The preparation of 2-iodoamides from glucals and their further transformations into oxazolines

Article abstract of DOI:10.1016/j.tetlet.2004.06.082

2-Deoxy-2-iodo-glycosylamides have been prepared from a variety of protected d-glucals by their reaction with N-iodosuccinimide and amides. Benzyl protected 2-iodoamides, when treated with sodium hydride and 15-crown-5, gave stable C1 N-linked 2-glycooxaz

Full text of DOI:10.1016/j.tetlet.2004.06.082

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6501–6504
The preparation of 2-iodoamides from glucals and their
further transformations into oxazolines
Michael De Castro and Cecilia H. Marzabadi*
Department of Chemistry and Biochemistry, Seton Hall University, 400 South Orange Ave., South Orange, NJ 07079, USA
Received 9 March 2004; revised 22 May 2004; accepted 21 June 2004
Available online 20 July 2004
Abstract—2-Deoxy-2-iodo-glycosylamides have been prepared from a variety of protected D-glucals by their reaction with N-iodo-
succinimide and amides. Benzyl protected 2-iodoamides, when treated with sodium hydride and 15-crown-5, gave stable C1
N-linked 2-glycooxazolines as the major products. Silyl protected 2-iodoamides afforded the C1 O-linked 2-glycooxazolines; pre-
sumably by the rearrangement of unstable N-acylaziridine intermediates.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The haloglycosylation reaction, developed by Lemieux
et al.1 and Thiem et al.2 has been used extensively for
the preparation of trans-configured 2-haloglycosides
from glycals and alcohols. Although a variety of halo-
genating agents have been used to effect this transforma-
tion, the greatest selectivity is obtained when sources of
I+ (e.g., N-iodosuccinimide (NIS)) are employed. The a-
manno products are obtained preferentially from
protected D-glucals and axial, bridging, iodonium ion
intermediates have been proposed. Subsequent reductive
deiodination of the 2-iodoglycosides with trialkylstann-
anes leads to the formation of 2-deoxy-a-glycosides
(Scheme 1).
that have been shown to exist preferentially in the alter-
1
nate C4 chair conformation.7
As part of a research program aimed at the synthesis of
carbohydrate-fused heterocycles, we became interested
in the iodine promoted addition of primary, aliphatic,
and aromatic amides to glycals. We envisioned that it
should be possible to prepare both oxazolines and
N-acylaziridines from the cyclization of the resulting
2-iodoamide products using different reaction condi-
tions (Scheme 2).
There have been numerous reports detailing the synthe-
sis and isolation of C1 O-linked 2-glycooxazolines from
N-acyl-2-amino-2-deoxy-glycosyl acetates8 and these
cyclic molecules have been shown to be effective glycosyl
donors.9 However, there have only been limited
Other nucleophiles have also been incorporated at the
C1 position of sugars using this protocol.3–5 When the
nucleophiles employed in the glycal addition reactions
are weak, the imide anion byproduct formed from NIS
is frequently observed to compete for the C1 position.
This has lead to the isolation of glycosyl succinimides6
RO
O
RO
RO
O
N
RO
RO
RO
I
RO
RO
RO
R'
NIS
O
O
8 R' = Ph
9
= CH3
NH
C
R'CONH2
RO
RO
RO
1
O
O
N
4 R' = Ph
R'
a, R = Ac
b, R = Bn
c, R = TBDMS
5
6
7
= CH3
= CH2CH3
= CCl3
Scheme 1. Iodoglycosylation reaction of D-glucals.
Keywords: Iodoamidation; Glucals; 2-Glycooxazolines.
C
O
R'
10 R' = Ph
*
Corresponding author. Tel.: +1-973-761-9032; fax: +1-973-761-
9772; e-mail: marzabce@shu.edu
Scheme 2. Alternate cyclization routes for 2-iodoglycosylamides.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.082

6502
M. De Castro, C. H. Marzabadi / Tetrahedron Letters 45 (2004) 6501–6504
previous accounts detailing the synthesis and isolation
of the C1 N-linked analogs by Ritter-like reactions.10
The 1,2-aziridino sugars have been even more elusive
targets and have been proposed as unstable intermedi-
ates in several reactions.11–13
compound isolated from the reaction mixture exists in
the alternate C4 chair conformer. So it appears as if
1
the tendency of the silyloxy groups to prefer axial posi-
tions16 and the inverse anomeric effect, override the
steric demands of the bulky substituents in the C1 and
C2 position in this compound.17 This conformation
may be experiencing attractive steric interactions
between the silicon groups and the aromatic ring of
the amide, which help stabilize this conformer.18 Similar
diastereoselectivities were observed with the TBDMS
protected glycal and propionamide, however, with acet-
amide and trichloroacetamide as the coupling partners,
a higher proportion of the 4C1 conformers were
observed. This may be because of fewer stabilizing inter-
actions in the alternate 1C4 conformers with the less
bulky alkyl groups. The addition of the electron defi-
cient amide, trichloroacetamide, also gave rise to a
reverse in diastereoselectivity similar to that observed
with tri-O-acetyl-D-glucal.
Herein, we report on our synthetic studies towards the
preparation of oxazolines and aziridines. The effects of
the type of primary amide (alkyl or aryl) and the sugar
protecting groups on the addition and subsequent cycli-
zation reactions will be discussed.
Iodoamidation reactions were carried out on a variety of
protected glucals: tri-O-acetyl-D-glucal, tri-O-benzyl-
D-glucal and tris-O-tert-butyldimethylsilyl-D-glucal
(Scheme 2, 1) with several primary alkyl and aryl
amides.3,14,15 Diastereomeric mixtures of gluco and
manno iodoamides 4–7 were obtained from these reac-
tions (Table 1).
In general, the highest yields and greatest selectivities
were obtained when benzamide was used as the nucleo-
phile (Table 1, entries 1–3). In the reactions with benz-
amide, the benzyl protected sugar afforded primarily
the a-manno addition product, whereas the acetyl pro-
tected glucal gave mainly the b-gluco product. Further-
more, the electron poor acetylated glucal reacted more
sluggishly than the benzyl protected precursor and gave
lower yields of product.
Methods were then evaluated to cyclize the iodobenz-
amides using both the amide nitrogen and oxygen as
the potential nucleophiles (Table 2).
We carried out the cyclization of the benzyl protected
benzamide analog 4b with sodium hydride and 15-
crown-5 in dichloromethane (Table 2, entry 1), antici-
pating that we would isolate aziridine 10b.19 Spectro-
scopic analysis of the exclusive product isolated from
this reaction suggested that instead, the C1 N-linked
oxazoline 8b was prepared; a result of cyclization
through the amide carbonyl oxygen.15
Interestingly, the tert-butyldimethylsilyl (TBDMS) pro-
tected glucal afforded only a single addition product in
high yield when reacted with NIS and benzamide. Care-
ful analysis of the proton NMR spectrum (500MHz;
CDCl3) of this compound showed a large 3J value
(10.5Hz) for coupling between the protons at C1 and
C2, a small 3J2,3 (1.5Hz) and the remaining ring protons
at C4 and C5 appeared as singlets. This suggests that the
When we applied these same conditions to the TBDMS
protected iodobenzamide 4c (Table 2, entry 2), unex-
pectedly, the C1 O-linked oxazoline 13c (Scheme 4)8b
was obtained and not the predicted aziridino sugar
10c20 nor the C1 N-linked oxazoline 8c.10a
Table 1. Proportions of diastereomeric iodoamides obtained from glucalsa
Entry
Iodoamide
Sugar R=
Amide R0 =
a-Manno
b-Manno
a-Gluco
b-Gluco
Isolated
yield (%)b
1
2
3
4
5
6
4a
4b
4c
5c
6c
7c
Ac
Bn
Ph
Ph
6
Trace
0
1
0
0
0
0
2
10
1
42
85
82
50
81
62
2
TBDMS
TBDMS
TBDMS
TBDMS
Ph
1 (1C4)
0
0
CH3
CH2CH3
CCl3
1 (1C4) 10 (4C1)
1 (1C4)
0
0
0
1.5
0
Trace (4C1)
3
a Determined by integration of the anomeric protons in the 1H NMR spectrum obtained in CDCl3.
b Represents product recovered following extractive workup and subsequent chromatographic purification (SiO2).
Table 2. Basic cyclization of iodobenzamides 4
Entry
Iodoamide
Base
Conditions
N-Oxazolinea
O-Oxazolinea
N-Aziridinea
1
2
3
4
5
6
7
4b
4c
4b
4c
4b
4b
4c
NaH, 15-crown-5
NaH, 15-crown-5
NaH, 15-crown-5
NaH, 15-crown-5
NaH
CH2Cl2, ꢀ78ꢁC (2h)––rt (5h)
CH2Cl2, ꢀ78ꢁC (2h)––rt (5h)
CH2Cl2, 25ꢁC, 2h
CH2Cl2, 25ꢁC, 2h
CH2Cl2, 25ꢁC, 24h
THF, 25ꢁC, 48h
8b, 81%
––
––
––
––
––
––
––
––
––
13c, 82%
13b, 25%
13c, 82%
13b, 95%
––
8b, 65%
––
––
NaH
NaH
8b, 77%
––
THF, 25ꢁC, 5h
13c, 79%
a Represents yields of isolated products.

M. De Castro, C. H. Marzabadi / Tetrahedron Letters 45 (2004) 6501–6504
6503
room temperature failed to cause equilibration. There-
fore, the aziridine intermediate seems likely. The azir-
idine forms more readily when the amide oxygen is
coordinated to the sodium counter ion thus prohibiting
cyclization to produce the C1 N-linked oxazoline. The
exclusive formation of the C1 O-linked oxazoline from
the TBDMS protected iodoamide is probably a conse-
quence of stereoelectronic effects operating at the C1
position in the altered chair conformer, which lead to
the facile formation of the equatorially disposed azir-
idine. The aziridine then rearranges to the O-linked
oxazoline with retention of the 1C4 chair. Further mech-
anistic studies are in progress to further validate the pro-
posed pathway.
Scheme 3. Hydrolysis of benzyl protected oxazolines.
The basic cyclization reactions were also carried out at
room temperature both with and without added crown
ether and in different solvents (Table 2, entries 3–7).
For the benzyl protected sugar, the use of crown ether
or coordinating solvent served to accelerate the cycliza-
tion reaction and favored nucleophilic attack at C2 by
the amide oxygen. Without crown ether (Table 2, entry
5), C1 O-linked oxazoline was formed as the major
product. For the TBDMS protected sugar, the C1 O-
linked product was obtained under all reaction condi-
tions studied.
Acknowledgements
The authors would like to acknowledge the donors of
the Petroleum Research Fund, administered by the
American Chemical Society, for financial support of this
research and the National Science Foundation (CRF
0091895) for funding to purchase the 500MHz NMR
spectrometer used in these studies. CM is grateful to
the Clare Boothe Luce Fund for a Professorship.
Structural characterization of both the C1 N-linked and
C1 O-linked oxazolines was carried out using spectro-
scopic techniques, elemental analysis, comparison to
similar known reference compounds and by acid hydro-
lysis of the oxazolines to their acyclic products. Treat-
ment of the C1 N-linked oxazoline 8b with HCl in
aqueous THF provided glycosylamine 11b in 48% yield
along with unreacted starting material (Scheme 3).
Hydrolysis of the C1 O-linked analog 13b gave 2-amino-
2-deoxy-N-benzoyl-D-glucopyranose 14b in 38% yield
along with recovered oxazoline.
References and notes
1. Lemieux, R. U.; Hendriks, K. B.; Stick, R. V.; James, K.
J. Am. Chem. Soc. 1975, 97, 4056–4062.
2. Thiem, J.; Karl, H.; Schwentner, J. Synthesis 1978, 696.
3. Roush, W. R.; Briner, K.; Sebesta, D. P. Synlett 1993,
264–265.
4. Marzabadi, C.; Spilling, C. D. J. Org. Chem. 1993, 58,
3761–3766.
5. Kottenhahn, M.; Kessler, H. Liebigs Ann. Chem. 1991,
727–744.
6. Thieme, J.; Klaffke, W. Top. Curr. Chem. 1990, 154,
285–333.
7. The preferential formation of these products has been
explained by the existence of an inverse anomeric effect
caused by the C1 nitrogen. See: Deslongchamps, P.
Stereoelectronic Effects in Organic Chemistry; Pergamon:
New York, 1983.
This surprising formation of two distinct oxazoline
products from these reactions suggests two possible
mechanistic pathways. Either the two oxazolines are di-
rectly equilibrating via dissociation and recombination,
or an unstable, N-acylaziridino sugar intermediate is
formed that rearranges via nucleophilic ring opening
at C1 by the amide carbonyl oxygen to form the C1
O-linked oxazoline (Scheme 4). Attempts to interconvert
C1 N-linked oxazoline 8b into C1 O-linked oxazoline
13b by stirring the compound with NaH in CH2Cl2 at
8. (a) Zurabyan, S. E.; Volosyuk, T. P.; Khorlin, A.
J. Carbohydr. Res. 1969, 9, 215–220; (b) Kiso, M.;
Scheme 4. Possible mechanism for the transformation from iodobenzamide to O-oxazoline.

6504
M. De Castro, C. H. Marzabadi / Tetrahedron Letters 45 (2004) 6501–6504
Anderson, I. Carbohydr. Res. 1985, 136, 309–323; (c)
(SiO2, 1:1 ratio of hexane–ethyl acetate) on the crude
mixture afforded 0.32g (81%) of a light yellow oil. 1H
NMR (500MHz CDCl3): d 6.10 (d, 1H, J=7.5Hz), 4.86
(d, 1H, J=11.5Hz), 4.76–4.71 (m, 2H), 4.68 (dd, 1H,
J=8.0, 5.0Hz), 4.61 (d, 1H, J=11.5Hz), 4.52–4.48 (m,
2H), 3.89 (dd, 1H, J=7.0, 5.0Hz), 3.83 (dd, 1H, J=9.0,
7.0Hz), 3.73 (m, 2H), 3.63 (apparent d, 1H, J=9.0Hz).
13C NMR: d 166.1, 138.5, 138.3, 132.5, 128.9, 128.7, 128.6,
128.55, 128.5, 128.3, 128.1, 127.9, 127.8, 127.1, 94.4, 81.4,
80.4, 74.7, 74.0, 73.8, 72.9, 71.9, 69.5. HR ES+ Calcd
536.2437; Found 536.2441; (b) Data for C1 O-linked
oxazoline 13b: 1H NMR (500MHz, CDCl3): d 6.23 (d, 1H,
J=7.0Hz), 4.77 (d, 1H, J=11.5Hz), 4.68 (d, 1H,
J=11.5Hz), 4.54 (dd, 2H, J=9.0, 9.0Hz), 4.48 (d,
1H, J=12Hz), 4.47 (dd, 1H, J=7.0, 3.0Hz), 4.29 (d, 1H,
J=12 Hz), 4.14 (dd, 1H, J=3.0, 2.5Hz), 3.72 (dd, 1H,
J=2.5, 1.5Hz), 3.60–3.53 (m, 3H). 13C NMR: d 164.5,
137.9, 137.8, 137.7, 131.8, 128.5, 128.4, 128.38, 128.3,
128.2, 128.0, 127.94, 127.92, 127.8, 127.7, 127.6, 126.9,
100.7, 76.8, 75.1, 73.3, 71.8, 71.6, 70.4, 69.4, 66.1; MS
(API–CI+) 428, 536 (M+H), 558 (M+Na).
Gonzalez, M. A.; Moreno, P. C.; Monterrey, I. G.;
Requejo, J. J.; Albarran, J. P.; Vicente, F. R. Carbohydr.
Res. 1990, 197, 310–317.
9. Banoub, J.; Boullanger, P.; Lafont, D. Chem. Rev. 1992,
92, 1167–1195.
10. (a) Gordon, D. M.; Danishefsky, S. J. J. Org. Chem. 1991,
56, 3713–3715; (b) Klein, H.; Mietchen, R.; Reinke, H.;
Michalik, M. J. Prakt. Chem. 1999, 341, 41–46.
11. Griffith, D. A.; Danishefsky, S. J. J. Am. Chem. Soc. 1990,
112, 5811–5819.
12. Lafont, D.; Descotes, G. Carbohydr. Res. 1988, 175, 35.
13. Kozlowska-Gramsz, E.; Descotes, G. Tetrahedron Lett.
1981, 22, 563–566.
14. Stoddart, J. F. Stereochemistry of Carbohydrates; Wiley
Interscience: New York, 1971; Chapter 4.
15. (a) Representative experimental procedures: Preparation
of N-benzoyl-3,4,6-tri-O-benzyl-2-deoxy-2-iodo-a-D-man-
nosamine and N-benzoyl-3,4,6-tri-O-benzyl-2-deoxy-2-
iodo-b-D-glucosamine 4b: To tri-O-benzyl-D-glucal 1b
(0.25g, 0.60mmol) in dry propionitrile at ꢀ75ꢁC, was
added N-iodosuccinimide (0.27g, 1.20mmol) and benz-
amide (0.43g, 3.6mmol). The mixture was kept at ꢀ75ꢁC
for 8h, warmed to rt, and stirred an additional 48h. The
mixture was quenched with water (20mL), extracted with
ethyl acetate (3·60mL), and dried (MgSO4). Purification
(SiO2, 230–400 mesh, 6:1 hexane–ethyl acetate) afforded
16. (a) Kozlowski, J.; Marzabadi, C.; Rath, N.; Spilling, C. D.
Carbohydr. Res. 1997, 300, 301–313; (b) Walford, C.;
Jackson, R. F. W.; Rees, N. H.; Clegg, W.; Heath, S. L.
Chem. Commun. 1997, 1855–1856; (c) Ichikawa, S.;
Shuto, S.; Matsuda, A. J. Am. Chem. Soc. 1999, 121,
10270–10280; (d) Shuto, S.; Terauchi, M.; Yahiro, Y.;
Abe, H.; Ichikawa, S.; Matsuda, A. Tetrahedron Lett.
2000, 41, 4151–4155; (e) Abe, H.; Shuto, S.; Tamura, S.;
Matsuda, A. Tetrahedron Lett. 2001, 42, 6159–6161.
17. Franck, R. W. Conformational Behavior of Six-Membered
Rings; VCH: New York, NY, 1995; Chapter 5, p 188.
18. Marzabadi, C. H.; Anderson, J. E.; Gonzalez-Outeirino,
J.; Gaffney, P. R. J.; White, C. G.; Tocher, D. A.; Todaro,
L. J. J. Am. Chem. Soc. 2003, 125, 15163–15173.
1
0.33g (85%) of mixed diastereomers: H NMR (500MHz,
CDCl3) anomeric protons: a-manno 5.99 (b s), a-gluco
5.63 (dd, J=8.0, 4.0Hz); 9:1 manno:gluco. MS (ES+)
(M+1) m/z 665 (100), 536 (65). Preparation of the C1 N-
linked oxazoline 8b. To compound 4b (0.5g, 0.68mmol) in
CH2Cl2 (20mL) at ꢀ78ꢁC, NaH (0.3g, 1.02mmol) and 15-
crown-5 (0.1mL, 0.50mmol) were added. The reaction
was kept at ꢀ78ꢁC for 5h, then was quenched with the
addition of water. The mixture was diluted to a volume of
50mL with CH2Cl2 and was extracted with water
(3·60mL). The organics were dried (Na2SO4), filtered,
and concentrated in vacuo. Column chromatography
19. Cesare, V.; Lyons, T. M.; Lengyel, I. Synthesis 2002, 12,
1716–1720.
20. Liu, J.; Gin, D. Y. J. Am. Chem. Soc. 2002, 124,
9789–9797.