Activation of Fmoc-protected N, O-acetals using trimethylsilyl halides: Mechanistic and synthetic studies

Article abstract of DOI:10.1021/ol100494z

Trimethylsilyl halide activation of Fmoc-protected N,O-acetals yields reactive intermediates capable of efficiently adding to a variety of enamines. NMR studies have provided evidence that a stable halomethyl carbamate intermediate forms in solution. Good yields are obtained over a broad range of enamine nucleophiles encompassing both cyclic and acyclic ketone-derived and aldehyde-derived enamines. Preliminary studies suggest that the enamine additions occur through a concerted, S_N2-type mechanism.

Full text of DOI:10.1021/ol100494z

ORGANIC
LETTERS
2010
Vol. 12, No. 11
2464-2467
Activation of Fmoc-Protected
N,O-Acetals Using Trimethylsilyl
Halides: Mechanistic and Synthetic
Studies
Nicholas C. Boaz, Nathaniel C. Bair, Thanh T. Le, and Timothy J. Peelen*
Department of Chemistry, Lebanon Valley College, AnnVille, PennsylVania 17003
peelen@lVc.edu
Received February 26, 2010
ABSTRACT
Trimethylsilyl halide activation of Fmoc-protected N,O-acetals yields reactive intermediates capable of efficiently adding to a variety of enamines.
NMR studies have provided evidence that a stable halomethyl carbamate intermediate forms in solution. Good yields are obtained over a
broad range of enamine nucleophiles encompassing both cyclic and acyclic ketone-derived and aldehyde-derived enamines. Preliminary studies
suggest that the enamine additions occur through a concerted, SN2-type mechanism.
N-Fluoren-9-ylmethoxycarbonyl (Fmoc)-protected amines
and amino acids are valuable building blocks for synthesis,
particularly for the solid-phase synthesis of peptides.1,2
Despite their importance, the methods for the preparation
of unnatural Fmoc-protected amines and amino acids are
limited. Due to the base lability of the Fmoc-protecting
group, Fmoc protection is typically reserved for the final step
of synthetic sequences. Often, these syntheses require dif-
ferent protecting groups early in the synthesis, resulting in
inefficient procedures requiring multiple protection and
deprotection steps.
We envisioned efficient routes to Fmoc-protected amines
through C-C bond-forming reactions involving Fmoc-
protected acyl iminium ion precursors. While acyl iminium
ion chemistry is well established,3 there were only two
reported carbon-carbon bond-forming reactions using Fmoc-
protected N,O-acetals prior to our studies.4 Recently, we
reported a model study of additions of weakly basic
nucleophiles to an Fmoc-protected N,O-acetal.5 Catalyzed
by Lewis acids (10 mol %), allylsilane, silyl enol ether/silyl
ketene acetal, and ketone enamine nucleophiles were found
to be compatible with the Fmoc-protecting group in these
reactions.
The addition of the ketone enamine, which was the most
basic of our nucleophiles, to the Fmoc-protected N,O-acetal
required careful control of reaction conditions. Surprisingly,
no Lewis acid was required for the enamine addition.
Furthermore, competing reaction pathways, mostly involving
Fmoc-deprotection, severely limited the scope and yields of
enamine additions. Examination of the prior literature
(3) For recent reviews, see: (a) Yazici, A.; Pyne, S. G. Synthesis 2009,
339–368. (b) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56,
3817–3856. (c) Hiemstra, H.; Speckamp, W. N. ComprehensiVe Organic
Synthesis, 1st ed.; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, UK,
1991; Vol. 2, pp 1047-1082.
(1) For references related to the Fmoc protecting group, see: (a) Carpino,
L. A. Acc. Chem. Res. 1987, 20, 401–407. (b) Greene, T. W.; Wuts, P. G. M.
ProtectiVe Groups in Organic Synthesis, 3rd ed.; John Wiley & Sons: New
York, 1999; pp 506-507.
(4) (a) Sugiura, M.; Hagio, H.; Hirabayashi, R.; Kobayashi, S. J. Am.
Chem. Soc. 2001, 123, 12510–12517. (b) Mentink, G.; van Maarseveen,
J. H.; Hiemstra, H. Org. Lett. 2002, 4, 3497–3500.
(2) For an overview of solid-phase peptide synthesis, see: Amblard, M.;
Fehrentz, J.-A.; Martinez, J.; Subra, G. Mol. Biotechnol. 2006, 33, 239–
(5) Hartman, A. E.; Brophy, C. L.; Cupp, J. A.; Hodge, D. K.; Peelen,
T. J. J. Org. Chem. 2009, 74, 3952–3954.
254
.
10.1021/ol100494z  2010 American Chemical Society
Published on Web 05/03/2010

revealed that there were few examples of enamine additions
to N,O-acetals or acyl iminium ions.6
4 h using a 10-fold excess of TMSCl; the intermediate
appears to be relatively stable under the reaction conditions.
Following addition of morpholinocyclohexene, the interme-
diate is completely consumed before an NMR spectrum can
be acquired (not shown).9 Workup affords the expected
Fmoc-protected amino ketone 3.
We assign the intermediate in the reaction as the chlo-
romethyl carbamate 2. The observed 1H NMR chemical shift
for the chloromethyl group agrees well with the chemical
shifts observed for stable chloromethyl carbamates and
amides reported previously.10,11 Further evidence for the
chloromethyl carbamate was obtained by examining inter-
mediates formed from the addition of TMSCl to Fmoc-
protected N,O-acetals 1a-c (Figure 2). When starting with
either the hydroxy, acetoxy, or isopropoxy N,O-acetal, the
reactions converge to a common intermediate (eq 2).9 This
result is consistent with replacement of the oxygen group
resulting in the formation of a chloromethyl carbamate.
To expand the scope of enamine additions to Fmoc-
protected N,O-acetals, we were interested in identifying
alternative strategies for activating Fmoc-protected N,O-
acetals. We felt that the ability to exchange the oxygen
leaving group in the N,O-acetal for a more reactive halide,
as had recently been done using TMSCl, held great promise
for expanding the scope of N,O-acetal chemistry.7,8 Herein,
we report a mechanistic and synthetic study of the activation
of Fmoc-protected N,O-acetals using trimethylsilyl halides
and subsequent addition of enamines.
Preliminary experiments using N,O-acetal 1a with TMSCl
followed by addition of morpholinocyclohexene cleanly
afford the desired Fmoc-protected amino ketone 3 (eq 1).
Reaction optimization indicated that using an excess of
TMSCl was beneficial and that the reaction worked best if
the TMSCl was premixed with the N,O-acetal compound
prior to addition of the enamine. Simultaneous addition of
TMSCl and the enamine resulted in little or no product
formation.
Additional evidence for formation of a halomethyl car-
bamate intermediate was obtained by treating N,O-acetals
with different trimethyl silyl halide reagents. Reaction of
Fmoc-protected N,O-acetal 1a in CDCl3 with TMSBr af-
forded an insoluble white precipitate, presumably the cor-
responding bromide, that could not be characterized using
NMR. Addition of enamine to the intermediate results in
rapid consumption of the solid and smooth conversion to
the corresponding Fmoc-protected amino ketone. Spectro-
scopic evidence of soluble halide-containing intermediates
1H NMR experiments clarified the operative reaction
pathway (Figure 1). Reaction of N,O-acetal 1a with TMSCl
(6) (a) Statkova-Abeghe, S.; Angelov, P. A.; Ivanov, I.; Nikolova, S.;
Kochovska, E. Tetrahedron Lett. 2007, 48, 6674–6676. (b) Attrill, R.; Tye,
H.; Cox, L. R. Tetrahedron: Asymmetry 2004, 15, 1681–1684.
(7) For the first report of a TMSCl activation approach to Pictet-Spengler
reactions, see: Cheung, G. K.; Earle, M. J.; Fairhurst, R. A.; Heaney, H.;
Shuhaibar, K. F.; Eyley, S. C.; Ince, F. Synlett 1991, 721–723. For a related
opening of a cyclic acetal using dialkylboron bromide, see: Guindon, Y.;
Ogilvie, W. W.; Bordeleau, J.; Cui, W. L.; Durkin, K.; Gorys, V.; Juteau,
H.; Lemieux, R.; Liotta, D.; Simoneau, B.; Yoakim, C. J. Am. Chem. Soc.
2003, 125, 428–436.
(8) (a) Peterson, E. A.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2009,
48, 6328–6331. (b) Raheem, I. T.; Thiara, P. S.; Jacobsen, E. N. Org. Lett.
2008, 10, 1577–1580. (c) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.;
Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404–13405.
(9) See the supporting information.
(10) (a) Hartung, R.; Golz, G.; Schlaf, S.; Silvennoinen, G.; Polborn,
K.; Mayer, P.; Pfaendler, H. R. Synthesis 2009, 495–501. (b) Aciro, C.;
Davies, S. G.; Garner, A. C.; Ishii, Y.; Key, M.-S.; Ling, K. B.; Prasad,
R. S.; Roberts, P. M.; Rodriguez-Solla, H.; O’Leary-Steele, C.; Russell,
A. J.; Sanganee, H. J.; Savory, E. D.; Smith, A. D.; Thomson, J. E.
Tetrahedron 2008, 64, 9320–9344. (c) Majumdar, S.; Sloan, K. B. Synth.
Commun. 2006, 36, 3537–3548. (d) Williams, G. D.; Wade, C. E.; Clarkson,
G. J.; Wills, M. Tetrahedron: Asymmetry 2007, 18, 664–670. (e) Bo¨hme,
H.; Raude, E. Chem. Ber. 1981, 114, 3421–3429. (f) Smith, M. B.;
Dembofsky, B. T.; Son, Y. C. J. Org. Chem. 1994, 59, 1719–1725. (g)
Ortiz, J.; Guijarro, A.; Yus, M. Tetrahedron 1999, 55, 4831–4842.
(11) halomethylcarbamates 2, and the other halomethylcarbamates
described herein, can can be isolated, though they are very sensitive to
moisture and are less pure upon isolation than they were in situ. Thus, we
prefer to avoid handling the halomethylcarbamate compounds directly.
Figure 1. Activation of N,O-acetal 1a with TMSCl over 4 h.
in CDCl3 afforded slow conversion to a new intermediate.
The conversion is roughly complete at room temperature after
Org. Lett., Vol. 12, No. 11, 2010
2465

was obtained using Cbz-protected hydroxy N,O-acetal 4 (eq
3). Activation of 4 with TMSCl or TMSBr led to intermedi-
The effect of enamine N-substitution was also investigated
(Table 2). Morpholino-, piperidino-, and pyrrolidinocyclo-
1
ates with distinct H and 13C NMR spectra, consistent with
formation of different halide-containing intermediates 5a and
5b.9 Intermediates 5a and 5b were both competent electro-
philes in subsequent reactions with enamines.
Table 2. Effect of Enamine Nitrogen Substitutiona
Activation of Fmoc-protected N,O-acetal 1a with even
more strongly electrophilic silyl reagents TMSI and TMSOTf
did not afford activated intermediates. Instead, treatment of
a variety of N,O-acetals with both TMSI and TMSOTf
resulted in decomposition of the N,O-acetal and formation
of FmocNH2. TMSOTf12 and TIPSOTf13 have previously
been used as promoters of N,O-acetals in reactions proposed
to involve acyl iminium ion intermediates. Our inability to
identify a stable triflate-containing intermediate may suggest
that these reactions proceed through acyl iminium ion
intermediates without significant participation of stable
triflate-containing intermediates.
a TMSCl (2 equiv), CDCl3, 60 min; then enamine (3 equiv), 10 min.
b CH2Cl2 was used as the solvent.
hexene all afford addition products in good yields. The
enamine scope contrasts with our previous studies of enamine
additions to unactivated N,O-acetal 1a, where only the most
nucleophilic pyrrolidinocyclohexene added with an accept-
able yield.5
Next, we examined the synthetic scope of enamine
additions to TMSCl-activated N,O-acetals. The TMSCl
activation of Fmoc-protected N,O-acetals 1a-c containing
different oxygen leaving groups was explored (Table 1). The
The TMSCl activation strategy has broadened the scope
of additions of enamines to N,O-acetals (Table 3). A wide
Table 1. Effect of Oxygen Leaving Group
Table 3. Addition of Enamines to TMSCl-Activated
Fmoc-Protected N,O-Acetalsa
entry
-OR
TMSCl (equiv) activation time (h) yield (%)
1
2
3
-OAc (1a)
-OiPr (1b)
-OH (1c)
10
10
2
2
16
1
60
46
71
amount of TMSCl, the activation time required, and the
extent of activation all vary on the basis of the oxygen
leaving group. TMSCl activation of N,O-acetals 1a and 1c
1
typically occurs in >90% conversion (based upon H NMR
integrations), and subsequent enamine addition affords good
yields of ketone product. Hydroxy-substituted N,O-acetal 1c
activates the most rapidly and cleanly and also affords the
highest yield of enamine addition products and, thus, was
used in further synthetic studies.
(12) For selected recent examples, see: (a) Mancey, N. C.; Butlin, R. J.;
Harrity, J. P. A. Synlett 2008, 2647–2650. (b) Xiao, Q.; Floreancig, P. E.
Org. Lett. 2008, 10, 1139–1142. (c) Liu, G.; Meng, J.; Feng, C.-G.; Huang,
P.-Q. Tetrahedron: Asymmetry 2008, 19, 1297–1303. (d) Romero, A.;
Woerpel, K. A. Org. Lett. 2006, 8, 2127–2130. (e) Shirakawa, S.; Lombardi,
P. J.; Leighton, J. L. J. Am. Chem. Soc. 2005, 127, 9974–9975.
(13) Othman, R. B.; Bousquet, T.; Fousse, A.; Othman, M.; Dalla, V.
Org. Lett. 2005, 7, 2825–2828.
a TMSCl (2 equiv), CH2Cl2, 60 min; then enamine (3 equiv), 10 min.
b 10 equiv of TMSCl was used. c CDCl3 was used as the solvent.
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Org. Lett., Vol. 12, No. 11, 2010

variety of enamines react smoothly with N,O-acetal 1c
following TMSCl activation. Good yields are observed with
enamines derived from cyclic (entries 1 and 2) and acyclic
ketones (entry 3). Notable is the reactivity observed with
the aldehyde-derived enamine (entry 4), which has been
shown to be difficult in the past.14
enamine nucleophile, consistent with a second-order reaction
pathway.9,17
An SN2 mechanism is also consistent with our previous
studies of an enamine addition to N,O-acetal 1a (without
TMSCl activation).5 This enamine addition to acetate 1a
proceeded in the absence of Lewis or Brønsted acids, which
are typically required for acyl iminium ion formation.
Nucleophile strength proved to be critical when comparing
enamine additions to N,O-acetal 1a with chloromethylcar-
bamate 2. Only the most nucleophilic pyrrolidine enamine
reacts with acetate 1a, while chloride 2 reacts with a variety
of enamines.18
Two features of the likely reaction mechanism are notable
(Scheme 1). First, since the reaction is conducted using
Scheme 1. Proposed Mechanism
In summary, TMSCl activation has been investigated in
enamine addition reactions to Fmoc-protected N,O-acetals.
Activation results in formation of a halomethyl carbamate
intermediate, which undergoes SN2 addition with a variety
of enamine nucleophiles. The TMSCl activation strategy
yields reaction pathways that are complementary to acyl
iminium ions.
undistilled solvents, the formation of the chloromethylcar-
bamate intermediate likely proceeds through the action of
HCl generated in situ by hydrolysis of the TMSCl.8a,c
Second, the subsequent enamine addition to the chlorom-
ethylcarbamate intermediate appears to proceed through a
concerted, SN2 displacement of the chloride. While prior
studies using related chloroalkyl carbamate15 and
chlorolactam8a,c intermediates (albeit with weaker nucleo-
philes) have implicated a SN1 mechanism, enamine alkylation
reactions are generally believed to proceed through SN2
mechanisms.16 Preliminary kinetic studies of the enamine
addition display a dependence on the concentration of the
Acknowledgment. This research was supported by an
award from Research Corporation.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL100494Z
(16) (a) Fu, A.; List, B.; Thiel, W. J. Org. Chem. 2006, 71, 320–326.
(b) Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.; Terrell, R.
J. Am. Chem. Soc. 1963, 85, 207–222
.
(17) The dependence on the concentration of enamine is also consistent
with rate-limiting addition of the enamine to an acyliminium ion, which
cannot be discounted but seems unlikely.
(14) Hodgson, D. M.; Bray, C. D.; Kindon, N. D.; Reynolds, N. J.; Coote,
S. J.; Um, J. M.; Houk, K. N. J. Org. Chem. 2009, 74, 1019–1028.
(15) Barnes, D. M.; Barkalow, J.; Plata, D. J. Org. Lett. 2009, 11, 273–
275.
(18) For a study of enamine nucleophilicity, see: Kempf, B.; Hampel,
N.; Ofial, A. R.; Mayr, H. Chem.sEur. J. 2003, 9, 2209–2218.
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