Unsaturated Amino Alcohols via Cyclization of Allylic Bistrichloroacetimidates

Abstract

In intramolecular allylic substitution of bistrichloroacetimidates, one of the imidate groups can serve as a N-nucleophile while the other can serve as a leaving group, leading to 2-vinyloxazolines. Two approaches based on different mechanisms for allylic substitution can be applied to achieve cyclization of the bisimidates. The reaction, catalyzed by palladium(II), presumably involves aminometalation of the double bond followed by deoxypalladation. Enantioenriched products can be obtained using chiral palladium(II) catalysts as demonstrated for the cyclization of achiral bisimidates derived from (E/Z)-butene-1,4-diol. Allylic substitution can proceed via a competing mechanism that involves carbenium ion formation from a metal-complexed imidate. This enables the use of Lewis acids as nonexpensive and less toxic alternative to palladium catalysts. Regioselectivity of Lewis acid catalyzed bisimidate cyclization is controlled by formation of the most stable carbenium ion as proposed intermediate. This approach provides an efficient access to vinylglycinols, butadienylglycinol, and C-quaternary vinylglycinols.

Efficient construction of the unsaturated amino alcohol substructure provides an access to a variety of amino alcohol derivatives via modification of the double bond in the resulting products.[1] In addition, oxidation of the primary alcohol functionality gives pharmacologically relevant unsaturated amino acids.[2]

We have focused our research on the cyclization of allylic bistrichloroacetimidates 1 to oxazolines 2 as a key step for the synthesis of unsaturated amino alcohols (Scheme [1]). Bisimidates 1 can be prepared in a one-step reaction from diols in high yield. In these substrates, one of the imidates can act as a N-nucleophile while the other as a leaving group in an allylic substitution reaction. This avoids the need to discriminate between hydroxyl groups in the diols if different functionalities are present and also enables a concise synthesis of the substrates.[3]

Cyclization of trichloroacetimidate (Z)-3 derived from (Z)-butane-1,4-diol on vinyloxazoline 4 using PdCl₂(MeCN)₂ as catalyst was reported by Sabat and Johnson as a method to prepare racemic vinylglycinol.[4] The authors proposed a π–allyl mechanism; however, our studies have revealed that allylic substitution for such structural types takes place via an aminopalladation–deoxypalladation route.[3] Motivated by the high synthetic value of vinyloxazoline 4, we have developed an asymmetric version for the cyclization of bisimidates 3 (Scheme [2]).[5] Both imidate isomers (E)- and (Z)-3 could be transformed into the enantioenriched vinyloxazoline 4 in high yield using a catalyst system consisting of PdCl₂(MeCN₂), a chiral biphenyldiphosphine ligand, and AgBF₄. We propose that the active catalyst for the reaction is the cationic palladium(II) complex 5 (simplified representation in Scheme [2]).

The enantiomeric excess of the product 4 was higher when starting from isomer (E)-3 in the case of all ligands investigated. Noteworthy, the relatively less expensive BINAP could be used as a ligand to achieve a 94% enantiomeric excess of oxazoline 4. The isomeric bisimidate (Z)-3 was a more challenging substrate, but ligands with bulkier substituents such as Xyl-BINAP, DM-SEGPHOS, 3,5-DM-MeO-BIPHEP, and TMO-MeO-BIPHEP allowed synthetically useful enantiomeric excesses of oxazoline 4 to be achieved.

Bisimidate 3 represents a special substrate case that is compatible with cationic palladium(II) complexes. Typically, under these conditions, allylic trichloroacetimidates are prone to ionization by abstraction of the palladium(II)-complexed imidate and tolerate only neutral palladium(II) catalysts.[6]

Possible mechanistic pathways involving aminopalladation were considered to explain vinyloxazoline 4 formation (Scheme [3]). Pathway A involves Overman rearrangement (6-endo aminopalladation–deoxypalladation) of bisimidate 3 to trichloroacetamide 6 via intermediate A.[6] Trichloroacetamide 6 theoretically can undergo O-alkylation to give vinyloxazoline 4. However, when the potential reaction intermediate 6, prepared by an alternative method, was subjected to the palladium(II) catalyst system no reaction was observed. This allows pathway A to be excluded. Based on our previous studies,[3] pathway B, which involves 5-exo aminopalladation to intermediate B followed by deoxypalladation to product 4, is favored.

Abstraction of the imidate group from substrate 3 to form carbenium ion C with a chiral counterion could also be envisaged as a pathway for oxazoline 4 formation (Scheme [4]). When imidate 7 derived from butene-1,2-diol was subjected to the chiral palladium(II) catalyst system, oxazoline 4 was obtained in quantitative yield, but in practically racemic form.[7] The most probable mechanism for the cyclization of bisimidate 7 involves the formation of carbenium ion C via ionization of palladium(II)-complexed imidate. Since this leads to racemic oxazoline 4, ionization of the complexed imidate can be excluded as a pathway for the cyclization of bisimidate 3.

Vinyloxazoline 4 can be transformed to vinylglycinol 8 under strong acidic hydrolysis conditions[4] [8] or to N-trichloroacetylvinylglycinol 9 under milder hydrolytic conditions (Scheme [5]).[8] The oxazoline ring in 4 can be cleaved with HBr to give allylamine derivative 10 (Scheme [5]).[8] We have confirmed that these transformations take place with complete conservation of enantiomeric integrity.

As discussed above, allylic substitution in bisimidates is possible not only via the aminopalladation route, but also by the activation of the trichloroacetimidate group.[9] There are a few precedents for the cyclization of allylic bisimidates reported in the literature. Bistrichloroacetimidate 12 prepared in situ from cyclic unsaturated 1,2-diol 11 was transformed into oxazoline 13 in a BF₃-catalyzed reaction in order to introduce the amino alcohol substructure in the total synthesis of staurosporine by Danishefsky et al. (Scheme [6]).[10] Similarly, the BF₃-catalyzed cyclization of bisimidate 14 to oxazoline 15 was used to achieve 1,2-bis-epi-valienamine by Cumpstey et al. (Scheme [6]).[11]

We have performed studies on Lewis acid catalyzed cyclizations of acyclic allylic bisimidates as a route to unsaturated amino alcohols. Substrates 19 and 20 derived from substituted butene-1,4-diol 17 or pentene-1,5-diol 18 can be prepared via a short synthetic route from aldehydes 16 (Scheme [7]).

Bisimidates 19 and 20 can be regioselectively transformed into vinyl oxazolines 21 and oxazines 22 in good yield and in a very short reaction time when exposed to Lewis acid catalysts (Scheme [7, ]Figure [1]). [12] The Brønsted acid (TsOH·H₂O) also catalyzed the cyclization of imidates (E/Z)-19, although the reaction time was considerably longer (4.5–16 h). Both E- and Z-configured bisimidates 19 and 20 could be successfully used for the cyclization reaction. Bisimidates 19e,d and 20b containing a carbenium ion stabilizing group (R = Ar) formed oxazoline 21e,d and oxazine 22b during their synthesis. Bisimidate (Z)-19d could be isolated and cyclized in the presence of Lewis acid catalysts which gave an improved yield of the product 21d compared to the uncatalyzed reaction (Figure [1]).

An S_N1-type reaction mechanism involving carbenium ion intermediate D is proposed for the cyclization of allylic bisimidates 19 and 20 (Scheme [8]). This is based on the observation that the imidate group at the secondary carbon atom in substrate 19 was substituted forming 4-vinyloxazoline 21 as the only detectable regioisomer.

Enantiomerically enriched imidates (E)-19b and (Z)-19b gave vinyloxazoline 21b with a very poor enantiomeric excess (4–16%) when exposed to FeCl₃, AlCl₃, BF₃·OEt₂, and TMSOTf catalysts and this provides additional proof for the S_N1-type mechanism.

Oxazolines 21 and oxazines 22 can be readily transformed to N-Boc-protected amino alcohols 23 and 24 by a one-pot, two-step procedure (Scheme [9]). These in turn can be used to prepare protected unsaturated amino acids 25 and 26.

We also aimed to prepare vinyloxazoline 4 via Lewis acid catalyzed cyclization of bisimidate 3.[8] Lewis acid (FeCl₃ or AlCl₃) catalyzed reaction turned out to be very slow and problematic due to the formation of byproducts (Scheme [10]). A reason for this could be slow dissociation of the Lewis acid complexed imidate group in compound 3 to give carbenium ion C (see Scheme [4]). Bistrichloroacetimidate 7 derived from commercially available but-3-ene-1,2-diol underwent rapid cyclization to vinyloxazoline 4 in excellent yield in the presence of Lewis acid catalysts (Scheme [10]). More facile dissociation of the Lewis acid complexed secondary imidate group in compound 7 can explain the difference in reactivity between bisimidates 3 and 7.

Bisimidate 27 of hexadiene-1,6-diol that is vinylogous to bisimidate 3 was also investigated as a substrate for the Lewis acid catalyzed cyclization.[13] Bisimidate 27 was prepared in three steps from propargylic alcohol and subjected to AlCl₃ catalysis. This provided butadienyloxazoline 28, presumably via carbenium ion E intermediate. Oxazoline 28 was transformed into protected butadienylglycinol 29 in a one-pot, two-step procedure (Scheme [11]).

Allylic bisimidates 30 substituted at the double bound are readily available from butyn-1,4-diol or from 3-substituted furans. Exposure of allylic bisimidates 30 to Lewis acid catalysis provided 4,4-disubstituted oxazolines 31 in good yields.[14] The high regioselectivity can be explained based on the proposed S_N1 reaction mechanism. According to this, acid-promoted abstraction of the imidate group should lead to the most stable tertiary carbenium ion F which is trapped by the second imidate group to give 4,4-disubstituted oxazoline 31. Several cyclization products were transformed into protected C-quaternary vinylglycinols 32 in a one-pot, two-step procedure (Scheme [12]).

In conclusion, cyclization of allylic bistrichloroacetimidates to oxazolines or oxazines is a versatile method for the synthesis of unsaturated amino alcohols. It can be performed by two different approaches using palladium(II) or Lewis acid catalysis proceeding via different reaction mechanisms. Asymmetric palladium(II) catalysis can be applied to achieve enantioenriched product formation from achiral bisimidates. However, palladium(II) catalysis is limited to substrates that are not prone to ionization of the metal-complexed imidate. Lewis acid catalysts, on the other hand, activates the imidate group, leading to a carbenium ion intermediate which is trapped by the second imidate group. Abstraction of the imidate group in the substrate leading to the most stable carbenium ion determines the high regioselectivity of product formation. Lewis acids are more economical alternatives to palladium(II), therefore it is an important goal to achieve ­stereoselective bisimidate cyclization with these catalysts. Work in this direction is currently carried out in our group.

Acknowledgment

Financial support from the European Regional Development Fond (grant number ERAF 2010/2DP/2.1.1.1.0./10/APIA/VIAA/074) is gratefully acknowledged.

• References


Selected references:
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  Thieme Connect
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  CrossrefSearch in Google Scholar
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  CrossrefSearch in Google Scholar
• 5 Maleckis A, Klimovica K, Jirgensons A. J. Org. Chem. 2010; 75: 7897
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For leading references, see:
• 6a Donde Y, Overman LE. J. Am. Chem. Soc. 1999; 121: 2933
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• 6b Anderson CE, Overman LE. J. Am. Chem. Soc. 2003; 125: 12412
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• 7 Grigorjeva, L.; Jirgensons, A. unpublished results.
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  CrossrefSearch in Google Scholar
• 9a Kokotos G, Chiou A. Synthesis 1997; 168
  Thieme Connect
• 9b Wessel H.-P, Iversen T, Bundle DR. J. Chem. Soc., Perkin Trans. 1 1985; 2247
  Crossref
• 10a Link JT, Gallant M, Danishefsky SJ, Huber S. J. Am. Chem. Soc. 1993; 115: 3782
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• 10b Link JT, Raghavan S, Danishefsky SJ. J. Am. Chem. Soc. 1995; 117: 552
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• 11 Ramstadius C, Hekmat O, Eriksson L, Stålbrand H, Cumpstey I. Tetrahedron: Asymmetry 2009; 20: 795
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• 12 Grigorjeva L, Jirgensons A. Eur. J. Org. Chem. 2011; 2421
• 13 Klimovica, K.; Maleckis, A.; Jirgensons, A. unpublished results.
• 14 Klimovica K, Grigorjeva L, Maleckis A, Popelis J, Jirgensons A. Synlett 2011; 284

• References


Selected references:
• 1a Muncipinto G, Moquist PN, Schreiber SL, Schaus SE. Angew. Chem. Int. Ed. 2011; 50: 8172
  CrossrefSearch in Google Scholar
• 1b Cresswell AJ, Davies SG, Lee JA, Morris MJ, Roberts PM, Thomson JE. J. Org. Chem. 2012; 77: 7262
  CrossrefSearch in Google Scholar
• 1c Joosten A, Persson AK. Å, Millet R, Johnson MT, Bäckvall J.-E. Chem. Eur. J. 2012; 18: 15151
  CrossrefSearch in Google Scholar
• 1d Ghosal P, Shaw AK. J. Org. Chem. 2012; 77: 7627
  CrossrefSearch in Google Scholar
• 1e Liang H, Zhou Y, Ciufolini M. Synthesis 2010; 2515
  Thieme Connect
• 2 For a review see: Berkowitz DB, Charette BD, Karukurichi KR, McFadden JM. Tetrahedron: Asymmetry 2006; 17: 869
  CrossrefSearch in Google Scholar
• 3 We have previously developed the Pd(II)-catalyzed cyclization of δ-acetoxy allylic imidates to vinyloxazolines: Maleckis A, Jaunzeme I, Jirgensons A. Eur. J. Org. Chem. 2009; 6407
• 4 Sabat M, Johnson CR. Org. Lett. 2000; 2: 1089
  CrossrefSearch in Google Scholar
• 5 Maleckis A, Klimovica K, Jirgensons A. J. Org. Chem. 2010; 75: 7897
  CrossrefSearch in Google Scholar

For leading references, see:
• 6a Donde Y, Overman LE. J. Am. Chem. Soc. 1999; 121: 2933
  Search in Google Scholar
• 6b Anderson CE, Overman LE. J. Am. Chem. Soc. 2003; 125: 12412
  CrossrefSearch in Google Scholar
• 6c Jautze S, Seiler P, Peters R. Chem. Eur. J. 2008; 14: 1430
  CrossrefPubMedSearch in Google Scholar
• 6d Watson MP, Overman LE, Bergman RG. J. Am. Chem. Soc. 2007; 129: 5031
  CrossrefPubMedSearch in Google Scholar
• 7 Grigorjeva, L.; Jirgensons, A. unpublished results.
• 8 Grigorjeva L, Maleckis A, Klimovica K, Skvorcova M, Ivdra N, Leitis G, Jirgensons A. Chem. Heterocycl. Compd. 2012; 48: 919
  CrossrefSearch in Google Scholar
• 9a Kokotos G, Chiou A. Synthesis 1997; 168
  Thieme Connect
• 9b Wessel H.-P, Iversen T, Bundle DR. J. Chem. Soc., Perkin Trans. 1 1985; 2247
  Crossref
• 10a Link JT, Gallant M, Danishefsky SJ, Huber S. J. Am. Chem. Soc. 1993; 115: 3782
  CrossrefSearch in Google Scholar
• 10b Link JT, Raghavan S, Danishefsky SJ. J. Am. Chem. Soc. 1995; 117: 552
  CrossrefSearch in Google Scholar
• 11 Ramstadius C, Hekmat O, Eriksson L, Stålbrand H, Cumpstey I. Tetrahedron: Asymmetry 2009; 20: 795
  CrossrefSearch in Google Scholar
• 12 Grigorjeva L, Jirgensons A. Eur. J. Org. Chem. 2011; 2421
• 13 Klimovica, K.; Maleckis, A.; Jirgensons, A. unpublished results.
• 14 Klimovica K, Grigorjeva L, Maleckis A, Popelis J, Jirgensons A. Synlett 2011; 284