Phosphine-catalyzed one-pot isomerization of 3-alkynoates and [2 + 3]-cycloaddition with imines: formal synthesis of Securinegaalkaloid (±)-allosecurinine

Abstract

Trimethylphosphine-induced isomerization and cycloaddition of 3-alkynoates with imines for the synthesis of 2,5-syn di-substituted pyrrolines were described. In addition, the utility of this protocol was demonstrated in the efficient formal synthesis of the Securinegaalkaloid ‘allosecurinine’.

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Heterocycles and carbocycles are known to be of great importance in identifying biologically significant molecules.¹ Many natural products and drug molecules possess nitrogen heterocycles as the core structural unit. Amongst them, pyrrolines are featured widely in many natural products.² Consistent with their biological importance, various methods have been developed for the synthesis of pyrrolines.

An efficient protocol to construct such heterocycles, using metal free catalysis, has been attracting much attention. Amongst the available methods, Lu's phosphine-catalyzed [2 + 3]-cycloaddition using electron-deficient allenoates/2-alkynoates and imines is considered to be an efficient strategy for the construction of pyrrolines.³ The asymmetric version of this reaction was successfully examined by Jacobsen,^3q Marinetti^3r–t and Gladysz.^3u Inspired by this strategy, Kwon and Fu elegantly demonstrated the [4 + 2] approach in the synthesis of tetrahydropyridine derivatives.⁴ Although Lu's [3 + 2]-cycloaddition with olefins have been widely utilized in the synthesis of natural products,⁵ surprisingly, there is no documentation of this reaction with imines in the natural product synthesis. This is probably due to the difficulty of executing this reaction using aliphatic aldimines which contain α-C–H functionality. Another limitation is the difficulty of synthesizing the allenoate/2-alkynoate starting material and their limited substrate scope.⁶

Inspired by our previous studies on the use of 3-alkynoates in [2 + 3]-cycloaddition reaction,^6d in this report we describe trimethylphosphine catalyzed in situisomerization of 3-alkynoate to allenoate and cycloaddition with various activated aromatic and aliphatic imines in the synthesis of 2,5-disubsituted pyrrolines as single syn diastereomers and applied this methodology to the formal synthesis of Securinegaalkaloid ‘allosecurinine’ (Scheme 1).

Scheme 1 Proposed synthesis of 2,5-syn substituted pyrrolines and its application in formal synthesis of allosecurinine.

For the preliminary investigation, ethyl-4-phenylbut-3-ynoate 1a and N-tosylimine 2a were chosen as model substrates and the reactions were attempted with various commercially available phosphines (for detailed optimization studies please refer to supplementary information†). To our delight, the reaction proceeded smoothly with a catalytic amount of trimethylphosphine (20 mol%) to afford functionalized pyrrolines 3aa in 84% yield with excellent regio- and diastereoselectivities (Table 1, entry 1). However with nitrogen nucleophiles instead of phosphines, such as DABCO® (1, 4-diazabicyclo[2.2.2]octane) or triethylamine yields only the isomerized product, not the required cyclized product. To examine the generality of this protocol, various electron-deficient aldimines^7a (Table 1; entries 1–8) and alkynoates⁸ (Table 1, entries 9–15) were screened, and in all the cases, excellent yields were observed. Electron withdrawing or releasing substituents on both aldimines and alkynoates provided products in moderate to good yields. Interestingly, the reaction with heteroaromatic containing 3-alkynoate 1f and imine 2h proceeded smoothly to afford product 3fh in 79% yield.

Table 1 Scope of [2 + 3]-cycloaddition with respect to the various electron deficient imines^a,b

Entry	R^1	R^2	Product	Yield (%)
a See the ESI for detailed experimental procedure;† 3-alkynoates (1a–1h) were contaminated with 2–5% of the corresponding allenoates. b Isolated yield. c The relative stereochemistry of product 3ad was assigned by ^1H–^1H Noesy. All other product was assigned by analogy.
1	C6H5 (1a)	C6H5 (2a)	3aa	84
2	C6H5 (1a)	4-Et–C6H4 (2b)	3ab	76
3	C6H5 (1a)	4-Me–C6H4 (2c)	3ac	68
4^c	C6H5 (1a)	4-OMe–C6H4 (2d)	3ad	71
5	C6H5 (1a)	2-OMe–C6H4 (2e)	3ae	70
6	C6H5 (1a)	4-Br–C6H4 (2f)	3af	54
7	C6H5 (1a)	4-Cl–C6H4 (2g)	3ag	89
8	C6H5 (1a)	2-Furyl (2h)	3ah	64
9	4-Me–C6H4 (1b)	2-Furyl (2h)	3bh	77
10	4-OMe–C6H4 (1c)	2-Furyl (2h)	3ch	68
11	6-OMe–2-naphthyl (1d)	2-Furyl (2h)	3dh	61
12	4-CF3–C6H4 (1e)	2-Furyl (2h)	3eh	83
13	Thien-2-yl (1f)	2-Furyl (2h)	3fh	79
14	H (1g)	2-Furyl (2h)	3gh	70
15	CO2Et (1h)	C6H5 (2a)	3ha	55

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To further examine the synthetic value of the method, various methanesulfonamide protected imines^7b were subjected to the previously optimized reaction conditions. In most of the cases, the results were similar with N-tosylaldimines. Both electron withdrawing and releasing groups on phenyl group of N-mesylimine proceeded smoothly to afford the cyclized product in good yields and excellent diastereoselectives (Table 2, entries 1–7). When using 4-nitro substituted N-mesylimines 4c, a considerable decrease in the yield was observed (Table 2, entry 3) due to the decomposition of imine in reaction condition.

Table 2 Scope with respect to the various methanesulfonamide imines^a,b

Entry	R	Product	Yield (%)
a See the ESI for detailed experimental procedure;† 3-butynoate (1a) was contaminated with 2% of corresponding allenoate. b Isolated yield.
1	Ph (4a)	5aa	84
2	4-CF3–C6H4 (4b)	5ab	76
3	4-NO2–C6H4 (4c)	5ac	47
4	4-Cl–C6H4 (4d)	5ad	71
5	4-CN–C6H4 (4e)	5ae	64
6	4-OMe–C6H4 (4f)	5af	70
7	2-Furyl (4g)	5ag	89

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Pyrrolines with aliphatic substitutions are important building blocks featured widely in many natural products and drug molecules. With this in mind, we next turned our attention to using aliphatic aldimines with α-H functionality. Surprisingly, to the best of our knowledge, there is just one example where using such an aldimine (N-tosylcinnamaldimine) was reported.^3b Under previously optimized reaction conditions, the aliphatic imines containing α-H functionality reacted smoothly to afford cyclized products in excellent yields (Table 3, entries 1–7). Moreover, THP protected hex-3-ynoates 1o and imine 6a provided 2,5-di-alkyl substituted pyrrolidine 7oa in 70% yield with 1.2 : 1 diastereomeric mixture (Table 3, entry 2).

Table 3 Scope of cycloaddition with respect to the various aliphatic aldimines^a,b,c

a See the ESI for detailed experimental procedure;† 3-butynoate (1a) was contaminated with 2% of corresponding allenoate. b Isolated yield. c Imine 6b was used in 2.0 equiv.

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Encouraged by these results, next we sought application of this method in the synthesis of the Securinegaalkaloid.⁹ The most representative examples of this family includes securinine (1), its C-2 epimer allosecurinine (2) and their corresponding enantiomers, virosecurinine (3) and viroallosecurinine (4) (Scheme 2). Due to the interesting structural features and potential biological activities of this alkaloid, many research groups are continuing to focus on the synthesis.⁹ In 2008, Kerr et al. demonstrated the total synthesis of allosecurinine through the key intermediate 18.^9h We envisioned the previously developed cycloaddition between aliphatic aldimines and alkyl substituted 3-alkynoates in the synthesis of pyrrolidine skeleton of key intermediate 18.

Scheme 2 Structure of Securinegaalkaloids.

Our retrosynthetic approach for the synthesis of intermediate 18 is shown in Scheme 3. The crucial steps involve (i) assembly of alkynoates 8 and imine 9 by PMe₃-catalyzed [2 + 3]-cyclization to obtain 10 and (ii) reductive opening of epoxide to obtain the key intermediate 1,2-diol 18.

Scheme 3 Proposed synthesis of 2,5-syn substituted pyrrolines and its application in formal synthesis of allosecurinine.

To commence our synthetic plan, alkynoate 8 and N-tosylimine 9 were readily prepared following reported procedures.^7,8 Using previously optimized conditions, the [2 + 3]-cycloaddition reaction was executed smoothly between 8 and 9 in the presence of a catalytic amount of trimethylphosphine to furnish the desired product 10 in 82% isolated yields as the single syn-diastereomers.

With the racemic product 10 in hand, aforethought, reduction of ethyl ester with DIBAL-H furnished the primary alcohol 11 and subsequent epoxidation with m-CPBA yields the required product 12.

In the next step, various reducing agents for epoxide opening such as Red-Al, lithium aluminum hydride and sodium hydride were tested. However, only a trace amount of products was obtained. To our delight, with di-isobutylaluminium hydride (DIBAL-H), the required product 13 was isolated in 64% yield. The resulting 1,2-diol moiety in product 13 was protected using 2,2′-dimethoxypropane to provide 14 and the remaining primary alcohol was iodinated to afford 15 in 87% yield with a trace amount of di-iodide product 15a (X-ray). The iodinated product 15 undergoes E₂-elimination with sodium hydride to furnish 16. Although removal of the tosyl group failed with various mild protocols, eventually sodium naphthalide in DMSO was found to work smoothly to afford the product 17 in 69% yields.¹⁰ Finally, deprotection of the 1,2-diol and Boc protection were carried out in one-pot to furnish the key intermediate 18 (88% yield from 17; Scheme 4) and the structure was confirmed by comparison with a previous report.^9h

Scheme 4 Synthesis of key intermediate 18. Reaction conditions: a) PMe₃ 20 mol%, toluene, 2 h, 25 °C, 82%; b) 2.0 equiv. DIBAL-H (1.0 M in THF), −78 °C, CH₂Cl₂, 74%; c) m-CPBA, CH₂Cl₂, 12 h, 81%; d) 4.0 equiv. DIBAL-H (1.0 M in THF); −78 °C, −25 °C, CH₂Cl₂, 24 h, 64%; e) 10 equiv. 2-2′-dimethoxypropane, 0.1 equiv. CSA, CH₂Cl₂; 77% yield; f) I₂, PPh₃, imidazole; THF; 87%; g) NaH (60%), TBAI, THF, 78 °C, 88%; h) Na-naphthalenide, DME, 69%; i) 3M HCl, THF–H₂O (1 : 1) and j) (Boc)₂O, TEA; THF, 88% (over 2 steps). CSA = camphorsulfonic acid, DME = dimethoxyethane, TEA = triethylamine.

In conclusion, an effective procedure for the synthesis of 2,5-syn-di-subsituted pyrrolines is described. This one-pot isomerization of 3-alkynoates and cycloaddition sequence with imines provided an efficient alternative to existing protocols for the synthesis of 2,5-syn-disubsituted pyrrolines. Moreover, pyrrolines with both aromatic and aliphatic substitutions were synthesized in excellent yields. In addition, the utility of this protocol was demonstrated in the efficient formal synthesis of the natural product allosecurinine. Further investigations on the asymmetric version for the synthesis of optically pure cis 2,5-disubstituted pyrrolines which enroute to enantioselective synthesis of both allosecurinine and viroallosecurinine are in progress.

Acknowledgements

We gratefully acknowledge Nanyang Technological University and Biomedical Research Council (A*STAR Grant No 05/1/22/19/408) for the funding support for this research

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Detailed experimental procedures analytical data. CCDC 829904 contains supplementary crystallographic data of 15a. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c1sc00311a

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