Angewandte
Communications
Chemie
Table 1: Optimization of the gold-catalyzed annulation of 1,3-diynes and
removal of the tert-butyl group. Thus, the reaction was
pyrroles.[a]
conducted on a gram scale (10d: 2.76 g; 11d: 6.69 g) with
a decreased amount of the catalyst (162 mg, 2 mol%), and
product 12dd (2.27 g) was isolated in 58% yield.[19]
Having successfully constructed the pyrrolo[2,3-c]carb-
azole core, we proceeded to investigate the total synthesis of
dictyodendrins C and F (Scheme 5), which are 2,5-dioxo
Entry 10
R1
R2
11
R3
H
Yield[b] [%] 12/13[c]
1
10a
H
H
H
H
H
H
H
H
11a
11b Bn
11c Ts
11d Boc
11d Boc
11d Boc
<62
62
34
25:75 (aa)
2
10a
10a
10a
18:82 (ab)
58:42 (ac)
92:8 (ad)
3[d]
4
60
5
10b OMe OMs
10c OMe OBn
10d OMe OtBu 11d Boc
83
68
79
75:25 (bd)
81:19 (cd)
84:16 (dd)
6[e]
7[e]
[a] Reaction conditions: 10 (1 equiv), 11 (5 equiv), [BrettPhosAu-
(MeCN)SbF6] (5 mol%), 1,2-dichloroethane (DCE), 808C. [b] Combined
1
yield of the isolated products. [c] Ratio was determined by H NMR
spectroscopy. [d] The reaction was carried out with [BrettPhosAu-
(MeCN)SbF6] (10 mol%) in 1,1,2,2-tetrachloroethane (TCE) at 1408C.
[e] When the catalyst loading was decreased to 2 mol%, slightly lower
yields were observed (47% yield for 12cd; 58% yield for 12dd).
Bn=benzyl, Cy=cyclohexyl, Ms=methanesulfonyl (mesyl), Ts=tolue-
nesulfonyl (tosyl).
12aa and 13aa in around 62% yield, along with several minor
impurities. Unfortunately, however, detailed spectroscopic
analysis of the separated isomers, including NOE, HMBC,
and HMQC experiments, revealed that the undesired isomer
13aa was obtained as the major product (12/13 25:75; Table 1,
entry 1). This result was attributed to the higher reactivity of
the C2 position of pyrrole (11a) towards arylation relative to
the C3 position.[11c]
Scheme 5. Total synthesis of dictyodendrins C and F.
congeners with an oxidized core structure (Scheme 1). Our
first attempt at the direct introduction of the C1 aryl group
Considering that the regioselectivity of gold-carbenoid-
mediated reactions can be influenced by steric and electronic
factors,[12b] we subsequently evaluated the impact of adding
different substituents to the pyrrole nitrogen atom. Among
pyrroles 11b–d bearing a benzyl, tosyl, or Boc protecting
group (Table 1, entries 2–4), Boc derivative 11d showed the
highest regioselectivity for the desired isomer 12ad (12/13
92:8; entry 4). This result could be attributed in part to the
steric bulk of the Boc group, thus leading to a decrease in the
reactivity of the neighboring 2-position. The introduction of
the oxygen functional groups required for the synthesis of
dictyodendrin had a noticeable impact on the outcome of the
annulation reaction. For example, the reaction of 10b bearing
methoxy and mesyloxy groups (as R1 and R2, respectively)
with 11d delivered the annulation products with relatively
low regioselectivity (12/13 75:25; entry 5), although we did
observe an increase in the combined yield to 83%. Fortu-
nately, the reactions of alkyl ether derivatives 10c (R2 = OBn)
and 10d (R2 = OtBu) showed better regioselectivity (12/13
81:19 and 84:19) and good yields (68 and 79%). We
subsequently decided to use the annulation product 12dd
(entry 7) for the total synthesis of dictyodendrins, on the basis
of the efficacy of the annulation reaction as well as the facile
into 12dd by C H arylation[18] led only to the recovery of the
ꢀ
staring material or the formation of a complex mixture. To
increase the reactivity of the pyrrole ring, we removed the
ꢀ
Boc group with NaOMe to give 25. Although the C H
arylation of 25 was also unsuccessful, bromination proceeded
smoothly with N-bromosuccinimide (NBS; 1.05 equiv) to give
the desired C1-brominated product. However, this material
decomposed during the evaporation of the reaction solvent,
and was therefore subjected to a one-pot C1-bromination/N-
alkylation sequence, followed by a Suzuki–Miyaura coupling
reaction. We screened various conditions for the N-alkylation
reaction (i.e., the electrophile, the base, the temperature, the
solvent, and the use of additives) and found that the treatment
of the C1-brominated material with alkyl bromide 26 and
NaOH in the presence of H2O and 18-crown-6 in THF[20]
afforded the desired 1,3-disubstituted product 28 after
a Suzuki–Miyaura coupling reaction.[8]
Our final challenge for the total synthesis of dictyoden-
drins C and F was the introduction of a methoxy group at the
less reactive C5 position. After several failed attempts at the
borylation[21] or lithiation[22] of the C5 position, we success-
fully introduced a methoxy group through a dibromination–
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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