20 = +16.41 (c = 1.20, CH2Cl2). IR (cast film): ν = 3265,
˜
(ESI) calcd. for C28H30N2NaO5S2 [M + Na]+ 561.1488; found 561.1476.
2918, 2864, 1495, 1453, 1332, 1266 cm–1. 1H NMR (400 MHz, CDCl3):
(2S,3S,4R,5R)-2,5-Bis[(benzyloxy)methyl]tetrahydro-4-thio-
cyanato-N-tosylfuran-3-amine (25b): Pale yellow oil; Rf = 0.50
δ = 7.63 (d, J = 8.0 Hz, 2 H), 7.41–7.30 (m, 10 H), 7.21 (d, J = 8.0 Hz,
2 H), 5.55 (d, J = 9.6 Hz, 1 H), 4.55 (d, J = 11.6 Hz, 1 H), 4.54 (s, 2
H), 4.47 (d, J = 11.6 Hz, 1 H), 4.31 (ddd, J = 5.2, 2.4, 2.4 Hz, 1 H),
4.16 (ddd, J = 9.6, 5.2, 5.2 Hz, 1 H), 4.04 (ddd, J = 5.2, 5.2, 3.6 Hz, 1
H), 3.97 (dd, J = 5.2, 5.2 Hz, 1 H), 3.69 (dd, J = 11.2, 2.4 Hz, 1 H),
3.62–3.54 (m, 3 H), 2.41 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 143.2, 137.6, 137.1, 136.7, 129.3, 128.3, 127.9, 127.8, 127.7, 127.3,
127.2, 126.9, 85.3, 83.6, 73.6, 73.0, 69.9, 69.7, 63.1, 48.9, 21.2 ppm.
HRMS (ESI) calcd. for C27H31BrNO5S [M + H]+ 560.1101; found
560.1090.
(98:2, DCM/acetone). [α]D20 = +31.89 (c = 1.2, CH2Cl2). IR: ν = 3277,
˜
2917, 2863, 2155, 1453, 1349, 1164 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 7.54 (d, J = 8.0 Hz, 2 H), 7.46–7.31 (m, 10 H), 7.17 (d, J = 8.4 Hz,
2 H), 5.74 (d, J = 8.8 Hz, 1 H), 4.63 (d, J = 12.0 Hz, 1 H), 4.50–4.44
(m, 4 H), 4.22–4.18 (m, 2 H), 3.92 (dd, J = 8.4, 8.4 Hz, 1 H), 3.71 (app
d, J = 2.8 Hz, 2 H), 3.58 (dd, J = 11.5, 2.0 Hz, 1 H), 3.41 (dd, J = 11.5,
1.6 Hz, 1 H), 2.41 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 143.7,
137.3, 136.9, 136.8, 129.7, 128.9, 128.5, 128.4, 128.1, 128.0, 127.8,
127.2, 112.0, 77.0, 76.8, 74.2, 73.7, 70.5, 69.7, 60.5, 54.0, 21.6 ppm.
HRMS (ESI) calcd. for C28H30N2NaO5S2 [M + Na]+ 561.1488; found
561.1484.
(2S,3S,4R,5R)-2,5-Bis[(benzyloxy)methyl]-4-bromo-tetrahydro-
N-tosylfuran-3-amine (23b): Pale yellow oil; Rf = 0.60 (98:2, DCM/
acetone). IR (cast film): ν = 3265, 2918, 2864, 1495, 1453, 1332,
˜
1
1266 cm–1. H NMR (500 MHz, CDCl3): δ = 7.61 (d, J = 8.4 Hz, 2 H),
(2S,3R,4S,5S)-2,5-Bis[(benzyloxy)methyl]tetrahydro-4-(tosyl-
amino)furan-3-carbonitrile (26a): Pale yellow oil; Rf = 0.50 (98:2,
7.41–7.32 (m, 10 H), 7.22 (d, J = 8.4 Hz, 2 H), 6.33 (d, J = 7.5 Hz, 1
H), 4.66–4.45 (m, 4 H), 4.41–4.34 (m, 4 H), 4.18 (ddd, J = 7.5, 7.5,
4.6 Hz, 1 H), 3.75 (dd, J = 10.5, 5.3 Hz, 1 H), 3.70 (dd, J = 11.4, 3.3 Hz,
1 H), 3.66 (dd, J = 10.5, 4.4 Hz, 1 H), 3.44 (dd, J = 11.4, 1.6 Hz, 1 H),
2.42 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 143.6, 137.9, 136.9,
136.8, 129.7, 128.8, 128.4, 128.3, 128.1, 127.8, 127.7, 127.1, 78.0, 76.5,
74.4, 73.5, 71.9, 69.3, 63.8, 54.3, 21.6 ppm. HRMS (ESI) calcd. for
DCM/acetone). [α]D20 = +19.80 (c = 0.52, CHCl3). IR (cast film): ν =
˜
3441, 3270, 2921, 2865, 2246, 1597, 1495, 1453, 1336, 1306, 1185,
1
1162, 1091 cm–1. H NMR (500 MHz, CDCl3): δ = 7.60 (d, J = 8.0 Hz,
2 H), 7.45–7.31 (m, 10 H), 7.27 (d, J = 8.0 Hz, 2 H), 5.40 (d, J = 9.5 Hz,
1 H), 4.63–4.56 (m, 1 H), 4.54–4.50 (m, 2 H), 4.47 (ddd, J = 4.4, 2.2,
2.2 Hz, 1 H), 4.17 (ddd, J = 8.6, 4.6, 4.6 Hz, 1 H), 4.06 (app q, J =
4.4 Hz, 1 H), 3.78–3.73 (m, 2 H), 3.54 (dd, J = 10.6, 2.5 Hz, 1 H), 3.51
(dd, J = 10.5, 4.2 Hz, 1 H), 3.46 (dd, J = 10.5, 5.0 Hz, 1 H), 2.95 (dd,
J = 4.6, 4.6 Hz, 1 H), 2.44 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 144.0, 137.5, 136.8, 136.6, 129.9, 128.9, 128.7, 128.4, 128.1, 127.9,
127.8, 127.1, 118.8, 84.8, 81.5, 74.1, 73.5, 71.1, 69.5, 59.7, 38.0, 21.6
C
27H31BrNO5S [M + H]+ 560.1101; found 560.1099.
(2S,3R,4S,5R)-2,5-Bis[(benzyloxy)methyl]-4-chloro-tetrahydro-
N-tosylfuran-3-amine (24a): Pale yellow oil; Rf = 0.40 (98:2, DCM/
acetone). [α]D20 = +24.24 (c = 0.50, CHCl3). IR (cast film): ν = 3265,
˜
1
2920, 2863, 1598, 1495, 1453, 1360, 1333 cm–1. H NMR (500 MHz,
+
ppm. HRMS (ESI) calcd. for C28H30NaN2O5S [M + Na] 529.1768;
CDCl3): δ = 7.59 (d, J = 8.0 Hz, 2 H), 7.41–7.26 (m, 10 H), 7.20 (d, J =
8.0 Hz, 2 H), 5.52 (d, J = 9.0 Hz, 1 H), 4.58 (d, J = 11.5 Hz, 1 H), 4.52
(s, 2 H), 4.47 (d, J = 11.5 Hz, 1 H), 4.22 (ddd, J = 4.2, 2.5, 2.5 Hz, 1
H), 4.06–4.03 (m, 2 H), 3.97 (dd, J = 4.2, 4.2 Hz, 1 H), 3.68 (dd, J =
10.8, 2.5 Hz, 1 H), 3.58 (dd, J = 10.8, 2.5 Hz, 1 H), 3.58–3.53 (m, 2 H),
2.40 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 143.6, 137.9, 137.5,
136.9, 129.6, 128.8, 128.3, 128.3, 128.1, 127.7, 127.6, 127.1, 85.6, 84.1,
74.1, 73.4, 70.5, 70.2, 63.5, 61.1, 21.5 ppm. HRMS (ESI) calcd. for
found 529.1759.
(2S,3S,4R,5S)-2,5-Bis[(benzyloxy)methyl]tetrahydro-4-(tosyl-
amino)furan-3-carbonitrile (26b): Pale yellow oil; Rf = 0.60 (98:2,
DCM/acetone). [α]D20 = +60.62 (c = 1.20, CHCl3). IR (cast film): ν =
˜
3280, 3063, 3031, 2921, 2865, 2246, 1597, 1495, 1453, 1255, 1163,
1
1091 cm–1. H NMR (500 MHz, CDCl3): δ = 7.59 (d, J = 8.0 Hz, 2 H),
7.43–7.29 (m, 10 H), 7.22 (d, J = 8.0 Hz, 2 H), 5.79 (d, J = 9.5 Hz, 1
H), 4.60 (dd, J = 12, 2.2 Hz, 2 H), 4.52–4.44 (m, 4 H), 4.23 (ddd, J =
7.8, 2.1, 2.1 Hz, 1 H), 3.5 (app d, J = 3.5 Hz, 2 H), 3.63 (dd, J = 11.6.
2.4 Hz, 1 H), 3.49 (dd, J = 11.6, 1.8 Hz, 1 H), 3.32 (dd, J = 7.8, 7.8 Hz,
1 H), 2.42 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 144.0, 137.5,
136.8, 136.7, 129.8, 128.8, 128.5, 128.4, 128.0 (2 C), 127.9, 127.1,
117.0, 77.8, 76.4, 74.2, 73.9, 71.1, 69.9, 58.8, 38.3, 21.6 ppm. HRMS
(ESI) calcd. for C28H30NaN2O5S [M + Na] + 529.1768; found 529.1762.
C
27H31ClNO5S [M + H]+ 516.1606; found 516.1603.
(2S,3S,4R,5R)-2,5-Bis[(benzyloxy)methyl]-4-chloro-tetrahydro-
N-tosylfuran-3-amine (24b): Pale yellow oil; Rf = 0.50 (98:2, DCM/
acetone). [α]D20 = +25.83 (c = 0.37, CH2Cl2). IR (cast film): ν = 3263,
˜
1
2918, 2865, 1598, 1495, 1453, 1343, 1305 cm–1. H NMR (400 MHz,
CDCl3): δ = 7.61 (d, J = 8.0 Hz, 2 H), 7.42–7.31 (m, 10 H), 7.22 (d, J =
8.0 Hz, 2 H), 6.32 (d, J = 6.8 Hz, 1 H), 4.66–4.33 (m, 6 H), 4.30 (ddd,
J = 6.4, 3.2, 1.6 Hz, 1 H), 4.07 (ddd, J = 6.8, 6.8, 4.0 Hz, 1 H), 3.74–
3.65 (m, 3 H), 3.44 (dd, J = 11.2, 2.0 Hz, 1 H), 2.41 (s, 3 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 143.6, 137.9, 136.9 (two overlapping
carbons), 129.7, 128.8, 128.4, 128.3, 128.1, 127.8, 127.7, 127.1, 78.3,
76.5, 74.4, 73.6, 70.0, 69.2, 63.5, 63.4, 21.6 ppm. HRMS (ESI) calcd.
for C27H31ClNO5S [M + H]+ 516.1606; found 516.1608.
(2R,3S,4R,5S)-2,5-Bis[(benzyloxy)methyl]tetrahydro-4-(tosyl-
amino)furan-3-yl Acetate (27a): Pale yellow oil; Rf = 0.40 (98:2,
DCM/acetone). [α]D20 = +30.69 (c = 1.00, CHCl3). IR (cast film): ν =
˜
3270, 2923, 2864, 1741, 1453, 1366, 1337, 1234, 1163 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 7.48 (d, J = 8.0 Hz, 2 H), 7.43–7.26 (m, 10 H),
7.18 (d, J = 8.0 Hz, 2 H), 5.57 (d, J = 10.0 Hz, 1 H), 4.78 (dd, J = 2.1,
2.1 Hz, 1 H), 4.56 (d, J = 11.0 Hz, 1 H), 4.53 (s, 2 H), 4.50 (d, J =
(2S,3R,4S,5R)-2,5-Bis[(benzyloxy)methyl]tetrahydro-4-thio- 11.0 Hz, 1 H), 4.08 (ddd, J = 6.0, 4.1, 4.1 Hz, 1 H), 4.09–4.04 (m, 1
cyanato-N-tosylfuran-3-amine (25a): Pale yellow oil; Rf = 0.40
H), 3.91 (ddd, J = 10.0, 4.1, 2.1 Hz, 1 H), 3.74–3.67 (m, 2 H), 3.51 (dd,
(98:2, DCM/acetone). [α]D20 = +31.31 (c = 0.70, CH2Cl2). IR: ν = 3264, J = 10.4, 4.1 Hz, 1 H), 3.48 (dd, J = 10.4, 6.0 Hz, 1 H), 2.39 (s, 3 H),
˜
2917, 2864, 2155, 1453, 1334, 1161 cm–1. 1H NMR (400 MHz, CDCl3): 1.90 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 169.8, 143.0, 137.6,
δ = 7.59 (d, J = 8.0 Hz, 2 H), 7.43–7.28 (m, 10 H), 7.23 (d, J = 8.0 Hz,
137.3, 136.5, 129.1, 128.5, 128.0, 127.9, 127.8, 127.3, 127.2, 126.6,
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84.1, 82.9, 80.7, 73.8, 73.0, 71.4, 69.5, 59.6, 21.1, 20.0 ppm. HRMS
(ESI) calcd. for C29H34NO7S [M + H]+ 540.2050; found 540.2041.
Acknowledgments
The authors acknowledge create Molecular Imaging Probes
(cMIP), the Natural Sciences and Engineering Research Council
of Canada (NSERC) and the Canadian Institutes of Health Re-
search (CIHR) for their funding and support. Dr. Bob McDonald
is thanked for obtaining the crystal structure of 16, and Mark
Miskolzie for valuable discussions related to NMR spectroscopy.
(2R,3R,4S,5S)-2,5-Bis[(benzyloxy)methyl]tetrahydro-4-(tosyl-
amino)furan-3-yl Acetate (27b): (Partial data obtained from 16a/
1
b mixture): H NMR (400 MHz, CDCl3): δ = 5.69 (d, J = 8.0 Hz, 1 H),
5.28 (t, J = 6.0 Hz, 1 H), 1.60 (S, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 129.1, 128.3, 127.9, 127.5, 127.3, 126.6 ppm.
General Procedure for Azide Reduction: LiAlH4 (0.07 g, 1.9 mmol)
was added in a single portion to a solution of azide adduct 19a or
19b, (0.20 g, 0.38 mmol) in dry THF (13 mL) at 0 °C. The reaction
mixture was stirred at 0 °C for one hour and then warmed to room
temperature and stirred for one extra hour. After reaction comple-
tion, the mixture was cooled down to 0 °C and quenched by satu-
rated Na2SO4 (10 mL). The mixture was then filtered through Celite
and the Celite plug was washed with Et2O. The organic layer was
separated and the aqueous layer was then extracted with Et2O (3 ×
10 mL). The combined organic layers was dried with MgSO4 and
concentrated under reduced pressure. Desired product was ob-
tained quantitatively as a pure single isomer.
Keywords: Oxygen heterocycles · Nitrogen heterocycles ·
Carbohydrates · Small-ring systems · Ring opening · Michael
addition
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(2S,3S,4S,5S)-2,5-Bis[(benzyloxy)methyl]tetrahydro-N3-tosyl-
furan-3,4-diamine (28a): Pale yellow oil; Rf = 0.30 (98:2, DCM/
MeOH). [α]D20 = +37.30 (c = 0.58, CHCl3). IR (cast film): ν = 3276,
˜
2862, 1598, 1495, 1453, 1328, 1160 cm–1. 1H NMR (500 MHz, CDCl3):
δ = 7.57 (d, J = 8.0 Hz, 2 H), 7.35–7.22 (m, 10 H), 7.15 (d, J = 8.0 Hz,
2 H), 5.39 (broad, 1 H), 4.56 (d, J = 11.7 Hz, 1 H), 4.50 (d, J = 11.7 Hz,
1 H), 4.44 (d, J = 12.0 Hz, 1 H), 4.39 (d, J = 12.0 Hz, 1 H), 3.86 (ddd,
J = 5.5, 4.5, 4.5 Hz, 1 H), 3.82 (ddd, J = 5.5, 3.5, 3.5 Hz, 1 H), 3.63
(dd, J = 10.3, 3.5 Hz, 1 H), 3.56 (dd, J = 10.3, 3.5 Hz, 1 H), 3.51–3.49
(m, 1 H), 3.42 (dd, J = 10.3, 3.5 Hz, 1 H), 3.32 (dd, J = 10.3, 4.5 Hz,
1 H), 3.21–3.19 (m, 1 H), 2.39 (s, 3 H), 1.54 (br. s, 2 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 143.4, 137.9, 137.7, 137.5, 129.7, 128.6, 128.4,
128.0, 127.7, 127.6, 127.1, 84.8, 83.0, 73.9, 73.4, 71.6, 70.5, 63.6, 62.0,
21.5 ppm. HRMS (ESI) calcd. for C27H33N2O5S 497.2105 [M + H]+;
found 497.2098.
(2S,3R,4R,5S)-2,5-Bis[(benzyloxy)methyl]tetrahydro-N3-tosyl-
furan-3,4-diamine (28b): Pale yellow oil; Rf = 0.30 (98:2, DCM/
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˜
1
2918, 2862, 1495, 1453, 1332, 1162, 1093 cm–1. H NMR (500 MHz,
CDCl3): δ = 7.51 (d, J = 8.0 Hz, 2 H), 7.45–7.32 (m, 10 H), 7.16 (d, J =
8.0 Hz, 2 H), 5.53 (d, J = 8.5 Hz, 1 H), 4.63 (d, J = 11.7 Hz, 1 H), 4.54
(s, 2 H), 4.41 (d, J = 11.7 Hz, 1 H), 4.18 (ddd, J = 7.7, 2.5, 2.5 Hz, 1
H), 4.03 (ddd, J = 8.5, 2.2, 2.2 Hz, 1 H), 3.89 (ddd, J = 8.5, 8.5, 8.5 Hz,
1 H), 3.74 (dd, J = 10.5, 2.5 Hz, 1 H), 3.65 (dd, J = 10.5, 2.5 Hz, 1 H),
3.51 (dd, J = 11.0, 2.2 Hz, 1 H), 3.48 (m, 1 H), 3.23 (dd, J = 11.0,
2.2 Hz, 1 H), 2.41 (s, 3 H), 1.35 (br. s, 2 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 143.3, 138.1, 137.8, 137.3, 129.7, 128.7, 128.5, 128.1,
128.0, 127.8, 127.6, 126.9, 77.7, 76.2, 74.0, 73.7, 70.7, 70.3, 63.3, 59.4,
21.5 ppm. HRMS (ESI) calcd. for C27H33N2O5S 497.2105 [M + H]+;
found 497.2097.
Procedure for Asymmetric Conjugate Addition: A mixture of 28a
or 28b (0.099 g, 0.20 mmol), D-mandelic acid (0.03 g, 0.20 mmol)
DMAP (0.024 g, 0.20 mmol), and enone 30 (0.18 g, 1.0 mmol) was
stirred in nitropropane 29 (8 mL) at room temperature for 4 d. The
reaction mixture was concentrated under reduced pressure and the
residue was then purified by flash chromatography on silica gel to
afford the desired Michael adduct 31.[34] Enantiomeric excess: (70 %
with 28a), determined by HPLC (Chiralpak AS-H column, hexane/
iPrOH, 80:20, flow rate 1.00 mL/min, tmajor = 8 min, tminor = 9.5 min,
λ = 254 nm), [α]D20 = +33.89 (c = 0.8, CH2Cl2). Enantiomeric excess:
(76 % with 28b), determined by HPLC (Chiralpak AS-H column, hex-
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ane/iPrOH, 80:20, flow rate 1.00 mL/min, tminor = 8 min, tmajor
=
9.5 min, λ = 254 nm), [α]D20 = –31.83 (c = 0.88, CH2Cl2).
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Received: December 8, 2015
Published Online: February 10, 2016
Eur. J. Org. Chem. 2016, 1367–1379
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