Evaluation of the efficiency of the macrolactonization using MNBA in the synthesis of erythromycin a aglycon

Article abstract of DOI:10.1002/tcr.200900017

Various intermediates for the synthesis of erythronolide A, an aglycon of erythromycin A, are prepared from the corresponding seco-acids using 2-methyl-6-nitrobenzoic anhydride (MNBA) in the presence of 4-(dimethylamino)pyridine (DMAP) with or without tri

Full text of DOI:10.1002/tcr.200900017

Evaluation of the Efficiency of the
Macrolactonization Using MNBA in the
Synthesis of Erythromycin A Aglycon
T H E
C H E M I C A L
R E C O R D
ISAMU SHIINA*, TAKASHI KATOH, SHUNSUKE NAGAI, MINAKO HASHIZUME
Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka,
Shinjuku-ku, Tokyo 162-8601, Japan
Received 7 August 2009
ABSTRACT: Various intermediates for the synthesis of erythronolide A, an aglycon of erythromycin
A, are prepared from the corresponding seco-acids using 2-methyl-6-nitrobenzoic anhydride (MNBA)
in the presence of 4-(dimethylamino)pyridine (DMAP) with or without triethylamine. The efficiency
of the MNBA lactonization is assessed by studying this method and comparing the results with those
of the other established macrocyclization protocols. It has been finally concluded that (i) the
conformationally appropriate substrate for the monomeric cyclization gave the desired lactone in
excellent yield under mild reaction conditions in the presence of MNBA and DMAP, (ii) the highly-
strained substrate for the cyclization also afforded the monomeric lactone in relatively good yield
at 100°C in toluene, and (iii) the seco-acid having stable linear conformation, which preferred
dimerizing more than forming the monomeric lactone, provided the corresponding diolide in
high yield with the constant ratio of the monomer to dimeric lactone (approximately 1/5).
© 2009 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 9: 305–320;
2009: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/
tcr.200900017
Keywords: erythromycin A; erythronolide A; lactonization; 2-methyl-6-nitrobenzoic anhydride;
MNBA
Introduction
In 1981, Woodward et al. reported the total synthesis of
erythromycin A (1, Figure 1)1 via the effective construction of
the lactone moiety by the thiol ester-activation method,2,3
which had been utilized for the total synthesis of erythronolide
A (2) by Corey et al. in 1979.4 These successful syntheses of
1 and 2 were monumental studies in the field of organic
synthesis and the associated methodologies, including the
lactonization protocol, represented significant developments in
synthetic reaction technology.
seco-acid 4 was synthesized from 3 as shown in Scheme 1, but
the lactonization of 4 via the S-Py ester 5 did not proceed at
all even under very severe reaction conditions in the first of
their trials for the generation of the basic skeleton of 1.
In order to explore the synthetic pathway to access
erythromycin A (1), they attempted to prepare several kinds
of model seco-acids by the degradation of 1 via two
᭤
*Corresponding author: E-mail: Shiina@rs.kagu.tus.ac.jp
First, Woodward et al. prepared a linear polyoxy thioester
3 as an intermediate for the synthesis of 1. The corresponding
Additional Supporting Information may be found in the online version of this
article.
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T H E C H E M I C A L R E C O R D
other substrates, such as 10a and 12a, did not produce the
desired lactones 15a and 17a at all.1b
They assumed that these structural requirements for the
facilering-closureof11aprobablyarisefromtheconformational
properties of the substrates, which were derived from the
absolute configurations at the C-9 position as well as other
combinations of the protective groups masking the hydroxyl
groups in the seco-acids.
Based on the assumption from the experimental results,
they newly designed a seco-acid 18, which might have a
suitable structure for the facile cyclization (Scheme 3). Actually,
the lactonization of the S-Py ester generated from 18 in
situ smoothly proceeded at 110°C in toluene to afford the
desired product 19 in 70% yield. The (9S)-amino analogue
of erythronolide 19 was successfully transformed into the
appropriate glycosyl donor for couplings with sugar segments
and finally converted into the targeted molecule, erythromycin
A (1) by Woodward et al. in 1981.1
Fig. 1. Chemical structures of erythromycin A (1) and erythronolide A (2).
intermediates, (9R)-dihydroerythronolide A (7a) and (9S)-
dihydroerythronolide A (7b) as shown in Scheme 2, and then
the resulting seco-acids underwent macrocyclization using the
S-Py ester method. Very interesting results were obtained from
their lactonization experiments; that is, only three compounds
8, 9, and 11a afforded the corresponding lactones 13, 14, and
16a in 15%, 10%, and 70% yields, respectively, although
In 1987, Stork and Rychnovsky revealed the origin
of the efficiency for the cyclization to afford the (9S)-
dihydroerythronolide A backbone by the conformational
analysis of the precursors and products.5 Systematic studies on
᭤
Isamu Shiina was born in Tokyo in 1967. He completed his BSc and MSc at Tokyo University
of Science (TUS), and he joined the group of Prof. Teruaki Mukaiyama in TUS as an Assistant
Professor in 1992. After receiving his PhD from the University of Tokyo (UT) in 1997, he was
promoted to Lecturer at theTUS, and then appointed to an Associate Professor (2003) and a Full
Professor (2008). He has received the Chemical Society of Japan Award for Young Chemists
(1997) and the Banyu Young Chemist Award (2006). His research interests include the develop-
ment of useful synthetic methods and the total synthesis of natural products.
᭿
᭤
Takashi Katoh completed his BSc at Tokyo University of Science (TUS). In 2006, he received
his MSc degree from TUS under the direction of Prof. Isamu Shiina. He is now a research fellow
at Daicel Chemical Industries, Ltd., Hiroshima.
᭿
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E v a l u a t i o n o f t h e E f f i c i e n c y
Scheme 1. Attempted synthesis of erythromycin A (1) aglycon from seco-acid 4 by Woodward.
᭤
Shunsuke Nagai completed his BSc at Tokyo University of Science (TUS). In 2008, he received
his MSc degree from TUS under the direction of Prof. Isamu Shiina. He is now a research fellow
at Hitachi Chemical Co. Ltd., Chikusei.
᭿
᭤
Minako Hashizume completed her BSc at Tokyo University of Science (TUS). In 2004, she
received her MSc degree from TUS under the direction of Prof. Isamu Shiina. She is now a
research fellow at Eisai Co. Ltd., Tsukuba.
᭿
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T H E C H E M I C A L R E C O R D
Scheme 2. Woodward’s macrocyclization model studies for the synthesis of polyoxy 14-membered lactones using
the S-Py ester method.
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E v a l u a t i o n o f t h e E f f i c i e n c y
the structure of the cyclic compounds suggested that the close
Actually, only the cyclization of 22a (R1¨Me, R2¨H) under
Keck’sconditions6 couldtakeplacetoproducethecorresponding
14-membered lactone 25a in good yield (64%) because 22a
had a suitable structure around the C9-C11 portion for the
ring-closure, whereas macrocyclization of the other substrates
20 and 21 failed to produce the desired lactones 23 and 24
owing to the unfavorable structures of the C9-C11 acetal
moieties in 20 and 21.
proximity of R2 to the C-8 surroundings produced a very large
1,3-diaxial repulsion and severe presentation of the ring-
forming reaction as depicted in Figure 2.
According to this structural analysis, the difficulty of the
cyclization using seco-acids 20 (R1¨R2¨Me) and 21 (R1¨H,
R2¨Me) to form the corresponding lactones 23 and 24,
respectively, was logically induced (Scheme 4, see Figure 2).
Furthermore, the total syntheses of erythronolide A (2)
was accomplished by Yonemitsu et al.7 and Kochetkov et al.8
as shown in Scheme 5 (see also Figure 2) by the effective
formation of the 14-membered lactones 16b and 25b starting
from seco-acids 11b (R1¨Mes, R2¨H) and 22b (R1¨PMP,
R2¨H), which have similar structures to those of 11a
(R1¨Mes, R2¨H) and 22a (R1¨Me, R2¨H). In the former
cyclization, the desired lactone 16b was easily obtained in 98%
yield from the seco-acid 11b by the modified Yamaguchi
lactonization,9 and the later ring-closure reaction was also
successfully carried out using Corey’s improved double-
activation method3,4 through a thiol ester intermediate
generated from 22b to provide the corresponding lactone 25b
in 71% yield. In Paterson’s total synthesis of oleandomycin,10
and Evans’ total synthesis of 6-deoxyerythronolide B,11 similar
conformationally favorable substrates for the cyclization were
used as key intermediates to establish the effective construction
Scheme 3. Completion of Woodward’s total synthesis of erythromycin (1)
from 3 by the effective lactonization via 18 to form 19.
Fig. 2. The systematic studies performed to show the close proximity of R2 to the C-8 surroundings produces a very
large 1,3-diaxial repulsion.
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T H E C H E M I C A L R E C O R D
Scheme 4. Stork’s macrocyclization studies for the synthesis of erythronolide A (2) using the Keck method.
Scheme 5. Yonemitsu’s and Kochetkov’s macrocyclization studies for the synthesis of erythronolide A (2) using the
Yamaguchi and Corey methods.
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E v a l u a t i o n o f t h e E f f i c i e n c y
Scheme 6. The present studies for the synthesis of the erythronolide A skeleton using the MNBA lactonization.
of the lactone parts on the basis of Stork’s analysis. Advanced
12a (Scheme 2) so that there would be a considerable difficulty
to cyclize 12b to form the corresponding lactone 17b. In
this paper, we disclose very interesting results for the
lactonization of 10b, 10c, 11c, and 12b by promotion
using 2-methyl-6-nitrobenzoic anhydride (MNBA)13–15 in
the presence of 4-(dimethylamino)pyridine (DMAP) with or
without triethylamine.
theoretical studies of the conformations of seco-acids for the
facile lactonization based on the molecular mechanics
calculation were also carried out by Yonemitsu and Osawa.12
Founded on the above history and background of the
developments for the lactonization during the synthesis of the
aglycons of 1, we selected four typical seco-acids 10b, 10c,
11c, and 12b as precursors of lactones 15b, 15c, 16c, and 17b
for the evaluation of the efficiency of our lactonization protocol
(Scheme 6, see also Figure 2). The seco-acids 10b and 10c
(R1¨H, R2¨Ph) have unfavorable structures for the
cyclization as well as 10a (R1¨H, R2¨Mes) and therefore
the lactonization of 10b and 10c might be prevented by the
conformational disadvantage to produce 15b and 15c owing
to the generation of the 1,3-diaxial repulsion between the
phenyl substituent and C-8 surroundings of the aglycon. On
the other hand, the seco-acid 11c (R1¨Ph, R2¨H) has a
structure similar to those of 11a and 11b (R1¨Mes, R2¨H),
and easy cyclization might be attained when we use 11c as a
precursor of the lactone 16c because 11c should have a suitable
conformation to produce the desired monomeric lactone 16c.
Furthermore, according to the pioneering research of
Woodward, 12b (Scheme 6) is placed in the same category as
Results and Discussion
Preparation of seco-acids 10b, 10c, 11c, and 12b: We first
prepared (9S)-dihydroerythronolide A (7b) by the degradation
of erythromycin A (1) through 1′ and (9S)-1″ according to the
known method reported by Jones and Rowley16 with some
improvements (Scheme 7). The oxidation of 1 with hydrogen
peroxide and successive Cope elimination of the amino group
in D-desosamine produced the glycoside 1′ in good yield
under the optimized conditions described in the additional
Supporting Information (88 and 90%, respectively). The
reduction of 1′ with NaBH4 in methanol smoothly proceeded
toaffordtwodiastereomersattheC-9position(9S/9R = 82/18),
which were treated with 3% hydrochloric acid for cleavage of
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T H E C H E M I C A L R E C O R D
Scheme 7. Synthesis of (9S)-dihydroerythronolide A (7b) from erythromycin A (1).16
Scheme 8. Preparation of the seco-acids 10b, 10c, and 11c from 7b.
the L-cladinose moiety. The stereoisomeric mono-glycosides
9/C-11 positions (Scheme 8). As depicted in Figure 3, an
NOE experiment using H NMR revealed that the former
1
were separated at this stage and the desired alcohol (9S)-1″ was
obtained in pure form in 75% yield, although (9S)-1″ had not
been isolated in the literature method.16 The remaining sugar
part of 1″ was then disconnected by the acidic hydrolysis under
refluxing conditions in methanol with 3% hydrochloric acid
to afford 7b as the key intermediate for our synthesis of several
seco-acids.
Next, 7b was treated with benzaldehyde dimethylacetal
in the presence of p-toluenesulfonic acid to afford two
diastereomers of benzylideneacetals (15b/16c = 10/90) in
which the 1,3-dioxane structures exist at the C-3/C-5 and C-
minor compound 15b (R1¨H, R2¨Ph) has a similar acetal
conformation around the C-9 to 11 to 15a (R1¨H, R2¨Mes)
and 24 (R1¨H, R2¨Me) in Figure 2, and the conformation
ofthestablelatercompound16c(R1¨Ph, R2¨H)corresponds
to those of 16a (R1¨Mes, R2¨H) and 25a (R1¨Me,
R2¨H). Saponification of these lactones was carried out by
using aqueous NaOH in ethanol to produce the corresponding
seco-acids 10b and 11c, respectively. Furthermore, 15b was
transformed into its protected structure 15c as shown in
Scheme 8, that is, the two hydroxyl groups in 15b were masked
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E v a l u a t i o n o f t h e E f f i c i e n c y
as their MOM ether followed by saponification to produce
another seco-acid 10c (R¨MOM). In accordance with Stork’s
suggestion, it is assumed that the cyclization of the seco-acid
11cwillbeeasilyattainedtoform16c, whereasthelactonization
of 10b/10c to give 15b/15c might be effectively prevented by
thestericrepulsionofthesubstituents(R2 andC-8surroundings)
in 15b/15c.
The acetalization of 7b using 2,2-dimethoxypropane was
also performed in the presence of p-toluenesulfonic acid to give
the corresponding thermodynamically stable compound 26, in
which the 1,2-diol moieties at the C-5/C-6 and C-11/C-12
positions were protected as their isopropylidene ketal
equivalents (Scheme 9). The diol 26 was protected by the
treatment with TBSOTf and 2,6-lutidine to afford the
corresponding 3-O- and 9-O-diTBS ether 17b, but the desired
seco-acid 12b was not directly obtained from 17b as a result
of the facile elimination of the TBSO group at the C-3 position
to form 27 under basic conditions. Therefore, the lactone 17b
was first reduced to produce the corresponding diol 28 and
the resulting primary hydroxy was temporarily protected as its
trityl ether. After introducing an acetyl group on the remaining
Fig. 3. Representation of the observations from an NOE experiment using
1H NMR.
Scheme 9. Preparation of seco-acid 12b from 7b.
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T H E C H E M I C A L R E C O R D
C-13 secondary hydroxy in 29, the trityl group in 30 was
Woodward et al.,1b Yonemitsu et al.,7 Hoffmann et al.,18
and Woerpel et al.19 have independently reported the effective
macrolactonization of seco-acids 11a and 11b (R1¨Mes,
R2¨H) in Figure 2, as well as 11d and 11e (R1¨PMP,
R2¨H) in Scheme 10 which have structures similar to that
of the present seco-acid 11c (R1¨Ph, R2¨H) in Figure 2,
therefore, it is assumed that the MNBA lactonization could
also be applicable to the cyclization of these kinds of seco-acids
to give the corresponding lactones in high yields.
cleaved to produce the desired primary alcohol 31 in good
yield. Stepwise oxidation of the alcohol to the carboxylic acid
was attained via the aldehyde intermediary, followed by
saponification of the 3-O-Ac group that afforded the targeted
seco-acid 12b in a reasonable yield. The structure of 12b
(Scheme 9) is similar to that of 12a (Scheme 2) which has a
form unsuitable for the macrocyclization reported by
Woodward, but we anticipated that the systematic studies
of the lactonization of 12b using MNBA might provide
important information concerning the substrate limitation of
this ring-closure.
Synthesis of macrolides 15b and 15c from seco-acids
10b and 10c using MNBA lactonization: We next examined
the cyclization of seco-acids 10b and 10c, which have unfavor-
able conformations for the lactonization. In these cases for the
preparation of the corresponding lactones 15b and 15c, we
gradually added a solution of the substrates to a mixture of the
reaction promoters using a syringe pump to keep the reactants
in low concentrations. However, the desired lactone 15b was
obtained in only 3% yield when the reaction was carried out
at room temperature in dichloroethane as the solvent (Table
2, Entry 1). The yield of 15b was not drastically improved by
changing the reaction temperature and solvent as shown in
Entry 2 because of the decomposition of 10b, therefore, we
decided to use the more stable seco-acid 10c, in which the
tertiary hydroxyl groups are protected as their MOM ether
forms. As shown in Entry 3, in the presence of an excess
amount of DMAP (6.0 equiv) without using triethylamine,
the reaction of 10c proceeded at room temperature, but unfor-
tunately the lactone 15c was produced in an unsatisfactory
yield (11%). Next, the reaction temperature was increased to
70, 100, and 120°C in toluene solution, and it was found that
the yields of the lactone 15c were gradually improved to 32,
57, and 55%, respectively (Entries 4–6). The concentration of
DMAP in the reaction mixture was then optimized as shown
by Entries 7 and 8, and the yield of the targeted lactone 15c
finally reached an acceptable yield (62%, Entry 8). Woodward
et al. reported the failure of the cyclization of the seco-acid 10a
(R1¨H, R2¨Mes) in Figure 2 to produce the lactone 15a,
and Stork et al. also found that the lactonization of the seco-
acid 21 (R1¨H, R2¨Me) did not take place at all owing to
the severe steric repulsion among the R2 group and neighbor-
ing functionalities near the C-8 position. It is noteworthy that
the desired lactone 15c was produced in a relatively good yield
from 10c (R1¨H, R2¨Ph) using the MNBA protocol,
although the structure of the present seco-acid 10c is similar
to those of 10a and 21.
Synthesis of macrolide 16c from seco-acid 11c using
MNBA lactonization: Because it had been anticipated that
the reaction of the seco-acid 11c rapidly proceeded on the
basis of other reports (vide supra), we directly added 11c in
one portion to a solution of a 1.3 molar amount of MNBA,
0.2 molar amount of DMAP, and 2.6 molar amount of
triethylamineindichloromethane(5 mM)atroomtemperature,
and fortunately, the reaction smoothly proceeded to produce
the desired monomeric lactone 16c in quite high yield (95%)
as shown in Entry 1 (Table 1). Other results of the lactonization
forming 16c starting from 11c using a symmetric anhydride
as the coupling reagent are summarized in the same table. The
yield increased to quantitative after a 2 h stirring of the reaction
mixture using an excess amount of triethylamine (Entry 2),
however, a medium yield (64%) was observed by quenching
the lactonization after 10 min (Entry 3); therefore, we noticed
that the catalytic use of DMAP required a sufficient time for
regeneration of the promoter during the reaction process.
Other coupling reagents, such as 4-trifluoromethylbenzoic
anhydride (TFBA)17 and 4-nitrobenzoic anhydride (PNBA),
also provided the monomeric lactone 16c in reasonable yields,
but the highest yield was expectedly attained by the MNBA-
promoted reaction (Entries 4–7; cf. 2). In order to determine
the necessity of requiring DMAP in this reaction, we examined
the lactonization without using DMAP, and the formation of
only a trace amount of 16c was detected in this case (Entry 8).
On the other hand, the use of 6.0 molar amount of DMAP
afforded the desired lactone 16c in quantitative yield after 2 h
(Entry9).Furthermore,thestartingmaterialrapidlydisappeared
after 10 min when using a 6.0 molar amount of DMAP, and
the corresponding lactone 16c was obtained in 94% yield by
this simple operation (Entry 10). It is noteworthy that the
present method is applicable to a large-scale synthesis, from
which the desired macrolactone 16c was isolated in 97% yield
starting from 2.0g of the seco-acid 11c in the presence of 1.3
molar amount of MNBA, 0.2 molar amount of DMAP, and
6.0 molar amount of triethylamine as shown in Entry 11. The
yields of 16c gradually decreased in accordance with the
increasing concentrations of the reaction as shown in Entries
12–15.
Synthesis of macrolide 17b and diolide 17c from seco-
acid 12b using MNBA lactonization: Our attention next
focused on the lactonization of the seco-acid 12b, which is also
one of the challenging substrates, to form the corresponding
lactone 17b because Woodward reported that cyclization of
12a (Scheme 2) did not give the desired compound. Indeed,
highly dilute conditions using the slow charge method of the
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E v a l u a t i o n o f t h e E f f i c i e n c y
Table 1. Synthesis of lactone 16c from seco-acid 11c using MNBA cyclization.
Yielda/%
Recoverya/%
Entry
Reagent
x
y
z
16c
11c
1
2
MNBA
MNBA
MNBA
TFBAd
PNBAe
Bz2O
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0
6.0
6.0
0.2
0.2
0.2
0.2
0.2
2.6
6.0
6.0
6.0
6.0
6.0
6.0
6.0
0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
95
quant.
64
92
90
30
7
2
quant.
94
97
95
91
0
0
0
0
3b
4
5
6
7
8
0
21(49)f
Piv2O
32(42)f
MNBA
MNBA
MNBA
MNBA
MNBA
MNBA
MNBA
MNBA
49(16)f
9
0
0
0
0
0
0
0
10b
11c
12
13
14
15
0
6.0
6.0
6.0
6.0
6.0
10
20
50
89
74
100
a)Isolated yield.
b)Reaction time; 10 min.
c)A large amount of 11c (2.0 g) was used as a substrate for the lactonization.
d)TFBA = 4-trifluoromethylbenzoic anhydride.
e)PNBA = 4-nitrobenzoic anhydride.
f)Data in parentheses show yields of homogeneous anhydride of 11c.
substrate 12b to the reaction mixture containing a 1.3 molar
amount of MNBA, 0.2 molar amount of DMAP, and 6.0
molar amount of triethylamine in dichloromethane (1.8 mM)
at 45°C did not produce the monomeric lactone 17b, but the
corresponding 28-membered diolide 17c that was obtained in
18% yield along with the formation of a significant amount
(43%) of a symmetric anhydride of seco-acid 12b (Table 3,
Entry 1). We used an excess amount of DMAP (6.0 equiv)
instead of employing triethylamine in this reaction, and
observed the formation of the monomeric lactone 17b in 4%
yield with the 30% formation of the dimer 17c and 10% yield
of the anhydride derived from 12b (Entry 2). Further studies
of the reaction in toluene solution at higher temperatures as
shown in Entries 3–5 showed an improvement in the total
yields of 17b and 17c, up to 87% at 120°C, in the presence
of a greater excess amount of DMAP (Entry 5). The final
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T H E C H E M I C A L R E C O R D
Scheme 10. Hoffmann’s and Woerpel’s macrocyclization studies for the synthesis of erythronolide A (2) using the
Yamaguchi method.
Table 2. Synthesis of lactones 15b and 15c from seco-acids 10b and 10c using MNBA cyclization.
Yielda/%
Entry
x
y
z
Solvent
Temp/°C
Seco-acid/Lactone
15b or 15c
1
2
3
4
5
6
7
8
0.2
0.2
6.0
6.0
6.0
6.0
6.0
12.0
6.0
6.0
0
0
0
0
0
0
1.8
1.8
1.8
1.8
1.8
1.8
0.9
0.9
CH2Cl2
toluene
CH2Cl2
toluene
toluene
toluene
toluene
toluene
rt
100
rt
10b/15b
10b/15b
10c/15c
10c/15c
10c/15c
10c/15c
10c/15c
10c/15c
3
25
11
32
57
55
48
62
70
100
120
100
100
a)Isolated yield.
optimization of the concentrations of DMAP during the
cyclization afforded the corresponding lactone 17b in 16%
yield with the diolide 17c in 78% yield (Entry 8), and the total
yield of the cyclized compounds reached 94%. Based on the
above experimental results, it is postulated that the substrates
12a and 12b might possess stable linear conformations and
their structures are not appropriate for forming the monomeric
lactones, but suitable to produce the corresponding diolides.
These tendencies of the substrates, which give dimers as the
major products, depend on the nature of the seco-acid
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E v a l u a t i o n o f t h e E f f i c i e n c y
Table 3. Syntheses of lactone 17b and diolide 17c from seco-acid 12b using MNBA cyclization.
Yielda/%
17b 17c
Recoverya/%
Entry
x
y
z
w
Solvent
Temp/°C
12b
1
2
3
4
5
6
7
8
1.3
1.3
3.0
3.0
3.0
3.0
10.0
10.0
0.2
6.0
6.0
6.0
0
0
0
0
0
0
0
1.8
1.8
1.8
1.8
1.8
0.9
0.9
0.36
CH2Cl2
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
45
45
80
120
120
120
120
120
0
4
18
30
28
69
73
56
73
78
27(43)b
26(10)b
30(6)b
4(4)b
0(4)b
0(18)b
0
14
13
14
16
16
16
6.0
20.0
20.0
20.0
20.0
0
a)Isolated yield.
b)Data in parentheses show yields of homogeneous anhydride of 12b.
structures, and therefore, we could determine that controlling
the ratio of the monomer to dimer is impossible by modifica-
tion of the reaction conditions. This important but overlooked
principle of the lactonization using the 12b-type seco-acids
to provide the aglycons of erythromycin A is first disclosed
in this paper based on the studies of the rapid ring-closure
reaction using MNBA, an ultimately effective coupling
reagent.
Conclusions
We have developed a new method employing MNBA with
DMAP for the preparation of various intermediates used for
the synthesis of erythronolide A from the corresponding seco-
acids. It is notable that the experimental procedure is quite
simple, and the nearly pure aglycons of erythromycin A are
obtained by only adding the substrates to the mixture of
The Chemical Record, Vol. 9, 305–320 (2009) © 2009 The Japan Chemical Journal Forum and Wiley Periodicals, Inc.
www.tcr.wiley-vch.de 317

T H E C H E M I C A L R E C O R D
K.; Tolbert, L. M.; Truesdale, E. A.; Uchida, I.; Ueda, Y.;
MNBA and a nucleophilic catalyst in a one-pot operation.
This systematic study of the lactonization using several
intermediates with MNBA as the promoter revealed that
(i) the conformationally appropriate substrate for the
monomeric cyclization, such as 11c, gave the desired lactone
in excellent yield under mild reaction conditions in the presence
of MNBA and DMAP, (ii) the highly-strained substrate for
the cyclization, such as 10c, also afforded the monomeric
lactone in relatively good yield at gently refluxing temperature
of toluene solvent, and (iii) the seco-acid having a stable linear
conformation, such as 12b, which preferred dimerizing more
than forming a monomeric lactone, provided the corresponding
diolide in high yield with a reasonable chemoselectivity
(monomer/dimer = ca.1/5). It might absolutely depend on the
reaction rates of the macrocyclization corresponding to the
ring size of the 14- and 28-membered lactones.
Uyehara, T.; Vasella, A. T.; Vladuchick, W. C.; Wade, P. A.;
Williams, R. M.; Wong, H. N.-C. J. Am. Chem. Soc. 1981,
103, 3213–3215. (c) Woodward, R. B.; Logusch, E.; Nambiar,
K. P.; Sakan, K.; Ward, D. E.; Au-Yeung, B.-W.; Balaram, P.;
Browne, L. J.; Card, P. J.; Chen, C. H.; Chenevert, R. B.;
Fliri, A.; Frobel, K.; Gais, H.-J.; Garratt, D. G.; Hayakawa,
K.; Heggie, W.; Hesson, D. P.; Hoppe, D.; Hoppe, I.; Hyatt,
J. A.; Ikeda, D.; Jacobi, P. A.; Kim, K. S.; Kobuke, Y.; Kojima,
K.; Krowicki, K.; Lee, V. J.; Leutert, T.; Malchenko, S.;
Martens, J.; Matthews, R. S.; Ong, B. S.; Press, J. B.; Rajan
Babu, T. V.; Rousseau, G.; Sauter, H. M.; Suzuki, M.; Tatsuta,
K.; Tolbert, L. M.; Truesdale, E. A.; Uchida, I.; Ueda, Y.;
Uyehara, T.; Vasella, A. T.; Vladuchick, W. C.; Wade, P. A.;
Williams, R. M.; Wong, H. N.-C. J. Am. Chem. Soc. 1981,
103, 3215–3217.
[2] (a) Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96,
5614–5616. (b) Corey, E. J.; Nicolaou, K. C.; Melvin Jr., L. S.
J. Am. Chem. Soc. 1975, 97, 653–654. (c)Corey, E. J.;Nicolaou,
K. C.; Melvin Jr., L. S. J. Am. Chem. Soc. 1975, 97, 654–655.
(d) Corey, E. J.; Nicolaou, K. C.; Toru, T. J. Am. Chem. Soc.
1975, 97, 2287–2288. (e) Corey, E. J.; Ulrich, P.; Fitzpatrick,
J. M. J. Am. Chem. Soc. 1976, 98, 222–224. See also, (f)
Gerlach, H.; Thalmann, A. Helv. Chim. Acta 1974, 57, 2661–
2663. (g) Gerlach, H.; Oertle, K.;Thalmann, A.; Servi, S. Helv.
Chim. Acta 1975, 58, 2036–2043. (h) Gerlach, H.; Oertle, K.;
Thalmann, A. Helv. Chim. Acta 1976, 59, 755–760.
Acknowledgments
This study was partially supported by a Research Grant from
the Center for Green Photo-Science and Technology, and
Grants-in-Aid for Scientific Research from the Ministry of
Education, Science, Sports and Culture, Japan.
[3] (a) Corey, E. J.; Brunelle, D. J.; Stork, P. J. Tetrahedron Lett.
1976, 17, 3405–3408. (b) Corey, E. J.; Brunelle, D. J.
Tetrahedron Lett. 1976, 17, 3409–3412. (c) Corey, E. J.;
Bhattacharyya, S. Tetrahedron Lett. 1977, 18, 3919–3922.
[4] (a) Corey, E. J.; Hopkins, P. B.; Kim, S.; Yoo, S.; Nambiar,
K. P.; Falck, J. R. J. Am. Chem. Soc. 1979, 101, 7131–7134.
See also, (b) Corey, E. J.; Kim, S.; Yoo, S.; Nicolaou, K. C.;
Melvin Jr., L. S.; Brunelle, D. J.; Falck, J. R.; Trybulski, E. J.;
Lett, R.; Sheldrake, P. W. J. Am. Chem. Soc. 1978, 100,
4620–4622.
[5] (a) Stork, G.; Rychnovsky, S. D. J. Am. Chem. Soc. 1987, 109,
1565–1567. See also, (b) Blankenstein, J.; Zhu, J. Eur. J. Org.
Chem. 2005, 1949–1964.
[6] (a) Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50, 2394–
2395. (b) Keck, G. E.; Boden, E. P.; Wiley, M. R. J. Org.
Chem. 1989, 54, 896–906. See also, (c) Neises, B.; Steglich,
W. Angew. Chem., Int. Ed. 1978, 17, 522–524. (d) Hofle, G.;
Steglich, W.; Vorbruggen, H. Angew. Chem., Int. Ed. 1978,
17, 569–583.
[7] (a) Hikota, M.; Tone, H.; Horita, K.; Yonemitsu, O. J. Org.
Chem. 1990, 55, 7–9. (b) Hikota, M.; Tone, H.; Horita, K.;
Yonemitsu, O. Tetrahedron 1990, 46, 4613–4628. See also,
(c) Tone, H.; Nishi, T.; Oikawa, Y.; Hikota, M.; Yonemitsu,
O. Tetrahedron Lett. 1987, 28, 4569–4572. (d) Tone, H.;
Nishi, T.; Oikawa, Y.; Hikota, M.; Yonemitsu, O. Chem.
Pharm. Bull. 1989, 37, 1160–1166.
[8] Kochetkov, N. K.; Sviridov, A. F.; Ermolenko, M. S.;
Yashunsky, D. V.; Borodkin, V. S. Tetrahedron 1989, 45,
5109–5136.
Supporting Information Available: Experimental proce-
dures, details, and spectroscopic data.
REFERENCES
[1] (a) Woodward, R. B.; Logusch, E.; Nambiar, K. P.; Sakan, K.;
Ward, D. E.; Au-Yeung, B.-W.; Balaram, P.; Browne, L. J.;
Card, P. J.; Chen, C. H.; Chenevert, R. B.; Fliri, A.; Frobel,
K.; Gais, H.-J.; Garratt, D. G.; Hayakawa, K.; Heggie, W.;
Hesson, D. P.; Hoppe, D.; Hoppe, I.; Hyatt, J. A.; Ikeda, D.;
Jacobi, P. A.; Kim, K. S.; Kobuke, Y.; Kojima, K.; Krowicki,
K.; Lee, V. J.; Leutert, T.; Malchenko, S.; Martens, J.;
Matthews, R. S.; Ong, B. S.; Press, J. B.; Rajan Babu, T. V.;
Rousseau, G.; Sauter, H. M.; Suzuki, M.; Tatsuta, K.; Tolbert,
L. M.; Truesdale, E. A.; Uchida, I.; Ueda, Y.; Uyehara, T.;
Vasella, A. T.; Vladuchick, W. C.; Wade, P. A.; Williams, R.
M.; Wong, H. N.-C. J. Am. Chem. Soc. 1981, 103, 3210–
3213. (b) Woodward, R. B.; Logusch, E.; Nambiar, K. P.;
Sakan, K.; Ward, D. E.; Au-Yeung, B.-W.; Balaram, P.;
Browne, L. J.; Card, P. J.; Chen, C. H.; Chenevert, R. B.;
Fliri, A.; Frobel, K.; Gais, H.-J.; Garratt, D. G.; Hayakawa,
K.; Heggie, W.; Hesson, D. P.; Hoppe, D.; Hoppe, I.; Hyatt,
J. A.; Ikeda, D.; Jacobi, P. A.; Kim, K. S.; Kobuke, Y.; Kojima,
K.; Krowicki, K.; Lee, V. J.; Leutert, T.; Malchenko, S.;
Martens, J.; Matthews, R. S.; Ong, B. S.; Press, J. B.; Rajan
Babu, T. V.; Rousseau, G.; Sauter, H. M.; Suzuki, M.; Tatsuta,
318 www.tcr.wiley-vch.de
The Chemical Record, Vol. 9, 305–320 (2009) © 2009 The Japan Chemical Journal Forum and Wiley Periodicals, Inc.

E v a l u a t i o n o f t h e E f f i c i e n c y
[9] Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
16, 3176–3182. (f) Dinh, M.-T.; BouzBouz, S.; Peglion; J.-L.;
Cossy, J. Synlett 2005, 2851–2853. (g) Doi, T.; Iijima, Y.;
Shin-ya, K.; Ganesan, A.; Takahashi, T. Tetrahedron Lett.
2006, 47, 1177–1180. (h) Hosokawa, S.; Seki, M.; Fukuda,
H.; Tatsuta, K. Tetrahedron Lett. 2006, 47, 2439–2442. (i)
Nicolaou, K. C.; Xu, H. Chem. Commun. 2006, 600–602. (j)
Tsuchikawa, H.; Matsushita, N.; Matsumori, N.; Murata, M.;
Oishi, T. Tetrahedron Lett. 2006, 47, 6187–6191. (k) Wu, Y.;
Yang, Y.-Q. J. Org. Chem. 2006, 71, 4296–4301. (l) Matsuya,
Y.; Kawaguchi, T.; Ishihara. K.; Ahmed, K.; Zhao, Q.-L.;
Kondo, T.; Nemoto, H. Org. Lett. 2006, 8, 4609–4612. (m)
Yamashita, K.; Kobayashi, S.; Tsukamoto, S.; Numazawa, M.
Steroids, 2007, 72, 50–59. (n) Saito, T.; Takeuchi, T.;
Matsuhashi, M.; Nakata, T. Heterocycles, 2007, 72, 151–156.
(o) Trost, B. M.; Yang, H.; Thiel, O. R.; Frontier, A. J.;
Brindle, C. S. J. Am. Chem. Soc. 2007, 129, 2206–2207. (p)
Ren, F.; Hogan, P. C.; Anderson, A. J.; Myers, A. G. J. Am.
Chem. Soc. 2007, 129, 5381–5383. (q) Falck, J. R.; He, A.;
Fukui, H.; Tsutsui, H.; Radha, A. Angew. Chem., Int. Ed.
2007, 46, 4527–4529. (r) Ito, T.; Ito, M.; Arimoto, H.;
Takamura, H.; Uemura, D. Tetrahedron Lett. 2007, 48, 5465–
5469. (s) Scheerer, J. R.; Lawrence, J. F.; Wang, G. C.; Evans,
D. A. J. Am. Chem. Soc. 2007, 129, 8968–8969. (t) Pettit, G.
R.; Smith, T. H.; Feng, S.; Knight, J. C.; Tan, R.; Pettit, R.
K.; Hinrichs, P. A. J. Nat. Prod. 2007, 70, 1073–1083. (u)
Schweitzer, D.; Kane, J. J.; Strand, D.; McHenry, P.;
Tenniswood, M.; Helquist, P. Org. Lett. 2007, 9, 4619–4622.
(v) Amans, D.; Bellosta, V.; Cossy, J. Org. Lett. 2007, 9,
4761–4764. (w) Honda, A.; Yamashita, K.; Numazawa, M.;
Ikegami, T.; Doy, M.; Matsuzaki, Y.; Miyazaki, H. J. Lipid
Res. 2007, 48, 458–464. (x) Takada, Y.; Mori, E.; Umehara,
M.; Nakao, Y.; Kimura, J. Tetrahedron Lett. 2007, 48, 7653–
7656. (y) Kito, K.; Ookura, R.; Yoshida, S.; Namikoshi, M.;
Ooi, T.; Kusumi, T. J. Nat. Prod. 2007, 70, 2022–2025. (z)
Yadav, J. S.; Reddy, P. M. K.; Gupta, M. K.; Chary, C. J.
Synthesis 2007, 3639–3646. (aa) Yamashita, K.; Takahashi,
M.; Tsukamoto, S.; Numazawa, M.; Okuyama, M.; Honma,
S. J. Chromatogr. A 2007, 1173, 120–128. (bb) Yurek-George,
A.; Cecil, A. R. L.; Mo, A. H. K.; Wen, S.; Rogers, H.;
Habens, F.; Maeda, S.; Yoshida, M.; Packham, G.; Ganesan,
A. J. Med. Chem. 2007, 50, 5720–5726. (cc) Takizawa, T.;
Watanabe, K.; Narita, K.; Oguchi, T.; Abe, H.; Katoh, T.
Chem. Commun. 2008, 1677–1679. (dd) Wu, Y.; Gao, J. Org.
Lett. 2008, 10, 1533–1536. (ee) Takizawa, T.; Watanabe, K.;
Narita, K.; Kudo, K.; Oguchi, T.; Abe, H.; Katoh, T.
Heterocycles 2008, 76, 275–290. (ff) Dinh, M.-T.; Bouzbouz,
S.; Peglion, J.-L.; Cossy, J. Tetrahedron 2008, 64, 5703–5710.
(gg) Yamashita, K.; Nakagawa, R.; Okuyama, M.; Honma, S.;
Takahashi, M.; Numazawa, M. Steroids 2008, 73, 727–737.
(hh) Yamashita, K.; Okuyama, M.; Nakagawa, R.; Honma, S.;
Satoh, F.; Morimoto, R.; Ito, S.; Takahashi, M.; Numazawa,
M. J. Chromatogr. A 2008, 1200, 114–121. (ii) Fenlon, E.;
Ito, B. R. Eur. J. Org. Chem. 2008, 3065–3068. (jj) Radosevich,
A. T.; Chan, V. S.; Shih, H.-W.; Toste, F. D. Angew. Chem.,
Int. Ed. 2008, 47, 3755–3758. (kk) Eggert, U.; Diestel, R.;
Sasse, F.; Jansen, R.; Kunze, B.; Kalesse, M. Angew. Chem.,
Bull. Chem. Soc. Jpn. 1979, 52, 1989–1993.
[10] Paterson, I.; Ward, R. A.; Romea, P.; Norcross, R. D. J. Am.
Chem. Soc. 1994, 116, 3623–3624.
[11] Evans, D. A.; Kim, A. S.; Metternich, R.; Novack, V. J. J. Am.
Chem. Soc. 1998, 120, 5921–5942.
[12] (a) Yonemitsu, O. J. Synth. Org. Chem. Jpn. 1994, 52, 946–
955. (b) Osawa, E.; Goto, H.; Hata, T.; Deretey, E. Theochem-
J. Mol. Struct. 1997, 398–399, 229–236. See also, (c)
Matsushima, T.; Horita, K.; Nakajima, N.; Yonemitsu, O.
Tetrahedron Lett. 1996, 37, 385–388. (d) Hamada, T.;
Kobayashi, Y.; Kiyokawa, M.; Yonemitsu, O. Tetrahedron Lett.
2003, 44, 4343–4346. (e) Hamada, T.; Kiyokawa, M.;
Kobayashi, Y.; Toshioka, T.; Sano, J.; Yonemitsu, O.
Tetrahedron 2004, 60, 4693–4704.
[13] (a) Shiina, I.; Ibuka, R.; Kubota, M. Chem. Lett. 2002, 286–
287. (b) Shiina, I.; Kubota, M.; Ibuka, R. Tetrahedron Lett.
2002, 43, 7535–7539. (c) Shiina, I.; Kubota, M.; Oshiumi,
H.; Hashizume, M. J. Org. Chem. 2004, 69, 1822–1830. (d)
Shiina, I.; Oshiumi, H.; Hashizume, M.; Yamai, Y.; Ibuka, R.
Tetrahedron Lett. 2004, 45, 543–547. (e) Shiina, I.; Hashizume,
M.; Yamai, Y.; Oshiumi, H.; Shimazaki, T.; Takasuna, Y.;
Ibuka, R. Chem. Eur. J. 2005, 11, 6601–6608. (f) Shiina, I.;
Hashizume, M. Tetrahedron 2006, 62, 7934–7939. (g) Shiina,
I.; Kikuchi, T.; Sasaki, A. Org. Lett. 2006, 8, 4955–4958. (h)
Shiina, I.; Takasuna, Y.; Suzuki, R.; Oshiumi, H.; Komiyama,
Y.; Hitomi, S.; Fukui, H. Org. Lett. 2006, 8, 5279–5282. (i)
Shiina, I.; Fukui, H.; Sasaki, A. Nat. Protoc. 2007, 2, 2312–
2317. (j) Shiina, I.; Sasaki, A.; Kikuchi, T.; Fukui, H. Chem.
Asian J. 2008, 3, 462–472. (k) Fukui H.; Shiina, I. Org. Lett.
2008, 10, 3153–3156. (l) Fukui, H.; Hitomi, S.; Suzuki, R.;
Ikeda, T.; Umezaki, Y.; Tsuji, K.; Shiina, I. Tetrahedron Lett.
2008, 49, 6514–6517. (m) Fukui, H.; Tsuji, K.; Umezaki, Y.;
Shiina, I. Heterocycles 2009, 79, 403–410. (n) Shiina, I.;
Fukui, H. Chem. Commun. 2009, 385–400. See also for amide
and peptide synthesis, (o) Shiina, I.; Kawakita, Y. Tetrahedron
2004, 60, 4729–4733. (p) Shiina, I.; Ushiyama, H.; Yamada,
Y.; Kawakita, Y.; Nakata, K. Chem. Asian J. 2008, 3,
454–461.
[14] Our successful cyclization of erythromycin A aglycons was first
presented in 2006. (a) Shiina, I.; Katoh, T.; Hashizume, M.
Abstracts of Papers, 86th National Meeting of the Chemical
Society of Japan, Chiba, 2006; Vol. 2, p1384, 4L428. (b)
Shiina, I.; Katoh, T.; Komiyama, Y.; Sasaki, A.; Suzuki, R.;
Hitomi, S.; Fukui, H. Abstracts of Papers, 48th Symposium on
the Chemistry of Natural Products, Sendai, 2006; pp199–204,
34. (c) Shiina, I.; Katoh, T.; Nagai, S. Abstracts of Papers,
127th National Meeting of the Pharmaceutical Society of
Japan, Toyama, 2007; Vol. 4, p26, 29R-pm09.
[15] (a) Shiina, I. Chem. Rev. 2007, 107, 239–273. Applications of
MNBA-condensation by other authors, see: (b) Tian, J.;
Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2003,
5, 3021–3024. (c) Inoue, M.; Sasaki, T.; Hatano, S.; Hirama,
M. Angew. Chem., Int. Ed. 2004, 43, 6500–6505. (d) Inoue,
M. Bull. Chem. Soc. Jpn. 2006, 79, 501–510. (e) Morita, M.;
Mase, N.; Yoda, H.; Takabe, K. Tetrahedron: Asymmetry 2005,
The Chemical Record, Vol. 9, 305–320 (2009) © 2009 The Japan Chemical Journal Forum and Wiley Periodicals, Inc.
www.tcr.wiley-vch.de 319

T H E C H E M I C A L R E C O R D
Int. Ed. 2008, 47, 6478–6482. (ll) Yamashita, K.; Tadokoro,
D.; Bellosta, V.; Cossy, J. Chem. Eur. J. 2009, 15, 3457–3473.
(fff) Taichi, M.; Yamazaki, T.; Kimura, T.; Nishiuchi, Y.
Tetrahedron Lett. 2009, 50, 2377–2380. (ggg) Iijima, Y.;
Munakata, A.; Shin-ya, K.; Ganesan, A.; Doi, T.; Takahashi,
T. Tetrahedron Lett. 2009, 50, 2970–2972. (hhh) Yildizhan,
S.; van Loon, J.; Sramkova, A.; Ayasse, M.; Arsene, C.; ten
Broeke, C.; Schulz, S. ChemBioChem 2009, 10, 1666–1677.
(iii) Makarasen, A.; Nishikawa, T.; Isobe, M. Synthesis 2009,
2184–2204. (jjj) Trost, B. M.; Sieber, J. D.; Qian, W.;
Dhawan, R.; Ball, Z. T. Angew. Chem., Int. Ed. 2009, 48,
5478–5481. (kkk) Lozama, A.; Prisinzano, T. E. Bioorg. Med.
Chem. Lett. 2009, 19, 5490–5495. (lll) Trost, B. M.; O’Boyle,
B. M.; Hund, D. J. Am. Chem. Soc. 2009, 131, 15061–15074.
(mmm) Honda, A.; Yamashita, K.; Ikegami, T.; Hara, T.;
Miyazaki, T.; Hirayama, T.; Numazawa, M.; Matsuzaki, Y. J.
Lipid Res. 2009, 50, 2124–2130. (nnn) Kim, H.; Park, Y.;
Hong, J. Angew. Chem., Int. Ed. 2009, 48, 7577–7581. (ooo)
Kojima, M.; Nakamura, Y.; Ito, S.; Takeuchi, S. Tetrahedron
Lett. 2009, 50, 6143–6149.
Y.; Takahashi, M.; Numazawa, M. Chem. Pharm. Bull. 2008,
56, 873–877. (mm) Donohoe, T. J.; Ironmonger, A.; Kershaw,
N. M. Angew. Chem., Int. Ed. 2008, 47, 7314–7316. (nn)
Takeuchi, T.; Matsuhashi, M.; Nakata, T. Tetrahedron Lett.
2008, 49, 6462–6465. (oo) Numazawa, M.; Komatsu, S.;
Tominaga, T.; Yamashita, K. Chem. Pharm. Bull. 2008, 56,
1304–1309. (pp) Miura, T.; Kanemoto, K.; Natsume, S.;
Atsumi, K.; Fushimi, H.; Yoshida, T.; Ajito, K. Bioorg. Med.
Chem. 2008, 16, 10129–10156. (qq) Gao, J.; Huang, Y.-X.;
Wu, Y. Tetrahedron 2008, 64, 11105–11109. (rr) Kobayashi,
N.; Kuniyoshi, H.; Ishigami, K.; Watanabe, H. Biosci.
Biotechnol. Biochem. 2008, 72, 2708–2715. (ss) Eiseman, J.
L.; Bai, L.; Jung, W.-H.; Moura-Letts, G.; Day, B. W.; Curran,
D. P. J. Med. Chem. 2008, 51, 6650–6653. (tt) Bock, M.;
Dehn, R.; Kirschning, A. Angew. Chem., Int. Ed. 2008, 47,
9134–9137. (uu) Rodriguez-Escrich, C.; Urpi, F.; Vilarrasa, J.
Org. Lett. 2008, 10, 5191–5194. (vv) Yadav, J. S.; Swamy, T.;
Subba Reddy, B. V. Synlett, 2008, 2773–2776. (ww) Trost,
B. M.; O’Boyle, B. M. J. Am. Chem. Soc. 2008, 130, 16190–
16192. (xx) Takamura, H.; Yamagami, Y.; Ito, T.; Ito, M.;
Arimoto, H.; Kadota, I.; Uemura, D. Heterocycles 2009, 77,
351–364. (yy) Wu, J.-Z.; Gao, J.; Ren, G.-B.; Zhen, Z.-B.;
Zhang, Y.; Wu, Y. Tetrahedron 2009, 65, 289–299. (zz)
Kikuchi, H.; Hoshi, T.; Kitayama, M.; Sekiya, M.; Katou, Y.;
Ueda, K.; Kubohara, Y.; Sato, H.; Shimazu, M.; Kurata, S.;
Oshima, Y. Tetrahedron 2009, 65, 469–477. (aaa) Matsushita,
N.; Matsuo, Y.; Tsuchikawa, H.; Matsumori, N.; Murata, M.;
Oishi, T. Chem. Lett. 2009, 38, 114–115. (bbb) Ogawa, K.;
Koyama, Y.; Ohashi, I.; Sato, I.; Hirama, M. Angew. Chem.,
Int. Ed. 2009, 48, 1110–1113. (ccc) Pettit, G. R.; Hu, S.;
Knight, J. C.; Chapuis, J.-C. J. Nat. Prod. 2009, 72, 372–379.
(ddd) Ogawa, K.; Koyama, Y.; Ohashi, I.; Sato, I.; Hirama,
M. Angew. Chem., Int. Ed. 2009, 48, 1110–1113. (eee) Amans,
[16] Jones, P. H.; Rowley, E. K. J. Org. Chem. 1968, 33,
665–670.
[17] (a) Shiina, I. Tetrahedron 2004, 60, 1587–1599. (b) Shiina,
I.; Miyoshi, S.; Miyashita, M.; Mukaiyama, T. Chem. Lett.
1994, 515–518. (c) Shiina, I.; Mukaiyama, T. Chem. Lett.
1994, 677–680. (d) Shiina, I.; Miyashita, M.; Nagai, M.;
Mukaiyama, T. Heterocycles 1995, 40, 141–148. (e) Shiina, I.;
Fukuda, Y.; Ishii, T.; Fujisawa, H.; Mukaiyama, T. Chem.
Lett. 1998, 831–832. (f) Shiina, I.; Fujisawa, H.; Ishii, T.;
Fukuda, Y. Heterocycles 2000, 52, 1105–1123.
[18] (a) Sturmer, R.; Ritter, K.; Hoffmann, R. W. Angew. Chem.
Int. Ed. Engl. 1993, 32, 101–103. (b) Sturmer, R.; Hoffmann,
R. W. Chem. Ber. 1994, 127, 2519–2526.
[19] Peng, Z.-H.; Woerpel, K. A. J. Am. Chem. Soc. 2003, 125,
6018–6019.
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