Practical synthesis of α-amino acid N-carboxy anhydrides of polyhydroxylated α-amino acids from β-lactam frameworks. Model studies toward the synthesis of directly linked peptidyl nucleoside antibiotics

Article abstract of DOI:10.1021/jo980354x

A straightforward method for the synthesis of polyhydroxylated α-amino acid N-carboxy anhydrides (NCAs) is described as the means by which short peptide segments comprised of a polyhydroxylated chain are easily affordable. The entire sequence lies in the

Full text of DOI:10.1021/jo980354x

5838
J . Org. Chem. 1998, 63, 5838-5846
P r a ctica l Syn th esis of r-Am in o Acid N-Ca r boxy An h yd r id es of
P olyh yd r oxyla ted r-Am in o Acid s fr om â-La cta m F r a m ew or k s.
Mod el Stu d ies tow a r d th e Syn th esis of Dir ectly Lin k ed P ep tid yl
Nu cleosid e An tibiotics
Claudio Palomo,*,† Mikel Oiarbide,† Aitor Esnal,† Aitor Landa,† J ose´ I. Miranda,† and
Anthony Linden‡
Departamento de Quı´mica Orga´nica, Facultad de Qu´ımica, Universidad del Paı´s Vasco, Apdo 1072,
20080 San Sebastia´n, Spain, and Organisch-chemisches Institut der Universita¨t Zu¨rich,
Winterthurerstrasse 190, CH-8057, Zu¨rich, Switzerland
Received February 24, 1998
A straightforward method for the synthesis of polyhydroxylated R-amino acid N-carboxy anhydrides
(NCAs) is described as the means by which short peptide segments comprised of a polyhydroxylated
chain are easily affordable. The entire sequence lies in the preparation of nonracemic 3-hydroxy
â-lactams through the highly diastereoselective Staudinger reaction of hydroxyketene equivalents
with chiral R-oxyaldehyde-derived imines, followed by TEMPO radical assisted cycloexpansion to
the corresponding NCA and subsequent peptide coupling with R-amino acid esters. The method
has been applied to the synthesis of short peptide segments derived from carbamoylpolyoxamic
acid, some glycoglycines, as well as C2 symmetric hydroxy amino acids.
In tr od u ction
In recent years, polyhydroxylic R-amino acids have
been the focus of major interest, in part due to their
utility as precursors of alkaloidal sugar mimics with a
nitrogen in the ring (azasugars), including both mono-
cyclic and bicyclic derivatives1 and, in part, because of
their occurrence in complex nucleoside antibiotics that
exhibit a variety of biological activities.2 One example
of the latter, Figure 1, is the family of polyoxins 1, which
has as a common structural feature a dipeptide com-
prised of an unusual hydroxylated R-amino acid 3, linked
to one of the related nucleoside R-amino acids.3 The free
form 2 of 3 is commonly called polyoxamic acid. As a
consequence of the potent antifungal activity associated
with this type of peptidyl nucleosides, many methods for
the preparation of both 2 and 3 have been proposed over
the past few years.4 Since most of these methods involve
a relatively large number of steps, a practical short route
to this amino acid still remains of interest. In addition,
a strategy that allows the combination of the synthesis
of the polyhydroxylated R-amino acid with a peptide
coupling step would represent a conceptually new ap-
proach to peptidyl nucleoside antibiotics.4,5 We have
recently reported the first synthesis of a derivative of
polyoxamic acid 2 that fulfills this criterion.6 The
strategy, Figure 2, is based on the use of glycolic acid
that derivatizes imines in the primary step in such a way
that a four membered ring is formed. Then the oxidation
of the alcohol and subsequent Baeyer-Villiger rear-
rangement of the resulting intermediate R-keto â-lactam
F igu r e 1.
provides, in an one-pot procedure, an R-amino acid
N-carboxy anhydride (NCA) ready for peptide cou-
plings.7,8 Thus, the access to NCAs, which has tradition-
ally relied on dehydration procedures of R-amino acids,9
can now be achieved from non-R-amino acid precursors
in a very concise and practical fashion. We now report
the implementation of this strategy to the synthesis of
(4) (a) Saksena, A. K.; Lovey, R. G.; Girigavallabhan, V. M.; Ganguly,
A. K. J . Org. Chem.. 1986, 51, 5024. (b) Savage, I.; Thomas, E. J . J .
Chem. Soc., Chem. Commun. 1989, 717. (c) Mukaiyama, T.; Suzuki,
K.; Yamada, T.; Tabuga, F. Tetrahedron 1990, 46, 265. (d) Dondoni,
A.; Franco, S.; Mercha´n, F. L.; Merino, P.; Tejero, T. Tetrahedron Lett.
1993, 34, 5479. (e) J ackson, R. F. W.; Palmer, N. J .; Wythes, M. J .;
Clegg, W.; Elsegood, M. R. J . J . Org. Chem. 1995, 60, 6431. (f) Kang,
S. H.; Choi, H.-w. Chem. Commun. 1996, 1521. (g) Dondoni, A.; Franco,
S.; J unquera, F.; Mercha´n, F. L.; Merino, P.; Tejero, T. J . Org. Chem.
1997, 62, 5497. (h) Garner, P.; Park, J . M. J . Org. Chem. 1988, 53,
2979. (i) Dureault, A.; Carreaux, F.; Depezay, J . C. Synthesis 1991,
150. (j) Irama, M.; Hioki, H.; Ito, S. Tetrahedron Lett. 1988, 29, 3125.
(k) Banik, B. K.; Manhas, M. S.; Bose, A. K. J . Org. Chem. 1993, 58,
307. (l) Paz, M. M.; Sardina, F. J . J . Org. Chem. 1993, 58, 6990. (m)
Matsuura, F.; Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1994, 35, 733.
(n) Trost, B. M.; Krueger, A. C.; Bunt, R. C.; Zambrano, J . J . Am. Chem.
Soc. 1996, 118, 6520. (o) Marshall, J . A.; Seletsky, B. M.; Coan, P. S.
J . Org. Chem. 1994, 59, 5139. (p) Bandini, E.; Martelli, G.; Spunta,
G.; Bongini, A.; Panunzio, M.; Piersanti, G. Tetrahedron: Asymmetry
1997, 8, 3717. (q) Veeresa, G.; Datta, A. Tetrahedron Lett. 1998, 39,
119.
† Universidad del Pa´ıs Vasco.
‡ Organisch-chemisches Institut der Universita¨t Zu¨rich.
(1) For recent reviews, see: Casiraghi, G.; Zanardi, F.; Rassu, G.;
Spanu, P. Chem. Rev. 1995, 95, 1677.
(2) (a) Isono, K. J . Antibiot. 1988, 41, 1711. (b) Isono, K. Pharmac.
Ther. 1991, 52, 269. (c) Knapp, S. Chem. Rev. 1995, 95, 1859.
(3) Garner, P. In Studies in Natural Product Chemistry, Vol 1,
Stereoselective Synthesis; Rahman, A.-U., Ed.; Elsevier: Amsterdam,
1988; Part A, p 397.
S0022-3263(98)00354-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/31/1998

Directly Linked Peptidyl Nucleoside Antibiotics
J . Org. Chem., Vol. 63, No. 17, 1998 5839
Sch em e 1
F igu r e 2. General strategy for the asymmetric carboxylation
of imines with concomitant carboxyl group activation.
NCAs formally derived from polyhydroxylated R-amino
acids, such as the carbamoyl polyoxamic acid 3 and some
glycoglycines,10 and demonstrate the benefit of the entire
process for the synthesis of directly linked peptidyl
nucleoside antibiotics.
â-lactams, Scheme 1, are obtained essentially as single
diastereomers. For example, the cycloaddition reaction
of acetoxyketene, generated from (acetoxy)acetyl chloride
and triethylamine, with imines 413 and 5,14 afforded 6
and 7 in yields of 86% and 90%, respectively. Mild
deprotection of these compounds with lithium hydroper-
oxide led to the R-hydroxy â-lactam 9 and 10 in 90% and
95% yield. Likewise, the cycloaddition reaction of ben-
zyloxyketene, generated from (benzyloxy)acetyl chloride
and triethylamine, to the imine 5 furnished 8 in 85%
yield. In each case, a single diastereomer was produced
whose relative cis configuration was established on the
basis of the value of the proton NMR coupling constant
(J 3,4 ) 5 Hz). When both 9 and 10 were subjected to
treatment with a solution of commercial bleach and a
catalytic amount of TEMPO within about 1-2 min, the
corresponding NCAs 11 and 12, the latter formally
derived from polyoxamic acid 2, were produced in 90%
and 95% yield, respectively.
Next, the synthesis of the carbamoylpolyoxamic acid-
derived NCA 16 was addressed as shown in Scheme 2.
In this regard, the introduction of the carbamoyl group
at the terminal position of the â-lactam C4-side chain
could be accomplished by chemoselective deprotection of
the primary hydroxy group in 8. This was cleanly
performed by exposure of 8 to H2 over Pd on charcoal at
room temperature for 5-7 h to give 13 in 95% isolated
yield, provided the reaction progress is carefully moni-
tored by TLC in order to avoid overexposure to H2.
Further carbamoylation15 of the free hydroxy group in
13 provided 14 in 90% isolated yield, which on prolonged
exposure to the above hydrogenolytic conditions led to
the 5-O-carbamoylpolyoxamic NCA precursor 15 in 91%
isolated yield. Thus, treatment of 15 with a solution of
commercial bleach and a catalytic amount of TEMPO
Resu lts a n d Discu ssion
Ap p r oa ch to Ca r ba m oylp olyoxa m ic Acid -Der ived
NCAs. The approach to the NCA formally derived from
the carbamoylpolyoxamic acid 3 takes advantage of the
highly stereocontrolled cycloaddition reaction of hydrox-
yketene equivalents with R-oxy aldehyde-derived imi-
nes,11 independently pionered by Hubschwerlen12 and
Bose.13 By this means, the required starting R-hydroxy
(5) For some additional examples on the synthesis of hydroxylated
R-amino acids, see: (a) Shioiri, T.; Hamada, Y. Heterocycles 1988, 27,
1035. (b) Ariza, J .; Font, J .; Ortun˜o, R. M. In Trends Org. Chem. 1992,
3, 53. (c) Varela, O. Pure Appl. Chem. 1997, 69, 621. (d) Dondoni, A.;
Perrone, D. Aldrichim. Acta 1997, 30, 35. (e) Rassu, G.; Zanardi, F.;
Corria, M.; Casiragi, G. J . Chem. Soc., Perkin Trans. 1 1994, 2431. (f)
Kirihata, M.; Nakao, Y.; Mori, M.; Ichimoto, I. Heterocycles 1995, 41,
2271. (g) Cativiela, C.; D´ıaz-de-Villegas, M. D.; Ga´lvez, J . A.; Garc´ıa,
J . I. Tetrahedron 1996, 52, 9563. (h) Ojea, V.; Ruiz, M.; Quintela, J .
M. Synlett 1997, 83. (i) Merino, P.; Franco, S.; Merchan, F. L.; Tejero,
T. Tetrahedron: Asymmetry 1997, 8, 3489. (j) Kimura, T.; Vassilev, V.
P.; Shen, G.-J .; Wong, C.-H. J . Am. Chem. Soc. 1997, 119, 11734. For
general reviews on R-amino acid synthesis, including hydroxylated
R-amino acids, see: (k) Williams, R. M. Synthesis of Optically Active
R-Amino Acids; Pergamon Press: Oxford, 1988. (l) Duthaler, R. O.
Tetrahedron 1994, 50, 1539. For R-amino acids from sugars, see: (m)
Cintas, P. Tetrahedron 1991, 47, 6079. For R-amino acids from R-cation
equivalents, see: (n) Bailey, P. D.; Clayson, J .; Boa, A. N. Contemp.
Org. Synth. 1995, 2, 173. For a recent review on coupling methods for
the incorporation of noncoded amino acids into peptides, see: (o)
Humphrey, J . M.; Chamberlain, A. R. Chem. Rev. 1997, 97, 2243.
(6) Palomo, C.; Oiarbide, M.; Esnal, A. Chem. Commun. 1997, 691.
(7) For a conceptually different â-lactam route to the nonnatural
enantiomer of polyoxamic acid, see ref 4k. For a recent review on the
use of â-lactams as buildig-blocks of â-amino acid derivatives, see:
Palomo, C.; Aizpurua, J . M.; Ganboa, I. In Enantioselective Synthesis
of â-Amino Acids; J uaristi, E., Ed.; Wiley VCH: New York, 1997; p
279.
(8) (a) Palomo, C.; Aizpurua, J . M.; Ganboa, I.; Carreaux, F.; Cuevas,
C.; Maneiro, E.; Ontoria, J . M. J . Org. Chem. 1994, 59, 3123. (b)
Palomo, C.; Aizpurua, J . M.; Cuevas, C.; Urchegui, R.; Linden, A. J .
Org. Chem. 1996, 61, 4400.
(9) To date, the synthesis of NCA’s invariably requires the prior
construction of the desired R-amino acid followed by dehydration. For
a detailed discussion on this topic, see: (a) Kricheldorf, H. R. R-Amino
Acid N-Carboxy-Anhydride and Related Heterocycles; Springer-Ver-
lag: Berlin, 1987. (b) Reference 8a.
(10) We adopted the term of glycoglycines instead of C-glycosylgly-
cines according to the recent observation made by Dondoni, who
indicated that the usual name of C-glycosyl R-amino acids appears
appropriate only for compounds wherein the amino acid moiety is
linked to the sugar anomeric carbon. See: Dondoni, A.; J unquera, F.;
Mercha´n, F. L.; Merino, P.; Ascherrmann, M.-C.; Tejero, T. J . Org.
Chem. 1997, 62, 5484.
(11) For a review on ketene-imine cycloadditions, see: Georg, G.
I.; Ravikumar, V. T. In The Organic Chemistry of â-Lactams; Georg,
G. I., Ed.; VCH: New York, 1992; p 295. For a review on the
construction of chiral molecules using R-hydroxy acids or aldehydes,
see: Coppola, G. M.; Schuster, H. F. R-Hydroxy Acids in Enantiose-
lective Syntheses; VCH: Weinheim, 1997.
(12) Hubschwerlen, C.; Schmid, G. Helv. Chim. Acta 1983, 66, 2206.
(13) (a) Wagle, D. R.; Garai, G.; Chiang, J .; Monteleone, M. G.;
Kurys, B. E.; Strohmeyer, T. W.; Hedge, V. R.; Mahnas, M. S.; Bose,
A. K. J . Org. Chem. 1988, 53, 4227. (b) Banik, B. K.; Manhas, M. S.;
Kaluza, Z.; Barakat, J . K.; Bose, A. K. Tetrahedron Lett. 1992, 33, 3603.
(14) For the use of this imine in the synthesis of 3-amino â-lactams,
via the cycloaddition approach, see: Saito, S.; Ishikawa, T.; Morinake,
T. Synlett 1993, 139.

5840 J . Org. Chem., Vol. 63, No. 17, 1998
Palomo et al.
Sch em e 2
chloride, only 23a was obtained. Likewise, the coupling
in methylene chloride of the NCA 16 with (S)-LeuOBn
afforded 24a in 87% yield as the sole diastereomeric
product. As Scheme 4 illustrates, both 24a and 24b were
then converted under usual conditions into 25a and 25b,
respectively. Then 25a was N-debenzylated to give the
corresponding free carbamoylpolyoxamic dipeptide 26 in
98% over the two steps. Finally, to corroborate the
configuration of the carbamoyl polyoxamic acid and hence
the otherwise stated products, the NCA 16 was trans-
formed into the known methyl ester 27, as shown in eq
1.
furnished the NCA 16 in 90% isolated yield.16 For
reasons that will be outlined later, the NCA 20, Scheme
3, was also prepared following the same sequence of
reactions as above. Namely, the cycloaddition reaction
of benzyloxyketene with the imine 17, prepared from the
corresponding aldehyde and benzylamine,17 gave the
â-lactam 18 in 87% yield essentially as the sole diaste-
reomer. Subsequent O-debenzylation with H2 over Pd
on charcoal carried out in ethyl acetate as solvent led to
the 3-hydroxy â-lactam 19, which was converted into 20
by following the protocol used for compounds 11, 12, and
16 in 90% yield for the entire sequence. It should also
be mentioned that when the O-debenzylation of 18 was
carried out in methanol as solvent, a simultaneous
opening of the dioxolane ring took place, affording triol
21 as the major isolated product.
From the above approach, two key elements are
especially noteworthy. First, the creation of the R
stereogenic center of the polyoxamic acid or its carbamoyl
derivative is virtually diastereoselectively complete, which
contrasts with the mixtures obtained by reported proce-
dures employing Mukaiyama’s aldehyde as the starting
material.4a-g Second, the generation of an activated
derivative of the carbamoylpolyoxamic acid 3 ready for
further coupling reactions has been achieved for the first
time. On pursuing this latter aspect we found, however,
that the coupling reaction of the above NCAs 11, 12, and
16 with R-amino acid esters, Scheme 4, proceeded to give
the expected coupling products 22, 23, and 24 along with
the corresponding epimerized products epi-22, epi-23, and
epi-24, respectively, depending upon the nature of the
solvent employed. For example, the coupling reaction of
the NCA 11 with (S)-LeuOBn carried out in methylene
chloride gave 22a as the only diastereomeric product, but
when the reaction was performed in DMF as solvent, a
mixture of 22a /epi-22a was formed in a 75:25 ratio. In
a similar way, the coupling reaction of the NCA 12 with
(S)-LeuOBn in DMF furnished an equimolar mixture of
23a /epi-23a , whereas in either diethyl ether or methylene
The results obtained in these coupling reactions upon
the use of different solvents are summarized in Table 1,
which also includes some solvent physical constants.
From these data, a good agreement between the magni-
tude of the dipolar moment of the solvent µ and the
degree of isomerization is observed. With two exceptions,
a plausible correlation could also be established between
the value of the dielectric constant of the solvent used,
ꢀ, and the degree of isomerization. However, it appears
that there is not any obvious relationship between the
polarity of the solvent, as ET, and the isomerization
degree. Although at this point of the study we did not
have a well-evidenced explanation for the observed
epimerization nor for the influence of the solvent on it,
we speculated on the role played by the rigid dioxolane
ring. Hence, Dreiding stereomodel structures for 11, 12,
and 16 suggest an unfavorable disposition of the CdO(oxa-
zolidin-2,3-dione ring)/C-O(dioxolane ring) dipoles that
could in part be circumvented in the epimeric structures.
This circumstance could actually be the driving force that
induces the epimerization process to take place. In fact,
we prepared the NCA 20, vide supra, which possesses a
higher conformational freedom allowing a better CdO/
C-O relative orientation, and subjected it to treatment
with (S)-LeuOBn. Regardless of the reaction solvent
employed, compound 28 was the only dipeptide product
formed (eq 2).
(15) Tabusa, F.; Yamada, T.; Suzuki, K.; Mukaiyama, T. Chem. Lett.
1984, 405. See also ref 4c.
To further demonstrate the scope of this method for
coupling NCAs under racemization free conditions, we
have prepared the C2-symmetric bis-NCA 31 according
to the reactions depicted in Scheme 5. The cycloaddition
of the bis-imine 2918 with benzyloxyacetyl chloride and
triethylamine provided 30 after usual O-deprotection of
the resulting intermediate adduct. Exposure of this
(16) NCA 11 and 16 rapidly became white solids and could be stored
under nitrogen in a cool room for several days without appreciable
decomposition. All other NCAs so far described in this article did not
solidify easily and were used within a few hours of isolation.
(17) The imine was prepared from the commercially available methyl
3,4-O-isopropylidene-L-threonate by standard tert-butyldimethylsilyl-
ation of the secondary hydroxy group and subsequent reduction of the
methyl ester by treatment with DIBAL at -78 °C in toluene. The
resulting aldehyde was treated with equimolar amounts of benzyl-
amine in methylene chloride in the presence of magnesium sulfate at
0 °C for 1 h. After usual workup, the crude imine was used as such.
(18) J ayaraman, M.; Deshmukh, A. R. A. S.; Bhawal, B. M. J . Org.
Chem. 1994, 59, 932.

Directly Linked Peptidyl Nucleoside Antibiotics
J . Org. Chem., Vol. 63, No. 17, 1998 5841
Ta ble 1. Dia ster eom er ic Ra tios of th e Rea ction P r od u cts Obta in ed in Differ en t Solven ts by th e Cou p lin g of
(S)-Leu OBn w ith NCA 11, 12, 16, a n d 20, Resp ectivelya
solvent
µb
ꢀ
ET
22a :epi-22a c
23a :epi-23a c
24a :epi-24a c
28:epi-28c
Et2O
3.8
5.2
11.9
11.8
13.5
4.2
8.93
0.117
0.309
0.481
0.460
0.444
0.404
0.315
100:0d
100:0d
92:8
85:15
51:49
50:50
28:72
100:0
100:0
CH2Cl2
MeNO2
MeCN
DMSO
DMF
100:0d
100:0
35.94
35.94
46.45
36.71
29.6
10.8/12.88e
18.5
75:25d
64:36d
100:0
mixture
HMPA
a
b
Reactions conducted on a 0.25 mmol scale at room temperature in the corresponding solvent (2.5 mL); NCA/(S)-LeuOBn 1:2. From
Reichardt, C. In Solvent Effects in Organic Chemistry; Ebel, H. F., Ed.; Verlag Chemie GmbH: Weinheim, 1990; p 407 [µ (10-30 Cm) at
20-30 °C; ꢀ, relative permitivity at 25 °C; ET at 25 °C]. c Determined by 1H NMR analysis of the crude products. Corroborated by
N
d
HPLC analysis. e From the same book as in (b), 1978 ed.
Sch em e 3
Sch em e 4
compound to commercial bleach and a catalytic amount
of TEMPO cleanly led to the expected bis-NCA 31 in
almost quantitative yield. The coupling of this bis-NCA
31 with 2 equiv of (S)-PheOMe, carried out in methylene
chloride as solvent, furnished the peptide product 32,
which contains a C2-symmetric diaminodiol unit. Inspec-
tion of the 1H NMR of the crude reaction mixture
revealed the absence of epimerization, which was further
confirmed by HPLC analysis. Again, after carrying out
the coupling reaction in DMF as solvent, an intractable
mixture of compounds was formed. On the other hand,
given the prominence of C2-symmetric diaminodiols in
biologically important peptide sequences relevant to
antiviral chemotherapy,19 the method reported herein
could be beneficial for the creation of small peptide
libraries containing the 3,4-dihydroxylated 2,5-diami-
noadipic acid as part of the backbone.20
Ap p r oa ch t o Glycoglycin e-NCAs. The potential
utility of this method for the synthesis of densely func-
tionalized NCAs was also explored. In particular, the
synthesis of some illustrative carbon-linked glycoglycines,
such as R-aminofuranuronic acid derivatives,21 was un-
dertaken. To this end, we chose to use the â-lactam 34,
(19) For some representative reviews, see: (a) Erickson, J . W.
Perspect. Drug Discovery Des. 1993, 1, 109. (b) Abdel-meguid, S. S.
Med. Res. Rev. 1993, 6, 731. (c) March, D. R.; Fairlie, D. P. In Designing
New Antiviral Drugs for AIDS: HIV-1 Protease and Its Inhibitors;
Wise, R., Ed.; R. G. Landes Publishers: Austin, TX, 1996; p 1. (d)
Dorsch, D.; Raddatz, P.; Schmitges, C.-d.; von der Helm, K.; Rippmann,
F. Kontackte 1993, 48.
(20) Recently, a homologated amino acid, the 4,5-dihydroxy-3,6-
diamino-1,6-hexanedicarboxylic acid, has been employed for the con-
struction of a pseudo-C2-symmetric cyclic urea as intermediate in the
synthesis of HIV-protease inhibitors; see: Schreiner, E. P.; Pruckner,
A. J . Org. Chem. 1997, 62, 5380.
(21) For the syntheses of R-aminofuranuronic acids, see: (a) ref 4g,
10, and references therein. (b) Bouifraden, S.; Lavergne, J .-P.; Mar-
t´ınez, J .; Viallefont, P.; Riche, C. Tetrahedron: Asymmetry 1997, 8,
949. (c) Bouifraden, S.; Lavergne, J .-P.; Martinez, J .; Viallefont, P.
Synth. Commun. 1997, 27, 3909. (d) Gethin, D. M.; Simpkins, N. S.
Tetrahedron 1997, 53, 14417.

5842 J . Org. Chem., Vol. 63, No. 17, 1998
Palomo et al.
Sch em e 5
Sch em e 7
Sch em e 8
Sch em e 6
wise, the coupling of 36 with the dipeptide (S,S)-Leu-
LeuOBn afforded the tripeptide 40 in 87% isolated yield,
which was then converted into the N-Boc derivative 41.
Finally, the glycoglycine methyl ester 42, prepared from
37, Scheme 8, was coupled with the NCA 16 to give the
unnatural carbamoylpolyoxamic derivative 43. Although
the configuration of the carbon atom at the R-position of
the amino group of the sugar moiety in compound 43 is
opposite to that found in natural polyoxins, the above
example illustrates the potential of the approach to the
synthesis of directly linked peptidyl nucleoside antibiot-
ics.23
Next, the synthesis of pyranose type glycoglycine NCAs
and derived peptides was investigated. In these in-
stances, an unexpected lowering in the stereoselectivity
of the ketene-R-oxyimine cycloaddition reaction was
observed. In general, the ketene-imine cycloaddition
reaction affords only one of the two possible cis diaster-
eomers, and the absolute configuration of the R carbon
to the â-lactam nitrogen atom is that predicted by the R
stereogenic center of the starting R-oxy aldehyde-derived
imine.24 However, as Scheme 9 illustrates, the cycload-
dition reaction of benzyloxyketene to the imine 44
furnished an inseparable mixture of 45 and its cis
diastereomer 46 in a 85:15 ratio. Likewise, the reaction
Scheme 6, prepared in 45% yield by addition of benzy-
loxyacetyl chloride to the imine 33 and triethylamine,
according to the method of Bose.22 A better yield was
obtained, however, when a solution of the imine in
toluene was added to the preformed ketene in methylene
chloride. In this way, 34 was isolated in 63% yield and
then O-debenzylated to give 35 in 87% yield. As ex-
pected, the cycloexpansion of 35 promoted by TEMPO
proceeded cleanly to afford the NCA 36 in 91% yield,
ready for subsequent couplings. These coupling reactions
were successfully carried out with both O- and N-
nucleophiles, Scheme 7. Thus, the exposure of 36 to a
large excess of methanol smoothly produced the methyl
ester 37 in 80% yield after 2 h at room temperature.
Likewise, treatment of 36 with a slight excess of benzyl
alcohol in methylene chloride as solvent for 16 h provided
the benzyl ester 38 in 90% isolated yield. In both cases,
no epimerization at the sensitive stereocenters occurred
during ring opening as judged by 13C NMR and HPLC
analyses of the corresponding reaction crudes. Next, the
coupling of the R-aminofuranuronic-NCA 36 with some
representative R-amino acid esters was examined. For
example, the coupling reaction of 36 with (S)-LeuOBn,
carried out in methylene chloride at room temperature,
furnished the dipeptide product 39 in 95% yield. Like-
(23) Attempts to epimerize the amino acid ester at the R-position
through the benzaldimine intermediate were unsuccessful, and the
starting material was recovered without change. For this epimerization
process, see: (a) Clark, J . C.; Phillipps, G. H.; Steer, M. R. J . Chem.
Soc., Perkin Trans. 1 1976, 475. (b) Honnoraty, A.-M.; Mion, L.; Collet,
H.; Teissedre, R.; Commeyras, A. Bull. Soc. Chim. Fr. 1995, 132, 709.
(22) Wayle, D. R.; Garai, C.; Monteleone, M. G.; Bose, A. K.
Tetrahedron Lett. 1988, 29, 1649.

Directly Linked Peptidyl Nucleoside Antibiotics
J . Org. Chem., Vol. 63, No. 17, 1998 5843
Sch em e 9
of 44 with acetoxyacetyl chloride and triethylamine gave
47 along with its cis diastereoisomer 48 in a ratio of 80:
20. Again, the relative cis configuration of the ring
forms of polyhydroxylated R-amino acids without the
necessity to have previously prepared each individual
R-amino acid.
1
substituents was established on the basis of the H NMR
coupling constants at the C3 and C4 positions of the
â-lactam ring (J 3,4 ) 4.8-5.0 Hz). Despite this relatively
low diastereoselectivity,25 compound 47, which serves to
illustrate the utility of the approach to NCAs derived
from R-aminopyranuronic acids,26 could easily be isolated
by column chromatography and subjected to saponifica-
tion affording the R-hydroxy â-lactam 49 in 95% yield.
Accordingly, exposure of 49 to a solution of commercial
bleach and a catalytic amount of TEMPO gave within
about 1-2 min the NCA 50, which on coupling with (S)-
PheOBn and (S)-LeuOBn in methylene chloride led to
the sugar dipeptides 51 and 52 in good overall yields over
the last two steps. Finally, single-crystal X-ray analysis
of 34, 39, and 48 confirmed the assigned configuration
for the products.27
Exp er im en ta l Section
Melting points were determined with capillary apparatus
and are uncorrected. Proton nuclear magnetic resonance (300
MHz) spectra and 13C spectra (75 MHz) were recorded at room
temperature for CDCl3 solutions, unless otherwise stated. All
chemical shifts are reported as δ values (ppm) relative to
residual CHCl3 δH (7.26 ppm) and CDCl3 δC (77.0 ppm) as
internal standards, respectively. Mass spectra were obtained
on a mass spectrometer (70 eV) using GC-MS coupling
(column: fused silica gel, 15 m, 0.25 mm, 0.25 mn phase SPB-
5). Optical rotations were measured at 25 ( 0.2 °C in
methylene chloride unless otherwise stated. HPLC analyses
were performed on analytical columns (25 cm, phase Li-
chrosorb-Si60 and 25 cm, phase Chiralcel OD) with flow rates
of 1 and 0.5 mL/min respectively, using a DAD detector. Flash
chromatography was executed with Merck Kiesegel 60 (230-
400 Mesh) using mixtures of ethyl acetate and hexane as
eluants. Et2O and THF were distilled over sodium. Methylene
chloride was shaken with concentrated sulfuric acid, dried over
potassium carbonate, and distilled. DMF was purified by
distillation on barium oxide. CH3CN was dried by refluxing
over calcium hydride and distilled. DMSO was distilled from
potassium hydroxide. MeOH was dried over magnessium
metal and iodine.
Gen er a l P r oced u r e for th e P r ep a r a tion of 3-Ben zyl-
oxy a n d 3-Acetoxy â-La cta m s. Meth od A. A mixture of
the corresponding aldehyde (25 mmol), 4A MS, and benzyl-
amine (2.14 g, 20 mmol) in methylene chloride (100 mL) was
stirred at 0 °C under a nitrogen atmosphere for 1 h. The
solution was filtered, the solvent evaporated, and the residue
analyzed by 1H NMR to ensure complete comsuption of the
amine. The crude thus obtained was dissolved in dry meth-
ylene chloride and cooled to -78 or 0 °C under a nitrogen
atmosphere, and to the resulting solution were succesively
In summary, the results reported here set the basis
for the development of a pratical and short access to
simultaneously amino-protected and carboxy-activated
(24) For a mechanistic discussion on this subject, see: (a) Palomo,
C.; Coss´ıo, F. P, Cuevas, C.; Lecea, B.; Mielgo, A.; Roma´n, P.; Luque,
A.; Mart´ınez-Ripoll, M. J . Am. Chem. Soc. 1992, 114, 9360. (b) Coss´ıo,
F. P., Arrieta, A.; Lecea, B.; Ugalde, J . M. J . Am. Chem. Soc. 1994,
116, 2085. For further experimental evidence on the stereochemical
outcome of cycloaddition reactions involving R-oxy aldehyde-derived
imines, see: (c) Palomo, C.; Coss´ıo, F. P.; Ontoria, J . M.; Odriozola, J .
M. Tetrahedron Lett. 1991, 32, 3105. (d) Brown, A. D.; Colvin, E. W.
Tetrahedron Lett. 1991, 32, 5187. (e) Kobayashi, Y.; Takemoto, Y.;
Kamijo, T.; Harada, H.; Ito, Y.; Terashima, S. Tetrahedron 1992, 48,
1853. (f) Palomo, C.; Aizpurua, J . M.; Urchegui, R.; Garc´ıa, J . M. J .
Org. Chem. 1993, 58, 1646. (g) Alcaide, B.; Miranda, M.; Pe´rez-Castells,
J .; Polanco, C.; Sierra, M. A. J . Org. Chem. 1994, 59, 8003. (h) Kramer,
B.; Franz, T.; Picasso, S.; Pruschek, P.; J ager, V. Synlett 1997, 295.
(25) These results contrast with those previously reported by Bose
and his colleagues who achieved a complete diastereoselectivity in the
reactions of alkoxyketenes with the imine 44. For pertinent informa-
tion, see: (a) Bose, A. K.; Mathur, C.; Wagle, D. R.; Nagui, R.; Manhas,
M. S. Heterocycles 1994, 39, 491. (b) Kaluza, Z.; Manhas, M. S.;
Barakat, K. J .; Bose, A. K. Biorg. Med. Chem. Lett. 1993, 3, 2357.
(26) For the synthesis of R-aminopyranuronic acids, see: (a) ref 10
and references therein. (b) Czerniecki, S.; Horns, S.; Valery, J .-M. J .
Org. Chem. 1995, 60, 650. (c) Czerniecki, S.; Franco, S.; Horns, S.;
Valery, J .-M. Tetrahedron Lett. 1996, 37, 4003. (d) Czerniecki, S.;
Franco, S.; Valery, J .-M. J . Org. Chem. 1997, 62, 4845.
(27) The X-ray crystal structure analyses have been performed by
one of us (A.L.) at the Organisch-chemisches Institut der Universita¨t
Zu¨rich. Atomic coordinates, bond lengths and angles, and thermal
parameters for compounds 34, 39, and 48 have been deposited at the
Cambridge Crystallographic Data Center. The coordinates can be
obtained, on request, from the Director, Cambridge Crystallographic
Data Center, 12 Union Road, Cambridge, CB2, 1EZ, UK. E-mail:
deposit@ccdc.cam.ac.uk.

5844 J . Org. Chem., Vol. 63, No. 17, 1998
Palomo et al.
added triethylamine (10 mL, 70 mmol) and dropwise a solution
of either (benzyloxy)acetyl chloride or (acetoxy)acetyl chloride
(30 mmol) in dry methylene chloride (35 mL). The resulting
mixture was stirred overnight at room temperature and then
was washed with water (3 × 50 mL), 0.1 N HCl (3 × 50 mL),
and a saturated solution of NaHCO3 (50 mL). The organic
layer was dried over MgSO4 and filtered, and the solvent was
evaporated under reduced pressure to give the corresponding
crude â-lactam, which was further purified by column chro-
matography. Meth od B. A solution of the imine, prepared
as before, in toluene was dropwise added to a cooled solution
of the acid chloride and triethylamine in methylene chloride.
After the mixture was stirred at room temperature overnight,
the workup procedure described in method A was followed.
(2R,3R,4R,5R)-5-((3′S,4′R)-1-Ben zyl-3-ben zyloxya zet i-
d in -2-on e-4-yl)-3,4-d ih yd r oxy-3,4-d i-O-isop r op ylid en e-2-
m eth oxytetr a h yd r ofu r a n (34). Method B was followed,
starting from the corresponding sugar aldehyde: yield 5.53 g
(63%); mp 140-142 °C; [R]25 ) -62.6 (c ) 1.0, CH2Cl2); IR
D
(KBr) 1737 cm-1 (CO); 1H NMR (CDCl3, δ) 7.40-7.13 (m, 10H),
4.97 (d, 1H, J ) 12.3 Hz), 4.88 (s, 1H), 4.82 (d, 1H, J ) 15.7
Hz), 4.71 (d, 1H, J ) 12.3 Hz), 4.67 (d, 1H, J ) 5.0 Hz), 4.61
(dd, 1H, J ) 1.1 Hz, J ′ ) 6.0 Hz), 4.51 (dd, 1H, J ) 1.1 Hz, J ′
) 10.1 Hz), 4.42 (d, 1H, J ) 6.0 Hz), 4.30 (d, 1H, J ) 15.8 Hz),
3.75 (dd, 1H, J ) 5.0 Hz, J ′ ) 10.1 Hz), 2.90 (s, 3H), 1.45 and
1.28 (s, 3H). 13C NMR (CDCl3, δ) 168.1, 137.1, 136.0, 128.6,
128.3, 127.8, 127.6, 127.4, 127.2, 112.3, 110.1, 88.8, 84.5, 81.8,
80.5, 72.6, 59.1, 55.1, 44.4, 26.5, 24.9; EIMS m/z 440 (M + 1).
Anal. Calcd for C25H29NO6 (439.3): C, 68.35; H, 6.65; N, 3.19.
Found: C, 67.97; H, 6.73; N, 3.26.
(3R,4S)-1-Ben zyl-4-[(1S)-3,3-d im et h yl-2,4-d ioxa cyclo-
p en ta n e-1-yl]-3-a cetoxya zetid in -2-on e (6). Method A was
followed starting from D-glyceraldehyde dimethylacetonide:
(2R,3R,4S,5S,6R)-6-((3′S,4′R)-3-Acetoxy-1-ben zyla zeti-
d in -2-on e-4-yl)-2,3,4,5-t et r a h yd r oxy-2,3:4,5-b is(d i-O-iso-
p r op ylid en e)tetr a h yd r op yr a n (47). Method B was fol-
lowed starting from the corresponding sugar aldehyde: yield
yield 4.43 g (70%); mp 97-98 °C; [R]25 ) -54.1 (c ) 0.51,
D
CH2Cl2); IR (KBr) 1759 (CO), 1744 cm-1 (CO); 1H NMR (CDCl3,
δ) 7.36-7.27 (m, 5H), 5.76 (d, 1H, J ) 4.9 Hz), 4.85 (d, 1H, J
) 14.6 Hz), 4.28 (d, 1H, J ) 14.7 Hz), 4.82-4.25 (m, 1H), 3.92
(dd, 1H J ) 6.7 Hz, J ′ ) 8.7 Hz), 3.63 (dd, 1H, J ) 4.9 Hz, J ′
) 8.9 Hz), 3.50 (dd, 1H, J ) 6.0 Hz, J ′ ) 8.7 Hz), 2.12 (s, 3H),
1.35 and 1.34 (s, 3H); 13C NMR (CDCl3, δ) 169.2, 164.2, 135.1,
128.8, 128.6, 127.8, 109.9, 76.3, 74.0, 66.2, 59.1, 45.4, 26.5, 25.0,
20.4. Anal. Calcd for C17H21NO5 (397.47): C, 63.94; H, 6.63;
N, 4.38. Found: C, 63.63; H, 6.57; N, 4.33.
5.15 g (58%); oil; [R]25 ) -54.4 (c ) 1.0, CH2Cl2); IR (film)
D
1770 (CO), 1754 cm-1 (CO); 1H NMR (CDCl3, δ) 7.29-7.26 (m,
5H), 5.84 (d, 1H, J ) 4.8 Hz), 5.59 (d, 1H, J ) 5.0 Hz), 4.83 (d,
1H, J ) 14.4 Hz), 4.57 (dd, 1H, J ) 2.4 Hz, J ′ ) 7.7 Hz), 4.34
(dd, 1H, J ) 2.4 Hz, J ′ ) 5.0 Hz), 4.26 (d, 1H, J ) 14.4 Hz),
4.05-3.95 (m, 3H), 2.11 (s, 3H), 1.53 (s, 3H), 1.33 (s, 6H), 1.26
(s, 3H); 13C NMR (CDCl3, δ) 168.9, 164.5, 135.3, 128.7, 128.4,
127.5, 109.7, 108.8, 96.1, 74.2, 70.6, 70.0, 68.6, 55.0, 45.6, 25.8,
25.7, 24.8, 24.5, 20.5; MS m/z 448 (M + 1).
(3R,4S)-1-Ben zyl-4-[(1S,5S)-5-ben zyloxym eth yl-3,3-d i-
m eth yl-2,4-d ioxa cyclop en ta n e-1-yl]-3-ben zyloxya zetid in -
2-on e (7). Method A was followed starting from Mukaiyama’s
aldehyde: yield 8.29 g (85%); mp 74-76 °C; [R]25D ) -1.6 (c )
1.0, MeOH); IR (KBr) 1738 cm-1 (CO); 1H NMR (CDCl3, δ)
7.36-7.17 (m, 15H), 4.85 (d, 1H, J ) 14.5 Hz), 4.84 (d, 1H, J
) 11.4 Hz), 4.57 (d, 1H, J ) 11.4 Hz), 4.57 (d, 1H, J ) 4.8 Hz),
4.36 (s, 2H), 4.20 (dd, 1H, J ) 6.6 Hz, J ′ ) 8.9 Hz), 4.18 (d,
1H, J ) 14.5 Hz), 3.97 (td, 1H, J ) 2.4 Hz, J ′ ) 6.6 Hz), 3.64
(dd, 1H, J ) 2.4 Hz, J ′ ) 10.4 Hz), 3.58 (dd, 1H, J ) 4.8 Hz,
J ′ ) 8.9 Hz), 3.42 (dd, 1H, J ) 6.6 Hz, J ′ ) 10.4 Hz), 1.85 and
1.45 (s, 3H); 13C NMR (CDCl3, δ) 167.3, 138.1, 136.6, 135.7,
128.7, 128.6, 128.5, 128.4, 128.2, 128.1, 127.6, 127.5, 110.5,
80.4, 79.3, 78.4, 73.2, 72.8, 70.7, 59.0, 45.0, 27.6, 27.4; MS m/z
(M+) 488. Anal. Calcd for C30H33NO5 (487.6): C, 73.89; H,
6.82; N, 2.87. Found: C, 73.76; H, 7.14; N, 2.92.
(2R,3R,4S,5S,6R)-6-((3′R,4′S)-3-Acetoxy-1-ben zyla zeti-
d in -2-on e-4-yl)-2,3,4,5-t et r a h yd r oxy-2,3:4,5-b is(d i-O-iso-
p r op ylid en e)p yr a n (48): yield 1.29 g (14%); mp 132-134
°C; [R]25D ) -78.5 (c ) 1.0, CH2Cl2); IR (film) 1770 (CO), 1758
cm-1 (CO); 1H NMR (CDCl3, δ) 7.30-7.25 (m, 5H), 5.93 (d, 1H,
J ) 4.8 Hz), 5.40 (d, 1H, J ) 5.1 Hz), 4.66 (d, 1H, J ) 15 Hz),
4.56 (dd, 1H, J ) 2.5 Hz, J ′ ) 7.9 Hz), 4.28 (dd, 1H, J ) 2.5
Hz, J ′ ) 5.1 Hz), 4.22 (d, 1H, J ) 15 Hz), 4.01 (dd, 1H, J ) 2.1
Hz, J ′ ) 7.9 Hz), 3.94 (dd, 1H, J ) 4.8 Hz, J ′ ) 9.2 Hz), 3.79
(dd, 1H, J ) 2.1 Hz, J ′ ) 9.2 Hz), 2.15 (s, 3H), 1.54 (s, 3H),
1.37 (s, 3H), 1.35 (s, 3H), 1.29 (s, 3H); 13C NMR (CDCl3, δ)
169.4, 166.8, 136.1, 128.5, 128.2, 127.7, 109.5, 108.6, 95.9, 73.6,
70.8, 70.5, 69.7, 66.4, 56.7, 45.9, 25.8, 25.8, 24.8, 24.5, 20.7;
MS m/z 448 (M + 1).
Mon od eben zyla tion of 7. To a solution of 7 (12.7 g, 26
mmol) in methanol (200 mL) was added 10% palladium on
charcoal (1.5 g), and the mixture was kept under hydrogen (1
atm). The reaction mixture was stirred at room temperature
until the dissappearance of the starting material as monitored
by TLC (5-7 h). Then, the suspension was filtered through a
pad of Celite and evaporated to yield 13, which was purified
by column chromatography and further crystallization from
Et2O/hexane: yield 9.82 g (95%); mp 76-78 °C; [R]25D ) +22.4
(c ) 1.0, CH2Cl2); IR (KBr) 3433 (OH), 1738 cm-1 (CO); 1H
NMR (CDCl3, δ) 7.42-7.26 (m, 10H), 5.01 (d, 1H, J ) 11.4
Hz), 4.86 (d, 1H, J ) 14.5 Hz), 4.72 (d, 1H, J ) 14.5 Hz), 4.64
(d, 1H, J ) 5.0 Hz), 4.22 (dd, 1H, J ) 6.9 Hz, J ′ ) 8.9 Hz),
4.20 (d, 1H, J ) 11.4 Hz), 3.80 (dt, 1H, J ) 4.9 Hz, J ′ ) 6.9
Hz), 3.66 (dd, 2H, J ) 4.9 Hz, J ′ ) 5.9 Hz), 3.59 (dd, 1H, J )
5.0 Hz, J ′ ) 8.9 Hz), 1.39 (s, 3H), 1.26 (s, 3H); 13C NMR (CDCl3,
δ) 166.8, 136.0, 135.6, 128.8, 128.7, 128.6, 128.5, 128.3, 127.7,
109.7, 80.2, 80.0, 78.7, 73.0, 62.7, 58.5, 45.1, 27.3; MS m/z (M+)
398. Anal. Calcd for C23H27NO5 (397.47): C, 69.50; H, 6.85;
N, 3.52. Found: C, 69.87; H, 7.24; N, 3.62.
Ca r ba m oyla tion of 13. To a solution of p-nitrophenyl
chloroformate (31.12 g, 87.77 mmol) and pyridine (73.14 mL,
0.9 mol) in dry methylene chloride (250 mL) at 0 °C was added
a solution of 13 (9.82 g, 24.7 mmol) in methylene chloride (250
mL) dropwise. The resulting mixture was stirred at room
temperature for 45 min, the solution was washed with 0.5 M
H2SO4 (3 × 300 mL), saturated solution of NaHCO3 (3 × 300
mL), and brine (3 × 300 mL), dried over MgSO4, and filtered,
and the solvent was evaporated under reduced pressure. The
resulting residue was redissolved in THF (200 mL), cooled to
0 °C, and treated with a 25% aqueous solution of NH3 (55 mL).
After the mixture was stirred for 30 min at room temperature,
(3R,4S)-3-Acetoxy-1-ben zyl-4-[(1S,5S)-5-ben zyloxym eth -
yl-3,3-d im et h yl-2,4-d ioxa cyclop en t a n e-1-yl]a zet id in -2-
on e (8). Method A was followed starting from the correspond-
ing aldehyde: yield 7.91 g (90%); mp 82-84 °C; [R]25D ) -15.8
(c ) 1.0, CH2Cl2); IR (KBr) 1759 (CO), 1744 cm-1 (CO); 1H
NMR (CDCl3, δ) 7.40-7.22 (m, 10H), 5.82 (d, 1H, J ) 5 Hz),
4.91 (d, 1H, J ) 15.0 Hz), 4.53 (s, 2H), 4.21 (d, 1H, J ) 15.0
Hz), 4.17 (dd, 1H, J ) 6.2 Hz, J ′ ) 7.7 Hz), 3.93 (dt, 1H, J )
5.7 Hz, J ′ ) 6.2 Hz), 3.79 (dd, 1H, J ) 5 Hz, J ′ ) 7.7 Hz), 3.45
(d, 2H, J ) 5.7 Hz), 1.90, 1.40 and 1.30 (s, 3H); 13C NMR
(CDCl3, δ) 169.3, 164.8, 137.5, 135.1, 128.7, 128.4, 128.3, 127.8,
127.6, 110.5, 78.2, 77.9, 74.0, 73.3, 70.0, 58.0, 45.5, 27.8, 27.5,
20.2; MS m/z (M+) 440. Anal. Calcd for C25H29NO6 (439.50):
C, 68.32; H, 6.65; N, 3.19. Found: C, 67.92; H, 7.05; N, 3.28.
(3R,4R)-1-Ben zyl-4-[(S)-1-ter t-b u t yld im et h ylsilyloxy-
[(1S)-3,3-d im eth yl-2,4-d ioxa cyclop en ta n e-1-yl]m eth yl]-3-
ben zyloxya zetid in -2-on e (18). Method A was followed
starting from the corresponding imine 17:17 yield 8.9 g (87%);
mp 66-68 °C; [R]25 ) -6.1 (c ) 1.0, CH2Cl2); IR (KBr) 1735
D
cm-1 (CO); H NMR (CDCl3, δ) 7.40-7.20 (m, 10H), 4.95 (d,
1
1H, J ) 15 Hz), 4.84 (d, 1H, J ) 11.9 Hz), 4.73 (d, 1H, J )
11.9 Hz), 4.54 (d, 1H, J ) 5.0 Hz), 4.13 (dd, 1H, J ) 4.2 Hz, J ′
) 6.2 Hz), 4.03 (d, 1H, J ) 15 Hz), 4.02 (ddd, 1H, J ) 6.2 Hz,
J ′ ) 6.2 Hz, J ′′ ) 7.3 Hz), 3.69 (dd, 1H, J ) 6.2 Hz, J ′ ) 8.2
Hz), 3.50 (dd, J ) 7.3 Hz, J ′ ) 8.2 Hz), 3.47 (dd, 1H, J ) 4.2
Hz, J ′ ) 5.0 Hz), 1.83 and 1.30 (s, 3H), 0.94 (s, 9H), 0.12 and
0.09 (s, 3H); 13C NMR (CDCl3, δ) 168.2, 137.1, 135.6, 128.9,
128.6, 128.4, 128.2, 128.0, 109.4, 81.2, 78.1, 73.2, 69.8, 65.4,
56.6, 45.8, 26.6, 26.2, 25.2, 18.4, -4.4, -4.6; EIMS m/z (M+)
511. Anal. Calcd for C29H41NO5Si (511.73): C, 68.07; H, 8.07;
N, 2.74. Found: C, 67.90; H, 8.06; N, 2.79.

Directly Linked Peptidyl Nucleoside Antibiotics
J . Org. Chem., Vol. 63, No. 17, 1998 5845
it was washed with a saturated solution of NaHCO3 (3 × 200
mL), the organic layer was then dried over MgSO4 and filtered,
and the solvent was evaporated under reduced pressure. The
crude product thus obtained was subjected to column chro-
matography (eluent EtOAc/hexane 1:3) to afford compound 14
440 (M + 1). Anal. Calcd for C17H22N2O6 (439.3): C, 58.30;
H, 6.33; N, 8.00. Found: C, 57.98; H, 6.61; N, 7.86.
(2R,3R,4R,5R)-5-((3′S,4′R)-1-Ben zyl-3-h yd r oxya zetid in -
2-on e-4-yl)-3,4-dih ydr oxy-3,4-di-O-isopr opyliden e-2-m eth -
oxytetr a h yd r ofu r a n (35). Method A was followed, starting
as a white solid: yield 9.95 g (92%); mp 190-193 °C; [R]25
)
from 34: yield 2.37 g (97%); mp 194-196 °C; [R]25 ) -35.3
D
D
+13.7 (c ) 1.0, CH2Cl2); IR (KBr) 3433 (NH2), 1748 (CO), 1691
(c ) 1.0, CH2Cl2); IR (KBr) 3229 (OH), 1720 cm-1 (CO); 1H
NMR (CDCl3, δ) 7.38-7.20 (m, 5H), 5.0 (s, 1H), 4.96 (d, 1H, J
) 4.7 Hz), 4.88 (d, 1H, J ) 15.7 Hz), 4.81 (dd, 1H, J ) 1.6 Hz,
J ′ ) 6.0 Hz), 4.55 (d, 1H, J ) 6.0 Hz), 4.51 (dd, 1H, J ) 1.6
Hz, J ′ ) 7.2 Hz), 4.18 (d, 1H, J ) 15.7 Hz), 3.80 (dd, 1H, J )
cm-1 (CO); H NMR (CDCl3, δ) 7.38-7.22 (m, 10H), 4.93 (d,
1
1H, J ) 11.5 Hz), 4.85 (d, 1H, J ) 14.7 Hz), 4.72 (d, 1H, J )
11.5 Hz), 4.61 (d, 1H, J ) 5.1 Hz), 4.48 (d, 1H, J ) 10.0 Hz),
4.22 (dd, 1H, J ) 6.7 Hz, J ′ ) 9.0 Hz), 4.17 (d, 1H, J ) 14.7
Hz), 4.00 (m, 1H), 3.96 (m, 1H), 3.58 (dd, J ) 5.1 Hz, J ′ ) 9.0
Hz), 1.40 and 1.27 (s, 3H); 13C NMR (CDCl3, δ) 167.3, 156.3,
135.6, 128.6, 128.5, 128.2, 127.6, 110.6, 79.9, 78.2, 77.9, 72.8,
65.1, 58.6, 45.0, 27.5, 27.3; EIMS m/z 382 (M - 58). Anal.
Calcd for C24H28N2O6 (440.27): C, 65.47; H, 6.41; N, 6.36.
Found: C, 65.77; H, 6.49; N, 6.11.
Gen er a l P r oced u r e for th e P r ep a r a tion of 3-Hyd r oxy
â-La cta m s. Meth od A. To a solution of the corresponding
3-(benzyloxy)azetidin-2-one (7 mmol) in methanol (40 mL) was
added 10% palladium on charcoal (10% w/w), and the mixture
was kept under hydrogen (1 atm). The reaction mixture was
stirred at room temperature for 16 h. Then, the suspension
was filtered through a pad of Celite and evaporated to yield
the corresponding 3-hydroxyazetidin-2-one, which was purified
by column chromatography and further crystallization. Meth od
B. To a solution of the corresponding 3-acetoxyazetidin-2-one
(17.5 mmol) in a mixture of THF (175 mL) and water (60 mL)
at 0 °C were added LiOH (0.84 g, 35 mmol) and a 30% solution
of H2O2 (10.82 mL, 105 mmol). The resulting solution was
stirred at the same temperature for 3 h, and then a solution
of Na2S2O3 (1.5 M, 140 mL, 93.3 mmol) was added. Most of
the THF was removed under vacuum from the mixture, the
resulting residue was dissolved in methylene chloride (250
mL), the solution washed with a saturated solution of NaHCO3
(2 × 250 mL) and dried over MgSO4, and the solvent was
finally removed under reduced pressure. The crude product
thus obtained was purified by crystallization.
4.7 Hz, J ′ ) 7.2 Hz), 3.14 (s, 3H), 1.50 (s, 3H), 1.32 (s, 3H); 13
C
NMR (CDCl3, δ) 169.8, 135.5, 128.7, 127.6, 127.4, 112.6, 110.0,
88.3, 84.7, 81.5, 75.9, 59.9, 55.3, 44.6, 26.4, 24.9; EIMS m/z
350 (M + 1). Anal. Calcd for C18H23NO6 (349.38): C, 61.86;
H, 6.63; N, 4.01. Found: C, 61.48; H, 6.92; N, 4.05.
(2R,3R,4S,5S,6R)-6-((3′S,4′R)-1-Ben zyl-3-h yd r oxya zeti-
d in -2-on e-4-yl)-2,3,4,5-t et r a h yd r oxy-2,3:4,5-bis(d i-O-iso-
p r op ylid en e)p yr a n e (49). Method B was followed: yield 6.74
g (95%); oil [R]25 ) -49.7 (c ) 1.0, CH2Cl2); IR (film) 3330
D
(OH), 1735 cm-1 (CO); 1H NMR (CDCl3, δ) 7.29-7.25 (m, 5H),
6.57 (d, 1H, J ) 5.1 Hz), 4.83 (d, 1H, J ) 4.9 Hz), 4.76 (d, 1H,
J ) 14.5 Hz), 4.59 (dd, 1H, J ) 2.4 Hz, J ′ ) 7.9 Hz), 4.40 (dd,
1H, J ) 1.6 Hz, J ′ ) 7.9 Hz), 4.33 (dd, 1H, J ) 2.4 Hz, J ′ )
5.1 Hz), 4.25 (d, 1H, J ) 14.5 Hz), 4.12 (dd, 1H, J ) 1.6 Hz, J ′
) 6.6 Hz), 3.80 (dd, 1H, J ) 4.9 Hz, J ′ ) 6.6 Hz), 1.54, 1.41,
1.32 and 1.31 (s, 3H); 13C NMR (CDCl3, δ) 169.8, 135.9, 128.6,
128.5, 127.5, 109.4, 108.9, 96.2, 75.9, 71.0, 70.7, 70.4, 68.0, 57.1,
45.1, 25.9, 24.9, 24.4; EIMS m/z 406 (M + 1).
Syn th esis of Bis-â-la cta m 30. To a solution of (4R,5R)-
(-)-diethyl-2,3-O-isopropylidene-L-tartrate (2.44 g, 10 mmol)
in dry toluene (30 mL) at -78 °C was added dropwise a 1 M
solution of DIBAL (22 mL) in hexane. The resulting solution
was stirred for 3 h, and then benzylamine (2.18 mL, 20 mmol)
was added in one portion and the reaction mixture allowed to
warm to room temperature and stirred for 14 h. The nitrogen
balloon was then removed, and the reaction mixture was
stirred under air for 8 h. The precipitate formed was filtered
off, and the filtrate was concentrated to get the diimine 29,
which was used without further purification. A solution of
benzyloxyacetyl chloride (3.94 mL, 25 mmol) in anhydrous
methylene chloride (30 mL) was added to a solution of the
diimine (18 mmol) and triethylamine (7.48 mL, 54 mmol) in
methylene chloride (100 mL) at -20 °C under a nitrogen
atmosphere. The resulting mixture was allowed to warm to
room temperature and stirred for 14 h. The reaction mixture
was washed with water (100 mL), a solution of HCl 1 M (100
mL), and a saturated solution of NaHCO3 (100 mL). The
organic layer was dried over MgSO4, the solvent evaporated
under vaccum, and the thus obtained crude was purified by
column chromatography (silica gel 60, eluent EtOAc/hexane
1:4). The resulting product was dissolved in ethanol (50 mL),
and 10% Pd/C (0.6 g) was added. The mixture was stirred
under 1 atm H2 for 15 h and then filtered off using a path of
Celite. Evaporation of the solvent afforded compound 30 as a
(3R,4S)-1-Ben zyl-4-[(1S)-3,3-d im et h yl-2,4-d ioxola n -1-
yl]-3-h yd r oxya zetid in -2-on e (9). Method B was followed
starting from 6: yield 4.46 g (92%); mp 159-160 °C; [R]25
)
D
-42.7 (c ) 1.0, CH2Cl2); IR (KBr) 3270 (OH), 1722 cm-1 (CO);
1H NMR (CDCl3, δ) 7.34-7.22 (m, 5H), 4.81 (d, 1H, J ) 14.8
Hz), 4.80 (m, 1H), 4.54-4.52 (m, 1H), 4.38-4.32 (m, 1H), 4.14
(d, 1H, J ) 14.9 Hz), 4.15 (dd, 1H, J ) 6.44, J ′ ) 8.4 Hz), 3.71
(dd, 1H, J ) 5.1 Hz, J ′ ) 9.0 Hz), 3.53 (dd, 1H, J ) 4.9 Hz, J ′
) 6.8 Hz), 1.39 and 1.32 (s, 3H); 13C NMR (CDCl3, δ) 170.7,
135.9, 129.2, 128.3, 110.2, 77.1, 75.8, 67.2, 61.2, 45.7, 27.2, 25.6.
Anal. Calcd for C15H19NO4 (277.31): C, 64.96; H, 6.91; N, 5.05.
Found: C, 65.91; H, 6.59; N, 5.07.
(3R,4S)-1-Ben zyl-4-[(1S,5S)-5-ben zyloxym eth yl-3,3-d i-
m eth yl-2,4-d ioxa cyclop en ta n e-1-yl]-3-h yd r oxya zetid in -2-
on e (10). Method B was followed starting from 8: yield 6.61
g (95%); mp 98-102 °C; [R]25 ) -12.9 (c ) 1.0, CH2Cl2); IR
D
(KBr) 3270 (OH), 1723 cm-1 (CO); H NMR (CDCl3, δ) 7.4-
1
7.2 (m, 10H), 4.82 (d, 1H, J ) 14.5 Hz), 4.77 (d, 1H, J ) 4.5
Hz), 4.52 (s, 2H), 4.19 (dd, 1H, J ) J ′ ) 6.6 Hz), 4.16 (d, 1H,
J ) 14.5 Hz), 4.13 (s, 1H), 3.98 (dt, 1H, J ) 5.6 Hz, J ′ ) 6.6
Hz), 3.64 (d, 2H, J ) 5.6 Hz), 3.60 (dd, 1H, J ) 4.5 Hz, J ′ )
6.6 Hz), 1.37 (s, 3H), 1.35 (s, 3H); 13C NMR (CDCl3, δ) 168.8,
137.0, 135.4, 128.7, 128.6, 128.5, 128.0, 127.9, 127.8, 110.0,
78.8, 77.7, 76.0, 73.8, 70.4, 59.3, 45.4, 27.1, 27.0; MS m/z 382
(M - 15). Anal. Calcd for C23H27NO5 (397.47): C, 69.50; H,
6.85; N, 3.52. Found: C, 69.15; H, 7.16; N, 3.91.
white solid: yield 1.80 g (40%); mp 212-214 °C (EtOAc); [R]25
D
) +17.2 (c ) 1.0, DMSO); IR (KBr) 3250 (OH), 1748, 1727
1
cm-1 (CO); H NMR (DMSO-d6, δ) 7.36-7.20 (m, 10H), 6.12
(d, 2H, J ) 3.9 Hz), 4.70 (d, 2H, J ) 4.4 Hz), 4.56 (d, 2H, J )
14.9 Hz), 4.12 (d, 2H, J ) 14.9 Hz), 3.98 (dd, 2H, J ) 5.9 Hz,
J ′ ) 1.7 Hz), 3.60 (dd, 2H, J ) 5.1 Hz, J ′ ) 1.7 Hz), 1.25 (s,
6H); 13C NMR (CDCl3, δ) 168.8, 136.5, 128.5, 127.4, 127.2,
108.5, 78.7, 75.7, 58.6, 44.7, 26.8. Anal. Calcd for C25H28N2O6
(452.49): C, 66.55; H, 6.23; N, 6.19. Found: C, 66.20; H, 6.56;
N, 6.12.
Gen er a l P r oced u r e for t h e P r ep a r a t ion of r-Am in o
Acid N-Ca r boxya n h yd r id es (NCAs). To a magnetically
stirred solution of 3-hydroxyazetidin-2-one (1 mmol) in 5 mL
of methylene chloride were added 2,2,6,6-tetramethylpiperidin-
1-oxyl (TEMPO) (0.002 g, 0.01 mmol) and a solution of
potassium bromide (0.012 g, 0.1 mmol) in water (0.15 mL) at
room temperature. The solution was cooled to -5 to 0 °C (ice-
salt bath), and aqueous sodium hypochlorite (Aldrich, cat. no.
23,930-5) (10 mL) buffered at pH 7 (0.6 g of sodium hydrogen
carbonate for 30 mL of a concentrate buffer solution phosphate,
(3R,4S)-1-Ben zyl-4-[(1S,5S)-5-ca r ba m oyloxym eth yl-3,3-
dim eth yl-2,4-dioxacyclopen tan e-1-yl]-3-h ydr oxyazetidin -
2-on e (15). Method A was followed starting from 14: yield
2.79 g (91%); mp 176-178 °C; [R]25 ) -25.4 (c ) 1.0, CH2-
D
Cl2); IR (KBr) 3473 (NH), 3359 (OH), 1714 (CO), 1704 cm-1
(CO); 1H NMR (CDCl3, δ) 7.36-7.26 (m, 5H), 4.86 (d, 1H, J )
4.8 Hz), 4.72 (d, 1H, J ) 14.9 Hz), 4.40 (m, 1H), 4.27 (d, 1H,
J ) 14.9 Hz), 4.20 (dd, 1H, J ) 6.4 Hz, J ′ ) 8.6 Hz), 4.07 (m,
2H), 3.72 (dd, 1H, J ) 4.8 Hz, J ′ ) 8.6 Hz), 1.39 and 1.29 (s,
3H); 13C NMR (CDCl3, δ) 168.1, 156.1, 135.0, 127.5, 126.6,
109.3, 77.7, 76.1, 74.8, 63.8, 59.5, 44.1, 26.6, 26.4; EIMS m/z

5846 J . Org. Chem., Vol. 63, No. 17, 1998
Palomo et al.
Aldrich, cat. no. 22,358-1) was added. The resulting reaction
mixture was stirred at 0 °C for 0.5-2 min. The organic layer
was separated and washed with 20 mL of 10% HCl containing
0.25 g of KI, a 10% solution of Na2S2O3 (10 mL), and water
(10 mL). The resulting solution was dried over MgSO4, and
the solvent was evaporated under reduced pressure to afford
the corresponding NCA.
mp 128-130 °C; [R]25 ) -28.6 (c ) 1.0, CH2Cl2); IR (KBr)
D
3293 (NH), 1748, 1720, 1655, 1649 cm-1 (CO); 1H NMR (CDCl3,
δ) 6.65 (d, 1H, J ) 8.4 Hz), 6.52 (d, 1H, J ) 8.2 Hz), 6.10 (d,
1H, J ) 8.1 Hz), 4.92 (s, 1H), 4.85 (d, 1H, J ) 3.9 Hz), 4.68 (d,
1H, J ) 5.9 Hz), 4.58-4.45 (m, 3H), 4.30-4.24 (m, 1H), 3.71
(s, 3H), 3.37 (s, 3H), 1.69-1.51 (m, 6H), 1.45 (s, 9H), 1.45 (s,
3H), 1.29 (s, 3H), 1.25-0.87 (m, 12H); 13C NMR (CDCl3, δ)
172.9, 171.3, 169.6, 155.7, 112.7, 110.0, 87.1, 85.3, 81.9, 80.7,
56.9, 55.8, 52.2, 51.3, 50.7, 41.2, 40.6, 28.2, 26.4, 25.0, 24.6,
24.5, 22.9, 22.8, 21.9, 21.7. Anal. Calcd for C28H49N3O10
(587.71): C, 57.22; H, 8.40; N, 7.15. Found: C, 57.25; H, 8.70;
N, 7.17.
(4S)-3-Ben zyl-4-[(1S,5S)-5-car bam oyloxym eth yl-3,3-dim -
et h yl-2,4-d ioxa cyclop en t a n e-1-yl]oxa zolid in e-3,5-d ion e
(16): yield 0.33 g (90%); mp 120-124 °C; [R]25 ) -24.6 (c )
D
0.5, DMSO); IR (KBr) 3456, 3353 (NH2), 1835, 1764, 1707 cm-1
(CO); 1H NMR (CDCl3, δ) 7.33-7.32 (m, 5H), 5.28 (m, 2H),
5.03 (d, 1H, J ) 15.0 Hz), 4.42 (d, 1H, J ) 15.0 Hz), 4.39-
4.34 (m, 1H), 4.32-4.19 (m, 3H), 4.11-4.04 (m, 1H), 1.40 and
1.34 (s, 3H); 13C NMR (CDCl3, δ) 165.6, 156.5, 152.1, 134.3,
128.9, 128.4, 110.6, 77.2, 75.9, 64.0, 60.7, 46.9, 26.8, 26.7.
Anal. Calcd for C17H20N2O7 (364.35): C, 56.04; H, 5.53; N,
7.64. Found: C, 55.68; H, 5.71; N, 7.86.
Dip ep tid e p r od u ct 43: yield 0.460 g (90%); mp 142-144
°C; [R]25 ) -54.8 (c ) 1.0, MeOH); IR (KBr) 3452, 3343 (NH,
D
NH2), 1733, 1720, 1666 cm-1 (CO); H NMR (CDCl3, δ) 8.26
1
(d, 1H, J ) 8.6 Hz), 7.32-7.21 (m, 5H), 4.98 (s, 1H), 4.91-
4.84 (m, 2H), 4.66 (d, 1H, J ) 6.0 Hz), 4.49 (d, 1H, J ) 6.0
Hz), 4.46 (dd, 1H, J ) 4.1 Hz, J ′ ) 5.9 Hz), 4.17 (dd, 1H, J )
4.1 Hz, J ′ ) 11.6 Hz), 4.03 (m, 2H), 3.96 (d, 1H, J ) 13.4 Hz),
3.79 (s, 3H), 3.59 (d, 1H, J ) 13.4 Hz), 3.37 (s, 3H), 3.29 (d,
1H, J ) 7.0 Hz), 2.41 (s, 2H), 1.43, 1.35, 1.26 and 1.22 (s, 3H);
13C NMR (CDCl3, δ) 173.0, 170.2, 157.3, 139.6, 128.9, 128.6,
127.8, 113.2, 110.5, 110.2, 87.4, 86.0, 81.9, 78.6, 77.1, 65.4, 64.6,
56.0, 54.7, 53.2, 52.8, 27.8, 27.7, 26.9, 25.4. Anal. Calcd for
Bis NCA 31. The general procedure was followed starting
from 0.45 g of 30: yield 0.47 g (98%); 1H NMR (CDCl3, δ) 7.35-
7.25 (m, 10H), 5.02 (d, 2H, J ) 15.0 Hz), 4.55 (d, 2H, J ) 4.4
Hz), 4.38 (d, 2H, J ) 15.0 Hz), 1.33 (s, 6H); 13C NMR (CDCl3,
δ) 166.2, 151.8, 134.3, 129.0, 128.6, 128.5, 111.8, 61.3, 47.0,
26.6.
5-(Ben zyla m in o)-5-d eoxy-1-O-m et h yl-2,3-d i-O-isop r o-
p ylid en e-â-D-a llofu r a n u r on ic a cid NCA (36): yield 0.33 g
(91%); oil; IR (film) 1843 (CO), 1778 cm-1 (CO); 1H NMR
(CDCl3, δ) 7.35-7.20 (m, 5H), 5.11 (dd, 1H, J ) 2.2 Hz, J ′ )
5.9 Hz), 5.09 (d, 1H, J ) 15.7 Hz), 5.00 (s, 1H), 4.57 (d, 1H, J
) 5.9 Hz), 4.44 (dd, 1H, J ) 2.2 Hz, J ′ ) 6.3 Hz), 4.36 (d, 1H,
J ) 13.7 Hz), 4.21 (d, 1H, J ) 6.3 Hz), 3.16 (s, 3H), 1.45 (s,
3H), 1.30 (s, 3H); 13C NMR (CDCl3, δ) 165.7, 152.1, 134.3,
129.1, 128.4, 127.5, 113.4, 110.1, 88.1, 84.3, 80.2, 61.1, 56.0,
46.6, 26.6, 25.0; EIMS m/z 364 (M + 1).
C
27H39N3O11 (581.62): C, 55.76 H, 6.76; N, 7.22. Found: C,
55.63; H, 7.05; N, 7.28.
Meth yl 5-(Ben zylam in o)-5-deoxy-â-D-allofu r an u r on ate,
1-O-Meth yl-2,3-d i-O-isop r op ylid en e (37). Compound 36
(0.36 g, 1 mmol) was dissolved in MeOH (8 mL), and the
solution was stirred at room temperature for 2 h. The
evaporation of the solvent afforded crude 37, which was
purified by crystallization from hexane: yield 0.17 g (96%);
mp 82-84 °C; [R]25 ) -10.0 (c ) 1.0, CH2Cl2); IR (KBr) 3342
D
(NH), 1739 cm-1 (CO); 1H NMR (CDCl3, δ) 7.30-7.20 (m, 5H),
4.91 (s, 1H), 4.82 (d, 1H, J ) 6 Hz), 4.64 (d, 1H, J ) 3.8 Hz),
4.62 (d, 1H, J ) 6.0 Hz), 3.96 (d, 1H, J ) 13.3 Hz), 3.73 (s,
3H), 3.52 (d, 1H, J ) 13.3 Hz), 3.31 (d, 1H, J ) 3.8 Hz), 3.30
(s, 3H), 2.66 (m, 1H), 1.44 and 1.30 (s, 3H); 13C NMR (CDCl3,
δ) 172.1, 139.7, 128.1, 127.9, 126.7, 111.8, 110.9, 87.7, 85.9,
82.2, 62.2, 55.4, 51.7, 26.3, 24.8; EIMS m/z (M + H)+ 352, 353.
Anal. Calcd for C18H26NO6 (351.4): C, 61.52; H, 7.17; N, 3.98.
Found: C, 61.48; H, 7.19; N, 4.06.
(2R,3R,4S,5S,6R)-6-((4′R)-3-Ben zyloxazolidin e-2,3-dion e-
4-yl)-2,3,4,5-tetr ah ydr oxy-2,3:4,5-bis(di-O-isopr opiliden e)-
p yr a n (50): yield 0.40 g (95%); oil; IR (film) 1848, 1778 cm-1
1
(CO); H NMR (CDCl3, δ) 7.5-7.2 (m, 5H), 5.62 (d, 1H, J )
5.0 Hz), 5.06 (d, 1H, J ) 14.6 Hz), 4.62 (dd, 1H, J ) 8.0 Hz, J ′
) 2.7 Hz), 4.5-4.2 (m, 3H), 4.34 (d, 1H, J ) 14.6 Hz), 4.2-4.0
(m, 1H), 1.52, 1.37, 1.34 and 1.32 (s, 3H); 13C NMR (CDCl3, δ)
165.6, 152.4, 134.4, 129.0, 128.9, 128.5, 110.2, 109.3, 96.2, 70.4,
70.1, 69.8, 68.8, 57.1, 47.5, 26.0, 25.4, 24.7, 24.4; EIMS m/z
(M+) 419.
Met h yl 5-Am in o-5-d eoxy-â-D-a llofu r a n u r on a t e, 1-O-
Meth yl-2,3-d i-O-isop r op ylid en e 42. To a solution of 37
(0.28 g, 0.8 mmol) in methanol (5 mL) was added 10%
palladium on charcoal (10% w/w, 0.03 g), and the mixture was
kept under hydrogen (1 atm). The reaction mixture was
stirred at room temperature for 4 h. Then, the suspension
was filtered through a pad of Celite and evaporated to afford
crude compound 42, which was purified by column chroma-
Gen er a l P r oced u r e for th e Cou p lin g of NCAs w ith
r-Am in o Acid Ester s. To a solution of the corresponding
NCA (1 mmol) in the corresponding solvent (10 mL) was added
the R-amino acid ester (2 mmol), and the resulting mixture
stirred at room temperature for 24 h. Then diethyl ether (40
mL) was added, and the organic layer was washed with 0.1 N
HCl (2 × 50 mL) and a saturated solution of NaHCO3 (2 × 50
mL) and dried over MgSO4 and the solvent evaporated under
reduced pressure to afford the corresponding peptide, which
was purified by column chromatography.
Tr ip ep tid e p r od u ct 40: yield 0.50 g (87%); mp 108-110
°C; [R]25D ) -34.0 (c ) 0.5, CH2Cl2); IR (KBr) 3318 (NH), 1746,
1682, 1652 cm-1 (CO); 1H NMR (CDCl3, δ) 7.80 (d, 1H, J )
7.9 Hz), 7.38-7.27 (m, 5H), 6.52 (d, 1H, J ) 8.4 Hz), 5.05 (d,
1H, J ) 6.0 Hz), 4.92 (s, 1H), 4.59 (d, 1H, J ) 6.0 Hz), 4.60-
4.40 (m, 2H), 4.17 (d, 1H, J ) 9.0 Hz), 3.74 (d, 1H, J ) 12.9
Hz), 3.72 (s, 3H), 3.63 (d, 1H, J ) 12.9 Hz), 3.28 (s, 3H), 3.23
(d, 1H, J ) 9.0 Hz), 1.76-1.45 (m, 6H), 1.42 and 1.28 (s, 3H),
1.04-0.9 (m, 12H); 13C NMR (CDCl3, δ) 173.0, 171.7, 171.3,
138.9, 128.7, 128.0, 127.5, 112.3, 110.3, 87.1, 85.0, 81.6, 65.5,
55.7, 52.9, 52.2, 51.1, 50.7, 41.2, 40.3, 26.4, 25.0, 24.7, 22.8,
22.7, 21.9. Anal. Calcd for C30H47N3O8 (577.72): C, 62.37; H,
8.20; N, 7.27. Found: C, 62.62; H, 8.48; N, 7.41.
tography: yield 0.167 g (80%); mp 36-38 °C; [R]25 ) -44.4 (c
D
) 1.0, CH2Cl2); IR (KBr) 3391 (NH), 1746 cm-1 (CO); 1H NMR
(CDCl3, δ) 4.80 (d, 1H, J ) 5.7 Hz), 4.79 (s, 1H), 4.56 (d, 1H,
J ) 4.5 Hz), 4.45 (d, 1H, J ) 5.7 Hz), 3.62 (s, 3H), 3.41 (d, 1H,
J ) 4.5 Hz), 3.21 (s, 3H), 1.84 (s, 2H) 1.34 and 1.18 (s, 3H);
13C NMR (CDCl3, δ) 173.6, 111.9, 110.4, 88.1, 85.7, 81.6, 56.8,
55.2, 51.9, 26.2, 24.6. EIMS m/z 262 (M + 1). Anal. Calcd
for C11H19NO6 (261.27): C, 50.57; H, 7.32; N, 5.36. Found:
C, 50.78; H, 7.53; N, 5.39.
Ack n ow led gm en t. This work was financially sup-
ported by Comisio´n Interministerial de Ciencia y Tec-
nolog´ıa (Project SAF: 95/0749) and in part by Gobierno
Vasco (Project PI 95/93) and by Diputacio´n Foral de
Gipuzkoa. Grants from Gobierno Vasco to A.E. and
J .I.M. are gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for 11, 12, 19-21, 22a ,b, 23a , epi-23a , 23b, 23c, 24a ,b,
25a ,b, 26-28, 32, 38, 39, 45, 51, and 52, ORTEP representa-
tions of 34, 39, and 48, and NMR spectra of representative
compounds (30 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
Tr ip ep tid e P r od u ct 41. To a solution of 40 (0.29 g, 0.5
mmol) and (Boc)2O (0.45 g, 2 mmol) in ethanol (13 mL) was
added 10% Pd(OH)2 on charcoal (0.030 g), and the mixture was
kept under hydrogen (1 atm). The reaction mixture was
stirred at room temperature until the dissappearance of the
starting material as monitored by TLC (24 h). Then, the
suspension was filtered through a pad of Celite and evaporated
to yield 41, which was purified by column chromatography and
further crystallization from EtOAc/Hex: yield 0.21 g (71%);
J O980354X