Key words parvistemonine A - natural product - total synthesis - aza-Wittig reaction - Mitsunobu
reaction
In 2016, Zhao and co-workers isolated a series of new alkaloids from the roots of
Stemona parviflora . Parvistemonine A (1 ) was among them, and its structure was determined by NMR and MS analysis.[1 ]
Stemona parviflora is a relatively small monocotyledonous plant of the Stemonaceae family. The roots
of Stemona species have antitussive and insecticidal activities, and they have been used in
folk medicine for thousands of years in East Asia. Antinematode activity has been
identified for several isolated Stemona alkaloids.
As shown in Figure [1 ], the structure of parvistemonine A (1 ) is characterized by a fused tricyclic framework including a γ-lactone and a pyrrole,
with a butyl side chain. For the total synthesis, three consecutive asymmetric centers
and an acid-sensitive pyrrole ring bearing three electron-donating alkyl groups must
be efficiently constructed at the appropriate times. From the viewpoint of medicinal
chemistry, the functional groups on this framework could be arranged in various relative
positions by introducing various substituents, because the central seven-membered
ring disrupts the planarity of the molecule. Therefore, a concise and effective route
for the synthesis of 1 might serve as a useful access to drug-discovery leads and scaffolds.
Figure 1 Structure of parvistemonine A (1 )
Because of the intriguing structures and the bioactivities of Stemona alkaloids, their total synthesis has been an intense area of research in recent decades.[2 ] To our knowledge, only one total synthesis has been reported to date. In 2019, Ma
and co-workers reported the preparation of parvistemonine A in a racemic form by using
a cross-metathesis, a Friedel–Crafts-type cyclization, a lactonization, a Vilsmeier–Haack
formylation, and a Julia–Kocienski olefination. They obtained (±)-parvistemonine A
in 11 steps and in 2.3% overall yield.[3 ]
Our retrosynthetic analysis of (±)-1 is shown in Scheme [1 ]. We planned to introduce the methyl group at the 1-position in the lactone ring
at a late stage in the total synthesis by methylation of an ester enolate. We planned
to construct the seven-membered ring by an intramolecular conjugated cycloaddition
of an electron-rich pyrrole ring promoted by an acid. We assumed that the cyclization
precursor 2 could be constructed by nucleophilic substitution with 2-butyl-1H -pyrrole (3 ) as the pyrrole moiety and iodide 4 as the butenolide moiety. Furthermore, iodide 4 could be synthesized by several functionalizations from the product of a Mukaiyama–Michael
addition of commercially available 2-[(trimethylsilyl)oxy]furan (5 ) and acrolein (6 ).
Scheme 1 Retrosynthetic analysis of parvistemonine A (1 )
We began our synthesis from readily available pyrrole (7 ). 2-Butyl-1H -pyrrole (3 ) was prepared as follows. First, pyrrole (7 ) was converted into a magnesium reagent, which was treated with butanoyl chloride
to give 1-(1H -pyrrol-2-yl)butan-1-one (8 ).[4 ] Reduction of 8 by NaBH4 in refluxing propan-2-ol gave 2-butylpyrrole (3 ) (Scheme [2 ]).[5 ]
Scheme 2 Synthesis of 2-butylpyrrole (3 )
A Mukaiyama–Michael addition of 2-[(trimethylsilyl)oxy]furan (5 ) to acrolein (6 ) at –60 °C gave aldehyde 9 in 87% yield.[6 ] However, when we attempted to reduce the aldehyde group in 9 with NaBH4 , the butenolide ring was also reduced. In contrast, reduction by borane at –20 °C
afforded the desired alcohol 10 in good yield.[7 ] Next, sequential mesylation and iodination proceeded smoothly to give iodide 4 (Scheme [3 ]).[8 ]
Scheme 3 Synthesis of iodide 4
We then investigated the coupling reaction of 2-butyl-1H -pyrrole (3 ) and iodide 4 . In all our attempts using NaH, DBU, or LHMDS, the reaction was complicated, and
the desired product 2 was not obtained. In most of these attempts, decomposition of the iodide 4 was observed, whereas the pyrrole 3 remained intact (Scheme [4 ]).[9 ]
Scheme 4 Attempted coupling reaction of pyrrole 3 and iodide 4
We attributed these results to the low reactivity of the anion derived from pyrrole
3 and the labile nature of iodide 4 under basic conditions. We therefore planned a new synthetic route that avoided strongly
basic reaction conditions. In the new synthetic strategy (Scheme [5 ]), we envisioned that an in situ Paal–Knorr pyrrole synthesis using keto aldehyde
13 just after an aza-Wittig reaction of azide 12 might lead to the desired product 2 . Keto aldehyde 13 can be easily prepared from γ-lactone 14 in two steps.
Scheme 5 Revised retrosynthetic analysis of compound 2
First, keto aldehyde 13 for the Paal–Knorr pyrrole synthesis was prepared in two steps. Addition of butyllithium
to γ-lactone 14 to form hydroxy ketone 15
[10 ] and subsequent IBX oxidation furnished 13 smoothly (Scheme [6 ]).[11 ] For the butenolide moiety, treatment of iodide 4 with sodium azide in DMF gave azide 12 in 89% yield.[12 ] In this procedure, the formation of tricyclic compound 16 by an intramolecular [3 + 2]-pericyclic reaction of the azide moiety and the double
bond in the butenolide was observed when the reaction temperature was increased. We
therefore minimized the amount of time taken for reaction workup and column purification.
The aza-Wittig reaction of azide 12 and keto aldehyde 13 , followed by the Paal–Knorr pyrrole synthesis in one pot gave the desired coupling
product 2 in 65% yield.[13 ] In this step, we detected none of the desired primary amine when we attempted a
selective reduction of the azide moiety in 12 .
Scheme 6 Synthesis of compound 2
Next, the intramolecular conjugated cycloaddition of 2 under acidic conditions to form tricyclic compound 17 was investigated (Table [1 ]).[14 ] With Lewis acids, the reproducibility of the reaction yield was low, because the
pyrrole ring bearing alkyl groups was not sufficiently stable under strongly acidic
conditions. During optimization of the reaction conditions with various sulfonic acids,
we predominantly obtained the cis -fused tricyclic compound 17 in 72% yield when toluenesulfonic acid was employed in acetonitrile at 70 °C under
dilute conditions. Moreover, the reaction did not proceed with PPTS.[15 ]
Table 1 Optimization of the Acid-Mediated Annulation of Compound 2
a
Entry
Acid (equiv)
Solvent
Temp. (°C)
Time (h)
Yield (%)
17
18
2
b
1
BF3 ·OEt2 (10.0)
CH2 Cl2
25
16
31
trace
69
2
AlCl3 (15.0)
CH2 Cl2
25
94
45
trace
trace
3
MsOH (15.0)
CH2 Cl2
0–39
173
47
trace
10
4
CSA (10.0)
MeCN
50
19
39
trace
trace
5
TsOH·H2 O (2.1)
MeCN
55
15
46
trace
5
6c
TsOH·H2 O (10.5)
MeCN
70
18
72
6
–
7
PPTS (5.0)
MeCN
50
13
–
–
100
a Reaction conditions: 2 (10.0 mg, 40.5 µmol), solvent (810 µL).
b Recovered starting material.
c The reaction was performed under five-times diluted conditions.
In this reaction, cis -fused 17 was obtained with high selectivity, as we had expected at the beginning of our synthetic
plan. Furthermore, subsequent methylation of cis -fused 17 was expected to occur selectively from the convex face. On the other hand, Ma and
co-workers obtained a mixture of diastereomeric methylated compounds when they methylated
trans -fused 18 . They therefore synthesized (±)-parvistemonine A by isomerization of the resulting
mixture of diastereomers under basic conditions (two steps; 49%).[2a ]
[2b ]
[2e ]
[3 ]
After deprotonation by LHMDS, tricyclic compound 17 was treated with methyl iodide.[16 ] As expected, the methylation proceeded preferentially from the β-side (i.e., the
convex face) and the desired methylated derivative 19 was obtained stereoselectively in 83% yield. Finally, to invert the stereochemistry
at the 3a-position, the lactone ring of 19 was opened by alkaline hydrolysis and the product was rapidly subjected to a Mitsunobu
reaction with di-2-methoxyethyl azodicarboxylate (DMEAD) and PPh3 to give (±)-parvistemonine A[17 ] in 77% yield over the two steps (Scheme [7 ]).[17 ] At this stage, precise pH control was essential during the hydrolysis workup procedure
to suppress the reverse reaction to re-form cis -lactone 19 . Moreover, the Mitsunobu reaction was carried out at room temperature to accelerate
the forward reaction and to prevent the reverse reaction. The 1 H NMR, 13 C NMR, and HRMS of the synthetic samples were in good agreement with those reported
for natural parvistemonine A (1 ). Furthermore, recrystallization of (±)-1 from hexane afforded single crystals suitable for X-ray crystallographic analysis,
which confirmed the complete structure of (±)-1 .[18 ]
Scheme 7 Completion of the total synthesis of (±)-1, and the structure of (±)-1 obtained by X-ray diffraction
In summary, we have described a total synthesis of (±)-parvistemonine A. From the
commercially available furan 5 , this synthesis proceeded with a longest linear sequence of ten steps and in 19.6%
overall yield. The synthesis included a Mukaiyama–Michael addition, an aza-Wittig
reaction, a Paal–Knorr pyrrole synthesis, an acid-mediated annulation, and a Mitsunobu
reaction as key steps. X-ray crystallographic analysis of (±)-1 clearly confirmed the relative stereochemistry of parvistemonine A (1 ). This concise synthesis might be useful in syntheses of derivatives of (±)-1 or the purpose of medicinal chemistry and for providing drug-discovery scaffolds.
