Bifurcated synthesis of methylene-lactone- And methylene-lactam-fused spirolactams via electrophilic amide allylation of γ-phenylthio-functionalized γ-lactams

Article abstract of DOI:10.3762/BJOC.16.227

New synthetic methods for spirolactams bearing an α-methylene-γ-butyrolactone or its analogous methylene-lactam have been developed. The allylation of γ-phenylthio-functionalized γ-lactams with 2-(acetoxy)methyl acrylamides was accomplished by using 2.5 equivalents of NaH to give the corresponding adducts in excellent yields. The remaining phenylthio group was substituted with a hydroxy group by treatment with CuBr, and the resulting γ-hydroxyamides were cyclized under acidic conditions to afford the corresponding methylene-lactam-fused spirolactams in high yields. On the other hand, methylene-lactone-fused spirolactams could be delivered from the allyl adducts in high yields through a sequential N-Boc protection/desulfinative lactonization.

Full text of DOI:10.3762/BJOC.16.227

Bifurcated synthesis of methylene-lactone- and methylene-
lactam-fused spirolactams via electrophilic amide allylation of
γ-phenylthio-functionalized γ-lactams
Tetsuya Sengoku1, Koki Makino1, Ayumi Iijima1, Toshiyasu Inuzuka2 and Hidemi Yoda*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2020, 16, 2769–2775.
1Department of Applied Chemistry, Faculty of Engineering, Shizuoka
University, 3-5-1 Johoku, Naka-ku, Hamamatsu 432-8561, Japan and
2Division of Instrumental Analysis, Life Science Research Center,
Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
https://doi.org/10.3762/bjoc.16.227
Received: 07 September 2020
Accepted: 06 November 2020
Published: 13 November 2020
Email:
Hidemi Yoda* - yoda.hidemi@shizuoka.ac.jp
Associate Editor: B. Nay
* Corresponding author
© 2020 Sengoku et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
bifurcated synthesis; electrophilic amide allylation;
α-methylene-γ-butyrolactam; α-methylene-γ-butyrolactone;
spirolactams
Abstract
New synthetic methods for spirolactams bearing an α-methylene-γ-butyrolactone or its analogous methylene-lactam have been de-
veloped. The allylation of γ-phenylthio-functionalized γ-lactams with 2-(acetoxy)methyl acrylamides was accomplished by using
2.5 equivalents of NaH to give the corresponding adducts in excellent yields. The remaining phenylthio group was substituted with
a hydroxy group by treatment with CuBr, and the resulting γ-hydroxyamides were cyclized under acidic conditions to afford the
corresponding methylene-lactam-fused spirolactams in high yields. On the other hand, methylene-lactone-fused spirolactams could
be delivered from the allyl adducts in high yields through a sequential N-Boc protection/desulfinative lactonization.
Introduction
α-Methylene-γ-butyrolactone is a pharmaceutically important lactone derivatives spiro-fused to an oxindole (A), one of which
motif which is found in a wide variety of bioactive molecules exhibited a potent cytotoxic activity [9]. Our research group
including natural products (Scheme 1a) [1-3]. For example, succeeded the enantiopure synthesis of these compounds, in
sesquiterpene lactones represented by parthenolide and hele- which enantioselective allylation of an isatin derivative with an
nalin have attracted interest because of their useful biological amido-functionalized allylstannane was employed as a key
activities, and many synthetic efforts have been made so far reaction (Scheme 1b) [10,11]. More recently, an amide-functio-
[4-6]. On the other hand, syntheses and biological evaluation of nalized allyl boronate was developed as an alternative reagent
nonnatural methylene-lactones also have been reported [4,6-8]. for the allylstannane [12-16], which led to the syntheses of not
For instance, Heindel and his co-worker synthesized methylene- only cytotoxic methylene-lactones spiro-fused to a lactam
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Scheme 1: Examples of (a) bioactive compounds bearing an α-methylene-γ-butyrolactone structure, (b) syntheses of spirocyclic compounds through
nucleophilic amide allylation, and (c) syntheses of spirocyclic compounds through electrophilic amide allylation.
ring (B) but also their analogous methylene-lactams (C) tions depicted in Scheme 1b, seems to be accessible from the
through zinc-catalyzed addition to N-carbonyl imides common precursor 3 prepared through the reaction between 1
[13,14,16].
and 3-heterosubstituted isoindolinones 2 followed by cycliza-
tion. Considering that 2 is estimated to be less reactive com-
Meanwhile, we also developed an umpolung electrophilic ally- pared with the oxindole derivative D which show excellent
lation of 3-heterosubstituted oxindole D for the synthesis of nucleophilicity arising from the oxindole–hydroxyindole tau-
lactam analog of A (Scheme 1c) [17]. The oxindole D readily tomerization [18,19], this synthetic approach is undoubtedly
reacted with 2-(acetoxy)methyl acrylamides 1 in the presence of attractive because it could complement our previous one using
a catalytic amount of Pd(PPh3)4 to give the corresponding nucleophilic amido-functionalized allyl boronates in terms
adducts which could be delivered into an methylene-lactam- of the structural diversity as well as understanding of the struc-
fused oxindole. On the basis of this umpolung strategy, spiro- ture–cytotoxicity relationship [14]. Therefore, we were moti-
lactams 4 and 5, which are N-alkyl or N-phenyl-substituted vated to develop a new synthetic methodology for N-alkyl and
analogs of B and C and unable to be obtained under the condi- N-phenyl derivatives 4 and 5 starting from 2 with 1.
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Results and Discussion
ing adduct in 50% and 81% yields, respectively (Table 1,
Our studies began with an exploration of a promising substrate entries 6 and 7). Surprisingly, the desired allylation underwent
for the desired electrophilic allylation. We initially chose even in the absence of palladium catalyst, probably due to high
N-phenyl-3-(acetoxy)isoindolinone (2a) as a reactant. However, nucleophilicity of the deprotonated intermediate, to give 3b in
2a showed no reactivity under the reaction conditions deter- 87% yield (Table 1, entry 8). Optimization studies were con-
mined for the palladium-catalyzed allylation in our previous ducted by screening solvents, reagent amount, and reaction tem-
work and was recovered in 98% yield [17] (Table 1, entry 1). perature, showing that 3b was produced in the highest yield of
The use of strong bases such as potassium tert-butoxide or sodi- 97% when the reaction was carried out with 2.5 equivalents of
um hydride resulted in no formation of the desired product 3a sodium hydride in THF at −10 °C (Table 1, entries 9–13) [22].
because 2a was decomposed under the harsh reaction condi-
tions (Table 1, entries 2 and 3). Thus we opted to employ With the optimal reaction conditions for electrophilic allylation
another substrate 2b bearing a phenylthio group which polar- of 2b with 1a in hand, we turned to demonstrate the versatility
izes the α-C–H bond to lead the corresponding stabilized anion of this method. In our previous work relating to nucleophilic
[20] and is readily transformed into a hydroxy group by treat- allylation of imide derivatives, we succeeded the syntheses of
ment with copper bromide according to our previous work [21]. N-carbonyl-functionalized γ-hydroxy amides bearing an amide
Allylation of 2b with 1a at room temperature proceeded in the side chain [14]. Therefore, we here examined reactions using
presence of a catalytic amount of Pd(PPh3)4 by using potas- N-alkyl derivatives in order to gain the structural diversity.
sium tert-butoxide or sodium hydride, affording the correspond- Reactions of 3-(phenylthio)isoindolinone derivatives bearing an
Table 1: Screening of reaction conditions for electrophilic amide allylation.
entry
2
reagents (equiv)
solvent
THF
THF
THF
THF
THF
THF
THF
time (h)
24
3 (%)
1
2
3
4
5
6
7
2a
2a
2a
2b
2b
2b
2b
Et3N (2.5)
Pd(PPh3)4 (0.1)
3a (0)
3a (0)
3a (0)
3b (0)
3b (0)
3b (50)
3b (81)
t-BuOK (2.5)
Pd(PPh3)4 (0.1)
24
NaH (2.5)
Pd(PPh3)4 (0.1)
24
Pyridine (2.5)
Pd(PPh3)4 (0.1)
24
Et3N (2.5)
Pd(PPh3)4 (0.1)
24
t-BuOK (2.5)
Pd(PPh3)4 (0.1)
24
NaH (2.5)
Pd(PPh3)4 (0.1)
1
8
2b
2b
2b
2b
2b
2b
NaH (2.5)
NaH (1.0)
NaH (2.5)
NaH (2.5)
NaH (2.5)
NaH (2.5)
THF
1
2
1
1
1
1
3b (87)
3b (62)
3b (74)
3b (18)
3b (97)
3b (87)
9
THF
10
11
12a
13b
toluene
DMF
THF
THF
aThe reaction was performed at −10 °C. bThe reaction was performed at −20 °C.
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N-benzyl (2c), N-methyl (2d), and N-(n-pentyl) group (2d) with tion sequence consisting of copper-mediated hydroxylation and
1a readily proceeded under the optimized reaction conditions acid-mediated lactonization based on our previous reports
for 3b to afford the corresponding products 3c–e in 90–95% [10,11,14,21]. Substitution of the phenylthio group of 3b with a
yields (Figure 1). As for the substituents on the methacryl- hydroxy group was readily achieved by treatment with CuBr
amide side chain, not only aryl groups (p-tolyl and p-anisyl in aqueous media (THF/H2O) to afford the corresponding
groups) but also an n-pentyl group were tolerated, providing hydroxylactam in 90% yield (Scheme 2). However, the subse-
3f–h in excellent yields. On the other hand, a reaction of a quent spirolactonization with p-toluenesulfonic acid (p-TsOH)
nonaromatic lactam derivative prepared from N-phenyl-2,3- was unsuccessful, leading to predominant production of
dimethylmaleimide was accompanied by the formation of struc- bislactam derivative 4a (97%) [23-25]. Although acidic spiro-
ture-unidentified side products, resulting in relatively low prod- lactamization was contrary to our initial expectations, a new
uct yield (3i, 78% yield). This problem was overcome by type of N-phenyl spirobislactam, which could not be obtained
carrying out the reaction at −20 °C. Under these conditions, by our previous method, became accessible through this reac-
3i–o were predominantly formed in 92–99% yields. Thus, we tion. Therefore, we decided to evaluate its applicability to other
could obtain a wide variety of 3-phenylthio lactams bearing an substrates. Reactions of isoindolinone derivatives 3c–h under
amide functionality by electrophilic allylation with 1.
the comparable conditions used for 3b were successful,
furnishing the corresponding N-alkyl and N-phenyl bislactams
Having completed the installation of an acrylamide side chain 4b–g in 79–91% two-step yields. Similarly, non-aromatic sub-
into 3-phenylthio lactams, we subsequently proceeded to the strates 3i–o were also converted into 4h–n in 84–94% yields,
construction of the spiro skeleton of 4 and 5. For this purpose, indicating widespread applicability of this sequential transfor-
we initially attempted to transform 3b to 5a through the reac- mation.
Figure 1: Syntheses of 3b–o via electrophilic amide allylation of γ-phenylthio lactams. Reactions were carried out with 1 (1.2 equiv), 2 (1.0 equiv),
and NaH (2.5 equiv) in THF (0.2 M for 2) at −10 °C for 1 h. aReactions were performed at −20 °C.
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Scheme 2: Syntheses of N-phenyl and N-alkyl-substituted spirolactams (two-step yields from 3).
Since the cyclization under acidic conditions led to the predom- lactonization occurred spontaneously under the reaction condi-
inant formation of the methylene-lactam-fused spirolactam, we tions and led to methylene-lactone-fused spirolactams 5a–h in
set another route toward 5 via cyclization of N-Boc-functionali- excellent yields without exception (88–98% two-step yields).
zed γ-hydroxymethacrylamide [26]. We initially treated the Thus, we established the bifurcated synthetic routes toward
hydroxylactam prepared through CuBr-mediated hydroxylation lactams spiro-fused to α-methylene-γ-butyrolactone or α-methy-
of 3b with di-tert-butyl dicarbonate (Boc2O) in the presence of lene-γ-butyrolactam by using 3-phenylthiolactams bearing an
N,N-dimethyl-4-aminopyridine (DMAP), but a mixture of struc- acrylamide side chain as a common intermediate.
turally unidentified products was formed. Meanwhile, when the
reaction was carried out with 2.0 equivalents of n-butyllithium Finally, we subjected methylene-lactone-fused spirolactams to
and 1.1 equivalents of Boc2O in THF at −78 °C, 5a was ob- the assay of cytotoxicity on P388 cells (Figure 2). N-Methyl-
tained as a mixture including unreacted starting material (<11% substituted spirolactam 5c exhibited potent cytotoxicity (IC50
yield), indicating that installation of an N-Boc group on the 0.32 μg/mL) which was comparable to that of the N-acetyl
terminus amide should trigger the desired lactonization. There- analog E (0.16 μg/mL) [14]. It should be noted that the IC50
fore, we next examined the transposed reaction sequence, values of our recently reported non-conjugated lactone F [27]
N-Boc protection followed by hydroxylation (Scheme 2). N-Boc was >100 μg/mL. In addition to 5c, we tested the cytotoxicity of
amides were readily obtained by treatment of 3b–o with Boc2O methylene-lactam-based compound 4o, which exhibited weak
and DMAP, which were successively subjected to hydroxyl- activity (IC50 12.4 μg/mL) against the P388 cell line. These
ation in the presence of CuBr. Expectedly, the desired results suggest that cytotoxic activity of this type of spirolac-
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Figure 2: Cytotoxicity of spirolactams on P388 cells (IC50 values).
tams against P388 cells is simply related to the methylene
lactone structure [28].
ORCID® iDs
Tetsuya Sengoku - https://orcid.org/0000-0002-5208-9460
Toshiyasu Inuzuka - https://orcid.org/0000-0001-6976-6993
Hidemi Yoda - https://orcid.org/0000-0001-8843-6850
Conclusion
In conclusion, we have achieved a new bifurcated syntheses
of N-alkyl and N-phenyl-substituted spirolactams bearing a
methylene-lactone or methylene-lactam structure. The key
intermediates were synthesized by electrophilic allylation
of γ-phenylthio-functionalized γ-lactam derivatives with
2-(acetoxy)methyl acrylamides in the absence of any metal
catalyst and delivered into each type of spirolactams through
desulfinative hydroxylation/lactamization or N-Boc protection/
desulfinative lactonization. The increase of diversity of
structure accessible led to further understanding of the
structure–cytotoxicity relationship of spirolactams on P388
cells.
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