A practical method for selective cleavage of a tert-butoxycarbamoyl N-protective group from N,N-diprotected α-amino acid derivatives using montmorillonite K-10

Article abstract of DOI:10.1002/ejoc.200700296

A new, practical, and mild procedure for the selective cleavage of a tert-butoxycarbonyl group (Boc) in N-Boc-N-acyl-diprotected amines is described. When applied to α-amino acids, complete integrity of the stereochemistry was observed. The use of N,N-di-Boc-α-amino-δ- and γ-hydroxy esters provided both δ- and γ-lactones in very good yields. The method is based on the use of Montmorillonite K-10 either in CH ₂Cl₂ at room temperature or in toluene at 65°C and is compatible with the presence of a large range of functional and other protecting groups in the substrates. In most cases virtually pure samples are obtained after filtration and removal of solvents. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700296

FULL PAPER
DOI: 10.1002/ejoc.200700296
A Practical Method for Selective Cleavage of a tert-Butoxycarbamoyl
N-Protective Group from N,N-Diprotected α-Amino Acid Derivatives Using
Montmorillonite K-10
J. Nicolás Hernández,[a] Fernando R. Pinacho Crisóstomo,[a] Tomás Martín,[a,b] and
Víctor S. Martín*[a]
Dedicated to Professor Miguel Yus on the occasion of his 60th birthday
Keywords: α-Amino acids / Clays / Heterogeneous catalyst / Protecting groups / Lactones / Asymmetric synthesis
A new, practical, and mild procedure for the selective cleav-
age of a tert-butoxycarbonyl group (Boc) in N-Boc-N-acyl-
diprotected amines is described. When applied to α-amino
acids, complete integrity of the stereochemistry was ob-
served. The use of N,N-di-Boc-α-amino-δ- and γ-hydroxy es-
ters provided both δ- and γ-lactones in very good yields. The
method is based on the use of Montmorillonite K-10 either in
CH2Cl2 at room temperature or in toluene at 65 °C and is
compatible with the presence of a large range of functional
and other protecting groups in the substrates. In most cases
virtually pure samples are obtained after filtration and re-
moval of solvents.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
cation of N,N-di-Boc-α-amino esters produces partial race-
mization[3b] (Scheme 1).[4] Many methods for the removal
of Boc groups in N-protected amines can be found in the
literature,[1] but only a few are suited for selective cleavage
of the group in diprotected N-Boc-N-acyl amines.[5]
Introduction
The tert-butoxycarbonyl group is one of the most useful
amine-protecting groups in organic synthesis, thanks to its
chemical stability over a large pH range and its ease of re-
moval under specific conditions.[1] Although the protecting
group is usually employed in the form of an N-Boc deriva-
tive, its use in diprotected N,N-Boc-acyl nitrogen derivatives
is essential for the success of several reactions. Thus, di-
tert-butyl imidodicarbonates and tosyl carbamates are very
useful as phthalimide substitutes in Mitsunobu[1] and
Gabriel-type processes.[1] The selective reduction of N,N-di-
Boc-α-amino acid derivatives, obtained from natural α-
amino acids (glutamic or aspartic acids) or the homolo-
gated compounds, produced ω-semialdehydes in very good
yields and with complete integrity at the stereocenters.[4]
Moreover, the introduction of the second N-Boc group pro-
duces several changes in the reactivity of the vicinal ester.
For instance, whereas the alkaline hydrolysis of N-Boc-α-
amino esters occurs without any racemization, the saponifi-
Scheme 1. Selectivity and modification in reactivity in N,N-di-Boc
α-amino diesters.
[a] Instituto Universitario de Bio-Orgánica “Antonio González”,
Universidad de La Laguna,
On the other hand, the use of solid acidic materials such
as Montmorillonite clays is very attractive since they can be
easily recovered from reaction mixtures by simple filtration
and can be reused after activation, thereby making the pro-
cess economically viable and environmentally friendly.
Montmorillonite K-10 has been reported to promote acid-
dependent reactions.[6] Moreover, it has been used to cleave
N-Boc groups selectively from aromatic amines.[7] We now
report on a new and practical method for selective depro-
Astrofísico Francisco Sánchez 2, 38206 La Laguna, Tenerife,
Islas Canarias, Spain
Fax: +34-922318579
E-mail: vmartin@ull.es
[b] Instituto de Productos Naturales y Agrobiología, Consejo Su-
perior de Investigaciones Científicas,
Astrofísico Francisco Sánchez 3, 38206 La Laguna, Tenerife,
Islas Canarias, Spain
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
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Selective tert-Butoxycarbamoyl Group Cleavage
tection of an N-Boc group in N-Boc-N-acyl-protected any detectable racemization.[8] The use of Montmorillon-
amines and α-amino acids, in this case taking place without ite K-10 either in CH2Cl2 at room temperature or in toluene
Table 1. Selective cleavage of N,N-di-Boc-protected amines and α-amino acids using Montmorillonite K-10.
[a] Except in cases indicated, substrates and products are reported in ref.[5f] [b] A: CH2Cl2, room temperature; B: toluene, 65 °C.
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FULL PAPER
at 65 °C proved to be an excellent combination with which no reaction occurred (Entry 11). Evidence of possible com-
to achieve selectivity, mildness, and generality in the desired petition with the reaction sites at the clay in the above case
conversion.[9]
was obtained when the corresponding silyl-protected com-
pound was used: this compound underwent straightforward
selective N-Boc cleavage (Entry 12).[10] The Montmorillon-
ite K-10 system cleaved silyl ethers (TBS and TBDPS; En-
Results and Discussion
In order to explore the scope and limitations of our tries 12, 14) present in some N,N-di-Boc-α-amino-protected
method, we investigated a series of N,N-di-Boc amino de- compounds, but in others the silyl group remained unaffec-
rivatives containing several protecting groups and function- ted (Entries 8, 9, 13).[11] The reason for this behavior is not
alities (Table 1). We found the procedure to be highly gene- completely clear, but presumably is related to the longer
ral, affording the corresponding N-Boc amino derivatives reaction rate relative to the N-Boc cleavage in Entries 12
in excellent yields. The possibility of applying this method- and 14. Interestingly, the cleavage of the N-Boc group could
ology to an α-amino acid derivative containing an aldehyde be achieved in the presence of O-Boc protective groups (En-
function in its structure was of particular interest (En- try 10). In addition, the tert-butyl ester function remains
try 3).[4] When a hydroxy group is present in the substrate, unaffected under these conditions (Entry 16). In general,
the reaction behavior depends on the position of this group the reaction times were shorter when toluene at 65 °C was
relative to the N,N-di-Boc amino derivatives; thus, when the used rather than CH2Cl2 at room temperature. Addition-
hydroxy group was far from the N-Boc functions, almost ally, the Montmorillonite K-10 could be recovered by sim-
no influence was detected (Entry 5), while when it was close ple filtration from the reaction mixture and was successfully
to the protected nitrogen, a negative influence was seen and reused four times without losing its activity in the cleavage
Table 2. Selectivity in the cleavage of N,N-diprotected α-amino acids and amines.
[a] Except in cases indicated, substrates and products are reported in ref.[5f] [b] A: CH2Cl2, room temperature; B: toluene, 65 °C.
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Selective tert-Butoxycarbamoyl Group Cleavage
of N,N-di-Boc-α-amino-protected derivatives.[12] It should
Taking into account the observation that the use of
be emphasized that in most cases virtually pure samples Montmorillonite K-10 had produced the lactonization of
were obtained after filtration and removal of solvents. methyl (S)-2-(tert-butoxycarbonylamino)-5-hydroxypenta-
As the method works with the N,N-di-Boc fragment, we noate (Entry 14 in Table 1), through concomitant cleavage
wondered whether the methodology could also be extended of the TBS protecting group and one of the two Boc groups,
to other situations in which the nitrogen is doubly protected we pondered the possibility of using Montmorillonite to
with different protecting groups together with the N-Boc promote lactonization of δ- and γ-hydroxy-α-amino acids
protection (Table 2). We found that when another carbam- derivatives (Table 3). The process is effective for primary
oyl-based protecting group, such as Cbz, was used the cleav- and secondary alcohols since both γ- and δ-lactones were
age of the Boc group was accomplished cleanly and selec- obtained in very good yields. However, when a tertiary
tively, yielding the corresponding N-Cbz amino derivative alcohol was used the lactone was not obtained (Entry 5). In
(Entry 1). However, when the nitrogen was protected as the addition, we found that in acetonitrile as solvent the depro-
N-Cbz-N-acyl derivative the substrate remained unaltered tected δ-hydroxy-α-amino ester was obtained as sole prod-
in the presence of Montmorillonite K-10 even after 24 h at uct (Entry 1), but in toluene the reaction afforded the corre-
65 °C (Entries 2, 8) demonstrating the high selectivity in sponding δ-lactone (Entry 2). In this last case, the originally
favor of N-Boc cleavage. When the additional protecting formed mixture of the hydroxy ester and the δ-lactone, de-
group on the nitrogen atom was an acyl group, cleavage of tected after 12 h, evolved to the cyclic product after a longer
the N-Boc group proceeded in excellent yields with N-Boc- reaction time (30 h). On the contrary, during the lactoniz-
N-acyl-α-amino acids (Entries 3, 5) but only in moderate ation process to γ-lactones we observed only the cyclic
yields with the protected N-Boc-N-acyl-benzylamine (En- product from the very beginning of the reaction (Entries 6,
try 4). The procedure also worked very well for N-Boc-N- 7).
sulfonyl-α-amino acids, in which case the N-carbamoyl
In our previous report regarding the use of LiBr as an
cleavage was accomplished in excellent yields (Entries 6, effective catalysis to cleave one carbamoyl group in N,N-
7).[16] Finally, the procedure leaves N-Boc protected second- dicarbamoyl-protected amines,[5f] we provided arguments
ary amines unaffected (Entries 9, 10).
accounting for the different behavior, regarding selectivity,
Table 3. Lactonization of N,N-di-Boc-α-amino-δ- and -γ-hydroxy esters using Montmorillonite K-10, at 65 °C.
[a] With a shorter reaction time (12 h), a 94% yield of a mixture (1:1) of mono-deprotected hydroxy-N-Boc amino ester (see Entry 1)
and lactone was isolated. [b] At 25 °C.
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FULL PAPER
in comparison with the use of Mg(ClO4)2.[5b] The lithium
induces a weak covalent C–O bond (tert-butyl oxygen), but
this part of the molecule adopts a more ionic character in
the case of the magnesium complex. This is coincident with
the experimental observations that indicate a greater decar-
boxylative facility for magnesium-assisted breaking. As the
selectivity found with Montmorillonite is roughly similar to
that achieved using Mg2+ [5f] we propose that interlayer cat-
ions (magnesium) may be responsible for the activity, al-
though interstitial water may also exert a general acidic ef-
fect.
C11H19NO6 (261.27): calcd. C 50.57, H 7.33, N 5.36; found C
50.54, H 7.36, N 5.36.
5-[Bis(tert-butoxycarbonyl)amino]pentyl tert-Butyl Carbonate (19):
Et3N (2.11 mL, 15 mmol) and (Boc)2O (6.6 g, 30 mmol) were
added sequentially to a stirred suspension of commercially available
5-aminopentan-1-ol (1.03 g, 10 mmol) in dry CH2Cl2 (100 mL).
The reaction mixture was stirred until TLC showed complete pro-
tection. The solvent was removed under reduced pressure, and the
residue was triturated, washed with Et2O, and filtered through a
pad of Celite. The combined organic layers were concentrated to
yield an oily residue. (Boc)2O (2.5 g, 11 mmol) was added at room
temperature to a solution of this compound and DMAP (244 mg,
2 mmol) in dry CH3CN (15 mL). The reaction mixture became
slightly red with gas evolution. The mixture was stirred for 4 h,
after which time TLC showed that some starting material still re-
mained. More (Boc)2O (1.1 g, 5 mmol) was then added, and the
mixture was additionally stirred overnight. The solvent was evapo-
rated, and the crude product was purified by silica gel column
chromatography to afford 19 (3.6 g, 89% yield) as an oil: 1H NMR
(CDCl3): δ = 1.42 (s, 27 H), 1.49 (m, 6 H), 3.47 (t, J = 6.6 Hz, 2
H), 3.96 (t, J = 7.4 Hz, 2 H) ppm. 13C NMR (CDCl3): δ = 22.8 (t),
27.5 (q), 27.8 (q), 28.1 (t), 28.4 (t), 45.9 (t), 62.1 (s), 66.6 (t), 81.5
Conclusions
In conclusion, we have found that clay Montmorillon-
ite K-10 promotes the selective cleavage of a Boc group in
N-Boc-N-acyl-diprotected amines. The methodology is
practical, simple to use, easily scalable, and compatible with
a wide range of functional groups. Commercially available
Montmorillonite K-10 is nontoxic, inexpensive, environ-
mentally friendly, and reusable. In addition, we found that
Montmorillonite promotes concomitant Boc cleavage and
lactonization when primary or secondary γ- or δ-hydroxy-
N,N-di-Boc-protected α-amino acids are used as substrates.
(s), 81.8 (s) 152.4 (s), 153.4 (s) ppm. IR (CHCl ): ν = 3690, 2979,
˜
3
1789, 1709, 1698, 1457, 1368, 1279, 1126, 1037 cm–1. MS: m/z =
426 [M + Na]+, 404 [M + 1]+, 236 [M + Na – 2ϫBoc]. HRMS:
calcd. for C20H37NNaO7 [M + Na]+: 426.246; found 426.2463.
C20H37NO7 (403.51): calcd. C 59.53, H 9.24, N 3.47; found C
59.52, H 9.45, N 3.60.
5-(tert-Butoxycarbonylamino)pentyl tert-Butyl Carbonate (20): The
general procedure described above was applied to 19 on a 5 mmol
scale (2 g), yielding 20 (1.29 g, 85% yield) as an oil: 1H NMR
(CDCl3): δ = 1.36 (s, 9 H), 1.39 (m, 4 H), 1.40 (s, 9 H), 1.59 (m, 3
H), 3.04 (br., 2 H), 3.97 (t, J = 6.6 Hz, 2 H), 4.5 (br., 1 H) ppm.
13C NMR (CDCl3): δ = 22.8 (t), 27.5 (q), 28.2 (q), 29.5 (t), 66.6
Experimental Section
General Methods: 1H and 13C NMR spectra were recorded at 25 °C
with Bruker Avance 400 and/or 300 spectrometers in CDCl3 as sol-
vent, and chemical shifts are reported relative to Me4Si. Low- and
high-resolution mass spectra were taken with a Micromass Au-
tospec spectrometer. Elemental analyses were performed on a Fi-
sons Instruments EA 1108 CHNS-O. Optical rotations were deter-
mined for solutions in chloroform or n-hexane with a Perkin–Elmer
Model 241 polarimeter. Infrared spectra were recorded on a Bruker
IFS 55 spectrophotometer. Column chromatography was per-
formed on Merck silica gel, 60 Å and 0.2–0.5 mm. Visualization of
spots was performed with the aid of UV light and/or phosphomol-
ybdic acid in ethanol stain. All solvents were purified by standard
techniques.[19] Reactions requiring anhydrous conditions were per-
formed under argon. Anhydrous magnesium sulfate was used for
drying solutions.
(t), 81.6 (s), 153.4 (s) ppm. IR (CHCl ): ν = 3691, 2977, 1741, 1519,
˜
3
1393, 1254, 1169 cm–1. MS: m/z = 304 [M + 1]+. HRMS: calcd.
for C15H30NO5 [M + 1]+: 304.2124; found 304.2111. C15H29NO5
(303.39): calcd. C 59.38, H 9.63, N 4.62; found C 59.39, H 9.76, N
4.49.
Methyl (S)-2-[Bis(tert-butoxycarbonyl)amino]-5-(tert-butyldiphenyl-
silyloxy)pentanoate (24): Imidazole (0.62 g, 9 mmol) was added to
a stirred solution of methyl (S)-2-[bis(tert-butoxycarbonyl)amino]-
5-hydroxypentanoate[20] (1 g, 3 mmol) in dry CH2Cl2 (15 mL). The
reaction mixture was cooled to 0 °C, and tert-butylchlorodiphenyl-
silane (0.94 mL, 3.6 mmol) was added. The mixture was stirred for
3 h at the same temperature. After that, the cooling bath was re-
moved, water was added, and the products were extracted with
CH2Cl2. The organic solution was dried with MgSO4 and filtered
through a pad of Celite. The solvent was evaporated, and the crude
product was purified by silica gel column chromatography to afford
24 (1.6 g, 91% yield) as an oil; [α]D25 = –19.2 (c = 3, CHCl3). 1H
NMR (CDCl3): δ = 1.02 (s, 9 H), 1.45 (s, 18 H), 1.63 (m, 2 H),
1.99 (m, 1 H), 2.22 (m, 1 H), 3.66 (s, 3 H), 4.84 (m, 1 H), 7.35 (m,
6 H), 7.64 (m, 4 H) ppm. 13C NMR (CDCl3): δ = 19.0 (s), 26.3 (t),
26.4 (q), 26.7 (q), 29.2 (t), 51.8 (q), 57.8 (d), 63.2 (t), 82.7 (s), 127.4
(d), 129.3 (d), 133.7 (s), 134.6 (s), 135.3 (d), 151.8 (s), 171.0 (s) ppm.
General Procedure for the Selective Cleavage of One Boc Group in
an N,N-Boc,acyl-diprotected Amine: N-Boc--aspartic dimethyl es-
ter (2). Commercially available Montmorillonite K-10 (9 g) was
added to a stirred solution of N,N-di-Boc--aspartic dimethyl ester
(1,[4a] 2.95 g, 8.2 mmol) in toluene (80 mL). The mixture was stirred
at 65 °C for 0.5 h, after which time the reaction was complete. The
reaction mixture was filtered, and the solid was washed with ethyl
acetate. The solution was concentrated to yield pure N-Boc--
aspartic dimethyl ester (2, 2 g, 93% yield) as a white solid with m.p.
66–65 °C. [α]2D5 = +28.0 (c = 5, CHCl3).[5f] 1H NMR (CDCl3): δ =
1.36 (s, 9 H), 2.77 (dd, J = 4.75, 16.9 Hz, 1 H), 2.92 (dd, J = 4.1,
17.0 Hz, 1 H), 3.61 (s, 3 H), 3.67 (s, 3 H), 4.48 (br., 1 H), 5.47 (br.,
1 H) ppm. 13C NMR (CDCl3): δ = 28.2 (q), 36.5 (t), 49.9 (d), 51.8
(q), 52.5 (q), 79.9 (s), 155.3 (s), 171.4 (s), 171.2 (s) ppm. IR
IR (CHCl ): ν = 3676, 2933, 1757, 1589, 1473, 1367, 1129 cm–1.
˜
3
MS: m/z = 608 [M + Na]+, 486 [M – Boc]+, 386 [M – 2ϫBoc]+,
372 [M – Boc – 2ϫtBu]+. HRMS: calcd. for C32H47NNaO7Si [M
+ Na]+: 608.3020; found 608.3071. C32H47NO7Si (585.80): calcd. C
65.61, H 8.09, N 2.39; found C 65.61, H 8.11, N 2.23.
(CHCl ): ν = 3374, 2979, 1742, 1438, 1166, 1046 cm–1. HRMS:
˜
3
calcd. for C11H19NO6 [M – 1]+: 261.121; found 261.1225. MS: m/z
284 [M + Na]+, 262 [M + 1]+, 206 [M – tBu]+, 162 [M – Boc]+.
Methyl (S)-2-(tert-Butoxycarbonylamino)-5-(tert-butyldiphenylsilyl-
oxy)pentanoate (25): The general procedure described above was
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Selective tert-Butoxycarbamoyl Group Cleavage
applied to 24 on a 1.5 mmol scale (0.88 g), yielding 25 (0.685 g,
94% yield) as an oil. [α]D25 = +9.0 (c = 3, CHCl3). 1H NMR
(CDCl3): δ = 1.02 (s, 9 H), 1.39 (s, 9 H), 1.52 (m, 2 H), 1.72 (m, 1
H), 1.99 (m, 1 H), 3.62 (t, J = 6.0 Hz, 2 H), 3.65 (s, 3 H), 4.27 (br.,
gel column chromatography, to afford 37 (1.8 g, 72% yield) as an
1
oil. H NMR (CDCl3): δ = 1.38 (s, 9 H), 2.51 (s, 3 H), 4.87 (s, 2
H), 7.2 (m, 5 H) ppm. 13C NMR (CDCl3): δ = 26.6 (q), 27.8 (q),
47.0 (t), 83.1 (s), 127.0 (d), 127.5 (d), 128.2 (d), 138.3 (s), 153.1 (s),
1 H), 5.08 (br., 1 H), 7.36 (m, 6 H), 7.60 (m, 4 H) ppm. 13C NMR 172.9 (s) ppm. IR (CHCl ): ν = 2980, 1737, 1698, 1369, 1281, 1040.
˜
3
(CDCl3): δ = 19.0 (s), 26.6 (q), 28.1 (q), 28.9 (t), 51.9 (q), 53.1 (d),
MS: m/z = 250 [M + 1]+, 194 [M – tBu]+. HRMS: calcd for
62.8 (t), 79.6 (s), 127.4 (d), 129.4 (d), 133.5 (s), 134.6 (s), 135.3 (d), C14H20NO3 [M + 1]+: 250.1443; found 250.1414. C14H19NO3
155.2 (s), 173.1 (s) ppm. IR (CHCl ): ν = 3688, 3071, 2931, 2858,
(249.31): calcd. C 67.45, H 7.68, N 5.82; found C 67.43, H 7.77, N
5.62.
˜
3
1717, 1589, 1473, 1391, 1248, 1170, 1008 cm–1. MS: m/z = 486 [M
+ 1]+, 386 [M – Boc]+, 372 [M – 2ϫtBu]+. HRMS: calcd. for
C27H40NO5Si [M + 1]+: 486.2676; found 486.2722. C27H39NO5Si
(485.69): calcd. C 66.77, H 8.09, N 2.88; found C 67.79, H 7.93, N
2.68.
Dimethyl (S)-2-[N-(tert-Butoxycarbonyl)benzamido]pentanedioate
(39): Na2CO3 (2.4 g, 22.5 mmol) and benzoyl chloride (1.29 mL,
11 mmol) were added at room temperature to a stirred suspension
of commercially available (S)-glutamic acid (1.47 g, 10 mmol) in
water (100 mL). The reaction mixture was heated at reflux over-
night. The reaction mixture was then diluted with EtOAc, treated
twice with HCl, washed with brine, dried, and concentrated, yield-
Methyl (S)-2-[Bis(tert-butoxycarbonyl)amino]-5-(tert-butyldimethyl-
silyloxy)pentanoate (26): Imidazole (0.47 g, 6.9 mmol) was added
to a stirred solution of methyl (S)-2-[bis(tert-butoxycarbonyl)-
amino]-5-hydroxypentanoate[20] (0.8 g, 2.3 mmol) in dry CH2Cl2 ing an oily residue. A solution of this compound in dry MeOH
(23 mL). The reaction mixture was cooled to 0 °C and tert-butyl-
chlorodimethylsilane (0.43 g, 2.8 mmol) was added. The mixture
was stirred for 3 h at the same temperature. The cooling bath was
then removed, water was added, and the products were extracted
with CH2Cl2.The organic solution was dried with MgSO4 and fil-
tered through a pad of Celite. The solvent was evaporated, and the
crude product was purified by silica gel column chromatography to
afford 26 (0.95 g, 89% yield) as an oil. [α]D25 = –11.9 (c = 3, CHCl3).
(33 mL) was added slowly to Me3SiCl (5.6 mL, 44 mmol) in an ice-
cold bath. After the addition was complete, the ice-cold bath was
removed and the reaction mixture was stirred overnight until TLC
showed complete conversion. The mixture was then concentrated
to yield the corresponding N-Bz-amino ester, which was used with-
out purification. (Boc)2O (2.5 g, 11 mmol) was added at room tem-
perature to a stirred solution of this crude product and DMAP
(244 mg, 2 mmol) in dry CH3CN (15 mL). The reaction became
1H NMR (CDCl3): δ = –0.05 (s, 6 H), 0.8 (s, 9 H), 1.4 (s, 18 H), slightly red with gas evolution. The mixture was stirred for 4 h,
1.52 (m, 2 H), 1.84 (m, 1 H), 2.0 (m, 1 H), 3.54 (t, J = 6.3 Hz, 2 after which time TLC showed that some starting material still re-
H), 3.54 (s, 3 H), 4.79 (dd, J = 9.6, 5.2 Hz, 1 H) ppm. 13C NMR
(CDCl3): δ = –5.6 (q), 18.0 (s), 25.7 (t), 26.2 (q), 27.7 (q), 29.3 (t),
51.8 (q), 57.7 (d), 62.4 (t), 82.7 (s), 151.8 (s), 171.1 (s) ppm. IR
mained. More (Boc)2O (1.1 g, 5 mmol) was then added, and the
mixture was additionally stirred overnight. The solvent was evapo-
rated, and the crude product was purified by silica gel column
(CHCl ): ν = 3692, 2954, 1796, 1753, 1460, 1368, 1254, 1124,
chromatography, to afford 39 (3 g, 80% yield) as an oil. [α]2D5
=
˜
3
1005 cm–1. MS: m/z = 462 [M + 1]+, 362 [M – Boc]+, 262 [M – –37.3 (c = 3, CHCl3). 1H NMR (CDCl3): δ = 1.07 (s, 9 H), 2.37
2ϫBoc]+. HRMS: calcd. for C22H44NO7Si [M + 1]+: 462.2887;
found 462.2863. C22H43NO7Si (461.66): calcd. C 57.24, H 9.39, N
3.03; found C 57.25, H 9.54, N 2.98.
(m, 1 H), 2.41 (m, 2 H), 2.42 (m, 1 H), 3.59 (s, 3 H), 3.68 (s, 3 H),
5.01 (m, 1 H), 7.39 (m, 4 H) ppm. 13C NMR (CDCl3): δ = 24.4 (t),
27.0 (q), 30.5 (t), 51.4 (q), 52.2 (q), 56.7 (d), 83.5 (s), 127.4 (d),
127.9 (d), 131.1 (d), 136.9 (s), 152.4 (s), 170.3 (s), 172.6 (s), 172.7
tert-Butyl [(S)-2-Oxotetrahydro-2H-pyran-3-yl]carbamate (27): The
general procedure described above was applied to 26 on a
1.37 mmol scale (0.63 g) using toluene at 65 °C instead of CH2Cl2
at room temperature, yielding 27 (250 mg, 85% yield) as a white
(s) ppm. IR (CHCl ): ν = 2980, 2360, 1748, 1449, 1369, 1235, 1149,
˜
3
1016. MS: m/z = 380 [M + 1]+, 280 [M – Boc]+. HRMS: calcd. for
C19H26NO7 [M + 1]+, 380.170; found 380.1729. C19H25NO7
(379.40): calcd. C 60.15, H 6.64, N 3.69; found C 60.16, H 6.64, N
3.48.
1
solid with m.p. 110–111 °C. [α]D25 = +58 (c = 3, CHCl3). H NMR
(CDCl3): δ = 1.38 (s, 9 H), 1.55 (m, 1 H), 1.94 (m, 2 H), 2.5 (m, 1
H), 4.27 (t, J = 6.0 Hz, 2 H), 4.33 (br., 1 H), 5.32 (br. s, 1 H) ppm. Dimethyl (S)-2-Benzamidopentanedioate (40): The general pro-
13C NMR (CDCl3): δ = 20.8 (t), 25.4 (t), 28.0 (q), 49.0 (d), 67.1 cedure described above was applied to 39 on a 2 mmol scale (0.76 g)
(t), 79.9 (s), 155.1 (s), 172.4 (s) ppm. IR (CHCl ): ν = 3365, 2977, using toluene at 65 °C instead of CH2Cl2 at room temperature,
˜
3
1741, 1687, 1524, 1464, 1368, 1238, 1154, 1080 cm–1. MS: m/z =
216 [M + 1]+. HRMS: calcd. for C10H18NO4 [M + 1]+: 216.1236;
found 216.1239. C10H17NO4 (215.25): calcd. C 55.80, H 7.96, N
6.51; found C 55.82, H 7.84, N 6.44.
yielding 40 (519 mg, 93% yield) as a white solid with m.p. 69–
70 °C. [α]D25 = +5.4 (c = 3, CHCl3). 1H NMR (CDCl3): δ = 2.01
(m, 1 H), 2.26 (m, 1 H), 2.44 (m, 2 H), 3.60 (s, 3 H), 3.73 (s, 3 H),
4.77 (m, 1 H), 6.99 (br., 1 H), 7.42 (m, 3 H), 7.76 (d, J = 8.1 Hz,
1 H) ppm. 13C NMR (CDCl3): δ = 27.0 (t), 30.0 (t), 51.7 (q), 52.0
(t), 52.4 (q), 126.9 (d), 128.4 (d), 131.6 (d), 133.3 (s), 172.2 (s), 173.4
tert-Butyl Acetyl(benzyl)carbamate (37): A solution of benzylamine
(1 g, 9.3 mmol) in CH2Cl2 (50 mL) was treated with Et3N (1.7 mL,
12 mmol) and AcCl (0.8 mL, 11 mmol). The mixture was stirred at
room temperature for 12 h. The reaction mixture was then diluted
with EtOAc, treated with HCl (5%), washed with brine, dried, and
concentrated to yield the corresponding N-Ac amino ester, which
was used without purification. (Boc)2O (2.5 g, 11 mmol) was added
at room temperature to a stirred solution of the crude N-benzyl-
(s) ppm. IR (CHCl ): ν = 3335, 2954, 1739, 1579, 1438, 1213, 1103,
˜
3
1027 cm–1. HRMS: calcd. for C14H18NO5 [M + 1]+: 280.1185;
found 280.1184. MS: m/z 280 [M + 1]+. C14H17NO5 (279.29): calcd.
C 60.21, H 6.14, N 5.02; found C 60.21, H 6.21, N 4.72.
Dimethyl (S)-2-[N-(tert-Butoxycarbonyl)-4-methylphenylsulfonami-
do]succinate (41): Na2CO3 (2.4 g, 22.5 mmol) and p-toluenesulfonyl
acetamide and DMAP (244 mg, 2 mmol) in dry CH3CN (15 mL). chloride (2.1 g, 11 mmol) were added at room temperature to a
The reaction became slightly red with gas evolution. The mixture
was stirred for 4 h, after which time TLC showed that some starting
material still remained. More (Boc)2O (1.1 g, 5 mmol) was then
added, and the mixture was additionally stirred overnight. The sol-
vent was evaporated, and the crude product was purified by silica
stirred suspension of commercially available (S)-aspartic acid
(1.33 g, 10 mmol) in water (100 mL). The reaction mixture was
heated at reflux overnight. The reaction mixture was then diluted
with EtOAc, treated twice with HCl, washed with brine, dried, and
concentrated to yield an oily residue. To a solution of this com-
Eur. J. Org. Chem. 2007, 5050–5058
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5055

J. N. Hernández, F. R. P. Crisóstomo, T. Martín, V. S. Martín
FULL PAPER
pound in dry MeOH (33 mL) was added slowly Me3SiCl (5.6 mL,
44 mmol) in an ice-cold bath. After the addition was complete, the
ice-cold bath was removed and the reaction mixture was stirred
overnight until TLC showed complete conversion. The mixture was
then concentrated to yield the corresponding N-Ts-amino ester,
which was used without purification. (Boc)2O (2.5 g, 11 mmol) was
added at room temperature to a stirred solution of the crude N-Ts-
amino ester and DMAP (244 mg, 2 mmol) in dry CH3CN (15 mL).
The reaction mixture became slightly red with gas evolution. The
mixture was stirred for 4 h, after which time TLC showed that some
starting material still remained. More (Boc)2O (1.1 g, 5 mmol) was
then added and the mixture was additionally stirred overnight. The
solvent was evaporated, and the crude product was purified by sil-
ica gel column chromatography, to afford 41 (3.4 g, 82% yield) as
(t, J = 6.4 Hz, 2 H), 3.64 (s, 3 H), 4.81 (dd, J = 9.1, 5.4 Hz, 1
H) ppm. 13C NMR (CDCl3): δ = 26.2 (t), 27.7 (q), 29.1 (t), 51.9
(q), 57.6 (d), 62.0 (t), 82.9 (s), 151.9 (s), 171.1 (s) ppm. IR (CHCl3):
ν = 3691, 2980, 1748, 1368, 1252, 1144 cm–1. MS: m/z = 360 [M
˜
+ Na]+, 248 [M – Boc]+, 148 [M – 2ϫBoc]+. HRMS: calcd. for
C16H29NNaO7 [M + Na]+ 360.1842; found 360.1859. C16H29NO7
(347,40): calcd. C 55.32, H 8.41, N 4.03; found C 55.33, H 8.41, N
3.94.
Methyl (S)-2-[Bis(tert-butoxycarbonyl)amino]-5-hydroxyhexanoate
(50): Trimethylaluminium (2.0  in toluene, 1.8 mL, 3.6 mmol) was
added by syringe pump at –78 °C over 40 min to a solution of
methyl (2S)-2-{(tert-butoxy)-N-[(tert-butyl)oxycarbonyl]carbonyl-
amino}-5-oxopentanoate[4a] (1 g, 3 mmol) in toluene (60 mL,
0.05 ). After the mixture had been stirred for 15 min at the same
temperature, BF3·OEt2 (0.46 mL, 3.6 mmol) in Et2O (6 mL) was
added slowly along the walls of the flask over 15 min. The contents
were stirred at –78 °C for 1 h. The reaction mixture was warmed
to –50 °C over 25 min before saturated aqueous NH4Cl was added.
After stirring at room temperature for additional 30 min, the con-
tents were diluted with water, extracted with diethyl ether, dried
with MgSO4, filtered, and concentrated. The solvent was evapo-
rated, and the crude product was purified by silica gel column
chromatography to afford 50 (0.95 g, 88% yield) as an oil: 1H
NMR (CDCl3): δ = 1.02 (d, J = 6.1 Hz, 3 H), 1.32 (m, 2 H), 1.33
(s, 18 H), 1.54 (m, 1 H), 2.05 (m, 1 H), 2.22 (br., 1 H), 3.54 (s, 3
H), 3.64 (m, 1 H), 4.69 (m, 1 H) ppm. 13C NMR (CDCl3): δ = 23.1
(q), 25.8 (t), 26.0 (t), 27.6 (q), 35.3 (t), 51.7 (t), 57.5 (d), 57.8 (d),
66.6 (d), 67.1 (d), 151.8 (s), 151.8 (s), 170.9 (s), 171.1 (s) ppm. IR
1
a white solid with m.p. 91–92 °C. [α]D25 = –56.1 (c = 3, CHCl3). H
NMR (CDCl3): δ = 1.23 (s, 9 H), 2.36 (s, 3 H), 2.75 (m, 1 H), 3.29
(m, 1 H), 3.62 (s, 3 H), 3.63 (s, 3 H), 5.57 (m, 1 H), 7.23 (d, J =
8.3 Hz, 2 H), 7.81 (d, J = 8.2 Hz, 2 H) ppm. 13C NMR (CDCl3): δ
= 21.4 (q), 27.3 (t), 27.5 (q), 36.2 (t), 51.8 (q), 52.5 (q), 55.2 (d),
85.2 (s), 128.4 (d), 128.8 (d), 136.2 (s), 144.3 (s), 149.7 (s), 169.3
(s), 170.3 (s) ppm. IR (CHCl ): ν = 3667, 2955, 1743, 1438, 1355,
˜
3
1255, 1147, 1088 cm–1. MS: m/z = 416 [M + 1]+, 360 [M – tBu]+,
316 [M – Boc]+. HRMS: calcd. for C18H26NO8S [M + 1]+:
416.1379; found 430.1519. C18H25NO8S (415.46): calcd. C 52.04,
H 6.07, N 3.37, S 7.72; found C 52.08, H 5.95, N 3.29, S 7.62.
Dibenzyl (S)-2-(tert-Butoxycarbonyl)pentanedioate (47): CAN
(2.1 equiv.) was added portionwise at room temperature to a stirred
solution of dibenzyl (S)-2-(dibenzylamino)pentanedioate[4a]
(5.07 g, 10 mmol) in MeCN/H2O (5:1). The reaction was quenched
by the addition of saturated aqueous sodium hydrogen carbonate
solution and the mixture was stirred vigorously for 10 min before
extraction with Et2O. The combined organic layers were dried with
MgSO4, filtered, and concentrated to yield an oily residue. To a
solution of this compound and DMAP (244 mg, 2 mmol) in dry
CH3CN (15 mL, 0.68 ) was added (Boc)2O (2.5 g, 11 mmol) at
room temperature. The reaction mixture became slightly red with
gas evolution. The mixture was stirred for 4 h, after which time
TLC showed that some starting material still remained. More (Boc)
2O (1.1 g, 5 mmol, 0.5 equiv.) was then added and the mixture was
additionally stirred overnight. The solvent was evaporated, and the
crude product was purified by silica gel column chromatography,
to afford 47 (4.2 g, 81% yield) as an oil: [α]D25 = –40.7 (c = 3,
(CHCl ): ν = 3529, 2978, 2860, 1749, 1458, 1368, 1257, 1128 cm–1.
˜
3
MS: m/z = 391 [M + K]+, 362 [M + 1]+. HRMS: calcd. for
C17H32NO7 [M + 1]+ 362.2179; found 362.2209. C17H31NO7
(361.43): calcd. C 56.49, H 8.65, N 3.88; found C 56.47, H 8.75, N
3.91.
tert-Butyl [(3S)-6-Methyl-2-oxotetrahydro-2H-pyran-3-yl]carbamate
(51): The general procedure described above was applied to 50 on
a 0.67 mmol scale (0.242 g) using toluene at 65 °C instead of
CH2Cl2 at room temperature, yielding 51 (0.137 g, 89% yield) as a
1
white solid with m.p. 104–105 °C. H NMR (CDCl3): δ = 1.32 (m,
3 H), 1.39 (s, 9 H), 1.64 (m, 2 H), 1.95 (m, 1 H), 2.52 (m, 1 H),
4.00 (br., 0.5 H), 4.48 (m, 1.5 H), 5.24 (br., 0.5), 5.33 (br., 0.5
H) ppm. 13C NMR (CDCl3): δ = 23.1 (q), 25.8 (t), 26.0 (t), 27.6
(q), 35.3 (t), 51.7 (t), 57.5 (d), 57.8 (d), 66.6 (d), 67.1 (d), 151.8 (s),
1
CHCl3). H NMR (CDCl3): δ = 1.36 (s, 9 H), 2.07 (m, 1 H), 2.30
151.8 (s), 170.9 (s), 171.1 (s) ppm. IR (CHCl ): ν = 2930, 1702,
˜
3
(m, 3 H), 4.25 (m, 1 H), 4.65 (br., 1 H), 5.01 (m, 4 H), 7.29 (m, 15
H) ppm. 13C NMR (CDCl3): δ = 28.0 (q), 30.4 (t), 58.5 (d), 66.1
(t), 66.6 (t), 128.0 (d), 128.0 (d), 128.1 (d), 128.3 (d), 128.3 (d),
1647, 1530, 1367, 1167 cm–1. MS: m/z = 230 [M + 1]+. HRMS:
calcd. for C11H20NO4 [M + 1]+: 230.1392; found 230.1404.
C11H19NO4 (229.27): calcd. C 57.62, H 8.35, N 6.11; found C
57.66, H 8.17, N 5.95.
135.6 (s), 155.2 (s) 170.7 (s), 172.4 (s) ppm. IR (CHCl ): ν = 3542,
˜
3
2976, 1731, 1695, 1454, 1366, 1029 cm–1. MS: m/z = 518 [M + 1],
418 [M – Boc]. HRMS: calcd for C31H36NO6 [M + 1]+: 518.2543;
found 518.2529. C31H35NO6 (517.61): calcd. C 71.93, H 6.82, N
2.71; found C 71.92, H 6.71, N 2.88.
Methyl
(2S)-2-[N-(tert-Butoxycarbonyl)-4-methylphenylsulfon-
amido]-5-hydroxyhexanoate (52): The procedure described to obtain
50 was applied to 43 on a 3.3 mmol scale (1.32 g), yielding 52 (1.2 g,
1
Methyl (S)-2-[Bis(tert-butoxycarbonyl)amino]-5-hydroxypentanoate
(48): DIBAL (12 mL, 1.0  in hexane, 12 mmol) was added drop-
wise at –78 °C to a stirred solution of 3[4a] (3.45 g, 10 mmol) in dry
Et2O (27 mL). The reaction mixture was stirred for 5 min and then
quenched with H2O. The mixture was stirred for 30 min, dried with
MgSO4, and filtered through a pad of Celite. The solvent was evap-
orated, and the crude aldehyde was used in the next step without
purification. The procedure used to obtain the aldehyde was again
applied to provide the corresponding alcohol, which was purified
by silica gel column chromatography to afford 48 (3 g, 86% overall
88% yield) as an oil: H NMR (CDCl3): δ = 1.16 (m, 3 H), 1.24
(s, 9 H), 1.58 (m, 2 H), 2.06 (m, 1 H), 2.29 (m, 1 H), 2.38 (s, 3 H),
3.64 (s, 3 H), 3.82 (m, 1 H), 5.03 (m, 1 H), 5.24 (m, 1 H), 7.24 (m,
2 H), 7.88 (m, 2 H) ppm. 13C NMR (CDCl3): δ = 21.4 (q), 23.2
(q), 23.4 (q), 26.0 (t), 26.4 (t), 27.5 (q), 35.5 (t), 35.6 (t), 52.2 (q),
58.9 (s), 59.2 (s), 67.0 (s), 67.5 (s), 84.7 (s), 128.4 (d), 128.8 (d),
136.3 (s), 144.1 (s), 149.7 (s), 170.3 (s), 170.4 (s) ppm. IR (CHCl3):
ν = 3676, 2976, 2360, 1736, 1351, 1254, 1148, 1047 cm–1. MS: m/z
˜
= 454 [M + K]+, 316 [M – Boc]+, 416 [M + 1]+. HRMS: calcd.
for C19H30NO7S [M + 1]+, 416.1743; found 416.1728. C19H29NO7S
(415.50): calcd. C 54.92, H 7.03, N 3.37, S 7.72; found C 54.92, H
7.21, N 3.54, S 7.58.
1
yield) as an oil. [α]2D5 = –34 (c = 3, CHCl3). H NMR (CDCl3): δ
= 1.42 (s, 18 H), 1.58 (m, 2 H), 1.84 (m, 1 H), 2.16 (m, 1 H), 3.59
5056
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5050–5058

Selective tert-Butoxycarbamoyl Group Cleavage
(3S)-4-Methyl-N-(6-methyl-2-oxotetrahydro-2H-pyran-3-yl)benzene-
sulfonamide (53): The general procedure described above was ap-
plied to 52 on a 0.8 mmol scale (0.33 g) using toluene at 65 °C
instead of CH2Cl2 at room temperature, yielding 53 (0.214 g, 95%
(s, 9 H), 2.14 (m, 1 H), 2.69 (br., 1 H), 4.22 (m, 3 H), 5.07 (br., 1
H) ppm. 13C NMR (CDCl3): δ = 28.0 (q), 30.3 (t), 50.0 (d), 65.5
(t), 80.4 (s), 155.2 (s), 175.1 (s) ppm. IR (CHCl ): ν = 3367, 2933,
˜
3
1777, 1685, 1529, 1364, 1254, 1164 cm–1. MS: m/z = 202 [M + 1]+.
HRMS: calcd. for C9H16NO4 [M + 1]+, 202.1079; found 202.1077.
C9H15NO4 (201.22): calcd. C 53.72, H 7.51, N 6.96; found C 53.71,
H 7.57, N 6.85.
1
yield) as a white solid with m.p. 112–114 °C. H NMR (CDCl3): δ
= 1.25 (d, J = 6.0 Hz, 3 H), 1.6 (m, 2 H), 1.97 (m, 2 H), 2.34 (s, 3
H), 3.5 (m, 0.5 H), 3.91 (m, 0.5 H), 4.39 (br., 1 H), 5.65 (br., 1 H),
7.23 (m, 2 H), 7.70 (m, 2 H) ppm. 13C NMR (CDCl3): δ = 20.5
(q), 21.3 (q), 21.5 (q), 25.7 (t), 27.6 (t), 28.3 (t), 29.9 (t), 50.0 (d),
52.9 (d), 74.1 (d), 79.6 (d), 126.8 (d), 127.0 (d), 129.4 (s), 129.6 (d),
Acknowledgments
143.7 (s), 169.7 (s) ppm. IR (CHCl ): ν = 3279, 2978, 1739, 1598,
˜
3
This research was supported by the Ministerio de Educación y Ci-
encia (MEC), co-financed by the European Regional Development
Fund (CTQ2005-09074-C02-01/BQU) and the Canary Islands
Government. N. H. thanks the Canary Islands Government and
the MEC for an FPU fellowship. F. R. P. C. thanks CajaCanarias
for a FPI fellowship.
1449, 1332, 1162, 1091 cm–1. MS: m/z = 284 [M + 1]+. HRMS:
calcd. for C13H18NO4S [M + 1]+, 284.0957; found 284.0964.
C13H17NO4S (283.34): calcd. C 55.11, H 6.05, N 4.94, S 11.32;
found C 55.11, H 6.22, N 4.97, S 11.43.
Methyl
(S)-2-{(tert-Butoxy)-N-[(tert-butyl)oxycarbonyl]carbonyl-
amino}-5-hydroxy-7-(trimethylsilyl)-5-[2-(trimethylsilyl)ethynyl]-
hept-6-ynoate (54): nBuLi (1.5  in hexane, 5.28 mL, 8.0 mmol) was
added at –78 °C over 20 min to a solution of trimethylsilylacetylene
(1.24 mL, 8.6 mmol) in THF (9 mL). After the mixture had been
stirred at –78 °C for an additional 20 min, trimethylaluminium
(2.0  in toluene, 4.0 mL, 8.0 mmol) was added by syringe pump
over 40 min. The reaction mixture was stirred at –78 °C for 30 min,
–45 °C for 30 min, and then cooled to –78 °C, whereupon 3 (1.24 g,
3.31 mmol) in toluene (23 mL) was added over 15 min. The content
was stirred at –78 °C for 1 h, whereupon methanol was added along
the walls of the flask. The reaction was warmed to –50 °C over
25 min, after which saturated aqueous NH4Cl (20 mL) was added.
After stirring at room temperature for additional 30 min, the con-
tents were diluted with water, extracted with diethyl ether, dried
with MgSO4, filtered, and concentrated. The residue was purified
by flash column chromatography on silica gel, yielding 54 (1.5 g,
84% yield) as an oil; [α]D25 = +22.4 (c = 3, CHCl3). 1H NMR
(CDCl3): δ = 0.12 (s, 18 H), 1.45 (s, 18 H), 1.90 (m, 2 H), 2.11 (m,
1 H), 2.37 (m, 1 H), 3.67 (s, 3 H), 4.88 (m, 1 H) ppm. 13C NMR
(CDCl3): δ = –0.5 (q), 24.9 (t), 27.7 (q), 40.2 (t), 51.9 (q), 57.7 (d),
82.9 (s), 88.1 (s), 88.2 (s), 104.4 (s), 104.6 (s), 151.6 (s), 170.7
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¸
[5] a) R. A. T. M. Van Benthem, H. Hiemstra, W. N. Speckamp, J.
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(s) ppm. IR (CHCl ): ν = 3691, 2961, 1749, 1457, 1368, 1251, 1128,
˜
3
846 cm–1. MS: m/z = 578 [M + K]+, 438 [M – Boc]+, 322 [M –
2ϫTMS – Boc – tBu]+. HRMS: calcd. for C26H45KNO7Si2 [M +
K]+: 578.2372; found 578.2333. C26H45NO7Si2 (539.81): calcd. C
57.85, H 8.40, N 2.59; found C 57.86, H 8.27, N 2.52.
Methyl (S)-2-(tert-Butoxycarbonyaminol)-5-hydroxy-7-(trimethyl-
silyl)-5-[2-(trimethylsilyl)ethynyl]hept-6-ynoate (55): The general
procedure described above was applied to 54 on a 1.4 mmol scale
(0.78 g) using toluene at 65 °C instead of CH2Cl2 at room tempera-
ture, yielding 55 (0.51 g, 91% yield) as a white solid with m.p. 109–
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10802; d) Mannich aminoalkylation: C.-C. Chu, M.-L. Chiang,
C.-M. Tsai, J.-J. Lin, Macromolecules 2005, 38, 6240–6243; e)
Hosumi–Sakurai allylation: T. Kawabata, M. Kato, T. Mi-
zugaki, K. Ebitani, K. Kaneda, Chem. Eur. J. 2005, 11, 288–
297; f) Synthesis of γ-lactones: J.-F. Roudier, A. Foucaud, Tet-
rahedron Lett. 1984, 25, 4375–4378; g) Synthesis of fused het-
erocycles: (i) L. Chunchatprasert, K. R. N. Rao, P. V. R. Shan-
non, J. Chem. Soc. Perkin Trans. 1 1992, 1779–1783; (ii) A.
Ben-Alloum, S. Bakkas, M. Soufiaoui, Tetrahedron Lett. 1997,
38, 6395–6396; (iii) R. S. Varma, D. Kumar, Tetrahedron Lett.
1999, 40, 7665–7669; (iv) K. Bougrin, A. Loupy, A. Petit, B.
Daou, M. Soufiaoui, Tetrahedron 2001, 57, 163–168; h) Acetal
1
110 °C. [α]D25 = –12.8 (c = 3, CHCl3). H NMR (CDCl3): δ = 0.07
(s, 18 H), 1.34 (s, 9 H), 1.82 (m, 3 H), 2.06 (m, 1 H), 3.55 (s, 3 H),
4.26 (br., 1 H), 5.04 (br., 1 H) ppm. 13C NMR (CDCl3): δ = 27.5
(t), 39.2 (t), 52.0 (q), 52.8 (d), 65.1 (s), 88.0 (s), 88.1 (s), 155.2 (s),
172.8 (s) ppm. IR (CHCl ): ν = 2957, 2857, 1745, 1498, 1343, 1216,
˜
3
1079 cm–1. MS: m/z = 422 [M – OH]+, 322 [M – OH – Boc]+.
HRMS: calcd. for C21H36NO4Si2 [M – OH]+: 422.2183; found
422.2172. C21H37NO5Si2 (439.69): calcd. C 57.36, H 8.48, N 3.19;
found C 57.35, H 8.57, N 3.36.
(S)-tert-Butyl (2-Oxotetrahydrofuran-3-yl)carbamate (57): The ge-
neral procedure described above was applied to 56[18] on a
1.4 mmol scale (0.467 g) using toluene at 65 °C instead of CH2Cl2
at room temperature, yielding (S)-tert-butyl (2-oxotetrahydrofuran-
3-yl)carbamate (0.25 g, 88% yield) as a white solid with m.p. 120–
1
122 °C. [α]D25 = +8.6 (c = 1, CHCl3). H NMR (CDCl3): δ = 1.39
Eur. J. Org. Chem. 2007, 5050–5058
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5057

J. N. Hernández, F. R. P. Crisóstomo, T. Martín, V. S. Martín
FULL PAPER
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and further N-Boc cleavage sequence using the present method-
ology provided compounds with identical specific rotations.
[9] Montmorillonite,molecularformula(Na,Ca)(Al,Mg)6(Si4O10)3-
(OH)6-nH2O, is made up of one octahedral aluminate layer
sandwiched between two octahedral silicate layers. This clay is
nontoxic, noncorrosive, economical, and recyclable.
[10] N. Hernández, V. S. Martín, J. Org. Chem. 2001, 66, 4934–
4938.
[11] From the beginning of the reaction, a mixture of free and pro-
tected hydroxy group coexists, evolving to the unprotected ma-
terial at the time shown.
[12] For instance, reaction times for the selective cleavage of one
Boc group in N,N-di-Boc--aspartic dimethyl ester using com-
mercially available Montmorillonite K-10 (Table 1, Entry 1) in
toluene at 65 °C (Method B) and the clay obtained after four
consecutive filtrations were 0.5 h (93% yield), 0.5 h (94%
yield), 0.5 h (94% yield), 0.5 h (93% yield), and 3 h (92%
yield), respectively.
[13] L. Grehn, U. Ragnarsson, Synthesis 1987, 3, 275–276.
[14] Commercially available.
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[19] W. L. F. Armarego, D. D. Perrin, Purification of Laboratory
Chemicals, 4th ed., Butterworth-Heinemann, Oxford, 1996.
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[7] a) N. S. Shaikh, A. S. Gajare, V. H. Deshpande, A. V. Bedekar,
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[8] Comparative analysis of N-acyl-protected α-amino acids and
similar materials obtained by the N-Boc-N-acyl-di-protection
Received: April 3, 2007
Published Online: August 8, 2007
5058
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5050–5058