Stereoselective lodocyclization of (S)-allylalanine derivatives: γ-lactone vs cyclic carbamate formation

Article abstract of DOI:10.1021/ol070764k

An efficient procedure for highly chemo- and stereoselective cyclization of (S)-allylalanine derivatives is reported (diastereomeric ratios up to 96:4) where the reaction course can be completely controlled by switching from γ-lactones to cyclic carbamate

Full text of DOI:10.1021/ol070764k

ORGANIC
LETTERS
2
007
Vol. 9, No. 12
365-2368
Stereoselective Iodocyclization of
S)-Allylalanine Derivatives: -Lactone
vs Cyclic Carbamate Formation
2
(
γ
†
†
‡
‡
Mariella Pattarozzi, Cristiano Zonta, Quirinus B. Broxterman, Bernard Kaptein,
§
§
,†
,†
Rita De Zorzi, Lucio Randaccio, Paolo Scrimin,* and Giulia Licini*
Dipartimento di Scienze Chimiche and ITM-CNR, UniVersit a` di PadoVa, Via Marzolo
, I-35131 PadoVa, Italy, Dipartimento di Scienze Chimiche, UniVersit a` di Trieste,
1
Via Giorgieri 1, I-34127 Trieste, Italy, and DSM Research, Pharmaceutical
Product-AdVanced Synthesis & Catalysis, NL-6160 MD Geleen, The Netherlands
paolo.scrimin@unipd.it; giulia.licini@unipd.it
Received March 29, 2007
ABSTRACT
An efficient procedure for highly chemo- and stereoselective cyclization of (S)-allylalanine derivatives is reported (diastereomeric ratios up to
6:4) where the reaction course can be completely controlled by switching from -lactones to cyclic carbamates simply with the proper choice
9
γ
of the amino acid protecting groups. Both processes are stereoconvergent and afford the (S,S)-products in high yields, short reaction times,
and mild reaction conditions.
2
Nonproteinogenic R,R-disubstituted amino acids are becom-
ing very appealing building blocks for the synthesis of natural
and artificial compounds endowed with biological activity
and for applications in the field of de novo design of proteins
devices drove us to explore methods for the selective
functionalization of CR tetrasubstituted amino acids to
broaden the repertoire of available building blocks and to
obtain potentially interesting chiral ligands. (S)-R-Allyl-
alanine (1), characterized by the presence of an easily
derivatizable allylic double bond on the side chain, constitutes
an appealing starting compound. Enantiopure (S)-1 used in
the present work has been obtained via an economically
attractive and generally applicable chemoenzymatic approach
1
and enzyme mimetics. This is due, inter alia, to two peculiar
features of these molecules: their stability to racemization
and the limited conformational freedom they impart to a
peptide sequence.
Our recent interest in the use of conformationally con-
trolled peptides for the preparation of catalysts or molecular
3
developed by DSM Research. However, other stereoselec-
tive syntheses of 1 have been reported.
4
†
University of Padova.
DSM Research.
University of Trieste.
‡
(2) (a) Rossi, P.; Tecilla, P.; Baltzer, R.; Scrimin, P. Chem.-Eur. J. 2004,
10, 4163-4170. (b) Pengo, P.; Pasquato, L.; Moro, S.; Brigo, A.; Fogolari,
F.; Broxterman, Q. B.; Kaptein, B.; Scrimin, P. Angew. Chem., Int. Ed.
2003, 42, 3388-3392. (c) Scarso, A.; Scheffer, U.; G o¨ bel, M.; Broxterman,
Q. B.; Kaptein, B.; Formaggio, F.; Toniolo, C.; Scrimin, P. Proc. Natl.
Acad. Sci. U.S.A. 2002, 99, 5144-5149. (d) Scrimin, P.; Tecilla, P.;
Tonellato, U.; Veronese, A.; Crisma, M.; Formaggio, F.; Toniolo, C.
Chem.-Eur. J. 2002, 8, 2753-2763. (e) Valente, S.; Gobbo, M.; Licini,
G.; Scarso, A.; Scrimin, P. Angew. Chem., Int. Ed. 2001, 40, 3899-3902.
§
(
1) Recent reviews: (a) Vogt, H.; Br a¨ se, S. Org. Biomol. Chem. 2007,
5
, 406-430. (b) Cativiela, C.; D ´ı az-de-Villegas, M. D. Tetrahedron:
Asymmetry 2007, 18, 569-623. (c) Ohfune, Y.; Shinada, T. Eur. J. Org.
Chem. 2005, 5127-5143. (d) Licini, G.; Prins, L.; Scrimin, P. Eur. J. Org.
Chem. 2005, 969-977. (e) Venkatraman, J.; Shankaramma, S. C.; Balaram,
P. Chem. ReV. 2001, 101, 3131-3152. (f) Andrews, M. J. I.; Tabor, A. B.
Tetrahedron 1999, 55, 11711-11743.
1
0.1021/ol070764k CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/16/2007

Among the different functionalizations of carbon-carbon
double bonds, iodine-based electrophilic addition provides
an efficient entry to heterocyclic intermediates, especially
employing bifunctional substrates. Since the first example
can be totally controlled by choosing the appropriate protect-
ing groups on the amino acid. Both reactions are stereocon-
vergent, affording the new stereocenter with the same (S)-
absolute configuration.
5
reported by Bougault in 1904, this useful process has been
Iodocyclizations have been carried out using two different
6
widely used in asymmetric synthesis. The investigation of
2
iodinating systems: I in THF/water 1:1 (method A) and
1
0
the scope of the reaction includes the effect of the nucleo-
philes and the iodinating agents on stereoselections. The most
common and reactive nucleophiles employed in these
transformations were carboxylic acids and their derivatives,
such as esters and amides. The iodocyclization of 4-pentenoic
acids, structural analogues of 1, generates preferentially
γ-iodolactones. The generally accepted mechanism involves
a favored exo-trig intramolecular nucleophilic attack to the
double bond activated by an electrophilic iodinating reagent
as an iodonium ion or, more likely, in the presence of an
N-iodo succinimide (NIS) (method B). In the second case,
the reactions have been carried out also in the presence of
amines or Lewis acids. Because all attempts to perform the
halocyclization on the unprotected amino acid 1 were
11
unsuccessful, N-protected derivatives were used. Protecting
groups considered were para-toluenesulfonyl (Ts, 2a), tert-
butyloxycarbonyl (Boc, 2b), and benzyloxycarbonyl (Z, 2c).
The carboxylic function was also orthogonally protected as
a methyl ester (3a) or a benzylic ester (3b) (Scheme 1).
7
intramolecular nucleophile, an iodine-π complex. Concern-
ing the new stereocenter generation, good degrees of
Scheme 1. Synthesis of (S)-Allylalanine Derivatives 2a-c and
stereoselectivity have been reached with 4-pentenoic acids
3
a,b and Iodolactonization of 2a-c
8
under substrate control. On the contrary, despite the valuable
synthetic potential, examples of efficient stereoselective
9
halolactonizations with reagent control are quite rare.
Here, we report that iodolacyclization of N- and C-
protected derivatives of (S)-1 affords efficiently and in high
yields two different cyclic products, γ-lactones or tetrahydro-
1,3-oxazine-2-ones, and in both cases, a new stereocenter
forms with high stereoselectivity (up to 96:4) even in the
presence of a remote homoallylic stereocenter. Furthermore,
the chemoselective γ-lactones or cyclic carbamate formation
(3) (a) Kaptein, B.; Broxterman, Q. B.; Schoemaker, H. E.; Rutjes, F. P.
J. T.; Veerman, J. J. N.; Kamphuis, J.; Peggion, C.; Formaggio, F.; Toniolo,
C. Tetrahedron 2001, 57, 6567-6577. (b) Kaptein, B.; Boesten, W. H. J.;
Broxterman, Q. B.; Peters, P. J. H.; Schoemaker, H. E.; Kamphuis, J.
Tetrahedron: Asymmetry 1993, 4, 1113-1116.
A thorough investigation with tosylamide 2a as a model
substrate was carried out (Scheme 1, Table 1).
(4) (a) Belokon, Y. N.; Maleev, V. I.; Petrosyan, A. A.; Savel’eva, T.
Reactions were monitored following the disappearance of
the reagent (double bond proton resonances) and product
formation. Both methods gave complete conversion of 2a
into the corresponding γ-lactones 4 that could be isolated in
good chemical yields by radial chromatography (Table 1,
entries 1 and 2).
The absolute stereochemistry of the two diastereomeric
products 4a and 4b was assigned by NOESY experiments
on the two isolated lactones (see Supporting Information).
Diagnostic cross-peaks for the assignment of the two
diastereoisomers turned out to be the ones between C(5)H
F.; Ikonnikov, N. S.; Peregudov, A. S.; Khrustalev, V. N.; Saghiyan, A. S.
Russ. Chem. Bull. Int. Ed. 2002, 51, 1593-1599. (b) Laue, K. W.; M u¨ ck-
Lichtenfeld, C.; Haufe, G. Tetrahedron 1999, 55, 10413-10424. (c)
Badoerrey, R.; Cativiela, C.; D ´ı az-de-Villegas, M. D.; G a´ lvez, J. A.; Lape n˜ a,
Y. Tetrahedron: Asymmetry 1997, 8, 311-317. (d) Aidene, M.; Barbot,
F.; Miginiac, L. J. Organomet. Chem. 1997, 534, 117-127. (e) Ferey, V.;
Toupet, L.; Gall, T. L.; Mioskowski, C. Angew. Chem., Int. Ed. Engl. 1996,
3
5, 430-432. (f) Berkowitz, D. B.; Smith, M. K. J. Org. Chem. 1995, 60,
1
233-1238. (g) Hua, D. H.; Lagneau, N.; Wang, H.; Chen, J. Tetrahe-
dron: Asymmetry 1995, 6, 349-352. (h) Seebach, D.; Gees, T.; Schuler,
F. Liebigs Ann. Chem. 1993, 785-799. (i) Williams, R. M.; Im, M.-N. J.
Am. Chem. Soc. 1991, 113, 9276-9286. (j) Sch o¨ llkopf, U.; Hartwig, W.;
Groth, U. Angew. Chem., Int. Ed. 1979, 18, 863-864. (k) Ojima, I.; Qui,
X. J. Am. Chem. Soc. 1987, 109, 6537-6538.
(
5) Bougault, M. J. R. Acad. Sci. 1904, 139, 864-867.
(
6) French, A. N.; Bissmire, S.; Wirth, T. Chem. Soc. ReV. 2004, 33,
and C(3)CH
isomer 4a) and between C(6)H
3
protons (only present in the major diastereo-
I and C(3)CH (only present
3
2
54-362.
2
3
(7) Bernett, R. G.; Doi, J. T.; Musker, W. K. J. Org. Chem. 1985, 50,
in 4b). Therefore, the cyclization affords preferentially the
syn-lactone (3S,5S)-4a over the anti-one (3S,5R)-4b. Interest-
048-2050.
(
8) (a) Maeda, K.; Miller, R. A.; Szumigala, R. H.; Shafiee, A.; Karady,
S.; Armstrong, J. D., III. Tetrahedron Lett. 2005, 46, 1545-1549. (b)
1
ingly, lactones 4a and 4b have rather different H NMR
Anderson, J. C.; Flaherty, A. J. Chem. Soc., Perkin Trans. 1 2001, 267-
2
69. (c) Kitagawa, O.; Hanano, T.; Kikuchi, N.; Taguchi, T. Tetrahedron
Lett. 1993, 34, 2165-2168. (d) Ohfune, Y.; Hori, K.; Sakaitani, M.
(10) Preliminary experiments carried out with ICl in CH2Cl2 afforded
comparable reactivity as far as reaction rates and stereoselectivity but with
significantly lower chemical yields (59%).
Tetrahedron Lett. 1986, 27, 6079-6082.
(
9) (a) Sakakura, A.; Ukai, A.; Ishihara, K. Nature 2007, 445, 900-
9
5
03. (b) Haas, J.; Bissmire, S.; Wirth, T. Chem.-Eur. J. 2005, 11, 5777-
785. (c) Kang, S. H.; Kang, S. Y.; Park, C. M.; Kwon, H. Y.; Kim, M.
(11) When the unprotected substrate (S)-1 was used, complex reaction
mixtures were obtained where complete substrate disappearance and no
significant amount of iodocyclization products were detected. Reactions
between iodine and and amines have been reported to afford N-iodination,
formation of molecular complexes, and in some cases, unusual oxidation
processes, and therefore N-protection is required. See: Jones, A. D.; Knight,
D. W.; Hibbs, D. E. J. Chem. Soc., Perkin Trans. 1 2001, 1182-1203 and
refs therein.
Pure Appl. Chem. 2005, 77, 1269-1276. (d) Wang, M.; Gao, L. X.; Mai,
W. P.; Xia, A. X.; Wang, F.; Zhang, S. B. J. Org. Chem. 2004, 69, 2874-
2
1
2
876. (e) Sung, H. K.; Sung, B. L.; Chul, M. P. J. Am. Chem. Soc. 2003,
25, 15748-15749. (f) Haas, J.; Piguel, S.; Wirth, T. Org. Lett. 2002, 4,
97-300. (g) Katagawa, O.; Taguchi, T. Synlett 1999, 1191-1199. (h)
Grossman, R. B.; Trupp, R. J. Can. J. Chem. 1998, 76, 1233-1237.
2366
Org. Lett., Vol. 9, No. 12, 2007

Table 1. Iodolactonization of (S)-2a
Table 2. Iodolactonization of (S)-2b and (S)-2c
temp time convn yield
(°C) (h)
(%)b (%)c a/bd
rt
rt
temp time convn yield
no.
conditionsa
(°C)
(h)
(%)b
(%)c 4a/4bb
substrate
conditionsa
1
2
3
4
5
6
7
A
rt
rt
-20
rt 72
rt
0.5
0.5
0.5
100
100
100
100
100
94
84
87
81
61
98
90
66
70:30
73:27
72:28
80:20
80:20
87:13
90:10
2b
A
1
1
100
100
95
41 89:11
82 86:14
58 93:7
45 94:6
92 87:13
52 93:7
B, CHCl3
B, CH2Cl2
B, CHCl3
B, Ti(O Pr)4, CH2Cl2
B, Ti(O Pr)4, CH2Cl2 -20 18
B, CHCl3
i
B, Ti(O Pr)4, CH2Cl2 -20 20
d
2c
A
rt
rt
3
2
100
100
86
i
B, CHCl3
B, Ti(O Pr)4, CH2Cl2 -20 19
0.5
i
i
i
B, Ti(O Pr)4,
-20 18
73
a
Reaction conditions. A: [substrate]0 ) 0.04 M, I2 (3 equiv), THF/
b
1
(
R)-BINOL, CH2Cl2
H2O 1:1. B: [substrate]0 ) 0.1 M, NIS (1.2 equiv). Determined by H
c
i
NMR of the reaction crude. Determined on isolated material after
8
B, Ti(O Pr)4,
-20 20
84
80
78:22
chromatography. d Determined by GC-MS of the reaction crude.
(S)-BINOL, CH2Cl2
a
Reaction conditions. A: [2a]0 ) 0.04 M, I2 (3 equiv), THF/H2O 1:1.
b
1
B: [2a]0 ) 0.1 M, NIS (1.2 equiv). Determined by H NMR of the reaction
crude. Determined on isolated material after chromatography. The
Substrates 2b and 2c gave the corresponding γ-lactones
5a,b and 6a,b with even higher selectivities in favor of the
syn-lactones. In this case, the stereochemistry of the products
c
d
reaction was carried out in the presence of (()-1-phenylethylamine (2 equiv).
1
could be assigned by comparison of the H NMR spectra
spectra, in particular, for C(6)H
in the 1.50-3.50 ppm region.12
The efficiency of I and NIS as an I source appears to
be comparable as far as reactivity, stereoselectivity, and
chemical yields are concerned (Table 1). Typically, after 30
min, complete conversion of the starting material was
observed. Due to the more feasible reaction conditions using
NIS, method B was explored more in detail, testing the effect
of different parameters such as solvent, temperature, and the
presence of a base or a Lewis acid (Table 1, entries 3-8).
2
and C(4)H
2
proton signals
with those of the Ts analogues 4a and 4b. Both series of
derivatives show very similar H NMR patterns for meth-
ylenes C(6)H I and C(4)H . Both (S)-2b and (S)-2c gave the
2 2
1
+
2
highest dr with NIS in the presence of Ti(O-iPr)
in THF/H O with (S)-2c gave high selectivities as well
6a/6b ) 94:6).15
The iodocyclization was also tested with two ester deriva-
4 2
(93:7). I
2
(
tives, (S)-3a and (S)-3b, to verify if increased stereoselection
could be achieved. Interestingly, both substrates were
converted quantitatively but via two different reaction
pathways: (S)-3a gave the two γ-iodolactones 4a and 4b
but without any increase of stereoselectivity and with a
significant decrease of the reaction rates. This last aspect is
consistent with the diminished nucleophilic character of the
ester CdO function compared to that of the carboxylic acid
2 2
The reaction in CH Cl at -20 °C gave complete conversion
of the reagent and comparable diastereomeric ratios in the
same reaction times (Table 1, entry 3). The presence of (()-
1-phenylethylamine, which should favor deprotonation of the
acid and speed up the reaction, gave the products with higher
dr’s (4a/4b ) 80:20), although at a slower rate (Table 1,
entry 4). Disappointingly, no significant differences were
(Table 3, entries 1 and 2). On the other hand, carbamate
9
b,f
found using enantiopure (R)- and (S)-1-phenylethylamine.
+
The use of Ti(O-iPr)
4
(1 equiv), a NIS activator as an I
donor, gave a higher dr (4a/4b ) 80:20) (Table 1, entry
) which could be increased up to 87:13 working at lower
Table 3. Iodolactonization of (S)-3a and (S)-3b
1
3
5
temperatures (Table 1, entry 6). However, at this temperature,
the reaction did not go to completion. With the aim to
increase the stereoselectivity under double stereoselection
conditions, we tested the use of enantiopure Ti complexes
4
prepared in situ from Ti(O-iPr) and (R)- or (S)-1,1′-bi(2-
naphtol) (BINOL).14 This time a different response was
observed with the two enantiomeric catalysts, and (R)-
BINOL gave the matched pair with an increased 4a/4b ratio
of 90:10. (Table 1, entry 7).
time convn yield
no. substrate conditiona (h)
(%)b
(%)c 4a/4bb 7a/7bd
The same set of reactions with both methods was carried
out also on derivatives (S)-2b and (S)-2c (Table 2).
1
2
3
4
(S)-3a
(S)-3b
A
B
A
B
2
72
2
100
100
100
100
84
68
90
65
70:30
56:44
-
-
-
96:4
77:23
(12) The syn diastereomer 4a shows an ABX system for the distereotopic
72
-
C(6)H2I protons at 3.26 and 3.41 ppm, respectively, whereas in anti-4b the
same systems can be found at 3.30 and 3.37 ppm, respectively. Also, the
endocyclic C(4)H2 appears as an ABX system at 2.42 and 2.71 ppm in 4a,
whereas in anti-4b it is at 1.96 and 3.12 ppm, respectively.
a
Reaction conditions. A: [substrate]0 ) 0.04 M, I2 (3 equiv), THF/
b
H2O 1:1, rt. B1: [substrate]0 ) 0.1 M, NIS (1.2 equiv) CHCl3, rt.
c
Determined by H NMR of the reaction crude. Determined on isolated
material after chromatography. d Determined by GC-MS of the reaction
(
13) Madsen, R.; Fraser-Reid, B. J. Org. Chem. 1995, 60, 772-779.
(
14) Inoue, T.; Kitagawa, O.; Kurumizawa, S.; Ochiai, O.; Taguchi, T.
crude.
Tetrahedron Lett. 1995, 36, 1497-1482.
Org. Lett., Vol. 9, No. 12, 2007
2367

(
9
S)-3b gave in high yields and stereoselectivities (up to
6:4) two diastereomeric tetrahydro-1,3-oxazoline-2-one
derivatives, 7a and 7b (Table 3, entries 3 and 4).
The different reaction pathways originate from a competi-
tive intramolecular nucleophilic attachment to the activated
double bond by the two CdO’s present in the molecule: the
carbamate and the carboxylic ester. Such competition was
not observed with acids 2b and 2c, because of the much
higher nucleophilicity of the carboxylate compared to the
carbamate, and with derivative 3a, because of the presence
of a noncompetitive SdO in the N-protecting group. Analysis
of the conformation of substrate 2 yielding the γ-lactones
reveals the possible formation of an intramolecular hydrogen
bond between the carboxylic acid and the carbamate CdO,
both favoring the lactone formation and increasing the
nucleophilicity of the carboxylic CdO (Figure 1).
Figure 2. ORTEP view of (4S,6R)-7b. Ellipsoids are represented
at 50% probability level.
Therefore, in this case also the preferential formation of a
new stereocenter with S absolute configuration has been
obtained. This is rather significant because both reaction
pathways provide high stereocontrol in the formation of a
new stereocenter with the same absolute configuration.
We may conclude that an efficient procedure for the highly
stereoselective synthesis (dr’s up to 96:4) of new, highly
functionalized amino acids has been developed, where the
chemoselective outcome of the reaction (formation of cyclic
carbamates or γ-lactones) can be completely controlled by
choosing the proper amino acid derivative. Mechanistic
studies to understand the origin of the chemo- and stereo-
selection of the reaction are currently under investigation,
along with the use of the enantiopure lactones and cyclic
carbamates as building blocks for the synthesis of new chiral
ligands, taking advantage of the presence of two function-
alized arms on the same side of the cycle.
Figure 1. Competitive nucleophilic attacks for the synthesis of
carbamate 7 from (S)-3b (path a) or of γ-lactone 5 from (S)-2b
(path b).
To the best of our knowledge, this is the first example of
a complete switch of reactivity between the formation of a
γ-lactone and a cyclic carbamate, both occurring with high
degrees of stereoselectivity.16 Determination of the X-ray
Acknowledgment. The sponsorship by MIUR, PRIN
2006 contract no. 2006039071, is kindly acknowledged.
19
structure of the minor diastereoisomer 7b allowed us to
assign the absolute configuration of the two diastereoisomers,
Supporting Information Available: Experimental details
and spectroscopic characterization for new compounds
together with the crystallographic data are reported. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(4S,6S)-7a and (4S,6R)-7b (Figure 2).
(
15) Although the diastereomeric mixtures 4a/4b and 6a/6b are separable
through radial chromatography, the isomers 5a/5b remain unseparable.
16) Examples of intramolecular cyclic carbamate formation with good
(
stereoselectivities have been reported in the iodocyclization of a few acyclic
homoallyl-â-amino esters (carbamates vs δ-lactones) (ref 17) and in one
case on the bromocyclization of a bicyclic allyl R-amino ester where, for
steric reasons, only the CdO carbamate could give the nucleophilic attack
OL070764K
(19) Crystal Data for 7b: C14H16INO4, MW ) 389.18, T ) 293(2) K, l
) 0.71073 Å, orthorhombic, space group P212121, a ) 6.725 Å, b ) 13.858
(
ref 18).
3
3
(17) (a) Davies, S. G.; Haggitt, J. R.; Ichihara, O.; Kelly, R. J.; Leech,
Å, c ) 16.061 Å, V ) 1496.7 Å , Z ) 4, Dc ) 1.727 g/cm , F(000) ) 768,
3
M. A.; Price Mortimer, A. J.; Roberts, P. M.; Smith, A. D. Org. Biomol.
Chem. 2004, 2, 2630-2649. (b) Wang, Y.-F.; Izawa, T.; Kobayashi, S.;
Ohno, M. J. Am. Chem. Soc. 1982, 104, 6465-6466.
crystal size 0.5 × 0.5 × 0.5 mm , 24 277 reflections measured, 4577
2
independent reflections (Rint ) 0.0206); the final wR(F ) was 0.1534 (all
data) and final R was 0.0536 for 3704 unique data [I > 2s(I)]. The crystal
structure of (4S,6R)-7b has been deposited at the Cambridge Crystal-
lographic Data Centre (CCDC 635632).
(
18) Crossley, M. J.; Davies, S. R.; Hambley, T. W. Aust. J. Chem. 1994,
4
7, 2221-2233.
2368
Org. Lett., Vol. 9, No. 12, 2007