Diastereoselective [2+2]-cycloaddition reactions of unsymmetrical cyclic ketenes with imines: Synthesis of modified prolines and theoretical study of the reaction mechanism

Article abstract of DOI:10.1021/jo040163w

The synthesis of enantiomerically pure modified proline derivatives was achieved by using spiro β-lactams as starting material that were prepared in turn by the [2+2]-cycloaddition of unsymmetrical cyclic ketenes with optically active imines. A theoretica

Full text of DOI:10.1021/jo040163w

Dia ster eoselective [2+2]-Cycloa d d ition Rea ction s of
Un sym m etr ica l Cyclic Keten es w ith Im in es: Syn th esis of Mod ified
P r olin es a n d Th eor etica l Stu d y of th e Rea ction Mech a n ism
Alberto Mac´ıas,† Eduardo Alonso,† Carlos del Pozo,† Alessandro Venturini,‡ and
J avier Gonza´lez*,†
Departamento de Quı´mica Orga´nica e Inorga´nica, Universidad de Oviedo, J ulia´n Claverı´a 8,
33006 Oviedo, Spain, and I.S.O.F.-C.N.R., Area della Ricerca di Bologna, Via P. Gobetti 101,
40129 Bologna, Italy
fjgf@uniovi.es
Received March 30, 2004
The synthesis of enantiomerically pure modified proline derivatives was achieved by using spiro
â-lactams as starting material that were prepared in turn by the [2+2]-cycloaddition of unsym-
metrical cyclic ketenes with optically active imines. A theoretical study of the [2+2]-cycloaddition
reaction, using density-functional methods, gave insights on the origin of the observed stereose-
lectivity of the Staudinger reaction. The spiro â-lactams were transformed in the N-Boc derivatives
and subjected to nucleophilic ring opening, affording the corresponding enantiomerically pure
modified proline derivatives, isolated as orthogonally protected compounds.
SCHEME 1
In tr od u ction
The development of new methodology directed to the
preparation of modified R-1 and â-amino acids2 is a very
active field in organic synthesis. The synthesis of con-
formationally constrained amino acids, which could
present interesting biological properties, e.g., peptides
derived from these modified amino acids could be more
resistant to the degradative action of proteases, is of
special interest. An interesting approach to conforma-
tionally constrained systems is the use of cyclic struc-
tures.3 L-Proline constitutes a good example of how the
presence of a ring can influence the secondary structure
of peptides and proteins, and thus, methodology for the
synthesis of several types of modified proline derivatives
has been developed.4 On the other hand, Seebach and
Gellman and co-workers have shown that â-peptides
formed by cyclic â-amino acids are able to form stable
secondary structures in solution.5a-c
ketene-imine cycloaddition route (Staudinger reaction),7
will undergo a ring-opening reaction leading to â-amino
acids. The use of â-lactams as starting material following
the aforementioned protocol would lead to the stereose-
lective synthesis of R,R-geminally disubstituted â-amino
acids (Scheme 1).8
Herein we report the results obtained following the
synthetic route outlined in Scheme 1 that allowed us to
achieve the synthesis of optically active proline deriva-
tives 1, which can also be considered as R,R-geminally
disubstituted â-amino acids (Figure 1). Proline deriva-
tives 1 were obtained by the nucleophile-promoted ring
opening of spiro â-lactams prepared through an asym-
metric Staudinger reaction of imines with unsymmetrical
cyclic ketenes.
One of the most successful routes to access â-amino
acids involves the use of â-lactams as synthetic interme-
diates.6 These â-lactams, usually prepared through the
In addition, the results of a theoretical study aimed at
understanding the factors controlling the stereochemical
outcome of the Staudinger reaction are presented.
† Universidad de Oviedo.
‡ I.S.O.F.-C.N.R., Area della Ricerca di Bologna.
(1) For a recent review see: Kotha, S. Acc. Chem. Res. 2003, 36,
342-351.
Resu lts a n d Discu ssion
(2) Enantioselective Synthesis of â-Aminoacids; J uaristi, E., Ed.:
Wiley-VCH: New York, 1997.
Syn th esis of En a n tiom er ica lly P u r e Sp ir o â-La c-
ta m s. According to previous results of our group,8b the
(3) The synthetic methodology for the synthesis of cyclic amino acid
derivatives has been extensively reviewed: Park, K.-H.; Kurth, M. J .
Tetrahedron 2002, 58, 8629-8659.
(4) See, for example: (a) Blanco, M. J .; Paleo, M. R.; Penide, C.;
Sardina, F. J . J . Org. Chem. 1999, 64, 8786. (b) Ibrahim, H. H.; Lubell,
W. D. J . Org. Chem. 1993, 58, 6438. (c) Koskinen, A. M. P.; Rapoport,
H. J . Org. Chem. 1989, 54, 1859.
(5) (a) Seebach, D.; Abele, S.; Gademann, K.; Guichard, G.; Hinter-
mann, T.; J aun, B.; Matthews, J . L.; Schreiber, J . V.; Oberer, L.;
Hommel, U.; Widmer, H. Helv. Chim. Acta 1998, 81, 932. (b) Gellman,
S. H. Acc. Chem. Res. 1998, 31, 173. (c) Apella, D. H.; Christianson, L.
A.; Karle, I.; Powell, D. R.; Gellman, S. H. J . Am. Chem. Soc. 1996,
118, 13071.
(6) Palomo, C.; Aizpurua, J . M.; Ganboa, I. In Enantioselective
Synthesis of â-Aminoacids; J uaristi, E., Ed.; Wiley-VCH: New York,
1997; pp 279-389.
(7) For
a review of the synthetic utility of the ketene-imine
cycloaddition, see: Georg, G. I.; Ravikumar, V. T. In The Organic
Chemistry of â-Lactams; Georg, G. I., Ed.;, VCH Publishers: New York,
1993; pp 295-368.
(8) (a) Alonso, E.; Pozo, C. del; Gonza´lez, J . J . Chem. Soc., Perkin
Trans. 1 2002, 571. (b) Alonso, E.; Lo´pez-Ortiz, F.; Pozo, C. del; Peralta,
E.; Mac´ıas, A.; Gonza´lez, J . J . Org. Chem. 2001, 66, 6333.
10.1021/jo040163w CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/10/2004
7004
J . Org. Chem. 2004, 69, 7004-7012

Synthesis of Modified Prolines
F IGURE 1. Proline derivatives obtained from the ring open-
ing of spiro â-lactams.
F IGURE 3. Determination of the relative configuration of
spiro â-lactams.
diastereoisomers 4 and 5 that were separated by column
chromatography.13
As expected, the Staudinger reaction proceed with total
cis stereoselectivity, giving the â-lactams 4 and 5, with
a cis relative disposition of the pyrrolidine nitrogen and
the phenyl group, but no asymmetric induction was
observed. A comparable stereochemical result was ob-
tained when the reaction was carried out at -78 °C.
The relative configuration of the stereogenic centers
of â-lactams 4 and 5 was deduced from the corresponding
NOESY spectra of the deprotected (the Cbz and silyl
F IGURE 2. Unsymmetrical cyclic ketenes.
SCHEME 2
1
protecting groups were removed to simplify the H NMR
spectra, avoiding the presence of rotamers) compounds
6 and 7 (see Figure 3 and Supporting Information). The
methine proton of the â-lactam ring (at C3) showed a
correlation with one proton (at C8) of the methylene
group linked to the spiranic carbon atom. Taking into
account the rigid geometry of the spiranic system, this
correlation indicates a syn relationship between the
imine hydrogen at C3 and the methylene group in the
pyrrolidine ring. According to this result we can conclude
that in the cycloaddition reactions between cyclic ketenes
3 and imines only the cis stereoisomer is formed.
The absolute configuration of â-lactam 4 was deter-
mined after its conversion in â-aminoester 1a (see the
next section on the synthesis of â-aminoester derivatives
1 and Supporting Information for details).
[2+2]-cycloaddition of the unsymmetrical ketene 2a (see
Figure 2), derived from the dehydrohalogenation of
N-benzyloxycarbonyl L-proline acid chloride (see Scheme
2, 3a , R ) H) with triethylamine, takes place with
complete stereoselectivity, giving the spiro â-lactam with
a cis relative disposition of the substituent at the iminic
carbon atom and the proline nitrogen.
To achieve asymmetric induction in the Staudinger
reaction7 we tried three different approaches: (i) the
reaction of a ketene bearing a protected amino acid
attached to the nitrogen of the L-proline, (ii) the use of
an optically active ketene derived from trans-4-hydroxy-
L-proline, 2b (Figure 2), and (iii) the reaction of optically
active imines derived from D-gliceraldehyde acetonide9
and Garner’s aldehyde.10
In sharp contrast with the precedent results, very good
levels of asymmetric induction were achieved in the
Staudinger reaction of ketene 2a (Figure 2) with optically
10
active imines 89and 9 (Scheme 3). Thus, the reaction
While the reaction of the acid chloride of the dipeptide
N-phthaloyl-L-alanilproline with different imines failed
to give the expected â-lactam (probably due to the steric
hindrance of the intermediate ketene), the expected spiro
â-lactams were obtained in the reactions, either of imines
with ketene 2b or of optically active imines with ketene
2a . However, the stereochemical result of these two
Staudinger reactions was quite different.
The reaction of the O-silyl-protected N-benzyloxycar-
bonyl trans-4-hydroxy-L-proline acid chloride 3b or 3c
(Scheme 2)11 with N-p-methoxyphenylbenzaldimine12 in
the presence of triethylamine, at room temperature, gave
the corresponding spiro â-lactams as a 1:1 mixture of
of N-benzyloxycarbonyl-L-proline acid chloride with the
imine 8 gave the diastereomeric spiro â-lactams 10 and
11 which were separated by column chromatography. The
diastereomeric ratio was determined to be 95:5 respec-
1
tively by H and 13C NMR.
The cis relative configuration of â-lactam 10 was
determined by analysis of the NOESY spectra of com-
pound 10a , in which the Cbz group was removed (as in
the case of 4; see Supporting Information).
On the other hand, the Staudinger reaction of imine 9
gave the â-lactam 12, isolated as one diastereoisomer.
The diastereomeric excess was determined by 1H and 13C
NMR analysis of the reaction mixture, after hydrogenoly-
sis to remove the Cbz protecting group (compound 12a ,
see Supporting Information)
(9) (a) Bose, A. K.; Hedge, V. R.; Wagle, D. R.; Bari, S. S.; Manhas,
M. G. J . Chem. Soc., Chem. Commun. 1986, 161. (b) Wagle, D. R.;
Garai, C.; Chiang, J .; Monteleone, M. G.; Kurys, B. E.; Strohmeyer, T.
W.; Hedge, V. R.; Manhas, M. S.; Bose, A. K J . Org. Chem. 1988, 53,
4227. (c) Banik, B. K.; Manhas, M. S.; Kaluza, Z.; Barakat, K. J .; Bose,
A. K. Tetrahedron Lett. 1992, 33, 3603.
Having determined the cis relative stereochemistry of
â-lactams 10 and 12, we studied the sense of the
asymmetric induction in the corresponding [2+2]-cy-
(10) (a) Garner, P.; Park, J . M. J . Org. Chem. 1987, 52, 2361. (b)
Palomo, C.; Coss´ıo, F. P.; Cuevas, C. Tetrahedron Lett. 1991, 32, 3109.
(11) (a) Palomo, C.; Oiarbide, M.; Landa, A. J . Org. Chem. 2000,
65, 41. (b) Mayer, S. C.; Ramanjulu, J .; Vera, M. D.; Pfizenmayer, A.
J .; J oullie´, M. M. J . Org. Chem. 1994, 59, 5192.
(13) N-p-Methoxyphenylbenzaldimine was used, as it allows easy
oxidative removal of the p-methoxyphenyl group, with ammonium
cerium (IV) nitrate, to give the N-unsubstituted â-lactam, as shown
in: Kronenthal, D. R.; Han, C. Y.; Taylor M. K. J . Org. Chem. 1982,
47, 2765.
(12) Taguchi, K.; Westheimer, F. H. J . Org. Chem. 1971, 36, 1570.
J . Org. Chem, Vol. 69, No. 21, 2004 7005

Mac´ıas et al.
SCHEME 3
SCHEME 4
[2+2]-cycloaddition of unsymmetrical ketenes such as 2a
or 2b (see Figure 2) took place with complete stereose-
lectivity, giving the spiro â-lactams with a cis relative
disposition of the substituent at the iminic carbon atom
and the nitrogen of the pyrrolidine ring. In addition,
excellent asymmetric induction was achieved when opti-
cally active imines were employed (Scheme 3).
To get a deeper insight on the origins of the observed
stereoselectivity, density-functional calculations18 on the
model reaction of cyclic ketene I with imine II (Figure 4)
were carried out.
Previous theoretical studies, carried out at different
levels of theory, on the mechanism of the [2+2]-ketene-
imine cycloaddition showed that this reaction is a two-
step process, involving the initial formation of a zwitte-
rionic intermediate, which undergo a conrotatory ring
closure to give the â-lactam.19 Also, the stereoselectivity
of the Staudinger reaction of unsymmetrical cyclic ketenes
derived from 2- or 3-tetrahydrofuroyl chlorides has been
studied with ab initio methods.8a
The stationary points located for the reaction of ketene,
I, with N-methylacetaldimine, II, were fully optimized
at the Becke3LYP/6-31+G* level of theory.20 Two differ-
ent reaction pathways were identified: the anti, in which
the initial nucleophilic addition of the imine to the ketene
cloaddition reactions. Taking into account the absolute
configuration of imines 8 and 9 and the results of the
theoretical study on the reaction mechanism described
later, it could be expected that the two chiral fragments
exert an opposite effect. To verify this assertion, the
â-lactams 10 and 12 were transformed in the 4-formyl
derivatives 15 by a sequence of reactions involving the
hydrolysis of the acetonide group in 10 and the simul-
taneous deprotection/hydrolysis in 12, followed by oxida-
tion of the intermediates 13 and 14 (see Scheme 4).14,10b
Compounds 15a and 15b are enantiomers, and their
optical rotations should be opposed, as it happens,15 thus
confirming the effect of the two chiral groups present in
imines 8 and 9.16
The enantiomeric purity of compounds 15a and 15b
was determined by 1H NMR, using europium shift
reagents, and comparing with the data for the racemic
4-formyl derivative, rac-15-cis (see Supporting Informa-
tion for details).17
The absolute configuration of 10 (and therefore of 12)
was determined after its conversion in the â-aminoester
derivative 1d (see the next section on the synthesis of
â-aminoester derivatives 1).
(17) The racemic 4-formyl â-lactam, rac-15-cis was prepared ac-
cording to a procedure previously described: (a) Alcaide, B.; Mart´ın-
Cantalejo, Y.; Plumet, J .; Rodr´ıguez-Lo´pez, J .; Sierra, M. A. Tetrahe-
dron Lett. 1991, 32, 803. (b) Alcaide, B.; Mart´ın-Cantalejo, Y.; Pe´rez-
Castells, J .; Rodr´ıguez-Lo´pez, J .; Sierra, M. A. J . Org. Chem. 1992,
57, 5921.
(18) For a description of the theoretical methodology, see: J ensen,
F.; Introduction to Computational Chemistry; Wiley: New York, 1999;
pp 177-194.
(19) (a) Venturini, A.; Gonza´lez, J . J . Org. Chem. 2002, 67, 9089.
(b) Sordo, J . A.; Gonza´lez, J .; Sordo, T. L. J . Am. Chem. Soc. 1992,
114, 6249.
(20) The program Gaussian 98 was used: Frisch, M. J .; Trucks, G.
W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J . R.;
Zakrzewski, V. G.; Montgomery, J . A., J r.; Stratmann, R. E.; Burant,
J . C.; Dapprich, S.; Millam, J . M.; Daniels, A. D.; Kudin, K. N.; Strain,
M. C.; Farkas, O.; Tomasi, J .; Barone, V.; Cossi, M.; Cammi, R.;
Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J .;
Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J . B.; Cioslowski, J .; Ortiz,
J . V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi,
I.; Gomperts, R.; Martin, R. L.; Fox, D. J .; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P.
M. W.; J ohnson, B. G.; Chen, W.; Wong, M. W.; Andres, J . L.; Head-
Gordon, M.; Replogle, E. S.; Pople, J . A. Gaussian 98, revision A.11.3;
Gaussian, Inc.: Pittsburgh, PA, 2002.
Th eor etica l Stu d y of th e [2+2]-Cycloa d d ition of
Cyclic Keten es w ith Im in es. As reported above, the
(14) (a) Alcaide, B.; Polanco, C.; Sierra, M. A. J . Org. Chem. 1998,
63, 6786. (b) Wagle, D. R.; Garai, C.; Monteleone, M. G. Tetrahedron
Lett. 1988, 29, 1649.
(15) The values of the optical rotation [R]20 of 15a and 15b,
D
measured in CHCl3 (c 0.7), are +134.0 and -134.0, respectively.
(16) The relative stereochemistry of 15a (and therefore 15b) was
studied by NMR (NOESY spectra), and was confirmed to be cis, thus
excluding a possible epimerization of the carbon atom C3 (see Supor-
ting Information).
7006 J . Org. Chem., Vol. 69, No. 21, 2004

Synthesis of Modified Prolines
F IGURE 4. Model ketene and imine used in the density-
functional study.
F IGURE 7. Becke3LYP/6-31+G* reaction profile correspond-
ing to the formation of â-lactams III and IV.
F IGURE 5. Anti and syn transition structures and zwitteri-
onic intermediates in the addition of II to I.
F IGURE 8. Model asymmetric Staudinger reaction.
the same, but in ET2ou t, the nitrogen atom rotates
outward, while in ET2in w , the nitrogen is placed inward.
According to previous work, there is a strong stereoelec-
tronic preference (torquoelectronic effect)21 in these types
of transition structures for the ring closure in which the
heteroatom rotates outward.8a,22
The relative energies of the anti and syn reaction
pathways are shown in Figure 7, and according to these
data, though the syn approach is favored, the rate-
determining step corresponds to the outward transition
structure, ET2ou t, which is 3.5 kcal mol-1 more stable
than ET2in w . Thus, the cis â-lactam III is predicted to
be the favored stereoisomer, in good agreement with the
experimental evidence.
This result indicates that the cis stereoselectivity of
the reaction is dictated by the stereoelectronic preference
in the second transition structure for the outward posi-
tion of the nitrogen atom of the pyrrolidine ring.
In addition to the electronic preference for the outward
transition structure, steric effects should govern the high
diastereoselectivity found in the reaction of the optically
active imines 8 and 9 (Scheme 3).
The asymmetric Staudinger reaction was studied by
using V as a model of the optically active imine (see
Figure 8). The calculations were carried out at the
Becke3LYP/6-31G* level of theory, and the transition
structures corresponding to the two possible cyclization
modes leading to the diastereomeric â-lactams VI and
VII were located.
F IGURE 6. Outward and inward conrotatory ring closure
transition structures.
takes place by the opposite side of the nitrogen atom of
the pyrrolidine ring, and the syn, corresponding to the
addition by the same side of the nitrogen.
For each reaction pathway, a transition structure for
the nucleophilic attack, ET1a n ti and ET1syn (see Figure
5), in which a bond is being formed between the imine
nitrogen and the central carbon atom of the ketene, was
located. Following the first transition structure, a zwit-
terionic intermediate, having a fully formed carbon-
nitrogen bond (IZa n ti and IZsyn , Figure 5), was found.
The conrotatory ring closure of the zwitterionic inter-
mediates results in the â-lactam derivatives: IZa n ti
provides the cis â-lactam III, via the transition structure
ET2ou t, where the nitrogen is placed in the outward
According to the reaction profile shown in Figure 6,
the favored reaction pathway involves the outward
position, while IZsyn , through transition structure ET2in w
leads to the trans â-lactam IV (see Figure 6).
As can be seen in Figure 6, the carbon-carbon forming
bond length in the two transition structures is almost
,
(21) For a description of the torquoelectronic effect, see: (a) Rondan,
G. N.; Houk, K. N. J . Am. Chem. Soc. 1985, 107, 2099. (b) Kirmse, W.;
Rondan, N. G.; Houk, K. N. J . Am. Chem. Soc. 1984, 106, 7989.
(22) Lo´pez, R.; Sordo, T. L.; Sordo, J . A.; Gonza´lez, J . J . Org. Chem.
1993, 58, 7036.
J . Org. Chem, Vol. 69, No. 21, 2004 7007

Mac´ıas et al.
F IGURE 9. Two diastereomeric transition structures for the
outward ring closure in the reaction of I with V.
SCHEME 5
F IGURE 10. Optically active R-(1-aminoalkyl)proline methyl
esters 1.
The â-lactams 4, 10, and 12 were treated with am-
monium cerium(IV) nitrate to remove the p-methoxyphe-
nyl group;13 the reaction of the N-unsubstituted deriva-
tives 16 with (Boc)2O in the presence of catalytic amounts
of DMAP furnished the N-Boc-protected â-lactams 17,
which, in the presence of methanol and potassium
cyanide,24 underwent ring opening to give the enantio-
merically pure â-aminoester derivatives 1 (see Scheme
5 and Figure 10).
In addition, this synthetic sequence allows for the
preparation of side-chain functionalized â-aminoesters,
as 1d . The reduction of 4-formyl â-lactam 15a and
O-silylation of the hydroxy group, followed by the oxida-
tive cleavage of PMP, gave the N-unsubstituted â-lactam
18; then, the cyanide-promoted ring opening of the N-Boc
derivative 19 afforded the O-silyl-protected R-(1-ami-
noalkyl)proline 1d , in 30% yield (5 steps).
The absolute configuration of the â-aminoester deriva-
tives 1 was determined by the Mosher method,25 and this
allowed us to establish the configuration of the precursor
spiro â-lactams (see Supporting Information).
transition structure ET2ou t; in the case of the imine V,
two diastereomeric outward transition structures, ET2A
and ET2B (Figure 9), are possible, depending upon the
sense of the relative rotation of the ketene and imine
moieties.
The transition structure ET2A is 3.9 kcal mol-1 more
stable than ET2B, and leads to the formation of the
â-lactam VI, which presents the same absolute configu-
ration as 10, the major diastereoisomer observed in the
reaction of the optically active imine 8 (see Scheme 3).
The examination of ET2A shows that it is a less sterically
crowded transition structure than ET2B, in which the
dioxolane ring of the imine is pointing to the formyl
substituent of the ketene. This result is also in good
agreement with the fact that in the reaction of the
optically active ketenes 3b and 3c (Scheme 2), having
the stereogenic center far from the carbon-carbon bond
forming, no stereoselectivity was found.
Syn th esis of Op tica lly Active r-(1-a m in oa lk yl)-
p r olin e Meth yl Ester s 1. According to the proposed
synthetic plan, as shown in Scheme 1, the ring opening
of the spiro â-lactams 4, 10, and 12 would provide the
modified prolines in an enantiomerically pure form. The
â-lactam ring can be hydrolyzed under strong acid or
basic conditions to give directly the â-amino acids, but
these reaction conditions could affect the integrity of the
spiranic system. It seemed more convenient to follow a
route involving the synthesis of the N-Boc â-lactam
derivatives 17 (Scheme 5).23 This procedure, while re-
quiring more steps, allows for the â-lactam ring-opening
reaction to be carried out in very mild conditions, due to
the electron-withdrawing effect of the Boc group.24 In
addition, the â-aminoester derivatives 1 are isolated as
orthogonally protected compounds simplifying any ulte-
rior manipulation.
Con clu sion s
The stereoselective synthesis of proline derivatives was
achieved by the sequential [2+2]-cycloaddition reaction
of an unsymmetrical cyclic ketene with optically active
imines, and nucleophilic ring opening of the â-lactam
formed. The reaction of the imines derived from D-
gliceraldehyde acetonide and Garner’s aldehyde took
place with a high stereoselectivity. According to the
density-functional calculations carried out on model
reactions, the origin of this stereoselectivity appears to
be related to steric and electronic factors operating in the
transition structure during the cyclization of the zwitte-
rionic intermediate formed in the nucleophilic attack of
the imine to the ketene.
The methodology described here allows the preparation
of the optically active R-(1-aminoalkyl)prolines as ortho-
gonally protected compounds. Further developments and
applications of these compounds on the synthesis of con-
formationally restricted peptides are currently underway.
Exp er im en ta l Section
Gen er al P r ocedu r e for th e P r epar ation of Spir o â-Lac-
ta m s (4 a n d 5). To a stirred solution of N-p-methoxyphenyl-
benzaldimine (2 mmol) and dry triethylamine (0.41 mL, 3
(25) (a) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512.
(b) A survey of the use of MTPA as chiral derivatizing agent can be
found in: Seco, J . M.; Quin˜oa´, E.; Riguera, R. Chem. Rev. 2004, 104,
17.
(23) Palomo, C.; Oiarbide, M.; Bindi, S. J . Org. Chem. 1998, 63, 2469.
(24) Herzig, J .; Antebi, A. J . Org. Chem. 1986, 51, 730.
7008 J . Org. Chem., Vol. 69, No. 21, 2004

Synthesis of Modified Prolines
mmol) in dry dichloromethane (10 mL) was added dropwise
the acid chloride 3b, or 3c (2 mmol) dissolved in dry dichlo-
romethane (5 mL). The mixture was stirred for 16 h at room
temperature, and was then quenched with saturated aqueous
NaHCO3. The aqueous layer was washed twice with CH2Cl2
(15 mL), and the combined organic layers were washed with
brine (20 mL) and dried over anhydrous Na2SO4. The solution
was then concentrated and purified by column chromatography
over SiO2 with the appropriate mixture of ethyl acetate/
hexane, affording the spiro â-lactams 4 and 5 as a 1:1 mixture
of diastereoisomers. The diastereomers 4b, 5b and 4c, 5c were
separated by flash chromatography (20% EtOAc/hexane).
55.4, 57.1, 57.9, 66.7, 67.6, 68.7, 69.4, 70.4, 71.4, 75.9, 114.2,
114.7, 118.5, 118.7, 127.4, 127.5, 127.6, 127.7, 127.8, 127.9,
128.0, 128.1, 128.3, 128.6, 129.9, 130.0, 130.1, 130.2, 135.4,
135.5, 131.3, 131.5, 132.7, 132.8, 132.9, 133.9, 134.1, 135.7,
136.4, 153.4, 156.0, 165.0, 165.5; IR (KBr) 1697, 1760 cm-1
;
MS (ESI+) m/z (rel intensity) 697 [(M + H), 35]. Anal. Calcd
for C43H44N2O5Si: C, 74.11; H, 6.36; N, 4.02. Found: C, 73.81;
H, 6.37; N, 3.99.
Syn th esis of Sp ir o â-La cta m s (10 a n d 12). To a stirred
solution of the imine 8 or 9 (2 mmol) and dry triethylamine
(0.41 mL, 3 mmol) in dry dichloromethane (10 mL) at -78 °C
was added dropwise the N-benzyloxycarbonyl L-proline acid
chloride 3a (2 mmol) dissolved in dry dichloromethane (5 mL).
The mixture was allowed to warm to room temperature over-
night and then quenched with saturated aqueous NaHCO3.
The aqueous layer was extracted twice with CH2Cl2 (15 mL),
and the combined organic layers were washed with brine (20
mL), and dried over anhydrous Na2SO4. The solution was then
concentrated and purified by column chromatography over
SiO2 with the appropriated mixture of ethyl acetate/hexane.
(3RS,4RS)-cis-5-Ben zyloxyca r bon yl-2-(4-m eth oxyp h e-
n yl)-3-[(S)-2,2-d im eth yl-1,3-d ioxola n -4-yl]-2,5-d ia za sp ir o-
[3.4]octa n -1-on e (10 a n d 11). Prepared from imine 8 (2
mmol), according to the general procedure described above,
to afford a 95:5 mixture of the diastereoisomers 10, 11 (52%
overall yield, 4 steps), which were separated by flash chroma-
tography (50% EtOAc/hexane).
(-)-(3R,4R)-5-Ben zyloxycar bon yl-2-(4-m eth oxyph en yl)-
3-[(S)-2,2-d im eth yl-1,3-d ioxola n -4-yl]-2,5-d ia za sp ir o[3.4]-
octa n -1-on e (10). Major isomer: Rf 0.37 (50% EtOAc/hexane),
0.456 g of 10, 49% yield (4 steps). White solid, [R]D -9.6 (c
0.4, CHCl3), mp 125-130 °C. 1H and 13C NMR show the
presence of rotamers about the carbamate bond in ca. 2:1 ratio.
1H NMR (300 MHz, CDCl3) δ 1.13, 1.24 (s, 3H); 1.44, 1.48 (s,
3H), 1.78-2.27 (m, 3H), 2.40 (m, 1H), 3.40-3.65 (m, 3H), 3.69-
3.87 (m, 1H), 3.79, 3.81 (s, 3H), 3.93, 3.99 (d, J ) 8.3, 1H),
4.29, 4.63 (m, 1H), 5.04 (m, 1H), 5.25 (m, 1H), 6.85 (m, 2H),
7.10-7.74 (m, 7H); 13C NMR (75 MHz, CDCl3) δ 22.3, 23.0,
24.9, 26.6, 34.8, 36.1, 48.0, 48.7, 55.4, 66.3, 67.5, 68.1, 71.5,
72.0, 73.6, 73.9, 75.2, 109.3, 113.8, 119.5, 128.1, 128.2, 128.3,
128.4, 131.1, 131.5, 135.0, 136.1, 153.8, 154.2, 156.1, 156.2,
165.4; IR (KBr) 1710, 1752 cm-1; MS (ESI+) m/z (rel intensity)
505 [(M + K), 100], 489 [(M + Na), 20], 467 [(M + H), 7]. Anal.
Calcd for C26H30N2O6: C, 66.94; H, 6.48; N, 6.00. Found: C,
67.11; H, 6.50; N, 6.03.
(-)-(3R,4S,7R)-5-Ben zyloxyca r bon yl-7-(ter t-bu tyld im -
et h ylsilyloxy)-2-(4-m et h oxyp h en yl)-3-p h en yl-2,5-d ia za -
sp ir o[3.4]octa n -1-on e (4b). Rf 0.60 (33% EtOAc/hexane), 0.40
g of 4b, 35% yield. White solid, [R]D -45.1 (c 0.5, CHCl3), mp
1
175-178 °C. H and 13C NMR show the presence of rotamers
about the carbamate bond in 1:1 ratio. 1H NMR (300 MHz,
CDCl3) δ 0.09, 0.11, 0.12, 0.13 (s, 6H), 0.89, 0.91 (s, 9H), 2.50-
2.65 (m, 2H), 3.19, 3.31 (AB syst, J ) 10.2, 8.0 Hz; AB syst, J
) 10.5, 8.0 Hz, 1H), 3.45, 3.60 (AB syst, J ) 10.2, 7.4 Hz; AB
syst, J ) 10.5, 7.4 Hz, 1H), 3.76, 3.77 (s, 3H), 4.43-4.78 (m,
2H), 4.91-5.05 (m, 2H), 6.75-6.89 (m, 3H), 7.01 (m, 1H), 7.14-
7.40 (m, 10H); 13C NMR (75 MHz, CDCl3) δ -5.0, -4.9, 17.8,
25.5, 42.7, 44.0, 53.7, 54.4, 55.2, 66.5, 67.5, 67.6, 68.3, 69.6,
70.3, 76.0, 76.8, 114.0, 118.3, 118.4, 126.7, 127.3, 127.5, 127.6,
127.8, 127.9, 128.1, 130.8, 131.1, 133.1, 133.3, 135.2, 136.3,
153.2, 153.4, 155.9, 164.0, 164.2; IR (KBr) 1715, 1756 cm-1
;
MS (ESI+) m/z (rel intensity) 595 [(M + Na), 10], 573 [(M +
H), 100]. Anal. Calcd for C33H40N2O5Si: C, 69.20; H, 7.04; N,
4.89. Found: C, 69.47; H, 7.02; N, 4.87.
(+)-(3S,4R,7R)-5-Ben zyloxyca r bon yl-7-(ter t-bu tyld im -
et h ylsilyloxy)-2-(4-m et h oxyp h en yl)-3-p h en yl-2,5-d ia za -
sp ir o[3.4]octa n -1-on e (5b). Rf 0.27 (33% EtOAc/hexane),
0.395 g of 5b, 35% yield. Colorless oil, [R]D +22.8 (c 0.3, CHCl3).
1H and 13C NMR show the presence of rotamers about the
1
carbamate bond in a 1:1 ratio. H NMR (300 MHz, CDCl3) δ
0.06, 0.08 (s, 3H), 0.19, 0.22 (s, 3H), 0.87, 0.99 (s, 9H), 2.30-
2.70 (m, 2H), 3.25-3.90 (m, 5H), 4.30-4.75 (m, 2H), 4.90-
5.25 (m, 2H), 6.78-7.50 (m, 14H); 13C NMR (75 MHz, CDCl3)
δ -5.0, -4.9, 17.9, 18.3, 25.6, 25.8, 43.7, 45.1, 55.4, 57.4, 58.1,
66.6, 67.4, 68.7, 69.5, 70.4, 75.8, 113.9, 114.1, 118.5, 118.6,
127.4, 127.5, 127.9, 128.2, 128.5, 131.1, 131.5, 134.0, 135.0,
136.4, 153.4, 156.1, 165.5; IR (neat) 1702, 1765 cm-1; MS
(ESI+) m/z (rel intensity) 573 [(M + H), 70]. Anal. Calcd for
C
33H40N2O5Si: C, 69.20; H, 7.04; N, 4.89. Found: C, 68.85; H,
(+)-(3R,4S)-5-Ben zyloxyca r bon yl-3-[(R)-3-ter t-bu toxy-
ca r bon yl-2,2-d im eth yl-1,3-oxa zolid in -4-yl]-2-(4-m eth ox-
yp h en yl)-2,5-d ia za sp ir o[3.4]oct a n -1-on e (12). Prepared
from imine 9 (2 mmol) according to the general procedure
described above to afford 12 as a single diastereomer. Rf 0.37
(50% EtOAc/hexane), 0.450 g of 12, 40% yield (3 steps). White
foam, [R]D +2.5 (c 0.5, CHCl3). 1H and 13C NMR show the
presence of rotamers. 1H NMR (300 MHz, CDCl3) δ 0.89, 1.03,
1.17, 1.43, 1.49, 1.67, 1.69, 1.79 (s, 15H), 1.90-2.45 (m, 4H),
3.44-3.71 (m, 4H), 3.75 (s, 3H), 4.07 (m, 1H), 4.56 (m, 1H),
7.01; N, 4.92.
(-)-(3R,4S,7R)-5-Ben zyloxycar bon yl-7-(ter t-bu tyldiph e-
n ylsilyloxy)-2-(4-m eth oxyph en yl)-3-ph en yl-2,5-diazaspir o-
[3.4]octa n -1-on e (4c). Rf 0.55 (33% EtOAc/hexane), 0.42 g of
1
4c, 30% yield. White foam, [R]D -34.0 (c 0.5, CHCl3). H and
13C NMR show the presence of rotamers about the carbamate
bond in a 1:1 ratio. 1H NMR (300 MHz, CDCl3) δ 1.08, 1.09 (s,
9H), 2.24-2.40 (m, 1H), 2.59-2.74 (m, 1H), 3.30-3.45 (m, 2H),
3.74, 3.76 (s, 3H), 4.40-4.78 (m, 3H), 5.00 (m, 1H), 6.50-7.90
(m, 24H); 13C NMR (75 MHz, CDCl3) δ 18.9, 26.6, 42.2, 43.4,
53.2, 53.8, 55.3, 66.6, 67.6, 68.4, 69.1, 69.5, 70.2, 75.8, 114.1,
114.3, 118.3, 118.4, 126.6, 127.1, 127.5, 127.6, 127.8, 128.0,
128.1, 128.2, 130.0, 135.5, 130.8, 131.1, 132.9, 133.0, 133.1,
135.3, 136.3, 153.2, 153.4, 156.0, 156.1, 163.9; IR (KBr) 1712,
1760 cm-1; MS (ESI+) m/z (rel intensity) 697 [(M + H), 35].
Anal. Calcd for C43H44N2O5Si: C, 74.11; H, 6.36; N, 4.02.
Found: C, 73.85; H, 6.34; N, 4.04.
4.95-5.34 (m, 2H), 6.75-6.89 (m, 2H), 7.27-7.60 (m, 7H); 13
C
NMR (75 MHz, CDCl3) δ 22.0, 22.9, 22.7, 24.0, 27.0, 27.3, 27.7,
34.7, 36.0, 34.8, 36.0, 48.1, 48.9, 55.3, 57.1, 65.0, 65.5, 67.2,
69.1, 74.0, 80.0, 94.1, 94.5, 113.6, 113.7, 114.0, 117.7, 119.5,
127.9, 128.0, 128.2, 132.5, 136.3, 152.3, 154.2, 155.8, 165.9;
IR (KBr) 1694, 1746, 1762 cm-1; MS (ESI+) m/z (rel intensity)
604 [(M + K), 100], 588 [(M + Na), 40]. Anal. Calcd for
C
31H39N3O7: C, 65.82; H, 6.95; N, 7.43. Found: C, 65.59; H,
6.93; N, 7.40.
(+)-(3S,4R,7R)-5-Ben zyloxycar bon yl-7-(ter t-bu tyldiph e-
n ylsilyloxy)-2-(4-m eth oxyph en yl)-3-ph en yl-2,5-diazaspir o-
[3.4]octa n -1-on e (5c). Rf 0.45 (33% EtOAc/hexane), 0.42 g of
P r ep a r a t ion of (-)-(3R,4R)-5-Ben zyloxyca r b on yl-3-
(1,2-dih ydr oxyeth yl)-2-(4-m eth oxyph en yl)-2,5-diazaspir o-
[3.4]octa n -1-on e (13). To a solution of the â-lactam 10 (1
mmol) in THF/H2O (1/1, 10 mL) was added solid p-TsOH‚H2O
(1.1 mmol), and the resulting solution was refluxed overnight.
The reaction mixture was allowed to cool to room temperature,
the THF was removed under vacuum, and the aqueous residue
was neutralized with saturated aqueous NaHCO3. The aque-
1
5c, 30% yield. White foam, [R]D +25.6 (c 0.12, CHCl3). H and
13C NMR show the presence of rotamers about the carbamate
bond in a 1:1 ratio. 1H NMR (300 MHz, CDCl3) δ 1.20, 1.21 (s,
9H), 2.32-2.58 (m, 2H), 3.43-3.78 (m, 2H), 3.79, 3.80 (s, 3H),
4.28-4.73 (m, 2H), 4.97 (m, 1H), 5.32 (m, 1H), 6.60-7.75 (m,
24H); 13C NMR (75 MHz, CDCl3) δ 19.1, 26.8, 27.1, 43.4, 44.8,
J . Org. Chem, Vol. 69, No. 21, 2004 7009

Mac´ıas et al.
ous layer was extracted twice with CH2Cl2 (15 mL) and the
organic layer dried over anhydrous Na2SO4. The solution was
then concentrated and purified by flash chromatography (66%
EtOAc/hexane) to afford 367 mg of 13, 86% yield. White foam,
[R]D -17.6 (c 0.8, CHCl3). 1H and 13C NMR show the presence
solution was then concentrated and purified by column chro-
matography over SiO2 with the appropriate mixture of ethyl
acetate/hexane. Compound 16a , prepared from 4b, was used
in the next step without further purification.
(-)-(3R,4R)-5-Ben zyloxyca r bon yl-3-[(S)-2,2-d im eth yl-
1,3-d ioxola n -4-yl]-2,5-d ia za sp ir o[3.4]oct a n -1-on e (16b ).
Prepared from 10, and purified through flash chromatography
(50% EtOAc/hexane), to afford 234 mg of 16b, in 65% yield.
Pale yellow oil, [R]D -2.4 (c 0.7, CHCl3). 1H and 13C NMR show
the presence of rotamers about the carbamate bond in ca. 3:1
ratio. 1H NMR (300 MHz, CDCl3) δ 1.12, 1.26, 1.35, 1.39 (s,
6H), 1.71-2.42 (m, 4H), 3.35-3.54 (m, 4H), 3.72-3.88 (m, 1H),
4.18, 4.53 (m, 1H), 4.97-5.37 (m, 2H), 6.33, 6.50 (br s, 1H),
7.34 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 22.3, 23.1, 24.8,
26.6, 34.8, 36.1, 48.0, 48.6, 66.0, 66.7, 67.3, 67.4, 67.9, 75.0,
75.4, 109.3, 128.0, 128.1, 128.2, 128.4, 135.5, 136.1, 153.9,
154.3, 168.4; IR (KBr) 1706, 1781, 3290 cm-1; MS (ESI+)
m/z (rel intensity) 743 [(2M + Na), 100], 399 [(M + K), 29],
383 [(M + Na), 64], 361 [(M + H), 42]. Anal. Calcd for
1
of rotamers. H NMR (300 MHz, CDCl3) δ 1.75-2.46 (m, 4H),
3.52-3.70 (m, 4H), 3.77 (s, 3H), 3.88 (br s, 1H), 4.00-4.10 (m,
2H), 5.17 (m, 2H), 6.76-6.89 (m, 2H), 7.27-7.48 (m, 7H); 13C
NMR (75 MHz, CDCl3) δ 23.0, 35.2, 48.4, 55.4, 65.1, 67.7, 68.0,
69.7, 74.8, 114.0, 120.4, 128.0, 128.2, 128.5, 131.1, 135.7, 155.7,
156.5, 165.8; IR (KBr) 1682, 1734, 3282, 3500 cm-1; MS (ESI+)
m/z (rel intensity) 875 [(2M + Na), 25], 449 [(M + Na), 10],
427 [(M + H), 100]. Anal. Calcd for C23H26N2O6: C, 64.78; H,
6.15; N, 6.57. Found: C, 64.94; H, 6.13; N, 6.55.
P r ep a r a tion of (+)-(3R,4R)-cis-5-Ben zyloxyca r bon yl-
3-for m yl-2-(4-m eth oxyp h en yl)-2,5-d ia za sp ir o[3.4]octa n -
1-on e (15a ). To a solution of the â-lactam 13 (0.8 mmol) in
MeOH/H2O (1/1, 10 mL) was added NaIO4 (1.6 mmol) and the
mixture was maintained below 20 °C and stirred vigorously
until total disappearance of the starting material (3 h,
monitored by TLC). The MeOH was removed under vacuo and
the resulting solution was diluted with water. The aqueous
layer was extracted twice with CH2Cl2 (15 mL) and the organic
layer dried over anhydrous Na2SO4. The solution was then
concentrated and purified by flash chromatography (33%
EtOAc/hexane) to afford 284 mg of 15a , 90% yield. White foam,
C
19H24N2O5: C, 63.32; H, 6.71; N, 7.77. Found: C, 63.09; H,
6.73; N, 7.80.
(+)-(3R,4S)-5-Ben zyloxyca r bon yl-3-[(R)-3-ter t-bu toxy-
car bon yl-2,2-dim eth yl-1,3-oxazolidin -4-yl]-2,5-diazaspir o-
[3.4]octa n -1-on e (16c). Prepared from 12, and purified
through flash chromatography (50% EtOAc/hexane), to afford
285 mg of 16c, in 62% yield. White solid, [R]D +0.8 (c 0.65,
1
[R]D +134 (c 0.7, CHCl3). H and 13C NMR show the presence
1
CHCl3), mp 182-184 °C. H and 13C NMR show the presence
of rotamers about the carbamate bond in ca. 4:1 ratio. 1H NMR
(300 MHz, CDCl3) δ 1.95-2.10 (m, 2H), 2.29 (m, 1H), 2.46 (m,
1H), 3.40-3.69 (m, 2H), 3.80, 3.81 (s, 3H), 4.17, 4.30 (d, J )
2.2, 1H), 5.02-5.16 (m, 2H), 6.80-6.92 (m, 2H), 7.10-7.38 (m,
7H), 9.34, 9.83 (d, J ) 2.2, 1H); 13C NMR (75 MHz, CDCl3) δ
22.1, 22.9, 34.4, 35.9, 47.6, 48.3, 55.2, 67.3, 68.2, 70.6, 70.9,
76.8, 77.2, 114.2, 114.4, 117.5, 117.6, 127.5, 127.9, 128.3, 130.4,
130.7, 135.5, 153.8, 156.3, 165.2, 196.7, 197.1; IR (KBr) 1693,
1722, 1765 cm-1; MS (ESI+) m/z (rel intensity) 426 [(M +
MeOH), 40]. Anal. Calcd for C22H22N2O5: C, 66.99; H, 5.62;
N, 7.10. Found: C, 67.11; H, 5.59; N, 7.12.
(-)-(3S,4S)-cis-5-Ben zyloxycar bon yl-3-for m yl-2-(4-m eth -
oxyp h en yl)-2,5-d ia za sp ir o[3.4]oct a n -1-on e (15b). To a
solution of the â-lactam 12 (0.5 mmol) in MeOH (10 mL) was
added solid p-TsOH‚H2O (0.55 mmol), and the resulting
solution was stirred overnight. The MeOH was removed under
vacuo, and the aqueous residue was neutralized with saturated
aqueous NaHCO3. The aqueous layer was extracted twice with
EtOAc (15 mL) and the organic layer dried over anhydrous
Na2SO4. The solvent was removed in vacuo to give â-lactam
14 as a colorless oil, which was used without further purifica-
tion. Pb(OAc)4 (0.45 mmol) was added to a benzene solution
(5 mL) of 14, and the mixture was stirred at room temperature
until total disappearance of the starting material (3 h,
monitored by TLC). The solvent was removed in vacuo and
an aqueous solution of saturated NaHCO3 (15 mL) was added.
The aqueous layer was extracted twice with CH2Cl2 (15 mL)
and the organic layer dried over anhydrous Na2SO4. The
solution was then concentrated and purified by flash chroma-
tography (33% EtOAc/hexane) to afford 83 mg of 15b, 42%
(overall yield). [R]D -134 (c 0.7, CHCl3).
Syn th esis of N-Un su bstitu ted â-La cta m s. The N-un-
substituted â-lactams (16a -c, 18) were prepared according
to the published procedure.13 A solution of the N-PMP-â-lactam
(1 mmol) in acetonitrile (10 mL) was cooled to 0 °C and treated
with a solution of CAN (3 mmol) in water (15 mL) over 5 min.
The reaction was stirred at 0 °C for 45 min and diluted with
50 mL of water. The mixture was extracted with EtOAc (2 ×
25 mL). The organic extracts were washed with 5% sodium
bicarbonate (25 mL) and the aqueous extracts back-washed
with EtOAc (25 mL). The combined organic solutions were
washed with 10% sodium sulfite (3 × 25 mL), 5% sodium
bicarbonate (25 mL), and brine. The resulting solution was
swirled over charcoal for 30 min, anhydrous Na2SO4 was
added, and the mixture was filtered through Celite. The
of rotamers. 1H NMR (300 MHz, CDCl3) δ 1.25-1.60 (m, 15H),
1.79-2.42 (m, 4H), 3.37-4.50 (m, 6H), 4.97-5.50 (m, 2H), 6.67,
6.86 (br s, 1H), 7.26-7.50 (m, 5H); 13C NMR (75 MHz, CDCl3)
δ 22.2, 23.0, 27.1, 28.3, 34.8, 36.2, 48.2, 48.9, 57.9, 58.1, 64.6,
64.7, 67.4, 67.5, 67.8, 68.0, 75.8, 76.1, 80.7, 93.6, 94.1, 128.0,
128.1, 128.4, 129.2, 135.6, 136.2, 153.1, 153.8, 154.1, 168.4,
168.6; IR (KBr) 1694, 1770, 3215 cm-1; MS (ESI+) m/z (rel
intensity) 482 [(M + Na), 100]. Anal. Calcd for C24H33N3O6:
C, 62.73; H, 7.24; N, 9.14. Found: C, 62.54; H, 7.27; N, 9.11.
(+)-(3R,4R)-5-Ben zyloxyca r bon yl-3-(ter t-bu tyld im eth -
ylsilyloxym eth yl)-2,5-d ia za sp ir o[3.4]octa n -1-on e (18). To
a solution of 15a (1 mmol) in MeOH (5 mL) cooled to 0 °C was
added sodium borohydride (2.5 mmol). The mixture was stirred
for 2 h and then quenched with saturated aqueous NaHCO3.
The MeOH was removed in vacuo, and the aqueous layer
extracted twice with CH2Cl2 (15 mL). The combined organic
layers were washed with brine (15 mL), dried over anhydrous
Na2SO4, and concentrated to afford the corresponding alcohol,
which was employed without further purification. This alcohol
(0.9 mmol) was silylated by using tert-butyldimethylsilyl
chloride (1.08 mmol) and imidazole (1.17 mmol) in DMF
according to the general procedure11a to afford the protected
O-silylated â-lactam, which was employed without further
purification. The deprotection of the PMP group according to
the general procedure13afford after flash chromatography (50%
EtOAc/hexane) 182 mg of 18, in 45% yield (3 steps). White
foam, [R]D +22.2 (c 0.1, CHCl3). 1H and 13C NMR show the
presence of rotamers about the carbamate bond in ca. 3:1 ratio.
1H NMR (300 MHz, CDCl3) δ -0.12, -0.04, -0.01 (s, 6H), 0.79,
0.84 (s, 9H), 1.75-2.33 (m, 4H), 3.38-3.87 (m, 5H), 4.99-5.28
(m, 2H), 6.30, 6.47 (br s, 1H), 7.25-7.41 (m, 5H); 13C NMR
(75 MHz, CDCl3) δ -5.8, 18.0, 22.0, 22.7, 25.6, 34.4, 35.8, 47.8,
48.5, 61.7, 61.8, 64.2, 64.4, 67.1, 67.5, 75.5, 76.0, 127.9, 128.3,
135.7, 136.2, 154.1, 154.5, 169.2, 169.3; IR (KBr) 1704, 1777,
3314 cm-1; MS (ESI+) m/z (rel intensity) 831 [(2M + Na), 30],
809 [(2M + H), 45], 405 [(M + H), 100]. Anal. Calcd for
C
21H32N2O4Si: C, 62.34; H, 7.97; N, 6.92. Found: C, 62.17; H,
7.96; N, 6.89.
Syn th esis of N-Boc-â-la cta m s (17 a n d 19). To a stirred
solution of the N-unsubstituted â-lactam (16, 18) (0.6 mmol)
in acetonitrile (10 mL), cooled to 0 °C, were added di-tert-butyl
dicarbonate (1.2 mmol) and a catalytic amount of DMAP, and
the mixture was stirred at room temperature overnight. Then,
methylene chloride (25 mL) was added, and the mixture was
washed with 1 M KHSO4 (15 mL) and brine. The organic layer
7010 J . Org. Chem., Vol. 69, No. 21, 2004

Synthesis of Modified Prolines
was dried over Na2SO4, and the solvent removed in vacuo.
Products were purified by column chromatography over SiO2
with the appropriate mixture of ethyl acetate/hexane. Com-
pound 19, prepared from 18, was used in the next step without
further purification.
Meth yl (-)-(2S,3R)-2-[(R)-1-Ben zyloxyca r bon yl-4-(ter t-
bu tyld im eth ylsilyloxy)p yr r olid in -2-yl]-3-(N-ter t-bu toxy-
ca r bon yla m in o)p r op a n oa te (1a ). Prepared from 17a , and
purified through flash chromatography (20% EtOAc/hexane),
to afford 270 mg of 1a , in 93% yield. Colorless oil, [R]D -26.1
(c 0.6, CHCl3). 1H NMR (300 MHz, CDCl3) δ -0.10 (s, 3H),
-0.09 (s, 3H), 0.80 (s, 9H), 1.37 (s, 9H), 2.17-2.38 (m, 2H),
3.12 (dd, J ) 11.1, 5.4 Hz, 1H), 3.35-3.50 (m, 2H), 3.77 (s, 3H),
5.16-5.40 (m, 3H), 7.12-7.45 (m, 10H), 8.02 (d, J ) 9.1 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ -5.1, 17.7, 25.5, 28.3, 45.7,
52.4, 57.1, 59.6, 67.1, 67.2, 72.9, 78.8, 127.4, 127.6, 127.9, 128.1,
128.4, 128.8, 136.5, 138.0, 155.2, 156.5, 170.9; IR (neat) 1711,
1757, 3356 cm-1; MS (ESI+) m/z (rel intensity) 637 [(M + K),
100], 621 [(M + Na), 85]; HRMS calcd for (C32H46N2O7Si-tBuO)
525.2415, found 525.2414. Anal. Calcd for C32H46N2O7Si: C,
64.19; H, 7.74; N, 4.68. Found: C, 64.38; H, 7.71; N, 4.70.
Meth yl (+)-(2R,3R)-2-[1-Ben zyloxyca r bon ylp yr r olid in -
2-yl]-3-(N-ter t-bu toxyca r bon yla m in o)-3-[(S)-2,2-d im eth -
yl-1,3-d ioxola n -4-yl]p r op a n oa te (1b). Prepared from 17b,
and purified through flash chromatography (25% EtOAc/
hexane), to afford 172 mg of 1b, in 70% yield. White foam,
[R]D +36.9 (c 0.3, CHCl3). 1H and 13C NMR show the presence
of rotamers in ca. 2:1 ratio. 1H NMR (300 MHz, CDCl3) δ 1.20-
1.45 (m, 15H), 1.62-2.43 (m, 4H), 3.28-3.89 (m, 6H), 4.03-
4.18 (m, 1H), 4.30-4.61 (m, 2H), 4.85-5.45 (m, 2H), 6.19 (d,
J ) 9.4, 1H), 7.32 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 23.2,
25.7, 26.0, 28.3, 34.3, 35.4, 48.7, 48.9, 51.9, 52.3, 53.4, 66.9,
67.1, 67.5, 67.8, 71.0, 74.0, 74.7, 79.0, 79.5, 109.2, 109.5, 127.7,
127.8, 128.2, 128.3, 128.5, 136.5, 136.7, 153.6, 155.1, 155.7,
155.9, 172.9, 173.5; IR (neat) 1707, 1739, 3368 cm-1; MS (ESI+)
m/z (rel intensity) 493 [(M + H), 38], 393 [(M - Boc + 2H),
58]; HRMS calcd for C25H36N2O3 492.2472, found 492.2496.
Anal. Calcd for C25H36N2O8: C, 60.96; H, 7.37; N, 5.69.
Found: C, 60.79; H, 7.39; N, 5.71.
(-)-(3R,4S,7R)-5-Ben zyloxyca r bon yl-2-(ter t-bu toxyca r -
bon yl)-7-(ter t-bu tyld im eth ylsilyloxy)-3-p h en yl-2,5-d ia za -
sp ir o[3.4]octa n -1-on e (17a ). Prepared from 16a (1 mmol)
according to the general procedure described above to afford,
after flash chromatography (33% EtOAc/hexane), 329 mg of
17a , in 58% yield (2 steps). Pale yellow solid, [R]D -84.9 (c
0.4, CHCl3), mp 110-112 °C. 1H and 13C NMR show the
presence of rotamers about the carbamate bond in ca. 1:1 ratio.
1H NMR (300 MHz, CDCl3) δ 0.08, 0.11, 0.12, 0.13 (s, 6H),
0.89, 0.90 (s, 9H), 1.41, 1.50 (s, 9H), 2.42-2.58 (m, 2H), 3.17,
3.30 (dd, J ) 10.2, 7.7 Hz; dd, J ) 10.5, 7.7 Hz, 1H), 3.46,
3.60 (dd, J ) 10.2, 7.4 Hz; dd, J ) 10.5, 7.4 Hz, 1H), 4.45,
4.71 (d, J ) 12.0 Hz; d, J ) 12.5 Hz, 1H), 4.50-4.66 (m, 1H),
4.85-5.01 (m, 2H), 6.69 (m, 1H), 6.98 (m, 1H), 7.12-7.45 (m,
8H); 13C NMR (75 MHz, CDCl3) δ -5.0, -4.9, 17.9, 25.6, 27.8,
27.9, 43.1, 44.4, 53.7, 54.4, 66.9, 67.9, 67.7, 68.4, 69.0, 69.3,
75.6, 76.1, 83.5, 83.6, 126.0, 126.5, 127.6, 127.8, 128.0, 128.3,
128.4, 133.0, 133.3, 135.0, 136.1, 147.9, 148.3, 152.8, 153.4,
164.8, 165.5; IR (KBr) 1713, 1814 cm-1; MS (ESI+) m/z (rel
intensity) 1155 [(2M + Na), 100], 589 [(M + Na), 25]. Anal.
Calcd for C31H42N2O6Si: C, 65.69; H, 7.47; N, 4.94. Found: C,
65.82; H, 7.50; N, 4.93.
(-)-(3R,4R)-5-Ben zyloxyca r bon yl-2-(ter t-bu toxyca r bo-
n yl)-3-[(S)-2,2-d im eth yl-1,3-d ioxola n -4-yl]-2,5-d ia za sp ir o-
[3.4]octa n -1-on e (17b). Prepared from 16b (0.6 mmol) ac-
cording to the general procedure described above to afford,
after flash chromatography (50% EtOAc/hexane), 260 mg of
17b, in 94% yield. White solid, [R]D -0.4 (c 3, CHCl3), mp
)113-117 °C. 1H and 13C NMR show the presence of rotamers
about the carbamate bond in ca. 2.5:1 ratio. 1H NMR (300
MHz, CDCl3) δ 1.05-1.50 (m, 15H), 1.60-2.41 (m, 4H), 3.30-
3.94 (m, 5H), 4.07, 4.53 (m, 1H), 4.89-5.32 (m, 2H), 7.32 (m,
5H); 13C NMR (75 MHz, CDCl3) δ 22.3, 23.1, 24.9, 25.0, 26.3,
26.4, 27.7, 27.8, 35.3, 36.6, 47.8, 48.5, 65.9, 67.6, 68.1, 70.1,
70.6, 73.9, 74.1, 74.8, 74.9, 83.0, 109.0, 128.0, 128.2, 128.3,
128.4, 128.5, 134.8, 135.8, 147.4, 147.6, 153.3, 154.0, 166.2,
166.6; IR (KBr) 1704, 1738, 1796 cm-1; MS (ESI+) m/z (rel
intensity) 483 [(M + Na), 100]. Anal. Calcd for C24H32N2O7:
C, 62.59; H, 7.00; N, 6.08. Found: C, 62.38; H, 7.01; N, 6.06.
Meth yl (-)-(2S,3R)-2-[1-Ben zyloxyca r bon ylp yr r olid in -
2-yl]-3-(N-ter t-bu toxyca r bon yla m in o)-3-[(R)-3-ter t-bu tox-
yca r b on yl-2,2-d im et h yl-1,3-oxa zolid in -4-yl]p r op a n oa t e
(1c). Prepared from 17c, and purified through flash chroma-
tography (33% EtOAc/hexane), to afford 250 mg of 1c, in 85%
yield. White foam, [R]D -42.8 (c 0.5, CHCl3). 1H and 13C NMR
1
show the presence of rotamers in ca. 1:1 ratio. H NMR (300
MHz, CDCl3) δ 1.30-1.55 (m, 24H), 1.70-2.46 (m, 4H), 3.42-
3.96 (m, 8H), 4.64, 4.75 (dd, J ) 10.1, 4.4 Hz; dd, J ) 9.7, 4.8
Hz, 1H), 5.09 (m, 2H), 6.05, 6.26 (d, J ) 10.5 Hz; d, J ) 10.2
Hz, 1H), 7.34 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 22.9, 23.3,
24.2, 26.1, 26.8, 28.2, 28.4, 28.6, 36.0, 36.6, 48.5, 48.6, 51.8,
52.1, 56.7, 57.2, 57.4, 67.1, 67.2, 67.6, 67.7, 70.7, 70.9, 78.6,
79.3, 80.0, 80.5, 93.0, 93.6, 127.7, 128.0, 128.3, 128.4, 129.2,
136.3, 136.5, 152.4, 153.7, 154.9, 155.3, 156.2, 156.5, 171.5,
171.9; IR (KBr) 1697, 1701, 1747, 3447 cm-1; MS (ESI+) m/z
(rel intensity) 630 [(M + K), 100], 614 [(M + Na), 80]; HRMS
calcd for C30H45N3O9 591.3156, found 591.3178. Anal. Calcd
for C30H45N3O9: C, 60.90; H, 7.67; N, 7.10. Found: C, 60.99;
H, 7.70; N, 7.13.
Meth yl (+)-(2R,3R)-2-[1-Ben zyloxyca r bon ylp yr r olid in -
2-yl]-3-(N-ter t-bu toxyca r bon yla m in o)-4-(ter t-bu tyld im e-
th ylsilyloxy)bu ta n oa te (1d ). Prepared from 19 (0.5 mmol),
and purified through flash chromatography (33% EtOAc/
hexane), to afford 166 mg of 1d , in 62% yield (2 steps).
Colorless oil, [R]D +3.1 (c 0.16, CHCl3). 1H NMR (300 MHz,
CDCl3) δ 0.00 (s, 3H), 0.03 (s, 3H), 0.86 (s, 9H), 1.42 (s, 9H),
1.65-1.96 (m, 2H), 2.32 (m, 1H), 2.58 (m, 1H), 3.38-3.84 (m,
7H), 4.34 (m, 1H), 5.10-5.24 (m, 2H), 6.47 (d, J ) 10.0, 1H),
7.35 (m, 5H); 13C NMR (75 MHz, CDCl3) δ -5.7, 18.0, 22.1,
25.7, 28.3, 36.8, 49.0, 52.3, 54.6, 63.2, 67.1, 72.7, 78.7, 127.5,
127.9, 128.3, 128.4, 136.5, 155.5, 155.9, 172.1; MS (ESI+) m/z
(rel intensity) 575 [(M + K), 42], 559 [(M + Na), 18]. Anal.
Calcd. for C27H44N2O7Si: C, 60.42; H, 8.26; N, 5.22. Found:
C, 60.23; H, 8.24; N, 5.25.
(-)-(3R,4S)-5-Ben zyloxyca r bon yl-2-(ter t-bu toxyca r bo-
n yl)-3-[(R)-3-ter t-bu toxyca r bon yl-2,2-d im eth yl-1,3-oxa zo-
lid in -4-yl]-2,5-d ia za sp ir o[3.4]octa n -1-on e (17c). Prepared
from 16c (0.6 mmol) according to the general procedure
described above to afford, after flash chromatography (33%
EtOAc/hexane), 238 mg of 17c, in 71% yield. Colorless oil, [R]D
-4.6 (c 0.9, CHCl3). 1H and 13C NMR show the presence of
1
rotamers. H NMR (300 MHz, CDCl3) δ 1.35-1.65 (m, 24H),
1.70-2.42 (m, 4H), 3.36-3.82 (m, 4H), 3.88-4.09 (m, 1H),
4.42-4.63 (m, 1H), 4.95-5.30 (m, 2H), 7.34 (m, 5H); 13C NMR
(75 MHz, CDCl3) δ 22.2, 22.9, 23.2, 24.5, 26.9, 27.5, 28.1, 28.3,
28.4, 35.7, 37.2, 48.3, 49.0, 56.5, 56.8, 64.8, 65.1, 67.5, 67.7,
68.4, 74.4, 74.6, 79.7, 79.9, 80.6, 82.7, 83.6, 93.8, 94.4, 128.1,
128.3, 129.4, 136.0, 136.3, 148.3, 148.7, 152.2, 152.3, 152.7,
153.9 154.3, 165.6, 166.4; IR (KBr) 1698, 1732, 1821 cm-1; MS
(ESI+) m/z (rel intensity) 598 [(M + K), 10], 582 [(M + Na),
100]. Anal. Calcd for C29H41N3O8: C, 62.24; H, 7.38; N, 7.51.
Found: C, 62.36; H, 7.35; N, 7.54.
Syn t h esis of r-(1-Am in oa lk yl)p r olin e Met h yl E st er s
(1). To a stirred solution of the N-Boc-â-lactam (17 and 18)
(0.5 mmol) in MeOH (10 mL) was added potassium cyanide
(0.5 mmol) and the mixture was stirred overnight. The MeOH
was removed in vacuo and saturated aqueous NaHCO3 (10 mL)
and EtOAc (10 mL) were added. The aqueous layer was
extracted with EtOAc (2 × 15 mL) and the combined organic
layers washed with brine, dried over anhydrous Na2SO4, and
concentrated in vacuo. Flash chromatography afforded the
desired N-Boc-protected proline derivatives.
Ack n ow led gm en t. A.M. acknowledges a fellowship
from FICYT (Regional Government of Principado de
Asturias). The authors are very grateful to Prof. F.
J . Org. Chem, Vol. 69, No. 21, 2004 7011

Mac´ıas et al.
of proline derivatives 1 by the Mosher method; NOESY spectra
of 6, 7, 10a , and rac-15-cis; 1H and 13C NMR spectra of all
new compounds; energies and Cartesian coordinates of the
Becke3LYP/6-31G* optimized stationary points. This material
is available free of charge via the Internet at http://pubs.acs.org.
Lo´pez Ortiz (Universidad de Almer´ıa) for his advice in
the NMR studies.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal methods, synthesis, and data for compounds 6, 7, 10a , 12a ,
rac-15-cis,15a , and 15b, and determination of the optical
purity of 15a and 15b; assignation of absolute configuration
J O040163W
7012 J . Org. Chem., Vol. 69, No. 21, 2004