Addition of carbon-based nucleophiles to Fmoc-protected acyl iminium ions

Article abstract of DOI:10.1021/jo8027714

(Chemical Equation Presented) Weakly basic carbon nucleophiles add efficiently to a Fmoc-protected N,O-acetal compound. The new reactions highlight the compatibility of the Fmoc protecting group with moderately basic reaction conditions and should serve a

Full text of DOI:10.1021/jo8027714

SCHEME 1. General Reaction Scheme of Acyl Iminium
Ions Derived from N,O-Acetals
Addition of Carbon-Based Nucleophiles to
Fmoc-Protected Acyl Iminium Ions†
Alison E. Hartman, Cheryl L. Brophy, Julia A. Cupp,
Daniel K. Hodge, and Timothy J. Peelen*
Department of Chemistry, Lebanon Valley College,
AnnVille, PennsylVania 17003
and convergent approach for the assembly of complex carbam-
ate-protected amines (Scheme 1).
peelen@lVc.edu
Despite the wealth of literature pertaining to acyl iminium
ions, there are few examples of reactions of Fmoc-protected
acyl iminium ions. We are aware of only two C-C bond-
forming reactions using Fmoc-protected acyl iminium ions:
Hiemstra performed additions using an allenyl silane (eq 1)
while Kobayashi added a silyl enol ether to cyclic acyl imines
(eq 2).4,5
ReceiVed December 19, 2008
Weakly basic carbon nucleophiles add efficiently to a Fmoc-
protected N,O-acetal compound. The new reactions highlight
the compatibility of the Fmoc protecting group with mod-
erately basic reaction conditions and should serve as a model
for the development of more efficient syntheses of Fmoc-
protected amino acids.
The base lability of the Fmoc protecting group precludes its
use with strongly basic nucleophiles that would result in
competitive deprotection (Figure 1). Nevertheless, we suspect
that there exists a set of weakly basic nucleophiles that are
compatible with the Fmoc group. Exploration of these nucleo-
philes should provide an attractive, efficient route to precursors
of unnatural amino acids. Herein, we describe a study of weakly
basic carbon nucleophiles with a model N,O-acetal.
We have prepared N,O-acetal 3 through a simple condensation
reaction (Scheme 2).6 The condensation reaction produces a
crystalline, bench stable N,O-acetal in a single step from
inexpensive, commercially available starting materials. More
complex N,O-acetals have been prepared by others using a
variety of oxidative methods, including electrochemical oxida-
tion of N-alkyl carbamates7 and electrochemical8 or chemical9
oxidative fragmentation of carbamate-protected amino acids or
amino alcohols.
The base-labile N-fluoren-9-ylmethoxycarbonyl (Fmoc) amine
protecting group plays a central role in solid phase peptide
synthesis.1 The prominence of Fmoc-protected amines is
underscored by a recent literature search: over 37 000 different
Fmoc-protected amines have been synthesized, of which 2261
are commercially available.2
Despite their importance, the methods for preparing Fmoc-
protected amines and amino acids are limited. The base
sensitivity of the Fmoc group often precludes its use early in
synthetic sequences. Thus, Fmoc-protected amines are almost
exclusively prepared by a final protection of a free amine with
the Fmoc group. The need for late stage incorporation of the
Fmoc protecting group typically leads to an inefficient “protect-
ing group shuffle”, in which deprotection and protection steps
end the synthesis.
The inefficiency of current methods for the synthesis of Fmoc-
protected amines makes more efficient methods desirable. A
common strategy for the synthesis of carbamate-protected
amines involves the reaction of an acyl iminium ion intermedi-
ate.3 Nucleophilic additions to acyl iminium ions 2, generated
in situ from an N,O-acetal 1 or a similar adduct, provide a direct
Our study shows that a variety of nucleophiles add efficiently
to N,O-acetal 3 in C-C bond-forming reactions (Table 1).
Selection of an appropriate Lewis acid is essential for obtaining
(4) Mentink, G.; van Maarseveen, J. H.; Hiemstra, H. Org. Lett. 2002, 4,
3497–3500.
(5) Sugiura, M.; Hagio, H.; Hirabayashi, R.; Kobayashi, S. J. Am. Chem.
Soc. 2001, 123, 12510–12517.
(6) (a) Oleksyszyn, J.; Subotkowska, L. Synthesis 1980, 906. (b) Harding,
K. E.; Marman, T. H.; Nam, D.-H. Tetrahedron 1988, 44, 5605–5614.
(7) (a) Shono, T.; Hamaguchi, H.; Matsumura, Y. J. Am. Chem. Soc. 1975,
97, 4264–4268. (b) Shono, T.; Matsumura, Y.; Tsubata, K. Org. Synth. 1985,
63, 206–213.
(8) Zietlow, A.; Steckhan, E. J. Org. Chem. 1994, 59, 5658–5661.
(9) (a) Harayama, Y.; Yoshida, M.; Kamimura, D.; Kita, Y. Chem. Commun.
2005, 1764–1766. (b) Harayama, Y.; Yoshida, M.; Kamimura, D.; Wada, Y.;
Kita, Y. Chem.sEur. J. 2006, 12, 4893–4899.
† Dedicated to the memory of H. Anthony Neidig, 1924-2008.
(1) (a) Carpino, L. A. Acc. Chem. Res. 1987, 20, 401–407. (b) Greene, T. W.;
Wuts, P. G. M. In ProtectiVe Groups in Organic Synthesis, 3rd ed.; John Wiley
& Sons: New York, 1999; pp 506-507.
(2) Search using SciFinder Scholar 2007 performed 11/2008.
(3) For recent reviews, see: (a) Speckamp, W. N.; Moolenaar, M. J.
Tetrahedron 2000, 56, 3817–3856. (b) Hiemstra, H.; Speckamp, W. N. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon:
Oxford, UK, 1991; Vol. 2, pp 1047-1082.
3952 J. Org. Chem. 2009, 74, 3952–3954
10.1021/jo8027714 CCC: $40.75 2009 American Chemical Society
Published on Web 04/14/2009

of product. Screening of other Lewis acids identified ZnCl2 as
the optimal Lewis acid for reactions involving silyl enol ethers
and silyl ketene acetals.12 The need to match Lewis acid with
nucleophile suggests that the Lewis acid not only is involved
in the formation of the acyl iminium ion, but also has a role in
the nucleophilic addition step. Entries 6 and 7 are notable as
they produce products that can be readily converted to Fmoc-
protected ꢀ-amino acids, either through oxidation of the
aldehyde or hydrolysis of the ester.13,14
The ZnCl2-catalyzed additions of silyl enol ethers and silyl
ketene acetals to Fmoc-protected N,O-acetal 3 are operationally
simple and tolerant of a wide variety of reaction conditions.
The silyl enol ethers and silyl ketene additions proceed equally
well in toluene, acetonitrile, and methylene chloride solvent.
The reactions can be performed under ambient conditions with
no prior purification of the solvent. The reaction also proceeds
in chloroform, though ethanol-stabilized chloroform must be
distilled prior to use, or else the ethanol-derived Fmoc-protected
N,O-acetal is also obtained. Silyl enol ethers and silyl ketene
acetal additions are typically complete (using 10 mol % of
ZnCl2) over several hours, though the Fmoc-protected products
are stable to the reaction conditions and no diminution of product
is observed over extended reaction times. The ZnCl2-catalyzed
additions afford complete conversion to product by using as
low as 10 mol % of catalyst loadings, though higher catalyst
loadings and even stoichiometric Lewis acid are also effective.
FIGURE 1. Reaction pathways available to Fmoc-protected iminium
ions.
SCHEME 2. Preparation of Model N,O-Acetal
TABLE 1. Addition of Weakly Basic Nucleophiles to
Fmoc-Protected N,O-Acetals
Ketone-derived enamines also react with N,O-acetal 3 to
afford ꢀ-amino ketones (entry 8). The moderate yield for this
reaction is due primarily to competing side reactions. These side
reactions include Fmoc deprotection, indicating that we are
approaching the limits of nucleophile basicity that can be
tolerated with Fmoc-protected compounds. The reaction also
proceeds with the morpholine-derived enamine, though much
more slowly and with a lower yield. The enamine addition
proceeds best in the absence of Brønsted or Lewis acid additives,
which is unusual given that acids are typically required to form
the acyl iminium ion intermediate. Addition of Lewis acids such
as ZnCl2 or BF3 results in rapid consumption of starting material
to a complex mixture of byproducts with negligible product
formation. One of the side products that we have isolated is
11, which can form either through nucleophilic displacement
of the Lewis acid-activated carbamate by the enamine or,
alternatively, by reaction of the enamine with dibenzofulvene
formed in Fmoc deprotection.15 In the enamine addition, the
reaction time must be monitored carefully to avoid decomposi-
tion of the product under the basic reaction conditions; we have
obtained optimal yields after 4 h.
good yields. As an initial test reaction, we examined addition
of allyl silane; BF3 effectively catalyzed this reaction as observed
previously (entry 1).4,10
A variety of silyl enol ether (entries 2-6) and silyl ketene
acetal (entry 7) nucleophiles react with N,O-acetal 3.5,11 Unlike
the reactions with allyl silane, BF3 does not afford a high yield
(12) Several different Lewis and Brønsted acids were screened. ZnCl2 was
clearly the best catalyst; BF3 was moderately effective (∼80% conversion) while
no product was observed with AlCl3, TiCl4, or trifluroacetic acid.
(13) For an example of an oxidation of a Fmoc-protected amino aldehyde,
see: Spino, C.; Gobdout, C. J. Am. Chem. Soc. 2003, 125, 12106–12107.
(14) For a recent example of an ester hydrolysis of a Fmoc-protected amino
ester, see: Triola, G.; Brunsveld, L.; Waldmann, H. J. Org. Chem. 2008, 73,
3646–3649.
(10) Meester, W. J. N.; van Dijk, R.; van Maarseveen, J. H.; Rutjes, F. P. J. T.;
Hermkens, P. H. H.; Hiemstra, H. J. Chem. Soc., Perkin Trans. 1 2001, 2909–
2911.
(11) For selected recent examples, see:(a) Liautard, V.; Desvergnes, V.; Itoh,
K.; Liu, H.-w.; Martin, O. R. J. Org. Chem. 2008, 73, 3103–3115. (b) Attrill,
R.; Tye, H.; Cox, L. R. Tetrahedron: Asymmetry 2004, 15, 1681–1684. (c)
Sugiura, M.; Hagio, H.; Kobayashi, S. HelV. Chim. Acta 2002, 85, 3678–3691.
(d) Sugiura, M.; Kobayashi, S. Org. Lett. 2001, 3, 477–480.
(15) For an addition of a silyl enol ether to dibenzofulvene, see: Cho, B. P.
Tetrahedron Lett. 1995, 36, 2403–2406.
J. Org. Chem. Vol. 74, No. 10, 2009 3953

concentrated in vacuo. The crude product was purified by liquid
chromatography (hexane and ethyl acetate, using a gradient elution)
to afford 44.6 mg (0.128 mmol, 64%) of Fmoc-protected amino
ketone 8 as a white solid: IR (KBr) ν 3350, 2937, 2852, 1688,
1538, 1447, 1272, 1007 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.76
(d, J ) 7.5 Hz, 2H), 7.58 (d, J ) 7.4 Hz, 2H), 7.40 (t, J ) 7.3 Hz,
2H), 7.31 (t, J ) 7.4 Hz, 2H), 5.27-5.43 (br s, 1H), 4.30-4.42
(m, 2H), 4.20 (t, J ) 7.0 Hz, 1H), 3.35 (ddd, J ) 13.9, 7.6, 3.8
Hz, 1H), 3.24 (ddd, J ) 14.0, 7.7, 5.7 Hz, 1H), 2.47-2.63 (m,
1H), 2.23-2.47 (m, 2H), 2.04-2.18 (m, 2H), 1.82-1.96 (m, 1H),
1.52-1.78 (m, 2H), 1.40 (qd, J ) 12.7, 3.4 Hz, 1H). A minor set
of resonances (∼10%), which we attribute to rotamers about the
carbamate C-N bond, is observed. The minor resonances begin to
coalesce with the main resonances upon heating the NMR sample.
These observed resonances for the minor rotamer appear at δ
4.85-4.99 (br s, 1H), 4.50-4.63 (br s, 2H), 2.86-3.14 (br s, 2H);
13C NMR (75 MHz, CDCl3): 213.6, 156.7, 144.2, 141.5, 127.8,
127.2, 125.3, 120.2, 66.8, 51.3, 47.5, 42.5, 41.1, 31.7, 28.0, 25.0;
HRMS (ESI, m/z) calcd for C22H23NO3Na [M + Na]+ 372.1570,
found 372.1564.
In summary, we describe Lewis acid-catalyzed additions of
carbon-based nucleophiles to Fmoc-protected N,O-acetals.
Expanding reactions of acyl iminium ions to include Fmoc-
protected versions is important in light of the central role that
Fmoc-protected amino acids play in automated peptide synthesis.
The base-lability of the Fmoc-protecting group presents unique
synthetic challenges that can be managed effectively by using
appropriate combinations of weakly basic nucleophiles and
Lewis acids.
Experimental Section
General Procedure for the Addition of Silyl Enol Ethers
and Silyl Ketene Acetals to Fmoc-Protected N,O-Acetals. To 3
in CHCl3 in a 1 dram vial equipped with a stir bar was added the
silyl enol ether or silyl ketene acetal (1.5-2 equiv) and ZnCl2 (0.5
M in THF, 0.1 equiv). After the indicated time, the reaction was
quenched with 1 M HCl and extracted into CH2Cl2 (3×). The
combined organic extracts were washed with sat. NaHCO3 and
brine, dried over MgSO4, and concentrated in vacuo. The crude
products were purified by liquid chromatography (hexane and ethyl
acetate, using a gradient elution) to afford the desired Fmoc-
protected amine product.
Acknowledgment. This research was supported by an award
from Research Corporation.
Procedure for the Addition of Enamine to Fmoc-Protected
N,O-Acetals. To N,O-acetal 3 (62.2 mg, 0.200 mmol) in toluene
(2 mL) in a 1 dram vial equipped with a stir bar was added
1-pyrrolidinocyclohexene (45 µL, 0.28 mmol, 1.4 equiv). After 4 h,
the reaction was quenched with 2 mL of 3 M HCl and stirred
vigorously for 5 min. The product was extracted into CH2Cl2 (3 ×
2 mL). The combined organic extracts were dried over MgSO4 and
Supporting Information Available: General experimental
methods, additional experimental procedures, compound char-
acterization data, and copies of spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO8027714
3954 J. Org. Chem. Vol. 74, No. 10, 2009