Total syntheses of chaetocin and ent-chaetocin

Article abstract of DOI:10.1016/j.tet.2011.05.081

The first total synthesis of chaetocin (1), a potent histone methyltransferase inhibitor, is described in detail. Key reactions were radical bromination for α-oxidation of the diketopiperazine ring, and reductive radical coupling for construction of the d

Full text of DOI:10.1016/j.tet.2011.05.081

Tetrahedron 67 (2011) 6587e6599
Contents lists available at ScienceDirect
Tetrahedron
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Total syntheses of chaetocin and ent-chaetocin
,
,
,
,b,
*
Eriko Iwasa a b, Yoshitaka Hamashima a y, Shinya Fujishiro a c, Daisuke Hashizume a, Mikiko Sodeoka a
a RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
b Sodeoka Live Cell Chemistry Project, ERATO, Japan Science and Technology Agency, Japan
c Graduate School of Biomedical Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 April 2011
Received in revised form 17 May 2011
Accepted 18 May 2011
Available online 26 May 2011
The first total synthesis of chaetocin (1), a potent histone methyltransferase inhibitor, is described in
detail. Key reactions were radical bromination for -oxidation of the diketopiperazine ring, and reductive
radical coupling for construction of the dimeric core structure. Stereoselective construction of the
disulfide bridges was achieved via substitution reaction with H2S. The total synthesis of 1 was accom-
plished in nine steps starting from known D-amino acid derivatives. Total synthesis of non-natural ent-
a
chaetocin (ent-1) was also achieved via the established synthetic route, starting from L-amino acid
derivatives.
Keywords:
Total synthesis
Chaetocin
Ó 2011 Elsevier Ltd. All rights reserved.
ent-Chaetocin
Histone methyltransferase inhibitor
Radical coupling
1. Introduction
drugs, because dysfunction of histone methylation is considered
to induce cancerous diseases.8 However, only a few compounds are
known that inhibit histone methyltransferases.9 Among them, 1 is
the only known naturally occurring inhibitor of lysine-specific
histone methyltransferases. The structural features of 1 include
a C2 symmetric octacyclic ring system with eight stereogenic car-
bon centers and chemically sensitive disulfide bridges on the
diketopiperazine (DKP) rings. Although more than 100 ETP alka-
loids have been isolated from natural sources, only a few of them
have been totally synthesized.10 For example, Kishi and Fukuyama
reported seminal work on the ETP alkaloids in 1970s, including
total syntheses of gliotoxin and sporidesmines.11 Quite recently,
Overman et al. achieved the first total synthesis of gliocladine C.12
Fig. 1 shows the dimeric ETP alkaloids for which total syntheses
have been achieved. Movassaghi and Kim reported an elegant total
synthesis of 11,110-dideoxyverticillin (2) in 2009.13 However, 1 is
considered to be one of the most challenging synthetic targets
among dimeric ETP alkaloids, because of the additional presence of
Chaetocin (1), a secondary metabolite isolated from fermenta-
tion broth of Chaetomium minutum in 1970,1 belongs to a family of
dimeric epidithiodiketopiperazine (ETP) alkaloids. Biological
activities of 1, such as antibacterial and cytostatic activities, have
been known for a long time,2 but recently, the potent inhibitory
activity of 1 against lysine-specific histone methyltransferases has
attracted increasing attention.3 Histone methylation is involved in
controlling gene expression patterns, in conjunction with DNA
methylation and histone acetylation.4 As for DNA methylation, 5-
azacytidine (VidazaÔ) has been developed as an anti-cancer drug
that acts by controlling the level of DNA methylation.5 Histone
acetylation has also been well studied, and several inhibitors of the
enzymes responsible for regulating the level of acetylation are
approved (e.g., ZolinzaÔ) or undergoing clinical trials for the
treatment of critical diseases.6 However, histone methylation is less
well understood, compared to DNA methylation and histone
acetylation.7
hydroxymethyl groups that may undergo facile
b-elimination
To clarify the molecular mechanism of histone methylation, the
development of selective inhibitors would be useful. Furthermore,
such selective inhibitors are expected to be candidate anti-cancer
during synthetic manipulations. Early in 2010, we achieved the first
total synthesis of chaetocin (1), ent-chaetocin (ent-1), and their
sulfur-deficient analogues.14 We also evaluated their histone
methyltransferase-inhibitory activity and demonstrated the sig-
nificance of the sulfur group for the inhibitory activity. Following
our report, Movassaghi’s group established a more general route to
chaetocin (1) and related poly sulfur natural products.15 In this
article, we present full details of our chemical synthesis of 1.
* Corresponding author. Fax: þ81 48 462 4666; e-mail address: sodeoka@riken.jp
(M. Sodeoka).
y
Present address: School of Pharmaceutical Sciences, University of Shizuoka,
52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.081

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E. Iwasa et al. / Tetrahedron 67 (2011) 6587e6599
route C starts from the a-oxidation of the tetracyclic compound 8,
followed by reductive dimerization of the resulting 7. Since enolate
chemistry seemed inappropriate, we planned to examine radical
bromination reaction for the a-oxidation. We expected that these
dimerization reactions of the bromide 7 or 8 would be feasible by
using the Co(I)-mediated reductive coupling reaction reported by
Movassaghi’s group.13,15,17,18 Because retention of the stereochem-
istry at the benzylic position is assured in the Co(I)-mediated
reductive coupling reaction, the absolute stereochemistry would
be directly transferred to the 3 and 30 positions of 1. Therefore, it is
essential that bromocyclization of 9 should occur stereoselectively.
Because the diastereoselectivity in this step was uncertain at the
planning stage and because the newly generated absolute stereo-
chemistry depends on that of the starting amino acids, the prepa-
ration of the bromide 8 was optimized using less expensive L-amino
acid derivatives.
2.2. Synthesis of diketopiperazine
According to the synthetic plan shown in Scheme 1, we syn-
thesized 2,5-diketopiperazines 9 as follows (Scheme 2). Based on
Hughes’s report, N-Cbz-protected N-methyl serine (10) was readily
Fig. 1. Dimeric epidithiodiketopiperazine (ETP) alkaloids that have been chemically
synthesized to date.
prepared in five steps.19 Condensation of the obtained N-methyl-
L-
serine 10 with L-tryptophan methyl ester using EDC/HOBt method
2. Results and discussion
gave dipeptide 11. The hydroxyl group and the nitrogen atom of the
indole ring within 11 were protected with a TBS group and a Boc
group, respectively.
2.1. Retrosynthesis of chaetocin
Our retrosynthetic analysis of chaetocin (1) is shown in
Scheme 1. Since the disulfide bridge is extremely labile under oxi-
dative, reductive, and basic conditions, we planned to carry out its
construction at the last stage of the synthesis, under acidic condi-
tions. We selected acid-sensitive protecting groups to protect the
hydroxyl group (P1) and the amino group (P2), anticipating that
such protecting groups could be removed simultaneously with
construction of the disulfide. If substitution reaction is employed
for this purpose, an appropriate leaving group (X) is required at the
a
-position of the DKP ring. The precursor 5 could be synthesized
through dimeric octacyclic DKP 6 or monomeric tetracyclic DKP 7.
Basically, these routes differ in the order in which -oxidation and
a
dimerization reactions are performed. Compounds 6 and 7 are
considered to be accessible from tetracyclic bromide 8, which
would be synthesized via bromocyclization of DKP 9. Alternatively,
compound 6 might also be accessible from the DKP 9 through
a sequential oxidative dimerizationecyclization process. In route A
Scheme 2. Synthesis of L-Ser-Trp dipeptide 13.
and route B, the a-positions of the DKP rings are oxidized after the
The resulting dipeptides 11e13 were subjected to hydro-
genolysis to afford the desired amines 14e16 (Scheme 3). The
construction of the dimeric core structure. Such late-stage oxida-
tion is proposed to occur in the biosynthesis.16 On the contrary,
Scheme 1. Retrosynthetic analysis of chaetocin (1).

E. Iwasa et al. / Tetrahedron 67 (2011) 6587e6599
6589
addition of a weak base is normally necessary for intramolecular
condensation reaction between an ester and a secondary amine.20
We first tried the reaction of 14e16 in the presence of ammo-
nium hydroxide (method A). DKP 17e19 were obtained without
difficulty, even though a trace amount of the epimer was obtained
in each case. We also used triethylamine in place of ammonium
hydroxide for amine 15. Unfortunately, the cyclized compound 18
was obtained in only 13% yield (method B). The concentration of
ammonium hydroxide should be kept under 7 vol %, otherwise
amide 20 is produced in an appreciable amount.
Scheme 5. Attempts at oxidative dimerizationecyclization of the DKPs.
of the starting material and the product under the oxidative con-
ditions used.22 We considered that it might be in part due to the
weak electrophilicity of the imine or iminium ion intermediates
(P2¼H). Therefore we next examined the reaction of the N-Boc-
protected substrate 19. However, the reaction of 19 did not afford
the desired product, but instead the starting material was
recovered in 53% yield. This may be with a result of the reduced
electron density on the indole ring.
Scheme 3. Syntheses of diketopiperazines.
Anticipating that a stepwise procedure (route B or C) would be
a more reliable approach, we next examined bromocyclization of
19.23 As shown in Table 1,19 reacted smoothly with NBS at ꢀ30 ꢁC to
give tetracyclic compound 26 in 88% yield (entry 2). Interestingly,
this bromocyclization reaction was highly stereoselective. The cor-
responding diastereomer was not detected even at higher temper-
atures, although the amount of over-brominated compound 28 was
increased (entries 3 and 4). The bulky TBS group is considered
unlikely to affect the stereoselectivity, since the reaction of depro-
tected 25 also proceeded in a stereoselective manner (entry 5).
The N-Boc-protected DKP 19 was also accessible from 18, as
shown in Scheme 4. However, di-Boc protection occurred con-
comitantly. Because the DKP ring is conformationally rigid, the
nucleophilicity of the lactam might be higher than that of the
acyclic amide.
Table 1
Optimization of bromocyclization
Scheme 4. Boc-protection of the indole ring of the DKP 18.
2.3. Synthesis of the octacyclic compound and attempts at its
a
-oxidation
As shown in Scheme 1, we envisaged that single-electron
transfer from the indole ring would give a radical cation in-
termediate, which might undergo radical homocoupling reaction
and subsequent intramolecular nucleophilic attack of the amide on
the resultant iminium ion (route A). This idea is supported by the
findings by Hino and Nakagawa’s group and more recently by
Takayama’s group.21 Based on the original report, the synthesized
diketopiperazines were treated with phenyliodine bis(tri-
fluoroacetate) (PIFA) as an oxidant (Scheme 5).
Unfortunately, the reaction of 17 and 18 gave a complex mixture,
and the desired compound was not detected. Movassaghi discussed
a similar observation in their review article, in which they sug-
gested that the complexity of the reaction arose from the instability
Entry
Substrate
Temperature
Monobromide
Dibromide
28: da
28: 6%
28: 24%
28: 28%
29: dc
1
2
3
4
5
19
19
19
19
25
ꢀ40 ꢁC
ꢀ30 ꢁC
ꢀ20 ꢁC
26: 28%
26: 88%
26: 32%
26: 46%
27: 58%b
0
ꢁC
ꢀ30 ꢁC
a
Not detected.
b
A trace amount of by-product assigned as isomeric endo-27 was detected by LC/
MS.
c
A trace amount of by-product assigned as 29 was detected by LC/MS.

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E. Iwasa et al. / Tetrahedron 67 (2011) 6587e6599
After the removal of the bromine atom and the TBS group, the
A
structure of 31 was determined by X-ray analysis, which revealed
that the bromine atom within 26 was positioned trans to the hy-
drogen atoms at the C11 position (Scheme 6). In this article, we refer
to the reaction giving the trans product as exo-selective, and that
giving the cis product as endo-selective.
B
Fig. 2. Stereochemical model of bromocyclization.
with that of 1. This indicates that the enantiomer of 1 (ent-chae-
tocin, ent-1) would be obtained starting from naturally abundant
Scheme 6. Conversion of 26 to 31, and X-ray crystallographic structure of 31.
L-amino acid derivatives. Therefore, we prepared its enantiomer
ent-26 using the corresponding D-amino acid derivatives as starting
materials (Scheme 8).
Similar bromocyclization reactions were examined by Movas-
saghi’s group in their total syntheses of (ꢀ)-ditryptophenaline
(2)17b and (þ)-11,110-dideoxyverticillin (4).13 The endo/exo-selec-
tivity of the reactions varied depending on the size of the a-sub-
stituent on the DKP ring and the reaction temperature
(Scheme 7).24 It should be noted that DKP substrates without the N-
methyl group were used in their work. Therefore, we speculated
that the difference in the diastereoselectivity might be caused by
the presence or absence of the N-methyl group.
Scheme 7. Halocyclization reaction of DKPs 32 and 33 reported by Movassaghi’s
group.13,17b
The excellent exo-selectivity observed in our reaction can be
explained as follows. The conformations of the DKP rings are
known to vary from planar to boat- or chair-like, depending on the
substitution pattern. In the case of N-methyl DKPs, side chains
would be preferentially located at the pseudo-axial position to
avoid steric interaction with the N-methyl group.25 Therefore, in
the case of compound 19, the TBS-oxymethyl group is expected to
be located at the pseudo-axial position to minimize steric in-
teraction with the N-methyl group (Fig. 2).
This speculation is supported by the X-ray structure of 31. It
seems that the reaction via transition state A proceeds without
difficulty to afford exo-26. In contrast, the formation of the endo-
oriented product is unfavorable, since the transition state B would
be destabilized considerably due to the severe steric repulsion
between the indole ring and the TBS-oxymethyl group.
As revealed by the X-ray analysis (Scheme 6), the absolute
configuration at the C2 and C3 positions of 26 was not coincident
Scheme 8. Reductive dimerization and attempts at a-oxidation of the octacyclic core
structure.

E. Iwasa et al. / Tetrahedron 67 (2011) 6587e6599
6591
According to route B, we next examined the reductive radical
coupling reaction. As shown in Scheme 8, the reductive coupling of
ent-26 was carried out based on Movassaghi’s procedure. The re-
action proceeded smoothly to give the desired dimeric compound
36 in 47% yield together with the reduced compound ent-30 in 10%
yield. For the introduction of the sulfur functionality onto the
simple DKP rings, Schmidt et al. examined electrophilic sulfenyla-
tion using enolate chemistry.26 However, the reactions of the
octacyclic compound 36 with various bases, including LDA,
LiHMDS, and KHMDS, led to complete decomposition, even at
hydrogen atom at the C3 position and the bromine atom at the C12
position are cis-oriented. This led us to hypothesize that the un-
desired third bromination at the C12 position would be suppressed
if the C3 position carried a bulky group. We expected that the tet-
racyclic bromide ent-26 would be a suitable compound for this
purpose (Scheme 10). As we hoped,
a-bromination occurred se-
lectively to give the desired compound 41 almost quantitatively as
a single stereoisomer, when the reaction was performed at room
temperature using V-7028 as a radical initiator. In contrast, ent-26
decomposed under standard reflux conditions with AIBN. These
results clearly indicate that the bulky bromine atom at the benzylic
ꢀ78 ꢁC, regardless of the presence or absence of electrophilic sulfur
t
compounds. Although the reaction with BuOLi was clean,
b
-elim-
position played an important role in this reaction. Importantly, b-
ination of the TBS-oxy group readily occurred to give exo-methy-
lene compound 37 in 63% yield. Therefore, we next investigated the
elimination of the silyloxy group was effectively suppressed by use
of the radical reaction. On the other hand, the instability observed
in the case of 36 may be associated with its dimeric structure. Due
to its high reactivity, the obtained crude 41 was used directly in the
next reaction after removal of precipitated succinimide by
filtration.
radical
that the undesired
a
-bromination reaction as planned in Scheme 1, expecting
-elimination of the TBS-oxy group would be
b
suppressed, because the formation of an oxy-radical species is
energetically disfavored. Even though only non-substituted dike-
topiperazines derived from glycine or sarcosine were employed for
the radical a
-bromination reaction,11,27 we tried the reaction of 36
with NBS. Unfortunately, the dimeric structure of 36 was extremely
unstable under the radical conditions even at room temperature,28
resulting in the formation of a complex mixture. Therefore, we had
to abandon the late-stage oxidation of the dimeric core.
2.4.
a
-Oxidation of tetracyclic compound ent-26
-bromination without b-elimina-
To confirm the feasibility of
a
tion, we first studied a model reaction using compound 30 under
standard reaction conditions using AIBN and NBS (Scheme 9).
Scheme 10. Successful a-oxidation of the tetracylic compound ent-26 (two-step yield
is given).
The obtained dibromide 41 was subjected to substitution
reactions using various oxygen nucleophiles, including water, al-
cohol, and acetate anion. Among them, water was found to be the
best nucleophile, affording hemiaminal 42. Thus, the treatment of
41 with phosphate buffer gave the diol 42a as a major stereoisomer,
accompanied with the other three stereoisomers 42bed and two
by-products (43 and 44). Since the completion of the radical bro-
mination was confirmed by 1H NMR, it is clear that the by-product
44 was formed from 41, and not from partial bromination of ent-26.
The stereochemistry of the major diastereomer 42a was un-
equivocally determined by X-ray crystallographic analysis, while
those of the minor diols remain unclear (Fig. 3).
Scheme 9. Radical bromination of 30 derived from L-amino acids.
Although the desired bromination proceeded smoothly, the C12
position was also brominated, affording tribromide 38 as a single
stereoisomer. It is likely that the undesired bromination occurred
quickly after the reactions at the a-positions, since the tribromide
38 was a major product even when only 2 equiv of NBS was used.
However, the reaction gave many by-products. It is well-known
that a hydrogen atom next to a bromine atom tends to be ab-
stracted by a radical species to give a carbon radical, because the
generated carbon radical is stabilized by positive interaction with
the bonding orbital of the CeBr bond.29 Accordingly, the second
bromine atom would attack the carbon radical from the opposite
side to the bromine atom already in the compound. Such stereo-
electronic and steric effects are considered to result in selective
bromination with trans stereochemistry. Although the obtained
tribromide could be converted to the corresponding methyl ether
39, the subsequent removal of the remaining bromine atom at the
C12 position was found to be difficult. An analysis of the coupling
constants in the 1H NMR spectrum of 38 suggested that the
Fig. 3. X-ray crystallographic analysis of 42a (protecting groups are omitted for
clarity).

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E. Iwasa et al. / Tetrahedron 67 (2011) 6587e6599
2.5. Completion of the total synthesis of chaetocin (1)
2.6. Effect of stereochemistry in the dimerization reaction
The final stage of the total synthesis is briefly summarized in
Scheme 11. With the hemiaminal 42a in hand, construction of the
octacyclic framework was investigated using Movassaghi’s
reductive coupling reaction. Since the hemiaminal moiety within
42a is likely to be unstable, we were afraid that 42a would
decompose under the reaction conditions. To our delight, however,
the desired octacyclic tetraol 45 was obtained in 55% yield as
a single isomer. As in the case of the synthesis of 36, a small amount
of reduced by-product 46 was isolated. As discussed later, the ef-
ficiency of this reaction was strongly influenced by the relative
stereochemistry of the hemiaminal moiety.
As mentioned above, the relative configuration of the hemi-
aminal moiety influenced the dimerization reaction. When a mix-
ture of 42a and its stereoisomer 42b was treated with the Co(I)
complex,13,15,17,18 symmetric 45 and non-symmetric 48 were
obtained in 30% and 20% yield, respectively (Scheme 12).31 In this
reaction, three isomers are potentially formed, but the homocou-
pling product of 42b was not isolated. To confirm this, we tested the
coupling reaction of the isolated 42b. The reaction gave a complex
mixture, but no homocoupling product was detected. It is likely
that the symmetric 45 arose from the homocoupling reaction of
42a, and non-symmetric 48 was formed via the heterocoupling
reaction between 42a and 42b. We speculate that the switch of the
stereochemistry at the
a-position caused strong steric repulsion
between the two tetracyclic ring systems, disfavoring their
approach.
Scheme 12. Dimerization reaction using a diastereomeric mixture of diols 42a and
42b.
Scheme 11. Completion of the total synthesis of chaetocin (1).
2.7. Stereochemical effects in the substitution reaction with
H2S
Based on previous reports, in which hydrogen sulfide was
reacted with a hemiaminal ether in the presence of ZnCl2,30 we
examined the substitution reaction using Lewis acids. Because
BF3$OEt2 is a widely used Lewis acid for the activation of hemi-
aminals and their ethers, we tested it in our case. Considering the
intrinsic nature of boron as a hard Lewis acid, we expected that
the resulting thiol would be sufficiently stable to BF3$OEt2. Thus,
the reaction of 45 with condensed hydrogen sulfide (bp: ꢀ60.7 ꢁC)
was attempted in the presence of BF3$OEt2 in a sealed tube, and
furnished the desired tetrathiol 47. The crude tetrathiol 47 was
subsequently oxidized with molecular iodine, and chaetocin (1)
was obtained in 44% yield (two steps). The obtained compound was
spectroscopically identical to a natural sample of 1. It should be
noted that the final step involved no less than 10 bond-forming and
breaking events: (1) four substitution reactions, (2) the removal of
four protecting groups (Boc and TBS groups), and (3) formation of
two disulfide bonds. Using this established route, we also achieved
While symmetric 45 underwent substitution reaction with H2S
in 44% yield, 48 was less reactive, affording only 6% yield of the final
product (Scheme 12). These results indicate that BF3$OEt2 could
access the hydroxyl groups of 45, and the substitution reaction
could proceed smoothly. It is inferred that at least one hydroxyl
group within 48 is oriented toward the inside of the core structure,
thereby preventing its activation by the Lewis acid. This result also
indicates the importance of the stereochemistry at the hemiaminal
moiety for the substitution reaction.
Examination of the 1H NMR spectrum of the crude product 47
suggested that hydrogen sulfide attacked the putative iminium
intermediate stereoselectively. Initially, we simply reasoned that
the steric bias caused by the double-decker structure would favor
the attack of hydrogen sulfide from the outside of the core struc-
ture. This idea may explain the stereochemical outcome at the C11
0
and C11 positions. However, a molecular modeling study suggested
0
that the C15 and C15 positions are more accessible, so that H2S can
the total synthesis of ent-chaetocin (ent-1) from L-amino acid
attack from the other side. Our alternative explanation is as follows
derivatives as starting materials.

E. Iwasa et al. / Tetrahedron 67 (2011) 6587e6599
6593
(Scheme 13): if the TBS group is removed before displacement, the
resulting hydroxyl group may attack the generated iminium ion to
form an epoxide with inversion of the stereochemistry, and re-
opening with hydrogen sulfide would produce the desired
stereochemistry.
Fig. 4. Possible explanation for the stereoselectivity of the substitution reaction by
hydrogen sulfide.
3. Conclusion
We have achieved the first total synthesis of chaetocin (1) and
ent-chaetocin (ent-1) in only nine steps starting from known
N-methyl-serine and tryptophan methyl ester. The key reactions
were two radical reactions. Firstly, the a-oxidation of the tetracyclic
DKP compound was successfully accomplished by radical bromi-
nation with NBS, followed by treatment with water. This trans-
Scheme 13. Alternative idea to explain the high stereoselectivity observed in the H2S
substitution reaction.
formation was useful to avoid undesired
b-elimination of the
oxygen functionality. Secondly, the obtained diol was subjected to
radical dimerization using the Co(I) complex. Though the diol
contained the relatively unstable hemiaminal moiety, the di-
merization reaction was successfully conducted to give a symmet-
rical octacyclic carbon framework. The final disulfide bridge
formation was achieved stereoselectively, and all the protective
groups were removed in a single step. We have discussed the origin
of the stereoselectivity observed in the stereoselective bromocyc-
lization reaction, the radical bromination reaction, and the sub-
stitution reaction by hydrogen sulfide. The established synthetic
route described in this paper should also be applicable to the
syntheses of various derivatives, which will facilitate the de-
velopment of molecular tools for epigenetic research. The results of
a detailed structureeactivity relationship study will be reported in
due course.
However, careful analysis of the reaction suggested that cleav-
age of the TBS group occurred after the substitution event. Namely,
when the reaction was quenched at ꢀ20 ꢁC, 52 was obtained with
the TBS group remaining (Scheme 14). Although the yield of 52 was
low, involvement of the hydroxyl group in the double inversion
mechanism is unlikely. Instead, the TBS-oxy group might act as
a bulky shielding group. Since the TBS-oxy group of 45 points to-
ward the inside of the core structure, the reactive iminium ion
might be formed with the TBS group keeping similar orientation. If
this is the case, it appears that the TBS group effectively interferes
with the attack of hydrogen sulfide from the inner surface of the
core structure, so that hydrogen sulfide should attack preferentially
from the outer surface of the core (Fig. 4).
4. Experimental section
4.1. General
NMR spectra were recorded on a JEOL JNM-ECP500 spectrom-
eter operating at 500 MHz for 1H NMR and 125 MHz for 13C NMR or
a JEOL JNM-ECP400 spectrometer operating at 400 MHz for 1H
NMR and 100 MHz for 13C NMR. Chemical shifts are reported
downfield from TMS (¼0) or relative to the solvent signal as an
internal reference for 1H NMR. For 13C NMR, chemical shifts are
reported relative to the solvent signal as an internal reference. IR
was measured on a Thermo Nicolet AVATAR 370 FTIR. Optical ro-
tations were measured on a JASCO DIP-370 polarimeter. In some
cases, purification was carried out using Yamazen medium-
pressure liquid chromatography (MPLC) systems [pump, 580-D;
UV-detector, prepUV-10VW; column, Yamazen HI-FLASHÔ or Ultra
PackÔ SI-40A or Kusano pre-packed SiO2 column; eluent, n-hex-
ane/ethyl acetate or chloroform/methanol]. Column chromatogra-
Scheme 14. Substitution reaction of tetraol 45 below ꢀ20 ꢁC.
phy was performed with silica gel 60 (40e100 mm) purchased from
Kanto Chemical Co., Inc. Dehydrated N,N-dimethylformamide
(DMF), acetonitrile, stabilizer-free tetrahydrofuran (THF), and
dichloromethane were purchased from Kanto Chemical Co., Inc.
Dehydrated acetone was purchased from Wako Pure Chemical In-
dustries, Ltd. N-Bromosuccinimide was recrystallized from water
and dried over P2O5 under vacuum before use. Other solvents and
Although further investigation, including computational struc-
tural analysis of 45 and its iminium forms, is required to elucidate
the reaction mechanism, we believe that the stereoselectivity of
this substitution reaction is controlled by its unique double-decker
structure, as well as the orientation of the TBS groups.

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E. Iwasa et al. / Tetrahedron 67 (2011) 6587e6599
reagents used in this paper were purchased and used as received.
N-Benzyloxycarbonyl-N-methyl- -serine (7) was synthesized from
-serine according to the reported procedure.19 Tris(triphenyl-
phosphine)cobalt(I) chloride (CoCl(PPh3)3) was freshly prepared
according to the literature.32 A natural sample of chaetocin (1) was
purchased from SigmaeAldrich.
(15.4 g, 226 mmol) under a nitrogen atmosphere. After having been
stirred overnight at room temperature, the reaction mixture was
concentrated in vacuo. The obtained residue was dissolved in ethyl
acetate (400 mL), then washed with water (3ꢂ200 mL) and brine
(150 mL). The organic layer was dried over anhydrous sodium sulfate
andconcentratedinvacuotogivecrudeent-12 (48.8g, quant.)asapale
yellow gum. A small crude sample was further purified by GPC for
D
D
spectroscopic analysis. 1H NMR (500 MHz, CDCl3, 55 ꢁC)
d: 0.00 (s, 3H,
4.2. Numbering system
SiCH3), 0.01 (s, 3H, SiCH3), 0.82 (9H, s, SiC(CH3)3), 2.72 (s, 3H, C18H),
3.23 (dd, J¼5.5 Hz, 11.9 Hz, 1H, C12H), 3.31 (dd, J¼5.5 Hz, 11.9 Hz, 1H,
C12H), 3.67 (s,3H, OCH3), 3.84(br,1H, C17H), 4.03 (dd, J¼6.4 Hz,10.5Hz,
1H, C17H), 4.08 (br, 1H, C15H), 4.88 (br, 1H, C11H), 5.10 (br s, 2H,
PhCH2OCON), 6.89 (br, 1H, C2H), 7.08 (t, J¼7.5 Hz, 1H, C6H), 7.16 (t,
J¼7.5 Hz, 1H, C7H), 7.29 (d, J¼7.5 Hz, 1H, C5H), 7.24e7.34 (m, 5H,
PhCH2OCON), 7.51 (br d, J¼7.5 Hz, 1H, C8H), 7.96 (br,1H, N1H); 13C NMR
Based on a numbering system employed in Movassaghi’s
paper,13 we use the following numbering system in this paper. The
numbers assigned to early synthetic intermediates to specify the
positions of interest are in accord with the corresponding carbons
within chaetocin.
(125 MHz, CDCl3, 55 ꢁC)
d
: ꢀ5.53 (SiCH3), ꢀ5.45 (SiCH3), 18.1
(SiC(CH3)3), 25.8 (SiC(CH3)3), 27.8 (C12), 31.6 (C18), 52.3 (OCH3), 52.9
(C11), 60.8 (C17), 61.4 (C15), 67.7 (PhCH2OCON), 110.3 (C4), 111.4 (C5),
118.7 (C8), 119.9 (C6), 122.4 (C7), 122.9 (C2), 127.8 (PhCH2OCON), 128.1
(PhCH2OCON), 128.2 (PhCH2OCON), 128.7 (PhCH2OCON), 136.5 (C9),
136.9 (PhCH2OCON), 169.3 (C16), 172.2 (C13); [
a
]
D ꢀ8.2 (c 0.86, CHCl3,
23 ꢁC); FTIR (neat) cmꢀ1: 3338 (br), 2952 (m), 2930 (m),1741 (s),1690
(s), 1676 (m), 1154 (s), 1112 (s), 839 (s), 742 (s); LRMS (ESI) m/z 590
[MþNa]þ.
Compound 12: [
a
]
D þ10 (c 1.0, CHCl3, 25 ꢁC).
4.3. Synthesis
4.3.3. Synthesis of dipeptide ent-13. To a solution of ent-12 (17.6 g,
30.9 mmol) in dry acetonitrile (80 mM, 390 mL) was added 4-
dimethylaminopyridine (378 mg, 3.09 mmol) at 0 ꢁC. Then di-
tert-butyl dicarbonate (7.44 g, 34.0 mmol) in dry acetonitrile
(30 mL) was added dropwise over 25 min. The reaction mixture was
stirred at 0 ꢁC for 5 h. Then additional di-tert-butyl dicarbonate
(733 mg, 3.36 mmol) in dry acetonitrile (30 mL) was added drop-
wise. After further stirring for 90 min, the reaction mixture was
concentrated in vacuo. Further purification by flash column chro-
matography (hexane/acetone¼20/80) was carried out to give ent-
13 (19.9 g, 96%) as a white amorphous foam. 1H NMR (400 MHz,
The following experimental procedures and characterization
data are given for the synthesis of natural chaetocin (1). For the
enantiomers of the synthetic intermediates, which were derived
from L-amino acid derivatives, only optical rotations are provided.
4.3.1. Synthesis of dipeptide ent-11. To a solution of ent-10 (14.3 g,
56.4 mmol), -tryptophan methyl ester hydrochloride (14.4 g,
D
56.4 mmol), and triethylamine (7.9 mL, 56.7 mmol) in N,N-dime-
thylformamide (180 mL) were added 1-ethyl-3-(3-dimethyl
aminopropyl)carbodiimide hydrochloride (11.9 g, 62.1 mmol) and
1-hydroxybenzotriazole monohydrate (9.15 g, 67.7 mmol) at ꢀ20 ꢁC.
The reaction mixture was allowed to warm up to room temperature
and then stirred overnight. After removal of the solvent in vacuo, the
obtained residue was diluted with ethyl acetate (700 mL). The or-
ganic layer was washed with 5% aqueous sodium bicarbonate so-
lution (4ꢂ500 mL),10% aqueous citric acid solution (4ꢂ500 mL), and
water (3ꢂ500 mL). The organic layer was dried over anhydrous so-
dium sulfate and concentrated in vacuo. Further purification was
performed by flash column chromatography (chloroform/meth-
anol¼99/1 to 95/5) to give ent-11 (23.4 g, 91%) as a colorless gum.1H
CDCl3, 50 ꢁC)
d: 0.00 (s, 3H, SiCH3), 0.01 (s, 3H, SiCH3), 0.81 (s, 9H,
SiC(CH3)3), 1.66 (s, 9H, (CH3)3COCON), 2.80 (s, 3H, C18H), 3.17 (dd,
J¼5.6, 14.6 Hz, 1H, C12H), 3.26 (dd, J¼5.6, 14.6 Hz, 1H, C12H), 3.69 (s,
3H, OCH3), 3.84 (br, 1H, C17H), 4.05 (dd, J¼6.6, 10.7 Hz, 1H, C17H),
4.63 (br, 1H, C15H), 4.90e4.92 (br m, 1H, C11H), 5.07e5.12 (m, 2H,
PhCH2OCON), 7.00 (br, 1H, N10H), 7.21 (t, J¼7.7 Hz, 1H, C6H),
7.27e7.36 (m, 7H, C2H, C7H, PhCH2OCON), 7.46 (br, 1H, C5H), 8.10 (d,
J¼7.7 Hz, 1H, C8H); 13C NMR (125 MHz, CDCl3)
: ꢀ5.56 (SiCH3),
d
ꢀ5.50 (SiCH3), 18.1 (SiC (CH3)3), 25.8 (SiC(CH3)3), 27.6 (C12), 28.4
((CH3)3COCON), 32.1 (C18), 52.4 (OCH3), 52.7 (C11), 61.0 (C17), 61.4
(C15), 67.7 (PhCH2OCON), 83.8 ((CH3)3COCON), 115.2 (C3), 115.5 (C5),
118.9 (C8), 122.8 (C6), 124.2 (C2), 124.7 (C7), 128.0 (PhCH2OCON),
128.1 (PhCH2OCON), 128.6 (PhCH2OCON), 130.7 (C4), 135.6 (C9),
136.7 (PhCH2OCON), 149.7 ((CH3)3COCON), 169.4 (C16), 171.8 (C13);
NMR (500 MHz, CDCl3, 55 ꢁC)
d: 2.59 (br s,1H, OH), 2.65 (s, 3H, C18H),
3.21 (dd, J¼6.6 Hz,14.9 Hz,1H, C12H), 3.29 (dd, J¼5.3 Hz,14.9 Hz,1H,
C12H), 3.69 (s, 3H, OCH3), 3.78 (br,1H, C17H), 3.95e4.00 (m,1H, C15H),
4.58 (br, 1H, C17H), 4.83e4.87 (m, 1H, C11H), 5.07 (br s, 2H, PhCH2),
6.50 (br s,1H, N10H), 6.84 (s,1H, C2H), 7.08 (t, J¼7.6 Hz,1H, C6H), 7.15
(t, J¼7.6 Hz, 1H, C7H), 7.28 (d, J¼7.6 Hz, 1H, C5H), 7.25e7.40 (m, 5H,
PhCH2OCON), 7.80 (d, J¼7.6 Hz, 1H, C8H), 7.84 (br s, 1H, N1H); 13C
[
a
]
D ꢀ18 (c 1.0, CHCl3, 26 ꢁC); FTIR (neat) cmꢀ1: 3322 (br), 2953 (m),
2929 (m), 2856 (m), 1729 (s), 1691 (s), 1678 (s), 1255 (s), 1158 (s),
839 (s), 748 (s); LRMS (ESI) m/z 690 [MþNa]þ.
NMR (125 MHz, CDCl3, 55 ꢁC)
d: 27.6 (C12), 31.8 (C18), 52.5 (OCH3),
Compound 13: [
a
]
D þ16 (c 1.0, CHCl3, 24 ꢁC).
52.8 (C11), 60.6 (C15), 61.1 (C17), 67.9 (PhCH2OCON), 109.9 (C3), 111.5
(C5), 118.5 (C8), 119.9 (C6), 122.5 (C7), 123.0 (C2), 127.5 (C4), 128.1
(PhCH2OCON), 128.4 (PhCH2OCON), 128.7 (PhCH2OCON), 136.5 (C9
4.3.4. Synthesis of dipeptides 14 and 15. Dipeptides 14 and 15 were
synthesized according to the same protocol used for the synthesis
of ent-16 (vide infra). 1H NMR data of each compound are sum-
marized below.
and PhCH2OCON), 170.3 (C16), 172.2 (C13); [
a
]
þ6.8 (c 1.0, CHCl3,
D
25 ꢁC); FTIR (neat) cmꢀ1: 3321 (br), 2953 (m),1666 (s), 744 (s); LRMS
(ESI) m/z 476 [MþNa]þ.
Compound 14: 1H NMR (400 MHz, CDCl3, 25 ꢁC)
d: 2.35 (s, 3H),
Compound 11: [
a
]
D ꢀ9.5 (c 0.63, CHCl3, 24 ꢁC).
3.01 (t, J¼5.5 Hz, 1H), 3.28 (dd, J¼5.9, 14.9 Hz, 1H), 3.35 (dd, J¼5.9,
14.9 Hz, 1H), 3.61 (d, J¼5.5, 11.2 Hz, 1H), 3.65 (dd, J¼5.5, 11.2 Hz, 1H),
3.72 (s, 3H), 4.93 (ddd, J¼5.9, 5.9, 8.4 Hz, 1H), 7.01 (app. d, J¼2.2 Hz,
1H), 7.11 (t, J¼7.7 Hz,1H), 7.18 (t, J¼7.7 Hz,1H), 7.35 (d, J¼7.7 Hz,1H),
7.53 (d, J¼7.7 Hz, 1H), 7.68 (d, J¼8.4 Hz, 1H), 8.17 (br, 1H).
4.3.2. Synthesis of dipeptide ent-12. To a solution of ent-11 (38.7 g,
85.2 mmol) and imidazole (13.9 g, 204 mmol) in dry N,N-dimethyl-
formamide (0.4 M, 210 mL) was added tert-butyldimethylchlorosilane

E. Iwasa et al. / Tetrahedron 67 (2011) 6587e6599
6595
Compound 15: 1H NMR (400 MHz, CDCl3, 22 ꢁC)
d
: 0.02 (s, 3H),
4.3.8. Synthesis of diketopiperazine ent-19 (method A). To a solution
of ent-16 (184 mg, 345 mol) in methanol (6 mM, 54 mL) was added
0.04 (s, 3H), 0.86 (s, 9H), 2.35 (s, 3H), 3.04 (dd, J¼4.2, 7.7 Hz, 1H),
3.26 (dd, J¼5.8, 14.8 Hz, 1H), 3.31 (dd, J¼5.8, 14.8 Hz, 1H), 3.47 (dd,
J¼7.7,10.0 Hz,1H), 3.79 (d, J¼4.2,10.0 Hz,1H), 4.93 (dt, J¼5.8, 8.6 Hz,
1H), 7.01 (d, J¼2.2 Hz, 1H), 7.10 (dt, J¼0.8, 8.1 Hz, 1H), 7.18 (dt, J¼0.8,
8.1 Hz, 1H), 7.34 (app. d, J¼8.1 Hz, 1H), 7.55 (app. d, J¼8.1 Hz, 1H),
7.86 (d, J¼8.6 Hz, 1H), 8.04 (br s, 1H).
m
28% aqueous NH4OH solution (2.0 mL) at room temperature. This
was stirred for 27 h, additional 28% aqueous NH4OH solution
(2.0 mL) was added, and stirring was continued for an additional
31 h, after which time TLC indicated complete consumption of the
starting material. The reaction mixture was concentrated in vacuo,
and further purification by flash column chromatography (hexane/
ethyl acetate¼30/70 to 0/100) gave ent-19 (136 mg, 79%) as a white
4.3.5. Synthesis of dipeptide ent-16. To a solution of ent-13 (21.4 g,
32.1 mmol) in ethanol (100 mM, 320 mL) was added 10% Pd/C
(3.39 g, 10 mol % Pd). After replacement of the inner gas with hy-
drogen (balloon), the resulting mixture was stirred for 5 h. The
reaction mixture was diluted with ethyl acetate, then filtered
through CeliteÒ with ethyl acetate washing. Concentration in vacuo
gave crude ent-16 (18.9 g, quant.) as a colorless gum. A small crude
sample was further purified by MPLC (column: Yamazen High
Flash, chloroform/methanol¼63/37 to 95/5) for spectroscopic
solid. 1H NMR (500 MHz, CDCl3, 50 ꢁC)
d: 0.13 (s, 6H, Si(CH3)2), 0.94
(s, 9H, SiC(CH3)3), 1.67 (s, 9H, (CH3)3COCON), 3.02 (s, 3H, C18H), 3.07
(dd, J¼11.0, 14.2 Hz, 1H, C12H), 3.58 (dd, J¼2.8, 14.2 Hz, 1H, C12H),
3.86e3.87 (m, 1H, C15H), 3.98 (dd, J¼2.8, 10.6 Hz, 1H, C17H), 4.08
(dd, J¼2.3, 10.6 Hz, 1H, C17H), 4.19e4.22 (m, 1H, C11H), 5.95 (s, 1H,
N10H), 7.25 (dt, J¼0.9, 8.1 Hz, 1H, C6H), 7.33 (dt, J¼0.9, 8.1 Hz, 1H,
C7H), 7.46 (s, 1H, C2H), 7.61 (app. d, J¼8.1 Hz, 1H, C5H), 8.16 (app. d,
J¼8.1 Hz, 1H, C8H); 13C NMR (125 MHz, CDCl3, 50 ꢁC)
: ꢀ5.20
d
analysis. 1H NMR (500 MHz, CDCl3, 50 ꢁC)
d: 0.02 (s, 3H, SiCH3), 0.04
(SiCH3), ꢀ5.13 (SiCH3), 18.8 (SiC(CH3)3), 26.2 (SiC(CH3)3), 28.3
((CH3)3COCON), 32.5 (C18), 32.8 (C12), 55.7 (C11), 62.3 (C17), 64.4
(C15), 84.0 ((CH3)3COCON), 115.4 (C3), 115.7 (C8), 119.3 (C5), 123.0
(C6), 124.7 (C2), 125.1 (C7), 129.8 (C4), 136.1 (C9), 149.5 ((CH3)3CO-
(s, 3H, SiCH3), 0.85 (s, 9H, SiC(CH3)3), 1.66 (s, 9H, (CH3)3COCON),
2.38 (s, 3H, C18H), 3.05 (dd, J¼4.2, 7.8 Hz, 1H, C15H), 3.19 (dd, J¼6.0,
14.8 Hz, 1H, C12H), 3.22 (dd, J¼6.0, 14.8 Hz, 1H, C12H), 3.52 (dd,
J¼7.8, 10.1 Hz, 1H, C17H), 3.67 (s, 3H, OCH3), 3.81 (dd, J¼4.2, 10.1 Hz,
1H, C17H), 4.92 (dt, J¼6.0, 8.3 Hz, 1H, C11H), 7.21 (t, J¼7.8 Hz, 1H,
C6H), 7.29 (t, J¼7.8 Hz, 1H, C7H), 7.39 (s, 1H, C2H), 7.50 (d, J¼7.8 Hz,
CON), 165.8 (C16), 166.2 (C13); [
a
]
þ79 (c 1.7, CHCl3, 26 ꢁC); FTIR
D
(neat) cmꢀ1: 3229 (br), 2931 (m), 2857 (m), 1732 (s), 1660 (s), 1158
(s), 1086 (s), 837 (s), 749 (s); HRMS (ESI) m/z calcd for
C26H39N3NaO5Si [MþNa]þ 524.25567, found: 524.25358.
1H, C5H), 7.86 (d, J¼8.3 Hz,1H, N10H), 8.10 (d, J¼7.8 Hz, 1H, C8H); 13
C
NMR (125 MHz, CDCl3, 50 ꢁC)
d
: ꢀ5.40 (SiCH3), ꢀ5.32 (SiCH3), 18.3
Compound 19: [
a
]
D ꢀ79 (c 1.0, CHCl3, 25 ꢁC).
(SiC (CH3)3), 25.9 (SiC(CH3)3), 27.9 (C12), 28.3 ((CH3)3COCON), 35.3
(C18), 52.1 (OCH3), 52.3 (C11), 63.2 (C17), 66.9 (C15), 83.6
((CH3)3COCON), 115.4 (C3 and C8), 119.0 (C5), 122.6 (C6), 124.1 (C2),
124.6 (C7), 130.7 (C4), 135.6 (C9), 149.6 ((CH3)3COCON), 171.8 (C16),
4.3.9. Synthesis of diketopiperazine 21. Compound 21 was obtained
as a by-product in the synthesis of 19. Refer to the synthesis of ent-
13 for the procedure. The analytical data were as follows.
172.1 (C13); [
a
]
ꢀ22 (c 1.4, CHCl3, 26 ꢁC); FTIR (neat) cmꢀ1: 3348
Compound 21: 1H NMR (400 MHz, CDCl3, 22 ꢁC)
d: 0.02 (s, 3H),
D
(br), 2952 (m), 2931 (m), 2884 (m), 2857 (s), 1735 (s), 1372 (s), 1255
0.05 (s, 3H), 0.87 (s, 9H), 1.13 (s, 9H), 1.64 (s, 9H), 2.98 (s, 3H), 3.35
(dd, 1H, J¼8.3, 14.6 Hz), 3.42 (dd, 1H, J¼8.3, 14.6 Hz), 3.79 (dd, J¼3.4,
10.9 Hz, 1H), 3.87 (dd, J¼2.7, 10.9 Hz, 1H), 4.02 (app. t, J¼3.4 Hz, 1H),
5.04 (dd, J¼4.6, 8.1 Hz, 1H), 7.24e7.32 (m, 2H), 7.38 (s, 1H), 7.62 (d,
J¼7.8 Hz, 1H), 8.12 (d, J¼7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3,
(s), 1158 (s), 1088 (s), 838 (s); LRMS (ESI) m/z 556 [MþNa]þ.
Compound 16: [
a]
þ24 (c 1.0, CHCl3, 26 ꢁC).
D
4.3.6. Synthesis of diketopiperazine 17 (method A). Compound 17
was synthesized according to the protocol used for the synthesis of
ent-19 (vide infra). The 1H NMR data were as follows.
23 ꢁC)
d
: ꢀ5.4, 18.7, 26.1, 27.4, 28.3, 32.1, 32.5, 58.8, 63.3, 64.4, 83.7,
84.3, 115.4, 115.6, 119.4, 123.0, 124.7, 124.8, 130.5, 135.6, 149.6, 149.7,
166.2, 166.5.
Compound 17: 1H NMR (400 MHz, CDCl3, 24 ꢁC)
d: 2.34 (dd,
J¼4.0, 7.0 Hz, 1H), 3.00 (s, 3H), 3.27 (dd, J¼9.5, 14.4 Hz, 1H),
3.49e3.56 (m, 2H), 3.83e3.88 (m, 2H), 4.28 (dt, J¼2.8, 13.5 Hz, 1H),
5.96 (br s, 1H), 7.09 (d, J¼2.4 Hz, 1H), 7.16 (dt, J¼1.0, 8.0 Hz, 1H), 7.23
(dt, J¼1.0, 8.0 Hz, 1H), 7.39 (dd, J¼1.0, 8.0 Hz, 1H), 7.65 (dd, J¼1.0,
8.0 Hz, 1H), 8.14 (br s, 1H).
4.3.10. Synthesis of diketopiperazine 25. To a solution of diketopi-
perazine 19 (300 mg, 598 mmol) in THF (0.1 M, 6.0 mL) were added
acetic acid (0.34 mL, 6.0 mmol) and tetrabutylammonium fluoride
(1 M THF solution, 1.2 mL, 1.2 mmol). The reaction mixture was
heated to 60 ꢁC and stirred for 2 h, then cooled to room tempera-
ture, and concentrated in vacuo. The residue was purified by flash
column chromatography (chloroform/methanol¼99/1) to give
diketopiperazine 25 (257 mg, quant.) as a white solid.
4.3.7. Synthesis of diketopiperazine 18 (method B). To a solution of
dipeptide 15 (26.1 mg, 60.2 mmol) in toluene (10 mM, 6.0 mL) was
added triethylamine (0.5 mL, 3.60 mmol). The reaction mixture was
refluxed for 18 h in an autoclave (0.04 MPa). After cooling to room
temperature, the reaction mixture was concentrated in vacuo. The
crude material was purified by preparative TLC (Merk TLC silica gel
60 F254, 0.25 mmꢂ20 cmꢂ20 cm, developed twice with chloro-
form/methanol¼98/2) to give diketopiperazine 18 (3.1 mg, 13%) as
a colorless gum.
Compound 25: 1H NMR (500 MHz, CDCl3)
d: 1.51 (s, 9H,
CO2C(CH3)3), 2.99 (s, 3H, C18H), 3.26 (dd, J¼10.8, 14.2 Hz, 1H, C12H),
3.45 (dd, J¼2.8, 14.2 Hz, 1H, C12H), 3.76e3.79 (m, 2H, C15H, C17H),
3.94 (dd, J¼3.0, 12.9 Hz, 1H, C17H), 4.14 (app. d, J¼10.8 Hz, 1H, C11H),
7.03 (br s, 1H, N10H), 7.19 (t, J¼7.4 Hz, 1H, C6H), 7.26 (t, J¼7.4 Hz, 1H,
C7H), 7.59, (s, 1H, C2H), 7.59 (d, J¼7.4 Hz, 1H, C5H), 7.98 (br, 1H, C8H);
1H NMR (500 MHz, CDCl3, 25 ꢁC)
d: 0.11 (s, 3H, SiCH3), 0.12 (s, 3H,
13C NMR (125 MHz, CDCl3)
d: 27.9 (CO2C(CH3)3), 31.9 (C18), 32.3
SiCH3), 0.93 (s, 9H, SiC(CH3)3), 3.02 (s, 3H, C18H), 3.12 (dd, J¼11.1,
14.0 Hz, 1H, C12H), 3.63 (dd, J¼2.0, 14.0 Hz, 1H, C12H), 3.87 (app. s,
1H, C15H), 3.96 (dd, J¼2.3, 10.6 Hz, 1H, C17H), 4.06 (dd, J¼2.3,
10.6 Hz, 1H, C17H), 4.15 (app. d, J¼11.1 Hz, 1H, C11H), 6.01 (s, 1H,
N10H), 7.01 (s, 1H, C2H), 7.11 (t, J¼7.7 Hz, 1H, C6H), 7.20 (t, J¼7.7 Hz,
1H, C7H), 7.36 (d, J¼7.7 Hz, 1H, C5H), 7.64 (d, J¼7.7 Hz, 1H, C2H), 8.59
(C12), 55.4 (C11), 60.2 (C17), 64.2 (C15), 84.1 (CO2C(CH3)3), 115.1 (C8),
115.3 (C3), 119.0 (C5), 122.7 (C6), 124.5 (C7), 125.0 (C2), 130.1 (C4),
135.3 (C9), 149.8 (CO2C(CH3)3), 166.3 (C13), 166.9 (C16); [
a
]
D
ꢀ57 (c
1.0, CHCl3, 26 ꢁC); IR (neat) cmꢀ1: 3369 (br m), 2975 (s), 1731 (s),
1670 (s), 1652 (s).
(s, 1H, N1H); 13C NMR (125 MHz, CDCl3, 23 ꢁC)
d
: ꢀ5.20 (SiCH3),
4.3.11. Synthesis of tetracyclic compound ent-26. To a solution of
ꢀ5.17 (SiCH3), 18.8 (SiC(CH3)3), 26.2 (SiC(CH3)3), 32.5 (C18), 32.8
(C12), 56.2 (C11), 62.2 (C17), 64.2 (C15), 110.4 (C3), 111.6 (C5), 119.0
(C8), 120.0 (C6), 122.6 (C7), 123.5 (C2), 127.0 (C4), 136.7 (C9), 166.0
ent-19 (426 mg, 849 mmol) in acetonitrile (40 mM, 21 mL) was
added N-bromosuccinimide (182 mg, 102
m
mol) at ꢀ30 ꢁC. The
reaction mixture was stirred for 9.5 h at ꢀ30 ꢁC, then diluted with
(C16), 166.6 (C13); [
a]
D ꢀ86 (c 3.6, CHCl3, 24 ꢁC).
dichloromethane (50 mL), and quenched with aqueous 5% sodium

6596
E. Iwasa et al. / Tetrahedron 67 (2011) 6587e6599
bicarbonate (16 mL). The mixture was warmed to room temper-
ature. The organic layer was separated, and the aqueous layer was
extracted with dichloromethane (50 mL). The combined organic
layers were washed with brine (20 mL), and then dried over
anhydrous sodium sulfate. After concentration in vacuo, purifica-
tion by flash column chromatography (chloroform), followed
by purification by MPLC (column: Yamazen Ultra Pack, hexane/
ethyl acetate¼63/37) gave ent-26 (211.8 mg, 88%, white amor-
phous foam) and dibromide ent-28 (35.2 mg, 6%, white amor-
C
17H), 6.77 (d, J¼7.8 Hz, 1H, C2H), 7.02 (t, J¼7.5 Hz, 1H, C6H), 7.19
(d, J¼7.5 Hz, 1H, C5H), 7.22 (t, J¼7.5 Hz, 1H, C7H), 7.71 (br, 1H, C8H);
13C NMR (125 MHz, CDCl3, 25 ꢁC)
d
: ꢀ5.24 (SiCH3), ꢀ5.21 (SiCH3),
18.7 (SiC(CH3)3), 26.1 (SiC(CH3)3), 28.6 ((CH3)3COCON), 31.8 (C18),
39.8 (C12), 42.7 (C3), 57.1 (C11), 61.6 (C17), 64.6 (C15), 75.5 (C2), 82.3
((CH3)3COCON), 115.1 (C8), 123.5 (C6), 125.0 (C5), 128.7 (C7), 130.3
(C4), 143.3 (C9), 152.2 ((CH3)3COCON), 163.8 (C16), 166.2 (C13); [a]
D
ꢀ95 (c 0.35, CHCl3, 25 ꢁC); FTIR (neat) cmꢀ1: 2949 (m), 2930 (m),
2857 (m), 1711 (s), 1678 (s), 1382 (s), 1149 (s), 836 (s); HRMS
(ESI) m/z calcd for C26H39N3NaO5Si [MþNa]þ 524.25567, found:
phous foam).
1
Compound ent-26: H NMR (500 MHz, CDCl3, 24 ꢁC)
d
: 0.11 (s,
524.25414.
1
6H, Si(CH3)2), 0.90 (s, 9H, SiC(CH3)3), 1.57 (s, 9H, (CH3)3COCON),
2.83 (t, J¼12.3 Hz, 1H, C12H), 2.91 (s, 3H, C18H), 3.12 (dd, J¼4.1,
11.9 Hz, 1H, C12H), 3.77 (dd, J¼4.1, 12.3 Hz, 1H, C11H), 3.92 (dd,
J¼2.8, 10.1 Hz, 1H, C17H), 3.98 (app. s, 1H, C15H), 4.27 (dd, J¼1.0,
10.1 Hz, 1H, C17H), 6.83 (s, 1H, C2H), 7.09 (dt, J¼0.9, 7.8 Hz, 1H,
C6H), 7.27 (dt, J¼0.9, 7.8 Hz, 1H, C7H), 7.40 (app. d, J¼7.8 Hz, 1H,
Compound 31: H NMR (500 MHz, CDCl3, 24 ꢁC)
d
: 1.58 (s, 9H,
(CH3)3COCON), 2.30 (ddd, J¼8.1, 11.9, 11.9 Hz, 1H, C12H), 2.52 (dd,
J¼5.1, 11.9 Hz, 1H, C12H), 2.57 (br s, 1H, OH), 3.00 (s, 3H, C18H),
3.88e3.94 (m, 2H, C11H and C17H), 4.00e4.03 (m, 2H, C3H and
C15H), 4.23 (ddd, J¼2.3, 6.9, 11.0 Hz, 1H, C17H), 6.76 (d, J¼7.8 Hz,
1H, C2H), 7.03 (t, J¼7.4 Hz, 1H, C6H), 7.20 (d, J¼7.4 Hz, 1H, C7H),
7.22 (t, J¼7.4 Hz, 1H, C5H), 7.68 (br s, 1H, C8H); 13C NMR
C5H), 7.70 (br, 1H, C8H); 13C NMR (125 MHz, CDCl3, 26 ꢁC)
d
: ꢀ5.27
(SiCH3), ꢀ5.12 (SiCH3), 18.7 (SiC(CH3)3), 26.2 (SiC(CH3)3), 28.4
((CH3)3COCON), 31.7 (C18), 50.5 (C12), 58.4 (C11), 59.6 (C3), 61.4
(C17), 64.3 (C15), 83.0 ((CH3)3COCON), 84.0 (C2), 115.4 (C8), 124.2
(C6), 125.3 (C5), 130.9 (C7), 131.0 (C4), 142.2 (C9), 151.6
(125 MHz, CDCl3, 25 ꢁC)
d: 28.5 ((CH3)3COCON), 31.8 (C18), 39.1
(C12), 42.8 (C3), 57.2 (C11), 60.3 (C17), 64.0 (C15), 75.5 (C2), 82.4
((CH3)3COCON), 115.2 (C8), 123.5 (C6), 124.8 (C5), 128.7 (C7), 130.3
(C4), 143.1 (C9), 152.1 ((CH3)3COCON), 164.4 (C16), 166.8 (C13); [a]
D
((CH3)3COCON), 163.9 (C16), 164.6 (C13); [
a
]
þ132 (c 1.0, CHCl3,
ꢀ125 (c 0.12, CHCl3, 26 ꢁC); FTIR (neat) cmꢀ1: 3408 (br), 2977 (m),
2927 (m), 1710 (s), 1659 (s), 1381 (s), 1149 (s), 753 (s); HRMS (ESI)
m/z calcd for C20H25N3NaO5 [MþNa]þ 410.16919, found:
410.17098.
D
25 ꢁC); FTIR (neat) cmꢀ1: 2953 (m), 2931 (m), 2886 (m), 2857 (m),
1717 (s), 1689 (s), 1668 (s), 1374 (s), 1152 (s), 754 (s); HRMS (ESI)
m/z calcd for C26H38BrN3NaO5Si [MþNa]þ 602.16618, found:
602.16369.
Compound 26: [
a]
ꢀ112 (c 1.0, CHCl3, 25 ꢁC).
4.3.14. Synthesis of octacyclic compound 36. To a solution of ent-26
(377 mg, 650 mmol) in dry acetone saturated with nitrogen was
D
1
Compound ent-28: H NMR (500 MHz, CDCl3, 25 ꢁC)
d: 0.11 (s,
6H), 0.90 (s, 9H), 1.56 (s, 9H), 2.82 (t, J¼12.0 Hz, 1H), 2.92 (s, 3H),
3.09 (dd, J¼4.4, 12.0 Hz, 1H), 3.78 (dd, J¼4.4, 12.0 Hz, 1H), 3.92 (dd,
J¼2.6, 10.0 Hz, 1H), 3.98 (app. s, 1H), 4.27 (app. d, J¼10.0 Hz, 1H),
6.81 (s, 1H), 7.37 (dd, J¼2.1, 8.6 Hz, 1H), 7.52 (app. d, J¼2.1 Hz, 1H),
7.61 (br, 1H).
added CoCl(PPh3)3 (1.14 g, 1.29 mmol) at room temperature under
a nitrogen atmosphere. The mixture was stirred for 3 h at room
temperature, then water (20 mL) was added for quenching. The
organic solvent was removed in vacuo. The obtained suspension
was extracted with dichloromethane (3ꢂ30 mL). The combined
organic layers were washed with water (50 mL) and brine (30 mL),
and then dried over anhydrous sodium sulfate. After concentration
in vacuo, purification by flash column chromatography (hexane/
ethyl acetate¼70/30) and GPC was carried out to give 36 (152 mg,
47%, white amorphous foam) and reduced by-product ent-30
4.3.12. Synthesis of tetracyclic compound 27. Compound 27 was
synthesized according to the protocol used for the synthesis of ent-
26, but with DKP 25 as the starting material. The analytical data
were as follows.
Compound 27: 1H NMR (400 MHz, CDCl3, 24 ꢁC)
d
: 1.59 (9H),
(31.2 mg, 10%, white amorphous foam).
1
2.95 (t, J¼12.4 Hz, 1H), 2.99 (s, 3H), 3.19 (dd, J¼4.8, 12.1 Hz, 1H), 3.82
(dd, J¼4.8,12.1 Hz,1H), 3.95 (br,1H), 4.00 (br, 1H), 4.24 (br, 1H), 6.80
(s, 1H), 7.12 (t, J¼7.2 Hz, 1H), 7.30 (app. dt, J¼1.5, 7.2 Hz, 1H), 7.43
(d, J¼7.2 Hz, 1H), 7.70 (br, 1H).
Compound 36: H NMR (500 MHz, CDCl3, 60 ꢁC)
d
: 0.10 (s, 6H,
SiCH3), 0.12 (s, 6H, SiCH3), 0.91 (18H, s, SiC(CH3)3), 1.61 (s, 18H,
(CH3)3COCON), 2.39 (t, J¼11.9 Hz, 2H, C12H), 2.81 (dd, J¼4.9, 11.9 Hz,
2H, C12H), 2.97 (s, 6H, C18H), 3.82 (dd, J¼4.9, 11.9 Hz, 2H, C11H), 3.86
(app. br s, 2H, C15H), 4.08 (dd, J¼2.5, 11.0 Hz, 2H, C17H), 4.28 (dd,
J¼2.8,11.0 Hz, 2H, C17H), 6.47 (s, 2H, C2H), 6.83 (t, J¼7.4 Hz, 2H, C6H),
7.05 (t, J¼7.4 Hz, 2H, C7H), 7.23 (d, J¼7.4 Hz, 2H, C5H), 7.48 (d,
4.3.13. Synthesis of 31. A solution of 26 (332 mg, 570
butyltin hydride (180 L, 690
mol), and 2,20-azobisisobutyronitrile
(11.5 mg, 69 mol) in toluene (5.8 mL) was heated to reflux for 3.5 h
mmol), tri-n-
m
m
m
J¼7.4 Hz, 2H, C8H); 13C NMR (125 MHz, CDCl3, 60 ꢁC)
: ꢀ5.24
d
under a nitrogen atmosphere. The reaction mixture was concen-
trated in vacuo. The resulting residue was purified by flash column
chromatography (chloroform) to give reduced 30 (261 mg, 91%) as
a white solid.
(SiCH3), ꢀ5.00 (SiCH3), 18.6 (SiC(CH3)3), 26.2 (SiC(CH3)3), 28.5
((CH3)3COCON), 31.1(C18), 38.8 (C12), 58.4(C11), 58.7(C3), 61.7(C17),
63.8(C15), 78.5 (C2), 82.5 ((CH3)3COCON),116.1 (C8), 122.7 (C5), 123.4
(C6), 129.8 (C7), 130.1 (C4), 143.4 (C9), 151.4 ((CH3)3COCON), 162.6
To a solution of 30 (198 mg, 0.39 mmol) in dry THF (10 mM,
(C16), 166.2 (C13); [
a
]
D þ213 (c 1.8, CHCl3, 25 ꢁC); FTIR (neat) cmꢀ1
:
4 mL) were added acetic acid (60
lammonium fluoride (1 M THF solution, 800
m
L, 1.0 mmol) and tetrabuty-
2953 (m), 2931 (m), 2887 (m), 2857 (m), 1715 (s), 1678 (m), 1155 (s),
752 (s); HRMS (ESI) m/z calcd for C52H76N6NaO10Si2 [MþNa]þ
1023.50591, found: 1023.50647.
m
L, 0.8 mmol) at 0 ꢁC.
The reaction mixture was stirred for 4 h at room temperature under
a nitrogen atmosphere, then concentrated in vacuo. The obtained
residue was purified by column chromatography (chloroform/
methanol¼100/0 to 98/2) to give 31 (180 mg, quant.) as a white
solid. Recrystallization from hexane/ethyl acetate afforded a crystal
Compound ent-30: [
a]
D þ96 (c 1.3, CHCl3, 26 ꢁC).
4.3.15. Synthesis of 37. To a solution of 36 (6.5 mg, 6.5
mmol) in THF
was added 1.0 M lithium tert-butoxide in hexane solution (30
m
L) at
suitable for X-ray structural analysis.
ꢀ40 ꢁC. After having been stirred for 10 min, the reaction mixture
turned orange, then the reaction was quenched with pH 7.0 phos-
phate buffer. The aqueous layer was extracted with ethyl acetate.
The combined organic layers were washed with brine and dried
over anhydrous sodium sulfate. After concentration in vacuo, pu-
rification by flash column chromatography (chloroform/ethyl
1
Compound 30: H NMR (500 MHz, CDCl3, 25 ꢁC)
d
: 0.07 (s, 3H,
SiCH3), 0.09 (s, 3H, SiCH3), 0.89 (9H, s, SiC(CH3)3), 1.58 (s, 9H,
(CH3)3COCON), 2.26 (ddd, J¼8.3, 11.8, 11.8 Hz, 1H, C12H), 2.45 (dd,
J¼4.8, 11.8 Hz, 1H, C12H), 2.94 (s, 3H, C18H), 3.89e3.95 (m, 3H, C3H,
C11H, C17H), 3.98 (app. s, 1H, C15H), 4.26 (dd, J¼1.4, 10.1 Hz, 1H,

E. Iwasa et al. / Tetrahedron 67 (2011) 6587e6599
6597
acetate¼5/1 to 3/1) was carried out to give 37 (3.0 mg, 63%) as
(125 MHz, CDCl3, 25 ꢁC)
(SiC(CH3)3), 25.9 (SiC(CH3)3), 27.9 (C18), 28.3 ((CH3)3COCON), 51.7
(C12), 58.3 (C3), 63.2 (C17), 83.1 ((CH3)3COCON), 85.4 (C15), 85.5 (C2),
87.6 (C11), 117.3 (C8), 124.1 (C5), 124.6 (C6), 130.5 (C7), 134.3 (C4),
d
: ꢀ5.44 (SiCH3), ꢀ5.24 (SiCH3), 18.3
a white solid.
1
Compound 37: H NMR (500 MHz, CDCl3, 25 ꢁC)
d
: 1.61 (s, 9H,
(CH3)3COCON), 2.35 (t, J¼11.9 Hz, 1H, C12H), 2.77 (dd, J¼5.2, 11.9 Hz,
1H, C12H), 3.13 (s, 3H, C18H), 3.95 (dd, J¼5.2, 11.9 Hz, 1H, C11H), 4.90
(s, 1H, C17H), 5.79 (s, 1H, C17H), 6.64 (s, 1H, C2H), 6.89 (t, J¼7.5 Hz,
141.0 (C9), 152.1 ((CH3)3COCON), 163.7 (C16), 167.9 (C13); [
a]
þ139
D
(c 1.0, CHCl3, 25 ꢁC); FTIR (neat) cmꢀ1: 3402 (br), 2954 (m), 2923
(m), 2883 (m), 2847 (m), 1710 (s), 1389 (s), 1155 (s), 842 (s); HRMS
(ESI) m/z calcd for C26H38BrN3NaO7Si [MþNa]þ 634.15601, found:
634.15453.
1H, C6H), 7.11 (t, J¼7.5 Hz, 1H, C7H), 7.21 (d, J¼7.5 Hz, 1H, C5H), 7.49
13
(br, 1H, C8H); C NMR (125 MHz, CDCl3, 25 ꢁC)
d
: 28.3 ((CH3)3CO-
CON), 29.9 (C18), 38.7 (C12), 58.0 (C11), 58.1 (C3), 78.6 (C2), 82.7
((CH3)3COCON), 103.8 (C17), 116.4 (C8), 123.3 (C5), 123.4 (C7), 129.4
(C4), 129.9 (C6), 138.3 (C15), 143.2 (C9), 151.3 ((CH3)3COCON), 156.2
ent-Diol 42a: [
a
]
D ꢀ134 (c 1.0, CHCl3, 26 ꢁC).
Diol 42b: 1H NMR (500 MHz, THF-d8, 25 ꢁC)
d: ꢀ0.27 (s, 3H,
(C15), 163.9 (C13); [
a
]
D
ꢀ190 (c 5.2, CHCl3, 23 ꢁC).
SiCH3), ꢀ0.11 (s, 3H, SiCH3), 0.59 (s, 9H, SiC(CH3)3), 1.58 (s, 9H,
(CH3)3COCON), 2.84 (s, 3H, C18H), 3.10 (d, J¼15.1 Hz, 1H, C12H), 3.56
(d, J¼10.1 Hz, 1H, C17H), 3.62 (d, J¼15.1 Hz, 1H, C12H), 4.08 (d,
J¼10.1 Hz, 1H, C17H), 5.74 (br s, 1H, C15OH), 6.47 (s, 1H, C2H), 6.52 (s,
1H, C11OH), 6.98 (dt, J¼0.9, 7.8 Hz, 1H, C7H), 7.16 (dt, J¼1.4, 7.8 Hz,
1H, C6H), 7.36 (dd, J¼0.9, 7.8 Hz, 1H, C5H), 7.62 (br, 1H, C8H); 13C
4.3.16. Synthesis of tribromide 38. To a solution of 30 (16.6 mg,
33.1 mol) and N-bromosuccinimide (17.6 mg, 99.4 mol) in carbon
tetrachloride (1.1 mL, 30 mM) was added V-70 (2.1 mg, 6.8 mol) at
m
m
m
room temperature. The mixture was stirred for 2 h at room tem-
perature, then precipitated succinimide was filtered off through
a cotton plug and washed with carbon tetrachloride. Concentration
in vacuo afforded crude 38 (single isomer) together with residual
succinimide (27.8 mg).
NMR (125 MHz, THF-d8, 25 ꢁC)
d: ꢀ5.47 (SiCH3), ꢀ5.02 (SiCH3), 19.0
(SiC(CH3)3), 26.4 (SiC(CH3)3), 27.2 (C18), 28.7 ((CH3)3COCON), 51.7
(C12), 60.0 (C3), 65.1 (C17), 82.7 ((CH3)3COCON), 86.6 (C2), 87.7 (C11),
87.7 (C15),118.1 (C8),125.1 (C7),125.6 (C5),131.1 (C6),136.0 (C4),141.7
Compound 38: 1H NMR (400 MHz, CDCl3, 24 ꢁC)
d: 0.09 (s, 3H),
(C9), 152.3 ((CH3)3COCON), 166.4 (C16), 167.7 (C13); [
a]
þ27 (c 1.3,
D
0.13 (s, 3H), 0.84 (9H, s), 1.73 (s, 9H), 3.16 (s, 3H), 4.10 (d, J¼10.9 Hz,
1H), 4.67 (d, J¼7.9 Hz, 1H), 4.70 (d, J¼10.9 Hz, 1H), 5.31 (s, 1H), 7.03
(d, J¼7.9 Hz, 1H), 7.09 (t, J¼7.2 Hz, 1H), 7.26e7.34 (m, 2H), 7.79 (d,
J¼7.2 Hz, 1H).
CHCl3, 26 ꢁC); FTIR (neat) cmꢀ1: 3358 (br), 2953 (m), 2931 (m),
2883 (m), 2857 (m), 1710 (s), 1368 (s), 1156 (s), 841 (s); HRMS (ESI)
m/z calcd for C26H38BrN3NaO7Si [MþNa]þ 634.15601, found:
634.15722.
Diol 42c: 1H NMR (500 MHz, CDCl3, 25 ꢁC)
d: ꢀ0.11 (s, 3H, SiCH3),
4.3.17. Synthesis of diol 42. To a solution of ent-26 (2.02 g,
3.48 mmol) and N-bromosuccinimide (1.26 g, 7.06 mmol) in carbon
tetrachloride (30 mM, 115 mL) was added V-70 (2,20-azobis(4-
methoxy-2,4-dimethylvaleronitrile), 255 mg, 0.83 mmol) at room
temperature. After having been stirred for 5 h at room temperature,
the reaction mixture was filtered through a cotton plug and the
remaining solid was washed with carbon tetrachloride. After re-
moval of the solvent in vacuo, crude tribromide 41 was obtained
almost quantitatively.
ꢀ0.06 (s, 3H, SiCH3), 0.75 (s, 9H, SiC(CH3)3), 1.62 (s, 9H, (CH3)3CO-
CON), 2.98 (s, 3H, C18H), 3.14 (dd, J¼2.3, 13.8 Hz, 1H, C12H), 3.49 (d,
J¼13.8 Hz, 1H, C12H), 3.61 (d, J¼10.6 Hz, 1H, C17H), 3.76 (d,
J¼10.6 Hz, 1H, C17H), 4.41 (d, J¼2.3 Hz, 1H, C11OH), 4.44 (s, 1H,
C15OH), 6.76 (s, 1H, C2H), 7.13 (dt, J¼0.9, 7.6 Hz, 1H, C6H), 7.26 (dt,
J¼1.4, 7.6 Hz, 1H, C7H), 7.45 (dd, J¼1.4, 7.6 Hz, 1H, C5H), 7.58 (br, 1H,
C8H); 13C NMR (125 MHz, CDCl3, 25 ꢁC)
d: ꢀ5.88 (SiCH3), ꢀ5.75
(SiCH3), 18.7 (SiC(CH3)3), 26.0 (SiC(CH3)3), 27.0 (C18), 28.3
((CH3)3COCON), 51.3 (C12), 58.3 (C3), 65.9 (C17), 82.9 ((CH3)3COCON),
84.7 (C15), 85.2 (C2), 88.0 (C11), 117.2 (C8), 124.3 (C5), 124.7 (C6), 130.1
(C7), 134.6 (C4), 140.6 (C9), 151.8 ((CH3)3COCON), 164.9 (C13), 166.3
The crude product 41 was dissolved in MeCN/10 mM pH 7.0
phosphate buffer¼1/1 (140 mL, 25 mM) at room temperature. After
having been stirred for 3 h, the reaction mixture was diluted with
ethyl acetate (3ꢂ100 mL). The separated organic layer was washed
with brine (100 mL) and then dried over anhydrous sodium sulfate.
After concentration in vacuo, purification by flash column chro-
matography (chloroform/ethyl acetate¼80/20) was carried out to
give a mixture of two diastereomers 42a, 42b (42a/42b¼87/13,
1.15 g, 54%, white solid). Recovered unpurified mixture of more
polar compounds was subjected to MPLC (column: Yamazen High
Flash, hexane/ethyl acetate¼20/80 and Kusano pre-packed SiO2
column, hexane/ethyl acetate¼50/50) to give other diastereomers
42c (53.4 mg, 3%), 42d (39.3 mg, 2%), and by-products 43 (64.4 mg,
3%) and 44 (102 mg, 6%). Preparative chiral HPLC (Chiralpak IC
(2 cm ɸꢂ25 cm), hexane/2-propanol¼95/5, 6 mL/min) separated
stereoisomers 42a and 42b. The major compound, 42a, was
obtained in 47% yield as a white solid, which was used in the fol-
lowing step.
(C16); [
a
]
þ121 (c 1.2, CHCl3, 24 ꢁC); FTIR (neat) cmꢀ1: 3366 (br),
D
2953 (m), 2931 (m), 2884 (m), 2859 (m), 1719 (s), 1677 (s), 1389 (s),
1156 (s), 838 (s); HRMS (ESI) m/z calcd for C26H38BrN3NaO7Si
[MþNa]þ 634.15601, found: 634.15445.
Diol 42d: 1H NMR (500 MHz, CDCl3, 23 ꢁC)
d: 0.16 (s, 6H,
Si(CH3)2), 0.92 (s, 9H, SiC(CH3)3), 1.63 (s, 9H, (CH3)3COCON), 2.87 (s,
3H, C18H), 3.32 (d, J¼15.1 Hz,1H, C12H), 3.67 (d, J¼15.1 Hz,1H, C12H),
3.70 (d, J¼10.6 Hz, 1H, C17H), 3.77 (d, J¼10.6 Hz, 1H, C17H), 4.04 (s,
1H, C15OH), 5.28 (s, 1H, C11OH), 6.57 (s, 1H, C2H), 7.10 (t, J¼7.4 Hz,
1H, C6H), 7.28 (t, J¼7.4 Hz, 1H, C7H), 7.39 (d, J¼7.4 Hz, 1H, C5H), 7.64
(br, 1H, C8H); 13C NMR (125 MHz, CDCl3, 25 ꢁC)
d
: ꢀ5.49 (SiCH3),
ꢀ5.46 (SiCH3), 18.8 (SiC(CH3)3), 26.0 (SiC(CH3)3), 27.0 (C18), 28.4
((CH3)3COCON), 49.9 (C12), 57.3 (C3), 65.7 (C17), 83.0 ((CH3)3CO-
CON), 85.0 (C15), 85.5 (C2), 87.2 (C11), 116.8 (C8), 124.7 (C5), 124.7
(C6), 130.6 (C7), 134.8 (C4), 139.8 (C9), 151.7 ((CH3)3COCON), 165.0
(C13), 166.6 (C16); [
a
]
þ21 (c 0.97, CHCl3, 25 ꢁC); IR (neat) cmꢀ1
:
D
Tribromide 41: 1H NMR (400 MHz, CDCl3, 23 ꢁC)
d: 0.09 (s, 3H),
3344 (br), 2954 (m), 2932 (m), 2886 (m), 2859 (m), 1725 (s), 1687
(s), 1391 (s), 1158 (s), 838 (s); HRMS (ESI) m/z calcd for
C26H38BrN3NaO7Si [MþNa]þ 634.15601, found: 634.15600.
0.13 (s, 3H), 0.85 (9H, s), 1.62 (s, 9H), 3.21 (s, 3H), 3.46 (d, J¼15.0 Hz,
1H), 3.83 (d, J¼15.0 Hz, 1H), 4.10 (d, J¼10.9 Hz, 1H), 4.65 (d,
J¼10.9 Hz, 1H), 6.74 (s, 1H), 7.19 (t, J¼7.7 Hz, 1H), 7.37 (t, J¼7.7 Hz,
1H), 7.49 (d, J¼7.7 Hz, 1H), 7.78 (d, J¼7.7 Hz, 1H).
Compound 43: 1H NMR (500 MHz, CDCl3, 23 ꢁC)
d
: ꢀ0.14 (s, 3H,
SiCH3), ꢀ0.04 (s, 3H, SiCH3), 0.60 (s, 9H, SiC(CH3)3), 1.68 (s, 9H,
(CH3)3COCON), 3.11 (s, 3H, C18H), 3.87 (d, J¼10.3 Hz, 1H, C17H), 4.09
(d, J¼10.3 Hz, 1H, C17H), 5.61 (br s, 1H, C15OH), 7.09e7.10 (m, 1H,
C12H), 7.12e7.19 (m, 2H, C6H, C7H), 7.34e7.35 (m, 1H, C5H), 7.82 (d,
Diol 42a: 1H NMR (500 MHz, CDCl3, 25 ꢁC)
d: 0.13 (s, 3H, SiCH3),
0.14 (s, 3H, SiCH3), 0.90 (s, 9H, SiC(CH3)3), 1.60 (s, 9H, (CH3)3CO-
CON), 3.00 (s, 3H, C18H), 3.18 (d, J¼14.2 Hz, 1H, C12H), 3.43 (d,
J¼14.2 Hz, 1H, C12H), 3.82 (br s, 1H, OH), 4.09 (d, J¼11.0 Hz, 1H,
C17H), 4.14 (d, J¼11.0 Hz,1H, C17H), 4.57 (br s,1H, C15OH), 6.63 (s,1H,
C2H), 7.14 (t, J¼7.8 Hz, 1H, C6H), 7.31 (dt, J¼0.9, 7.8 Hz, 1H, C7H), 7.44
(app. d, J¼7.8 Hz, 1H, C5H), 7.66 (d, J¼7.8 Hz, 1H, C8H); 13C NMR
J¼8.3 Hz, 1H, C8H); 13C NMR (125 MHz, CDCl3, 25 ꢁC)
: ꢀ5.76
d
(SiCH3), ꢀ5.64 (SiCH3), 17.8 (SiC(CH3)3), 25.5 (SiC(CH3)3), 26.6 (C18),
28.2 ((CH3)3COCON), 64.7 (C17), 85.3 ((CH3)3COCON), 87.5 (C15),
110.0 (C12), 115.5 (C8), 115.6 (C2), 119.6 (C5), 121.3 (C4), 123.6 (C6),

6598
E. Iwasa et al. / Tetrahedron 67 (2011) 6587e6599
124.9 (C7), 125.4 (C3), 134.4 (C11), 140.2 (C9), 148.7 ((CH3)3COCON),
(C16), 168.5 (C13); [
a
]
þ99 (c 0.59, CHCl3, 25 ꢁC); IR (neat) cmꢀ1
:
D
157.9 (C13), 163.5 (C16); [
a
]
þ1.2 (c 1.00, CHCl3, 24 ꢁC); IR (neat)
3256 (br), 2953 (m), 2931 (m), 2883 (m), 2857 (m), 1710 (s), 1391
(s), 1156 (s), 839 (s); HRMS (ESI) m/z calcd for C26H39N3NaO7Si
[MþNa]þ 556.24550, found: 556.24623.
D
cmꢀ1: 3260 (br m), 2932 (m), 1741 (s); HRMS (ESI) m/z calcd for
C26H35N3NaO6Si [MþNa]þ 536.21928, found: 536.21851.
1
Compound 44: H NMR (500 MHz, CDCl3, 25 ꢁC)
d
: 0.13 (s, 6H,
Compound ent-46: [
a]
D ꢀ86 (c 0.64, CHCl3, 24 ꢁC).
Si(CH3)2), 0.91 (s, 9H, SiC(CH3)3), 1.60 (s, 9H, (CH3)3COCON), 2.84 (t,
J¼12.2 Hz, 1H, C12H), 2.96 (s, 3H, C18H), 3.24 (dd, J¼4.8, 12.2 Hz, 1H,
C12H), 3.46 (br s, 1H, C15OH), 3.81 (d, J¼9.6 Hz, 1H, C17H), 3.91 (dd,
J¼4.8, 12.2 Hz, C11H), 4.05 (d, J¼9.6 Hz, 1H, C17H), 6.73 (s, 1H, C2H),
7.13 (t, J¼7.4 Hz, 1H, C6H), 7.31 (dt, J¼0.93, 7.4 Hz, 1H, C7H), 7.43
(app. d, J¼7.4 Hz, 1H, C5H), 7.67 (br, 1H, C8H); 13C NMR (125 MHz,
4.3.19. Synthesis of chaetocin (1). Hydrogen sulfide (bp ꢀ60 ꢁC, ca.
1 mL) was condensed at ꢀ78 ꢁC in a sealed tube capped with
a rubber septum. A solution of 45 (20.0 mg, 18.8
mmol) in
dichloromethane (0.76 mL) and boron trifluoride diethyl ether
complex (23 L, 186 mol) were added to the liquid hydrogen
m
m
CDCl3, 25 ꢁC)
d
: ꢀ5.31 (SiCH3), ꢀ5.19 (SiCH3), 18.5 (SiC(CH3)3), 26.0
sulfide. Then the rubber septum was replaced with a stopper, and
the mixture was allowed to warm to room temperature. The re-
action apparatus was placed behind a blast shield in a fume hood.
The reaction mixture was stirred for 90 min at room temperature,
then cooled to ꢀ78 ꢁC again, and the stopper was replaced with
a rubber septum having a needle connected to two traps arranged
linearly, filled with 20% aqueous sodium hydroxide. The cooling
bath was removed, and the solution was warmed to room tem-
perature. After purging with nitrogen gas, the reaction mixture was
diluted with ethyl acetate (3 mL) and washed with saturated
aqueous ammonium chloride (2 mL). The separated aqueous layer
was extracted with ethyl acetate (3ꢂ2 mL). To the combined or-
ganic layers was added a solution of 2 equiv of I2 in ethyl acetate
(50 mM, 0.73 mL) at room temperature. The organic solution
turned red immediately. It was stirred for 1 min, then 10% aqueous
sodium thiosulfate solution was added for quenching. The sepa-
rated aqueous phase was further extracted with ethyl acetate
(3ꢂ3 mL) and the combined organic phase was dried over anhy-
drous sodium sulfate. After concentration in vacuo, purification by
preparative TLC (Merck HPTLC Diol F254s, 0.25 mmꢂ10 cmꢂ10 cm,
(SiC(CH3)3), 27.2 (C18), 28.3 ((CH3)3COCON), 49.0 (C12), 58.3 (C11),
58.9 (C3), 64.7 (C17), 83.2 ((CH3)3COCON), 84.3 (C2), 85.9 (C15), 116.0
(C8), 124.5 (C6), 124.9 (C5), 131.0 (C7), 131.1 (C4), 142.1 (C9), 151.6
((CH3)3COCON), 164.6 (C16), 165.1 (C13); [
a
]
þ132 (c 0.95, CHCl3,
D
26 ꢁC); FTIR (neat) cmꢀ1: 3365 (br), 2949 (m), 2931 (m), 2883 (m),
2857 (m), 1711 (s), 1374 (s), 1153 (s), 842 (s); HRMS (ESI) m/z calcd
for C26H38BrN3NaO6Si [MþNa]þ 618.16109, found: 618.15806.
4.3.18. Synthesis of tetraol 45. Freshly prepared tris(triphenyl-
phosphine)cobalt chloride (CoCl(PPh3)3, 509 mg, 578
quickly added as a solid to a degassed (nitrogen bubbling for
10 min) solution of 42a (182 mg, 300 mol) in dry acetone (3.0 mL)
mmol) was
m
at room temperature under a nitrogen atmosphere. After 90 min,
the reaction mixture was diluted with dichloromethane (10 mL)
and quenched with saturated aqueous ammonium chloride
(10 mL). The organic layer was separated and the aqueous layer was
extracted with dichloromethane (3ꢂ10 mL). The combined organic
layers were washed with brine (10 mL) and then dried over anhy-
drous sodium sulfate. After removal of the solvent in vacuo, puri-
fication by flash column chromatography (chloroform/ethyl
acetate¼80/20 to 70/30) gave a crude mixture of 45 and 46 (2.4 mg,
3%). The obtained crude compound was subjected to purification
with MPLC system (column: High Flash M, hexane/ethyl
acetate¼70/30 to 50/50) to give pure 45 (86.6 mg, 55%) as a white
ethyl acetate) gave (þ)-chaetocin (1) (5.8 mg, 44%) as a white solid.
1
(þ)-Chaetocin (1): H NMR (500 MHz, CDCl3, 24 ꢁC)
d: 2.74 (d,
J¼15.1 Hz, 2H, C12H), 3.08 (s, 6H, C18H), 3.29 (dd, J¼6.0, 9.2 Hz, 2H,
C17OH), 3.84 (d, J¼15.1 Hz, 2H, C12H), 4.18 (dd, J¼9.2, 12.8 Hz, 2H,
C17H), 4.25 (dd, J¼6.0, 12.8 Hz, 2H, C17H), 5.25 (s, 2H, C2H), 5.25 (s,
2H, N1H), 6.74 (app. d, J¼7.5 Hz, 2H, C5H), 6.92 (dt, J¼0.9, 7.5 Hz, 2H,
C6H), 7.25 (dt, J¼1.4, 7.5 Hz, 2H, C7H), 7.42 (app. d, J¼7.5 Hz, 2H,
solid.
1
Compound 45: H NMR (400 MHz, CDCl3, 55 ꢁC)
d
: 0.17 (s, 6H,
SiCH3), 0.18 (s, 6H, SiCH3), 0.94 (s, 18H, SiC(CH3)3), 1.66 (s, 18H,
(CH3)3COCON), 2.83 (d, J¼14.1 Hz, 2H, C12H), 2.91 (d, J¼14.1 Hz, 2H,
C12H), 3.08 (s, 6H, C18H), 3.37 (s, 2H, C11OH), 4.15 (d, J¼11.0 Hz, 2H,
C17H), 4.22 (d, J¼11.0 Hz, 2H, C17H), 4.28 (s, 2H, C15OH), 6.89 (dt,
J¼1.0, 7.4 Hz, 2H, C6H), 7.10 (dt, J¼1.1, 7.4 Hz, 2H, C7H), 7.26 (app. d,
J¼7.4 Hz, 2H, C5H), 7.51 (app. d, J¼7.4 Hz 2H, C8H); 13C NMR
C8H); 13C NMR (125 MHz, CDCl3)
d: 27.5 (C18), 39.4 (C12), 60.0 (C3),
60.7 (C17), 73.5 (C11), 76.0 (C15), 80.7 (C2), 110.9 (C5), 120.5 (C6), 125.4
(C8), 127.6 (C4), 130.6 (C7), 149.3 (C9), 163.0 (C16), 165.8 (C13); [a]
D
þ537 (c 0.20, CHCl3, 26 ꢁC); IR (neat) cmꢀ1: 3374 (br), 2928 (m),
1677 (s), 751 (s); HRMS (ESI) m/z calcd for C30H28N6NaO6S4
[MþNa]þ 719.08508, found: 719.08494.
(125 MHz, CDCl3, 25 ꢁC)
(SiC(CH3)3), 25.9 (SiC(CH3)3), 27.9 (C18), 28.1 ((CH3)3COCON), 42.6
(C12), 56.7 (C3), 62.5 (C17), 79.7 (C15), 82.7 ((CH3)3COCON), 85.4 (C2),
86.8 (C11), 117.0 (C8), 122.4 (C5), 123.3 (C6), 129.7 (C7), 131.6 (C4),
d
: ꢀ5.57 (SiCH3), ꢀ5.14 (SiCH3), 18.4
ent-Chaetocin (ent-1): [
a
]
D
ꢀ527 (c 0.20, CHCl3, 24 ꢁC).
Chaetocin (1, from C. minutum): 1H NMR (500 MHz, CDCl3, 24 ꢁC)
: 2.74 (d, J¼15.2 Hz, 2H, C12H), 3.08 (s, 6H, C18H3), 3.26 (dd, J¼6.0,
d
9.6 Hz, 2H, C17OH), 3.84 (d, J¼15.1 Hz, 2H, C12H), 4.18 (dd, J¼9.6,
12.8 Hz, 2H, C17H), 4.25 (dd, J¼6.0, 12.8 Hz, 2H, C17H), 5.23 (s, 2H,
N1H), 5.25 (s, 2H, C2H), 6.74 (d, J¼7.8 Hz, 2H, C5H), 6.92 (t, J¼7.8 Hz,
141.7 (C9), 151.2 ((CH3)3COCON), 163.1 (C13),169.1 (C16); [
a
]
D þ182 (c
1.0, CHCl3, 24 ꢁC); IR (neat) cmꢀ1: 3367 (br), 2954 (m), 2932 (m),
2890 (m), 2858 (m), 1717 (s), 1390 (s), 1367 (s), 1157 (s), 841 (s);
HRMS (ESI) m/z calcd for C52H76N6NaO14Si2 [MþNa]þ 1087.48557,
found: 1087.48134.
2H, C6H), 7.25 (t, J¼7.8 Hz, 2H, C7H), 7.42 (d, J¼7.8 Hz, 2H, C8H); [
þ530 (c 0.04, CHCl3, 26 ꢁC).
a]
D
Compound ent-45: [
a]
ꢀ217 (c 1.0, CHCl3, 25 ꢁC).
4.3.20. Synthesis of asymmetric dimer 48. Asymmetric dimer 48
was synthesized according to the method used for 45. The analyt-
ical data were as follows.
D
Reduced by-product 46: 1H NMR (500 MHz, CDCl3, 23 ꢁC)
d: 0.06
(s, 3H, SiCH3), 0.09 (s, 3H, SiCH3), 0.85 (s, 9H, SiC(CH3)3), 1.56 (s, 9H,
(CH3)3COCON), 2.47 (dd, J¼7.8,13.8 Hz,1H, C12H), 2.67 (d, J¼13.8 Hz,
1H, C12H), 2.94 (s, 3H, C18H), 3.84 (d, J¼10.4 Hz, 1H, C17H), 3.99 (t,
J¼7.8 Hz, 1H, C3H), 4.09 (s, 1H, C11OH), 4.23 (d, J¼10.4 Hz, 1H, C17H),
5.00 (s, 1H, C15OH), 6.60 (d, J¼7.8 Hz, 1H, C2H), 7.01 (t, J¼7.8 Hz, 1H,
C6H), 7.18 (d, J¼7.8 Hz, 1H, C5H), 7.21 (t, J¼7.8 Hz, 1H, C7H), 7.68 (d,
Compound 48: 1H NMR (500 MHz, CDCl3, 25 ꢁC)
d: ꢀ0.54 (s, 3H),
ꢀ0.41 (s, 3H), 0.15 (s, 3H), 0.18 (s, 3H), 0.59 (s, 9H), 0.94 (s, 9H), 1.59
(s, 9H), 1.69 (s, 9H), 2.85 (s, 3H), 2.89 (app. dd, J¼1.9, 14.2 Hz, 1H),
3.01 (s, 3H), 3.08 (d, J¼14.2 Hz, 1H), 3.35 (d, J¼14.7 Hz, 1H), 3.57 (d,
J¼10.4 Hz, 1H), 3.73 (d, J¼10.6 Hz, 1H), 3.80 (d, J¼10.4 Hz, 1H), 3.89
(d, J¼14.7 Hz, 1H), 4.37 (d, J¼10.6 Hz, 1H), 4.67 (s, 1H), 5.81 (br s,
1H), 6.07 (s, 1H), 6.54 (s, 1H), 6.57 (br s, 1H), 6.75 (app. dt, J¼1.0,
7.8 Hz, 1H), 6.84 (app. dt, J¼0.9, 7.8 Hz, 1H), 6.94 (app. dt, J¼1.0,
8.3 Hz, 1H), 6.96e6.99 (m, 2H), 7.10 (d, J¼7.3 Hz, 1H), 7.14 (s, 1H),
7.30 (d, J¼7.4 Hz,1H), 7.32 (br,1H); 13C NMR (125 MHz, CDCl3, 26 ꢁC)
J¼7.8 Hz, 1H, C8H); 13C NMR (125 MHz, CDCl3, 25 ꢁC)
: ꢀ5.50
d
(SiCH3), ꢀ5.27 (SiCH3), 18.3 (SiC(CH3)3), 25.9 (SiC(CH3)3), 27.7 (C18),
28.3 ((CH3)3COCON), 41.6 (C3), 42.3 (C12), 63.5 (C17), 77.5 (C2), 82.3
((CH3)3COCON), 86.0 (C15), 87.6 (C11), 116.6 (C8), 123.6 (C6), 123.8
(C5), 128.3 (C7), 132.9 (C4), 142.2 (C9), 152.4 ((CH3)3COCON), 163.9

E. Iwasa et al. / Tetrahedron 67 (2011) 6587e6599
6599
€
10. (a) Wrobel, J. T. In The Alkaloids: Chemistry and Physiology; Brossi, A., Ed.; Ac-
ademic: New York, NY, 1985; Vol. 26, pp 53e87; (b) Hino, T.; Nakagawa, M. In
The Alkaloids: Chemistry and Pharmacology; Brossi, A., Ed.; Academic: New York,
NY, 1988; Vol. 34, pp 1e75; (c) Wrobel, J. T.; Wojtasiewicz, K. In The Alkaloids:
Chemistry and Pharmacology; Cordell, G. A., Ed.; Academic: New York, NY, 1992;
Vol. 42, pp 249e297; (d) Anthoni, U.; Christophersen, C.; Nielsen, P. H. In Al-
kaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Pergamon:
New York, NY, 1999; Vol. 13, pp 163e236; (e) Gardiner, M. D.; Waring, P.;
Howlett1, B. J. Microbiology 2005, 151, 1021e1032; (f) Rezanka, T.; Sobotka, M.;
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E.; Hamashima, Y.; Sodeoka, M. Isr. J. Chem. 2011, 51, 420e433.
d
: ꢀ6.34, ꢀ6.08, ꢀ5.63, ꢀ5.11, 18.2, 18.6, 25.9, 26.0, 27.1, 27.4, 28.1,
28.5, 41.7, 44.9, 56.7, 56.9, 62.7, 65.8, 79.7, 80.1, 82.0, 84.2, 85.1, 85.9,
86.7, 86.9, 115.7, 116.2, 122.0, 122.6, 123.4, 123.8, 128.7, 129.2, 131.5,
133.4, 139.4, 141.9, 151.1, 152.8, 162.7, 165.7, 170.1; [
a
]
D ꢀ118 (c 0.75,
CHCl3, 24 ꢁC); FTIR (neat) cmꢀ1: 3361 (br m), 2927 (m), 1711 (m),
1657 (s).
4.3.21. Synthesis of chaetocin analogue 52. Chaetocin analogue 52
was synthesized according to the method used for chaetocin (1).
The analytical data were as follows.
11. (a) Kishi, Y.; Fukuyama, T.; Nakatsuka, S. J. Am. Chem. Soc. 1973, 95, 6490e6492;
(b) Kishi, Y.; Nakatsuka, S.; Fukuyama, T.; Havel, M. J. Am. Chem. Soc. 1973, 95,
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12. DeLorbe, J. E.; Jabri, S. Y.; Mennen, S. M.; Overman, L. E.; Zhang, F.-L. J. Am. Chem.
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47, 1485e1487.
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Org Chem. 2004, 69, 9100e9108.
Compound 52: 1H NMR (500 MHz, CDCl3, 25 ꢁC)
d: 0.13 (s, 3H),
0.14 (s, 3H), 0.91 (s, 9H), 2.64 (d, J¼14.9 Hz, 1H), 3.13 (s, 3H), 3.75 (d,
J¼14.9 Hz, 1H), 4.28 (d, J¼12.1 Hz, 1H), 4.36 (d, J¼12.1 Hz, 1H), 5.28
(s, 1H), 5.36 (s, 1H), 6.69 (d, J¼8.0 Hz, 1H), 6.88 (t, J¼8.0 Hz, 1H), 7.21
(t, J¼8.0 Hz, 1H), 7.38 (d, J¼8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3,
25 ꢁC)
d
: ꢀ5.59, ꢀ5.30, 18.4, 25.8, 28.2, 29.8, 39.9, 60.2, 60.8, 74.0,
80.9, 110.7, 120. 0, 125.5, 128.0, 130.0, 149.6, 161.9, 165.8.
4.4. Crystallography
CCDC-764669 contains the supplementary crystallographic data
for 31 and CCDC-819081 contains the supplementary crystallo-
graphic data for 42a.
19. Aurelio, L.; Box, J. S.; Brownlee, R. T. C.; Hughes, A. B.; Sleebs, M. M. J. Org. Chem.
2003, 68, 2652e2667.
Acknowledgements
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Org. Lett. 2000, 2, 3027e3029.
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5637e5639.
This work was in part supported by Project Funding from RIKEN
and a Grant-in-Aid for Scientific Research (C) 22590034.
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