Letter pubs.acs.org/OrgLett
Organocatalytic Entry into 2,6-Disubstituted Aza-Achmatowicz Piperidinones: Application to (−)-Sedacryptine and Its Epimer Ferdi van der Pijl, Robert K. Harmel, Gaston J. J. Richelle, Peter Janssen, Floris L. van Delft, and Floris P. J. T. Rutjes* Institute for Molecules and Materials, Radboud University Nijmegen, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands S Supporting Information *
ABSTRACT: Enantiomerically pure 2,6-disubstituted piperidinones were synthesized from furfural involving an organocatalyzed Mannich reaction, aza-Achmatowicz reaction, and an N-acyliminium ion-mediated coupling step. This approach was also successfully applied to a total synthesis of (−)-sedacryptine and one of its epimers.
T
bonyl)-protected amines as substrates for the aza-Achmatowicz reaction.6 These N-Boc-protected amines were prepared via the proline-catalyzed asymmetric Mannich reaction by applying the conditions reported by List et al.6c,d Thus, under basic conditions, sulfone 5 was eliminated to give the corresponding crude imine,7 which was directly treated with L-proline (20 mol %) and an aldehyde to give the corresponding β-amino aldehydes (Table 1). The resulting crude Mannich products were directly in situ reduced, resulting in γ-amino alcohols 7a−f which were readily isolated by precipitation from n-heptane. Aliphatic (Table 1, entries 1−3), allylic (Table 1, entry 4), and aromatic substituents (Table 1, entries 5 and 6) were smoothly introduced in reasonable yields and with excellent selectivities.
he 3-hydroxypiperidine scaffold is considered a privileged structural moiety in Nature. Various natural products share this skeletal basis, and many of them exhibit relevant biological activities.1 Prominent examples of natural products containing this scaffold include (−)-sedacryptine (1) and (+)-febrifugine (2) (Figure 1). A number of synthetic
Table 1. Asymmetric Organocatalytic Mannich Reaction Figure 1. 3-Hydroxypiperidine-containing alkaloids.
approaches to this scaffold have been reported,2 including strategies that have been published by our group to synthesize (+)-febrifugine (2).3 Despite the existing methods, there is a need for preferably catalytic methodologies to asymmetrically synthesize these scaffolds and have access to new substitution patterns. We considered the substituted piperidinones 4 versatile precursors for the target 3-hydroxypiperidines, which in turn should be accessible via the aza-Achmatowicz reaction from the corresponding enantiopure aminomethyl furans 3.4 Based on our experience with the proline-catalyzed Mannich reaction,5 we envisioned that these enantiopure furans should be readily accessible from furfural. Considering the facile deprotection and their ability to induce high stereoselectivity in organocatalyzed Mannich reactions, we chose to work with N-Boc (N-tert-butyloxycar© 2014 American Chemical Society
entry
product
R
yielda (%)
drb
eeb (%)
1 2 3 4 5 6
7a 7b 7c 7d 7e 7f
Me Pr i-Pr allyl Ph 4-BrC6H4
54 57 58 71 50 43
>1:20 >1:20 >1:20 >1:20 >1:20 >1:20
>99 >99 97 99 >99 95c
a c
Isolated yield. bDetermined after precipitation from n-heptane. Absolute stereochemistry determined by X-ray structure analysis.9
Received: February 28, 2014 Published: March 26, 2014 2038
dx.doi.org/10.1021/ol500633u | Org. Lett. 2014, 16, 2038−2041
Organic Letters
Letter
Table 3. N-Acyliminium Ion Addition Reactions
The next step was the aza-Achmatowicz reaction, which according to the literature in the case of carbamoylated amines with NBS/MeOH is likely to result in formation of significant amounts of side products, in particular the overoxidized 3hydroxypyridine.4 By using m-CPBA as the oxidant, the pyridine formation could to a large extent be suppressed.8 Indeed, aza-Achmatowicz reactions with m-CPBA of γ-amino alcohols 7a−e afforded the intended hemiaminals, which due to the anticipated lability, were directly converted with CH(OEt)3 and BF3·Et2O into the N,O-acetals 10a−e in moderate to good yields (Table 2, entries 1−4 and 6). Nevertheless, we observed Table 2. Aza-Achmatowicz Reactionsa
entry
substrate
product
R
R1
R2
yieldb (%)
drc
1 2 3 4 5 6 7
7a 7b 7c 7d 7e 9 8
10a 10b 10c 10d 9e 10e 11
Me Pr i-Pr allyl Ph Ph Ph
H H H H H H Ac
Et Et Et Et H Et H
88 89 45 79 84 78 70
1:1.1 1:1.2 1:1.1 1:1.0 1:4 1:1.2 1:6
a
Isolated yield of major diastereoisomer after chromatography. bBased on 1 H NMR of crude product. c Isolated as a mixture of diastereoisomers. dReaction in CH2Cl2 at −50 °C. eWith BF3·Et2O (3 equiv) in CH2Cl2 at −78 °C.
(trimethylsiloxy)styrene surprisingly gave inversion of the selectivity so that the trans-isomer was formed as the major product (Table 3, entry 6). Having established a robust sequence of steps to prepare enantiopure piperidinones, we aimed to apply this pathway in a total synthesis of (−)-sedacryptine (1).11 A retrosynthetic analysis of (−)-1 is shown in Scheme 1. We envisioned that the 2-hydroxy-2-phenylethyl substituent of
Conditions: (a) Ac2O, Et3N, DMAP; (b) BF3·Et2O, CH(OEt)3. b Isolated yield. cBased on 1H NMR of crude product. a
that 9e was more stable than expected and could be purified by flash chromatography (Table 2, entry 5). NMR analysis revealed that N,O-acetals 10a−e and 9e were isolated as bicyclic hemiacetals rather than the corresponding hydroxyketones. The monocyclic piperidinone 11 was prepared by acetylation of the primary alcohol prior to the aza-Achmatowicz reaction (Table 2, entry 7). With these enantiopure N,O-acetal scaffolds in hand, we studied further functionalization via N-acyliminium ion chemistry.3,10 Initial attempts showed that allyltrimethylsilane addition to the N-acyliminium ion derived from 10e did not give the desired results. On the other hand, N-acyliminium ion reactions starting from 9e afforded the anticipated 2,6disubstituted products, although with poor diastereoselectivities. Preferred axial attack of the nucleophile is hampered by steric interactions with the concave side of the molecule. Consequently, we expected better selectivities when monocyclic piperidinone 11 was subjected to N-acyliminium ion chemistry. Gratifyingly, reacting 11 with allyltrimethylsilane in the presence of a catalytic amount of tin(II)triflate, followed by deprotection of the crude product with TFA, resulted in formation of 2,6-disubstituted piperidinone 12a as a single cisdiastereoisomer (Table 3, entry 1). We also observed that increasing the steric bulk of the nucleophile had a large effect on the selectivity of the reaction due to hindrance of the axially positioned 2-substituent (Table 3, entries 2 and 3), while addition of the smaller 3trimethylsilyl-1,2-butadiene afforded 12d again as a single diastereoisomer (Table 3, entry 4). Addition of 2(trimethylsiloxy)propene yielded a 1:1 mixture of diastereoisomers (Table 3, entry 5), while addition of α-
Scheme 1. Retrosynthetic Analysis
(−)-1 could be introduced either from 22 by ozonolysis and subsequent Grignard addition or via reduction of benzylic ketone 17. Both 17 and 22 can be traced back to Nacyliminium ion precursor 15, which in turn will be derived from β-amino ketone 13. The synthesis of 13 commenced with the conversion of αamido sulfone 5 into the corresponding imine (Scheme 2), which was subsequently reacted with acetone in a prolinecatalyzed asymmetric Mannich reaction affording 13 in 71% yield and excellent ee (99%). It appeared necessary to conduct this reaction under dilute conditions (0.02 M) to prevent the product from reacting with a second imine leading to the bisadduct. After protection of the ketone as a dioxolane with 2039
dx.doi.org/10.1021/ol500633u | Org. Lett. 2014, 16, 2038−2041
Organic Letters
Letter
Scheme 2. Preparation of the N-Acyliminium Ion Precursor
Scheme 3. Synthesis of 6-epi-sedacryptine
ethylene glycol and TsOH, the stage was set for the azaAchmatowicz reaction. Unfortunately, the reaction with mCPBA in CH2Cl2 resulted in oxidation of the desired hemiaminal into 3-hydroxypyridine derivative 16. We reason that 16 was formed via a 3-chlorobenzoic acid-facilitated dehydration of 15, followed by a Baeyer−Villiger type oxidation of the intermediate iminium ion, driven by the resulting aromatic character of the ring. Switching to nonacidic oxidants might suppress iminium ion formation and hence oxidation of the product. Investigating the aza-Achmatowicz reaction of 14 with alternative oxidants (e.g., singlet oxygen,12 NBS, Br2, or dioxiranes)13 showed that only dimethyldioxirane (DMDO) resulted in clean product formation (82% yield). However, since the preparation of large quantities of DMDO is rather laborious, we adjusted the initial procedure by introducing a biphasic system to remove the acidic remainder of the reaction. Indeed, conducting the aza-Achmatowicz reaction with m-CPBA in a CH2Cl2/phosphate buffer at pH 7.4 furnished 15 in 60% yield. At this point, introduction of the C-6 substituent had to be realized via N-acyliminium ion addition. Applying the conditions to prepare compounds 12 (vide supra) smoothly afforded ketone 17 as a single diastereoisomer in 88% yield. Since NMR did not give conclusive information of the stereochemistry at this stage, we chose to continue the synthesis with reduction of both ketones with (R)-CBS/BH3·Me2S and subsequent olefin hydrogenation to give diol 19. The stereochemistry of 19 was confirmed by 2D NOESY analysis of cyclic carbamate 21.11e,g Subsequent LiAlH4 reduction, deprotection, and acetal hydrolysis then provided 6-epi-sedacryptine 20 in 9% overall yield (Scheme 3). In order to synthesize the naturally occurring diastereoisomer of sedacryptine, we decided to continue with the cis-substituted piperidinone 22, readily obtained as a single diastereoisomer in 46% yield by addition of allyltrimethylsilane to the N-acyliminium ion derived from 15 (Scheme 4). Subsequent conjugate reduction with a copper hydride species followed by fluoride-mediated desilylation afforded ketone 23 in 85% yield.14 Stereoselective ketone reduction and ozonolysis of the double bond resulted in an inseparable mixture of the aldehyde and triphenylphosphine oxide, but subsequent silylation with TBSCl allowed us to obtain aldehyde 25 in pure form. Construction of the 2-hydroxy-2-phenylethyl substituent was finished by Grignard addition of PhMgBr to aldehyde 25 resulting in the benzylic alcohol obtained as a separable mixture of diastereoisomers. The action of LiAlH4 in refluxing THF then resulted in removal of the TBS group and reduction of the carbamate. Finally, ketone deprotection and
Scheme 4. Total Synthesis of (−)-Sedacryptine
isomerization of the resulting hemiacetal in hot aqueous HCl furnished (−)-sedacryptine (1) of which the optical rotation and NMR spectra were in accordance with literature values.11b,g In conclusion, we have developed an organocatalyzed Mannich/aza-Achmatowicz/N-acyliminium ion reaction sequence for straightforward preparation of enantiopure 2,6disubstituted piperidines. This sequence was successfully applied to a total synthesis of natural (−)-sedacryptine (1) and its C-6-trans epimer 20.
■
ASSOCIATED CONTENT
S Supporting Information *
Experimental procedures, characterization of new products, and copies of 1H and 13C NMR spectra, including NOESY analysis for the structural assignments of 12a, 12f, and 21. This material is available free of charge via the Internet at http://pubs.acs.org.
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. 2040
dx.doi.org/10.1021/ol500633u | Org. Lett. 2014, 16, 2038−2041
Organic Letters
Letter
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS This research was part of the CatchBio program, which was supported by the Smart Mix Program of The Netherlands Ministry of Economic Affairs and The Netherlands Ministry of Education, Culture and Science.
■
REFERENCES
(1) (a) Strunz, G. M.; Findlay, J. A. In The Alkaloids; Brossi, A., Ed.; Academic Press: San Diego, 1986; Vol. 26, p 89. (b) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435−446. (2) Wijdeven, M. A.; Willemsen, J.; Rutjes, F. P. J. T. Eur. J. Org. Chem. 2010, 2831−2844. (3) Wijdeven, M. A.; van den Berg, R. J. F.; Wijtmans, R.; Botman, P. N. M.; Blaauw, R. H.; Schoemaker, H. E.; van Delft, F. L.; Rutjes, F. P. J. T. Org. Biomol. Chem. 2009, 7, 2976−2980. (4) For a review, see: Ciufolini, M. A.; Hermann, C. Y. W.; Dong, Q.; Shimizu, T.; Swaminathan, S.; Xi, N. Synlett 1998, 105−114. (5) (a) Verkade, J. M. M.; van Hemert, L. J. C.; Quaedflieg, P. J. L. M.; Rutjes, F. P. J. T. Chem. Soc. Rev. 2008, 37, 29−41. (b) Verkade, J. M. M.; van der Pijl, F.; Willems, M. A. J. H. P.; Quaedflieg, P. J. L. M.; van Delft, F. L.; Rutjes, F. P. J. T. J. Org. Chem. 2009, 74, 3207−3210. (6) (a) Vesely, J.; Rios, R. Chem. Soc. Rev. 2014, 43, 611−630. (b) Vesely, J.; Rios, R.; Ibrahem, I.; Cordova, A. Tetrahedron Lett. 2007, 48, 421−425. (c) Yang, J. W.; Stadler, M.; List, B. Angew. Chem., Int. Ed. 2007, 46, 609−611. (d) Yang, J. W.; Stadler, M.; List, B. Nat. Protoc. 2007, 2, 1937−1942. (7) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964−12965. (8) Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2001, 3, 401−404. (9) Crystal structure data can be obtained free from charge via the Internet at www.ccdc.cam.ac.uk/conts/retreiving.html (deposition no. CCDC 988042). (10) Botman, P. N. M.; Dommerholt, F. J.; de Gelder, R.; Broxterman, Q. B.; Schoemaker, H. E.; Rutjes, F. P. J. T.; Blaauw, R. H. Org. Lett. 2004, 6, 4941−4944. (11) Isolation and X-ray structure analysis: (a) Hootelé, C.; Colau, B.; Halin, F.; Declercq, J. P.; Germain, G.; Vanmeerssche, M. Tetrahedron Lett. 1980, 21, 5061−5062. Absolute configuration: (b) Colau, B.; Hootelé, C. Can. J. Chem. 1983, 61, 470−472. For racemic syntheses: (c) Natsume, M.; Ogawa, M. Heterocycles 1983, 20, 601−605. (d) Sugiura, M.; Hagio, H.; Hirabayashi, R.; Kobayashi, S. J. Am. Chem. Soc. 2001, 123, 12510−12517. For syntheses of enantiomerically pure sedacryptine: (e) Akiyama, E.; Hirama, M. Synlett 1996, 100−102. (f) Plehiers, M.; Hootele, C. Can. J. Chem. 1996, 74, 2444−2453. (g) Wee, A. G. H.; Fan, G. J. Org. Lett. 2008, 10, 3869−3872. (12) Noutsias, D.; Kouridaki, A.; Vassilikogiannakis, G. Org. Lett. 2011, 13, 1166−1169. (13) Adger, B. M.; Barrett, C.; Brennan, J.; Mckervey, M. A.; Murray, R. W. J. Chem. Soc., Chem. Commun. 1991, 1553−1554. (14) Pelss, A.; Kumpulainen, E. T. T.; Koskinen, A. M. P. J. Org. Chem. 2009, 74, 7598−7601.
2041
dx.doi.org/10.1021/ol500633u | Org. Lett. 2014, 16, 2038−2041
