Utilization of Fukuyama's sulfonamide protecting group for the synthesis of N-substituted α-amino acids and derivatives

Article abstract of DOI:10.1016/S0040-4039(00)00424-X

A novel and general route for the solid phase synthesis of N-substituted α-amino acids has been developed. This synthesis employs Fukuyama's 2- nitrobenzenesulfonamide protecting group for preparation of secondary amines. The versatility of this methodology is demonstrated by the facile synthesis of a trisubstituted diketopiperazine (DKP) skeleton. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00424-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3309–3313
Utilization of Fukuyama’s sulfonamide protecting group for the
synthesis of N-substituted α-amino acids and derivatives
Xiaodong Lin, Hilary Dorr and John M. Nuss ∗
Chiron Corporation, 4560 Horton Street, Emeryville, CA 94608, USA
Received 26 January 2000; revised 21 March 2000; accepted 24 March 2000
Abstract
A novel and general route for the solid phase synthesis of N-substituted α-amino acids has been developed. This
synthesis employs Fukuyama’s 2-nitrobenzenesulfonamide protecting group for preparation of secondary amines.
The versatility of this methodology is demonstrated by the facile synthesis of a trisubstituted diketopiperazine
(DKP) skeleton. © 2000 Elsevier Science Ltd. All rights reserved.
Solid supported organic synthesis has been one of the most intensely investigated areas of organic
chemistry, due to its implications in combinatorial chemistry and, in turn, in accelerating the drug dis-
covery process. α-Amino acids continue to be useful chiral building blocks for the synthesis of peptides
and small molecule combinatorial libraries. Easy access to N-substituted α-amino acids would add even
more diversity to this set of chiral building blocks. However, few reports have documented the successful,
general synthesis of N-substituted α-amino acids directly from amino acid precursors. Perhaps one of the
reasons for this difficulty lies in the inability to control mono- and di-N-alkylation, particularly on the
solid support. Here we wish to report our results describing a general, high yielding method for the
synthesis of N-substituted α-amino acids on solid support utilizing Fukuyama’s sulfonamide technology
to protect and activate support bound amines.1
To evaluate the generality of the process, polystyrene based Wang and Rink Amide resins were
used as starting materials. Our protocol begins with resin bound L-Fmoc-α-amino acids (Scheme
1).2 Removal of the Fmoc protecting group, followed by sulfonylation under standard conditions,
affords 2-nitrobenzenesulfonamides 2. The subsequent alkylation was achieved using typical Mitsunobu
conditions.3 As summarized in Table 1, the reaction to form 3 was general for both Wang and Rink Amide
resins, a number of amino acids and a variety of primary alcohols. Among the examples investigated,
amino acids with aliphatic side chains (entries 1–6) and functionalized side chains (entries 7–11) gave the
desired products in high yields and purity. Primary alcohols were found to be the most desirable for the
Mitsunobu step. The reaction proceeded smoothly with relatively bulky substituents at both the R1 and
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00424-X
tetl 16704

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R2 positions (entry 5). Reactions using secondary alcohols resulted in either incomplete conversion or
complicated mixture under more forced conditions (heating to 60°C in THF). No detectable racemization
occurred during the four-step process.4
Scheme 1.
Table 1
Formation of N-substituted sulfonamide 3
Next, the scope of desulfonylation reaction was examined in detail. To obtain N-substituted amino
acids, Wang resin bound sulfonamides 4 were subjected to typical Fukuyama desulfonylation conditions
(Scheme 2). The results are summarized in Table 2.5 Overall, anticipated acids 6 were obtained with
satisfying yields and purity.
In sharp contrast to the above results, unexpected difficulties were encountered during the removal
of the sulfonyl group with Rink Amide resin bound sulfonamides 7 (Scheme 3). A number of reaction
conditions were examined6 and each failed to produce the desired product cleanly. Nevertheless, the

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Scheme 2.
Table 2
Desulfonylation of Wang resin bound sulfonamide to amino acid 6
amide analogue 8 (R1=Ala, R2=p-Cl-benzyl) was obtained in 60% purified yield from its resin free
sulfonamide precursor using Fukuyama’s thiophenol/K2CO3 condition.
Scheme 3.
The versatility of this methodology can be demonstrated by facile syntheses of trisubstituted DKPs
12 using N-substituted amino acids 9 (Scheme 4).7 Thus, acylation of N-alkyl amino acid 9 with
bromoacetic acid, followed by substitution with primary amines gave compound 10. Upon cleavage from
the resin, dipeptide 11 or a mixture of 11 and DKP 12 were obtained. The results depend highly upon
the nature of the amines used. As summarized in Scheme 4, when α-branched primary amines were used
in substitution step, the open chain N-substituted dipeptides 11 were obtained exclusively with good
purity and high yields (entries 1–2). However, as the steric bulkiness of the amine decreased (entry 3),
intramolecular cyclization spontaneously occurred during cleavage, affording a mixture of dipeptide 11
and DKP 12. When benzylamine (entry 4), a β-branched amine, was used, longer reaction time (2 h) led
to very poor mass recovery. This presumably arose from intramolecular cyclization of intermediate 10
and/or cleavage of the ester linkage by benzylamine during the substitution step. Shortening the reaction
time to 45 min afforded a higher yield of products, as a mixture of 11 and 12. To convert the dipeptide
11 into DKP 12, 11 (or a mixture of 11 and 12) was simply treated with TFAA (1.2 equiv.) in DCM at

3312
40°C for 0.5 to 2 h. Concentration in vacuo followed by lyophilization afforded pure DKP 12 in nearly
quantitative yield.8
Scheme 4.
In summary, we have demonstrated a general and efficient route for the synthesis of important N-
substituted amino acid building blocks. This route can be further expanded to synthesize heterocycles
such as DKPs. This approach allows the incorporation of three diversity elements on the DKP ring,
arising from readily available amino acids, primary alcohols and primary amines. Studies toward making
a DKP combinatorial library using this strategy are in progress.
References
1. (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373. Applications to solid phase synthesis were
reported as we were preparing this manuscript: (b) Seitz, O. Angew. Chem., Int. Ed. 1998, 37, 3109. (c) Mohamed, N.;
Bhatt, U.; Just, G. Tetrahedron Lett. 1998, 39, 8213. (d) Kung, P.-P.; Swayze, E. Tetrahedron Lett. 1999, 40, 5651.
2. (a) Resin bound α-amimo acids were either purchased from NovaBiochem or prepared by the following procedure. To load
amino acids on Wang resin: 4 equiv. DIC, 4 equiv. Fmoc-aa-OH, 2 equiv. DMAP, DCM, rt, 45 min and double coupling.
To load amino acids on Rink Amide resin: 4 equiv. Fmoc-aa-OH, 4 equiv. HBTU, 4 equiv. HOBT, 8 equiv. DIEA, NMP, rt,
1.5 h. (b) Functionalized side chains were protected by either tBu (Tyr, Ser, Asp) or Boc (Orn, Lys, Trp). Protecting groups
were removed simultaneously upon cleaving compounds off the resin. (c) All reactions were run in a vial using 100 mg of
resin in 2 mL solvent with constant agitation.
3. Mitsunobu, O. Synthesis 1981, 1.
1
4. H NMR analysis of compounds A and B showed racemization was <5% (within the limits of detection).

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5. Other amino acids such as Met, His(Trt), Arg (Tos), Asn (Trt) and Cys (tBu) resulted in complex mixtures, although the
desired compounds 6 were observed.
6. Conditions examined for desulfonylation of 7 include: (a) PhSH/K2CO3/DMF, rt–40°C, Ref.1. (b) Mercaptaacetic
acid/Et3N/DMF/rt–40°C, Ref. 1. (c) LiSPh/DMF/rt–40°C. (d) PhSH/K2CO3/CH3CN/50°C, Based upon: Maligres, P. E.;
See, M. M.; Askin, D.; Reider, P. J. Tetrahedron Lett. 1997, 38, 5253.
7. DKP formation on solid support with different strategies has been reported: (a) Hulme, C.; Peng, J.; Morton, G.; Salvino,
J. M.; Herpin, R.; Labaudiniere, R. Tetrahedron Lett. 1998, 39, 7227. (b) del Fresno, M.; Alsina, J.; Royo, M.; Barany, G.
Albericio, F. Tetrahedron Lett. 1998, 39, 2639. (c) Smith, R. A.; Bobko, M. A.; Lee, W. Bioorg. Med. Chem. Lett 1998, 8,
2369. (d) Szardenings, A. K.; Burkoth, T. S. Tetrahedron 1997, 53, 6573. (e) Kowalski, J.; Lipton, M. A. Tetrahedron Lett.
1996, 37, 5839. (f) Gordon, D. W.; Steele, J. Bioorg. Med. Chem. Lett. 1995, 5, 47.
8. NMR data for 12 (R3=t-Bu): 1H 7.317–7.050 (m, 9H, aromatic), 5.322, 3.888 (ABq, J=14.79 Hz, 2H, NCH2Ph-pCl), 4.018
(app. t, 1H, methine), 3.628, 2.312 (ABq, J=17.18 Hz, 2H, NCH2CO), 3.206 (dd, J=13.74, 3.85 Hz, 1H, PhCH2), 3.062 (dd,
J=13.74, 4.43 Hz, 1H, PhCH2), 1.280 (s, 9H, t-Bu). 13C 166.46 (CO), 165.59 (CO), 134.79 (ipso), 134.07 (ipso), 133.97
(ipso), 130.20, 129.85, 129.16, 128.69, 127.80 (aromatic CH), 61.35 (methine), 58.11 (quaternary), 46.21 (PhCH2), 46.14
(PhCH2), 36.83 (NCH2O), 27.74 (Me of t-Bu).