β-Lactams derived from phenylalanine and homologues: effects of the distance between the aromatic rings and the α-stereogenic reactive center on the memory of chirality

Article abstract of DOI:10.1016/j.tetlet.2006.06.057

The enantioselectivity in the base-promoted cyclization of N-chloroacetyl derivatives of Phe, Phg, and Hph is dependent on the side-chain length, with the best results for Phg analogues (up to 74% ee). In contrast, shortening of the N-substituent, from a

Full text of DOI:10.1016/j.tetlet.2006.06.057

Tetrahedron Letters 47 (2006) 5883–5887
b-Lactams derived from phenylalanine and homologues: effects
of the distance between the aromatic rings and the
a-stereogenic reactive center on the memory of chirality
a
b
a
´
´
M. Angeles Bonache, Carlos Cativiela, M. Teresa Garcıa-Lopez
a,
*
´
and Rosario Gonzalez-Muniz
˜
aInstituto de Quı´mica Me´dica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain
bDepartamento de Quı´mica Orga´nica, ICMA, Universidad de Zaragoza-CSIC, 50009 Zaragoza, Spain
Received 16 May 2006; revised 8 June 2006; accepted 12 June 2006
Available online 30 June 2006
Abstract—The enantioselectivity in the base-promoted cyclization of N-chloroacetyl derivatives of Phe, Phg, and Hph is dependent
on the side-chain length, with the best results for Phg analogues (up to 74% ee). In contrast, shortening of the N-substituent, from a
(p-methoxy)benzyl group to a (p-methoxy)phenyl moiety, led to a decrease in selectivity.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Processes occurring with memory of chirality are char-
acterized by an initial unique stereogenic element (chiral
center or chiral axis) that is destroyed during the gener-
ation of the corresponding reactive intermediates, but
these intermediates are able to retain the information
about the configuration of their precursors to transfer
the chirality to final compounds.1 Most of memory of
chirality transformations can be found among the chem-
istry of a-amino acids,2–21 with the a-alkylation reac-
tion, initially published by Fuji’s group, as the most
extensively studied process.12–21 A few years ago, we de-
scribed the first intramolecular version of this procedure
during the transformation of several N-benzyl-N-chloro-
acetyl amino acids to the corresponding 2-azetidi-
nones.22,23 From our previous results, we have
demonstrated that the stereoselectivity, due to memory
of chirality, is highly dependent on the substituents of
the starting N-chloroacetyl derivative, with the amino
acid side-chain as the principal stereodirecting ele-
ment.24 We have also determined the critical importance
of the base and solvent for final enantiomer distribu-
tion,25 and provided the first evidence for TADDOL
as a memory of chirality enhancer in the case of aro-
matic amino acids.26 Fuji’s group has proposed a chiral
non racemic enolate with restricted rotation around the
C–N axis as the crucial intermediate.1b Similar reactive
species were assumed to rationalize the observed selec-
tivity in the amino acid-derived b-lactam synthesis.
Thus, the presence of aromatic (Phe, Tyr), heteroaro-
matic (Trp), ramified-aliphatic (Leu, Val), and b-carb-
oxylate-derived (Asp) side-chains favored memory of
chirality in this reaction.24
Now, to gain further insight into the features governing
the selectivity due to memory of chirality during b-lac-
tam ring formation, in this paper we investigate the
influence of the distance between the side-chain phenyl
ring and the a-chiral reactive center, by comparison of
the result obtained for Phe (I, n = 1) with those got
for its lower and higher homologues, Phg (I, n = 0)
and Hph (I, n = 2), respectively. We also explore the
consequences derived from shortening the distance be-
tween the p-methoxyphenyl ring and the nitrogen atom
(I, m = 0,1). These two modifications should have
important effects in the rotational freedom around the
C–N bond in the respective enolate intermediates. In
addition, the modification of selectivity by TADDOL
in the cyclization of Phe homologues was also investi-
gated, since the essential p–p interactions are supposed
to be greatly influenced by the distance of the aromatic
side-chain phenyl ring to the reactive center.
*
Corresponding author. Tel.: +34915622900; fax: +34915644853;
e-mail: iqmg313@iqm.csic.es
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.057

5884
M. A. Bonache et al. / Tetrahedron Letters 47 (2006) 5883–5887
base in acetonitrile.31–33 It is worth mentioning that a
similar cyclization of the N-(p-methoxy)phenyl analogue
14 resulted in a complex mixture of reaction, from which
the expected b–lactam 18 was isolated in low yield
(30%).34
( )n CO2Me
N
( )n
N
CO2Me
( )m
Cl
( )m
O
O
The stereoselectivity in the formation of b-lactams 15
and 18 was measured by chiral HPLC, while the efforts
to determine the ees by this method in 16 and 17 were
ineffective. This problem was circumvented by measur-
ing the diastereoisomeric ratio, after derivatization to
dipeptide derivatives 19 and 20.23,25 The configuration
at C-4 position in these dipeptide derivatives was tenta-
I
II
OMe
OMe
As indicated in Scheme 1, the reductive amination of
commercially available a-amino esters with anisalde-
hyde afforded the corresponding N-(p-methoxy)benzyl-
substituted analogues 1–6 (m = 1).27 The synthesis of
the optically active N-(p-methoxy)phenyl derivative 7
(m = 0) was achieved, although in low yield, by reaction
of H–Phe–OMe with (p-methoxy)phenylboronic acid,
catalyzed by Cu(OAc)2.28–30 The required chloroacetyl
derivatives 8–14 were conveniently prepared by treat-
ment of compounds 1–7 with chloroacetyl chloride, in
the presence of propylene oxide as HCl scavenger. Cycli-
zation of the chloroacetyl derivatives 8–13 to b-lactams
15–17 was easily achieved by treatment with BTPP as
1
tively assigned on the basis of H NMR chemical shifts
of the b-Ala protons, which appeared at higher field in
the heterochiral isomers than in the homochiral ones,
as previously established for Phe-derived b-lactams.23,35
Thus, the major isomer of 19, coming from the D-Phg-
derived azetidinone 16, showed a signal for the b-Ala
methyl protons at 1.07 ppm, while the same signal for
the minor diastereoisomer appears at 0.99 ppm. Consid-
ering the change in the order of prelation of groups for
Phg b-lactam derivatives, the major and minor isomers
were assigned as the S,S (19b) and the R,S (19a) diaste-
( )n CO2Me
( )n CO2Me
( )n CO2Me
HN
iii
i or ii
N
NH2
Cl
( )m
( )m
O
H-L-Phe-OMe
H-D-Phe-OMe
H-L-Phg-OMe
1-7
8-14
H-D-Phg-OMe
H-L-Hph-OMe
H-D-Hph-OMe
OMe
OMe
iv
O
CH3
CO2Me
O
CH3
CO2Me
( )n
N
( )n
N
( )n
N
( )n
N
N
CO2Me
CO2Me
( )m
N
H
H
v
+
+
O
O
O
O
( )m
( )m
( )m
19a,20a
19b,20b
15a-18a
15b-18b
OMe
OMe
OMe
OMe
Compounds
Starting
n
m
amino acid
1,8,15
2,9,15
H-L-Phe
H-D-Phe
H-L-Phg
H-D-Phg
H-L-Hph
H-D-Hph
H-L-Phe
1
1
0
0
2
2
1
1
1
1
1
1
1
0
3,10,16,19
4,11,16,19
5,12,17,20
6,13,17,20
7,14,18
Scheme 1. Reagents and conditions: (i) for m = 1, MeOC6H4CHO/NABH4/MeOH; (ii) for m = 0, MeOC6H4B(OH)2/Cu(OAc)2/TEA/CH2Cl2; (iii)
ClCH2COCl/propylene oxide/CH2Cl2; (iv) BTPP/MeCN (with or without (À)-TADDOL as additive); (v) (a) 2N NaOH/MeOH; (b) H-L-Ala-
OMe · HCl/BOP/TEA/THF.

M. A. Bonache et al. / Tetrahedron Letters 47 (2006) 5883–5887
5885
CH3
O
S
( )n
i
N
CO2Me
S
H
NH
Z
( )n CO2H
21a: n = 0; β-Ala 1.32 ppm; tR = 17.54 min
22a: n = 2; β-Ala 1.31 ppm; tR = 20.96 min
NH
Z
CH3
O
S
Z-L-Phg-OH
Z-L-Hph-OH
( )n
ii
N
CO2Me
R
H
NH
Z
21b: n = 0; β-Ala 1.21 ppm; tR = 18.25 min
22b: n = 2; β-Ala 1.26 ppm; tR = 21.63 min
Scheme 2. Reagents and conditions: (i) H-L-Ala-OMe · HCl/BOP/DIEA/THF; (ii) H-D-Ala-OMe · HCl/BOP/DIEA/THF.
reoisomers, respectively. In contrast, in the L-Hph-de-
rived mixture 20, the major component was assigned
ring and the a-C in L-Phg derivative 10 is expected to en-
hance the rigidity of the corresponding enolate interme-
diate with respect to the L-Phe analogue, thus increasing
the selectivity (compare entries 1–5). In fact, a consider-
able raise in the ee value was observed when passing
from L-Phe (34%) to L-Phg (70%). In both cases, isomer
a was the major enantiomer formed, indicating similar
geometries of the respective intermediates. Considering
the high tendency of Phg derivatives to racemize,38
and the strong basic reaction conditions employed, it
may be possible that main isomeric b-lactam 16a were
formed after a thermodynamically favored equilibration
process of the starting chloroacetyl derivative 10. If that
is the case, the cyclization of enantiomeric D-Phg deriv-
ative 11 must provide exactly the same result as its L-Phg
counterpart. However, if memory of chirality applies,
isomer 16b should be the main product of the reaction.
As recorded in entry 6 of Table 1, treatment of D-Phg
derivative 11 with BTPP afforded b-lactam 16b in 74%
ee, corroborating that the cyclization of Phg-derived
compounds is driven by the configuration of the starting
amino acid derivative and therefore, memory of chirality
operates.
as the heterochiral R,S diastereoisomer 20b (dCH
=
3
0.98 ppm), and the minor as the S,S-configured isomer
20a (dCH = 1.08 ppm).
3
The dipeptide rule we have used for the configurational
assignment of 19 and 20 is well established for Phe-de-
rived dipeptides but, to the best of our knowledge, no
indication about its generality to Phe homologues is
described. Therefore, to be confident with the above
assignements, a series of Z-L-Xaa-L-Ala-OMe and Z-L-
Xaa-D-Ala-OMe dipeptide derivatives (Xaa = Phg,
Hph) were prepared and analyzed by 1H NMR and
HPLC (Scheme 2). From the chemical shifts of the b-
methyl protons and the retention times in HPLC for
each diastereomeric pair, it can be concluded that Phg-
and Hph-derived dipeptides follow the same general rule
than Phe analogues.36,37 As it can be seen in Scheme 2,
the b-methyl protons are more shielded in the hetero-
chiral diastereoisomers 21b and 22b than in their homo-
chiral counterparts 21a and 22a. Also as expected,36
the longest HPLC retention times were found for the
heterochiral dipeptides of each pair.
As expected, an increase in the aromatic side-chain
length, as in Hph derivatives, which should favor the
flexibility of the C–N bond, is associated to a decrease
in the observed selectivity (compare entries 1 and 3–8
The selectivity in the cyclization of Phe derivatives and
its homologues to the corresponding b-lactams are
shown in Table 1. The short distance between the phenyl
Table 1. Results of selectivity in the BTPP-induced cyclization of Phe-, Phg-, and Hph-N-chloroacetyl derivatives
Entry Starting amino acid N-Chloroacetyl derivative
n
m
Additive (10%) Final b-lactam Yield (%)a a:b
ee (Config.)
67:33b 34 (S)
1
H-L-Phe-OMe
8
1
1
—
15
68
87
70
75
61
67
74
55
51
69
30
39
2
(À)-TADDOL
85:15b 70 (S)
31:69b 36 (R)
86:14b 72 (R)d
85:15c 70 (R)d
13:87c 74 (S)d
19:81c 62 (S)d
40:60c 20 (R)
59:41c 18 (S)
43:57c 14 (R)
64:36b 28 (S)
56:44b 12 (S)
3
H-D-Phe-OMe
9
1
1
—
15
4
(À)-TADDOL
5
6
H-L-Phg-OMe
H-D-Phg-OMe
10
11
0
0
1
1
—
16
16
—
7
(À)-TADDOL
8
9
H-L-Hph-OMe
H-D-Hph-OMe
12
13
2
2
1
1
—
17
17
—
10
11
12
(À)-TADDOL
H-L-Phe-OMe
14
1
0
—
18
(À)-TADDOL
a Yield of isolated compound.
b Measured by chiral HPLC according to our previous work (Ref. 24).
c Diastereomeric excesses measured after derivatization to the corresponding dipeptide derivatives 19 or 20.
d In the Phg-derived b-lactams there is a change in the prelation of groups with respect to Phe and Hph analogues.

5886
M. A. Bonache et al. / Tetrahedron Letters 47 (2006) 5883–5887
and 9). It is worth noting that, up to date, the Hph is the
only amino acid in which isomer b (R) is mainly formed
from the L-chloroacetyl derivative (entry 8), while iso-
mer a (S) was the major component of the enantiomeric
mixture in the D-Hph-derived b-lactam (entry 9).
late memory of chirality was also greatly influenced by
the above indicated distances.
Acknowledgements
Concerning the N-substituent, deletion of the methylene
group of the p-methoxybenzyl moiety in the correspond-
ing N-aryl derivative led to a slight decrease in the selec-
tivity of the cyclization (Dee = À6%, compare entries 1
and 11).
This work was supported by CICYT (SAF 2003-07207-
C02). M.A.B. thanks a post-grade fellowship from the
CSIC (I3P).
References and notes
Attempts to improve memory of chirality in the cycliza-
tion of Phe homologues and of the N-(p-methoxy)-
phenyl-Phe derivative 14 by addition of TADDOL were
unsuccessful, but interesting conclusions can be drawn
from the results. To explain the enhanced selectivity in
Phe derivatives (entries 2 and 4) we have proposed sta-
bilizing interactions between the starting material and
the chiral additive.26 Main contacts were characterized
by a hydrogen bond between one OH of TADDOL
and the CO of the chloroacetyl group and by a p–p
stacking interaction between the aromatic phenyl ring
of the side-chain and a phenyl group of TADDOL.
Shortening the side-chain length by one methylene
group not only hinders the appropriate p–p contacts
with TADDOL, but leads to inappropriate interactions
that results in diminished selectivity, with a 12%
decrease in the ee value. For D-Hph derivative (n = 2),
the presence of TADDOL changed the selectivity to
the main formation of enantiomer b (entry 10), restoring
the same behavior than that observed for the corre-
sponding D-Phe derivative (entry 4). This seems to sug-
gest that for a given configuration, Phe and Hph
derivatives interact with TADDOL in the same topo-
graphical manner.
1. For reviews on memory of chirality, see: (a) Fuji, K.;
Kawabata, T. Chem. Eur. J. 1998, 4, 373–376; (b)
Kawabata, T.; Fuji, K. Top. Stereochem. 2003, 23, 175–
205; (c) Zhao, H.; Hsu, D. C.; Carlier, P. R. Synthesis
2005, 1–16.
2. Sauer, S.; Schumacher, A.; Barbosa, F.; Giese, B. Tetra-
hedron Lett. 1998, 39, 3685–3688.
3. Brewster, A. G.; Frampton, C. S.; Jayatissa, J.; Mitchell,
M. B.; Stoodley, R. J.; Vohra, S. Chem. Commun. 1998,
299–300.
4. Betts, M. J.; Pritchard, R. G.; Schofield, A.; Stoodley, R. J.;
Vohra, S. J. Chem. Soc., Perkin Trans. 1 1999, 1067–1072.
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burger, M.; Zehnder, M.; Wessig, P. Angew. Chem., Int.
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6. Matsumura, Y.; Shirakawa, Y.; Satoh, Y.; Umino, M.;
Tanaka, T.; Maki, T.; Onomura, O. Org. Lett. 2000, 2,
1689–1691.
7. Griesbeck, A. G.; Kramer, W.; Lex, J. Angew. Chem., Int.
Ed. 2001, 40, 577–579.
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1159–1166.
9. Griesbeck, A. G.; Kramer, W.; Bartoschek, A.; Schmic-
kler, H. Org. Lett. 2001, 3, 537–539.
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A.; Stoodley, R. J. Tetrahedron Lett. 2002, 43, 3919–3922.
11. Wanyoike, G. N.; Onomura, O.; Maki, T.; Matsumura, Y.
Org. Lett. 2002, 4, 1875–1877.
12. Kawabata, T.; Wirth, T.; Yahiro, K.; Suzuki, H.; Fuji, K.
J. Am. Chem. Soc. 1994, 116, 10809–10810.
13. Kawabata, T.; Suzuki, H.; Nagae, Y.; Fuji, K. Angew.
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T.; Chancharunee, S.; Fuji, K. Org. Lett. 2000, 2, 3883–
3885.
In the presence of TADDOL, cyclization of the N-aryl
derivative 14 resulted in a marked decrease in selectivity
with respect to the same reaction without additive
(Dee = À16%, compare entries 11 to 12). The same
experiment with its benzyl analogue 8 led to a big
increase of the ee value (Dee = 36%). These results seems
to indicate that the N-Pmb group could also be directly
implicated in the interaction with TADDOL, while the
shorter N-Pmp moiety, far to be able to reproduce the
favorable interaction with TADDOL, contributes to
its destabilization. Therefore, our initial model of recog-
nition by TADDOL should be fine-tuned by considering
this possible new element of interaction.
15. Kawabata, T.; Kawakami, S.; Fuji, K. Tetrahedron Lett.
2002, 43, 1465–1467.
16. Kawabata, T.; Kawakami, S.; Shimada, S.; Fuji, K.
Tetrahedron 2003, 59, 965–974.
17. Kawabata, T.; Ozturk, O.; Suzuki, H.; Fuji, K. Synthesis
¨
2003, 505–508.
18. Kawabata, T.; Kawakami, S.; Majumdar, S. J. Am. Chem.
Soc. 2003, 125, 13012–13013.
In conclusion, we have established that the selectivity of
the intramolecular alkylation of Phe homologues to the
corresponding b-lactams is highly dependent of the aro-
matic side-chain ring/a-CH distance. The best results
were found for the shorter Phg homologues (n = 0),
which reached up to 74% ee, and were associated to a
lower flexibility of the corresponding enolate intermedi-
ates, with high restricted mobility around the C–N
bond. Although in less extent, the existence or not of a
methylene linker between the p-methoxyphenyl group
and the nitrogen atom is also important for the control
of selectivity. Finally, the ability of TADDOL to modu-
19. Kawabata, T.; Majumdar, S.; Tsubaki, K.; Monguchi, D.
Org. Biomol. Chem. 2005, 125, 1609–1611.
20. Carlier, P. R.; Zhao, H.; DeGuzman, J.; Lam, P. C.-H.
J. Am. Chem. Soc. 2003, 125, 11482–11483.
21. Lam, P. C.-H.; Carlier, P. R. J. Org. Chem. 2005, 70,
1530–1538.
22. Gerona-Navarro, G.; Bonache, M. A.; Herranz, R.;
´
´
´
Garcıa-Lopez, M. T.; Gonzalez-Muniz, R. Synlett 2000,
˜
1249–1252.
23. Gerona-Navarro, G.; Bonache, M. A.; Herranz, R.;
´
´
´
Garcıa-Lopez, M. T.; Gonzalez-Muniz, R. J. Org. Chem.
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2001, 66, 3538–3547.

M. A. Bonache et al. / Tetrahedron Letters 47 (2006) 5883–5887
5887
´
24. Bonache, M. A.; Gerona-Navarro, G.; Garcıa-Aparicio,
33. (4R,S)-1-(p-Methoxy)benzyl-4-phenethyl-4-methoxycarbo-
nyl-2-azetidinone (17). Syrup. HPLC: tR = 5.01 min
(A:B = 45:55). 1H NMR (300 MHz, CDCl3): d 7.13 (m,
5H, C6H5 and C6H4), 6.85 (d, 2H, J = 6.8, C6H5), 6.78 (d,
2H, J = 8.7, C6H4), 4.40 (d, 1H, J = 15.2, CH2Pmb), 4.23
(d, 1H, J = 15.2, CH2Pmb), 3.71 (s, 3H, OMe), 3.53 (s,
3H, OMe), 3.18 (d, 1H, J = 14.7, 3-H), 2.81 (d, 1H,
J = 14.7, 3-H), 2.28 (m, 3H, c-H, b-H), 1.86 (m, 1H b-H).
13C NMR (75 MHz, CDCl3): d 171.73 (COO), 166.13
(CON), 159.16 (4-C Pmb), 140.26-114.02 (11C, Ar), 62.39
(4-C), 55.25 (OMe), 52.37 (OMe), 45.65 (CH2Pmb), 44.24
(3-C), 35.40 (c-H), 30.23 (b-H). ESI-MS: 354.2 (M+1)+.
Anal. Calcd for C21H23NO4: C, 71.37; H, 6.56; N, 3.96.
Found: C, 71.45, H, 6.75, N, 3.65.
´
´
´
´
´
C.; Alıas, M.; Martın-Martınez, M.; Garcıa-Lopez, M. T.;
´
´
Lopez, P.; Cativiela, C.; Gonzalez-Muniz, R. Tetrahedron:
˜
Asymmetry 2003, 14, 2161–2169.
´
´
25. Bonache, M. A.; Gerona-Navarro, G.; Martın-Martınez,
´
´
´
M.; Garcıa-Lopez, M. T.; Lopez, P.; Cativiela, C.;
Gonzalez-Muniz, R. Synlett 2003, 1007–1011.
26. Bonache, M. A.; Lopez, P.; Martın-Martınez, M.; Garcıa-
´
˜
´
´
´
´
´
´
Lopez, M. T.; Cativiela, C.; Gonzalez-Muniz, R. Tetra-
˜
hedron 2006, 62, 130–138.
27. Compounds 1, 2, 8, 9, and 15 were previously described by
us (see Refs. 23,24).
28. Chan, D. M. T.; Monaco, K. L.; Wang, R. P.; Winters, M.
P. Tetrahedron Lett. 1998, 39, 2933–2936.
29. Lam, P. Y. S.; Bonne, D.; Vincent, G.; Clark, C. G.;
Combs, A. P. Tetrahedron Lett. 2003, 44, 1691–1694.
30. Attempts to use (p-methoxy)phenyl bromide as the N-
arylating agent under palladium catalysis resulted in better
yield of compound 7, but it was obtained in totally
racemic form. For references related to this palladium
catalyzed N-arylation procedures, see: (a) Ma, D.; Zhang,
Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc. 1998, 120,
12459–12467; (b) Clement, J. B.; Hayes, J. F.; Sheldrake,
H. M.; Sheldrake, P. W.; Wells, A. S. Synlett 2001, 1423–
1427.
34. Attempt to optimize this reaction using different bases
(BTPP, BEMP, Cs2CO3) and solvents (MeCN, CH2Cl2,
THF) were unsuccessful. (4R,S)-4-Benzyl-4-methoxycar-
bonyl-1-(p-methoxy)phenyl-2-azetidinone (18).
Syrup.
HPLC: tR = 4.16 min (A:B = 50:50). 1H NMR
(300 MHz, CDCl3): d 7.26 (d, 2H, J = 6.8, C6H4), 7.04
(m, 5H, C6H5), 6.84 (d, 2H, J = 6.8, C6H4), 3.75 (s, 3H,
OMe), 3.44 (d, 1H, J = 12.9, 3-H), 3.40 (d, 1H, J = 12.9,
3-H), 3.07 (d, 1H, J = 14.9, 4-CH2), 2.90 (d, 1H, J = 14.9,
4-CH2). 13C NMR (75 MHz, CDCl3): d 172.14 (COO),
162.54 (CON), 156.13 (4-C Pmp), 135.24–113.92 (11C,
Ar), 61.85 (4-C), 55.29 (OMe), 52.90 (OMe), 44.98 (3-C),
36.36 (4-CH2). ESI-MS: 326.4 (M+1)+. Anal. Calcd for
C19H19NO4: C, 70.14; H, 5.89; N, 4.31. Found: C, 70.45,
H, 5.65, N, 4.25.
31. BTPP: tert-Butylimino-tri(pyrrolidino)phosphorane. BEMP:
2-tert-Butylimino-2-diethylamino-1,3-dimethylperhydro-
1,3,2-diaza-phosphorine.
32. (4R,S)-1-(p-Methoxy)benzyl-4-phenyl-4-methoxycarbonyl-
2-azetidinone (16). Syrup. HPLC: tR = 8.29 min
(A:B = 35:65). 1H NMR (300 MHz, CDCl3): d 7.19 (m,
5H, C6H5), 7.07 (d, 2H, J = 8.9, C6H4), 6.70 (d, 2H,
J = 8.9, C6H4), 4.58 (d, 1H, J = 15.3, CH2Pmb), 4.23 (d,
1H, J = 15.3, CH2Pmb), 3.70 (s, 3H, OMe), 3.67 (d, 1H,
J = 14.7, 3-H), 3.54 (s, 3H, OMe), 3.06 (d, 1H, J = 14.7, 3-
H). 13C NMR (75 MHz, CDCl3): d 170.94 (COO), 166.78
(CON), 158.75 (4-C Pmb), 136.41–113.63 (11C, Ar), 65.04
(4-C), 55.16 (OMe), 52.44 (OMe), 50.68 (CH2Pmb), 45.31
(3-C). ESI-MS: 326.2 (M+1)+. Anal. Calcd for
C19H19NO4: C, 70.14; H, 5.89; N, 4.31. Found: C, 70.15,
H, 5.75, N, 4.65.
35. The assignment of Phe-derived b–lactams was unambig-
uously done by conversion into a-benzyl aspartic acids of
´
known configuration: Gerona-Navarro, G.; Garcıa-
´
´
Lopez, M. T.; Gonzalez-Muniz, R. J. Org. Chem. 2002,
˜
67, 3953–3956.
´
36. Fournie-Zaluski, M. C.; Lucas-Soroca, F.; Devin, J.;
Roques, B. P. J. Med. Chem. 1986, 29, 751–757.
´
37. Gonzalez-Muniz, R.; Cornille, F.; Bergeron, F.; Ficheux,
˜
D.; Pothier, J.; Durieux, C.; Roques, B. P. Int. J. Pept.
Protein Res. 1991, 37, 331–340.
38. Mahlert, C.; Sieber, S. A.; Grunewald, J.; Marahiel, M. A.
¨
J. Am. Chem. Soc. 2005, 127, 9571–9580.