One-pot highly enantio- and diastereoselective synthesis of anti,anti vinylic 3-amino-1,2 diols via proline catalyzed sequential α-amination/ benzoyloxyallylation of aldehydes

Abstract

The first direct asymmetric synthesis of anti,anti vinylic 3-amino-1,2-diols from aldehydes is described via a one-pot sequential L-proline catalyzed α-amination/benzoyloxyallylation protocol. The reaction proceeds with exceptionally high diastereoselectivity (>99%) as can be explained based on the Felkin–Ahn transition state model. Its effectiveness is proven unambiguously by demonstrating a short asymmetric synthesis of D-ribo-phytosphingosine tetraacetate (93% ee).

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Vicinal amino diol subunits with three contiguous, heteroatom-bearing chiral carbons, constitute an important stereotriad pattern found in numerous pharmaceuticals and bioactive natural products.¹ The majority of synthetic strategies for these motifs often employ starting materials from the chiral pool^2a,b or utilize the ring-opening of chiral epoxy alcohols with amine nucleophiles.^2c A number of diastereoselective syntheses of these molecules have also been reported; some recent examples include the addition of Grignard reagents to α-substituted nitriles,^2d imines^2e or catalytic processes involving dihydroxylation of allylamines,^2f pinnacol coupling of chiral α-amino aldehydes^2g and an oxidation/reduction sequence of bicyclic methyleneaziridines.^2h However, the efficient construction of vicinal amino diol units with well-defined stereochemistry and derivatizable functional groups remains a challenge in organic synthesis. To the best of our knowledge, a direct method of synthesis for these stereotriads utilizing aldehydes as precursor remains elusive.

The synthetic methodology leading rapidly to structural complexity from readily available starting material through one-pot reaction sequence is widely recognized.³ In particular, proline catalyzed sequential reaction such as α-amination of aldehydes⁴ followed by Wittig,^5a,b aldol,^5c or Corey–Chaykovsky^5d have gained more prominence in recent years. This is necessitated because α-aminated aldehyde is prone to racemisation during isolation. In this communication, we wish to describe a one-pot procedure for a tandem α-amination/benzoyloxyallylation of aldehydes 1a–j that proceeds to give vicinal amino diols 2a–j in a highly enantio- and diastereoselective fashion (Scheme 1).

Scheme 1 In situ trapping of α-amino aldehydes (A) with benzoyloxyallyl bromide.

In the initial study, propanal 1a was α-aminated with diisopropyl azodicarboxylate (DIAD) catalyzed by L-proline (10 mol%) CH₃CN at 0 °C for 3 h that produced the corresponding α-aminated aldehyde (A) in situ, followed by the sequential addition of Zn powder (1.5 equiv.), 3-benzoyloxyallyl bromide⁶ (1.5 equiv.) and saturated aq. NH₄Cl at 0 °C, gave anti,anti vinylic 3-amino-1,2-diol 2a in 79% yield (dr = 7 : 3). Also, its diastereoselectivity could be marginally improved to 4 : 1 when the reaction was conducted at −10 °C. Finally, at −20 °C, we observed that 2a could be obtained as a single diastereomer with dr 99 : 1 and 77% ee. The subsequent investigation has shown that dibenzyl azadicarboxylate was found to be an excellent amine sources for this sequential reaction (entry 5) (Table 1).

Table 1 L-Proline catalyzed asymmetric sequential α-amination/benzoyloxyallylation reaction of propanal^a

No.	R′	T (°C)	Product (2a)
			Yield^b (%)	ee^c (%)	dr^c
a Propanaldehyde (5 mmol), amine (R′O2C–N=N–CO2^−R′) (5 mmol), L-proline (10 mol%), 3-benzoyloxyallyl bromide (7.5 mmol), Zn (7.5 mmol), saturated aq. NH4Cl (10 mL).b Isolated yield.c From chiral HPLC analysis.
1	iPr	0	79	69	7 : 3
2	iPr	−10	79	77	4 : 1
3	iPr	−20	79	77	99 : 1
4	tBu	−20	81	78	99 : 1
5	Bn	−20	84	93	99 : 1

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To extend the scope of this one-pot reaction, a series of aliphatic aldehydes bearing different functionalities (alkyl, aryl, alkenyl, benzoyloxy or methoxy methyl) were examined under the optimized condition (Table 2). For all the cases studied, the products 2a–j were indeed obtained in high yields (81–87%) and excellent enantioselectivity (91–99%) with de > 99%. The stereochemical assignment of this sequential reaction was made based on previously established absolute configuration of α-amino aldehydes.^4a The anti,anti stereochemistry in 2a was proven unambiguously from X-ray crystallographic analysis (Fig. 1).

Table 2 L-Proline-catalyzed asymmetric sequential α-amination/benzoyloxyallylation of aldehydes^a

No.	Aldehydes (R) (1a–j)	Products (2a–j)
		Amines (R′)	Yield^b (%)	ee^c (%)	de^c (%)
a Aldehyde (5 mmol), amine (R′O2C–N=N–CO2^−R′) (5 mmol), L-proline (10 mol%), CH3CN (25 mL), 0 °C, 3 h followed by 3-benzoyloxyallyl bromide (7.5 mmol), Zn (7.5 mmol), saturated aq. NH4Cl (10 mL), −20 °C, 2 h.b Isolated yield.c From chiral HPLC analysis.
1	Methyl (1a)	Bn	84	93	>99
2	Ethyl (1b)	iPr	87	91	>99
3	i-Propyl (1c)	iPr	83	95	>99
4	n-Propyl (1d)	iPr	86	93	>99
5	3-(Methoxymethoxy)-ethyl (1e)	iPr	87	93	99
6	3-(Benzyloxy)ethyl (1f)	tBu	84	93	99
7	But-3-enyl (1g)	iPr	82	95	>99
8	Benzyl (1h)	tBu	84	97	>99
9	4-Methoxybenzyl (1i)	tBu	81	99	>99
10	2-(Benzyloxy)methyl (1j)	Bn	85	93	>99

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Fig. 1 ORTEP diagram of compound 2a.

To rationalize the observed high anti,anti diastereoselectivity of vicinal amino diols, both Felkin–Ahn^6d (TS 1) and six membered transition state (TS II) model have been proposed (Fig. 2). Anti relationship at C₁–C₂ carbons is governed by the Felkin–Ahn model in which Zn atom of benzoyloxyallylzinc reagent is coordinated to the carbonyl oxygen and the nucleophilic attack of the corresponding reagent takes place at ‘Si’ face predominantly perpendicular to the bulky R¹N–NHR¹ group. Also, anti relationship at C₂–C₃ carbons can be explained based on the six membered transition state model (TS II) in which hydrazino alkyl group of aldehyde and OBz group of nucleophile are oriented in the pseudoequatorial position to deliver anti diol.

Fig. 2 Proposed transition state model (R¹ = CO₂iPr, CO₂tBu, CO₂Bn; R = alkyl, alkyl aryl).

To further extend its synthetic utility 1a was subjected to hydroboration/oxidation sequence that gave functionalized amino triol 3 in high yield. Also 1c was hydrogenated over RANEY® Ni followed by its Boc protection giving 4 in 89% yield (Scheme 2).

Scheme 2 Oxidative and reductive transformations of anti,anti vinylic 3-amino-1,2-diols.

Finally, a short enantioselective synthesis of D-ribo-phytosphingosine tetraacetate⁷ (7) seemed attractive to us because it is a bioactive lipid that has potential antitumor properties⁸ (Scheme 3). Its synthesis was achieved in 5 steps commencing from aldehyde 1j, which was subjected to D-proline catalyzed sequential α-amination/benzoyloxyallylation protocol to afford vinylic aminodiol ent-2j (85%, 93% ee). The LiOH-mediated hydrolysis of ent-2j gave oxazolidinone 5 in 75% yield. The cross-metathesis of 5 with 1-tetradecene over Grubbs' catalyst produced 6 (72% yield). The catalytic hydrogenation [RANEY® Ni, H₂ (60 psig), 24 h] of 6 followed by basic hydrolysis (K₂CO₃, MeOH) and its acetylation (Ac₂O, py, DMAP) produced the target phytosphingosine 7 in 76% yield and 93% ee.

Scheme 3 Synthesis of D-ribo-phytosphingosine tetraacetate (7).

In conclusion, we have described an unprecedented, one-pot procedure for a sequential α-amination/benzoyloxyallylation of aldehydes that leads to the synthesis of vinylic-3-amino-1,2-diols 2a–l in high yields with excellent enantio- and diastereoselectivities. This protocol generates three chiral centers consecutively with anti,anti relationship in a single step, and has been successfully applied to the short asymmetric synthesis of D-ribo-phytosphingosine tetraacetate, 7. We believe this one-pot sequential method will find tremendous application in the synthesis of bioactive natural products and pharmaceutical substances.

Acknowledgements

BBA thanks CSIR, New Delhi for the award of Senior Research Fellowship and DST (no. SR/S1/OC-67/2010), New Delhi for financial support. Authors thank Dr V. V. Ranade, Chair and Head, Chemical Engineering and Process Development Division for his constant encouragement.

Notes and references

1. (a) D. H. Rich, in Comprehensive Medicinal Chemistry, ed. P. G. Sammes, Pergamon Press, Oxford, 1990, vol. 2, p. 391; (b) S. C. Bergmeier, Tetrahedron, 2000, 56, 2561.
2. (a) S. Umezawa, Pure Appl. Chem., 1978, 50, 1453; (b) X. Liang, J. Andersch and M. Bols, J. Chem. Soc., Perkin Trans. 1, 2001, 2136; (c) C. Wang and H. Yamamoto, J. Am. Chem. Soc., 2014, 136, 6888; (d) P. Hutin and M. Larcheveque, Tetrahedron Lett., 2000, 41, 2369; (e) N. Meunier, U. Veith and V. Jager, Chem. Commun., 1996, 331; (f) J. S. Oh, J. Jeon, D. Y. Park and Y. G. Kim, Chem. Commun., 2005, 770; (g) A. W. Konradi and S. F. Pedersen, J. Org. Chem., 1990, 55, 4506; (h) J. W. Rigoli, I. A. Guzei and J. M. Schomaker, Org. Lett., 2014, 16, 1696 , and references cited therein.
3. (a) H. Sundén, I. Ibrahem, L. Eriksson and A. Córdova, Angew. Chem., Int. Ed., 2005, 44, 4877; (b) B. List, J. Am. Chem. Soc., 2000, 122, 9336; (c) D. B. Ramachary, Y. V. Reddy and M. Kishor, Org. Biomol. Chem., 2008, 6, 4188; (d) D. B. Ramachary, C. Venkaiah and Y. V. Reddy, Org. Biomol. Chem., 2014, 12, 5400; (e) M. Gruttadauria, L. A. Bivona, P. L. Meo, S. Riela and R. Noto, Eur. J. Org. Chem., 2012, 2635.
4. (a) B. List, J. Am. Chem. Soc., 2002, 124, 5656; (b) A. Bogevig, K. Juhl, N. Kumaragurubaran, W. Zhuang and K. A. Jorgensen, Angew. Chem., Int. Ed., 2002, 41, 1790; (c) N. Kumaragurubaran, K. Juhl, W. Zhuang, A. Bogevig and K. A. Jorgensen, J. Am. Chem. Soc., 2002, 124, 6254; (d) H. Vogt, S. Vanderheiden and S. Brase, Chem. Commun., 2003, 2448 , and references cited therein.
5. (a) A. J. Oelke, S. Kumarn, D. A. Longbottom and S. V. Ley, Synlett, 2006, 2548; (b) S. P. Kotkar, V. B. Chavan and A. Sudalai, Org. Lett., 2007, 9, 1001; (c) N. S. Chowdari, D. B. Ramachary and C. F. Barbas, Org. Lett., 2003, 5, 1685; (d) B. S. Kumar, V. Venkataramasubramanian and A. Sudalai, Org. Lett., 2012, 14, 2468; (e) V. Rawat, B. S. Kumar and A. Sudalai, Org. Biomol. Chem., 2013, 11, 3608.
6. (a) L. Keinicke, P. Fristrup, P. O. Norrby and R. Madsen, J. Am. Chem. Soc., 2005, 127, 15756; (b) M. Lombardo, R. Girotti, S. Morganti and C. Trombini, Chem. Commun., 2001, 2310; (c) M. Lombardo, R. Girotti, S. Morganti and C. Trombini, Org. Lett., 2001, 3, 2981; (d) M. Liu, X. W. Sun, M. H. Xu and G. Q. Lin, Chem.–Eur. J., 2009, 15, 10217 , and references cited therein.
7. (a) M. Miroslava, P. Kvetoslava and G. Jozef, Chem. Pap., 2013, 67, 84; (b) R. Mettu, N. R. Thatikonda, O. S. Olusegun, R. Vishvakarma and J. R. Vaidya, ARKIVOC, 2012, 421; (c) G. S. Rao and B. V. Rao, Tetrahedron Lett., 2011, 52, 4861.
8. (a) E. Kobayashi, K. Motoski, Y. Yamaguchi, T. Uchida, H. Fukushima and Y. Koezuka, Oncol. Res., 1995, 7, 529; (b) R. D. Goff, Y. Gao, J. Mattner, D. Zhou, N. Yin, C. Cantu, L. Teyton, A. Bendelac and P. B. Savage, J. Am. Chem. Soc., 2004, 126, 13602.

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Footnote

† Electronic supplementary information (ESI) available: ¹H NMR, ¹³C NMR, IR, and HRMS of new compounds. CCDC 1026336. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra02830b

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