HETEROCYCLES

Communication | Special issue | Vol. 79, No. 1, 2009, pp. 433-439
Received, 30th October, 2008, Accepted, 25th December, 2008, Published online, 26th December, 2008.
DOI: 10.3987/COM-08-S(D)75

■ New Entry to the Asymmetric Synthesis of (–)-Lasubine I and (+)-Subcosine I

Naoki Yamazaki,* Masakazu Atobe, Chihiro Kibayashi, and Sakae Aoyagi*

Faculty of Pharmaceutical Science, Iwaki Meisei University, , Japan

Abstract

A new synthetic entry to (–)-lasubine I and (+)-subcosine I has been established by employing the (S)-allylalkoxy benzylamine as a chiral synthon. The synthesis involves the formation of an α,β-unsaturated lactone by RCM reaction followed by an intramolecular Michael-type addition reaction as a key step, which enables the stereoselective construction of the cis-quinolizidine skeleton of lasubine I and subcosine I.

INTRODUCTION
Lasubine I (1) and lasubine II (2),2 and their ferulates subcosine I (3) and subcosine II (4)2 are members of the arylquinolizidine class of lythraceae alkaloids.3 The structural difference between lasubines I (1) and II (2) is the stereochemistry at C-10 of the quinolizidine ring, which generates the difference in the cis- and trans-relationship between C-10 and N-5 on the quinolizidine ring system (Figure 1).3 To date, many examples of the synthesis of lasubines in racemic and chiral forms have been reported.4, 5 On the other hand, reports of synthetic examples of subcosines in both racemic and chiral forms have been very few.6,7
During the course of our investigations on the diastereoselective addition of alkyllithiums to chiral oxime ethers,8 we found that the allylation proceeded in a moderate selectivity (5-4:1) by employing a η3-allyllithium complex with (R)-2'-(2-naphthyl)-bearing hydroxyoxime ethers 6 to give (S)-1-(aryl)homoallylic amino derivatives 7 (Scheme 1), one of which was successfully transformed into the trans-quinolizidine alkaloid, (+)-abresoline (5).9 In this paper we present a new synthetic entry to cis-qunolizidine alkaloids, (–)-lasubine I (1) and (+)-subcosine I (3), utilizing this (S)-1-(aryl)homoallylic amino derivative.

Our synthetic strategy for cis-qunolizidine alkaloids, 1 and 3, involves preparation of the bicyclic lactone 8 having a trans-2,6-piperidine skeleton, which was obtained in a stereospecific manner by an intramolecular Michael-type addition (9→8) of the α,β-unsaturated lactone 9 and the cyclization of diene 10 by ring-closing metathesis (RCM) (10→9) as illustrated in Scheme 2, starting with the (S)-1-(aryl)homoallylic amino derivative 11.9

RESULTS AND DISCUSSION
Reductive cleavage of the O-N bond of the (S)-1-(aryl)homoallylamine 11 proceeded successfully with zinc–AcOH in THF–H2O at reflux to give the homoallylamine 12 in an 80% yield. This material showed levorotatory optical rotation, [α]20D –13.5 (c 0.5, CHCl3) [lit.,10 [α]20D –13.5 (c 0.5, CHCl3)], which coincided with the S-configuration at the benzylic position. Boc-protection of the primary amine 12 was followed by transformation of the vinyl group to the formyl group by oxidative cleavage, and then re-oxidation of the formyl group with sodium chlorite yielded the Boc-protected carboxylic acid 13 in an 86% yield over three steps. The carboxylic acid 13 was converted to the Weinreb amide 14 with O,N-dimethylhydroxylamine hydrochloride and 2-chloro-1-methylpyridinium iodide in a 99% yield. Treatment of 14 with allylmagnesium bromide gave the β,γ-unsaturated ketone, which was reduced diastereoselectively by chelation controlled hydride addition with LS-Selectride in THF at –78 °C to give the 1,3-syn-aminoalcohol 15 accompanied by a small amount of anti-isomer (syn/anti = 9.1:1) in a combined yield of 76%.11 After separation of the S-isomer by column chromatography, esterification of 15 was affected with acryloyl chloride in the presence of Et3N to give the diene 16 in an yield of 75%. The RCM reaction of 16 with the second-generation Grubbs catalyst12 (10 mol%) in CH2Cl2 under reflux gave the α,β-unsaturated-δ-lactone 17 as a sole product in an excellent yield (98%). Deprotection of the N-Boc group of 17 by treatment of trifluoroacetic acid, followed by exposure to a saturated sodium bicarbonate solution, led to the Michael-type addition in a stereospecific manner to yield the bicyclic lactone 8 in an 88% yield as a single stereoisomer.13

With the bicyclic lactone having the desired stereochemistry in hand, we next examined its conversion to a cis-quinolizidine compound. Reduction of the bicyclic lactone 8 with DIBAL-H gave the 2,4,6-trisubstituted formylmethyl piperidine 18 in a 99% yield. The formyl substituent of 18 was elongated by Horner-Wadsworth-Emmons olefination and then hydrogenated to yield the (ethoxycarbonyl)propylpiperidine 19. The secondary hydroxy group of 19 was protected as a TMS ether and then treated with LiAlH4 to give the primary alcohol 20 in a 66% yield over two steps. Upon treatment of 20 with tetrabromomethane and triphenylphosphine14 in CH2Cl2 at room temperature, intramolecular cyclization occurred to give a quinolizidine, which was exposed to tetrabutylammonium fluoride in THF to furnish (–)-lasubine I (1), [α]20D –7.66 (c 1.0, MeOH) [lit.,4g [α]23D –7.03 (c 0.37, MeOH)], in a 69% yield over two steps. Conversion of (–)-lasubine I (1) to (+)-subcosine I (3) was effected by lithiation of the secondary alcohol and then treatment with dimethoxycinnamic anhydride to yield (+)-subcosine I (3) in a 70% yield. Our synthetic material of 3 was found to have [α]20D +95.5 (c 1.0, MeOH) [lit.,4g [α]23D +93.6 (c 0.14, MeOH)] and to be identical to those of authentic subcosine I by IR, 1H-NMR, and mass spectra.4b,g
In conclusion, we have established a new synthetic entry to (–)-lasubine I and (+)-subcosine I starting with the (S)-1-(aryl)homoallylic amine 11. This route employs, as the key steps, the RCM reaction of the diene 16 to afford the Boc protected monocyclic lactone 17, and the TFA–NaHCO3 mediated intramolecular Michael-type addition for the elaboration of the bicyclic lactone 8 having the necessary stereochemistry for 1 and 3.

References

1. This paper is dedicated to the great contribution to heterocyclic chemistry by the late Dr. John Daly, National Institutes of Health.
2. For isolation, see: K. Fuji, T. Yamada, E. Fujita, and H. Murata, Chem. Pharm. Bull., 1978, 26, 2515.
3. For reviews of the lythraceae alkaloids, see: (a) W. M. Golebiewski and J. T. Wróbel, ‘The Alkaloids,’ Vol. 18, ed. by R. G. A. Rodrigo, Academic Press, New York, 1981, Chapter 4; (b) K. Fuji, ‘The Alkaloids’, Vol. 35, ed. by A. Brossi, Academic Press, San Diego, 1989, Chapter 3.
4. For racemic syntheses of lasubine I, see: (a) H. Iida, M. Tanaka, and C. Kibayashi, J. Chem. Soc., Chem. Commun., 1983, 1143; CrossRef (b) H. Iida, M. Tanaka, and C. Kibayashi, J. Org. Chem., 1984, 49, 1909; CrossRef (c) H. Ent, H. De Koning, and W. N. Speckamp, Heterocycles, 1988, 27, 237; CrossRef (d) A. L. J. Beckwith, S. P. Joseph, and R. T. A. Mayadunne, J. Org. Chem., 1993, 58, 4198; CrossRef (e) V. Bardot, D. Gardette, Y. Gelas-Mialhe, J.-C. Gramain, and R. Remuson, Heterocycles, 1998, 48, 507; CrossRef (f) B. Furman, and G. Lipner, Tetrahedron, 2008, 64, 3464; CrossRef For asymmetric syntheses of (–)-lasubine I, see: (g) D. L. Commins and D. H. LaMunyon, J. Org. Chem., 1992, 57, 5807; CrossRef (h) P. Chalard, R. Remuson, Y. Gelas-Mialhe, and J.-C. Gramain, Tetrahedron Asymmetry, 1998, 9, 4361; CrossRef (i) H. Ratoni and E. P. Kuendig, Org. Lett., 1999, 1, 1997; CrossRef (j) F. A. Davis, A. Rao, and P. J. Carroll, Org. Lett., 2003, 5, 3855; CrossRef (k) S. Liu, Y. Fan, X. Peng, W. Wang, W. Hua, H. Akber, and L. Liao, Tetrahedron Lett., 2006, 47, 7681. CrossRef
5. For racemic syntheses of lasubine II, see: refs. 4a, b and R. A. Pilli, L. C. Dias, and A. O. Maldaner, J. Org. Chem., 1995, 60, 717, and references cited therein; CrossRef For asymmetric syntheses of (–)-lasubine II, see: ref. 4h and T. G. Back, M. D. Hamilton, V. J. J. Lim, and M. Parvez, J. Org. Chem., 2005, 70, 967, and references cited therein; CrossRef For a synthesis of 8-epi-(-)-lasubine II, see: J. Lim and G. Kim, Tetrahedron Lett., 2008, 49, 88; CrossRef For a synthesis of antipodal (+)-lasubines, see: O. G. Mancheño, R. G. Arrayás, J. Adrio, and J. C. Carretero, J. Org. Chem., 2007, 72, 10294, and references cited therein. CrossRef
6. For a racemic synthesis of subcosine I, see: refs. 4a, b.
7. For an asymmetric synthesis of (+)-subcosine I, see: ref. 4g. For an asymmetric synthesis of (+)-subcosine II, see: ref. 4h.
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9. M. Atobe, N. Yamazaki, and C. Kibayashi, Tetrahedron Lett., 2005, 46, 2669. CrossRef
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11. The stereochemistry of the 1,3-cis-aminoalcohol 15 was assigned tentatively on the basis of the NOESY spectra of ii, which was obtained by the chemical transformation of the minor 1,3-trans-aminoalcohol i in two steps as shown below. Direct stereochemical assignment of the major isomer was performed by means of the NOESY spectra of the bicyclic lactone 8, which was derived from 15 (vide infra).
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13. The selected NOESY correlation of the bicyclic lactone confirmed the structure 8 as shown below.
14. Y. Shishido and C. Kibayashi, J. Org. Chem., 1992, 57, 2876. CrossRef