Total synthesis of (+)-perophoramidine and determination of the absolute configuration

Article abstract of DOI:10.1021/ja1070043

The first asymmetric total synthesis of (+)-perophoramidine has been achieved in 17 steps with ～11% overall yield. The key step relies on an asymmetric biomimetic Diels-Alder reaction between the in situ-generated chiral diene T-24 and the substituted tryptamine 23 to assemble the core structure 27a in a highly efficient way. An acid-catalyzed thermodynamic equilibrium results in C N double-bond migration of the amidine moiety in 37, which guarantees a regioselective methylation on N₁ at the end of the synthesis. The absolute configuration of (+)-perophoramidine was determined by X-ray crystallographic analysis of the chiral intermediate 32 and comparison of the rotation of synthetic (+)-perophoramidine with that of the natural product.

Full text of DOI:10.1021/ja1070043

Published on Web 09/21/2010
Total Synthesis of (+)-Perophoramidine and Determination of the Absolute
Configuration
Haoxing Wu,† Fei Xue,† Xue Xiao, and Yong Qin*
Department of Medicinal Natural Products and Key Laboratory of Drug Targeting and Drug DeliVery Systems of
the Ministry of Education and State Key Laboratory of Biotherapy, West China School of Pharmacy, Sichuan
UniVersity, Chengdu 610041, P. R. China
Received August 5, 2010; E-mail: yongqin@scu.edu.cn
Following his own model reaction,4g Funk completed a biomimetic
Abstract: The first asymmetric total synthesis of (+)-perophora-
total synthesis of (()-perophoramidine.5a The key reactions were a
midine has been achieved in 17 steps with ∼11% overall yield.
stepwise formal Diels-Alder reaction of tryptamine derivative 5 with
The key step relies on an asymmetric biomimetic Diels-Alder
bromo-substituted oxindole 6, protection of the amide nitrogen with
reaction between the in situ-generated chiral diene T-24 and the
substituted tryptamine 23 to assemble the core structure 27a in
a highly efficient way. An acid-catalyzed thermodynamic equilib-
Boc, reductive opening of the lactam ring, and simultaneous cyclization
(Scheme 1).5a
rium results in CdN double-bond migration of the amidine moiety
in 37, which guarantees a regioselective methylation on N1 at
the end of the synthesis. The absolute configuration of (+)-
perophoramidine was determined by X-ray crystallographic analy-
sis of the chiral intermediate 32 and comparison of the rotation
of synthetic (+)-perophoramidine with that of the natural product.
Scheme 1. Previous Biomimetic Approaches to the Core
Structures
(+)-Perophoramidine1 and (-)-communesins2 are structurally re-
lated indole alkaloids (Figure 1). These indole alkaloids have archi-
tectures that are unique among known indole alkaloids. They possess
a complex multiring system, bisamidine or bisaminal functionality,
and two vicinal quaternary carbon centers between the two ethylene
groups. The two ethylene groups are trans to each other in perophora-
midine and cis in communesins. The challenging structures and
interesting cytotoxic activities of these indole alkaloids have attracted
substantial interest from synthetic chemists in recent years.3 Method
development4 for construction of the core structure has led to the total
syntheses of (()-perophoramidine by Funk5a and (()-dehalopero-
phoramidine by Rainier5b as well as two total syntheses of (()-
communesin F, one by us and the other by Weinreb,6 but syntheses
of enantiomerically pure perophoramidine and communesins have not
been achieved. Thus, the absolute configurations of the natural products
are unknown.
We previously reported a total synthesis of (()-communesin F that
uses a synthetic strategy of intramolecular cyclopropanation (9 to 10),
reductive ring opening and ring closure (10 to 11), and R-allylation
via Johnson-Claisen rearrangement (12) to provide the pentacyclic
intermediate 13 having the two ethylene groups at C7 and C8 in a cis
relationship (Scheme 2).6a Such a cis relationship occurs in commu-
nesins. During the total synthesis, while we were trying to reduce an
Scheme 2. Asymmetric Biomimetic Approach to the Core Structure
Figure 1. Structures of perophoramidine and communesins (communesin
F: R1 ) R2 ) Me; X ) double bond).
In view of the possible biosynthetic pathway of perophoramidine
and communesins based on a model reaction, Stoltz first proposed
that the architecture of these indole alkaloids might be biosynthetically
produced through a hetero-Diels-Alder reaction of the ergot alkaloid
(R)-aurantioclavine (1) with oxidized tryptamine 2 (Scheme 1).4f,i
† These authors contributed equally.
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C O M M U N I C A T I O N S
azide group in 14 to an amine group with a reductive Lewis acid (Zn
dust or SnCl2) on heating, a retro-Diels-Alder reaction unexpectedly
occurred, leading to the stable compound 16 (Scheme 2).7 Most likely,
16 was generated by solvent capture of the unstable diene 15. This
observation encouraged us to explore a new biomimetic approach for
the synthesis of the core skeleton by applying a reverse procedure from
a diene such as 15 and tryptamine derivatives such as 17 via an
intermolecular hetero-Diels-Alder reaction. The major challenge in
this designed Diels-Alder reaction is achieving the correct stereo-
chemistry of the adducts, since perophoramidine and communesins
have the opposite stereochemistry at the two vicinal quaternary carbon
centers. An advantage of this approach is that it readily allows an
asymmetric reaction induced by a preexisting chiral auxiliary (R*) on
the amide nitrogen. In this communication, we report the first
asymmetric total synthesis of (+)-perophoramidine, in which the key
reaction is an intermolecular hetero-Diels-Alder reaction that as-
sembles the core structure. We also report the determination of the
absolute configuration of the natural product.
the imine afforded chiral amine 20. Lactam ring opening by activation
with a Boc group and deprotection of TBS with TBAF gave alcohol
21. The hydroxyl group in 21 was replaced with chloride by treating
21 with SOCl2 and pyridine in CH2Cl2 at 0 °C, affording 22.
Initial attempts to carry out the Diels-Alder reaction with 22aa
gave promising results. Without purification, the unstable 22aa (1.2
equiv) was directly treated with 23 (1 equiv) and anhydrous AgBF4
(2 equiv) at -78 °C in dry CH2Cl2 for 2 h to afford the separable
major adduct 27a and minor adduct 27b in a 5.9:1 ratio with a
combined yield of 74%. A variety of silver salts were screened, and
AgClO4 was found to catalyze the reaction smoothly for 30 h to give
the highest ratio of 6.8:1 with a combined yield of 76%. Under the
same conditions, replacing the CH2Cl2 solvent with toluene increased
the ratio from 6.8:1 to 11:1 with 77% yield. The reaction yield was
further enhanced to 88% when 3 equiv of 22aa and 4.5 equiv of
AgClO4 were used. Under the optimal conditions (3 equiv of 22 and
4.5 equiv of AgClO4 at -78 °C in toluene), reactions with compounds
22ab, 22ba, and 22bb provided adducts 28, 29, and 30, respectively,
in ratios of 1.7:1 to 6.2:1 with yields of 69-81% (Scheme 3).
In diastereomers 27a and 27b, the ethylene groups on the two
quaternary carbon centers are trans to each other, consistent with the
geometry in perophoramidine but not in communesins. Although
multiple modes of addition are possible in the Diels-Alder reaction,
the stereochemistry of adducts 27a and 27b indicates that the
Diels-Alder reaction proceeds through an exo addition (T-26) with
an in situ-generated trans/trans diene T-24 rather than with the trans/
cis diene T-25. T-25 may not be produced during the reaction, perhaps
because of strong electron-pair repulsion in T-25 (Scheme 3).6
Scheme 3. Construction of the Core Structurea
Scheme 4. Determination of the Absolute Configurations of the
Major Adductsa
a Reagents and conditions: (a) TMSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 2 h,
82-85%; (b) MeNH2/MeOH, 25 °C, 12 h; (c) Boc2O, Na2CO3, CH2Cl2,
25 °C, 2 h, 78-80% over two steps; (d) Li/NH3, THF, -78 °C, 30 min,
83%; (e) NaOH, CH2Cl2, 25 °C, 12 h, 81%.
a Reagents and conditions: (a) allylMgBr, Et2O, 25 °C, 2 h, 85-88%;
(b) TBSOTf, 2,6-lutidine, CH2Cl2, 25 °C, 20 h, 95-97%; (c) O3/Me2S,
CH2Cl2, -78 to 25 °C, 30 h, 76-84%; (d) R*NH2, KHSO4, toluene, 50
°C, 2 h, or 4 Å molecular sieves, CH2Cl2, 25 °C; (e) NaBH4, MeOH, 0 °C,
30 min, 81-85% over two steps; (f) Boc2O, NaOH, CH2Cl2, 25 °C, 2 h,
87-93%; (g) TBAF, THF, 25 °C, 1 h, 89-90%; (h) SOCl2, pyridine,
CH2Cl2, 0 °C, 15 min; (i) 4.5 equiv of AgClO4, 1 equiv of 23, 3 equiv of
22, toluene, -78 °C, 17-43 h.
On the basis of the above hypothesis, our first task was to prepare
chiral diene precursor 22 (Scheme 3). Starting from isatins 18a and
18b, a parallel synthesis of 22aa-bb with different chiral substituents
was conducted using a similar procedure. Thus, Grignard addition
followed by protection of the resulting tertiary hydroxyl group with
TBS provided oxindole 19 in high yield. Ozonolysis of the double
bond in 19, condensation of the resulting aldehyde with (S)-R-
methylbenzylamine8a or (S)-tert-butylsulfinamide,8b,c and reduction of
Figure 2. ORTEP diagram of 32.
In order to determine the absolute configurations of the major
adducts, 29a and 30a were converted to 31 and 32 by removal of
the Boc protecting group with TMSOTf (Scheme 4). Fortunately,
compound 32 was easily recrystallized from MeOH to form a
solvated single crystal, X-ray analysis of which revealed a
4R,12S,20S configuration (Figure 2).9 The absolute configuration
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C O M M U N I C A T I O N S
of 29a and 30a was determined to be 4R,12R,20S by comparison
with the rotation of compound 33, which was prepared from 31
and 32 by a three-step conversion involving removal of the
phthaloyl group, protection of the amine, and removal of the chiral
auxiliary (Scheme 4). In view of the absolute configuration of 29a,
the absolute configuration of 27a with a bromo substituent was
deduced to be 4R,12R,20S by comparison of its rotation and NMR
spectra with those of 29a. This deduction was reasonable because
both 27a and 29a containing the same (S)-tert-butylsulfinyl group
were generated under the same conditions.
Having developed an efficient hetero-Diels-Alder reaction for
assembly of the core structure of perophoramidine and determined
the absolute configuration of the major adduct 27a (4R,12R,20S),
we then began to synthesize (+)-perophoramidine from 27a. As
shown in Scheme 5, chlorination of 27a on the indoline ring with
NaClO in AcOH at -40 °C resulted in removal of the tert-
butylsulfinyl group, providing amide 34 in high yield. After
oxidation of the methyl group to a formyl group, the resulting
compound was treated with excess Et3OBF4 and DIPEA at 25 °C
in CH2Cl2, which converted the amide bond to an imidate bond
and simultaneously removed the Boc protecting group, giving
compound 35. After removal of both the formyl and phthaloyl
protecting groups in 35 with MeNH2 without purification, the
resulting intermediate was heated at reflux for 10 h in CHCl3 to
give amidine 36 in 73% yield over two steps. The aminal group in
36 was oxidized with MnO2 as an amidine group to give kinetic
product 37 in 76% yield. In order to selectively add a methyl group
at N1, compound 37 was subsequently converted to its thermody-
namic product 38 in quantitative yield by heating with 0.5 equiv
of PPTs in CHCl3. The final step of selective methylation of 38
with MeOTf and NaHMDS in THF at -78 °C completed the total
synthesis of (+)-perophoramidine in 76% yield.
Because (+)-perophoramidine and (-)-communesin F have op-
posite configurations at the vicinal quaternary carbon centers, the
absolute configuration of (-)-communesin F can be inferred to be
6R,7R,8R,9S,11R on the basis of the relative stereochemistry of
natural (-)-communesins reported in the literature2a,b and the
proposed biosynthetic pathway in which (-)-communesins are
generated from the ergot alkaloid (R)-aurantioclavine 1.4f,i
In summary, the first asymmetric total synthesis of (+)-
perophoramidine has been accomplished in 17 steps in ∼11%
overall yield. The key step for diastereoselective assembly of the
core structure is a chiral-auxiliary-induced hetero-Diels-Alder
reaction that is efficiently catalyzed by AgClO4. The absolute
configuration of (+)-perophoramidine has been determined to be
4R,20S by X-ray analysis of a synthetic intermediate and compari-
son of the rotation of the synthetic sample with that of the natural
product.
Acknowledgment. This work was supported by grants from
NSFC (20772083, 20825207, 21021001), PCSIRT (IRT0846), the
National Basic Research Program of China (973 Program,
2010CB833200), and the State Key Laboratory of Bioorganic and
Natural Products Chemistry, Shanghai Institute of Organic Chem-
istry. We thank Prof. Weidong Li (Nankai University) for helpful
discussions.
Supporting Information Available: Experimental details, NMR
spectra of all new compounds, and crystallographic data (CIF). This
material is available free of charge via the Internet at http://pubs.acs.org.
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a Reagents and conditions: (a) NaClO, HOAc, MeOH, -40 °C, 0.5 h,
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25 °C, 12 h, 85%; (d) MeNH2/MeOH, 25 °C, 2 h; (e) CHCl3, reflux, 10 h,
77% over two steps; (f) MnO2, CH2Cl2, 25 °C, 3 h, 76%; (g) PPTs, CHCl3,
reflux, 2 h, quantitative; (h) MeOTf, NaHMDS, THF, -78 °C, 73%.
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These data are also available in the Supporting Information.
The synthetic sample showed NMR spectra identical to those of
natural product, and its rotation {[R]2D5 ) +3.9 (c 0.5, CHCl3)}
was consistent with that of the natural compound {[R]2D5 +3.8 (c
0.73, CHCl3)1}. These results unambiguously indicate that the
natural (+)-perophoramidine possesses a 4R,20S configuration.
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