Fine-Tuned Aminal Cleavage: A Concise Route to Differentially Protected Enantiopure syn-α,β-Diamino Esters

Article abstract of DOI:10.1021/jo035613j

A survey of routes for aminal cleavage of N-sulfinylimidazolidines has been carried out, and selective conditions to cleave the aminal moiety while preserving the sulfinamide group unaltered have been found. Thus, the treatment of enantiopure N-sulfinylimidazolidines with aqueous H₃PO ₄ in THF affords enantiopure N-sulfinyldiamino esters in excellent yields, while the presence of MeOH as cosolvent allows for the simultaneous removal of the sulfinamide group and aminal cleavage. The behavior of these substrates in a variety of chemical transformations has been explored.

Full text of DOI:10.1021/jo035613j

F in e-Tu n ed Am in a l Clea va ge: A Con cise Rou te to Differ en tia lly
P r otected En a n tiop u r e syn -r,â-Dia m in o Ester s
Alma Viso,*,† Roberto Ferna´ndez de la Pradilla,*,† Mar´ıa L. Lo´pez-Rodr´ıguez,‡ Ana Garc´ıa,†
Aida Flores,† and Marta Alonso†
Instituto de Qu´ımica Orga´nica, Consejo Superior de Investigaciones Cient´ıficas (CSIC),
J uan de la Cierva 3, E-28006 Madrid, and Departamento de Quı´mica Orga´nica I,
Facultad de Ciencias Qu´ımicas, Universidad Complutense, E-28040 Madrid, Spain
iqov379@iqog.csic.es; iqofp19@iqog.csic.es
Received November 3, 2003
A survey of routes for aminal cleavage of N-sulfinylimidazolidines has been carried out, and selective
conditions to cleave the aminal moiety while preserving the sulfinamide group unaltered have been
found. Thus, the treatment of enantiopure N-sulfinylimidazolidines with aqueous H3PO4 in THF
affords enantiopure N-sulfinyldiamino esters in excellent yields, while the presence of MeOH as
cosolvent allows for the simultaneous removal of the sulfinamide group and aminal cleavage. The
behavior of these substrates in a variety of chemical transformations has been explored.
In tr od u ction
During the past few years we have been engaged in
the development of efficient routes to enantiopure N-
sulfinylimidazolidines D from readily available precur-
sors, such as sulfinimines A and lithiated imino esters
B (Scheme 1).5 Our initial efforts to carry out the
Optically active R,â-diamino acids are components of
natural products with varied biological activities (anti-
fungal, antibiotic, etc.).1 This has attracted the attention
of many groups, and there are several routes of varying
length and complexity reported in the literature to
prepare these compounds,2 particularly the anti isomers.
In contrast, a short, simple, and general route to the syn
diastereomers remains elusive,3 particularly when the
molecule is disconnected retrosynthetically between CR
and Câ.4 In this paper we describe a general, concise, and
high-yielding route to syn-N-sulfinyl-R,â-diamino esters
from readily available N-sulfinyl-1,3-imidazolidines.
(3) Enantiopure syn-R,â-diamino acid derivatives have been pre-
pared by a number of routes: (a) From an L-allothreonine derivative
by Mitsunobu inversion with HN3: Schmidt, U.; Mundinger, K.; Riedl,
B.; Haas, G.; Lau, R. Synthesis 1992, 1201-1202. For
a related
approach, see: Nakamura, Y.; Hirai, M.; Tamotsu, K.; Yonezawa, Y.;
Shin, C. Bull. Chem. Soc. J pn. 1995, 68, 1369-1377. (b) Cleavage of
N-carboxyanhydrides derived from â-lactams: Palomo, C.; Aizpurua,
J . M.; Cabre´, F.; Cuevas, C.; Munt, S.; Odriozola, J . M. Tetrahedron
Lett. 1994, 35, 2725-2728. See also: Palomo, C.; Aizpurua, J . M.;
Gamboa, I.; Carreaux, F.; Cuevas, C.; Maneiro, E.; Ontoria, J . M. J .
Org. Chem. 1994, 59, 3123-3130 See also: Palomo, C.; Aizpurua, J .
M.; Galarza, R.; Mielgo, A. Chem. Commun. 1996, 633-634. (c) From
a hydroxyoxazolidinone obtained via Sharpless asymmetric epoxida-
tion: Rossi, E. T.; Yoon, R.; Rosenberg, L.; Meinwald, J . Tetrahedron
1996, 52, 10279-10286. (d) From enantiopure â-amino esters by
R-hydroxylation and inversion via mesylate: Bunnage, M. E.; Burke,
A. J .; Davies, S. G.; Millican, N. L.; Nicholson, R. L.; Roberts, P. M.;
Smith, A. D. Org. Biomol. Chem. 2003, 1, 3708-3715. (e) From
regioselective ring opening of an aziridine obtained via Sharpless
asymmetric aminohydroxylation: see ref 2a. (f) From (E)- R,â-bis(N-
acylamino)acrylates by enantioselective hydrogenation: see ref 2b. (g)
From a protected L-serine-derived nitrone by addition of Grignard
reagents: see ref 2c. (h) From a â-amino-R-hydroxy ester, obtained by
aminohydroxylation, by hydroxyl inversion followed by Mitsunobu with
HN3: see ref 2i. (i) From enamides by enantioselective hydrogena-
† CSIC.
‡ Universidad Complutense.
(1) (a) For a comprehensive summary of literature related to the
isolation and biological activity of R,â-diamino acids, see: Luo, Y.;
Blaskovich, M. A.; Lajoie, G. A. J . Org. Chem. 1999, 64, 6106-6111.
(b) Lucet, D.; Gall, T. L.; Mioskowski, C. Angew. Chem., Int. Ed. 1998,
37, 2580-2627. (c) Westermann, B. Angew. Chem., Int. Ed. 2003, 42,
151-153.
(2) For a summary of existing methodology, see ref 1. For recent
references, see: (a) Han, H.; Yoon, J .; J anda, K. D. J . Org. Chem. 1998,
63, 2045-2048. (b) Kuwano, R.; Okuda, S.; Ito, Y. Tetrahedron:
Asymmetry 1998, 9, 2773-2775. (c) Merino, P.; Lanaspa, A.; Merchan,
F. L.; Tejero, T. Tetrahedron: Asymmetry 1998, 9, 629-646. (d)
Knudsen, K. R.; Risgaard, T.; Nishiwaki, N.; Gothelf, K. V.; J ørgensen,
K. A. J . Am. Chem. Soc. 2001, 123, 5843-5844. (e) Nishiwaki, N.;
Knudsen, K. R.; Gothelf, K. V.; J ørgensen, K. A. Angew. Chem., Int.
Ed. 2001, 40, 2992-2995. (f) Zhou, X.-T.; Lin, Y.-R.; Dai, L.-X.
Tetrahedron: Asymmetry 1999, 10, 855-862. (g) Hennings, D. D.;
Williams, R. M. Synthesis 2000, 1310-1314. (h) Chuang, T.-H.;
Sharpless, K. B. Org. Lett. 2000, 2, 3555-3557. See also previous
papers by this group. (i) Lee, S. H.; Yoon, J .; Chung, S.-H.; Lee, Y.-S.
Tetrahedron 2001, 57, 2139-2145. (j) Robinson, A. J .; Stanislawski,
P.; Mulholland, D.; He, L.; Li, H.-Y. J . Org. Chem. 2001, 66, 4148-
4152. (k) Pei, W.; Timmons, C.; Xu, X.; Wei, H.-X.; Li, G. Org. Biomol.
Chem. 2003, 1, 2919-2921. (l) Ambroise, L.; Dumez, E.; Szeki, A.;
J ackson, R. F. W. Synthesis 2002, 2296-2308. (m) Brown, D.; Brown,
G. A.; Andrews, M.; Large, J . M.; Urban, D.; Butts, C. P.; Hales, N. J .;
Gallagher, T. J . Chem Soc., Perkin Trans. 1 2002, 2014-2021. (n)
Chhabra, S. R.; Mahajan, A.; Chan, W. C. J . Org. Chem. 2002, 67,
4017-4029.
tion: see ref 2j. (j) From 1,3-dihydro-2-imidazolone by
a rather
elaborate sequence including resolution: Seo, R.; Ishizuka, T.; Abdel-
Aziz, A. A.-M.; Kunieda, T. Tetrahedron Lett. 2001, 42, 6353-6355.
(k) Direct diamination of olefins: Mun˜iz, K.; Nieger, M. Synlett 2003,
211-214.
(4) (a) For a recent report on the asymmetric Mannich reaction of
glycine imino esters, see: Bernardi, L.; Gothelf, A. S.; Hazell, R. G.;
J ørgensen, K. A. J . Org. Chem. 2003, 68, 2583-2591. (b) For
a
noteworthy exception, see: Alker, D.; Harwood: L. M.; Williams, C.
E. Tetrahedron Lett. 1998, 39, 475-478. (c) See also a report describing
the oxidative dimerization of lithiated glycinates: AÄ lvarez-Ibarra, C.;
Csa´ky¨, A. G.; Colmenero, B.; Quiroga, M. L. J . Org. Chem. 1997, 62,
2478-2482. (d) Hayashi, T.; Kishi, E.; Soloshonok, V. A.; Vozumi, Y.
Tetrahedron Lett. 1996, 37, 4969-4972. (e) Soloshonok, V. A.; Avilov,
D. V.; Kukhar, V. P.; Van Meervelt, L.; Mischenko, N. Tetrahedron
Lett. 1997, 38, 4671-4674. (f) DeMong, D. E.; Williams, R. H.
Tetrahedron Lett. 2001, 42, 3529-3532.
10.1021/jo035613j CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/27/2004
1542
J . Org. Chem. 2004, 69, 1542-1547

Route to Enantiopure Diamino Esters
SCHEME 1. Syn th esis of r,â-Dia m in o Ester s fr om
ment to prevent the undesired fragmentation found
before. However, when 1c was submitted to oxidative
conditions, the expected N-tosylimidazolidines were not
formed.6 The different reactivity observed for this N-
sulfinylimidazolidine derived from glycine (1c, R1 ) H)
could be attributed to the less crowded arrangement at
N-3 compared with that of the N-sulfinylimidazolidine
precursor of 1a and 1b (R1 ) Bn).7 The above results
prompted us to explore a different strategy based on the
oxidative cleavage of the aminal moiety of D when the
phenyl group (Ar) was replaced with a PMP group at the
imidazolidine (1d , R ) Ph, R1 ) H) by reaction of the
sulfinimine A (R ) Ph) with the glycine imino ester B
(Ar ) PMP). Unfortunately, under treatment with CAN,
low yield of mixtures of N-sulfonyl- and N-sulfinyl-
diamino esters 3a were obtained. Continuing with the
search for an efficient method for breaking the aminal
fragment, we also examined the hydrogenolysis8 on
substrates where R is not an aromatic group, although a
low conversion along with complex mixtures of products
was obtained with these methods.9,10
En a n tiop u r e Su lfin im in esa
After all this fruitless experimentation, we decided to
reexamine the procedure that originally led to fragmen-
tation in some cases, namely, TFA in MeOH, under
controlled conditions, for glycine-derived imidazolidines
1 (R1 ) H), obtained by our Lewis-acid-assisted protocol5b
(Table 1). In this manner, unprotected diamino esters 4b
and 4c were obtained in fair yields along with 11% of
N-sulfinyldiamino ester 3b in the first case (entries 3 and
9). Comparable yields of 4b-d were obtained using
ethereal 2 N HCl although under these conditions
products of partial hydrolysis were not found (entries 4,
10, and 12). These results were encouraging since it
appeared that the undesired fragmentation observed
before was not a general outcome of the process, but
instead it was limited to a specific substitution pattern
derived from the uncatalyzed cycloaddition between
aromatic sulfinimines and azomethine ylides.
The isolation of a small amount of N-sulfinyldiamino
ester 3b under TFA/MeOH conditions (entry 3) prompted
us to devote considerable effort to fine-tuning these
solvolytic conditions with mixed results. Selective aminal
cleavage of 1f was produced at low temperature (-78 to
-20 °C) but with a low conversion (entry 5). Subse-
quently, acids weaker than TFA11 were used in an effort
to achieve selective solvolysis. Thus, the reaction of 1f
with Cl2CHCO2H afforded a mixture of 3b and 4b along
a
Reagents and conditions: (a) BF3‚Et2O, -78 °C, THF. (b)
CHCl3, 2-4 days, rt (60-93%). (c) LiAlH4, Et2O, 0 °C to rt, 2-7 h
(65-85%).
seemingly straightforward hydrolysis to produce N-
sulfinyldiamino esters of general structure F were fruit-
less, and a retro-Mannich fragmentation of the molecule
was observed instead (R ) Ph, R1 ) Bn) to give methyl
sulfinate and phenylalanine methyl ester.5b Carboxylate
reduction in D allowed for a smooth solvolysis, and totally
unprotected diamino alcohols were obtained in good
yields. Conditions to access partially protected N-sulfinyl-
N′-benzyldiamino alcohols E were later developed,5c and
the transformation of these intermediates to a variety of
piperazines was also described.5e While the transforma-
tion of these N-sulfinyl-N′-benzyldiamino alcohols E to
differentially protected syn-diamino esters (e.g., F) seemed
feasible by standard oxidation procedures, we sought a
more direct route to these targets from imidazolidines
D.
Resu lts a n d Discu ssion
At the inception of this work we planned different
strategies for the synthesis of diamino esters avoiding
the direct acidic cleavage of imidazolidines. The first
approach considered consisted of two consecutive steps,
oxidation at sulfur followed by hydrolysis, and it was
based on the smooth solvolysis of N-tosylimidazolidines
1a and 1b5b to afford racemic N-tosyldiamino esters 2a
and 2b (Table 1, entries 1 and 2). This behavior indicated
that the oxidation state at sulfur was a crucial require-
(6) A detailed account of these experiments is included in the
Supporting Information.
(7) On the other hand, addition of imino ester B (R1 ) H, Ar ) Ph)
to p-toluensulfonimine did not render N-tosylimidazolidines related
to 1a and 1b but a mixture of racemic N-sulfonyldiamino esters with
poor selectivity (syn:anti ) 70:30); see ref 5b.
(8) Several hydrogenolysis conditions were examined [Pd(OH)2-H2,
Pd(C)-H2]; see: Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; J ohn Wiley & Sons: New York, 1999;
Chapter 7, pp 579-580.
(5) (a) Viso, A.; Ferna´ndez de la Pradilla, R.; Guerrero-Strachan,
C.; Alonso, M.; Mart´ınez-Ripoll, M.; Andre´, I. J . Org. Chem. 1997, 62,
2316-2317. (b) Viso, A.; Ferna´ndez de la Pradilla, R.; Garc´ıa, A.;
Guerrero-Strachan, C.; Alonso, M.; Tortosa, M.; Flores, A.; Mart´ınez-
Ripoll, M.; Fonseca, I.; Andre´, I.; Rodr´ıguez, A. Chem.sEur. J . 2003,
9, 2867-2876. (c) Viso, A.; Ferna´ndez de la Pradilla, R.; Garc´ıa, A.;
Alonso, M.; Guerrero-Strachan, C.; Fonseca, I. Synlett 1999, 1543-
1545. (d) Viso, A.; Ferna´ndez de la Pradilla, R. Recent Res. Dev. Org.
Chem. 2000, 4, 327-334. (e) Viso, A.; Ferna´ndez de la Pradilla, R.;
Lo´pez-Rodr´ıguez, M. L.; Garc´ıa, A.; Tortosa, M. Synlett 2002, 755-
758.
(9) We also reconsidered the use of acidic conditions to hydrolyze
imine C; however, addition of different acids to the reaction mixture
gave erratic mixtures of imidazolidines and diamino esters probably
due to uncontrolled cyclization of the latter with benzaldehyde during
the workup process.
(10) For full details of all these experiments, see the Supporting
Information.
(11) For comparative purposes the standard values of pKa (25 °C,
H2O) have been considered: TFA, 0.23; Cl2CHCO2H, 1.48; H3PO4, 2.12;
HOAc, 4.75. For the use of H3PO4 in a related context see: Moreno-
Vargas, A. J .; Vogel, P. Tetrahedron: Asymmetry 2003, 14, 3173-3176.
J . Org. Chem, Vol. 69, No. 5, 2004 1543

Viso et al.
TABLE 1. Syn th esis of En a n tiop u r e Dia m in o Ester s a n d N-su lfin yld ia m in o Ester s u n d er Acid ic Con d ition s
2
3
4
entry
compd
R
R1
P
methoda
TFA/MeOH
TFA/MeOH
TFA/MeOH
HCl/Et2O
TFA/MeOH
Cl2CHCO2H/MeOH
HOAc/MeOH
H3PO4/THF
TFA/MeOH
HCl/Et2O
(yield, %)b
(yield, %)b
(yield, %)b
1
2
3
1a
1b
1f
1f
1f
1f
1f
1f
1g
1g
1g
1e
1e
1c
1c
1h
1i
2a (70)
2b (86)
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
p-FC6H4
p-FC6H4
p-FC6H4
i-Pr
i-Pr
Ph
Ph
Ph(CH2)2
1-Naph
Me
(CH2)4OTs
i-Pr
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
3b (11)
4b (61)
4b (59)
4
H
H
H
H
H
H
H
H
H
H
H
H
Cbz
H
H
H
H
5c
6d
7
3b (50)
3b (20)
see the text
3b (81)
4b (30)
see the text
8
9
4c (61)
4c (60)
10
11
12
13
14
15
16
17
18
19
20e
H3PO4/THF
HCl/Et2O
3c (76)
4d (60)
H3PO4/THF
H3PO4/THF
H3PO4/MeOH
H3PO4/MeOH
H3PO4/THF
H3PO4/THF
H3PO4/THF
H3PO4/THF
3d (88)
3a (73)
4a (20)
4a (59)
4e (65)
3e (75)
3f (81)
3g (68)
3h (84)
1j
1k
1l
a
Reagents and conditions: (a) TFA, MeOH, rt, 4-14 h. (b) 2 N HCl, Et2O, rt, 2 h. (c) 2 equiv of Cl2CHCO2H, MeOH, 0 °C to rt, 20 h.
(d) 8 equiv of HOAc, MeOH, rt to reflux, 24 h. (e) H3PO4, THF/H2O (7:3), 0 °C to rt, 1-5 h. (f) H3PO4, THF/MeOH/H2O (6:3:1), 0 °C, 90
b
min. Yields of isolated pure compounds. c Reaction performed from -78 to -20 °C; 30% of the starting material was also recovered.
d
50% of the starting material was recovered. e Starting material also contained a 35% yield of 1l′ (epimer at C-2).
with a high amount of recovered starting material (50%),
and HOAc led to recovered starting material or to its
decomposition under reflux (entries 6 and 7). After
considerable experimentation focused on the search for
optimal conditions for the selective hydrolysis process,
we found that treatment of imidazolidine 1c with aque-
ous 0.5 M H3PO4 in THF provided a good isolated yield
of N-sulfinyldiamino ester 3a (entry 14) as a single
isomer that was fully characterized. The generality of this
protocol was then examined, and to our delight, good to
excellent yields of enantiopure N-sulfinyldiamino esters
were obtained for R ) aryl (entries 11, 14, and 17) and
R ) alkyl (entries 8, 13, 18, and 19). The straightforward,
high-yielding, and expedient preparation of enantiopure
3h (entry 20), bearing an additional substituent at CR
(R1 ) Me), is particularly noteworthy since it illustrates
that the undesired fragmentation observed before is not
always related to additional substitution at CR, and also,
to our knowledge, it is the first known example of a
stereoselective preparation of an R,â-diamino ester bear-
ing additional substituents at both CR and Câ.12
Additionally, reaction of 1c with H3PO4 in MeOH
smoothly provided the simultaneous removal of the
aminal and sulfinyl moieties to give a fair yield of 4a ,
and similarly, when N-benzyloxycarbonylimidazolidine
1h was submmited to the above conditions, N-benzyloxy-
carbonyldiamino ester 4e was produced selectively (en-
tries 15 and 16). Finally, as expected, removal of the
sulfinyl group of N-sulfinyldiamino esters 3b and 3d was
achieved by using either TFA/MeOH or H3PO4/MeOH.
These results point to phosphoric acid as the reagent
of choice for these transformations probably due to a
combination of a suitable acidity and a low nucleophilicity
of the phosphate counterion. Indeed, H3PO4 (in THF/H2O)
protonates N-sulfinylimidazolidines 1, but attack at the
sulfinamide group does not take place, and this produces
the selective cleavage of the aminal moiety. However, the
presence of a nucleophilic solvent (methanol) or counter-
ion (HCl) in the reaction mixture leads to the simulta-
neous removal of the sulfinyl group, even for aminals
such as 1h with low basicity at N-3 due to the presence
of a carbamate functionality (Figure 1). Additionally, the
role of methanol is supported by the formation of sub-
stantial amounts of methyl p-toluenesulfinate in these
processes.
(12) For an isolated example of R-substituted â-unsubstituted
derivatives, see: Hartwig, W.; Mittendorf, J . Synthesis 1991, 939-
941.
1544 J . Org. Chem., Vol. 69, No. 5, 2004

Route to Enantiopure Diamino Esters
TABLE 2. Rea ctivity of N-Su lfin yld ia m in o Ester s
entry
substrate
conditions
BnBr/K2CO3/rt
6
yield, %
1
2
3
4
5
6
7
3c
3d
3c
3c
3c
3d
3d
6a (R ) p-FPh, P1 ) H, P2 ) Bn)
6b (R ) i-Pr, P1 ) H, P2 ) Bn)
93
BnBr/K2CO3/rt
79
BnBr/K2CO3/rt to ∆
6c (R ) p-FPh, P1 ) P2 ) Bn)
66a
65b
78
Br(CH2)4Br/NaHCO3/∆
6d [R ) p-FPh, P1 ) P2 ) (CH2)4]
6e (R ) p-FPh, P1 ) P2 ) CPh2)
6f (R ) i-Pr, P1 ) H, P2 ) COCH2Cl)
6g [R ) i-Pr, P1 ) H, P2 ) (S)COCH(OMe)Ph]
HNdC(Ph)2/rt
ClCH2COCl/NaHCO3/EtOAc/0 °C to rt
(S)-(+)-MPA/DCC/DMAP/rt
90
65
a
b
CH3CN was used as solvent. A 9% yield of 6a was also isolated. Toluene was used as solvent.
from N-benzyloxycarbonyl-N′-sulfinyldiamino ester 3i by
desulfinylation (H3PO4/MeOH) followed by cyclization
upon basic aqueous workup.15
To broaden the scope of the methodology, we chose to
explore the behavior of our N-sulfinyldiamino esters in
a variety of procedures commonly used in R-amino acid
chemistry. Table 2 shows selected examples of these
transformations.16 All cases examined allowed for smooth
monobenzylation under standard conditions17 to produce
N-sulfinyl-N′-benzyldiamino esters 6a ,b (entries 1 and
2). In fact, surprisingly, dibenzylation was achieved only
upon using an excess of reagents and refluxing the
reaction mixtures to produce N-sulfinyl-N′-dibenzyl-
diamino ester 6c in fair yields (entry 3), often accom-
panied by small amounts of the corresponding mono-
benzylated derivatives.18 Finally, 6c was desulfinylated
under standard conditions to produce the corresponding
di-N-benzyldiamino ester 7 in fair yield. On the other
hand, intramolecular dialkylation of 3c with 1,4-dibromo-
butane efficiently afforded pyrrolidine diamino ester 6d
(entry 4).
F IGURE 1. Aminal cleavage of N-sulfinylimidazolidines
under acidic conditions.
SCHEME 2. Syn th esis of Meth yl 2-P ip er id in yl
Glycin a te fr om N-Su lfin ylim id a zolid in esa
To gain insight into the reactivity of these substrates,
we carried out the reaction of diamino ester 3d with
benzophenone imine, giving rise to imine 6e in good yield.
Subsequently, amide formation was also explored with
excellent results, either under biphasic conditions with
ClCH2COCl to produce 6f, a potential precursor to
monoketopiperazines, or with DCC/DMAP using (S)-(+)-
methoxyphenylacetic acid to produce 6g19 (entries 6 and
7).
a
Reagents and conditions: (a) CbzCl, 1 N NaOH, CH2Cl2, 0 °C
to rt. (b) H3PO4, THF, 0 °C to rt. (c) H3PO4, MeOH, rt.
On the other hand, the application of this novel
reactivity of H3PO4 to N-sulfinylimidazolidine 1k pro-
vides a new route for the synthesis of enantiopure
2-piperidinyl glycinates (Scheme 2).13 The first attempts
to remove the sulfinamide and aminal moieties of 1k
using H3PO4/MeOH led to complex reaction mixtures;
however, treatment of N-benzyloxycarbonylimidazolidine
1m with H3PO4 in MeOH gave the bicyclic imidazolidine
5a as the major product in good yield, and although small
amounts of the piperidinyl glycinate 4f were occasionally
obtained upon standard handling of the samples, we did
not succeed in finding conditions to carry out complete
removal of this unusually stable bicyclic aminal.14 How-
ever, an efficient synthesis of 4f was finally carried out
In conclusion, different routes to transform readily
available N-sulfinylimidazolidines 1 into differentially
N-protected diamino esters have been explored. Selective
(14) Under typical solvolytic conditions we have mainly recovered
starting material 5a : 2 N HCl, Et2O, rt to reflux or TFA, MeOH, rt to
reflux.
(15) For a related procedure for the synthesis of piperidines from
p-tolylsulfinimines, see: Davis, F. A.; Prasad, K. R.; Nolt, M. B.; Wu,
Y. Org. Lett. 2003, 5, 925-927.
(16) For more examples of mono- and dibenzylation (6h , R ) Me,
P1 ) H, P2 ) Bn; 6i, R ) i-Pr, P1 ) P2 ) Bn; 6j, R ) Me, P1 ) P2
Bn), see the Supporting Information.
)
(17) For a recent reference, see: Hulme, A. N.; Montgomery, C. H.;
Henderson, D. K. J . Chem. Soc., Perkin Trans. 1 2000, 1837-1841.
See also: Reetz, M. T.; Drewes, M. W.; Schwickardi, R. Org. Synth.
1998, 76, 110-122.
(18) A small amount (<10%) of a tribenzylated derivative, 6c′, was
obtained upon dibenzylation of 3c. For full details see the Supporting
Information.
(13) (a) Herdeis, C.; Nagel, U. Heterocycles 1983, 20, 2163-62167.
(b) Chung, H.; Kim. H.; Chung, K. Heterocycles 1999, 51, 2983-2989.
J . Org. Chem, Vol. 69, No. 5, 2004 1545

Viso et al.
Gen er a l P r oced u r e for P r ep a r a tion of 2,3-Dia m in o
Ester s 4. The preparation of these compounds was carried out
by different methods.
acidic cleavage of the aminal moiety using H3PO4 allowed
for a very concise route to these products (three linear
steps, four total steps). The methodology appears to be
compatible with additional substitution at CR, and com-
plete removal of the aminal and the sulfinyl groups was
also produced using methanol as cosolvent even when a
Cbz moiety is attached to N-3. In addition, the N-
sulfinyldiamino esters are amenable to a number of
subsequent selective transformations at the free amino
functionality. Applications of this methodology are being
pursued in our laboratories.
F r om N-Su lfin ylim id a zolid in es. Meth od A. To a solu-
tion of the N-sulfinylimidazolidine 1 in MeOH (10 mL/mmol)
at room temperature and under an argon atmosphere was
added dropwise 4 equiv of TFA, and the reaction was moni-
tored by TLC of aliquots neutralized with solid NaHCO3. The
reaction mixture was heated under reflux to reach completion
when necessary. The crude mixture was evaporated under
vacuum, redissolved in CH2Cl2 (8 mL/mmol), and neutralized
with aqueous saturated NaHCO3 solution (5 mL/mmol). The
layers were separated, and the aqueous phase was further
basified to pH 10-11 with solid K2CO3 and extracted with
CH2Cl2 or CH2Cl2-MeOH (20:1, 3 × 10 mL/mmol). The
combined organic phases were dried over Na2SO4, filtered, and
concentrated under vacuum to give a product that was purified
by column chromatography on silica gel (ca. 1 g/mmol).
Meth od B. To a suspension of the N-sulfinylimidazolidine
1 in Et2O/H2O (1:1, 15 mL/mmol) at room temperature and
under an argon atmosphere was added dropwise an aqueous
2 N solution of HCl (5 mL/mmol), and the reaction was
monitored by TLC of aliquots neutralized with solid NaHCO3.
Upon completion, the layers were separated and the products
isolated as indicated in method A.
Exp er im en ta l Section
Gen er a l P r oced u r e for P r ep a r a tion of N-Su lfin yl-
d ia m in o Ester s by Selective Solvolytic Clea va ge of th e
Am in a l Moiety of N-Su lfin ylim id a zolid in es. To a solution
of N-sulfinylimidazolidine 15b in a mixture of THF and H2O
(7:3, 7 mL/mmol of H3PO4) was added 3-6 equiv of H3PO4 (85%
aqueous solution). The mixture was stirred from 0 °C to rt until
disappearance of 1 (TLC of aliquots neutralized with solid
NaHCO3). The mixture was diluted with Et2O (5 mL/mmol),
and the aqueous layer was basified with solid K2CO3 to pH
10-11 and extracted with CHCl3 (3 × 8 mL/mmol). The
combined organic extracts were dried over Na2SO4 and con-
centrated under vacuum to afford fairly pure diamino esters
3 that were further purified by column chromatography on
silica gel.
Meth od C. Alternatively, the TFA used in method A can
be replaced by 3-4 equiv of H3PO4 (85% aqueous solution) in
THF/MeOH/H2O (6:3:1, 10 mL/mmol), following the same
procedure for isolation as indicated before.
F r om N-Su lfin yld ia m in o Ester s. Meth od D. Desulfinyl-
ation of N-sulfinyldiamino esters 3 was performed using 4
equiv of TFA or 4 equiv of a 0.5 M aqueous solution of H3PO4
in MeOH (10 mL/mmol) following the same procedure indi-
cated in method A for isolation of the final products.
(+)-Meth yl [(2S,3R)-2,3-Dia m in o-4-m eth yl]p en ta n oa te,
4d . From 1e (80 mg, 0.207 mmol) and 1 mL of 2 N HCl,
according to general procedure B (1 h and 30 min), was
obtained after chromatography (5:1 CH2Cl2-MeOH) 4d (20 mg,
0.124 mmol, 60%) as a colorless oil. 4d was also obtained by
(+)-Met h yl [(2S,3R,SS )-2-Am in o-3-p h en yl-3-(p -t olyl-
su lfin yla m in o)]p r op a n oa te, 3a . From 1c (105 mg, 0.250
mmol), 4 equiv of H3PO4, and 2 additional equiv after 1 h and
15 min, according to the general procedure (3 h and 30 min),
was obtained an 80:20 mixture of diamino esters 3a and 4a .
Purification by chromatography (0-5% MeOH-CH2Cl2) gave
3a (61 mg, 0.183 mmol, 73%) as a white solid and 4a (10 mg,
20%) as a colorless oil. The following are the data for 3a . Rf )
0.24 (4% MeOH-CH2Cl2). Mp: 104-107 °C. [R]20 ) +25.1 (c
D
1
) 0.47). H NMR (300 MHz): δ 1.54 (br s, 2 H), 2.29 (s, 3 H),
desulfinylation of 3d (method D, 68%). Rf ) 0.20 (15% MeOH-
3.73 (s, 3 H), 3.81 (d, 1 H, J ) 4.0 Hz), 4.71 (dd, 1 H, J ) 7.6,
4.0 Hz), 5.48 (d, 1 H, J ) 7.6 Hz), 7.07-7.24 (m, 7 H), 7.40 (d,
2 H, J ) 8.3 Hz). 13C NMR (50 MHz): δ 21.1, 52.3, 58.1, 59.7,
125.8 (2 C), 126.8 (2 C), 127.2, 128.1 (2 C), 129.0 (2 C), 139.7,
140.8, 140.9, 173.0. IR (KBr): 3420, 3351, 3280, 3059, 1750,
1586, 1452, 1264, 1224, 1201, 1094, 1062, 999, 889, 806, 780,
704 cm-1. MS (ES): m/z 687 [2M + Na]+, 355 [M + Na]+, 333
[M + 1]+ (100). Anal. Calcd for C17H20N2O3S: C, 61.42; H, 6.06;
N, 8.43; S, 9.65. Found: C, 61.19; H, 6.40; N, 8.74; S, 9.21.
(+)-Met h yl [(2S,3R,SS )-2-Am in o-5-p h en yl-3-(p -t olyl-
su lfin yla m in o)]p en ta n oa te, 3b. From 1f (63 mg, 0.140
mmol) and 4 equiv of H3PO4, according to the general
procedure (1 h and 30 min), was obtained after purification
by chromatography (0-3% MeOH-CH2Cl2) 3b (41 mg, 0.114
1
CH2Cl2). [R]20 ) +3.1 (c ) 0.62). H NMR (200 MHz): δ 0.95
D
(d, 3 H, J ) 6.8 Hz), 0.97 (d, 3 H, J ) 6.8 Hz), 1.51 (br s, 4 H),
1.65 (m, 1 H), 2.69 (dd, 1 H, J ) 7.7, 3.8 Hz), 3.54 (d, 1 H, J
) 3.8 Hz), 3.72 (s, 3 H). 13C NMR (50 MHz): δ 18.6, 20.2, 30.8,
52.1, 56.4, 59.6, 175.8. IR (film): 3353, 2961, 2924, 2854, 1738,
1671, 1455, 1413, 1376, 1092, 865, 800 cm-1. MS (ES): m/z
399 [2M - CO2 + Na]+, 257 [2(M + 1 - CO2) + Na]+ (100),
161 [M + 1]+. Anal. Calcd for C7H16N2O2: C, 52.48; H, 10.07;
N, 17.48. Found: C, 52.23; H, 9.97; N, 17.33.
(-)-Meth yl [(2S,3R)-3-Am in o-2-ben zyloxyca r bon yla m i-
n o-5-p h en yl]p en ta n oa te, 4e. From 1h (40 mg, 0.069 mmol)
and 4 equiv of H3PO4 (0.275 mmol, 33 mg, 20 µL), according
to general procedure C (23 h), was obtained after purification
by chromatography (0-1% EtOH-Et2O) and crystallization
with Et2O 4e (16 mg, 0.045 mmol, 65%) as a colorless solid. Rf
mmol, 81%) as a colorless oil. Rf ) 0.20 (5% MeOH-CH2Cl2).
1
[R]20 ) +95.2 (c ) 1.20). H NMR (300 MHz): δ 1.61 (br s, 2
D
) 0.28 (0.05% EtOH-Et2O). Mp: 62-63 °C. [R]20 ) -1.3 (c
D
H), 1.86 (m, 2 H), 2.39 (s, 3 H), 2.52 (m, 1 H), 2.67 (m, 1 H),
3.67 (m, 2 H), 3.77 (s, 3 H), 4.49 (d, 1 H, J ) 8.4 Hz), 7.09-
7.28 (m, 7 H), 7.54 (d, 2 H, J ) 8.2 Hz). 13C NMR (50 MHz):
δ 21.3, 32.2, 35.1, 52.3, 57.1, 57.5, 125.7 (2 C), 125.9 (2 C),
128.3 (2 C), 128.4 (2 C), 129.5, 141.2, 141.3, 141.9, 174.3. IR
(film): 3302, 3026, 2949, 1737, 1602, 1429, 1454, 1227, 1089,
1059, 813, 750, 700 cm-1. MS (ES): m/z 743 [2M + Na]+, 383
[M + Na]+, 361 [M + 1]+ (100). Anal. Calcd for C19H24N2O3S:
C, 63.31; H, 6.71; N, 7.77; S, 8.90. Found: C, 63.72; H, 6.22;
N, 7.34; S, 8.79.
) 2.00). 1H NMR (300 MHz): δ 1.20 (br s, 2 H), 1.59 (m, 1 H),
1.75 (m, 1 H), 2.70 (ap t, 2 H, J ) 7.9 Hz), 3.30 (br s, 1 H),
3.73 (s, 3 H), 4.40 (d, 1 H, J ) 7.7 Hz), 5.12 (s, 2 H), 5.70 (d,
1 H, J ) 8.5 Hz), 7.14-7.20 (m, 4 H), 7.25-7.33 (m, 6 H). 13C
NMR (50 MHz): δ 32.5, 36.2, 52.2, 52.4, 57.9, 67.1, 126.0, 128.1
(2 C), 128.4 (2 C), 128.5 (2 C), 128.6 (2 C), 136.3, 141.3, 156.6,
172.3. IR (KBr): 3321, 3062, 3029, 2951, 2857, 1715, 1659,
1603, 1497, 1454, 1437, 1228, 1086, 1051, 1029, 774, 749, 699
cm-1. MS (ES): m/z 357 [M + 1]+ (100). Anal. Calcd for
C
20H24N2O4: C, 69.40; H, 6.79; N, 7.86. Found: C, 69.34; H,
6.63; N, 7.95.
(19) This experiment was also carried out with the racemic acid,
giving rise to a diastereomeric mixture with well-resolved signals in
the 1H NMR spectra. This conclusively established the optical purity
of 3d , as a representative example, to be g99%, with the other
diastereomer not being detected in a carefully recorded 300 MHz 1H
NMR spectrum.
Syn th esis of (+)-Meth yl [(2S,3R,SS)-2-(Ben zyla m in o)-
4-m eth yl-3-(p-tolylsu lfin yla m in o)]p en ta n oa te, 6b. To a
solution of 3d (78 mg, 0.261 mmol) in anhydrous CH3CN (15
mL/mmol) were added BnBr (63 µL, 0.522 mmol) and solid
K2CO3 (144 mg). The mixture was stirred at rt and monitored
1546 J . Org. Chem., Vol. 69, No. 5, 2004

Route to Enantiopure Diamino Esters
by TLC until completion (24 h). After removal of CH3CN under
vacuum, the residue was partitioned between CH2Cl2 (10 mL/
mmol) and H2O (10 mL/mmol). The aqueous phase was
extracted with CH2Cl2 (2 × 5 mL/mmol). The combined organic
layers were washed with brine (5 mL/ mmol), dried over
Na2SO4, filtered, and concentrated under vacuum. Purification
by chromatography (30-100% Et2O-hexane) afforded 6b (80
mg, 0.206 mmol, 79%) as a colorless oil along with dibenzylated
6i (8 mg, 0.011 mmol, 6%). The following are the data for 6b.
168.8. IR (KBr): 3424, 3276, 2954, 2841, 2809, 1721, 1601,
1510, 1430, 1316, 1297, 1224, 1170, 1135, 1089, 1065, 1031,
1015, 986, 916, 938, 816, 638 cm-1. MS (ES): m/z 405 [M +
1]+ (100). Anal. Calcd for C21H25FN2O3S: C, 62.35; H, 6.23; F,
4.70; N, 6.93; S, 7.93. Found: C, 62.72; H, 6.10; N, 6.88; S,
7.67.
Syn th esis of (+)-Meth yl [(2S,3R,SS)-2-[(S)-P h en ylm eth -
oxya cetyla m in o)]-4-m eth yl-3-(p-tolylsu lfin yla m in o)]p en -
ta n oa te, 6g. To a solution of 3d (20 mg, 0.067 mmol) in CH2Cl2
(10 mL/mmol) were added 1.05 equiv of (S)-(+)-MPA (11.63
mg, 0.070 mmol), 1 equiv of DCC (15.00 mg, 0.067 mmol), and
a catalytic amount of DMAP (1-2 crystals). The mixture was
stirred until completion monitored by TLC (1 h). The solvent
Rf ) 0.40 (Et2O). [R]20 ) +43.0 (c ) 1.70). 1H NMR (400
D
MHz): δ 0.79 (d, 3 H, J ) 6.6 Hz), 0.96 (d, 3 H, J ) 6.8 Hz),
1.81 (m, 1 H), 2.02 (br s, 1 H), 2.37 (s, 3 H), 3.36 (dt, 1 H, J )
8.3, 2.6 Hz), 3.40 (d, 1 H, J ) 2.6 Hz), 3.57 (d, 1 H, J ) 12.8
Hz), 3.77 (s, 3 H), 3.93 (d, 1 H, J ) 12.8 Hz), 4.02 (d, 1 H, J )
8.3 Hz), 7.21-7.32 (m, 7 H), 7.58 (d, 2 H, J ) 8.3 Hz). 13C
NMR (75 MHz)/HSQC: δ 19.5, 19.8, 21.3, 30.7, 52.0, 52.8, 62.0,
63.4, 125.7 (2 C), 127.1, 128.3 (2 C), 128.5 (2 C), 129.4 (2 C),
139.8, 141.2, 142.4, 174.5. IR (film): 3302, 3201, 3060, 3028,
2956, 2872, 1738, 1597, 1494, 1454, 1434, 1259, 1200, 1151,
1090, 1058, 1018, 994, 923, 812, 747, 701 cm-1. MS (ES): m/z
799 [2M + Na]+, 389 [M + 1]+ (100). Anal. Calcd for
1
was evaporated under reduced pressure. A H NMR sample
was prepared from this crude product, and the diastereomeric
excess of 6g and the optical purity of the N-sulfinyldiamino
ester 3d were measured by integration at the methoxy signals
(de > 99%). 6g (19 mg, 64%) was finally obtained after
purification by chromatography (50-100% Et2O-hexane) as
1
a white foam. Rf ) 0.23 (Et2O). [R]20 ) +106.1 (c ) 1.85). H
D
NMR (300 MHz): δ 0.76 (d, 3 H, J ) 6.6 Hz), 0.90 (d, 3 H, J )
6.8 Hz), 1.56 (m, 1 H), 2.41 (s, 3 H), 3.47 (s, 3 H, OMe), 3.58
(td, 1 H, J ) 7.5, 2.9 Hz), 3.75 (s, 3 H), 3.89 (d, 1 H, J ) 7.1
Hz), 4.69 (s, 1 H), 4.82 (dd, 1 H, J ) 9.5, 2.9 Hz), 7.25-1.37
(m, 5 H), 7.39 (m, 2 H), 7.57 (d, 2 H, J ) 8.3 Hz), 7.68 (d, 1 H,
J ) 9.5 Hz). 13C NMR (75 MHz)/HSQC: δ 19.1, 19.5, 21.4,
30.1, 52.6, 53.3 57.6, 61.8, 84.0, 125.7 (2 C), 126.6 (2 C), 128.5
(3 C), 129.6 (2 C), 137.1, 141.5, 141.7, 171.3, 171.2. MS (ES):
m/z 915 [2M + Na]+, 447 [M + 1]+ (100). Anal. Calcd for
C
21H28N2O3S: C, 64.92; H, 7.26; N, 7.21; S, 8.25. Found: C,
64.75; H, 7.52; N, 7.17; S, 8.34.
Syn th esis of (-)-Meth yl [(2S,3R,SS)-3-(p-F lu or op h en -
yl)-2-(pyr r olidin -1-yl)-3-(p-tolylsu lfin ylam in o)]pr opan oate,
6d . To a round-bottomed flask fitted with a Dean-Stark trap
was added a solution of 3c (70 mg, 0.199 mmol) in anhydrous
toluene (10 mL/mmol), 1,4-dibromobutane (69 µL, 0.259 mmol),
and solid NaHCO3 (42 mg, 0.498 mmol). The mixture was
heated under reflux for 14 h, then allowed to reach rt, and
filtered to remove inorganic salts, and the solid residue was
washed with toluene. The filtrate was washed with H2O, dried
over Na2SO4, and filtered, and the solvent was evaporated
under reduced pressure. 6d (52 mg, 0.129 mmol, 65%) was
obtained after chromatography on silica gel (50-100% Et2O-
hexane) as a white solid that was crystallized from 5%
C
23H30N2O5S: C, 61.86; H, 6.77; N, 6.27; S, 7.18. Found: C,
61.52; H, 6.43; N, 6.09; S, 7.07.
Ack n ow led gm en t. This research was supported by
CAM (Grants 08.5/0079/2000 and 08.5/0028/2003) and
DGI MCYT (Grants BQU2001-0582 and BQU2003-
02921). We thank J ANSSEN-CILAG for additional
support and CAM for a doctoral fellowship to A.F.
CH2Cl2-hexane to give white crystals. Rf ) 0.40 (80% Et2O-
1
hexane). Mp: 138-142 °C. [R]20 ) -2.9 (c ) 0.80). H NMR
D
(300 MHz): δ 1.76 (m, 4 H), 2.19 (s, 3 H), 2.67 (m, 2 H), 2.84
(m, 2 H), 3.38 (s, 3 H), 3.53 (d, 1 H, J ) 11.0 Hz), 4.75 (d, 1 H,
J ) 11.0 Hz), 5.74 (s, 1 H), 6.58 (t, 2 H, J ) 8.8 Hz), 6.87 (m,
4 H), 7.22 (d, 2 H, J ) 8.3 Hz). 13C NMR (75 MHz): δ 21.1,
23.6 (2 C), 48.2 (2 C), 49.7, 50.9, 68.7, 114.3 (d, 2 C, J o(C-F)
) 21.7 Hz), 125.6 (2 C), 128.6 (2 C), 130.1 (d, 2 C, J m(C-F) )
8.1 Hz), 135.3, 139.4, 140.7, 161.7 (d, J ipso(C-F) ) 245.3 Hz),
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization for new compounds (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O035613J
J . Org. Chem, Vol. 69, No. 5, 2004 1547