Copper catalyzed sequential arylation-oxidative dimerization of o-haloanilides: synthesis of dimeric HPI alkaloids

Article abstract of DOI:10.1039/c5cc05378a

In this communication, we report a copper catalyzed sequential arylation-oxidative dimerization reaction as the key step for the synthesis of hexahydropyrroloindole alkaloids (+)-chimonanthine, (+)-folicanthine and (-)-calycanthine.

Full text of DOI:10.1039/c5cc05378a

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ARTICLE TYPE
Copper Catalyzed Sequential Arylation-Oxidative Dimerization of o-
Haloanilides: Synthesis of Dimeric HPI Alkaloids
Xianfu Shen, Yongyun Zhou, Yongkai Xi, Jingfeng Zhao, and Hongbin Zhang*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
no asymmetric oxidative dimerization of oxindoles to form the
50 vicinal C3-C3’ all-carbon quaternary centers have been
conducted yet. Stereoselective oxidative dimerization of oxindole
derivatives remains a challenge. Herein we report our new
strategy towards the synthesis of (+)-chimonanthine, (+)-
folicanthine and (–)-calycanthine. Key feature in our route is a
55 novel copper catalyzed asymmetric arylation-oxidative
dimerization of o-haloanilide derivatives.
In this paper, we report a copper catalyzed sequential
arylation-oxidative dimerization reaction as the key step for
the synthesis of hexahydropyrroloindole alkaloids (+)-
chimonanthine, (+)-folicanthine and (–)-calycanthine.
10 The hexahydropyrroloindole (HPI) alkaloids constitute a large
class of natural products isolated from plants, microorganisms
and fungi.1 Among them, the vicinal C3a-C3a’ quaternary carbon
containing members are especially attractive due to its unique
architecture and its interesting biological activities (Figure 1).1
15 Stereocontrol synthesis of the congested all-carbon quaternary
stereocenters in these alkaloids presents a formidable challenge.2
In this field, Overman and his team have made pioneering
contribution towards the syntheses of dimeric and oligomeric HPI
alkaloids,3 and the key structure-units of dimeric HPI alkaloids
60
65
70
75
80
20 were synthesized either by a double Heck cyclization of o-
3b,3c
iodoanilide derivatives
or dialkylation of bis-oxindoles.3a,3d-k
In 2007, Mavassaghi reported a reductive radical dimerization
strategy for the synthesis of dimeric HPI alkaloids.4 Based on this
reductive dimerization, a number of important works have been
25 published towards the syntheses of dimeric HPI alkaloids.5
30
Figure 1. Natural HPI alkaloids.
35
To date, the total syntheses of dimeric HPI alkaloids are mainly
based on tryptamine or tryptophan derivatives,6 few examples
have been reported by application of non-indole and/or non-
oxindole starting materials.7 Although oxidative dimerizations of
40 tryptamine and tryptophan derivatives have been developed to be
a powerful method for the synthesis of dimeric HPI alkaloids,6,8
few oxidative dimerizations of oxindole derivatives have been
reported.9 To the best of our knowledge, only five papers reported
direct oxidative dimerization of oxindole derivatives. Except
45 method established by Rodrigo which provided the dimeric
intermediate in 61% overall yield and good diastereoselectivity
(dl : meso isomers =53 : 8, Scheme 1),9c other methods suffer
from low yields12a or poor diastereoselectivity.9b, 9d,9e In addition,
Scheme 1. Oxidative dimerization of oxindoles.
85
Our retrosynthetic analysis is outlined in Scheme 2. The dimeric
alkaloids shown in Figure 1 could be synthesized from o-
haloanilide 11. The metal mediated arylation of o-haloanilide 11
would provide oxindole 12,10 which, upon oxidative dimerization,
90 would give precursor 13. We were curious to know if the key
intermediates (13) could be formed diastereoselectively in a one-
pot manner by a copper catalyzed arylation of o-haloanilide (11)
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followed by an oxidative dimerization of the newly generated
oxindoles (12) in the presence of a suitable oxidant.
salts in an efficient and economic “one pot” operation.
60
The initial experiment was conducted under ouVriewpArertvicileouOsnline
DOI: 10.1039/C5CC05378A
H
N
Bn
N
X
optimized condition (Table 1, entry 1).10a This condition
H
+
R
O
NH2
5
10
15
20
25
30
35
40
unfortunately gave a complex mixture, with the isolated product
being N-benzyl-o-bromoaniline (19, 16% yield). After some more
O
Dimeric Alkaloids
shown in Figure 1
1, 2, 3 and 4
O
X
65 experiments, we found that the desired reaction could be realized
smoothly in toluene (Table 1, entry 6). Arylation of sulfinamide
11a with catalytic amount of CuI (10% eq.) and LiN(SiMe3)2 (2.0
eq.) in toluene, followed by oxidation with anhydrous tert-butyl
hydroperoxide resulted in dimeric diastereomers (13a+13b, as a
70 mixture of diastereoisomers in 78% yield, and 13c: the meso
isomer in 7% yield). Although a number of oxidants could be
used to generate the desire dimeric product (13a+13b), anhydrous
tert-butyl hydroperoxide proved to be the best additive for this
sequential arylation-oxidative dimerization.
N
N
H
R
H
N
O
Bn
Sequential Arylation-
Oxidative Dimerization
10 Bn
14
Bn
R
S
O
O
N
N
Bn
N
O
Bn
N
O
X
N
Bn
Bn
S
R
R
N
Bn
N
O
Bn
N
O
O
S
S
R
Bn
O
11, X = Br, I
13
12
: R = H, or Vinyl group
75 Table 1 Attempted conditions for Copper catalyzed sequential
arylation-oxidative dimerization of o-bromoanilide 11aa
Scheme 2. Synthetic analysis of dimeric HPI alkaloids.
O
X
OH
NH2
AlMe3, Toluene
+
O
N
H
O
X = Br, 96%
X = I, 96%
X
15a, 15b
80
a
: X = Br
b: X = I
5
-butyrolactone
CH3CN-DMF
BnBr, Cs2CO3
X = Br, 96%
X = I, 95%
O
X
X
OH
DMP, CH2Cl2
N
O
N
O
entry
Metal salts,
Solvents
Oxidants
Products: Yields (%)
X = Br, 92%
X = I, 93%
Bn
10a, 10b
Bn
16a 16b
,
1
2
CuI, THF
CuI, Toluene
CuI, Toluene
CuI, Toluene
CuI, Toluene
CuI, Toluene
CuI, Toluene
CuOAc, Toluene
Pd2(dba)3,Toluene
Pd2(dba)3, CuI
air
air
I2
19c: 16; complex mixtureb
20: 62; 13a+b: 18; 13c: 7b
20: 5; 13a+b: 53; 13c: 8b
20: 6; 13a+b: 43; 13c: 9b
(S)- tert-Butanesulfinamide,
Ti(OEt)4, THF, 60 o
C
Ph
3
1, NaBH4, MeOH
X = Br, 88%
X
N
O
Br
N
O
S
S
4
CI4
2, BnBr, NaH, THF
X = Br, 97%
Mn(OAc)3-2H2O 20: 4; 13a+b: 53; 13c: 10b
N
O
N
O
5
Bn
Bn
6
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
20: 2; 13a+b: 78; 13c: 7b
20: 2; 13a+b: 55; 13c: 6c
20: 7; 13a+b: 58; 13c: 10b
20: 51; 13a,13b+13c: noned
20: 8; 13a+b: 77; 13c: 8e
17a: X = Br, 94%; 17b: X = I, 92%
11a
7
CH2Cl2
MgBr
X
Ph
H
8
H
H
BnBr, NaH, THF
X = I, 95%
9
I
N
O
N
O
S
S
10
N
O
N
O
85 [a] Yields represent isolated yields, average of two runs. All arylation
reactions were conducted at 2 mmol scale under argon at 80 ºC for 5-6 h,
then addition of oxidants (2.2 mmol) or open to air. [b] Copper salts (0.1
eq), LiN(SiMe3)2 (2.0 eq). [c] CuI (0.1 eq), LiN(SiMe3)2 (1.5 eq). [d]
Pd2(dba)3 (0.05 eq), Ph3P (0.2 eq), LiN(SiMe3)2 (2.0 eq). [e] Pd2(dba)3
90 (0.05 eq), CuI (0.1 eq), Ph3P (0.2 eq), LiN(SiMe3)2 (2.0 eq), Toluene.
Bn
Bn
11b
18a
: X = Br, dr(SSs : RSs) = 3.4 : 1, major: 68%, minor: 20%
18b: X = I, dr(SSs : RSs) = 10 : 1, major: 78%, minor: 7.8%
Scheme 3. Syntheses of amides 11a and 11b
45 In order to test these hypotheses, amide 11a, which bearing a (S)-
(–)-tert-butanesulfinamide unit, was synthesized in 68% overall
In order to know whether the oxidative dimerization was
10a
yield and in 5 steps according to our previous procedure
promoted solely by t-BuOOH, we next carried out the arylation
(Scheme 3). Amide 11b was prepared from 17b in an 74% yield
via 1,2-addition of Grignard reagent and subsequent benzylation.
50 It is noteworthy that the 1,2-addition of vinyl magnesium
bromide to aldimines 17a and 17b resulted in two isolatable
diastereomers, with 17b providing better diastereoselectivity (dr
= 10:1, Scheme 3). The absolute configuration for the newly
generated chiral center of compound 18b was deduced by Cram’s
with
tris(dibenzylideneacetone)dipalladium
[Pd2(dba)3]12
95 followed by oxidation with t-BuOOH. It was noteworthy that
only C3-hydroxy-2-oxindole product (20, Table 1, entry 9, as a
mixture of diastereomers at C3 position; however, dimerization
was proceeded in the presence of CuI, Table 1, entry 10) was
obtained. No dimerization products (13a, 13b or 13c) being
100 formed in the absence of a copper salt suggests that copper (II)
ion, rather than t-BuOOH, plays the role of oxidizing the
carbanion to radical. tert-Butyl hydroperoxide just serves as an
oxidant to convert copper (I) to copper (II) in the oxidative
dimerization process.
11
55 chelation model and late confirmed by X-ray crystallography
(Scheme 6). Next, we began to explore the key copper mediated
sequential arylation-dimerization of o-haloanilides, in the hope
that the oxidative dimerization might also be effected by copper
2
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Although the major product (13a and 13b) of this reaction was
of only catalytic amount of cuprous iodide (10%). The absolute
configuration of compound 21a was confirmed by converting it
to sulfonyl ester 23 (Scheme 5) andDOaIn:a1l0y.1s0is3V9ie/wwCi5AtChrtCicl0eX5O-3rn7al8inyAe
crystallography.13
an unseparatable mixture of diastereoisomers (C3S-C3’S and
C3R-C3’R) by silica gel column chromatography, the ratio could
be readily determined by 1H-NMR (84:17, see supporting
information). The enantioselectivity of the major product (13a
and 13b) was also determined after oxidation of the tert-
butylsulfinyl group with 3-chloroperbenzoic acid (m-CPBA) in
dichloromethane (ee = 65%, see supporting information for chiral
HPLC analysis). To the best of our knowledge, this is the first
10 example of copper catalyzed sequential arylation-dimerization of
an o-bromoanilide, a high-yield procedure and also the first
asymmetric oxidative dimerization of an oxindole derivative with
good diastereoselectivity (dl : meso > 10:1) and enantioselectivity
(ee = 65%). The absolute stereochemistry for the vicinal C3-C3’
15 quaternary carbon center was late established by the total
synthesis of (+)-chimonanthine (see Scheme 6).
5
65
70
75
80
85
90
95
20
25
30
Scheme 4. Cu catalyzed arylation-oxidative dimerization of 11b
35
40
45
50
Scheme 6. Total Synthesis of (+)-Chimonanthine, (+)-Folicanthine
and (–)-Calycanthine
To demonstrate the usefulness of this cascade process, we next
100 carried out the synthesis of (+)-chimonanthine and its related
dimeric HPI alkaloids (Scheme 6). Starting from (R)-(–)-tert-
butanesulfinamide, the amide 11a’ was synthesized in 68%
overall yield by repeating the same procedure as indicated in
Scheme 2. The key arylation-dimerization of 11a’ afforded
105 13a’+13b’ in 78% yield (84:16, ee = 67%; see supporting
information). Treatment of 13a’+13b’ with 4N HCl in MeOH
gave diamine 24 in a 95% yield. After recrystallization in
methanol with 2N aqueous solution of HCl (2.0 eq.), the isomeric
purity of di-amine 24 was greater than 99%. The reductive
110 amination of 24 with formaldehyde and NaBH(OAc)3 provided
diamide 25 (96%).3c, 4a Selectively debenzylation of 25 by treated
Scheme 5. Determination of the absolute configuration of 21a by
X-ray crystallography with Cu-Ka radiation
14
with -chloroethyl chloroformate (ACE-Cl) afforded diamine
26 (95%). Reductive aminocyclization of diamine 26 with
diisobutylaluminum hydride (DIBAL-H) provided the desired
55 We next conducted the sequential reaction with substrate 11b.
The dimerization products were obtained in good yield, and all
diastereomers could be isolated by column chromatography, with
desired isomer 21a being obtained in 50% yield (Scheme 4). It
was noteworthy that this sequential arylation-dimerization
60 process could be conducted on multi-gram scale in the presence
115 HPI precursor (27) in 54% yield. Finally, removal of the benzyl
3c
protecting groups by
a
Birch reduction
afforded (+)-
chimonanthine in 95% yield. Treatment of chimonanthine with
4a
formaldehyde in the presence of sodium triacetoxyborohydride
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65
dimerization procedures, see: g) Y. Peng, L. Luo, C. Yan, J. Zhang,
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H. Oikawa, H. Oguri, Org. Biomol. Chem. 2014, 12, 298.
then furnished (+)-folicanthine (95%, see supporting information).
Upon exposure of chimonanthine to acid at reflux for 8 hours,3c, 4a
(–)-calycanthine was obtained in 52% isolated yield.
View Article Online
DOI: 10.1039/C5CC05378A
Oxidative dimerization of tryptamine and tryptophan derivatives as
6
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70
Conclusions
5
In summary, we have developed the first copper catalyzed
arylation-oxidative dimerization of o-haloanilides with a remote
assistance of an intramolecular sulfinyl amide unit. Based on this
method, a general synthetic strategy has been successfully
established for the total synthesis of chimonanthine, folicanthine,
10 and calycanthine. This copper catalyzed sequential arylation-
oxidative dimerization should be found further application in the
synthesis of HPI alkaloids as well as its medicinally interesting
analogues. We are currently investigating the synthesis and
bioactivities of dimeric HPI analogues and the results will be
15 reported in due course.
75
80
85
Notes and references
Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan
University), Ministry of Education, School of Chemical Science and
Technology, Yunnan University, Kunming, 650091, P. R. China. Fax: (+)
20 86-871-65035538; E-mail: zhanghb@ynu.edu.cn
90
† Electronic Supplementary Information (ESI) available: [details of
experimental procedure, spectral data and copies of all new compounds].
See DOI: 10.1039/b000000x/
25 ‡ This work was supported by grants from Natural Science Foundation of
China (20925205 and 21332007), the Program for Changjiang Scholars
and Innovative Research Team in University (IRT13095), and Yunnan
University (YN201404).
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4
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