Iodine(V) reagents in organic synthesis. Part 3. New routes to heterocyclic compounds via o-iodoxybenzoic acid-mediated cyclizations: Generality, scope, and mechanism

Article abstract of DOI:10.1021/ja012126h

The discovery and development of the o-iodoxybenzoic acid (IBX) reaction with certain unsaturated N-aryl amides (anilides) to form heterocycles are described. The application of the method to the synthesis of δ-lactams, cyclic urethanes, hydroxy amines, and amino sugars among other important building blocks and intermediates is detailed. In addition to the generality and scope of this cyclization reaction, this article describes a number of mechanistic investigations suggesting a single electron transfer from the anilide functionality to IBX and implicating a radical-based mechanism for the reaction.

Full text of DOI:10.1021/ja012126h

Published on Web 02/16/2002
Iodine(V) Reagents in Organic Synthesis. Part 3. New Routes
to Heterocyclic Compounds via o-Iodoxybenzoic
Acid-Mediated Cyclizations: Generality, Scope, and
Mechanism
K. C. Nicolaou,* P. S. Baran, Y.-L. Zhong, S. Barluenga, K. W. Hunt,
R. Kranich, and J. A. Vega
Contribution from the Department of Chemistry and The Skaggs Institute for Chemical Biology,
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, and
Department of Chemistry and Biochemistry, UniVersity of California, San Diego,
9500 Gilman DriVe, La Jolla, California 92093
Received September 4, 2001
Abstract: The discovery and development of the o-iodoxybenzoic acid (IBX) reaction with certain
unsaturated N-aryl amides (anilides) to form heterocycles are described. The application of the method to
the synthesis of δ-lactams, cyclic urethanes, hydroxy amines, and amino sugars among other important
building blocks and intermediates is detailed. In addition to the generality and scope of this cyclization
reaction, this article describes a number of mechanistic investigations suggesting a single electron transfer
from the anilide functionality to IBX and implicating a radical-based mechanism for the reaction.
Scheme 1. IBX-Mediated Cyclization of N-Aryl Amides,
Urethanes, and Ureas (I) Furnishing an Array of Five-Membered
Heterocycles (II)
Introduction
The task of the scientific community to develop potent,
selective therapeutic agents is dependent upon methods for
rapidly assembling compounds of high molecular diversity in
rational and efficient ways. Furthermore, the ability of chemists
to optimize newly discovered lead compounds, as well as to
produce analogues or mimics of biologically active natural
products, relies upon the advancement of synthetic technologies.
During endeavors in total synthesis,1 we discovered and
subsequently developed a novel cyclization reaction of N-aryl
amides (anilides) onto internally located unactivated olefins
induced by the Dess-Martin periodinane.2 This serendipitous
discovery3 led us to investigate the related and easily prepared
hypervalent iodide reagent IBX4 (o-iodoxybenzoic acid; 1-hy-
droxy-1,2-benziodoxol-3(1H)-one 1-oxide) as a potential agent
to carry out new reactions for accessing diverse libraries of
heterocycles, hydroxy amines, and amino sugars. The desir-
ability of such reactions can be appreciated if one considers
the importance of heterocyclic compounds, especially N-
heterocycles, to chemical biology and the drug discovery
process. Current methods for the formation of carbon-nitrogen
bonds generally involve the displacement, by N-nucleophiles,
of oxygen functionality, either intra-5 or intermolecularly,6
rearrangement of carbonyl functionalities,7 and reductive ami-
nation. However, methods for the direct introduction of nitrogen
onto non-oxygenated carbon without the formation of innocuous
byproducts are rare.8 Herein, we disclose the full account of
our discovery and development of the IBX-mediated cyclization
of amides, urethanes, and ureas with olefins for the rapid
construction of molecular diversity employing readily available
and inexpensive starting materials (Scheme 1).9a,b
(1) (a) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Choi, H.-S.; Yoon, W. H.;
He, Y.; Fong, K. C. Angew. Chem., Int. Ed. 1999, 38, 1669. (b) Nicolaou,
K. C.; Baran, P. S.; Zhong, Y.-L.; Fong, K. C.; He, Y.; Yoon, W. H.;
Choi, H.-S. Angew. Chem., Int. Ed. 1999, 38, 1676.
(2) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b) Dess, D.
B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277. (c) Meyer, S. D.;
Schreiber, S. L. J. Org. Chem. 1994, 59, 7549.
(3) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. Angew. Chem., Int. Ed. 2000,
39, 622.
(4) For the first preparation of IBX see: Hartman, C.; Meyer, V. Chem. Ber.
1893, 26, 1727. For a superior route to IBX, see: Frigerio, M.; Santagostino,
M.; Sputore, S. J. Org. Chem. 1999, 64, 4537. For the introduction of the
acronym “IBX”, see: Katrizky, A. R.; Duell, B. L.; Gallos, J. K. Org.
Magn. Reson. 1989, 27, 1007. For use as a selective oxidant for alcohols,
see: Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019.
Corey, E. J.; Palani, A. Tetrahedron Lett. 1995, 36, 7945.
(5) (a) Minami, N.; Ko, S. S.; Kishi, Y. J. Am. Chem. Soc. 1982, 104, 1109.
(b) Roush, W. R.; Adam, M. A. J. Org. Chem. 1985, 50, 3752.
(6) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Grashey, R. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford,
1991; Vol. 6, p 225.
(7) (a) Maruoka, K.; Yamamoto, H. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 6, p 763. (b) Shioiri,
T. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 6, p 795.
(8) (a) Du Bois, J.; Espino, C. G. Angew. Chem., Int. Ed. 2001, 40, 598 and
references therein. (b) Li, G.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl.
1996, 35, 451. (c) Magnus, P.; Lacour, J.; Evans, P. A.; Roe, M. B.; Hulme,
C. J. Am. Chem. Soc. 1996, 118, 3406. (d) Du Bois, J.; Tomooka, C. S.;
Hong, J.; Carreira, E. M. J. Am. Chem. Soc. 1997, 119, 3179. (e) Tamura,
Y.; Kimura, M. Synlett 1997, 749.
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Table 1. Discovery and Optimization of the IBX-Mediated Cyclization (1a f 1b)
entry
reagent
conditions
yield (%)
1
2
3
IBX (2.0 + 2.0 equiv)
IBX (2.0 + 2.0 equiv)
IBX (4.0 equiv)
THF:DMSO (10:1) (0.025 M) 90 °C, 12 h
THF:DMSO (4:1) (0.025 M), 90 °C, 12 h
DMSO, 90 °C, 12 h
86
86
0
4
5
6
7
8
9
10
11
12
IBX (4.0 equiv)
IBX (4.0 equiv)
IBA (10 equiv)
iodosobenzene (5.0 equiv)
Phl(OAc)2 (5.0 equiv)
Phl(CF3COO)2 (5.0 equiv)
trifluoro IBX (5.0 equiv)
KBrO3 (5.0 equiv)
H2O, 90 °C, 12 h
0
38
0
0
0
0
0
0
trace
THF:DMSO (10:1) (0.1 M), 90 °C, 12 h
THF:DMSO (4:1), 90 °C, 12 h
THF:DMSO (4:1), 90 °C, 12 h
THF, 50 °C, 12 h
CH3CN, 25 °C, 12 h
THF:DMSO (10:1), 90 °C, 12 h
THF:DMSO 4:1), 90 °C, 12 h
THF:DMSO (10:1), 90 °C, 12 h
oxone (2.0 equiv), IBX (catalyst)
Scheme 2. Various Failures of the IBX-Cyclization Make a
Compelling Case for the Essential Role of the N-Aryl Amide
Moiety for the Success of the Reaction
Results and Discussion
1. IBX-Mediated Cyclization of Amides. Once discovered,
the development of the IBX-mediated cyclization commenced
with the screening of a variety of solvent systems and reaction
temperatures (see Table 1). After some experimentation, optimal
conditions were found to be the heating of the anilide substrate
with IBX (2.0 equiv) in a mixed solvent system of THF:DMSO
(10:1) in a pressure tube at 90 °C for 8-12 h. To ensure com-
plete conversion, the reactions were cooled to room temperature,
and additional IBX (2.0 equiv) was added followed by heating
at 90 °C for an additional 8 h. The concentration of substrate
in THF/DMSO (10:1) was also critical (0.025 M, entries 1 and
2, Table 1). When the concentration of the substrate (1a) was
too high, very low conversions were observed (entry 5, Table
1). Using these conditions, a diverse series of γ-lactams were
prepared in good to excellent yields (Table 2). Interestingly, a
variety of iodine(III)-based reagents [PhI(OAc)2, PhI(OCCF3)2,
and IBA] and tri-fluro-IBX or KBrO3 failed to induce cyclization
with 1a, whereas oxone (3.0 equiv) in the presence of catalytic
amounts of IBX gave only traces of lactam 1b (Table 1).
As shown in Table 2, a broad range of anilides readily cyclize
in the presence of IBX. The reaction is tolerant of both electron-
donating and electron-withdrawing groups10 on the N-aryl ring,
including sensitive bromides and iodides. The ability of the
process to introduce nitrogen onto monosubstituted olefins
(entries 1-11, Table 2) or onto an enol silyl ether (entry 24,
Table 2) without any loss in efficiency is more impressive. The
efficient formation of quaternary centers is also evident from
the facile construction of 20b and 21b (Table 2, see Figure 1
for ORTEP structure of 20b).9c This remarkable reaction is
highly chemoselective, as shown by the example of entry 25
(Table 2), which leads to the bis-lactam 25b without affecting
the ester functionality. Finally, it should be noted that the
reaction is impervious to air or water, foregoing the requirement
of an inert environment or scrupulously dried solvents.
In defining the scope and limitations of the IBX-mediated
cyclization, the necessity of the anilide moiety was ascertained.
As seen from Scheme 2, the case for the necessary role of the
N-aryl amide moiety is compelling since a variety of related
substrates fail to enter the reaction. These results are consistent
with a single electron transfer (SET) mechanism in which the
aryl group plays an active role in the initial SET process (vide
(9) (a) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. Angew. Chem., Int. Ed.
2000, 39, 625. (b) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Vega, J. A.
Angew. Chem., Int. Ed. 2000, 39, 2525. (c) For crystallographic information
see ref 9a, footnote 4. (d) For crystallographic information see ref 9b,
footnote 27.
(10) An exception is the nitro group. We have not been able to induce ring
closure of nitro-aryl substrates.
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Iodine(V) Reagents in Organic Synthesis 3
A R T I C L E S
Table 2. IBX-Mediated Cyclization of N-Aryl Amides
infra). As a result, substrates 26a, 27a, 29a, and 32a lacking
the N-aryl moiety do not undergo the IBX-mediated cyclization
(Scheme 2). The N-aryl amine 31a also failed to cyclize,
demonstrating the necessity of the carbonyl moiety of the
anilides. Alkynes such as 30a were also unsuitable substrates
for the reaction. It should also be noted that the reaction cannot
be entrusted to produce δ-lactams as suggested by the failure
of 33a to furnish 33b under the usual reaction conditions. This
reflects the known propensity of radicals, stabilized by both
mesomerically donating and mesomerically withdrawing sub-
stituents, to be subject to additional stabilization to the extent
that their participation in less favored cyclizations (than the
5-exo variant)11 is quite limited. This stabilization is also
Figure 1. X-ray crystal structure of 20b.
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Table 3. IBX-Mediated Cyclization of N-Aryl Carbamates and Open-Chain Ureas
carbamates and ureas was investigated. Such investigations were
warranted not only because of the importance of the expected
products, but also due to the ready and extensive availability
of allylic alcohols, amines, and aryl isocyanates. Thus, a series
of carbamates and ureas were prepared from the corresponding
allylic alcohol (see entries 1-30, Table 3) or secondary amine
(see entries 31 and 32, Table 3) by reaction with the aryl
isocyanate in the presence of DBU (0.1-0.3 equiv). Using the
previously described conditions [IBX (2.0 + 2.0 equiv), THF:
DMSO (10:1), 90 °C, sealed tube], oxazolidinones (entries
1-30) and cyclic ureas (entries 31 and 32) were readily prepared
in fair to excellent yields (Table 3). It should be noted that only
ureas (64a and 65a) prepared from secondary allylic amines
readily cyclize. Ureas prepared from primary allylic amines
slowly decomposed under the above conditions without provid-
ing any cyclized products.
Figure 2. Hammett plot for the reaction shown in Scheme 11. See text for
details.
pertinent to the ease of formation of this radical and the
requirement for both the aryl and the carbonyl substituents.
2. IBX-Mediated Cyclization of Carbamates and Ureas.
In an effort to address the recently heightened need for increased
molecular diversity, the IBX-mediated cyclization of aryl
Again, a wide range of aryl substituents is tolerated, allowing
for the rapid assembly of small molecule libraries. The formation
of quaternary centers (entries 8, 9, 23, and 29, Table 3) and
spirocyclic compounds (entry 29, Table 3) is an additional
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Iodine(V) Reagents in Organic Synthesis 3
A R T I C L E S
Table 4. Preparation of 1,2-Amino Alcohols from Cyclic
Scheme 4. IBX-Mediated Synthesis of Cyclic Urethanes and
Carbamatesa
cis-1,2-Amino Alcoholsa
a
Reagents and conditions: (a) CAN (5.0 equiv), CH3CN:H2O (5:1),
25 °C, 20 min, 86%; (b) NaOH (10 equiv), EtOH, 75 °C, 1 h, 95%.
Scheme 5. Synthesis of Aminosugar 69ca
a
Reagents and conditions: (a) p-MeOC6H4NCO (1.1 equiv), DBU (0.1
equiv), CH2Cl2, 25 °C, 1 h, 95%; (b) IBX (2.0 equiv), THF:DMSO (10:1),
90 °C (sealed tube), 8 h; then IBX (2.0 equiv), 8 h, 84%; (c) CAN (5.0
equiv), CH3CN:H2O (5:1), 0 °C, 30 min, 90%.
undergoes a [3,3]-sigmatropic rearrangement to the correspond-
ing allylic thionocarbamate (66c), which then undergoes the
IBX-mediated cyclization to provide the observed product 67.
This laboratory has previously reported12 the use of tertiary
thionocarbamates (thionoimidazolides) to introduce allylic thiols
through a highly stereoselective [3,3]-sigmatropic rearrangement.
Unfortunately, application of the present method to other
substrates led to a mixture of products due to competitive [1,3]-
sigmatropic rearrangement and lack of stereoselectivity in this
process. These results are consistent with previous findings that
secondary thiocarbamates give rise to mixtures of [1,3]- and
[3,3]-sigmatropic rearrangement products.13
a Reactions were carried out on a 0.05 mmol scale with 1 N in EtOH at
70 °C. b Chromatographically pure compounds.
Scheme 3. Thionocarbamates in the IBX-Mediated Cyclization
3. Synthesis of Amino Sugars by the IBX-Mediated
Cyclization. The efficiency of the above process for forming
carbon-nitrogen bonds led us to extend our investigations to
the preparation of amino sugars. As amino sugars constitute
integral components of many biologically active natural prod-
ucts and medicinally relevant compounds, a variety of methods
feature of this new process. The exclusive stereocontrol
exhibited by the cyclic scaffolds (entries 10-30, Table 3) in
forming the nitrogen-carbon bond makes this an attractive
procedure for preparing 1,2-amino alcohols. Direct access to
this class of compounds is realized by hydrolysis (1 N NaOH)
of the resulting cyclic carbamates as shown in Table 4.
In contrast to aryl carbamates and ureas, aryl thionocarbam-
ates do not directly cyclize to provide heterocycles. Thus, when
thionocarbamate 66a (Scheme 3) was treated with the standard
conditions [IBX, THF:DMSO (10:1), 90 °C] for 12 h, thiazo-
lidinone 67 was isolated (84% yield) instead of the cyclic thione
66b (Scheme 3). Apparently, the thionocarbamate 66a first
(11) (a) Viehe, H. G.; Merenyi, R.; Stella, L.; Janousek, Z. Angew. Chem., Int.
Ed. 1979, 18, 917. (b) Curran, D. P.; Chang, C.-T. J. Org. Chem. 1989,
54, 3140.
(12) Nicolaou, K. C.; Groneberg, R. D. J. Am. Chem. Soc. 1990, 112, 4085.
Nicolaou, K. C.; Groneberg, R. D.; Miyazaki, G. T.; Stylianides, N. A.;
Schulze, T. J.; Stah, W. J. Am. Chem. Soc. 1990, 112, 8193. Groneberg,
R. D.; Miyazaki, T.; Stylianides, N. A.; Schulze, T. J.; Stahl, W.; Schreiner,
E. P.; Suzuki, T.; Iwabuchi, Y.; Smith, A. L.; Nicolaou, K. C. J. Am. Chem.
Soc. 1993, 115, 7593. Smith, A. L.; Pitsinos, E. N.; Hwang, C.-K.; Mizuno,
Y.; Saimoto, H.; Scarlato, G. R.; Suzuki, T.; Nicolaou, K. C. J. Am. Chem.
Soc. 1993, 115, 7612.
(13) Harayama, H.; Nagahama, T.; Kozera, T.; Kimura, M.; Fugami, K.; Tanaka,
S.; Tamura, Y. Bull. Chem. Soc. Jpn. 1997, 70, 445.
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Table 5. IBX-Mediated Synthesis of Amino Sugar Derivatives from Allylic Alcohols and Aryl Isocyanates
a Reagents and conditions: (i) (urethane formation) PMPNCO (1.1 equiv), DBU (0.1-0.3 equiv), CH2Cl2; (ii) (cyclization) IBX (4.0 equiv), THF:DMSO
(10:1), 90 °C (sealed tube), 12 h; then IBX (2.0-4.0 equiv), 12 h; (iii) (removal of PMP group) CAN (5.0 equiv), CH3CN:H2O (5:1), 0 °C. b NaHCO3 (4.0
equiv) was added to prevent TBS cleavage. c The CAN reaction was not performed due to the presence of the naphthalene ring. d NaHCO3 (4.0 equiv) was
added to prevent hydrolysis of the benzyl glycoside. e Yield over two steps. PMP ) p-methoxyphenyl; TBDPS ) tert-butyldiphenylsilyl; TBS ) tert-
butyldimethyl silyl; Bn ) benzyl; Bz ) benzoyl; Ac ) acetate. For the synthesis of compounds 79a and 80a, see Experimental Section.
for their synthesis have been reported and extensively re-
viewed.14 However, a general method that is highly stereose-
lective, relies upon inexpensive materials, and does not introduce
unwanted carbon functionality, remains an elusive goal in this
area. To develop such a method, the issue of removing the
extraneous but enabling aryl moiety required further research,
and there was also the question of whether carbohydrate-based
scaffolds would be compatible with the reaction conditions.
The first of these issues was addressed and clarified by the
employment of p-methoxyphenyl (PMP) isocyanate to convert
(14) (a) Anonymous in Carbohydr. Chem. 1998, 30, 123. (b) Jurczak, J. Prepr.
Carbohydr. Chem. 1997, 595. (c) ref 8d.
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Iodine(V) Reagents in Organic Synthesis 3
A R T I C L E S
Scheme 6. Synthesis of L-Vancosamine (81) Using IBXa
Scheme 7. Reaction of Urethane 86a with IBX Leads to a Mixture
of 1-Deoxy Aminosugar 86b and Aminosugar 86ca
a
Reagents and conditions: (a) CrCl2 (4.0 equiv)/NiCl2 (0.04 equiv),
DMSO, 25 °C, 12 h, 61%; (b) DMP (1.2 equiv), NaHCO3 (5.0 equiv),
CH2Cl2, 25 °C, 30 min, 98%; (c) NaBH4 (1.0 equiv), CeCl3 (1.0 equiv),
MeOH, -20 °C, 30 min, then 0 °C, 30 min, 90%; (d) p-MeOC6H4NCO
(2.0 equiv), DBU (0.3 equiv), CH2Cl2, 25 °C, 5 h, 86%; (e) HF‚py (5.0
equiv), THF, 25 °C, 5 h, 90%; (f) IBX (1.2 equiv), THF:DMSO (10:1), 25
°C, 20 min, 79%; (g) p-MeOC6H4OH (10.0 equiv), HCl (g), CH2Cl2,
a
Reagents and conditions: (a) IBX (2.0 equiv), THF:DMSO (10:1),
90 °C, 12 h, 85%, (86b:86c, ca. 1:2).
0
°C, 30 min, 77%; (h) IBX (4.0 equiv), NaHCO3 (4.4 equiv),
THF:DMSO (10:1), 90 °C, 24 h, 76%; (i) CAN (3.0 equiv), CH3CN:H2O
(5:1), 3 h, 0 °C, 92%; (j) NaOH (3 N), 90 °C, 1 h, 70%. DMP ) Dess-
Martin periodinane; CAN ) ceric ammonium nitrate; PMP ) p-meth-
oxyphenyl.
2-cyclohexenol to the corresponding carbamate 50a (Scheme
4, Table 3). The IBX-mediated cyclization of the latter
compound [IBX (4.0 + 2.0 equiv), THF:DMSO (10:1), 90 °C]
cleanly provided the bicyclic carbamate 50b (73% yield).
Removal of the PMP group with ceric ammonium nitrate
(CAN),15 followed by hydrolysis of the resulting cyclic car-
bamate 68a, cleanly provided the deprotected amino alcohol
68b (95% yield).
An extension of this method to carbohydrate scaffolds was
carried out as shown in Scheme 5. Thus, treatment of allylic
system 69 with PMP isocyanate in the presence of catalytic
amounts of DBU, followed by separation of the resulting
anomers,16 IBX-mediated cyclization of the â-anomer (69a),
and PMP group removal of the resulting protected amino sugar
69b, successfully provided the protected amino sugar 69c (72%
yield over three steps). The exclusive formation of the cis ring
fusion was assured due to the necessity of proper orbital
alignment between the nitrogen-centered radical (vida infra) and
the olefinic π-system.
The generality and scope of this reaction are displayed in
Table 5. The simplicity of the process as a means for introducing
nitrogen into carbohydrates makes it appealing, an attractiveness
augmented by its stereospecific and high yielding nature, and
the fact that the conditions involved do not interfere with a wide
variety of protecting groups. Acid labile groups can be accom-
modated by buffering the reaction medium with solid sodium
bicarbonate (entries 7, 10, and 11, Table 5). The process re-
mains efficient even when forming quaternary centers (entry
11, Table 5) and in the presence of an additional olefin (entry
9, Table 5).
Figure 3. X-ray structure of aminosugar 86c.
and executed (Scheme 6). Thus, intermolecular Kishi-Nozaki
coupling of the readily available vinyl iodide 82 and aldehyde
83 provided a mixture of alcohols that was oxidized to afford
a ketone which was reduced under Luche conditions18 to furnish
only the desired isomer 84 (54% overall yield from 83).
Carbamate formation [PMP isocyanate, DBU (catalyst)] and silyl
group removal (HF‚py), followed by selective oxidation of the
primary hydroxyl group (IBX) and treatment with p-methoxy-
benzyl alcohol in the presence of HCl, provided glycoside 85
in 47% overall yield. L-Vancosamine (81) was then reached, in
49% overall yield, by IBX-mediated cyclization, removal of the
PMB and PMP groups (CAN), and basic hydrolysis (3 N NaOH)
of the carbamate moiety. This short sequence provides one of
the most direct syntheses of 81 and attests to the potential of
this new technology for amino sugar construction.
During further investigations directed at the extension of this
methodology to the glycal arena, further benefits of the IBX-
(17) For selected syntheses of L-vancosamine and derivatives thereof, see: (a)
Thang, T. T.; Winternitz, F. J. Chem. Soc., Chem. Commun. 1979, 153.
(b) Dyong, I.; Friege, H. Chem. Ber. 1979, 112, 3273. (c) Thang, T. T.;
Winternitz, F. Tetrahedron Lett. 1980, 21, 4495. (d) Ahmad, H. I.;
Brimacombe, J. S.; Mengech, A. S.; Tucker, L. C. N. Carbohydr. Res.
1981, 93, 288. (e) Dyong, I.; Friege, H.; Luftmann, H.; Merten, H. Chem.
Ber. 1981, 114, 2669. (f) Fronza, G.; Fuganti, C.; Grasselli, P.; Pedrocchi-
Fantoni, G. Tetrahedron Lett. 1981, 22, 5073. (g) Brimacombe, J. S.;
Mengech, A. S.; Rahman, K. M. M.; Tucker, L. C. N. Carbohydr. Res.
1982, 110, 207. (h) Fronza, G.; Fuganti, C.; Grasselli, P.; Pedrocchi-Fantoni,
G. J. Carbohydr. Chem. 1983, 2, 225. (i) Hamada, Y.; Kawai, A.; Shioiri,
T. Tetrahedron Lett. 1984, 25, 5413. (j) Hauser, F. M.; Ellenberger, S. R.
J. Org. Chem. 1986, 51, 50. (k) Dyong, I.; Weigand, J.; Thiem, J. Liebigs
Ann. Chem. 1986, 577. (l) Klemer, A.; Wilbers, H. Liebigs Ann. Chem.
1987, 815. (m) Hamada, Y.; Kawai, A.; Matsui, T.; Hara, O.; Shioiri, T.
Tetrahedron 1990, 46, 4823. (n) Greven, R.; Jutten, P.; Scharf, H.-D.
Carbohydr. Res. 1995, 275, 83. (o) Nicolaou, K. C.; Mitchell, H. J.; van
Delft, F. L.; Ru¨bsam, F.; Rodr´ıguez, R. M. Angew. Chem., Int. Ed. 1998,
37, 1871.
To further demonstrate the synthetic utility of this process,
an expeditious synthesis of L-vancosamine (81)17 was designed
(15) (a) Kronenthal, D. R.; Han, C. Y.; Taylor, M. K. J. Org. Chem. 1982, 47,
2765. (b) Knapp, S.; Kukkola, P. J.; Sharma, S. J. Org. Chem. 1990, 55,
5700.
(16) The corresponding â-isomer was used in Table 4, entry 5.
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Table 6. IBX-Mediated Synthesis of 1-Deoxy Amino Sugar, Amino Sugars, and Amino Sugar Lactones from Glycals via Their
PMP-Protected Urethanesa
a Reagents and conditions: (i) (1-deoxy amino sugar formation) IBX (2.0 equiv), THF, 90 °C (sealed tube), 5 h; then IBX (2.0 equiv), 5 h; (ii) (amino
sugar formation) IBX (2.0 equiv), THF:DMSO:H2O (10:1:0.05), 12 h, 90 °C; (iii) (amino sugar lactone formation) IBX (6.0 equiv), THF:H2O (100:1), 8 h,
90 °C (sealed tube); then IBX (6.0 equiv), 8 h; (iv) (removal of PMP group) CAN (5.0 equiv), CH3CN:H2O (5:1), 0 °C, 30 min. b In addition to the lactones
the corresponding lactols (series c compounds) were obtained in yields ranging from 50 to 60%.
Scheme 8. Complete Control in the Synthesis of 1-Deoxy
mediated cyclizations were discovered. When glycal 86a
Aminosugars, Aminosugars, and Aminosugar Lactones from
(Scheme 7) was treated with IBX (2.0 equiv) in the typical
solvent system (THF:DMSO, 10:1), a mixture of 1-deoxy amino
sugar 86b and amino sugar 86c (see Figure 3 for ORTEP
structure)9d was produced in 85% combined yield and ca. 1:2
ratio (Scheme 7). Consistent with mechanistic studies (vide
infra), it became apparent that radical A, produced from the
IBX-mediated cyclization, now being heteroatom-stabilized, is
capable of undergoing further oxidation to the corresponding
oxocarbenium ion (B) which serves as a precursor to 86c. It
should be noted that, in principle, oxocarbenium ion B could
also lead to 1-deoxy amino sugar 86b via hydride transfer from
the large excess of THF present.19
Glycal 86aa
Following this hypothesis, treatment of 86a with IBX under
anhydrous conditions (dry THF) provided the 1-deoxy amino
sugar 86b in 85% yield (Scheme 8). However, exposure of 86a
to IBX (2.0 + 2.0 equiv) in the presence of water (THF:DMSO:
H2O, 10:1:0.5) provided the amino sugar 86c in 92% yield with
complete control of both newly formed stereocenters. Use of a
larger excess of IBX (6.0 + 6.0 equiv) provided the lactone
86d in 18% yield (along with 61% of 86c). These key
observations led us to probe the generality of this process for
the construction of diverse amino sugars from readily available
glycals. Table 6 summarizes these studies.
a
Reagents and conditions: (a) IBX (2.0 equiv), THF, 90 °C (sealed
tube), 5 h; then IBX (2.0 equiv), 5 h, 85%; (b) IBX (2.0 equiv), THF:
DMSO:H2O (10:1:0.05), 12 h, 90 °C, 92%; (c) IBX (6.0 equiv), THF:H2O
(100:1), 8 h, 90 °C (sealed tube); then IBX (6.0 equiv), 8 h, 18% 86d plus
61% 86c.
by employing ceric ammonium nitrate (CAN) as demonstrated
in entry 1 (Table 6). The IBX-mediated route to 1-deoxy amino
sugars and amino sugars is general and highly efficient. In
contrast, the direct, one-pot entry into the amino sugar lactones
is low yielding (the products being accompanied by the
corresponding lactols), and a stepwise approach is, therefore,
recommended in accessing these compounds.
Thus, beginning with either glucal- or galactal-derived glycals,
1-deoxy amino sugars, amino sugars, and amino sugar lactones
were readily obtained using the described conditions. The
enabling PMP group may also be removed from these products
4. Mechanistic Studies of IBX-Mediated Cyclizations of
N-Aryl Amides. Although the IBX-mediated cyclization readily
provided access to a host of diverse heterocyclic compounds
and other nitrogen-containing systems, the exact mechanism of
the reaction was not readily apparent. Other than observing the
(18) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226.
(19) For a study of hydride transfer kinetics from THF to triphenylmethyl cation,
see: Kabir-ud-Din; Plesch, P. H. J. Chem. Soc., Perkin Trans. 2 1978,
937.
9
2240 J. AM. CHEM. SOC. VOL. 124, NO. 10, 2002

Iodine(V) Reagents in Organic Synthesis 3
A R T I C L E S
Scheme 9. Mechanistic Rationale for the SET-Based
IBX-Mediated Cyclization of Anilides and Related Compounds (A)
and Plausible Role of the Solvent in These Reactions (B)
Scheme 10. Deuterium Labeling Studies To Determine the
Source of Hydrogen in the IBX-Mediated Cyclizationa
a
Reagents and conditions: (a) IBX (4.0 equiv), THF-d8:DMSO-d6
(10:1), 90 °C, 24 h, 24%; (b) IBX (1.0 equiv), THF:DMSO-d6 (10:1), 80
°C, 10 min, 15% conversion (NMR); (c) IBX (4.0 equiv), DMSO, 90 °C,
24 h; (d) see (e); (e) IBX (4.0 equiv), THF:DMSO (10:1), 90 °C, 24 h,
40%.
in the process, besides being a source of the hydrogen atom as
shown in Scheme 9B. The combined investigations21 into IBX-
mediated reactions emanating from these laboratories have
strongly suggested that heteroatom coordination to IBX is facile.
THF is uniquely suited for this transformation not only because
of its low R C-H bond dissociation energy (BDE), but because
it may readily coordinate to IBX through the oxygen atom lone
pair. A viable scenario accommodating the observed phenomena
might involve coordination of a molecule of THF to IBX,
leading to intermediate A (Scheme 9B). This species is expected
to be an extraordinarily strong oxidant, one that could initiate
the cyclization by SET to the aryl amide, furnishing intermedi-
ates II (Scheme 9A) and B (Scheme 9B). Rearrangement of B
to C followed by hydrogen abstraction may then lead to product
V (Scheme 9A) along with D (Scheme 9B), the latter rapidly
collapsing to iodosobenzoic acid (IBA) and 3-butenal (Scheme
9B). Notably, treatment of THF with only IBX at 90 °C for 24
h led to the isolation of 2-iodobenzoic acid along with polymeric
material and unidentified compounds containing aldehyde
residues, as judged by 1H NMR spectroscopy. In addition, when
IBA or other hypervalent iodine reagents were employed in the
cyclization (I f V, Scheme 9), no reaction was observed (vide
supra, entries 7-10, Table 1).
Further support for the SET mechanism was gained in a
straightforward fashion through a systematic evaluation of the
kinetics of the reaction with substrates designed to probe the
electronic effects of aromatic substituents on the rates of the
entire process (I f V) and of step III f IV (Scheme 9A). A
Hammett plot was generated by comparing the relative rates of
the para-substituted aromatic amides 19a, 91a-d with the
unsubstituted aromatic amide 17a (Scheme 11). Competing
equimolar mixtures of 17a and 19a, 91a, 91b, 91c, or 91d
were heated with 2.0 equiv of IBX in THF:DMSO (10:1) at
80 °C for 10 min. The ratios between the unsubstituted
product 17b and the para-substituted products 19b, 91a′-d′
necessity of THF for successful ring closure, the factors
influencing the reaction were not satisfactorily resolved. Perhaps
the most critical question was whether, as suspected, the reaction
was initiated by single electron transfer (SET) as shown in
Scheme 9.20 Second, the role of THF along the reaction pathway
required clarification. Next, the nature, and apparent require-
ment, of the nitrogen aryl group required further study in the
hope that light could be shed on the electronic nature and
properties of the reactive species involved in the cascade. In so
doing, it was hoped that the structural features of substrates
could be clearly defined to fully exploit the scope and limitations
of this new synthetic tool.
To probe the possibility of a SET mechanism, it was critical
to determine whether the hydrogen atom that must quench the
radical resulting from cyclization (IV f V, Scheme 9)
originated from the substrate, IBX, or the solvent (THF). Thus,
when the reaction of 17a (Scheme 10) was performed in THF-
d8/DMSO-d6 (10:1), deuterium was detected (NMR) in product
d-17b at the carbon predicted from the proposed mechanism.
However, carrying out the reaction of 17a in THF/DMSO-d6
(10:1) or of deuterated amide d-17a in THF/DMSO (10:1) led
to 17b containing no deuterium. Use of DMSO as solvent in
the absence of hydrogen-donating solvents (such as THF or
dioxane) returned only starting material, along with small
amounts of a number of unidentified decomposition products.
This strong reliance of the reaction on solvent choice led to the
conclusion that the solvent (THF) actually plays an active role
(20) Nicolaou, K. C.; Baran, P. S.; Kranich, R.; Zhong, Y.-L.; Sugita, K.; Zou,
(21) Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong, Y.-L. J. Am. Chem.
Soc. 2002, 124, 2245-2258.
N. Angew. Chem., Int. Ed. 2001, 40, 202.
9
J. AM. CHEM. SOC. VOL. 124, NO. 10, 2002 2241

A R T I C L E S
Nicolaou et al.
Scheme 11. NMR-Monitored Competition Reactions between
Anilides 17a and 19a, 91a-da
Scheme 13. Failure of Substrates 96a-98a to Cyclize under the
Influence of IBX
a
Reagents and conditions: (a) IBX (2.0 equiv), THF:DMSO (10:1),
is typical for a radical reaction22 and indicates a lower electron
density in the transition state relative to the initial ground state
of the substrate. It supports the hypothesis that the first step of
the reaction involves SET from the aromatic ring of the amide
to IBX to form a radical anion/radical cation pair as shown in
Scheme 9. After loss of a proton, radical cation II is converted
to radical III, which then undergoes cyclization onto the double
bond in a 5-exo-trig fashion to furnish the carbon-centered
radical species IV. Subsequent quenching of the latter spe-
cies (IV) by hydrogen atom transfer from THF then leads to
product V.
80 °C, 10 min.
Scheme 12. Synthesis and Reactions of N-Thiophenyl Amides
93a-c with n-Bu3SnHa
To determine if the rate-determining step of the reaction was
I f II or III f IV (Scheme 9A), a series of N-(phenylthio)-
amides25 (i.e., 93a-c) were prepared26 from 12a and 92a,b
(Scheme 12). Three cyclization experiments for each N-
(phenylthio)amide (93a-c) were conducted at 65 °C in toluene
in the presence of excess n-Bu3SnH at concentrations ranging
from 0.2 to 1.0 M. After determining the relative yields of
cyclized product (12b, 94a,b, Scheme 12) and acyclic amide
(12a, 92a,b) formed in the reactions by HPLC, and assuming
the rate of trapping of tin hydride to be the same for all
radicals,25 the relative rate constants for cyclization of the amide
centered radicals were inferred. According to this method, the
relative rates of cyclization for 93a, 93b, and 93c were
determined to be (0.66 ( 0.1), (0.30 ( 0.1), and (0.40 ( 0.1)
M, respectively. Because the opposite trend is observed when
the overall rate is evaluated (see Figure 2), and because the
amidyl radical cyclization is rapid for 93a-c, we concluded
that SET from the aromatic nucleus of the anilide to the IBX‚
THF complex (I f II, Scheme 9A) is the rate-determining step
of the reaction.
a
Reagents and conditions: (a) NaH (1.3 equiv), THF, reflux, 4 h; then
PhSCl (ca. 1 equiv, added until yellow color of PhSCl persisted), -78 °C,
1 h, 74-86%; (b) n-Bu3SnH (0.2-1.0 M), toluene, 65 °C, 2-5 h, 85-
92% total yield of cyclized product plus uncyclized anilide.
were determined by 1H NMR spectroscopy. Electron-do-
nating substituents [X ) OMe (19a) and Et (91a)] increased
the rate of cyclization, whereas electron-withdrawing substit-
uents [X ) Cl (91c) and C(O)Me (91d)] caused a decrease in
the reaction rate or had no significant effect on the rate [X )
F (91b)] relative to the unsubstituted substrate. For amides of
type 91 where X ) NO2 and CF3, no appreciable reaction was
observed under the reaction conditions utilized in the kinetic
study.
The Hammett plot,22 based on the ratio of the reaction rate
constants (ks/ku) and σp+ parameters,23 gave a linear graph with
a negative slope (F ) -1.4, R2 ) 0.97; Figure 2).24 This F value
Determination of the oxidation potentials of anilides 12a and
92a-d (see Scheme 12) provided further insights into the
electronic requirements for this cylization process. Thus, by
performing cyclic voltammetry on CH2Cl2 solutions of 12a and
+
(22) σp values: Zuman, P.; Patel, R. C. Techniques in Organic Reaction
Kinetics; Krieger Publishing Company: Malabar, Florida, 1992; p 230.
For a discussion of Hammett plots, see: Lowry, T. H.; Richardson, S. K.
Mechanism and Theory in Organic Chemistry, 3rd ed.; Harper & Row:
New York, 1987.
(23) ku: Rate constant of reaction 17a f 17a; ks: Rate constants of reactions
+
91a-d and 19a f 91a′-d′ and 19b. Because the σp parameter for the
(25) For seminal work in the area of amide-centered radicals, see: Horner, J.
H.; Musa, O. M.; Bouvier, A.; Newcomb, M. J. Am. Chem. Soc. 1998,
120, 7738. Newcomb, M.; Tanaka, N.; Bouvier, A.; Tronche, C.; Horner,
J.; Musa, O. M.; Martinez, F. N. J. Am. Chem. Soc. 1996, 118, 8505.
Newcomb, M. Tetrahedron 1993, 49, 1151 and references therein. Esker,
J. L.; Newcomb, M. In AdVances in Heterocyclic Chemistry; Katrizky, A.
R., Ed.; Academic Press: New York, 1993; Vol. 58, p 1.
acetate group was not defined in ref 20, substrate 91d was not plotted. For
the determination of F the following expression19 was used: ks/ku ) log[1
- sr/st]/log[1 - ur/ut]. F ) reaction constant; ur and sr ) millimoles of
anilide 19a and p-substituted anilides 91a-d that reacted, or by analogy,
millimoles of products 19b and 91a′-d′; ut and st ) initial millimoles of
anilide 19a and p-substituted anilides 91a-d.
(24) Higgins, R.; Foote, C. S.; Cheng, H. ACS Symp. Ser. 1968, 77, 102.
(26) Esker, J. L.; Newcomb, M. Tetrahedron Lett. 1993, 34, 6877.
9
2242 J. AM. CHEM. SOC. VOL. 124, NO. 10, 2002

Iodine(V) Reagents in Organic Synthesis 3
A R T I C L E S
Scheme 14. Cascade Reaction Sequence Supporting the Radical Nature of the IBX-Mediated Cyclizationsa
a
Reagents and conditions: (a) 99 (1.2 equiv), KHMDS (1.0 equiv), THF, 0-25 °C, 1 h, then 100, -78 °C, 2 h, warm to 25 °C, 6 h; (b) LiOH (5.0
equiv), THF:H2O (4:1), 25 °C, 24 h, 70% overall; (c) EDC (1.2 equiv), 4-DMAP (1.2 equiv), CH2Cl2, 25 °C, 10 h, 95%; (d) IBX (4.0 equiv every 24 h),
THF:DMSO (10:1), 90 °C, 48 h, 48%.
92a-d, the p-substituted anilides were determined to be more
difficult to oxidize than ferrocene by the following amounts:
1.20 V (12a), 0.82 V (93a), 1.23 V (93b), 1.48 V (93c), and
g1.57 V (93d).27 By comparing the measured oxidation
potentials with the observed relative rates of the reactions, a
direct correlation was immediately apparent. Thus, anilides with
lower oxidation potentials (i.e., 12a, 92a, and 92b) proceeded
to cyclize rapidly, while anilides with higher oxidation potentials
(i.e., 92c-d) entered the reaction only sluggishly.
In light of these findings, a number of unexplained failures
of the IBX-mediated cyclization previously encountered in these
laboratories can now be rationalized (see Scheme 13). The need
for an open position ortho to the nitrogen atom is evident
since 96a and 97a (Scheme 13) do not undergo the reac-
tion. This could be explained by an increase in the oxidation
potential caused by deconjugation of the lone pair of electrons
on the nitrogen atom from the arene ring,28 by a decreased rate
for the 5-exo-trig cyclization, or simply by the lack of depro-
tonation of the radical cation (II f III, Scheme 9A). The mildly
electrophilic nature of the nitrogen-centered radical25 is sup-
ported by the failure of R,â-unsaturated ester 98a to react
(Scheme 13). The notion that only N-aryl amides should undergo
the IBX-mediated cyclization is supported by the fact that sub-
strates 26a, 27a, and 29a are unresponsive to the conditions,
while 31a and 32a lead rapidly to decomposition products
(Scheme 2).
Further evidence pointing to the radical-based mechanism of
the cyclization is provided by the designed cascade reaction
depicted in Scheme 14. Thus, when cyclopropyl anilide 103a
was treated with IBX (4.0 equiv in two portions) in THF:DMSO
(10:1) at 90 °C for 48 h, the novel tetracycle 104 was obtained
in 48% yield. This striking transformation is rationalized by
invoking a radical-based mechanism involving species 103b,
which is postulated to lead to benzylic radical 103c by rupture
of the cyclopropyl ring as shown. A second SET from this
species to IBX provides benzylic cation 103d T 103e, which
after cationic cyclization and re-aromatization, provides the
observed product 104 via species 103f.
5. Solid-Phase Synthesis with IBX. After gaining significant
insight into the mechanism of the IBX-mediated cyclization,
we sought to determine the reaction’s applicability to solid phase
synthesis. Treatment of 10529 with IBX (excess) in THF/DMSO
(10:1) at 85 °C for 3 days led to the resin-bound product 106,
which upon cleavage with NaOMe in MeOH afforded only 15%
yield of γ-lactam 107 (based on 1.0 mmol/g loading of 105)
(Scheme 15).
(27) Anodic peak potentials, 0.2 M n-Bu4NBF4 in CH2Cl2, Pt disk electrode, Pt
wire auxiliary and pseudo-reference electrodes, 23 °C, 200 mV s-1
,
referenced to internal FeCp2 at +0.30 V. Irreversible and rapid fouling of
the electrode was observed, and, therefore, measured potentials are on first
scan only (reproducible on several independent runs). Professor M. G. Finn
is gratefully acknowledged for his assistance in these measurements. For
a systematic study of the bond dissociation energies of the N-H bonds in
anilines and their oxidation potentials see: Bordwell, F. G.; Zhang, X.-
M.; Cheng, J.-P. J. Org. Chem. 1993, 58, 6410.
The low efficiency observed in these reactions is likely
due to oxidative damage of the resin by IBX. Nevertheless, this
(28) For an insightful study of steric inhibition of resonance, see: Bo¨hm, S.;
Exner, O. Chem.-Eur. J. 2000, 6, 3391 and references therein.
9
J. AM. CHEM. SOC. VOL. 124, NO. 10, 2002 2243

A R T I C L E S
Nicolaou et al.
Scheme 15. Solid Phase Version of the IBX-Mediated Cyclization
mmol) in CH3CN:H2O (5:1, 0.6 mL) was added ceric ammonium
nitrate (CAN, 137 mg, 0.25 mmol) at 0 °C. After TLC indicated
complete consumption of the starting material, the reaction mixture
was diluted with EtOAc (2 mL) and washed with saturated aqueous
NaHCO3 (2 × 1 mL), water (2 × 2 mL), and brine (3 mL), dried
(MgSO4), and concentrated. The residue was purified by flash column
chromatography (silica gel) to provide pure deprotected amino sugar
derivatives.
of N-Aryl Amidesa
General Procedure for the Synthesis of 1-Deoxy-Aminosugars
(Procedure A). IBX (59.4 mg, 0.2 mmol) was added to a solution of
glycal-urethane (0.1 mmol) in anhydrous THF (4 mL). The solution
was placed in a sealed tube and heated at 90 °C for 5 h, followed by
another addition of IBX (59.4 mg, 0.20 mmol) and heating for a further
5 h period at the same temperature. The reaction mixture was diluted
with EtOAc (10 mL) and washed with 5% aqueous NaHCO3 (3 × 10
mL) and brine (10 mL), dried over MgSO4, and concentrated. After
purification by preparative thin-layer chromatography (PTLC, silica
gel, EtOAc:hexanes, 1:2) or flash column chromatography (silica gel),
the desired product was obtained in pure form.
a
Reagents and conditions: (a) IBX (excess), THF:DMSO (10:1), 90
°C, 72 h; (b) NaOMe (10 equiv), MeOH, 25 °C, 2 h, 15% 107.
IBX-mediated cyclization protocol may still be amenable to
further optimization through exploitation of other more ap-
propriate resins or in parallel solution formats yet to be
implemented.
General Procedure for the Synthesis of Aminosugars (Procedure
B). IBX (59.4 mg, 0.2 mmol) was added to a solution of glycal-urethane
(0.1 mmol) in THF:DMSO:H2O (10:1:0.5, 4 mL total volume). The
solution was placed in a sealed tube and heated at 90 °C for 12 h. The
reaction mixture was diluted with EtOAc (10 mL) and washed with
5% aqueous NaHCO3 (3 × 10 mL) and brine (10 mL), dried over
MgSO4, and concentrated. After purification by preparative thin-layer
chromatography (PTLC, silica gel, EtOAc:hexanes, 1:2) or flash column
chromatography (silica gel), the desired product was obtained in pure
form.
Conclusion
The discovery of the IBX-mediated cyclization of N-aryl
amides, carbamates, and ureas provides access to novel, struc-
turally diverse lactams and other heterocycles, as well as various
amino alcohols. Additionally, amino sugars and 1-deoxy amino
sugars are readily prepared from glucals and other carbohydrate-
based scaffolds. The operational simplicity of this reaction,
coupled with the ease of preparation of the cyclization precur-
sors, allow for the rapid diversification of allylic alcohols to
provide small molecule libraries for biological screening and
other applications. Furthermore, the ability to selectively intro-
duce nitrogen functionality onto unactivated alkenes provides
opportunities for the synthesis of natural and unnatural alkaloid-
type compounds. The versatility of IBX as a controllable SET-
based oxidation reagent is further demonstrated in the following
article.21
General Procedure for the Synthesis of Aminosugar Lactones
(Procedure C). IBX (178.2 mg, 0.6 mmol) was added to a solution of
glycal-urethane (0.1 mmol) in THF:H2O (100:1, 4 mL total volume).
The solution was placed in a sealed tube and heated at 90 °C for 8 h,
followed by another addition of IBX (178.2 mg, 0.6 mmol) and heating
for a further 8 h period at the same temperature. The reaction mixture
was diluted with EtOAc (10 mL) and washed with 5% aqueous
NaHCO3 (3 × 10 mL) and brine (10 mL), dried over MgSO4, and
concentrated. After purification by preparative thin-layer chromatog-
raphy (PTLC, silica gel, EtOAc:hexanes, 1:2) or flash column chro-
matography (silica gel), the desired product was obtained in pure form.
In all cases, amino sugar lactones were isolated as the minor products
with the corresponding lactols predominating. The lactols could be
easily oxidized to the lactones using Dess-Martin periodinane (DMP)
in CH2Cl2 at 25 °C.
Experimental Section
General Procedure for IBX-Induced Cyclization. IBX (59.4 mg,
0.20 mmol) was added to a solution of amide (0.1 mmol) in THF:
DMSO (10:1, 4 mL total volume). The solution was placed in a sealed
tube and heated at 90 °C for 12 h, followed by another addition of
IBX (59.4 mg, 0.20 mmol) and heating for a further 12 h period at the
same temperature. The reaction mixture was diluted with EtOAc (10
mL) and washed with 5% aqueous NaHCO3 (3 × 10 mL) and brine
(10 mL), dried over MgSO4, and concentrated. After purification by
preparative thin-layer chromatography (PTLC, silica gel, EtOAc:
hexanes, 1:2) or flash column chromatography (silica gel), the desired
product was obtained in pure form.
General Procedure for the Hydrolysis of Cyclic Urethanes to
Amino Alcohols. To a solution of cyclic urethane (0.05 mmol) in
ethanol (0.5 mL) was added NaOH (20 mg, 0.5 mmol), and the reaction
was heated to 70 °C until TLC indicated complete consumption of the
starting urethane. The reaction mixture was then diluted with EtOAc
(1 mL) and washed with water (3 × 2 mL) and brine (2 mL), dried
(MgSO4), and concentrated. The residue was purified by flash column
chromatography (silica gel) to provide the free amino alcohols.
General Procedure for the CAN-Induced Deprotection of Amino
Sugar Derivatives. To a solution of amino sugar derivative (0.05
Acknowledgment. We thank professors A. Eschenmoser, M.
Newcomb, J. Siegel, M. G. Finn, and H. M. R. Hoffmann for
helpful discussions. We also thank Drs. D. H. Huang, G.
Siuzdak, and R. Chadha for NMR spectroscopic, mass spec-
trometric, and X-ray crystallographic assistance, respectively.
This work was financially supported by the National Institutes
of Health (U.S.), The Skaggs Institute for Chemical Biology, a
postdoctoral fellowship from the Korea Science and Engineering
Foundation (to H.-S.C.), doctoral fellowships from the National
Science Foundation (to P.S.B.) and Boehringer Ingelheim (to
Y.H.), and grants from Pfizer, Glaxo, Merck, Schering Plough,
Hoffmann-La Roche, DuPont, and Abbott.
Supporting Information Available: Experimental procedures
and compound characterization (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
(29) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Sugita, K. J. Am. Chem. Soc.
2002, 124, 2212-2220.
JA012126H
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2244 J. AM. CHEM. SOC. VOL. 124, NO. 10, 2002