Total synthesis of dictyodendrin A and B

Article abstract of DOI:10.1002/anie.201001966

(Figure Presented) In-do-line of fire: A highly efficient total synthesis of the title compounds features a novel benzyne-mediated one-pot indoline formation/cross-coupling sequence for the construction of a highly substituted key indoline intermediate. The peripheral substituents were then introduced onto the intermediate in a modular fashion to complete the total syntheses of dictyodendrin A and B.

Full text of DOI:10.1002/anie.201001966

Angewandte
Chemie
DOI: 10.1002/anie.201001966
Natural Product Synthesis
Total Synthesis of Dictyodendrin A and B**
Kentaro Okano, Hideto Fujiwara, Toshiharu Noji, Tohru Fukuyama, and Hidetoshi Tokuyama*
Dictyodendrins were isolated by Fusetani and Matsunaga
from the marine sponge Dictyodendrilla verongiformis col-
lected off Nagashima Island in Southern Japan in 2003
(Scheme 1).[1] These compounds have been the first marine
In planning the synthesis of dictyodendrins, we designed a
flexible route involving introduction of peripheral segments
on the pivotal indoline intermediate 3 (Scheme 2). Thus, the
Scheme 1. Structures of dictyodendrin A (1) and B (2).
alkaloids known to possess inhibitory activity against telo-
merase. As telomerase is expressed in most tumor cell lines
and its activity is associated with cell proliferation, telomerase
inhibition represents a potential target for cancer chemo-
therapy. These compounds have received considerable atten-
tion as synthetic targets, not only owing to their intriguing
biological activity but also to their characteristic structure,
having the highly substituted pyrrolo[2,3-c]carbazole core.
Among numerous studies toward dictyodendrin synthesis,[2]
only Fꢀrstner and co-workers[3] succeeded in the total syn-
thesis of dictyodendrins B, C, and E, which was followed by
the recent total synthesis of dictyodendrin B by Iwao and co-
workers.[4] Herein, we report the first total synthesis of
dictyodendrin A (1) and a total synthesis of B (2) which
features a hitherto unprecedented benzyne-mediated one-pot
cyclization/cross-coupling sequence.
Scheme 2. Retrosynthetic analysis of dictyodendrin A (1). PG=protect-
ing group.
carbazole skeleton would be formed by installation of an aryl
À
azide segment and intramolecular C H insertion via a nitrene
intermediate generated by thermolysis. The para-anisylace-
tate moiety in 4 could be introduced on bromoindole 5 by
regioselective Friedel–Crafts alkylation. Since the para-ani-
sylethyl group in 5 should be easily attached to the nitrogen
atom by conventional alkylation, the key issue in the synthesis
should be the construction of the highly substituted indoline
intermediate 3. The relatively high electrophilic nature of the
aromatic rings and the sterically congested environment on
the benzene ring may hamper the utilization of a classical
heterocyclic synthesis and transition-metal-catalyzed cross-
coupling reactions or amination reactions. We successfully
circumvented these problems by developing a one-pot
[*] Dr. K. Okano, H. Fujiwara, T. Noji, Prof. Dr. H. Tokuyama
Graduate School of Pharmaceutical Sciences, Tohoku University
Aoba, Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
Fax: (+81)22-795-6877
E-mail: tokuyama@mail.pharm.tohoku.ac.jp
Dr. K. Okano, Prof. Dr. T. Fukuyama, Prof. Dr. H. Tokuyama
Graduate School of Pharmaceutical Sciences, University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
benzyne-mediated
indoline
formation/cross-coupling
sequence using 2,6-dibromo-b-phenylethylamine derivative 6.
The synthesis commenced with the preparation of 7,
employing the protocol developed in our total syntheses of
duocarmycins (Scheme 3). After conversion of para-nitro-
phenol (8) into 2,6-dibromo-iodobenzene derivative 9[5] in six
steps,[6a] halogen–lithium exchange on treatment with BuLi in
toluene at À788C,[6] followed by addition to nitroolefin 11
gave Michael adduct 12 in excellent yield.[6a,d] Then, the nitro
[**] This work was financially supported by the KAKENHI, Grant-in-Aid
for Scientific Research (B; 20390003), Young Scientists (Start-up;
19890014), Young Scientists (B; 21790006), and Suntory (Sunbor
Grant). The authors thank Profs. S. Matsunaga and N. Fusetani
(University of Tokyo) for providing valuable information and their
spectral data.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201001966.
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Scheme 3. Preparation of dibromide 7 for key reaction. Reagents and
conditions: a) nBuLi (1.0 equiv), toluene, À788C, 20 min; 11
(1.0 equiv), À788C, 25 min, 90%; b) Fe (10 equiv), FeCl2 (1.0 equiv),
EtOH/1m HCl (10:1), reflux, 3.5 h; c) Boc2O (1.0 equiv), Et3N
(1.1 equiv), MeCN/H2O (10:1), RT, 20 min, 85% (2 steps). Boc=tert-
butoxycarbonyl.
Scheme 4. Working hypothesis of the benzyne-mediated one-pot indo-
line formation/cross-coupling reaction.
group was chemoselectively reduced and the resultant
primary amine was protected as Boc-carbamate to give the
desired substrate 7.
Table 1: Optimization of trapping of the generated anion species using
metalated TMP as a base.[a] TMP=2,2,6,6-tetramethylpiperidine.
With substrate 7 in hand, we then investigated the key
benzyne-mediated cyclization/arylation sequence. Our work-
ing hypothesis is shown in Scheme 4. After generation of
dianion species 13 at low temperature, benzyne formation and
cyclization should proceeded by elevating the reaction
temperature to provide 7-metalated indoline 15. We consid-
ered the possibility that the metalated species 15 should serve
as a suitable substrate for the subsequent cross-coupling to
furnish the desired 7-anisyl derivative 16. However, an
extensive literature search revealed that no example of this
type of sequential reaction has been reported so far. Whilst
several examples of benzyne-mediated cyclization/function-
alization[7] with simple electrophiles have been described,
their scope is limited owing to the use of strong bases, such as
tBuLi or sBuLi.[8]
To establish the benzyne formation/cyclization process,
substrate 7 was treated with several bases and the reaction
was quenched with DCl/D2O. We observed that the yield of
the cyclized product and the D/H ratio depended dramatically
on the choice of base (Table 1). Thus, after treatment of 7 with
LiTMP[9] at À788C for 1 hour, the reaction mixture was
allowed to warm to 08C.[10] Next, the reaction was quenched
with CD3OD at À788C. Unfortunately, the desired deuter-
ated indoline 17 was obtained in low yield with substantial
amount of byproducts[11] (Table 1, entry 1). When the reaction
was affected by [Me2Zn(TMP)]Li,[12] the yield improved
dramatically. However, the level of deuteration was not
satisfactory (Table 1, entry 2). To our delight, we found that
Mg(TMP)2·2LiBr[13] quite effectively promoted the benzyne
Entry
Base
Yield [%][b]
R=D/H[c]
1[d]
2
LiTMP
30
80
quant.
95
30:–[e]
66:14
87:13
65:30
[Me2Zn(TMP)]Li
Mg(TMP)2·2LiBr
Mg(TMP)2·2LiBr
3
4[f]
[a] Reaction conditions: base (5 equiv), THF, À788C; then 08C; DCl/
D2O, À78 to 08C. [b] Yield of isolated product. [c] The ratio was
determined by 1H NMR spectroscopy. [d] The reaction was quenched
with CD3OD. [e] Not observed. [f] Mg(TMP)2·2LiBr: three equivalents.
formation/cyclization/deuteration sequence and a mixture of
the 7-deuterated indoline 17 (87%) and 7-protonated com-
pound 18 (13%) was obtained (Table 1, entry 3). Diminished
amounts of Mg(TMP)2·2LiBr resulted in lower yields and a
lower D/H ratio (Table 1, entry 4). We reasoned that the
success of Mg(TMP)2·2LiBr was due to the relative stability
of 7-magnesiospecies 15.
We next investigated an expansion of the benzyne-
mediated indoline formation protocol into a one-pot indoline
formation/cross-coupling sequence (Scheme 4). First, direct
coupling of 7-magnesiospecies 19 was examined under
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Table 2: Key one-pot indoline formation/cross-coupling sequence.[a]
Entry
CuI [equiv]
[Pd(PPh3)4] [mol%]
16 [%][b]
18 [%][b]
1
2
3
none
10
10
10
10
20
trace
76
77
13
93 (89[c])
5 (–[c,d]
)
[a] Reaction conditions: Mg(TMP)2·2LiBr (5 equiv), THF, À788C,
15 min; À78 to 08C, 1 h; CuI, À788C, 1 h; 20 (5 equiv), [Pd(PPh3)4],
À788C; RT, 1.5 h. [b] Yield of isolated product. [c] Performed on a gram
scale. [d] Not isolated.
Kumada–Tamao coupling conditions[14] (Table 2). After for-
mation of the indoline by elevating the reaction temperature
to 08C, the reaction mixture was re-cooled to À788C. para-
Iodoanisole (20) and [Pd(PPh3)4] were then added to the
mixture. Only a low yield of the desired cross-coupling
product 16 was isolated, associated with protonated indoline
18 as the major byproduct, thus suggesting that the rate of
protonation should be faster than that of the cross-coupling
reaction (Table 2, entry 1). Screening of a variety of phos-
phorus ligands did not improve the yield of 16. Eventually, we
found that transmetalation to the copper species was crucial
for a high yielding cross-coupling process.[15] Thus, after the
formation of indoline, the reaction mixture was recooled at
À788C, and CuI, 20, and [Pd(PPh3)4] were added. The desired
product 16 was obtained in 76% yield after stirring the
mixture for two hours at room temperature (Table 2, entry 2).
In addition, the yield of 16 was improved up to 93% when
20 mol% of [Pd(PPh3)4] was used (Table 2, entry 3). The
reaction was also conducted on a gram scale to give 16 in 89%
yield.
Scheme 5. Total synthesis of dictyodendrin A (1). Reagents and con-
ditions: a) TMSOTf (2 equiv), 2,6-lutidine (10 equiv), CH2Cl2, 08C, 2 h,
95%; b) DDQ (1.0 equiv), toluene, RT, 1 h, 98%; c) para-methoxyphe-
nylethyl bromide (5 equiv), KOH (20 equiv), DMF, RT, 2 h, 97%; d) 21
À
(3 equiv), AgOTf (4 equiv), THF, À788C, 2 h, 81%; e) pinB Bpin
(3 equiv), [PdCl2(dppf)]·CH2Cl2 (5 mol%), KOAc (9 equiv), 1,4-dioxane,
reflux, 3 h; f) 22 (3 equiv), [PdCl2(dppf)]·CH2Cl2 (5 mol%), 3m NaOH
(5 equiv), 1,4-dioxane, reflux, 20 min, 63% (2 steps); g) o-C6H4Cl2,
reflux, 20 min, 79%; h) BCl3 (2.5 equiv), C6HMe5 (3 equiv), CH2Cl2,
À788C, 25 min, 92%; i) Cl3CCH2OSO2Cl (2 equiv), DABCO (3 equiv),
CH2Cl2, RT, 2 h, 93%; j) BCl3 (24 equiv), nBu4NI (24 equiv), CH2Cl2,
08C to RT, 1.5 h, 67%; k) Zn dust (4 equiv), HCO2NH4 (6 equiv),
MeOH, RT, 2 h, 98%. TMS=trimethylsilyl, DDQ=2,3-dichloro-5,6-
dicyanobenzoquinone, DMF=N,N-dimethylformamide, Tf=trifluoro-
methanesulfonyl, dppf=1,1’-bis(diphenylphosphino)ferrocene, pin=
pinacol, Ac=acetyl, DABCO=1,4-diazabicyclo[2.2.2]octane.
AgOTf at À788C. After pinacolborylation at the bromo
group of 5, the azidephenyl group[17] was introduced by
Suzuki–Miyaura coupling to give 23.[18,19a] The azide group
remained untouched under these conditions. The carbazole
skeleton was formed at this stage by thermolysis of azide 23 at
Having developed a facile preparation for the pivotal core
structure 16 using a one-pot indoline formation/cross-cou-
pling sequence, we turned our attention to the introduction of
peripheral substructures (Scheme 5). Removal of the Boc
group followed by DDQ oxidation gave the corresponding
indole, which was subjected to SN2 reaction with para-
methoxyphenylethyl bromide to give 5. Friedel–Crafts alky-
lation with 21[16] proceeded under mild conditions using
1808C and subsequent insertion of the resultant nitrene into
[19]
À
the adjacent Csp2 H bond to give tetracyclic compound 24.
The endgame strategy leading to dictyodendrin A (1) was
established by modification of protocol reported by Fꢀrstner
et al.[3a,b] The tert-butyl group was removed using boron
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trichloride in the presence of pentamethylbenzene as a non-
Keywords: arynes · cross-coupling · cyclization ·
natural products · total synthesis
.
Lewis-basic cation scavenger.[20] The resultant phenol was
converted into trichloroethylsulfamate 25. Finally, five methyl
groups[21] and a trichloroethyl group were removed to provide
dictyodendrin A (1) in 8.2% overall yield over 21 steps from
para-nitrophenol (8).
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A notable feature of this synthetic strategy is a high
flexibility for the synthesis of a broad range of dictyodendrins
and derivatives based on the facile and efficient assembly of
the molecule in a modular fashion using key intermediate 5 as
a core structure.
We demonstrated the advantage of this synthetic strategy
by application to the synthesis of dictyodendrin B (2); 12%
overall yield from para-nitrophenol (8) over 21 steps
(Scheme 6). By starting from the common bromoindole 5,
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´
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[10] In this case, a benzyne species would be generated between À20
and 08C since most of the starting material was recovered when
the reaction was run below À208C.
[11] We did not isolate the protonated indoline 18 at all, presumably
because of side-reaction via in situ protonation of the unstable 7-
lithioindoline 15 with TMP. Once pro-
Scheme 6. Total synthesis of dictyodendrin B (2). Reagents and con-
ditions: a) 26 (3 equiv), ZnCl2 (10 equiv), Et2O, 08C, 1 h, 99%.
tonation of 7-lithioindoline took place,
the second deprotonation occurred at
the other site. Then, benzyne forma-
tion and subsequent nucleophilic addi-
tion of LiTMP proceeded to give the
major byproduct.
regioselective Friedel–Crafts acylation using ZnCl2[22] gave 27,
which was then transformed into dictyodendrin B (2) in seven
steps following the established synthetic route to dictyoden-
drin A (1).[23]
In conclusion, we have accomplished a highly efficient
total synthesis of dictyodendrin A and B by development of
an unprecedented one-pot benzyne-mediated indoline for-
mation/cross-coupling sequence using transmetalation to
copper species. This methodology provides direct access to
the highly substituted indoline, which would be applicable to
various nitrogen-containing heterocyclic compounds. In addi-
tion, the highly flexible modular approach should be a
powerful tool for the synthesis of not only natural dictyoden-
drins but also a range of artificial derivatives.
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[13] Mg(TMP)2·2LiBr has been used as a selective deprotonating
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Received: April 2, 2010
Published online: July 19, 2010
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Chemie
[15] The coupling reaction required both CuI and [Pd(PPh3)4].
[16] Preparation of 21 is described in the Supporting Information.
[17] Synthesis of the azidephenyl iodide 22 was carried out from
commercially available ortho-fluoronitrobenzene in six steps.
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7508 – 7510.
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[23] For the detail, see the Supporting Information.
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