Direct conversion of Fmoc-protected amines into O-alkyl carbamates by the Mitsunobu reaction: A practical strategy for the solid-phase synthesis of carbamates

Article abstract of DOI:10.1016/S0040-4039(00)00088-5

Support-bound, Fmoc-protected amines react with aliphatic alcohols in the presence of ADDP, PBu₃, and DIPEA to yield O-alkyl carbamates. The reaction presumably proceeds via O-alkylation of an intermediate carbamate anion. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00088-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2015–2017
Direct conversion of Fmoc-protected amines into O-alkyl
carbamates by the Mitsunobu reaction: a practical strategy for the
solid-phase synthesis of carbamates
Florencio Zaragoza ∗ and Henrik Stephensen
Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark
Received 1 December 1999; accepted 11 January 2000
Abstract
Support-bound, Fmoc-protected amines react with aliphatic alcohols in the presence of ADDP, PBu3, and DIPEA
to yield O-alkyl carbamates. The reaction presumably proceeds via O-alkylation of an intermediate carbamate
anion. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: amino acids and derivatives; carbamates; Mitsunobu reactions; solid-phase synthesis.
Synthetic protocols which enable the use of aliphatic alcohols are well suited for the preparation of
compound libraries, because a large number of alcohols are commercially available and can generally be
stored for long periods. One possibility to covalently bind alcohols to intermediates on solid phase is the
conversion of support-bound primary or secondary amines into carbamates (Scheme 1). For this purpose
the amine is generally first converted into a carbamoyl chloride by treatment with phosgene or a synthetic
equivalent thereof, and then with an alcohol in the presence of a strong base.1 Alternatively, support-
bound 4-nitrophenyl carbamates can be converted into other carbamates by treatment with alcohols,
again under strongly basic reaction conditions.2 We found none of these strategies to be suitable for
the automated production of compound libraries on solid phase, because variable results are frequently
obtained, and the strong bases often lead to precipitates and clogging of tubes.
Scheme 1. X: Cl, 4-(O2N)C6H4O
We present herein a new strategy for the conversion of support-bound amines into carbamates,
which requires soluble reagents only, and which is therefore well suited for robotic synthesizers.
∗
Corresponding author. Tel: +45 4443 4828; fax: +45 4466 3450; e-mail: flo@novo.dk (F. Zaragoza)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00088-5
tetl 16364

2016
This new synthesis is based on the O-alkylation of ammonium carbamates under the conditions of
the Mitsunobu reaction.3 The required ammonium carbamates were generated in situ by treatment
of Fmoc-amines with DIPEA or triethylamine (Scheme 2). For instance, treatment of support-bound
Fmoc-phenylalanine with primary aliphatic alcohols in the presence of azodicarboxylic acid dipiperidide
(ADDP), tributylphosphine, and a tertiary amine led to clean formation of the corresponding carbamates,
which were released from the support by treatment with trifluoroacetic acid (TFA) in dichloromethane
(DCM).4 The yields and purities of representative crude products are given in Table 1.5
Scheme 2. Wng: 1% cross-linked polystyrene with Wang linker. R3N: DIPEA or NEt3
Table 1
Yields and purities of the crude carbamates prepared according to Scheme 2
This new carbamate synthesis proceeds smoothly with primary aliphatic alcohols, whereas secondary
alcohols generally give poor results. When α-amino acids were used as the support-bound amine no
significant racemization could be detected5 making this procedure suitable for the solid-phase preparation
of chemically modified peptides.
In conclusion, a mechanistically new synthesis of carbamates has been developed, which is based
on readily available, stable reagents, and which is compatible with standard peptide synthesizers and
pipetting robots for parallel solid-phase synthesis.

2017
Acknowledgements
We thank Vibeke Rode for recording LC-MS spectra and Hanne Bultoft and Annemarie R. Varming
for analyzing products 1 and 5 by HPLC on chiral stationary phase.
References
1. For illustrative examples performed in solution, see: Derwing, C.; Hoppe, D. Synthesis 1996, 149–154; Carstens, A.; Hoppe,
D. Tetrahedron 1994, 50, 6097–6108.
2. Zaragoza, F. unpublished results. Alcohols can also be preactivated in homogeneous phase by conversion into 4-nitrophenyl
carbonates or chloroformates, and then coupled with a support-bound amine.
3. For a related synthesis of symmetric carbonates in solution, see: Hoffman, W. A. J. Org. Chem. 1982, 47, 5209–5210.
Oxazolidin-2-ones have been prepared from 2-aminoethanol and CO2 under Mitsunobu conditions: Kodaka, M.; Tomohiro,
T.; Okuno, H. J. Chem. Soc., Chem. Commun. 1993, 81–82. Carbamates have been prepared in solution by O-alkylation
of carbamate anions with alkyl halides: McGhee, W.; Riley, D.; Christ, K.; Pan, Y.; Parnas, B. J. Org. Chem. 1995, 60,
2820–2830; Gómez-Parra, V.; Sánchez, F.; Torres, T. J. Chem. Soc., Perkin Trans. 1 1987, 695–697; Gómez-Parra, V.;
Sánchez, F.; Torres, T. Synthesis 1985, 282–285; Yoshida, Y.; Ishii, S.; Yamashita, T. Chemistry Lett. 1984, 1571–1572.
4. Typical procedure: N-(Benzyloxycarbonyl)proline (5). To N-Fmoc proline esterified with Wang resin (0.104 g, 0.078 mmol;
Novabiochem) were added, in the order given, N-methylpyrrolidinone (NMP; 1.5 mL), benzyl alcohol (0.205 mL, 1.98 mmol,
25 equiv.), a suspension of ADDP (0.330 g, 1.31 mmol, 17 equiv.) in NMP (1.5 mL), PBu3 (0.25 mL, 1.00 mmol, 13 equiv.),
and DIPEA (0.6 mL). The mixture was shaken at 20°C for 20 h, filtered, and the support was extensively washed with NMP,
DCM, and methanol. DCM (1.5 mL) and TFA (1.5 mL) were added, and after shaking at 20°C for 0.5 h, the mixture was
filtered and the filtrate was concentrated under reduced pressure. 24 mg of the title compound was obtained, identical by 1H
NMR to an authentic sample (for purity and yield, see Table 1).
1
5. All crude products were analyzed by LC-MS, HPLC (214 nm, 254 nm, evaporative light-scattering (ELS)), and H NMR.
Yields were determined by 1H NMR using DMSO-d5 as internal standard. Compounds 1 and 5 were identical by 1H NMR to
authentic (purchased) samples. No significant racemization of products 1 and 5 occurred under the conditions of carbamate
anion generation/Mitsunobu reaction, as determined by HPLC on chiral stationary phase.