Iodine(V) reagents in organic synthesis. Part 1. Synthesis of polycyclic heterocycles via Dess-Martin periodinane-mediated cascade cyclization: Generality, scope, and mechanism of the reaction

Article abstract of DOI:10.1021/ja012124x

The scope, generality, and mechanism of the Dess-Martin periodinane-mediated cyclization reaction of unsaturated anilides discovered during the total synthesis of the CP-molecules (phomoidrides A and B) are delineated. A plethora of heterocyclic compounds

Full text of DOI:10.1021/ja012124x

Published on Web 02/16/2002
Iodine(V) Reagents in Organic Synthesis. Part 1. Synthesis of
Polycyclic Heterocycles via Dess-Martin
Periodinane-Mediated Cascade Cyclization: Generality,
Scope, and Mechanism of the Reaction
K. C. Nicolaou,* P. S. Baran, Y.-L. Zhong, and K. Sugita
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 scope, generality, and mechanism of the Dess-Martin periodinane-mediated cyclization
reaction of unsaturated anilides discovered during the total synthesis of the CP-molecules (phomoidrides
A and B) are delineated. A plethora of heterocyclic compounds are accessible by employing γ,δ-unsaturated
amides (derived from anilines and carboxylic acids), urethanes, or ureas (derived from isocyanates and
allylic alcohols and amines) as substrates. Optimization of the reaction led to room-temperature conditions,
while isotope labeling studies allowed a mechanistic rationale for this cascade reaction.
Introduction
compounds can be rapidly assembled and funneled into biologi-
cal screening programs.5 Recently, we unearthed a series of new
The importance of hypervalent iodine reagents in organic
synthesis has been amply demonstrated in recent years. Useful
synthetic reactions for the construction of carbon-heteroatom
and carbon-carbon bonds mediated by hypervalent iodine
species have been reviewed extensively.1 One of the field’s most
significant advances, the discovery of the Dess-Martin perio-
dinane (DMP),2 opened the door to a mild oxidation procedure
allowing a myriad of alcohols to be converted to the corre-
sponding carbonyl compounds. Its widespread use over the past
10 years attests to its benign nature and its uncanny ability to
succeed in the most difficult of oxidation circumstances.
o-Iodoxybenzoic acid (IBX),3 the precursor of DMP, has also
been shown to be a mild alcohol oxidant.4 Contemporary organic
synthesis is constantly striving for discovery and design of
reagents such as DMP and IBX which provide beneficial levels
of chemoselectivity and efficiency. In the postgenomic age, a
premium is placed on versatile, complexity-generating reactions
wherein a multitude of natural product-, drug-, and lead-like
paradigms for iodine(V)-mediated reactions with a variety of
organic substrates which go far beyond simple alcohol oxida-
tion.6 These discoveries, arising from our endeavors during the
total synthesis of the CP-molecules (phomoidrides A and B),7
allow the rapid and selective construction of complex polycycles,
including natural product analogues, diverse drug- and leadlike
molecules, amino sugars, R,â-unsaturated carbonyl compounds,
and an array of useful oxidized building blocks. In this series
of papers, we describe details of these processes and provide
new insights into their scope, generality, and mechanism. In
this article, we present a full account of the DMP-mediated
cascade polycyclization reaction of simple aryl amides (anilides),
urethanes, and ureas to complex phenoxazine-containing poly-
cycles (Scheme 1).
(5) Arya, P.; Chou, D. T. H.; Baek, M.-G. Angew. Chem., Int. Ed. 2001, 40,
339.
(6) (a) Nicolaou, K. C.; Zhong, Y.-L. Baran, P. S. Angew. Chem., Int. Ed.
2000, 39, 622. (b) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. Angew.
Chem., Int. Ed. 2000, 39, 625. (c) Nicolaou, K. C.; Baran, P. S.; Zhong,
Y.-L.; Vega, J. A. Angew. Chem., Int. Ed. 2000, 39, 2525. (d) Nicolaou,
K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000, 122, 7596. (e)
Nicolaou, K. C.; Sugita, K.; Baran, P. S.; Zhong, Y.-L. Angew. Chem.,
Int. Ed. 2001, 40, 207. (f) Nicolaou, K. C.; Baran, P. S.; Kranich, R.; Zhong,
Y.-L.; Sugita, K.; Zou, N. Angew. Chem., Int. Ed. 2001, 40, 202. (g)
Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L. J. Am. Chem. Soc. 2001, 123,
3183. (h) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S.; Sugita, K. Angew.
Chem., Int. Ed. 2001, 40, 2145.
(1) (a) Varvoglis, A.; Spyroudis, S. Synlett 1998, 221. (b) Varvoglis, A.
HyperValent Iodine in Organic Synthesis; Academic Press: San Diego,
1996; p 256. (c) Wirth, T.; Hirt, U. H. Synthesis 1999, 1271. (d) Varvoglis,
A. The Organic Chemistry of Polycoordinated Iodine; VCH: New York,
1992; p 414.
(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) First preparation of IBX: 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. Introduction of the acronym
“IBX”: Katritzky, A. R.; Duell, B. L.; Gallos, J. K. Org. Magn. Reson.
1989, 27, 1007.
(4) (a) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019. (b)
Corey, E. J.; Palani, A. Tetrahedron Lett. 1995, 36, 3485. (c) De Munari,
S.; Frigerio, M.; Santagostino, M. J. Org. Chem. 1996, 61, 9272. (d)
Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G. J. Org. Chem.
1995, 60, 7272.
(7) Part 1: 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. Part
2: 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. For a full
account, see preceding papers in this issue. Part 1: Nicolaou, K. C.; Jung,
J.; Yoon, W. H.; Fong, K. C.; Choi, H.-C.; He, Y.; Zhong, Y.-L.; Baran,
P. S. J. Am. Chem. Soc. 2002, 124, 2183-2189. Part 2: Nicolaou, K. C.;
Baran, P. S.; Zhong, Y.-L.; Fong, K. C.; Choi, H.-C. J. Am. Chem. Soc.
2002, 124, 2190-2201. Part 3: Nicolaou, K. C.; Zhong, Y.-L.; Baran, P.
S.; Jung, J.; Choi, H.-C.; Yoon, W. H. J. Am. Chem. Soc. 2002, 124, 2202-
2211.
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Iodine(V) Reagents in Organic Synthesis 1
A R T I C L E S
Table 1. Optimization of the DMP-Mediated Cyclization of Aryl Amides (1a to 1b)
entry
DMP (equiv)
additive(s)
solvent
temp (°C)
time
yield (%)a
1
2
3
4
5
6
7
8
9
2.0
2.0
2.0
4.0
4.0
2.0
4.0
4.0
2.2
2.2
4.0
4.0
none (open to atmosphere)
none (open to atmosphere)
none (under Ar)
1.0 equiv of H2O (under Ar)
0 or 1.0 equiv of H2O (under Ar)
0 or 1.0 equiv of H2O (under Ar)
0 or 1.0 equiv of H2O (under Ar)
0 or 1.0 equiv of H2O (under Ar)
1.0 equiv of TFA
1.0 equiv of pyridine (under Ar)
1.0 equiv of H2O, excess O2
1.0 equiv of H2O, 5.0 equiv of
galvinoxyl (under Ar)
benzene
BTF
benzene
CH2Cl2
THF
reflux
80
reflux
23
23
23
23
23
23
23
30-40 min
30-40 min
5 h
1.5 h
20 h
24 h
24 h
24 h
7 h
34-40
32-37
0
15
0
0
0
0
0
trace
15
14
CH3CN
DMF
DMSO
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
10
11
12
10 h
1.5 h
7 h
23
23
13
14
15
4.0
4.0
4.0
2.0 equiv of H2O (under Ar)
2.0 equiv of H2O (under Ar)
none (open to atmosphere)
CH2Cl2
toluene
toluene
23
80
80
15 h
30-40 min
30-40 min
40-42
27
16
a Chromatographically pure 1b. BTF ) benzotrifluoride, THF ) tetrahydrofuran, DMF ) dimethylformamide, DMSO ) dimethyl sulfoxide.
Scheme 2. Two Methods Utilized for the Preparation of Aryl
Amides (G), Urethanes, and Ureas (K) as Substrates for the
DMP-Mediated Cyclization
Figure 1. A serendipitous discovery during the CP-molecule campaign:
initial observation of the reaction of an unsaturated anilide (A) to a novel
heterocycle (B) upon heating with DMP in benzene solution at 80 °C.
Scheme 1. DMP-Mediated Formation of Complex Heterocycles
(D) in One Step from Readily Available Aryl Amides (Anilides),
Urethanes, and Ureas (C)
1, 2, and 13-15, Table 1). No detectable reaction was observed
in THF, CH3CN, DMF, or DMSO. Additives such as TFA
halted the reaction (entry 9, Table 1), whereas pyridine did not
Results and Discussion
accelerate the reaction (entry 10, Table 1) unless water was
present (vide infra). Hypothesizing that the presence or absence
of water may be intimately related with reaction efficiency, we
performed the reaction under strictly anhydrous conditions (entry
1. Discovery and Optimization of the DMP Reaction with
Anilides. In 1999, while attempting to oxidize the stubbornly
resisting CP-molecule intermediate A (Figure 1) with DMP at
elevated temperatures, we observed, much to our surprise, the
formation of the novel polycyclic system B. Upon short
reflection and mechanistic analysis we suspected a new mode
3, Table 1). It thus became clear that water was an essential
ingredient for the reaction to proceed, and this in turn implied
that Ac-IBX (see Scheme 6) was somehow involved.9 Polycycle
of reactivity for DMP which required an aryl amide moiety and
1b (Table 1) was obtained in similar yields at room temperature
a nearby double bond as demonstrated in structure A. An
in CH2Cl2 or at 80 °C in benzene, only when the correct
expedient investigation of the scope and generality of the
reaction led to a preliminary communication.6a Since our initial
disclosure, we have performed extensive optimization studies
of this process (Table 1) using aryl amide 1a as a substrate.
The results are shown in Table 1. Through the systematic fine-
tuning of this reaction, a plausible mechanistic pathway also
became clear (vide infra). When we probed solvent effects we
found that benzene, benzotrifluoride (R,R,R-trifluorotoluene,
BTF),8 toluene, and CH2Cl2 were all suitable solvents (entries
stoichiometry of DMP and H2O was employed. As shown in
Table 2, we found that 4.0 equiv of DMP and 2.0 equiv of H2O
was an ideal reagent combination for the reaction (entry 6, Table
2). It is interesting to note that using only DMP (no H2O present)
or DMP:H2O (1:1) resulted in no reaction. The remarkable
mechanistic implications of this finding will be discussed later
(vide infra).
(9) (a) For the first report of Ac-IBX see ref 2b. (b) Water-induced acceleration
of the DMP reagent (leading to Ac-IBX) was also observed by S. L.
Schreiber in the context of alcohol oxidation, see ref 2c; see also ref 4c.
(8) Ogawa, A.; Curran, D. P. J. Org. Chem. 1997, 62, 450.
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A R T I C L E S
Nicolaou et al.
Scheme 5. Proposed Mechanistic Underpinnings of the
Scheme 3. Amides Such as 23a, 38a, and 39a Give Rise to the
Corresponding Ketones 23c, 38b, and 39b Instead of the
Expected Polycycles, Presumably via an Epoxide Intermediate
Such as 40a
DMP-Mediated Polycyclization of Aryl Amides
Scheme 6. Enlisting o-Hydroxyanilide 50a in the DMP Cascade
Still Leads to the Same Polycycle 7b via 51a
a Reagents and conditions: (a) EDC (1.2 equiv), 4-DMAP (0.2 equiv),
CH2Cl2, 25 °C, 3 h; (b) 80% aqueous AcOH, 25 °C, 1 h, 81% overall; (c)
DMP (2.0 equiv), benzene, 75 °C, 0.5 h, 35%.
a Reagents and conditions: (a) DMP (2.0 equiv), benzene, 75 °C, 1 h,
43% 23c, 40% 38b, and 28% 39b.
Table 2. Optimization of the Stoichiometry of DMP and H2O
Employed in the DMP-Induced Cyclization of Aryl Amides (1a f
1b)
Scheme 4. Attempted Construction of Tetracycle 47 from
δ-Olefinic Substrate 46 and DMPa
a
Reagents and conditions: (a) DMP (4.0 equiv), benzene, 80 °C, 4 h.
entry
DMP (equiv)
H O (equiv)
yield (%)a
2
2. Scope and Generality of the Reaction. With two reliable
sets of conditions in hand (conditions A and B, see Table 3),
we probed the generality of the DMP reaction with a variety of
easily prepared anilides [from anilines (E) and γ,δ-unsaturated
carboxylic acids (F), see Scheme 2 and Table 3]. Our initial
attempts to determine the generality of the DMP-cascade were
disappointing. As shown in entries 1-8 in Table 3, the reactions
of simple anilides containing a terminal olefin led only to low
yields of the desired products. We attributed this observation
to a combination of two factors: (a) a high degree of
conformational freedom of the olefin in these substrates and
(b) the olefin’s comparatively electron-poor nature. We reasoned
that embedding a ring into the olefinic segment of the starting
material might restrict conformational mobility and increase
electron density of the olefinic bond, thereby increasing the
efficiency of the reaction. Indeed, as can be seen from entries
1
2
3
4
5
6
7
1.0
2.0
2.0
2.0
4.0
4.0
4.0
0
0
0
0
30
0
0
40
0
1.0
2.0
0
2.0
4.0
a Chromatographically pure 1b.
9-32 (Table 3), the cyclization yields were considerably
improved with this modification to provide a variety of complex
polycycles. The ability of this process to generate three new
stereocenters in a diastereocontrolled manner from simple
starting materials is both remarkable and highly productive in
terms of achieving molecular complexity. Throughout these
studies and using the new, ambient temperature-based conditions
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Iodine(V) Reagents in Organic Synthesis 1
A R T I C L E S
Table 3. DMP-Mediated Construction of Novel Polycycles and Quinones from Unsaturated Aryl Amidesa
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A R T I C L E S
Nicolaou et al.
Table 3. (continued)
b
a Reactions were carried out on 0.1-0.3 mmol scale. Chromatographically pure compounds.
(conditions B, Table 3; entry 13, Table 1), we often observed
the formation of p-quinones along with the desired polycycles.
When we enlisted the original conditions (conditions A, Table
3; entry 1, Table 1), the p-quinone byproducts were not
observed, presumably due to their thermal instability. It should
also be mentioned that a neutral workup protocol was essential
to isolate the p-quinone compounds in the case of the room
temperature experiments. Under basic workup conditions (5%
aqueous NaHCO3), the p-quinones were removed.
As seen from inspection of Table 3, a wide variety of groups
are tolerated on the aryl residue, ranging from the electron-
withdrawing nitro and trifluoromethyl groups (entries 16, 17,
and 24, Table 3) to the synthetically fertile halides (entries 13-
15, 21, 22, 25, and 27-31, Table 3). Remarkably, even the
electron-rich and overoxidation prone methoxy group (entry 20,
Table 3) was tolerated in this reaction leading to polycycle 15b.
In this case, however, the corresponding p-quinone was also
found in appreciable amounts (41%) (entry 20, Table 3).
Although the bulky tert-butyl group was well tolerated at the
p-position of the anilide (entry 19, Table 3), substitution at the
ortho position led to the novel o-imidoquinone 17b along with
the polycycle 7b, the latter missing the tert-butyl group. A
reasonable mechanistic scenario for the puzzling loss of the t-Bu
group in this reaction may involve ipso attack on the tert-butyl
bearing carbon (of intermediate II, Scheme 5) by Ac-IBX
followed by loss of the tert-butyl cation. A pathway leading to
the defluorinated p-quinone byproducts observed (entries 2 and
8, Table 3) is offered in the following paper, wherein the scope
of p-quinone generation is explored.10 Disubstitution on the
aromatic moiety was tolerated as seen in entry 25 (Table 3).
Given the complexity of the CP-based polycycle (Figure 1, B)
formed in the initial discovery of this reaction,7 we were not
surprised that even the amide 24a (entry 31, Table 3) cyclized
smoothly under the influence of DMP to give the complex
polycycle 24b with six contiguous stereocenters (one of them
quaternary). As a further test of the power of this process to
deliver complex molecular diversity, we enlisted the diamide
25a (entry 32, Table 3) as a substrate and observed the formation
of the complex polycycle 25b, harboring 10 rings and seven
stereocenters in 30% yield (mixture of four diastereomers).
Upon further investigation, substrate 23a (entry 30, Table 3),
first reported6a to furnish the polycycle 23b, actually gives rise
(10) Nicolaou, K. C.; Sugita, K.; Baran, P. S.; Zhong, Y.-L. J. Am. Chem. Soc.
2002, 124, 2221-2232.
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Iodine(V) Reagents in Organic Synthesis 1
A R T I C L E S
Table 4. DMP-Mediated Construction of Novel Polycycles and Quinones from Urethanes, Thiourethanes, and Ureasa
b
a Reactions were carried out on 0.1-0.3 mmol scale. Chromatographically pure compounds.
to the ketone 23c. As shown in Scheme 3, the same type of
reactivity is observed with nitro-substituted amide 38a and
unsubstituted amide 39a. Presumably, the lowered reactivity of
this type of amide coupled with the unique reactivity profile11
of the appended bicyclic olefin lead to an epoxidation with DMP
(leading to 40, Scheme 3) followed by ring opening with the
nearby amide (leading to 41) and oxidation of the resulting
alcohol to furnish the observed ketone 39b. The ability of DMP
to epoxidize certain substrates is addressed in the following
article.10
considered the nucleophilic attack of allylic alcohols (I) or
amines (J) on phenyl isocyanates (H) as a means to secure such
substrates (G, K) as shown in Scheme 2.12 Although in our
initial disclosure6a we reported the use of phenyl isothiocyanates,
we later found that a majority of the resulting allylic thioure-
thanes undergo rearrangement to give a mixture of products.13
As seen in Table 4, urethanes react efficiently to produce the
corresponding polycycles. As with the amides (Table 3), using
the room temperature conditions (conditions B, Table 4), we
were able to isolate the formed p-quinones in many cases (entries
2-5 and 13, Table 4). Electronic influences of the aromatic
Recognizing that the scope and versatility of the reaction
could be considerably enhanced if the pool of starting materials
was expanded to other effortlessly available compounds, we
(12) Patai, S., Ed. The Chemistry of Cyanates and Their Thio DeriVatiVes, Part
1; Wiley: Chichester, 1977; p 618. Patai, S., Ed. The Chemistry of Cyanates
and Their Thio DeriVatiVes, Part 2; Wiley: Chichester, 1977; p 700.
(13) Harayama, H.; Nagahama, T.; Kozera, T.; Kimura, M.; Fugami, K.; Tanaka,
S.; Tamura, Y. Bull. Chem. Soc. Jpn. 1997, 70, 445.
(11) Pinkerton, A. A.; Schwarzenbach, D.; Birbaum, J.-L.; Carrupt, P.-A.;
Schwager, L.; Vogel, P. HelV. Chim. Acta 1984, 67, 701.
9
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A R T I C L E S
Nicolaou et al.
Table 5. Hydrolysis of Protected Phenoxazines to Amino
Scheme 7. Informative Byproducts from the Reaction of Amide
Alcoholsa
52a with DMP and a Possible Mechanism for Their Formationa
a
Reagents and conditions: (a) DMP (2.0 equiv), benzene, 75 °C, 1 h,
43% 52b plus 25% 52c.
identical to treatment of the reaction mixture (DMP, substrate,
CH2Cl2) with H2O. As shown in Table 2, using only DMP
(strictly anhydrous conditions) or only Ac-IBX (DMP:H2O (1:
1)) led to no reaction. Recognition of the key synergy between
DMP and Ac-IBX in this process led to the proposition that
Ac-IBX acts as a nucleophile descending upon intermediate II
as depicted in Scheme 5 and leading to species III along with
a molecule of AcOH and the known byproduct IV. Subsequent
oxidative collapse of intermediate III then furnishes the
o-imidoquinone V14 which is accompanied by an additional
equivalent of IV. The fleeting o-imidoquinone system of V then
engages the proximate olefin in an inverse electron demand
hetero Diels-Alder reaction15 to furnish the observed polycycle
VI.
Because, at first, we had no hope of isolating the short-lived
o-imidoquinone intermediate V (at the higher temperatures
employed), we utilized the o-hydroxy anilide 50a to indirectly
implicate it in the cascade (Scheme 6). Indeed, treatment of
50a with DMP (2.0 equiv) in refluxing benzene led to the
desired polycycle 7b, presumably through the intermediacy of
o-imidoquinone 51. As our studies progressed, however, we
were able to isolate, at ambient temperature, pure o-imidoquino-
nes and study their chemistry (vide infra).
A unique observation was made in the case of the o-
methoxyanilide 52a (Scheme 7) which afforded the acetate 52c
and iodinane 52b upon treatment with DMP in refluxing
benzene. A possible mechanistic rationale for the formation of
these interesting byproducts is illustrated in Scheme 7, although
other plausible mechanisms cannot be excluded at present.
Presumably, the electron-rich anilide 52a attacks from the
aromatic ring (para to the NH group) rather than from the amide-
oxygen, leading to intermediate 53 whose fate diverges to give
52b and 52c, the latter via intermediates 54 and 55 (Scheme
7).
a Reactions were carried out on 0.05 mmol scale with NaOH in EtOH
at 70 °C. Chromatographically pure compounds.
b
ring substituents on the reaction course were similar to those
observed for the aryl amides (Table 3). The presumption that
restriction of conformational freedom should enhance reactivity
(vide supra) in these reactions appears to hold, since the more
rigid urea 37a cyclized to polycycle 37b in good yield (56%,
entry 15, Table 4).
As illustrated in Table 5, the phenoxazine derivatives
produced according to Table 4 could be easily hydrolyzed
(NaOH, EtOH, 70 °C) to the corresponding amino alcohols in
high yield (90-96%).
To extend the scope of the DMP-induced ring closure
reaction, we attempted the cyclization with a substrate in which
the olefin was located δ rather than γ to the carbonyl of the
amide or urethane group. Unfortunately, compounds such as
46 did not furnish the desired polycycle (47, Scheme 4).
3. Mechanistic Studies. One of the most interesting facets
of the new periodinane-based reactions reported in this series
of papers is the unique mechanism by which each appears to
be operating. A closer examination of the mechanism of the
DMP-mediated cascade cyclization led us to revise our original6a
mechanistic proposals to the one depicted in Scheme 5. Thus,
we now believe that an anilide molecule (I, Scheme 5) engages
DMP from the oxygen of the amide functionality leading to
intermediate II. Indeed, upon addition of freshly prepared DMP
to a solution of the model anilide N-phenylacetamide (I: R )
H; R′ ) Me) in CDCl3, a dark brown coloration appeared along
1
with new H NMR signals. This supported the formation of a
transient intermediate, presumed to be II (Scheme 5), although
TLC analysis (silica gel) revealed only starting materials and
traces of decomposition products. The performance of the
reaction even in the presence of the radical inhibitor galvinoxyl
(entry 12, Table 1) suggests that the reaction does not involve
discreet radical intermediates.
Isotope labeling studies using H218O were then initiated to
verify that the new oxygen atom in these reactions is derived
from Ac-IBX (Scheme 8). Thus, H218O (2.0 equiv) was added
(14) A multistep route to this type of diene is known; however, the reaction
requires the presence of chlorine substituents on the aryl ring, see: Heine,
H. W.; Barchiesi, B. J.; Williams, E. A. J. Org. Chem. 1984, 49, 2560.
(15) Boger, D. L.; Weinreb, S. M. Organic Chemistry, Vol. 47: Hetero Diels-
Alder Methodology in Organic Synthesis; Academic Press: San Diego,
1987; p 366.
During the optimization of the DMP-cascade (vide supra) we
had found that water was essential for the reaction to proceed.
If DMP was pretreated with H2O, thereby producing an equal
amount of Ac-IBX (as it is well documented),2 the result was
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Iodine(V) Reagents in Organic Synthesis 1
A R T I C L E S
Scheme 9. DMP-Cyclization on Solid Phase - First Attempta
Scheme 8. 18O Labeling Studies with the DMP Cascade Reactiona
Reagents and conditions: (a) H218O (2.0 equiv), CH2Cl2, 25 °C,
a
ultrasound, 1 min; then 25 °C, 10 min; (b) solution of Ac-IBX-18O/DMP,
1a (1.0 equiv), CH2Cl2, 25 °C, 4 h.
to a solution of DMP (4.0 equiv) in CH2Cl2. After ensuring
that all of the labeled water was consumed (sonication for 1
min, stirring for an additional 10 min at ambient temperature),
the resulting DMP/Ac-IBX-18O combination was added to
substrate 1a, leading to the 18O-labeled polycycle 1b-18O (44%
yield) as confirmed by mass spectrometric analysis (Scheme
8). This observation supports the notion that the newly installed
oxygen atom arises from Ac-IBX rather than from H2O, air, or
the substrate itself. Attempts to intercept the postulated o-
imidoquinone intermediate 56 were unsuccessful; however, we
were able to isolate and characterize the o-tert-butyl substituted
o-imidoquinone 17b (entry 23, Table 3). The minor product of
the labeling study, p-quinone 1c-18O2 (Scheme 8), was also
a
Reagents and conditions: (a) EDC (1.5 equiv), Et3N (1.5 equiv),
4-DMAP (0.1 equiv), CH2Cl2, 25 °C, 2 h; (b) 1 M aqueous HCl, 25 °C, 20
min, 95% overall; (c) EDC (1.5 equiv), Et3N (1.5 equiv), 4-DMAP (0.1
equiv), THF, 25 °C, 16 h, 37%; (d) DMP (5.0 equiv), H2O (3.5 equiv),
CH2Cl2, 25 °C, 12 h; (e) NaOMe (10 equiv), MeOH, 25 °C, 2 h, 25% 61
plus 20% 58.
crude reaction mixture following hydrolysis were clean, showing
only polycycle 61 and uncyclized amide 58 (ratio ca. 5:1) and
in 28% overall yield from 58 (based on weight difference of
the resin 60a after loading of the alcohol 58). This study pro-
vides proof of principle for the viability of a cyclization on solid
phase for possible large-scale combinatorial chemistry efforts.
isolated, characterized, and shown to have incorporated two 18
O
atoms by mass spectrometry. This intriguing observation led to
an understanding of the relation between the fleeting o-
imidoquinone 56 and p-quinone 1c-18O2, thus opening the door
to the design of a series of new reactions commencing with
DMP-accessible o-imidoquinones and leading to a variety of
diverse and complex polycyclic molecular architectures.10
4. Solid-Phase Synthesis with DMP. To explore the feasibil-
ity of employing the discovered DMP-cascade on solid phase
to generate libraries of medicinally relevant compounds,16 we
synthesized the resin-bound aniline 60a as shown in Scheme
9. Thus, EDC-mediated coupling of carboxylic acid 48 with
aniline 57 followed by desilylation (H3O+) led to the hydroxy
anilide derivative 58. Esterification (EDC) of the latter com-
pound (58) with resin-bound 59 furnished the desired anilide
60a which upon treatment with DMP in CH2Cl2 for 48 h led to
the resin-bound polycycle 60b. It was presumed that the cor-
responding p-quinone byproduct 62 was also formed, although,
upon basic cleavage (K2CO3/MeOH), only the polycycle 61 and
uncyclized anilide 58 were isolated, the quinone being too labile
Conclusion
In this article, we described the development of a serendipi-
tous observation made en route to the CP-molecules into a new
synthetic technology for the construction of complex phenox-
azine-containing heterocycles relevant to biological systems.
Requiring only two operations from ubiquitous and com-
mercially available starting materials, this reaction delivers
impressively complex structures equipped with numerous het-
eroatoms, useful functionalities, and stereochemical centers.
Systematic optimization of the reaction conditions led to a mild,
ambient temperature protocol for this fertile process and to
further observations which facilitated the accumulation of
important mechanistic insights. The significant discovery that
two periodinane species, DMP and Ac-IBX, are intimately
involved in this unique cascade sequence was verified empiri-
cally and through isotope labeling studies. Further evolution of
the understanding of this elaborate mechanism led to the
recognition of the potential of o-imidoquinones in organic
synthesis. This potential has been explored to a considerable
extent as will be discussed in the following paper.10
1
to survive these conditions. TLC and H NMR analysis of the
(16) Phenoxazines as amyloid fibril inhibitors: Petrassi, H. M.; Klabunde, T.;
Sacchettini, J.; Kelly, J. W. J. Am. Chem. Soc. 2000, 122, 2178.
Phenoxazines have been found to reverse drug resistance in cancer cells,
see: Horton, J. K.; Thimmaiah, K. N.; Harwood, F. C.; Kuttesch, J. F.;
Houghton, P. J. Mol. Pharmacol. 1993, 44, 552. For a review of antitumor
phenoxazines, see: Motohashi, N.; Mitscher, L. A.; Meyer, R. Med. Res.
ReV. 1991, 11, 239.
9
J. AM. CHEM. SOC. VOL. 124, NO. 10, 2002 2219

A R T I C L E S
Nicolaou et al.
products. Pure compounds were isolated in the yields listed below and
are shown in Tables 3 and 4 after flash column chromatography (silica
gel, EtOAc:hexane 1:2) (see Supporting Information Available).
Experimental Section
General Procedures for the DMP Cyclization. Conditions A: To
a solution of aryl amide G, urethane, or urea K (0.1 mmol) in benzene
(or BTF)8 (4 mL) was added DMP (2.0 equiv) in one portion. The
solution (open to the atmosphere) was heated at reflux (or at 80-85
°C for the case of BTF) for ca. 30 min (precise times listed in Tables
3 and 4), at which point TLC indicated complete consumption of the
starting material. Dilution with EtOAc followed by washing with 5%
aqueous NaHCO3 solution (2 × 5 mL) and brine (5 mL), drying over
MgSO4, and concentration led to the crude polycylic products. Pure
compounds were isolated in the yields listed below and are shown in
Tables 3 and 4 after flash column chromatography (silica gel, EtOAc:
hexane 1:2) (see Supporting Information Available). Conditions B:
To a solution of aryl amide G, urethane, or urea K (0.1 mmol) in dry
CH2Cl2 (4 mL) under an argon atmosphere was added DMP (4.0 equiv)
followed by water (2.0 equiv). The solution was stirred at room
temperature for the time indicated in Tables 3 and 4, at which point
TLC indicated complete consumption of the starting material. Dilution
with EtOAc followed by washing with water (2 × 5 mL) and brine (5
mL), drying over MgSO4, and concentration led to the crude polycylic
Acknowledgment. We thank Drs. D. H. Huang, G. Siuzdak,
and R. Chadha for NMR spectroscopic, mass spectrometric, 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 predoctoral
fellowship from the National Science Foundation (to P.S.B.),
and grants from Abbott, Amgen, ArrayBiopharma, Boehringer
Ingelheim, DuPont, Glaxo, Hoffmann-La Roche, Merck, Pfizer,
and Schering Plough.
Supporting Information Available: Experimental procedures
and compound characterization (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
JA012124X
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2220 J. AM. CHEM. SOC. VOL. 124, NO. 10, 2002