CC BY-NC-ND 4.0 · Synlett 2021; 32(06): 601-604
DOI: 10.1055/a-1308-0370
letter

Stereoselective Synthesis of (4S,5S)-5-Vinyloxazolidin-2-one-4-carboxylate as a β-Vinylserine Synthetic Equivalent by Vinyl Grignard Addition to an N-Tosyl Version of Garner’s Aldehyde

,
Yuqi M. Cao
,
Brynn D. Lewis
,
Madison H. Powers
,
Andrew W. Thompson
,
John M. Bennett
This work was supported by the National Institutes of Health (GM123534-01A1) and the National Science Foundation (MRI 1726308).
 


Abstract

A highly efficient synthesis of a β-vinylserine synthetic equivalent is reported that exploits the stereodirecting effect of the N-toluenesulfonamide in an anti-diastereoselective (8.5:1) vinyl Grignard addition to an analogue of Garner’s aldehyde. Both aryl and alkyl ­Grignards are shown to give increased anti-selectivity compared with N-Boc Garner’s aldehyde.


#

As part of our synthetic work directed toward glycopeptide mimetics, we required a suitably protected (2S,3S)-β-vinylserine (β-VSer) for use as a synthetic building block. Many noncanonical amino acids have been incorporated into protein and peptide structures to interrogate various cellular functions.[1] In particular, alkenyl amino acids incorporated into peptides have proven to be useful for peptide stapling by a cross-metathesis reaction to afford conformationally restricted peptidomimetics.[2] In addition, Zhang and van der Donk have examined the effect of direct alkenyl amino acid incorporation.[3] They incorporated a diastereomer of our desired β-VSer (referred to as a threonine analogue) into a peptide sequence of lacticin synthetase to examine substrate selectivity toward dehydration reactions. The pentenoic backbone of β-VSer itself is also a common scaffold for dipeptide isosteres,[4] which have been investigated as enzyme inhibitors and as receptor antagonists.[5] This platform has also been a versatile synthetic intermediate for preparing sphingomyelin analogues[6] and glycosidase inhibitors such as the deoxynojirimycins.[7] It has also served as a building block for antitumor agents such as 2-epi-pachastrissamine[8] or for glycopeptide[9] and β-lactam antibiotics.[10] For our purposes, we sought to elaborate the β-VSer alkene through cross-metathesis and/or Trost–Tsuji π-allylic alkylation chemistry for the development of novel glycopeptides.

Given the versatility and interest in this simple building block, we elected to exploit an oxazolidinone scaffold 1 as a β-VSer synthetic equivalent in which both the amine and the hydroxy functions are simultaneously protected (Scheme [1]). Although there are excellent reports on carbamate cyclizations[11] and an allylic C–H amination[12] that yield trans-4,5-disubstituted oxazolidinones stereospecifically, our studies required a cis-oxazolidinone. cis-4,5-Disubstituted oxazolidinones of this sort are known and are commonly derived from anti-2-aminopent-4-en-1,3-diols such as 2.

Zoom Image
Scheme 1 Target β-vinylserine (β-VSer) synthetic equivalent 1 and precursor

Both vinyl oxazolidinones and functionalized 2-aminopent-4-en-1,3-diols are valuable synthetic intermediates that have been used to prepare numerous natural products and medicinal targets, as discussed above. Although synthetic approaches from carbohydrates,[13] azide epoxide openings,[6a] and chiral glycine enolate aldols[14] are available, the more common synthetic approaches entailing nucleo­philic additions to α-amino-β-hydroxy aldehydes or ketones provide varying degrees of control of stereochemistry (Scheme [2]).

Zoom Image
Scheme 2 Approaches to cis-oxazolidinones

A survey of the literature indicated one could proceed by a vinyl Grignard addition onto the well-known d-serine-derived Boc-protected Garner’s aldehyde[15] or the OTBS-Boc-serinal 4,[7a] [10] followed by an intramolecular cyclization onto the Boc group to form an oxazolidinone. The Grignard approach has been widely used,[7b,9,16] but is limited due to the selectivity of the Grignard addition; this led Herold to develop a three-step approach employing trimethylsilyl acetylide additions for improved anti-stereoselectivity.[17] Although the tert-butyl(dimethyl)silyl ether substrate 4 gives 5 directly, it results in an undesirable 1:2 anti/syn diastereomeric ratio.[7a] The typical anti-selectivity for vinyl addition to Garner’s aldehyde is reported to range from 3:1[16a] to 6:1 anti/syn, and experimental details indicate that additional purification by chromatography is necessary. From the Grignard product of Garner’s aldehyde, hydrolysis of the N,O-acetal and selective protection of the primary hydroxy groups is needed, followed by formation of the oxazolidinone by a base-induced intramolecular cyclization onto the tert-butyl carbamate to afford 6.[18] In an improvement to these early approaches, the Weinreb amide 7 of a protected d-serine, available in four steps, has been employed to form an enone upon addition of vinylmagnesium bromide; this enone can be stereoselectively reduced with Li(t-BuO)3AlH in ethanol giving 5 with a 10:1 preference toward the anti-diastereomer.[19]

Here, we report a highly selective alternative approach in which the N-tosylamide 8 is used as a stereodirecting orthogonal protecting group; this approach is complementary to the approaches discussed above.

For our purpose, we had concerns about the N-Boc protecting group due to its potential for neighboring-group participation in our planned synthetic manipulations; we therefore initially desired an N-tosyl protected nitrogen on the oxazolidinone 9. Although one could simply tosylate the known oxazolidinone 6 to give 9, we considered initiating our synthesis with the acyclic silyl-protected N-tosyl-d-Ser[20] or the N-tosyl equivalent of Garner’s aldehyde.[21] Vinyl Grignard additions to N-sulfonyl-protected acyclic amino acids are not usually selective. Literature reports suggest that additions to the aldehydes of TsNH-Ala[22] and TsNH-Phe[23] give poor diastereoselectivities (2:3 anti/syn and 2:1 with the major isomer not identified, respectively). Given the poor selectivity of additions to acyclic amino aldehydes, we opted to pursue the use of a toluenesulfonamide derivative of Garner’s aldehyde 8. Surprisingly, no Grignard chemistry has been reported on this aldehyde. We found that vinylmagnesium bromide added cleanly to give a >95% yield[24] (Scheme [3]) and was more selective than the N-Boc-protected Garner’s aldehyde, giving the anti-allylic alcohol 10 with an 8.5:1 dr before chromatography. The use of LiCl as an additive in the vinylmagnesium bromide reaction did not alter the results. Although some trial runs using vinylmagnesium chloride directly did show >10:1 diastereoselectivity, these seemed highly dependent on the commercial source and age of the reagent. Conveniently, no rotamers are observed in the NMR spectra of the tosylamides, unlike the Boc-derivatives, making their interpretation more straightforward; moreover, TLC visualization and chromatographic detection is aided by the UV activity of the aromatic sulfonamide.

Zoom Image
Scheme 3 Synthesis of β-VSer derivatives 12 and 14; pNs = 4-O2NC6H4SO2.

The improved diastereoselectivity can be partially explained by examining the LUMO energies of the reactive Felkin–Anh conformations (Scheme [4]). With the N-sulfonamide there is a strong preference for the C–NTs bond of 9b to lie perpendicular to the plane defined by the aldehyde carbonyl as opposed to the C–CH2O bond in 9a. The LUMO of 9a is 3.46 kcal mol–1 higher in energy than that of 9b, as determined by ground-state gas-phase DFT calculations using an ω-897XD hybrid GGA functional. This predicts that nucleophilic approach should favor attack on 9b, leading to the 2,3-anti-product. In contrast, the N-Boc derivative has a smaller LUMO energy difference (2.77 kcal mol–1) between the two Felkin–Anh conformations, so it would not be expected to be as stereoselectively based on this analysis.

Zoom Image
Scheme 4 Felkin–Anh depiction of nucleophilic attacks

The trend favoring the 2,3-anti-diastereomer is also observed for aryl and methyl Grignards, with >7:1 ratios being observed (Table [1]). Interestingly, ethyl Grignard also afforded an 8:1 selectivity toward the anti-product, which is a near reversal of the syn-preference observed by Joullié and others.[25] The 2,3-syn-selectivity has been suggested to arise from chelation to the Boc carbonyl oxygen,[26] which might contribute to our observed anti-preference with the less chelation-prone tosylamide. Finally, the allyl Grignard gave poor selectivity in this reaction.

Table 1 Comparison of Grignard Additions to 8 and to Garner’s Aldehyde

Entry

R

Pg = Ts
anti/syn a

Yieldb (%)

Pg = Boc
anti/syn

Ref.

1

vinyl

 8.5:1

95

3–6:1

[7b] [9] [16]

2

Ph

12:1

70

1.5–5:1

[27] [25b]

3

4-MeOC6H4

14:1

n.d.c

5:1d

[27]

4

Me

 7:1

93

2:1

[25a]

5

Et

 8:1

87e

1:9

[25a]

6

All

 1:1.6

94

1.5:1

[28]

a Determined by 1H NMR integration on the crude sample or after hydrolysis to the diol.

b The crude product contained 1–4% of starting aldehyde.

c Not determined due to contamination by anisole. Hydrolysis gave the diol in 59% yield over two steps.

d Aryllithium rather than Grignard.

e anti-Configuration confirmed by comparison with hydrogenated 10.

For most of the N-tosyl Grignard products, we observed significant decomposition to the diol or rearrangement to dioxolanes on silica gel chromatography, so for 10, the crude product was always carried forward. Acidic hydrolysis of the N,O-acetal by using 4-toluenesulfonic acid in an ethanol/methanol mixture gave chromatographically pure diol 3,[24] which could be selectively protected at the primary hydroxy group with tert-butyl(dimethyl)silyl chloride to supply 11 in 80% over three steps from 8. Note that this silylation is much more easily achieved than that of the similar Boc-amine diol 2 derived from Garner’s aldehyde, which tends to give disilylation products if great care is not taken.

To confirm our stereochemical assignment of the vinyl addition, the known oxazolidinone[29] 9 was formed in 75% yield from 11 by using triphosgene and pyridine. Unfortunately, the 1H NMR spectrum reported in the literature was not sufficiently resolved to permit comparison of coupling constants, but, in general, the H-4 to H-5 coupling (oxazolidinone numbering) can be easily used to distinguish between the cis- and trans-diastereomers, with cis J 4,5 ≈ 7 Hz and the trans J 4,5 ≈ 4 Hz.[30] Oxazolidinone 9 has J 4,5 of 7.6 Hz, indicative of a cis-relationship. In addition, removal of the toluenesulfonyl protecting group could be accomplished in good yield (83%) by using Na/naphthalene in 1,2-dimethoxyethane, and the cis-coupling constant between H5 at δ = 5.04 ppm and H4 at δ = 3.83 ppm of oxazolidinone 6 was revealed to be 8.1 Hz, matching that reported by Ibuka,[18] and thereby confirming our assignment of the anti-diastereomer 10 from the Grignard chemistry. Note that this synthetic route to 6 via N-tosyl serinal 8 is a significant improvement compared with previously reported Grignard chemistry.

In our case, we had no desire to remove the N-tosyl protection; instead, we sought to deprotect the primary hydroxy and to oxidize it to a carboxylic acid to form our β-VSer synthetic equivalent. Although there are reports of both steps being achieved in one pot with KF, Jones reagent, or similar compounds[31] we found it better to do this in a stepwise manner by using HCl and MeOH to remove the silyl protection in 92% yield, and subsequent Jones oxidation to supply methyl ester 12 in 82% yield after diazomethane treatment. Unfortunately, attempts at oxidation with TEMPO-type reagents did not give a complete reaction, giving yields of around 50% in our hands.

Although we desired the N-tosyl protection, we recognize its versatility is limited for some cases, so we demonstrated that the final steps can also be carried out with a p-nosyl-protected nitrogen. From 6, the para-nosyl group can be introduced using sodium hydride in THF to give 13 in 90% yield. Similar reactions have been reported to run in DMF and to give concomitant silyl ether cleavage,[29] but in our case a mixture was always observed. Therefore, we removed the silyl ether under acidic conditions and employed a Jones oxidation, as described earlier for 12, to give 14 in similar yields.

In summary, an efficient synthesis of a β-vinyl serine (β-VSer) synthetic equivalent is reported that exploits the stereodirecting effect of the N-toluenesulfonamide group in a highly diastereoselective vinyl Grignard addition.


#

Acknowledgment

The authors thank the University of Florida’s Mass Spectrometry Research and Education Center for the HRMS measurements.

Supporting Information

  • References and Notes

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Corresponding Author

Ernest G. Nolen
Department of Chemistry, Colgate University
13 Oak Drive, Hamilton, NY 13346
USA   

Publication History

Received: 07 October 2020

Accepted after revision: 10 November 2020

Accepted Manuscript online:
10 November 2020

Article published online:
08 January 2021

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  • References and Notes

  • 1 Ngo JT, Tirrell DA. Acc. Chem. Res. 2011; 44: 677
    • 2a Blackwell HE, Grubbs RH. Angew. Chem. Int. Ed. 1998; 37: 3281
    • 2b Schafmeister CE, Po J, Verdine GL. J. Am. Chem. Soc. 2000; 122: 5891
    • 2c Aillard B, Robertson NS, Baldwin AR, Robins S, Jamieson AG. Org. Biomol. Chem. 2014; 12: 8775
    • 2d Yeo DJ, Warriner SL, Wilson AJ. Chem. Commun. 2013; 49: 9131
  • 3 Zhang X, van der Donk WA. J. Am. Chem. Soc. 2007; 129: 2212
  • 4 Ibuka T, Habashita H, Otaka A, Fujii N, Oguchi Y, Uyehara T, Yamamoto Y. J. Org. Chem. 1991; 56: 4370
    • 5a Oishi S, Narumi T, Ohno H, Otaka A, Fujii N. Yuki Gosei Kagaku Kyokaishi 2008; 66: 846
    • 5b Venkatesan N, Kim BH. Curr. Med. Chem. 2002; 9: 2243
    • 6a Hakogi T, Yamamoto T, Fujii S, Ikeda K, Katsumura S. Tetrahedron Lett. 2006; 47: 2627
    • 6b Yamamoto T, Hasegawa H, Hakogi T, Katumura S. Org. Lett. 2006; 8: 5569
    • 6c Wisse P, de Geus MA. R, Cross G, van den Nieuwendijk AM. C. H, van Rooden EJ, van den Berg RJ. B. H. N, Aerts JM. F. G, van der Marel GA, Codée JD. C, Overkleeft HS. J. Org. Chem. 2015; 80: 7258
    • 7a Knight JG, Tchabanenko K. Tetrahedron 2003; 59: 281
    • 7b Takahata H, Banba Y, Sasatani M, Nemoto H, Kato A, Adachi I. Tetrahedron 2004; 60: 8199
  • 8 Lee D. Synlett 2012; 23: 2840
  • 9 Wang B, Liu Y, Jiao R, Feng Y, Li Q, Chen C, Liu L, He G, Chen G. J. Am. Chem. Soc. 2016; 138: 3926
  • 10 Murphy-Benenato KE, Dangel B, Davis HE, Durand-Réville TF, Ferguson AD, Gao N, Jahic H, Mueller JP, Manyak EL, Quiroga O, Rooney M, Sha L, Sylvester M, Wu F. Zambrowski M., Zhao S. X. 2015; 6: 537
    • 11a Robertson J, Abdulmalek E. Tetrahedron Lett. 2009; 50: 3516
    • 11b Kim H, Yoo D, Choi SY, Chung YK, Kim YG. Tetrahedron: Asymmetry 2008; 19: 1965
    • 11c Martín R, Moyano A, Pericàs MA, Riera A. Org. Lett. 2000; 2: 93
    • 11d Amador M, Ariza X, Garcia J, Sevilla S. Org. Lett. 2002; 4: 4511
  • 12 Fraunhoffer KJ, White MC. J. Am. Chem. Soc. 2007; 129: 7274
  • 13 Lee JH, Kang JE, Yang MS, Kang KY, Park KH. Tetrahedron 2001; 57: 10071
    • 14a Kazmaier U, Pähler S, Endermann R, Häbich D, Kroll H.-P, Riedl B. Bioorg. Med. Chem. 2002; 10: 3905
    • 14b Dubreuil D, Pipelier M, Micouin L, Lecourt T, Lacone V, Bonneville M, Lependu J, Turcot-Dubois A.-L. WO 2008/047249, 2008
    • 15a Garner P, Park JM. J. Org. Chem. 1988; 53: 2979
    • 15b Garner P. Tetrahedron Lett. 1984; 25: 5855
    • 16a Passiniemi M, Koskinen AM. P. Beilstein J. Org. Chem. 2013; 9: 2641
    • 16b Coleman RS, Carpenter AJ. Tetrahedron Lett. 1992; 33: 1697
    • 16c Ojima I, Vidal ES. J. Org. Chem. 1998; 63: 7999
    • 16d Kumar G, Kaur S, Singh V. Helv. Chim. Acta 2011; 94: 650
    • 16e Ghosal P, Shaw AK. Tetrahedron Lett. 2010; 51: 4140
    • 16f Bhabak KP, Proksch D, Redmer S, Arenz C. Bioorg. Med. Chem. 2012; 20: 6154
  • 17 Herold J. Helv. Chim. Acta 1988; 71: 354
  • 18 Ibuka T, Mimura N, Aoyama H, Akaji M, Hono H, Miwa Y, Taga T, Nakai K, Tamamura H, Fujii N, Yamamoto Y. J. Org. Chem. 1997; 62: 999
    • 19a Myeong I.-S, Kim JS, Park M.-G, Jeon H.-H, Jung C, Lee Y.-T, Ham W.-H. Synthesis 2018; 50: 2058
    • 19b Yamamoto T, Hasegawa H, Hakogi T, Katsumura S. Org. Lett. 2006; 8: 5569
    • 19c Jin T, Mu Y, Kim J.-S, Park S.-H, Jin X, Kang J.-C, Oh C.-Y, Ham W.-H. Synth. Commun. 2014; 44: 2401
    • 20a Jurczak J, Golebiowski A. Chem. Rev. 1989; 89: 149
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Scheme 1 Target β-vinylserine (β-VSer) synthetic equivalent 1 and precursor
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Scheme 2 Approaches to cis-oxazolidinones
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Scheme 3 Synthesis of β-VSer derivatives 12 and 14; pNs = 4-O2NC6H4SO2.
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Scheme 4 Felkin–Anh depiction of nucleophilic attacks