Model studies toward the synthesis of dihydropyrimidinyl and pyridyl α-amino acids via three-component Biginelli and Hantzsch cyclocondensations

Article abstract of DOI:10.1021/jo0342830

A novel and versatile strategy for the synthesis of heterocyclic α-amino acids has been described. The use of components (aldehyde or β-ketoester) bearing a masked glycinyl moiety in Biginelli and Hantzsch cyclocondensations allowed access to the 4-dihydropyrimidinyl-α-glycines, 4-dihydropyrimidinyl-α-alanines, 4-pyridyl-α-alanines, and 2-pyridyl-α-alanines classes. Dihydropyrimidinylamino acids were obtained as a mixture of diastereoisomers due to the formation of the stereocenter at C4 of the dihydropyrimidinone ring. Individual stereoisomers were isolated as pure compounds and their structures were assigned with the aid of X-ray crystallography and chiroptical properties. The enantiomeric purity of a representative selection of the above amino acids was greater than 96% as verified by derivatization to the corresponding Mosher's amides and subsequent ¹H and ¹⁹F NMR spectroscopy. Incorporation of the 4-pyridyl-α-alanine derivative into a peptide chain is also described.

Full text of DOI:10.1021/jo0342830

Mod el Stu d ies tow a r d th e Syn th esis of Dih yd r op yr im id in yl a n d
P yr id yl r-Am in o Acid s via Th r ee-Com p on en t Bigin elli a n d
Ha n tzsch Cyclocon d en sa tion s
Alessandro Dondoni,*,‡ Alessandro Massi,‡ Erik Minghini,‡ Simona Sabbatini,‡ and
Valerio Bertolasi§
Dipartimento di Chimica, Universita` di Ferrara, Via L. Borsari 46, 44100 Ferrara, Italy
adn@dns.unife.it
Received March 4, 2003
A novel and versatile strategy for the synthesis of heterocyclic R-amino acids has been described.
The use of components (aldehyde or â-ketoester) bearing a masked glycinyl moiety in Biginelli and
Hantzsch cyclocondensations allowed access to the 4-dihydropyrimidinyl-R-glycines, 4-dihydropy-
rimidinyl-R-alanines, 4-pyridyl-R-alanines, and 2-pyridyl-R-alanines classes. Dihydropyrimidinyl-
amino acids were obtained as a mixture of diastereoisomers due to the formation of the stereocenter
at C4 of the dihydropyrimidinone ring. Individual stereoisomers were isolated as pure compounds
and their structures were assigned with the aid of X-ray crystallography and chiroptical properties.
The enantiomeric purity of a representative selection of the above amino acids was greater than
96% as verified by derivatization to the corresponding Mosher’s amides and subsequent 1H and
19F NMR spectroscopy. Incorporation of the 4-pyridyl-R-alanine derivative into a peptide chain is
also described.
In tr od u ction
tion of dehydroamino acid derivatives,5 and coupling
reactions of suitable functionalized heterocycles with
chiral glycine6 or alanine7 equivalents. More versatile
approaches appear where a range of heterocycles can be
generated either by cyclocondensations of alkynyl ketone
intermediates with bifunctional nucleophiles8 or by a
“ring switching” process.9 Nevertheless, the potential of
a combinatorial approach applicable to a parallel syn-
thesis of analogue families of heterocyclic R-amino acids
has not fully exploited so far.8,10 Furthermore both (D)-
and (L)-R-amino acids may have different properties and
thus are required in homochiral form. For these reasons
we report on the use of substrates A (aldehyde11 or
â-ketoester) bearing the N-Boc-2,2-dimethyl oxazolidine
ring as components in Biginelli12 and Hantzsch13 cyclo-
condensations to access two different series of heterocyclic-
A growing interest has recently been focused on the
synthesis of unnatural R-amino acids; their use in the
fields of peptide and combinatorial chemistry as confor-
mational constraints, molecular scaffolds, and chiral
auxiliaries is related to the development of new leads in
peptidic and nonpeptidic compounds.1 The class of non-
proteinogenic heterocyclic R-amino acids is of particular
interest in this context due to their diverse range of
chemical and biomedicinal applications not only as com-
ponents of peptides2 and peptide nucleic acids (PNAs)3
but also as free amino acids4 (e.g. the antitumor-anti-
biotic agent L-azatyrosine4a). A number of methods have
been developed for the synthesis of heterocyclic R-amino
acids; most of them are based on asymmetric hydrogena-
‡ Laboratorio di Chimica Organica.
(5) (a) Wang, W.; Cai, M.; Xiong, C.; Zhang, J .; Trivedi, D.; Hruby,
V. J . Tetrahedron 2002, 58, 7365. (b) Adamczyk, M.; Akireddy, S. R.;
Reddy, R. E. Tetrahedron: Asymmetry 2001, 12, 2385. (c) Adamczyk,
M.; Akireddy, S. R.; Reddy, R. E. Org. Lett. 2001, 20, 3157.
(6) (a) Dalla Croce, P.; La Rosa, C.; Pizzatti, E. Tetrahedron:
Asymmetry 2000, 11, 2635. (b) Myers, A. G.; Gleason, J . L. J . Org.
Chem. 1996, 61, 813. (c) Schow, S. R.; DeJ oy, S. Q.; Wick, M. M.;
Kerwar, S. S. J . Org. Chem. 1994, 59, 6850.
(7) (a) J ones, R. C. F.; Berthelot, D. J . C.; Iley, J . N. Tetrahedron
2001, 57, 6539. (b) J ones, R. C. F.; Berthelot, D. J . C.; Iley, J . N. Chem.
Commun. 2000, 2131. (c) Walker, M. A.; Kaplita, K. P.; Chen, T.; King,
H. D. Synlett 1997, 169. (d) Ye, B.; Burke, T. R. J . Org. Chem. 1995,
60, 2640.
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J .; Tang, L. T. J . Chem. Soc., Perkin Trans. 1 2000, 2311. (b) Adlington,
R. M.; Baldwin, J . E.; Catterick, D.; Pritchard, G. J .; Tang, L. T. J .
Chem. Soc., Perkin Trans. 1 2000, 303. (c) Adlington, R. M.; Baldwin,
J . E.; Catterick, D.; Pritchard, G. J . J . Chem. Soc., Perkin Trans. 1
1999, 855.
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Chem. Soc., Perkin Trans. 1 2002, 613. (b) Dinsmore, A.; Doyole, P.
M.; Young, D. W. J . Chem. Soc., Perkin Trans. 1 2002, 155.
§ Centro di Strutturistica Diffrattometrica. Address correspondence
concerning crystallography to this author. Fax: +39 0532 240709.
E-mail: m38@unife.it.
(1) (a) Hruby, V. J ., Soloshonok, V. A., Eds. Asymmetric Synthesis
of Novel Sterically Constrained Amino Acids; Symposium. Tetrahedron
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EDK: Paris, France, 2001. (c) Combinatorial Chemistry: A Practical
Approach; Fenniri, H., Ed.; Oxford University Press: Oxford, U.K.,
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S.; Yamaizumi, Z.; Weinstein, I. B.; Pincus, M. R. Anticancer Res. 1991,
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10.1021/jo0342830 CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/16/2003
6172
J . Org. Chem. 2003, 68, 6172-6183

Dihydropyrimidinyl and Pyridyl R-Amino Acids
SCHEME 1. Syn th esis of 4-DHP M-r-glycin esa
F IGURE 1. Synthetic strategy.
substituted R-amino acids, dihydropyrimidinyl (DHPM)-
and pyridyl-R-amino acids (Figure 1). The advantages of
this approach rely on exploiting both the potential of
multicomponent reactions (MCRs) in generating molec-
ular diversity and the existing configuration at the carbon
bearing the amino group in components A. It has in fact
been demonstrated that the N-Boc-2,2-dimethyl oxazo-
lidine ring serves as a convenient masked glycinyl moiety
maintaining unaltered the configuration of the stereo-
center under a variety of reaction conditions.14 We have
planned to reveal it in the final step of our synthetic
strategy to minimize potential racemization of intermedi-
ates. Therefore the unmasking protocol, which involves
a ring opening-oxidation procedure,14 should allow the
conversion of cyclocondensation products B into the
corresponding N-Boc protected amino acids C.
Resu lts a n d Discu ssion
To validate this strategy, the synthesis of 4-dihydro-
pyrimidinyl-R-glycine derivatives was chosen as the
initial synthetic target for investigation. Thus the ther-
mal, acid-catalyzed Biginelli cyclocondensation12 of (R)-
Garner aldehyde15 1 with ethyl acetoacetate 2a and urea
3 was first considered (Scheme 1). Crucial to this step
was finding a suitable acid promoter that would be
tolerated by the sensitive aldehyde 1 under the harsh
reaction conditions. Guided by our previous work on the
synthesis of novel classes of DHPM derivatives,16 we
found the use of Yb(OTf)3 to be quite beneficial. In the
presence of this Lewis acid the above cyclocondensation
(molecular sieves, THF, 70 °C, 14 h) afforded the 4-oxa-
zolidinyl-dihydropyrimidinone 4 in fair yield (60%) as a
5:1 mixture of diastereoisomers due to the formation of
the stereocenter at C4 of the DHPM ring.
a
Reagents and conditions: (a) Yb(OTf)3, 4-Å MS, THF, 70 °C,
14 h; (b) NaH, BnBr, DMF; (c) AcOH-H2O (5:1), rt; (d) 1 M J ones
reagent, 0 °C to rt, 3 h; (e) H2 (5 atm), Pd(OH)2, AcOH-EtOH
(1:1), rt, 7 d.
were separated chromatographically and, since we were
unable to obtain crystalline samples suitable for X-ray
analysis, their stereochemistry was assigned by using
NMR analysis in conjunction with circular dichroism
(CD) measurements. First, the enantiomeric excess of
both (4R)-5 and (4S)-5 was established to be >96% via
derivatization with Mosher’s acid and H and 19F NMR
1
analyses of the corresponding esters, thus indicating that
the stereochemical integrity of aldehyde 1 has been
retained during the cyclocondensation. Second, the (4R)-
configuration of the major isomer was determined by
comparing the CD spectra of each epimeric alcohol 5 with
those of various 4-alkyl DHPMs of known absolute
configuration.16a,17aThe CD spectra of (4R)-5 and (4S)-5
appeared as mirror images and exhibited two bands of
like sign at ca. 290 and 240 nm (Figure 2). The CD
spectrum showing two negative Cotton effects was ten-
tatively assigned to the (4R)-epimer in agreement with
similar CD data of various 4-alkyl DHPMs.16a,17a Al-
though the risk of deducing the absolute stereochemistry
by direct comparison of CD spectra has been stressed by
Removal of the acetonide protective group under
standard conditions (AcOH-H2O) transformed 4 into the
diastereomeric N′-Boc amino alcohols 5. These C4 epimers
(10) Amidocarbonylation, Passerini, Ugi, and Petasis multicompo-
nent reactions have been used for the synthesis of different classes of
amino acid derivatives: (a) Koolmeister, T.; So¨dergren, M.; Scobie, M.
Tetrahedron Lett. 2002, 43, 5969. (b) Owens, T. D.; Semple, E. Org.
Lett. 2001, 21, 3301. (c) Beller, M.; Eckert, M. Angew. Chem., Int. Ed.
2000, 39, 1010. (d) Linderman, R. J .; Binet, S.; Petrich, S. R. J . Org.
Chem. 1999, 64, 336. (e) Diker, G. Angew. Chem., Int. Ed. Engl. 1997,
36, 1700.
(11) N-Protected R-amino aldehydes have been used in Passerini
reactions: (a) Banfi, L.; Guanti, G.; Riva, R.; Basso, A.; Calcagno, E.
Tetrahedron Lett. 2002, 43, 4067. (b) Owens, T. D.; Araldi, G. L.; Nutt,
R. F.; Semple, E. Tetrahedron Lett. 2001, 42, 6271.
(12) (a) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360. For a review
see: (b) Kappe, C. O. Acc. Chem. Res. 2000, 33, 879.
(13) (a) Hantzsch, A. Ann. Chem. 1882, 215, 1. For a review see:
(b) Stout, D. M.; Meyers, A. I. Chem. Rev. 1982, 82, 233.
(14) (a) Dondoni, A.; Mariotti, G.; Marra, A. J . Org. Chem. 2002,
67, 4475. (b) Dondoni, A.; Marra, A.; Massi, A. J . Org. Chem. 1999,
64, 933. (c) Garner, P.; Yoo, J . U.; Sarubu, R.; Kennedy, V. O.; Youngs,
W. J . Tetrahedron 1998, 54, 9303. (d) D’Aniello, F.; Falorni, M.; Mann,
A.; Taddei, M. Tetrahedron: Asymmetry 1996, 4, 1217.
(15) (a) Garner, P.; Park, J . M. Org. Synth. 1992, 70, 18. (b) Dondoni,
A.; Perrone, D. Org. Synth. 1999, 77, 64.
(16) (a) Dondoni, A.; Massi, A.; Sabbatini, S.; Bertolasi, V. J . Org.
Chem. 2002, 67, 6979. (b) Dondoni, A.; Massi, A. Tetrahedron Lett.
2001, 42, 7975.
(17) (a) Uray, G.; Verdino, P.; Belaj, F.; Kappe, C. O.; Fabian, W.
M. F. J . Org. Chem. 2001, 66, 6685 and references therein. (b) Hansen,
A. E.; Bouman, T. D. Adv. Chem. Phys. 1980, 44, 545. (c) Ripa, L.;
Hallberg, A.; Sandstro¨m, J . J . Am. Chem. Soc. 1997, 119, 5701.
J . Org. Chem, Vol. 68, No. 16, 2003 6173

Dondoni et al.
SCHEME 2. Syn th esis of 4-DHP M-r-a la n in esa
F IGURE 2. Experimental CD spectra of (4S)-5 and (4R)-5.
several authors,17b,c this experimental approach has
proved to be reliable so far for the determination of the
C4 configuration of various biologically active
DHMPs.16a,17a
To complete the unmasking of the latent glycinyl
moiety, the use of several oxidative systems (TEMPO-
BAIB, J ones reagent, and RuO2-NaIO4) was next con-
sidered for the conversion of N′-Boc amino alcohols 5 into
the corresponding amino acids 8 (Scheme 1).18 Under
different reaction conditions (temperature and reaction
time) the use of the above reagents led to the pyrimidi-
none 9 as a result of the side oxidation of the DHPM ring,
which caused the loss of the 4-alkyl chain of 5.19 To
overcome this difficulty, we envisioned that alkylation
of the DHPM ring nitrogens could prevent the above side
reaction and thereby selective oxidation of the alcohol to
carboxylic acid could be accomplished. Accordingly, cy-
cloadducts 4 were first benzylated under standard condi-
tions (NaH, BnBr) and then subjected to removal of the
acetonide group to give the N,N-dibenzylated DHPMs 6.20
The conversion of amino alcohols 6 into the corresponding
N′-Boc amino acids 7 was then achieved in very good
yield (85%) by using 1 M J ones reagent as the optimal
oxidant.21 While the introduction of different alkyl chains
into the DHPM scaffold of 4 seems to be feasible by this
strategy for increasing molecular diversity, the synthesis
of unprotected DHPM-glycines of type 8 was instead
investigated. Hydrogenation of derivatives 7 was found
to proceed very slowly over 7 days (H2, Pd(OH)2, rt, 5
atm), affording amino acids 8 in moderate yield (30%).22
To diversify the methodology by varying the substitu-
tion at the DHPM 4 position, the above chemistry was
a
Reagents and conditions: see Scheme 1.
expanded to the use of aldehyde 10,23 the one-carbon-
higher homologue of Garner aldehyde 1. This would allow
access to the important class of â-heterocyclic substituted
R-alanines.5,6a,8a Under the previously reported condi-
tions, the Biginelli cyclocondensation of aldehyde 10 with
ethyl acetoacetate 2a and urea 3 (Scheme 2) afforded the
cyclocondensation product 11 (85%) as a mixture of two
diastereoisomers in a 1:1 ratio. The separation of the
isomers was carried out by preparative TLC.
The transformation of each epimeric 11 into the
corresponding amino alcohol 12 by acetonide removal was
then carried out for the stereochemical assignment by
CD measurements of the newly created C4 stereocenter
as previously described for amino alcohols 5. Very similar
CD spectra of the mirror-image type already reported in
Figure 2 were also observed for the pair of epimers (4S)-
12 and (4R)-12. On the basis of the previously described
experimental method,17a the (4R)-configuration was ten-
tatively assigned to that epimer showing in its CD
spectrum two positive Cotton effects (ca. 290 and 240
nm). It has to be noted that the assignment of the
opposite configuration with respect to alcohols 5 is due
to the different substituent priorities. The above struc-
ture assignment was then confirmed by the X-ray crys-
tallographic analysis of cycloadduct (4R)-11 (Figure 3),
(18) Conversion to amino acids 8 in two steps involving the forma-
tion of the corresponding amino aldehydes as intermediates (Swern
oxidation then TEMPO-BAIB) disappointingly gave decomposed prod-
ucts.
(19) The oxidation of DHPM and dihydropyridine (DHP) derivatives
is an issue that has been addressed by several authors. Dealkylation
(in addition to aromatization) usually occurs when the DHPM and DHP
rings bear a secondary alkyl group at the C4 position while dehydro-
genation takes place in the presence of a primary alkyl group at the
same position. This is a general trend in the oxidation of DHPMs and
DHPs and it is explained by a sequence proceeding by a hydride
abstraction in the first step. (a) Kappe, C. O. Tetrahedron 1993, 49,
6937. (b) Slavinskaya, V. A.; Duburs, G.; Sile, D.; Kreile, D.; Khanina,
E. L. USSR Patent 632,695, 1978. (c) Eynde, J . J . V.; Mayence, A.;
Maquestiau, A. Tetrahedron 1992, 3, 463. (d) Bo¨cker, R. H.; Guengerich
F. P. J . Med. Chem. 1986, 29, 1596.
(20) Each step occurred in fair yield (benzylation, 65%; hydrolysis,
50%) but after column chromatography it was possible to recover
monobenzylated (benzylation step) and dibenzylated (hydrolysis
step) derivatives of 4 that were reused in appropriate reactions of
Scheme 1.
(21) One-step oxidative cleavage of the oxazolidine ring with the
J ones reagent (see ref 14a,b) afforded the corresponding amino acid
in lower overall yield.
(22) A different protection strategy based on selective N3 acylation
(acetyl and pivaloyl groups) of cycloadducts 4 was also investigated to
allow a higher yielding deprotection to 8. Unfortunately, N,O-acyl
migration occurred during acetonide removal of N-acyl cycloadducts
affording undesired O-acyl derivatives of 5.
(23) Ksander, G. M.; de J esus, R.; Yuan, A.; Ghai, R. D.; Trapani,
A.; McMartin, C.; Bohacek, R. J . Med. Chem. 1997, 40, 495.
6174 J . Org. Chem., Vol. 68, No. 16, 2003

Dihydropyrimidinyl and Pyridyl R-Amino Acids
SCHEME 3. Abor tive Syn th esis of
4-P yr id yl-r-glycin esa
F IGURE 3. An ORTEP view of compound (4R)-11 displaying
the thermal ellipsoids at a 40% probability level.
the precursor of alcohol (4R)-12. As in other known solid-
state structures of 4-alkyl-DHPM derivatives,16a,17a the
DHPM ring of (4R)-11 is in a flattened boat conformation
with N1 and C4 as apical atoms and the 4-alkyl sub-
stituent in the pseudoaxial position. It is worth pointing
out that this evidence gratifyingly supported the assigned
absolute configurations at C4 of alcohols 5 as deduced
by CD measurements (Figure 2).
a
Reagents and conditions: (a) 4-Å MS, R1OH, 70 °C, 24 h; (b)
AcOH-H2O (5:1), rt, 24 h; (c) 1 M J ones reagent, 0 °C to rt, 3 h.
SCHEME 4. Syn th esis of 4-P yr id yl-r-a la n in esa
Also in this homologous series, direct conversion of 12
into the corresponding amino acids 15 failed due to a
competitive oxidation of the DHPM ring affording a
complex reaction mixture in which it was possible to
identify the pyrimidinyl-amino alcohol 16 and the amino
acid 17.19 Therefore the same reaction sequence, i.e.,
alkylation, deacetonization, oxidation, and hydrogena-
tion, employed to transform 4 into 8 (see Scheme 1) was
repeated starting from 11 to afford target 4-DHPM-R-
alanine derivatives 14 and 15.
The versatility of the MCR method was further inves-
tigated by varying the heterocyclic structure that func-
tionalizes the amino acid moiety. Pyridyl-R-glycines and
pyridyl-R-alanines,4a,5c,6b,7d which are among the most
important series of unnatural amino acids, were the next
classes of derivatives to be targeted. It is well-known that
three-component Hantzsch cyclocondensation13 of an
aldehyde, a ketoester, and an enamine leads to dihydro-
pyridyl (DHP) cycloadducts which readily undergo oxida-
tion to the corresponding pyridyl derivatives by a number
of reagents.19c,d In our synthetic strategy we thought that
this transformation would take place during the oxidative
unmasking of the glycinyl moiety. In an initial study we
considered the cyclocondensation of (R)-Garner aldehyde
1 with methyl acetoacetate 2b and methyl aminocroto-
nate 18b (Scheme 3).
This reaction proceeded smoothly in MeOH at 70 °C
(molecular sieves) and gave after 24 h the 4-oxazolidinyl-
dihydropyridine 19 in very good yield (87%). Subsequent
removal of the acetonide group afforded the amino alcohol
20, which in turn was converted to the corresponding
Mosher’s esters for the determination of its enantiomeric
purity. We were surprised to find that 20 was a 80:20
mixture of enantiomers, indicating that epimerization of
the stereocenter of aldehyde 1 had taken place during
the cyclocondensation. Mechanistically this result was
intriguing but no further investigation was carried out
at this stage since the next oxidative step proved fruitless
a
Reagents and conditions: see Scheme 3.
as well. In fact, oxidation of alcohol 20 under different
conditions (TEMPO-BAIB, J ones reagent, and RuO2-
NaIO4) led to the pyridine byproduct 21.19 This result
definitively precluded the use of our strategy for the
synthesis of 4-pyridyl-R-glycine derivatives. In contrast,
the approach to the class of 4-pyridyl-R-alanines by the
above method turned out to be successful. Optimized
Hantzsch cyclocondensation of the nonepimerizable al-
dehyde 10 with methyl acetoacetate 2b and methyl
aminocrotonate 18b delivered the DHP-cycloadduct 22b
in almost quantitative yield (Scheme 4). Subsequent
removal of the acetonide group followed by simultaneous
oxidation (J ones reagent) of the hydroxy group and the
DHP ring of amino alcohol intermediate 23b gave the
target 4-pyridyl-R-alanine derivative 24b in 75% overall
yield (3 steps).21 The same reaction sequence carried out
starting from 10, tert-butyl acetoacetate 2c, and tert-butyl
aminocrotonate 18c afforded the corresponding 4-pyridyl-
R-alanine derivative 24c in slightly lower overall yield
(Scheme 4).
Next, in an attempt to diversify this methodology by
installing the amino acid moiety at different heterocyclic
J . Org. Chem, Vol. 68, No. 16, 2003 6175

Dondoni et al.
SCHEME 5 a
SCHEME 7 a
a
Reagents and conditions: (a) HC(N2)CO2t-Bu, BF3‚Et2O, 4-Å
MS, CH2Cl2, 0 °C, 30 min.
SCHEME 6. Syn th esis of 2-P yr id yl-r-a la n in esa
a
Reagents and conditions: (a) CH2N2, CH2Cl2, 0 °C, 15 min;
then TFA-CH2Cl2 (1:4), 0 °C to rt, 1 h.
SCHEME 8 a
a
Reagents and conditions: (a) 4-Å MS, t-BuOH, 70 °C, 24 h;
(b) AcOH-H2O (5:1), rt, 24 h; (c) TEMPO-BAIB, rt, 3 h.
positions, it was decided to expand our strategy to the
use of oxazolidinyl-functionalized â-ketoesters as com-
ponents in Hantzsch cyclocondensation. The class of
2-pyridyl-R-alanines was chosen as a representative tar-
get for this study due to the pharmacological importance
exhibited by some members of this family of heterocyclic
R-amino acids (e.g. L-azatyrosine4a,5c,6b). To this aim, the
hitherto unreported oxazolidinyl â-ketoester 25 was first
prepared in satisfactory yield (65%) by BF3‚Et2O pro-
moted coupling of the corresponding aldehyde 10 with
tert-butyl diazoacetate according to a literature procedure
24
(Scheme 5).
a
Reagents and conditions: (a) H-Phe-OMe‚HCl, PyBOP, DIEA,
Hantzsch cyclocondensation of the oxazolidinyl ke-
toester 25 with benzaldehyde 26 and tert-butyl amino
crotonate 18c (molecular sieves, t-BuOH, 70 °C, 24 h)
gave the DHP-cycloadduct 27 in good yield (85%) as a
1.5:1 mixture of diastereoisomers (Scheme 6). Subsequent
acetonide removal led to amino alcohols 28 which in turn
were readily oxidized (TEMPO-BAIB)25 to the target
2-pyridyl-R-alanine derivative 29 in 52% overall yield (3
steps).
CH2Cl2, rt, 2 h; (b) TFA-CH2Cl2 (1:4), 0 °C to rt, 1 h; (c) Boc-Phe-
OH, PyBOP, DIEA, CH2Cl2, rt, 2 h.
result of an intramolecular condensation of the unpro-
tected amino group in the alanine moiety with a methyl
ester function at C3 or C5 of the pyridine ring.
An expanded scope of this work was demonstrating
that DHPM- and pyridyl-R-amino acids previously syn-
thesized could be incorporated into a peptide chain.
Amino acid 24c bearing two bulky tert-butyl ester groups
at the pyridine ring was chosen as a model. Coupling of
24c with L-phenylalanine methyl ester hydrochloride
(H-Phe-OMe‚HCl), using PyBop as coupling reagent and
DIEA in CH2Cl2, furnished the desired dipeptide 35 in
90% yield (Scheme 8). Extension from the N-terminus
was next carried out. After Boc removal (TFA-CH2Cl2)
in 35 the coupling reaction of the resulting free amine
with tert-butoxycarbonyl-L-phenylalanine (Boc-Phe-OH),
using PyBop and DIEA, afforded the target tripeptide 36
in 82% overall yield (two steps).
Having in hand the set of R-amino acids 7, 8, 14, 15,
24b,c, and 29 we next determined their enantiomeric
purity to verify that stereochemical integrity at R-carbon
was retained not only during the cyclocondensation but
also in the final oxidation step. Thus, selected amino
acids 7, 14, 24c, and 29 were first converted to the
corresponding N′-deprotected amino esters 30, 31, 32,
and 33 (Scheme 7) by treatment with diazomethane
followed by Boc deprotection (TFA-CH2Cl2). Subsequent
derivatization with Mosher’s acid and NMR analysis of
the corresponding amides proved the enantiomeric purity
of 7, 14, 24c, and 29 to be greater than 96%.
(24) Dhavale, D. D.; Bhujbal, N. N.; J oshi, P.; Desai, S. G. Carbo-
hydr. Res. 1994, 263, 303.
(25) The use of the J ones reagent gave a lower yield (ca. 50%) of
N′-Boc amino acid 29.
In the case of amino acid 24b the same esterification-
Boc deprotection sequence did not afford the correspond-
ing free amine but gave the lactam 34 (Scheme 7) as a
6176 J . Org. Chem., Vol. 68, No. 16, 2003

Dihydropyrimidinyl and Pyridyl R-Amino Acids
H, J ) 4.5, 5.0 Hz, H-4), 4.40 (dd, 0.84 H, J ) 4.5, 5.0 Hz,
H-4), 4.20-3.80 (m, 5 H, H-1′, 2 H-2′, CH2CH3), 2.23 (s, 0.48
H, CH3), 2.20 (s, 2.52 H, CH3), 1.55 and 1.42 (2 s, 0.96 H, 2
C(CH3)2), 1.48 and 1.40 (2 s, 5.04 H, 2 C(CH3)2), 1.46 (s, 1.44
H, t-Bu), 1.44 (s, 7.56 H, t-Bu), 1.25 (t, 0.48 H, J ) 7.0 Hz,
CH2CH3), 1.24 (t, 2.52 H, J ) 7.0 Hz, CH2CH3). MALDI-TOF
MS: 406.4 (M+ + Na), 422.2 (M+ + K). Anal. Calcd for
In summary we described model studies culminating
with the synthesis of various heterocyclic amino acid
derivatives, i.e., 4-DHPM-R-glycines, 4-DHPM-R-ala-
nines, 4-pyridyl-R-alanines, and 2-pyridyl-R-alanines. The
approach that has been employed relies on the use of
aldehydes 1 and 10 or â-ketoester 25 bearing a masked
glycinyl moiety as components in Biginelli and Hantzsch
MCRs. This strategy proved not to be viable for the
synthesis of 4-pyridyl-R-glycines. Nevertheless, we be-
lieve this versatile method, applicable to parallel syn-
thesis, to be of great value for the rapid generation of
structurally related compound libraries. Highly function-
alized amino acid derivatives have been obtained by this
approach in a suitably protected form and thus are
capable of incorporation into a peptide chain as demon-
strated by the synthesis of tripeptide 36. Further modi-
fications of DHPM and pyridyl scaffolds by this strategy
will be reported in due course.
C
18H29N3O6 (383.44): C, 56.38; H, 7.62; N, 10.96. Found: C,
56.36; H, 7.68; N, 10.91.
(4R,4′′S)- a n d (4S,4′′S)-4-(3′′-ter t-Bu toxyca r bon yl-2′′,2′′-
d im eth yl-oxa zolid in -4′′-ylm eth yl)-6-m eth yl-2-oxo-1,2,3,4-
tetr a h yd r op yr im id in e-5-ca r boxylic Acid Eth yl Ester s
(11). Column chromatography with 1:2 cyclohexane-AcOEt
(containing 0.3% of Et3N) afforded 11 (676 mg, 85%) as a 1:1
mixture of (4R,4”S) and (4S,4”S) diastereoisomers.
Analytical samples of each diastereoisomer were obtained
by preparative TLC (15:1:0.1 CH2Cl2-i-PrOH-28% NH4OH).
Eluted first was (4S)-11. [R]D -174 (c 0.4, CHCl3). 1H NMR
(DMSO-d6, 120 °C): δ 8.60 (br s, 1 H, NH), 6.70 (br s, 1 H,
NH), 4.22-4.04 (m, 3 H, H-4, CH2CH3), 3.98-3.88 (m, 2 H,
H-4′′, H-5′′a), 3.73-3.65 (m, 1 H, H-5′′b), 2.21 (s, 3 H, CH3),
1.95-1.80 and 1.70-1.50 (2 m, 2 H, 2 H-1′), 1.42 (s, 9 H, t-Bu),
1.21 (t, 3 H, J ) 7.0 Hz, CH2CH3). Anal. Calcd for C19H31N3O6
(397.47): C, 57.41; H, 7.86; N, 10.57. Found: C, 57.43; H, 7.82;
N, 10.54.
Exp er im en ta l Section
All moisture-sensitive reactions were performed under a
nitrogen atmosphere with oven-dried glassware. Solvents were
dried over standard drying agent and freshly distilled prior
to use. Commercially available powdered 4 Å molecular sieves
(5 µm average particle size) were used without further activa-
tion. Reactions were monitored by TLC on silica gel 60 F254
with detection by charring with sulfuric acid. Flash column
chromatography was performed on silica gel 60 (230-400
Eluted second was (4R)-11. [R]D 103.2 (c 0.6, CHCl3). 1H
NMR (DMSO-d6, 120 °C): δ 8.58 (br s, 1 H, NH), 6.92 (br s, 1
H, NH), 4.24-4.00 (m, 2 H, CH2CH3), 4.08 (dd, 1 H, J 4′′,5′′a
)
8.0, J 5′′a,5′′b ) 9.5 Hz, H-5′′a), 4.02 (dddd, 1 H, J 4′′,5′′b ) 2.8, J 1′a,4′′
) 3.0, J 1′b,4′′ ) 4.0 Hz, H-4′′), 3.91 (ddd, 1 H, J 4,1′a ) 1.5 Hz,
J 4,NH ) 6.2 Hz, J 4,1′b ) 10.5 Hz, H-4), 3.78 (dd, 1 H, H-5′′b),
2.21 (s, 3 H, CH3), 1.96 (ddd, 1 H, J 1′a,1′b ) 14.0 Hz, H-1′a),
1.56 (ddd, 1 H, H-1′b), 1.42 (s, 9 H, t-Bu), 1.24 (t, 3 H, J ) 7.0
Hz, CH2CH3). Anal. Calcd for C19H31N3O6 (397.47): C, 57.41;
H, 7.86; N, 10.57. Found: C, 57.49; H, 7.81; N, 10.51.
Crystallization from AcOEt afforded small crystals of (4R)-
11 suitable for X-ray diffraction analysis.
mesh). Melting points were determined with
a capillary
apparatus. Optical rotations were measured at 20 ( 2 °C in
the stated solvent; [R]D values are given in 10-1 deg cm2 g-1
1H (300 MHz), 19F (282 MHz), and 13C (75 MHz) NMR spectra
were recorded for CDCl3 solutions at room temperature unless
otherwise specified. Assignments were aided by homo- and
heteronuclear two-dimensional experiments. MALDI-TOF mass
spectra were acquired with useof R-cyano-4-hydroxycinnamic
acid as the matrix. CD measurements were carried out in a
0.1 cm path length cell with a volume of 350 µL at 20 °C with
methanol as solvent. Spectra were recorded between 360 and
200 nm with 1-nm resolution at a scan speed of 10 nm/min
and resulted from averaging two scans. The final spectra were
baseline-corrected by subtracting the corresponding methanol
spectrum obtained under identical conditions. Aldehydes 115
and 1023 were synthesized as described. tert-Butyl 3-amino-
crotonate 18c26 was prepared by reaction of the corresponding
â-ketoester with ammonium acetate in refluxing tert-butyl
alcohol. Pyridine 21 is a known compound.19d
.
The C4 configuration was also determined by converting
each epimer 11 into the corresponding alcohol 12 and then
performing their CD spectra.
Gen er a l P r oced u r e for Ha n tzsch Cyclocon d en sa tion s
Lea d in g t o Cycloa d d u ct s 19 a n d 22b ,c. A screw-capped
vial, containing a magnetic bar, was charged with aldehyde 1
or 10 (4.00 mmol), â-ketoester 2 (4.00 mmol), aminocrotonate
18 (4.00 mmol), powdered 4 Å molecular sieves (200 mg), and
R1OH (5 mL; MeOH for 2b-18b, and t-BuOH for 2c-18c).
The mixture was then vigorously stirred, degassed under
vacuum, and saturated with argon (by an Ar-filled balloon)
three times. The mixture was stirred at 90 °C for 24 h then
cooled to room temperature, diluted with AcOEt (10 mL),
filtered through a pad of Celite, and concentrated. The residue
was eluted from a column of silica gel with the suitable elution
system to give the corresponding dihydropyridines.
(4′S)- an d (4′R)-4-(3′-ter t-Bu toxycar bon yl-2′,2′-dim eth yl-
oxa zolid in -4′-yl)-2,6-d im et h yl-1,4-d ih yd r o-p yr id in e-3,5-
d ica r boxylic Acid Dim eth yl Ester s (19). Column chroma-
tography with 2:1 cyclohexane-AcOEt (containing 0.3% of
Et3N) afforded 19 (1.48 g, 87%) as a yellow foam. 1H NMR
(DMSO-d6, 120 °C): δ 8.50 (br s, 1 H, NH), 4.32 (d, 1 H, J 4,4′
) 5.5 Hz, H-4), 3.80-3.68 (m, 3 H, H-4′, 2 H-5′), 3.63 and 3.61
(2 s, 6 H, 2 OCH3), 2.25 and 2.23 (2 s, 6 H, 2 CH3), 1.43 (s, 9
H, t-Bu), 1.41 and 1.37 (2 s, 6 H, 2 C(CH3)2). Anal. Calcd for
Gen er a l P r oced u r e for Bigin elli Cyclocon d en sa tion s.
A screw-capped vial, containing a magnetic bar, was charged
with aldehyde 1 or 10 (2.00 mmol), ethyl acetoacetetate (255
µL, 2.00 mmol), urea (360 mg, 6.00 mmol), Yb(OTf)3 (620 mg,
1.00 mmol), powdered 4-Å molecular sieves (200 mg), and
anhydrous THF (5 mL). The mixture was stirred at 70 °C for
14 h then cooled to room temperature, diluted with AcOEt
(100 mL), filtered through a pad of Celite, and washed with
H2O (2 × 10 mL). The organic phase was dried (Na2SO4),
concentrated, and eluted from a column of silica gel with the
suitable elution system to give the corresponding dihydropy-
rimidinones.
(4R,4′S)- a n d (4S,4′S)-4-(3′-ter t-Bu toxyca r bon yl-2′,2′-
d im eth yl-oxa zolid in -4′-yl)-6-m eth yl-2-oxo-1,2,3,4-tetr a h y-
d r op yr im id in e-5-ca r boxylic Acid Eth yl Ester s (4). Col-
umn chromatography with 1:2 cyclohexane-AcOEt (containing
0.3% of Et3N) afforded 4 (460 mg, 60%) as a 5:1 mixture of
(4R,4′S) and (4S,4′S) diastereoisomers. 1H NMR (DMSO-d6,
120 °C): δ 8.59 (br s, 0.16 H, NH), 8.45 (br s, 0.84 H, NH),
6.78 (br s, 0.84 H, NH), 6.65 (br s, 0.16 H, NH), 4.51 (dd, 0.16
C
21H32N2O7 (424.49): C, 59.42; H, 7.60; N, 6.60. Found: C,
59.41; H, 7.67; N, 6.68.
(4′′S)-4-(3′′-ter t-Bu toxyca r bon yl-2′′,2′′-d im eth yl-oxa zo-
lid in -4′′-ylm eth yl)-2,6-d im eth yl-1,4-d ih yd r o-p yr id in e-3,5-
d ica r boxylic Acid Dim eth yl Ester (22b). Column chroma-
tography with 2:1 cyclohexane-AcOEt (containing 0.3% of
Et3N) afforded 22b (1.67 g, 95%) as a yellow foam. [R]D 16.9 (c
0.9, CHCl3). 1H NMR (DMSO-d6, 120 °C): δ 8.52 (br s, 1 H,
NH), 3.91-3.67 (m, 4H, H-4, H-4′′, 2 H-5′′), 3.66 and 3.64 (2 s,
6 H, 2 OCH3), 2.22 and 2.21 (2 s, 6 H, 2 CH3), 1.72 (ddd, 1 H,
(26) Bagley, M. C.; Dale, J . W. Bower, J . Synlett 2001, 1149.
J . Org. Chem, Vol. 68, No. 16, 2003 6177

Dondoni et al.
J ) 2.0, 12.0, 12.2 Hz, H-1′a), 1.43 and 1.38 (2 s, 6 H, 2
C(CH3)2), 1.38 (s, 9 H, t-Bu), 1.28 (ddd, 1 H, J ) 3.5, 12.0, 12.5
Hz, H-1′b). Anal. Calcd for C22H34N2O7 (438.51): C, 60.26; H,
7.82; N, 6.39. Found: C, 60.20; H, 7.88; N, 6.31.
) 3.8 Hz, J 4,NH ) 4.0 Hz, H-4), 4.21 (br t, 1 H, J ) 6.0 Hz,
OH), 4.13 (q, 2 H, J ) 7.0 Hz, CH2CH3), 3.67 (dddd, 1 H, J 1′,2′a
) 5.0 Hz, J 1′,2′b ) 6.0 Hz, H-1′), 3.50 (dd, 1 H, J 2′a,2′b ) 11.5
Hz, H-2′a), 3.42 (dd, 1 H, H-2′b), 2.18 (s, 3 H, CH3), 1.22 (t, 3
H, CH2CH3). Anal. Calcd for C15H25N3O6 (343.38): C, 52.47;
H, 7.34; N, 12.24. Found: C, 52.41; H, 7.30; N, 12.30.
(4′′S)-4-(3′′-ter t-Bu toxyca r bon yl-2′′,2′′-d im eth yl-oxa zo-
lid in -4′′-ylm eth yl)-2,6-d im eth yl-1,4-d ih yd r o-p yr id in e-3,5-
d ica r boxylic Acid Di-ter t-bu tyl Ester (22c). Column chro-
matography with 4:1 cyclohexane-AcOEt (containing 0.3% of
Et3N) afforded 22c (1.99 g, 95%) as a yellow foam. [R]D -24.3
(4R,1′S)- a n d (4S,1′S)-1,3-Di-N-ben zyl-4-(1′-ter t-bu toxy-
ca r bon yla m in o-2′-h yd r oxy-eth yl)-6-m eth yl-2-oxo-1,2,3,4-
t et r a h yd r op yr im id in e-5-ca r b oxylic Acid E t h yl E st er s
(6). Column chromatography with 1:1 cyclohexane-AcOEt
afforded 6 (262 mg, 50%) as a 5:1 mixture of (4R,1′S) and
1
(c 1.5, CHCl3). H NMR (DMSO-d6, 120 °C): δ 8.21 (br s, 1 H,
NH), 3.92-3.81 (m, 2 H, 2 H-5′′), 3.80-3.72 (m, 1 H, H-4′′),
3.67 (dd, 1 H, J 4,1′a ) 4.0, J 4,1′b ) 9.5 Hz, H-4), 2.20 and 2.18
(2 s, 6 H, 2 CH3), 1.70-1.50 and 1.40-1.20 (2 m, 2 H, 2 H-1′),
1.45 (s, 18 H, 2 t-Bu), 1.38 (s, 9 H, t-Bu). Anal. Calcd for
(4S,1′S) diastereoisomers.1H NMR (DMSO-d6, 120 °C):
δ
7.40-7.10 (m, 10 H, 2 Ph), 6.08 (br d, 0.84 H, J 1′,NH ) 9.0 Hz,
N′H), 5.68 (br d, 0.16 H, J 1′,NH ) 9.0 Hz, N′H), 5.18 and 4.27
(2 d, 2 H, J ) 15.5 Hz, PhCH2), 4.98 and 4.91 (2 d, 2 H, J )
16.0 Hz, PhCH2), 4.52 (d, 0.16 H, J 4,1′ ) 6.5 Hz, H-4), 4.48 (d,
0.84 H, J 4,1′ ) 6.8 Hz, H-4), 4.18 (br s, 1 H, OH), 4.12-4.00
(m, 2 H, CH2CH3), 3.82-3.71 (m, 1 H, H-1′), 3.46-3.38 (m, 2
H, 2 H-2′), 2.26 (s, 0.48 H, CH3), 2.22 (s, 2.52 H, CH3), 1.43 (s,
7.56 H, t-Bu), 1.39 (s, 1.44 H, t-Bu), 1.18 (t, 0.48 H, J ) 7.0
Hz, CH2CH3), 1.17 (t, 2.52 H, J ) 7.0 Hz, CH2CH3). MALDI-
TOF MS: 524.4 (M+ + H), 546.8 (M+ + Na), 562.9 (M+ + K).
Anal. Calcd for C29H37N3O6 (523.62): C, 66.52; H, 7.12; N, 8.02.
Found: C, 66.59; H, 7.18; N, 8.05. Starting compound Bn -4
(253 mg, 45%) was also isolated.
C
28H46N2O7 (522.67): C, 64.34; H, 8.87; N, 5.36. Found: C,
64.24; H, 8.81; N, 5.34.
Gen er a l P r oced u r e for Di-N-ben zyla tion of Dih yd r o-
p yr im id in on es 4 a n d 11. To a cooled (0 °C), stirred solution
of cycloadduct 4 or 11 (2.00 mmol) in DMF (10 mL) was added
NaH portionwise (192 mg, 4.80 mmol, of a 60% dispersion in
oil) and, after 30 min, benzyl bromide (0.71 mL, 6.00 mmol).
The mixture was stirred at 70 °C (room temperature for 11)
for 2 h, then treated with EtOH (1 mL), stirred at room
temperature for an additional 30 min, diluted with H2O (15
mL), and extracted with Et2O (2 × 100 mL). The combined
organic phases were dried (Na2SO4), concentrated, and eluted
from a column of silica gel with the suitable elution system to
give the corresponding di-N-benzyl-dihydropyrimidinones.
(4R,4′S)- a n d (4S,4′S)-1,3-Di-N-ben zyl-4-(3′-ter t-bu toxy-
ca r bon yl-2′,2′-d im eth yl-oxa zolid in -4′-yl)-6-m eth yl-2-oxo-
1,2,3,4-t et r a h yd r op yr im id in e-5-ca r b oxylic Acid E t h yl
Ester s (Bn -4). Column chromatography with 3:1 cyclohex-
ane-AcOEt (containing 0.3% of Et3N) afforded Bn -4 (732 mg,
65%) as a 5:1 mixture of (4R,4′S) and (4S,4′S) diastereoiso-
mers. MALDI-TOF MS: 586.4 (M+ + Na), 602.2 (M+ + K). A
mixture of recyclable monobenzylated derivatives (265 mg,
28%) was also isolated.
(4R,4′′S)- a n d (4S,4′′S)-1,3-Di-N-b en zyl-4-(3′′-ter t-b u -
toxyca r bon yl-2′′,2′′-d im eth yl-oxa zolid in -4′′-ylm eth yl)-6-
m et h yl-2-oxo-1,2,3,4-t et r a h yd r op yr im id in e-5-ca r b oxyl-
ic Acid Eth yl Ester s (Bn -11). Column chromatography with
4:1 cyclohexane-AcOEt (containing 0.3% of Et3N) afforded
Bn -11 (692 mg, 60%) as a 1:1 mixture of (4R,4′′S) and (4S,4′′S)
diastereoisomers. MALDI-TOF MS: 600.4 (M+ + Na), 616.8
(M+ + K). A mixture of recyclable monobenzylated derivatives
(341 mg, 35%) was also isolated.
Gen er a l P r oced u r e for Aceton id e Rem ova l in Cy-
cloa d d u cts 4, Bn -4, 11, Bn -11, 19, 22b,c, a n d 27. A solution
of DHPM- or DHP-cycloadduct (1.00 mmol) in acetic acid (7.5
mL) and H2O (1.5 mL) was stirred at room temperature for
24-48 h then concentrated and eluted from a column of silica
gel with the suitable elution system to give the corresponding
amino alcohol derivatives.
(4R,1′S)- a n d (4S,1′S)-4-(1′-ter t-Bu toxyca r bon yla m in o-
2′-h yd r oxy-eth yl)-6-m eth yl-2-oxo-1,2,3,4-tetr a h yd r op yr i-
m id in e-5-ca r boxylic Acid Eth yl Ester s (5). Column chro-
matography with 11:1:0.1 CH2Cl2-MeOH-28% NH4OH af-
forded 5 (227 mg, 66%) as a 5:1 mixture of (4R,4′S) and
(4S,4′S) diastereoisomers. Starting compound 4 (92 mg, 24%)
was also isolated. Analytical samples of each epimeric 5 were
obtained by preparative TLC (3:1:0.1 AcOEt-acetone-28%
NH4OH). Eluted first was (4S)-5. [R]D 41 (c 0.2, MeOH). 1H
NMR (DMSO-d6, 130 °C): δ 8.45 (br s, 1 H, NH), 6.50 (br s, 1
H, NH), 5.52 (br d, 1 H, J 1′,NH ) 9.0 Hz, N′H), 4.26 (dd, 1 H,
J 4,1′ ) 3.8 Hz, J 4,NH ) 4.0 Hz, H-4), 4.20-3.90 (m, 3 H, OH,
CH2CH3), 3.64-3.38 (m, 3 H, H-1′, 2 H-2′), 2.16 (s, 3 H, CH3),
1.20 (t, 3 H, J ) 7.0 Hz, CH2CH3). Anal. Calcd for C15H25N3O6
(343.38): C, 52.47; H, 7.34; N, 12.24. Found: C, 52.48; H, 7.38;
N, 12.25.
(4R,2′S)- a n d (4S,2′S)-4-(2′-ter t-Bu toxyca r bon yla m in o-
3′-h yd r oxy-p r op yl)-6-m eth yl-2-oxo-1,2,3,4-tetr a h yd r op y-
r im id in e-5-ca r boxylic Acid Eth yl Ester s (12). Column
chromatography with AcOEt (containing 1% of AcOH) afforded
12 (214 mg, 60%) as a 1:1 mixture of (4R,2′S) and (4S,2′S)
1
diastereoisomers. H NMR (DMSO-d6, 120 °C): δ 8.56 (br s,
0.5 H, NH), 8.48 (br s, 0.5 H, NH), 6.58 (br s, 0.5 H, NH), 6.50
(br s, 0.5 H, NH), 6.02 (br d, 0.5 H, J ) 8.0 Hz, N′H), 5.85 (br
d, 0.5 H, J ) 8.0 Hz, N′H), 4.30-4.20 (m, 1 H, H-4), 4.19-
4.02 (m, 3 H, OH, CH2CH3), 3.64-3.50 (m, 1 H, H-2′), 3.48-
3.32 (m, 2 H, 2 H-3′), 2.01 (s, 1.5 H, CH3), 2.00 (s, 1.5 H, CH3),
1.77-1.16 (m, 2 H, 2 H-1′), 1.42 (s, 4.5 H, t-Bu), 1.41 (s, 4.5 H,
t-Bu), 1.22 (t, 1.5 H, J ) 7.0 Hz, CH2CH3), 1.21 (t, 1.5 H, J )
7.0 Hz, CH2CH3). MALDI-TOF MS: 380.3 (M+ + Na), 396.3
(M+ + K). Anal. Calcd for C16H27N3O6 (357.40): C, 53.77; H,
7.61; N, 11.76. Found: C, 53.79; H, 7.65; N, 11.71. Starting
compound 11 (139 mg, 35%) was also isolated.
(4R,2′S)- a n d (4S,2′S)-1,3-Di-N-ben zyl-4-(2′-ter t-bu toxy-
car bon ylam in o-3′-h ydr oxy-pr opyl)-6-m eth yl-2-oxo-1,2,3,4-
t et r a h yd r op yr im id in e-5-ca r b oxylic Acid E t h yl E st er s
(13). Column chromatography with 1:1 cyclohexane-AcOEt
afforded 13 (296 mg, 55%) as a 1:1 mixture of (4R,2′S) and
(4S,2′S) diastereoisomers.1H NMR (DMSO-d6, 120 °C):
δ
7.40-7.10 (m, 10 H, 2 Ph), 5.95 (br d, 0.5 H, J ) 8.0 Hz, N′H),
5.80 (br d, 0.5 H, J ) 8.0 Hz, N′H), 5.16 and 4.22 (2 d, 1 H, J
) 15.5 Hz, PhCH), 5.15 and 4.85 (2 d, 2 H, J ) 16.0 Hz,
PhCH2), 5.09 and 4.20 (2 d, 1 H, J ) 15.0 Hz, PhCH), 4.44-
3.20 (m, 1 H, H-4), 4.24-4.16 (m, 1 H, OH), 4.14-3.92 (m, 2
H, CH2CH3), 3.62-3.50 (m, 0.5 H, H-2′), 3.45-3.20 (m, 2.5 H,
H-2′, 2 H-3′), 2.30 (s, 1.5 H, CH3), 2.28 (s, 1.5 H, CH3), 1.98-
1.68 and 1.65-1.40 (2 m, 2 H, 2 H-1′), 1.42 (s, 4.5 H, t-Bu),
1.41 (s, 4.5 H, t-Bu), 1.20-1.10 (m, 3 H, CH2CH3). MALDI-
TOF MS: 537.6 (M+), 560.4 (M+ + Na), 576.8 (M+ + K). Anal.
Calcd for C30H39N3O6 (537.65): C, 67.02; H, 7.31; N, 7.82.
Found: C, 67.09; H, 7.38; N, 7.87. Starting compound Bn -11
(202 mg, 35%) was also isolated.
(1′S)- a n d (1′R)-4-(1′-ter t-Bu toxyca r bon yla m in o-2′-h y-
d r oxy-et h yl)-2,6-d im et h yl-1,4-d ih yd r o-p yr id in e-3,5-d i-
ca r boxylic Acid Dim eth yl Ester s (20). Column chroma-
tography with 1:1 cyclohexane-AcOEt afforded 20 (250 mg,
65%) as a white foam. 1H NMR (DMSO-d6, 120 °C): δ 8.58 (br
s, 1 H, NH), 5.10 (br d, 1 H, J 1′,NH ) 8.0 Hz, N′H), 3.95 (d, 1 H,
J 4,1′ ) 6.5 Hz, H-4), 3.74 (br t, 1 H, J ) 5.0 Hz, OH), 3.65 and
3.64 (2 s, 6 H, 2 OCH3), 3.40-3.20 (m, 3 H, H-1′, 2 H-2′), 2.21
(s, 6 H, 2 CH3), 1.38 (s, 9 H, t-Bu). Anal. Calcd for C18H28N2O7
(384.42): C, 56.24; H, 7.34; N, 7.29. Found: C, 56.30; H, 7.31;
N, 7.21.
Eluted second was (4R)-5. [R]D -53 (c 0.4, MeOH). 1H NMR
(DMSO-d6, 120 °C): δ 8.42 (br s, 1 H, NH), 6.38 (br s, 1 H,
NH), 5.49 (br d, 1 H, J 1′,NH ) 9.0 Hz, N′H), 4.36 (dd, 1 H, J 4,1′
6178 J . Org. Chem., Vol. 68, No. 16, 2003

Dihydropyrimidinyl and Pyridyl R-Amino Acids
(2′S)-4-(2′-ter t-Bu toxyca r bon yla m in o-3′-h yd r oxy-p r o-
p yl)-2,6-d im et h yl-1,4-d ih yd r o-p yr id in e-3,5-d ica r b oxyl-
ic Acid Dim eth yl Ester (23b). Column chromatography with
1:3 cyclohexane-AcOEt afforded 23b (379 mg, 95%) as a white
foam. [R]D -8.9 (c 1.1, CHCl3). 1H NMR: δ 5.74 (br s, 1 H,
NH), 5.04 (br d, 1 H, J 2′,NH ) 5.5 Hz, N′H), 3.90 (br t, 1 H, J
) 6.0 Hz, H-4), 3.75 and 3.74 (2 s, 6 H, 2 OCH3), 3.70-3.50
(m, 3 H, H-2′, 2 H-3′), 3.25 (br s, 1 H, OH), 2.30 (s, 6 H, 2
CH3), 1.65-1.40 (m, 2 H, 2 H-1′), 1.42 (s, 9 H, t-Bu). Anal.
Calcd for C19H30N2O7 (398.45): C, 57.27; H, 7.59; N, 7.03.
Found: C, 57.35; H, 7.51; N, 7.08.
(2′S)-4-(2′-ter t-Bu toxyca r bon yla m in o-3′-h yd r oxy-p r o-
p yl)-2,6-d im et h yl-1,4-d ih yd r o-p yr id in e-3,5-d ica r b oxyl-
ic Acid Di-ter t-bu tyl Ester (23c). Column chromatography
with 2:1 cyclohexane-AcOEt afforded 23c (290 mg, 60%) as a
white foam. [R]D -14.9 (c 1.1, CHCl3). 1H NMR (DMSO-d6, 120
°C): δ 8.18 (br s, 1 H, NH), 5.38 (br s, 1 H, N′H), 3.85 (br s, 1
H, OH), 3.77 (br t, 1 H, J ) 6.5 Hz, H-4), 3.44-3.34 (m, 3 H,
H-2′, 2 H-3′), 2.20 and 2.18 (2 s, 6 H, 2 CH3), 1.50-1.38 and
1.35-1.18 (2 m, 2 H, 2 H-1′), 1.45 and 1.44 (2 s, 18 H, 2 t-Bu),
1.38 (s, 9 H, t-Bu). Anal. Calcd for C25H42N2O7 (482.61): C,
62.22; H, 8.77; N, 5.80. Found: C, 62.28; H, 8.71; N, 5.83.
1.20 (t, 3 H, J ) 7.0 Hz, CH2CH3). 19F NMR (DMSO-d6, 120
°C): δ -71.6. Anal. Calcd for C25H32F3N3O8 (559.53): C, 53.66;
H, 5.76; N, 7.51. Found: C, 53.68; H, 5.75; N, 7.52.
(1′S,2′′R)- an d (1′R,2′′R)-4-[1′-ter t-Bu toxycar bon ylam in o-
2′-(3′′,3′′,3′′-tr iflu or o-2′′-m eth oxy-2′′-ph en yl-pr opion yloxy)-
eth yl]-2,6-d im eth yl-1,4-d ih yd r o-p yr id in e-3,5-d ica r boxy-
lic Acid Dim et h yl E st er s (20 (R)-Mosh er E st er s). Pre-
parative TLC (5:1 i-Pr2O-AcOEt) gave 20 (R)-Mosh er ester
as a 4:1 mixture of (1′S,2′′R) and (1R′,2′′R) diastereoisomers.
1H NMR (DMSO-d6, 120 °C): δ 8.65 (br s, 1 H, NH), 7.60-
7.40 (m, 5 H, Ph), 5.56 (br d, 0.8 H, J 1′,NH ) 8.0 Hz, N′H), 5.52
(br d, 0.2 H, J 1′,NH ) 8.0 Hz, N′H), 4.30 (dd, 1 H, J 1′,2′a ) 4.2
Hz, J 2′a,2′b ) 11.0 Hz, H-2′a), 4.14 (dd, 1 H, J 1′,2′b ) 8.5 Hz,
H-2′b), 3.99 (br d, 1 H, J 4,1′ ) 6.5 Hz, H-4), 3.70-3.58 (m, 1 H,
H-1′), 3.64 (s, 4.8 H, 2 CO2CH3), 3.63 (s, 1.2 H, 2 CO2CH3),
3.50 (q, 2.4 H, J ) 0.7 Hz, OCH3), 3.47 (q, 0.6 H, J ) 0.7 Hz,
OCH3), 2.22 (s, 6 H, 2 CH3), 1.30 (s, 9 H, t-Bu). 19F NMR
(DMSO-d6, 120 °C): δ -71.8 (major diastereoisomer), -71.7
(minor diastereoisomer). Anal. Calcd for
C28H35F3N2O9
(600.58): C, 56.00; H, 5.87; N, 4.66. Found: C, 56.10; H, 5.81;
N, 4.63.
Gen er a l P r oced u r e for Oxid a tion w ith J on es Rea gen t
of N′-Boc Am in o Alcoh ols 5, 6, 12, 13, 20, a n d 23b,c. To a
cooled (0 °C), stirred solution of N′-Boc amino alcohol (1.00
mmol) in acetone (10 mL) was added freshly prepared 1 M
J ones reagent (3.00 mL, 3.00 mmol). The mixture was allowed
to warm to room temperature in 30 min, stirred at room
temperature for an additional 3 h, and then diluted with
i-PrOH (1 mL). The suspension was neutralized with satu-
rated aqueous NaHCO3, diluted with AcOEt (100 mL), and
washed with brine (2 × 15 mL). The organic phase was dried
(Na2SO4), concentrated, and eluted from a column of silica gel
with the suitable elution system to give the corresponding
oxidized derivative.
(4R,2′S)- a n d (4S,2′S)-2-(2′-ter t-Bu toxyca r bon yla m in o-
3′-h yd r oxy-p r op yl)-6-m eth yl-4-p h en yl-1,4-d ih yd r o-p yr i-
d in e-3,5-d ica r boxylic Acid Di-ter t-bu tyl Ester s (28). Col-
umn chromatography with 1.5:1 cyclohexane-AcOEt afforded
28 (354 mg, 65%) as 1.5:1 mixture of (4R,2′S) and (4S,2′S)
1
diastereoisomers. H NMR (DMSO-d6, 120 °C) selected data:
δ 7.85 (br s, 0.4 H, NH), 7.80 (br s, 0.6 H, NH), 7.40-7.00 (m,
5 H, Ph), 5.82 (br d, 0.6 H, J 2′,NH ) 8.0 Hz, N′H), 5.62 (br d,
0.4 H, J 2′,NH ) 8.0 Hz, N′H), 4.91 (s, 0.6 H, H-4), 4.89 (s, 0.4
H, H-4), 2.21 (s, 1.8 H, CH3), 2.20 (s, 1.2 H, CH3). MALDI-
TOF MS: 546.0 (M+ + H), 569,8 (M+ + Na), 585.7 (M+ + K).
Anal. Calcd for C30H44N2O7 (544.68): C, 66.15; H, 8.14; N, 5.14.
Found: C, 66.19; H, 8.12; N, 5.10.
(4R,1′S)- a n d (4S,1′S)-1,3-Di-N-ben zyl-4-(ter t-bu toxy-
ca r bon yla m in o-ca r boxy-m eth yl)-6-m eth yl-2-oxo-1,2,3,4-
t et r a h yd r op yr im id in e-5-ca r b oxylic Acid E t h yl E st er s
(7). Column chromatography with AcOEt (containing 1% of
AcOH) afforded 7 (457 mg, 85%) as a 5:1 mixture of (4R,1′S)
and (4S,1′S) diastereoisomers. 1H NMR (DMSO-d6, 120 °C):
δ 7.40-7.10 (m, 10 H, 2 Ph), 6.25 (br d, 0.84 H, J 1′,NH ) 9.0
Hz, N′H), 5.85 (br d, 0.16 H, J 1′,NH ) 9.0 Hz, N′H), 5.18 and
4.24 (2 d, 2 H, J ) 16.0 Hz, PhCH2), 5.00 and 4.87 (2 d, 0.32
H, J ) 16.5 Hz, PhCH2), 4.98 and 4.88 (2 d, 1.68 H, J ) 16.5
Hz, PhCH2), 4.82 (d, 0.84 H, J 4,1′ ) 6.0 Hz, H-4), 4.76 (d, 0.16
H, J 4,1′ ) 5.5 Hz, H-4), 4.41 (dd, 0.16 H, H-1′), 4.34 (dd, 0.84
H, H-1′), 4.14-3.96 (m, 2 H, CH2CH3), 2.26 (s, 0.48 H, CH3),
2.24 (s, 2.52 H, CH3), 1.41 (s, 7.56 H, t-Bu), 1.40 (s, 1.44 H,
t-Bu), 1.18 (t, 0.48 H, J ) 7.0 Hz, CH2CH3), 1.17 (t, 2.52 H, J
) 7.0 Hz, CH2CH3). MALDI-TOF MS: 538.8 (M+ + H), 560.9
(M+ + Na), 576.8 (M+ + K). Anal. Calcd for C29H35N3O7
(537.60): C, 64.79; H, 6.56; N, 7.82. Found: C, 64.71; H, 6.53;
N, 7.88.
6-Met h yl-2-oxo-1,2-d ih yd r o-p yr im id in e-5-ca r b oxylic
Acid Eth yl Ester (9). Column chromatography with 11:1:0.1
CH2Cl2-MeOH-28% NH4OH afforded 9 (173 mg, 95%) slightly
contaminated by uncharacterized byproducts. 1H NMR (DMSO-
d6 + D2O): δ 8.65 (s, 1 H, H-4), 4.24 (q, 3 H, J ) 7.0 Hz,
CH2CH3), 2.58 (s, 3 H, CH3), 1.22 (t, 3 H, CH2CH3). MALDI-
TOF MS: 183.8 (M+ + H), 205.7 (M+ + Na), 221.4 (M+ + K).
(4R,2′S)- a n d (4S,2′S)-1,3-Di-N-ben zyl-4-(2′-ter t-bu toxy-
ca r bon yla m in o-2′-ca r boxy-eth yl)-6-m eth yl-2-oxo-1,2,3,4-
t et r a h yd r op yr im id in e-5-ca r b oxylic Acid E t h yl E st er s
(14). Column chromatography with AcOEt (containing 1% of
AcOH) afforded 14 (469 mg, 85%) as a 1:1 mixture of (4R,2′S)
and (4S,2′S) diastereoisomers. 1H NMR (DMSO-d6, 120 °C):
δ 7.40-7.10 (m, 10 H, 2 Ph), 6.48 (br d, 0.5 H, J ) 8.0 Hz,
N′H), 6.34 (br d, 0.5 H, J ) 8.0 Hz, N′H), 5.18 and 4.28 (2 d,
1 H, J ) 15.0 Hz, PhCH), 5.16 and 4.88 (2 d, 1 H, J ) 16.0
Hz, PhCH), 5.12 and 4.18 (2 d, 1 H, J ) 15.0 Hz, PhCH), 5.06
and 4.84 (2 d, 1 H, J ) 16.0 Hz, PhCH), 4.52-4.40 (m, 1 H,
H-4), 4.14-3.92 (m, 2.5 H, H-2′, CH2CH3), 3.91-3.80 (m, 0.5
Gen er a l P r oced u r e for Mosh er Ester s F or m a tion . To
a stirred solution of amino alcohol (4R)-5 or 20 (0.10 mmol) in
anhydrous CH2Cl2 (1 mL) were added either (R)- or (S)-R-
methoxy-R-(trifluoromethyl)phenylacetic acid (29 mg, 0.12
mmol), 1,3-dicyclohexylcarbodiimide (25 mg, 0.12 mmol), and
a catalytic amount of 4-N,N-(dimethylamino)pyridine. The
mixture was stirred for an additional 12 h at room temperature
then concentrated. The residue was taken into AcOEt, washed
with saturated aqueous NaHCO3 and brine, dried over Na2-
SO4, and concentrated. The residue was purified by prepara-
tive TLC affording the corresponding Mosher ester in almost
quantitative yield.
(4R,1′S,2′′R)-4-[1′-ter t-Bu toxycar bon ylam in o-2′-(3′′,3′′,3′′-
tr iflu or o-2′′-m eth oxy-2′′-p h en yl-p r op ion yloxy)-eth yl]-6-
m et h yl-2-oxo-1,2,3,4-t et r a h yd r op yr im id in e-5-ca r b oxyl-
ic Acid Eth yl Ester ((4R)-5 (R)-Mosh er Ester ). Elution
system: 9:1:0.1 CH2Cl2-MeOH-28% NH4OH. 1H NMR (DMSO-
d6, 120 °C): δ 8.70 (br s, 1 H, NH), 7.60-7.40 (m, 5 H, Ph),
7.05 (br s, 1 H, NH), 6.07 (br d, 1 H, J 1′,NH ) 10.0 Hz, N′H),
4.48 (dd, 1 H, J 1′,2′a ) 4.0 Hz, J 2′a,2′b ) 11.5 Hz, H-2′a), 4.29
(dd, 1 H, J 1′,2′b ) 8.5 Hz, H-2′b), 4.26 (dd, 1 H, J 4,1′ ) 3.8 Hz,
J 4,NH ) 4.0 Hz, H-4), 4.20-4.04 (m, 2 H, CH2CH3), 3.98 (dddd,
1 H, H-1′), 3.49 (q, 3 H, J ) 0.7 Hz, OCH3), 2.20 (s, 3 H, CH3),
1.22 (t, 3 H, J ) 7.0 Hz, CH2CH3). 19F NMR (DMSO-d6, 120
°C): δ -71.7. Anal. Calcd for C25H32F3N3O8 (559.53): C, 53.66;
H, 5.76; N, 7.51. Found: C, 53.60; H, 5.71; N, 7.58.
(4R,1′S,2′′S)-4-[1′-ter t-Bu toxycar bon ylam in o-2′-(3′′,3′′,3′′-
tr iflu or o-2′′-m eth oxy-2′′-p h en yl-p r op ion yloxy)-eth yl]-6-
m et h yl-2-oxo-1,2,3,4-t et r a h yd r op yr im id in e-5-ca r b oxyl-
ic Acid Eth yl Ester ((4R)-5 (S)-Mosh er Ester ). Elution
system: 9:1:0.1 CH2Cl2-MeOH-28% NH4OH. 1H NMR (DMSO-
d6, 120 °C): δ 8.55 (br s, 1 H, NH), 7.60-7.40 (m, 5 H, Ph),
6.80 (br s, 1 H, NH), 6.05 (br d, 1 H, J 1′,NH ) 8.0 Hz, N′H),
4.37 (dd, 1 H, J 1′,2′a ) 8.0 Hz, J 2′a,2′b ) 11.0 Hz, H-2′a), 4.32
(dd, 1 H, J 1′,2′b ) 6.0 Hz, H-2′b), 4.27 (dd, 1 H, J 4,1′ ) 3.8 Hz,
J 4,NH ) 4.0 Hz, H-4), 4.18-4.02 (m, 2 H, CH2CH3), 3.97 (dddd,
1 H, H-1′), 3.51 (q, 3 H, J ) 0.7 Hz, OCH3), 2.20 (s, 3 H, CH3),
J . Org. Chem, Vol. 68, No. 16, 2003 6179

Dondoni et al.
H, H-2′), 2.36 (s, 1.5 H, CH3), 2.35 (s, 1.5 H, CH3), 2.20-1.76
(m, 2 H, 2 H-1′), 1.42 (s, 4.5 H, t-Bu), 1.41 (s, 4.5 H, t-Bu),
Anal. Calcd for C15H23N3O7 (357.36): C, 50.41; H, 6.49; N,
11.76. Found: C, 50.49; H, 6.51; N, 11.70. The fully hydroge-
nated hexahydro-pyrimidine derivative of 8 was also isolated
(∼15%).
1.20-1.08 (m, 3 H, CH2CH3). MALDI-TOF MS: 552.3 (M+
+
H), 574.9 (M+ + Na), 590.9 (M+ + K). Anal. Calcd for
30H37N3O7 (551.63): C, 65.32; H, 6.76; N, 7.62. Found: C,
C
(4R,2′S)- a n d (4S,2′S)-4-(2′-ter t-Bu toxyca r bon yla m in o-
2′-ca r boxy-eth yl)-6-m eth yl-2-oxo-1,2,3,4-tetr a h yd r op yr i-
m id in e-5-ca r boxylic Acid Eth yl Ester s (15). Treatment of
14 (165 mg, 0.30 mmol) as described for the preparation of 8
gave 15 (33 mg, 30%) as a 1:1 mixture of (4R,2′S) and (4S,2′S)-
65.31; H, 6.72; N, 7.58.
(2′S)-4-(2′-ter t-Bu toxyca r bon yla m in o-3′-h yd r oxy-p r o-
p yl)-6-m eth yl-2-oxo-1,2-d ih yd r o-p yr im id in e-5-ca r boxyl-
ic Acid Eth yl Ester (16) a n d (2′S)-4-(2′-ter t-Bu toxyca r -
bon ylam in o-2′-car boxy-eth yl)-6-m eth yl-2-oxo-1,2-dih ydr o-
p yr im id in e-5-ca r boxylic Acid Eth yl Ester (17). Column
chromatography with 9:1 AcOEt-MeOH (containing 1% of
AcOH) afforded first 16 (107 mg, 30%) contaminated by
uncharacterized byproducts. 1H NMR (DMSO-d6, 120 °C)
selected data: δ 7.38 (br s, 1 H, NH), 5.78 (br d, 1 H, J ) 8.0
Hz, N′H), 4.40-4.00 (m, 3 H, H-2′, CH2CH3), 3.28 (dd, 1 H,
1
diastereoisomers. H NMR (DMSO-d6, 120 °C): δ 8.55 (br s,
0.5 H, NH), 8.50 (br s, 0.5 H, NH), 6.55 (br s, 0.5 H, NH), 6.48
(br s, 0.5 H, NH), 6.00 (br d, 0.5 H, J 2′,NH ) 8.0 Hz, N′H), 5.82
(br d, 0.5 H, J 2′,NH ) 8.0 Hz, N′H), 4.30-4.20 (m, 1 H, H-4),
4.15-3.80 (m, 3 H, H-2′, CH2CH3), 2.30 (s, 1.5 H, CH3), 2.28
(s, 1.5 H, CH3), 2.20-1.75 (m, 2 H, 2 H-1′), 1.20-1.08 (m, 3 H,
CH2CH3). MALDI-TOF MS: 372.7 (M+ + H), 394.8 (M+ + Na),
410.8 (M+ + K). Anal. Calcd for C16H25N3O7 (371.39): C, 51.74;
H, 6.78; N, 11.31. Found: C, 51.68; H, 6.72; N, 11.34. The fully
hydrogenated hexahydro-pyrimidine derivative of 15 was also
isolated (∼15%).
J 1′a,2′ ) 6.5 Hz, J 1′a,1′b ) 14.0 Hz, H-1′a), 3.04 (dd, 1 H, J 1′b,2′
)
7.0 Hz, H-1′b), 2.30 (s, 3 H, CH3), 1.42 (s, 9 H, t-Bu), 1.22 (t,
3 H, J ) 7.0 Hz, CH2CH3). MALDI-TOF MS: 356.5 (M+ + H),
378.3 (M+ + Na), 394.3 (M+ + K).
Eluted second was 17 (55 mg, 15%) contaminated by
uncharacterized byproducts. 1H NMR selected data: δ 5.62
(br d, 1 H, J ) 8.0 Hz, N′H), 4.42 (q, 2 H, J ) 7.0 Hz,
CH2CH3), 3.44 (dd, 1 H, J 1′a,2′ ) 6.0 Hz, J 1′a,1′b ) 16.0 Hz, H-1′a),
3.34 (dd, 1 H, J 1′b,2′ ) 5.0 Hz, H-1′b), 2.40 (s, 3 H, CH3), 1.42
(s, 9 H, t-Bu), 1.22 (t, 3 H, CH2CH3). MALDI-TOF MS: 370.5
(M+ + H), 392.3 (M+ + Na), 408.3 (M+ + K).
(4S )-4-(3′-t er t -Bu t oxyca r b on yl-2-oxo-p r op yl)-2,2-d i-
m eth yl-oxa zolid in e-3-ca r boxylic Acid ter t-Bu tyl Ester
(25). A mixture of aldehyde 10 (486 mg, 2.00 mmol), tert-butyl
diazoacetate (0.33 mL, 2.40 mmol), activated 4-Å powdered
molecular sieves (300 mg), and anhydrous CH2Cl2 (20 mL) was
stirred at room temperature for 15 min, then cooled to 0 °C.
To the mixture a solution of BF3‚Et20 (127 µL, 1.00 mmol) in
anhydrous CH2Cl2 (1 mL) was added drop by drop, controlling
the N2 evolution at a low steady rate. The mixture was stirred
at 0 °C for an additional 30 min, diluted with 10% NaHCO3
(10 mL), warmed to room temperature, filtered through a pad
of Celite, and extracted with CH2Cl2 (3 × 30 mL). The organic
layer was dried (Na2SO4) and concentrated. The residue was
eluted from a short column of silica gel with 6:1 cyclohexane-
AcOEt to give 25 (465 mg, 65%) as a yellow amorphous solid;
[R]D +26.3 (c 0.8, CHCl3). 1H NMR (DMSO-d6, 120 °C): δ 4.17
(dddd, 1 H, J 4,5a ) 6.0 Hz, J 4,5b ) 2.0 Hz, J 4,1′a ) 3.3 Hz, J 4,1′b
) 9.5 Hz, H-4), 4.00 (dd, 1 H, J 5a,5b ) 9.0 Hz, H-5a), 3.65 (dd,
1 H, H-5b), 3.44 (s, 2 H, 2 H-3′), 3.03 (dd, 1 H, J 1′a,1′b ) 17.0
Hz, H-1′a), 2.77 (dd, 1 H, H-1′b), 1.44 (s, 9 H, t-Bu), 1.43 (s, 9
H, t-Bu), 1.42 and 1.41 (2 s, 6 H, 2 C(CH3)2). MALDI-TOF
MS: 358.6 (M+ + H), 380.5 (M+ + Na), 397.2 (M+ + K). Anal.
Calcd for C18H31NO6 (357.44): C, 60.48; H, 8.74; N, 3.92.
Found: C, 60.51; H, 8.72; N, 3.95.
(2′S)-4-(2′-ter t-Bu toxycar bon ylam in o-2′-car boxy-eth yl)-
2,6-d im eth yl-p yr id in e-3,5-d ica r boxylic Acid Dim eth yl
Ester (24b). Column chromatography with AcOEt (containing
1% of AcOH) afforded 24b (341 mg, 83%) as a white foam. [R]D
1
-21.1 (c 0.9, CHCl3). H NMR (DMSO-d6, 120 °C): δ 6.20 (br
s, 1 H, N′H), 4.17 (ddd, 1 H, J 1′a,2′ ) 5.0 Hz, J 2′,NH ) 9.0 Hz,
J 1′b,2′ ) 9.5 Hz, H-2′), 3.92 (s, 6 H, 2 OCH3), 3.20 (dd, 1 H,
J 1′a,1′b ) 14.0 Hz, H-1′a), 2.94 (dd, 1 H, H-1′b), 2.42 (2 s, 6 H,
2 CH3), 1.30 (s, 9 H, t-Bu). MALDI-TOF MS: 411.0 (M+ + H),
449.0 (M+ + K). Anal. Calcd for C19H26N2O8 (410.42): C, 55.60;
H, 6.39; N, 6.83. Found: C, 55.70; H, 6.31; N, 6.80.
(2′S)-4-(2′-ter t-Bu toxycar bon ylam in o-2′-car boxy-eth yl)-
2,6-d im eth yl-p yr id in e-3,5-d ica r boxylic Acid Di-ter t-bu tyl
Ester (24c). Column chromatography with AcOEt (containing
1% of AcOH) afforded 24c (321 mg, 65%) as a white foam. [R]D
1
-25.8 (c 0.9, MeOH). H NMR (DMSO-d6, 120 °C): δ 5.82 (br
d, 1 H, J 2′,NH ) 6.5 Hz, N′H), 4.28 (ddd, 1 H, J 1′a,2′ ) 6.0 Hz,
J 1′b,2′ ) 11.0 Hz, H-2′), 3.29 (dd, 1 H, J 1′a,1′b ) 14.5 Hz, H-1′a),
2.78 (dd, 1 H, H-1′b), 2.26 (s, 6 H, 2 CH3), 1.62 (s, 18 H, 2
t-Bu), 1.30 (s, 9 H, t-Bu). MALDI-TOF MS: 495.7 (M+ + H),
517.4 (M+ + Na), 533.9 (M+ + K). Anal. Calcd for C25H38N2O8
(494.58): C, 60.71; H, 7.74; N, 5.66. Found: C, 60.75; H, 7.71;
N, 5.68.
(4R,4′′S)- a n d (4S,4′′S)-2-(3′′-ter t-Bu toxyca r bon yl-2′′,2′′-
d im eth yl-oxa zolid in -4′′-ylm eth yl)-6-m eth yl-4-p h en yl-1,4-
d ih yd r o-p yr id in e-3,5-d ica r boxylic Acid Di-ter t-bu tyl Es-
ter s (27). A screw-capped vial, containing a magnetic bar, was
charged with benzaldehyde 26 (102 µL, 1.00 mmol), â-ketoester
25 (357 mg, 1.00 mmol), tert-butyl 3-aminocrotonate 18c (158
mg, 1.00 mmol,), powdered 4-Å molecular sieves (50 mg), and
t-BuOH (1 mL). The mixture was then vigorously stirred,
degassed under vacuum, and saturated with argon (by an Ar-
filled balloon) three times. The mixture was stirred at 70 °C
for 24 h then cooled to room temperature, diluted with AcOEt
(10 mL), filtered through a pad of Celite, and concentrated.
The residue was eluted from a column of silica gel with 7:1
cyclohexane-AcOEt to give 27 (497 mg, 85%) as a 1.5:1
(4R,1′S)- a n d (4S,1′S)-4-(ter t-Bu toxyca r bon yla m in o-
ca r boxy-m eth yl)-6-m eth yl-2-oxo-1,2,3,4-tetr a h yd r op yr i-
m id in e-5-ca r boxylic Acid Eth yl Ester s (8). A vigorously
stirred mixture of 20% palladium hydroxide on carbon (80 mg),
AcOH (4 mL), and EtOH (2 mL) was degassed under vacuum
and saturated with hydrogen (by a H2-filled balloon) three
times. To this mixture was added a solution of 7 (161 mg, 0.30
mmol) in EtOH (2 mL) previously degassed and saturated with
hydrogen as described before. After the solution was stirred
1
mixture of (4R,4′′S) and (4S,4′′S) diastereoisomers. H NMR
(DMSO-d6, 120 °C) selected data: δ 7.70 (br s, 0.6 H, NH),
7.68 (br s, 0.4 H, NH), 7.45-7.05 (m, 5 H, Ph), 4.91 (s, 0.4 H,
H-4), 4.88 (s, 0.6 H, H-4), 2.24 (s, 1.8 H, CH3), 2.23 (s, 1.2 H,
CH3). MALDI-TOF MS: 586.0 (M+ + H), 607.1 (M+ + Na),
623.8 (M+ + K). Anal. Calcd for C33H48N2O7 (584.74): C, 67.78;
H, 8.27; N, 4.79. Found: C, 67.75; H, 8.29; N, 4.80.
(2′S)-2-(2′-ter t-Bu toxycar bon ylam in o-2′-car boxy-eth yl)-
6-m et h yl-4-p h en yl-p yr id in e-3,5-d ica r b oxylic Acid Di-
ter t-bu tyl Ester (29). A mixture of 28 (136 mg, 0.25 mmol),
BAIB ([bis(acetoxy)-iodo]benzene, 338 mg, 1.05 mmol), TEMPO
(2,2,6,6-tetramethyl-piperidinyloxyl, 11 mg, 0.07 mmol), and
1:1 CH3CN-H2O (2 mL) was stirred for 3 h at room temper-
ature, then filtered through a pad of Celite and concentrated.
under
a positive pressure of hydrogen (5 atm) at room
temperature for 7 days, palladium hydroxide on carbon was
filtered off through a plug of cotton and washed thoroughly
with MeOH (2 mL), H2O (0.5 mL), and DMF (2 mL). The
combined filtrates were concentrated and eluted from a column
of silica gel with 9:1 AcOEt-MeOH (containing 1% of AcOH)
to give 8 (32 mg, 30%) as a 5:1 mixture of (4R,1′S) and (4S,1′S)
diastereoisomers. 1H NMR (DMSO-d6, 120 °C) selected data
for (4R)-isomer: δ 8.41 (br s, 1 H, NH), 6.38 (br s, 1 H, NH),
5.50 (br d, 1 H, J 1′,NH ) 9.0 Hz, N′H), 4.38 (dd, 1 H, J 4,1′ ) 3.8
Hz, J 4,NH ) 4.0 Hz, H-4), 4.16-3.90 (m, 3 H, H-1′, CH2CH3),
2.20 (s, 3 H, CH3), 1.18 (t, 3 H, J ) 7.0 Hz, CH2CH3). MALDI-
TOF MS: 358.7 (M+ + H), 380.4 (M+ + Na), 396.2 (M+ + K).
6180 J . Org. Chem., Vol. 68, No. 16, 2003

Dihydropyrimidinyl and Pyridyl R-Amino Acids
The residue was suspended with AcOEt (10 mL) and washed
with brine (10 mL). The organic phase was dried (Na2SO4),
concentrated, and eluted from a column of silica gel with 7:3
cyclohexane-AcOEt to give 29 (135 mg, 95%) as a white foam.
[R]D +77.0 (c 1.1, CHCl3). 1H NMR: δ 7.41-7.20 (m, 5 H, Ph),
1 H, J 1′a,2′ ) 4.5 Hz, J 1′b,2′ ) 9.5 Hz, H-2′), 2.41 (s, 3 H, CH3),
2.08 (ddd, 1 H, J 1′a,1′b ) 14.0 Hz, H-1′a), 1.73 (ddd, 1 H, H-1′b),
1.20 (t, 3 H, J ) 7.0 Hz, CH2CH3). 13C NMR: δ 175.2, 166.1,
154.3, 150.8, 138.2, 137.1, 128.7, 128.6, 128.5, 128.4, 127.8,
127.7, 127.5, 127.2, 126.7, 126.5, 104.1, 60.4, 52.2, 51.0, 50.9,
50.2, 46.9, 38.9, 16.7, 14.2. MALDI-TOF MS: 466.8 (M+ + H),
488.5 (M+ + Na), 504.3 (M+ + K). Anal. Calcd for C26H31N3O5
(465.54): C, 67.08; H, 6.71; N, 9.03. Found: C, 67.12; H, 6.79;
N, 9.08.
5.97 (br d, 1 H, J 2′,NH ) 8.0 Hz, N′H), 4.58 (ddd, 1 H, J 1′a,2′
)
2.0 Hz, J 1′b,2′ ) 9.0 Hz, H-2′), 3.45 (dd, 1 H, J 1′a,1′b ) 16.0 Hz,
H-1′a), 3.30 (dd, 1 H, H-1′b), 2.61 (s, 3 H, CH3), 1.41 (s, 9 H,
t-Bu), 1.20 and 1.19 (2 s, 18 H, 2 t-Bu). MALDI-TOF MS: 557.8
(M+ + H), 579.5 (M+ + Na), 595.3 (M+ + K). Anal. Calcd for
(2′S )-4-(2′-Am in o-2′-m e t h oxyca r b on yl-e t h yl)-2,6-d i-
m eth yl-p yr id in e-3,5-d ica r boxylic Acid Di-ter t-bu tyl Es-
ter (32). Column chromatography with 1:1 cyclohexane-
AcOEt afforded 32 (184 mg, 90%) as a white foam. [R]D -3.1
C
30H40N2O8 (556.65): C, 64.73; H, 7.24; N, 5.03. Found: C,
64.70; H, 7.26; N, 5.08.
Gen er a l P r oced u r e for Meth yl Ester Der iva tiza tion
a n d Boc Dep r otection of Am in o Acid s 7, 14, 24b,c, a n d
29. A solution of N′-Boc amino acid (0.50 mmol) in 1:1
CH2Cl2-MeOH (8 mL) was treated with ethereal diazo-
methane at 0 °C for 5 min and then concentrated to give the
corresponding methyl ester, at least 95% pure by NMR
analysis, suitable for the next step.
To a cooled (0 °C), stirred solution of the above N′-Boc amino
ester (∼0.50 mmol) in CH2Cl2 (1 mL) was slowly added a
solution of TFA-CH2Cl2 (1-3 mL). Stirring was continued at
0 °C for an additional 30 min, then the solution was warmed
to room temperature. After 30 min at room temperature the
solution was neutralized at 0 °C with saturated aqueous
Na2CO3 and extracted with CH2Cl2 (2 × 50 mL). The combined
organic phases were dried (Na2SO4), concentrated, and eluted
from a column of silica gel with the suitable elution system to
give the N′-deprotected amino esters 30, 31, 32, 33, and
byproduct 34.
1
(c 1.2, CHCl3). H NMR: δ 3.82 (dd, 1 H, J 1′a,2′ ) 4.5 Hz, J 1′b,2′
) 11.0 Hz, H-2′), 3.74 (s, 3 H, OCH3), 3.25 (dd, 1 H, J 1′a,1′b
)
14.0 Hz, H-1′a), 2.83 (dd, 1 H, H-1′b), 2.56 (s, 6 H, 2 CH3),
1.62 (s, 18 H, 2 t-Bu).13C NMR: δ 175.0, 167.7, 154.6, 140.8,
128.9, 83.3, 54.9, 52.1, 35.4, 28.0, 23.0. MALDI-TOF MS: 409.3
(M+ + H), 431.5 (M+ + Na), 447.8 (M+ + K). Anal. Calcd for
C
21H32N2O6 (408.49): C, 61.75; H, 7.90; N, 6.86. Found: C,
61.70; H, 7.99; N, 6.81.
(2′S)-2-(2′-Am in o-2′-m eth oxyca r bon yl-eth yl)-6-m eth yl-
4-p h en yl-p yr id in e-3,5-d ica r boxylic Acid Di-ter t-bu tyl Es-
ter (33). Column chromatography with 1:4 cyclohexane-
AcOEt afforded 33 (153 mg, 65%) as a white foam. [R]D +11.7
1
(c 0.9, CH3OH). H NMR: δ 7.40-7.20 (m, 5 H, Ph), 4.06 (dd,
1 H, J 1′a,2′ ) 4.2 Hz, J 1′b,2′ ) 8.2 Hz, H-2′), 3.74 (s, 3 H, OCH3),
3.33 (dd, 1 H, J 1′a,1′b ) 15.0 Hz, H-1′a), 3.13 (dd, 1 H, H-1′b),
2.59 (s, 3 H, CH3), 1,82 (br s, 2 H, N′H2), 1.20 and 1.19 (2 s, 18
H, 2 t-Bu). 13C NMR: δ 175.6, 166.7, 166.5, 154.4, 153.8, 145.3,
136.3, 128.7, 128.6, 128.5, 128.4, 128.2, 128.0, 127.9, 82.6, 82.3,
53.7, 52.0, 39.7, 27.5, 22.7. MALDI-TOF MS: 471.7 (M+ + H),
493.3 (M+ + Na), 509.6 (M+ + K). Anal. Calcd for C26H34N2O6
(470.56): C, 66.36; H, 7.28; N, 5.95. Found: C, 66.32; H, 7.29;
N, 5.92.
(4R,1′S)- an d (4S,1′S)-4-(Am in o-m eth oxycar bon yl-m eth -
yl)-1,3-d i-N-ben zyl-6-m eth yl-2-oxo-1,2,3,4-tetr a h yd r op y-
r im id in e-5-ca r boxylic Acid Eth yl Ester s (30). Column
chromatography with AcOEt afforded 30 (169 mg, 75%) as a
5:1 mixture of (4R,1′S) and (4S,1′S) diastereoisomers. 1H
NMR: δ 7.40-7.10 (m, 10 H, 2 Ph), 5.36 and 3.99 (2 d, 1.68
H, J ) 15.5 Hz, PhCH2), 5.23 and 3.99 (2 d, 0.32 H, J ) 15.5
Hz, PhCH2), 5.19 and 4.87 (2 d, 0.32 H, J ) 16.5 Hz, PhCH2),
5.15 and 4.93 (2 d, 1.68 H, J ) 16.5 Hz, PhCH2), 4.80 (d, 0.84
H, J 4,1′ ) 4.5 Hz, H-4), 4.73 (d, 0.16 H, J 4,1′ ) 4.5 Hz, H-4),
4.20-4.08 (m, 2 H, CH2CH3), 3.73 (s, 3 H, CO2CH3), 3.62 (d,
0.84 H, H-1′), 3.57 (d, 0.16 H, H-1′), 2.45 (s, 2.52 H, CH3), 2.43
(s, 0.48 H, CH3), 1.20 (t, 2.52 H, J ) 7.0 Hz, CH2CH3), 1.19 (t,
(3S)-6,8-Dim et h yl-1-oxo-1,2,3,4-t et r a h yd r o-[2,7]n a p h -
t h yr id in e-3,5-d ica r b oxylic Acid Dim et h yl E st er (34).
Column chromatography with 1:2 cyclohexane-AcOEt af-
forded 34 (139 mg, 95%) as a white foam. [R]D -129.0 (c 1.0,
CHCl3). 1H NMR: δ 6.43 (br s, 1 H, NH), 4.31 (ddd, 1 H, J 3,NH
) 2.5 Hz, J 3,4a ) 5.0 Hz, J 3,4b ) 10.5 Hz, H-3), 4.00 (s, 3 H,
OCH3), 3.82 (s, 3H, OCH3), 3.29 (dd, 1 H, J 4a,4b ) 16.0 Hz,
H-4a), 3.11 (dd, 1 H, H-4b), 2.92 and 2.60 (2 s, 6 H, 2 CH3).13
C
0.48 H, J ) 7.0 Hz, CH2CH3). MALDI-TOF MS: 452.5 (M+
H), 474.4 (M+ + Na), 490.5 (M+ + K). Anal. Calcd for
25H29N3O5 (451.51): C, 66.50; H, 6.47; N, 9.31. Found: C,
+
NMR: δ 170.0, 167.9, 163.8, 161.4, 157.8, 144.4, 124.9, 120.2,
53.1, 52.6, 51.8, 29.9, 25.2, 23.7. MALDI-TOF MS: 293.3 (M+
+ H), 315.4 (M+ + Na), 331.6 (M+ + K). Anal. Calcd for
C
66.58; H, 6.41; N, 9.34.
C
14H16N2O5 (292.29): C, 57.53; H, 5.52; N, 9.58. Found: C,
(4R,2′S)- a n d (4S,2′S)-4-(2′-Am in o-2′-m eth oxyca r bon yl-
eth yl)-1,3-d i-N-ben zyl-6-m eth yl-2-oxo-1,2,3,4-tetr a h yd r o-
p yr im id in e-5-ca r boxylic Acid Eth yl Ester s (31). Column
chromatography with AcOEt afforded 31 (182 mg, 78%) as a
1:1 mixture of (4R,2′S) and (4S,2′S) diastereoisomers.
57.58; H, 5.51; N, 9.50.
Gen er a l P r oced u r e for Mosh er Am id es F or m a tion . To
a stirred solution of amino ester (0.10 mmol) in anhydrous
CH2Cl2 (1 mL) were added either (R)- or (S)-R-methoxy-R-
(trifluoromethyl)phenylacetic acid (29 mg, 0.12 mmol), 1,3-
dicyclohexylcarbodiimide (25 mg, 0.12 mmol), and a catalytic
amount of 4-N,N-(dimethylamino)pyridine. The mixture was
stirred for an additional 12 h at room temperature then
concentrated. The residue was taken into AcOEt, washed with
saturated aqueous NaHCO3 and brine, dried over Na2SO4, and
concentrated. The residue was purified by preparative TLC
affording the corresponding Mosher amide in almost quantita-
tive yield.
Analytical samples of each diastereoisomer were obtained
by preparative TLC (AcOEt). Eluted first was (4S)-31. [R]D 5.2
(c 0.6, CHCl3). 1H NMR: δ 7.40-7.10 (m, 10 H, 2 Ph), 5.33
and 4.81 (2 d, 2 H, J ) 16.5 Hz, PhCH2), 5.27 and 4.36 (2 d, 2
H, J ) 15.0 Hz, PhCH2), 4.69 (dd, 1 H, J 4,1′b ) 5.5 Hz, J 4,1′a
)
9.0 Hz, H-4), 4.18-4.02 (m, 2 H, CH2CH3), 3.70 (s, 3 H,
CO2CH3), 3.50 (dd, 1 H, J 1′a,2′ ) 4.5 Hz, J 1′b,2′ ) 9.5 Hz, H-2′),
2.60 (s, 3 H, CH3), 2.10 (ddd, 1 H, J 1′a,1′b ) 14.0 Hz, H-1′a),
1.66 (ddd, 1 H, H-1′b), 1.20 (t, 3 H, J ) 7.0 Hz, CH2CH3). 13C
NMR: δ 176.4, 165.5, 154.1, 150.5, 138.3, 137.7, 128.7, 128.6,
128.5, 127.6, 127.5, 127.4, 127.3, 127.2, 127.1, 126.8, 104.7,
60.1, 52.1, 51.2, 51.1, 49.2, 46.8, 38.5, 16.3, 14.2. MALDI-TOF
MS: 466.7 (M+ + H), 488.4 (M+ + Na), 504.6 (M+ + K). Anal.
Calcd for C26H31N3O5 (465.54): C, 67.08; H, 6.71; N, 9.03.
Found: C, 67.10; H, 6.71; N, 9.04.
(4R ,1′S ,2′′R )-1,3-Di-N -b e n zyl-4-[m e t h oxyca r b on yl-
(3′′,3′′,3′′-tr iflu or o-2′′-m eth oxy-2′′-ph en yl-pr opion ylam in o)-
m eth yl]-6-m eth yl-2-oxo-1,2,3,4-tetr a h yd r op yr im id in e-5-
ca r boxylic Acid Eth yl Ester ((4R)-30 (R)-Mosh er Am id e).
Elution system: 2:1 cyclohexane-AcOEt. 1H NMR: δ 8.00 (d,
1 H, J 1′,NH ) 9.0 Hz, N′H), 7.60-7.10 (m, 15 H, 3 Ph), 5.42
and 4.04 (2 d, 2 H, J ) 15.5 Hz, PhCH2), 5.39 and 4.54 (2 d, 2
H, J ) 16.5 Hz, PhCH2), 5.00 (d, 1 H, J 4,1′ ) 2.5 Hz, H-4), 4.97
(dd, 1 H, H-1′), 4.22-4.06 (m, 2 H, CH2CH3), 3.78 (s, 3 H,
CO2CH3), 3.38 (q, 3 H, J ) 0.7 Hz, OCH3), 2.35 (s, 3 H, CH3),
1.22 (t, 3 H, J ) 7.0 Hz, CH2CH3). 19F NMR: δ -69.1. Anal.
Eluted second was (4R)-31. [R]D 25.9 (c 0.6, CHCl3). 1H
NMR: δ 7.40-7.10 (m, 10 H, 2 Ph), 5.34 and 4.84 (2 d, 2 H, J
) 16.5 Hz, PhCH2), 5.16 and 4.20 (2 d, 2 H, J ) 15.0 Hz,
PhCH2), 4.50 (dd, 1 H, J 4,1′b ) 5.0 Hz, J 4,1′a ) 9.2 Hz, H-4),
4.20-4.08 (m, 2 H, CH2CH3), 3.70 (s, 3 H, CO2CH3), 3.43 (dd,
J . Org. Chem, Vol. 68, No. 16, 2003 6181

Dondoni et al.
Calcd for C35H36F3N3O7 (667.67): C, 62.96; H, 5.43; N, 6.29.
Found: C, 63.00; H, 5.41; N, 6.20.
ter (33 (R)-Mosh er Am ide). Elution system: 2:1 cyclohexane-
1
AcOEt. [R]D +2.9 (c 1.1, CH3OH). H NMR: δ 8.75 (br d, 1 H,
J 2′,NH ) 8.0 Hz, N′H), 7.70-7.60 and 7.50-7.20 (2 m, 10 H, 2
Ph), 5.08 (ddd, 1 H, J 1′a,2′ ) 6.5 Hz, J 1′b,2′ ) 5.2 Hz, H-2′), 3.74
(s, 3 H, CO2CH3), 3.53 (dd, 1 H, J 1′a,1′b ) 15.5 Hz, H-1′a), 3.38
(dd, 1 H, H-1′b), 3.36 (q, 3 H, J ) 0.7 Hz, OCH3), 2.55 (s, 3 H,
CH3), 1.21 and 1.20 (2 s, 18 H, 2 t-Bu). 19F NMR: δ -69.9.
Anal. Calcd for C36H41F3N2O8 (686.71): C, 62.96; H, 6.02; N,
4.08. Found: C, 62.98; H, 6.03; N, 4.05.
(4R ,1′S ,2′′S )-1,3-Di-N -b e n zy l-4-[m e t h o x y c a r b o n yl-
(3′′,3′′,3′′-tr iflu or o-2′′-m eth oxy-2′′-ph en yl-pr opion ylam in o)-
m eth yl]-6-m eth yl-2-oxo-1,2,3,4-tetr a h yd r op yr im id in e-5-
ca r boxylic Acid Eth yl Ester ((4R)-30 (S)-Mosh er Am id e).
1
Elution system: 2:1 cyclohexane-AcOEt. H NMR: δ 7.70-
7.00 (m, 16 H, 3 Ph, N′H), 5.37 and 4.92 (2 d, 2 H, J ) 15.5
Hz, PhCH2), 5.28 and 4.98 (2 d, 2 H, J ) 16.5 Hz, PhCH2),
5.00 (dd, 1 H, J 4,1′ ) 3.0 Hz, J 1′,NH ) 9.0 Hz, H-1′), 4.82 (d, 1
H, H-4), 4.24-4.00 (m, 2 H, CH2CH3), 3.76 (s, 3 H, CO2CH3),
3.69 (q, 3 H, J ) 0.7 Hz, OCH3), 2.15 (s, 3 H, CH3), 1.20 (t, 3
H, J ) 7.0 Hz, CH2CH3). 19F NMR: δ -68.8. Anal. Calcd for
(2′S,2′′S)-2-[2′-Met h oxyca r b on yl-2′-(3′′,3′′,3′′-t r iflu or o-
2′′-m eth oxy-2′′-p h en yl-p r op ion yla m in o)-eth yl]-6-m eth yl-
4-p h en yl-p yr id in e-3,5-d ica r boxylic Acid Di-ter t-bu tyl Es-
ter (33 (S)-Mosh er Am ide). Elution system: 2:1 cyclohexane-
1
C
35H36F3N3O7 (667.67): C, 62.96; H, 5.43; N, 6.29. Found: C,
AcOEt. [R]D +21.9 (c 0.7, CHCl3). H NMR: δ 8.35 (br d, 1 H,
63.10; H, 5.44; N, 6.28.
J 2′,NH ) 8.0 Hz, N′H), 7.40-7.20 (m, 10 H, 2 Ph), 5.07 (ddd, 1
H, J 1′a,2′ ) 7.0 Hz, J 1′b,2′ ) 4.5 Hz, H-2′), 3.75 (s, 3 H, CO2CH3),
3.60 (q, 3 H, J ) 0.7 Hz, OCH3), 3.39 (dd, 1 H, J 1′a,1′b ) 15.5
Hz, H-1′a), 3.32 (dd, 1 H, H-1′b), 2.43 (s, 3 H, CH3), 1.21 and
1.18 (2 s, 18 H, 2 t-Bu). 19F NMR: δ -69.0. Anal. Calcd for
(4S,2′S,2′′R)-1,3-Di-N-ben zyl-4-[2′-m eth oxyca r bon yl-2′-
(3′′,3′′,3′′-tr iflu or o-2′′-m eth oxy-2′′-ph en yl-pr opion ylam in o)-
et h yl]-6-m et h yl-2-oxo-1,2,3,4-t et r a h yd r op yr im id in e-5-
ca r boxylic Acid Eth yl Ester ((4S)-31 (R)-Mosh er Am id e).
Elution system: AcOEt. 1H NMR: δ 7.80-7.10 (m, 16 H, 3
Ph, NH), 5.38 and 4.78 (2 d, 2 H, J ) 16.5 Hz, PhCH2), 5.26
and 4.14 (2 d, 2 H, J ) 15.0 Hz, PhCH2), 4.84-4.74 (m, 1 H,
H-2′), 4.45 (dd, 1 H, J 4,1′a ) 6.5 Hz, J 4,1′b ) 7.0 Hz, H-4), 4.20-
4.00 (m, 2 H, CH2CH3), 3.59 (s, 3 H, CO2CH3), 3.30 (q, 3 H, J
C
36H41F3N2O8 (686.71): C, 62.96; H, 6.02; N, 4.08. Found: C,
62.97; H, 6.04; N, 4.08.
(2′S,1′′S)-4-[2′-ter t-Bu toxyca r bon yla m in o-2′-(1′′-m eth -
oxyca r b on yl-2′′-p h en yl-et h ylca r b a m oyl)-et h yl]-2,6-d i-
m eth yl-p yr id in e-3,5-d ica r boxylic Acid Di-ter t-bu tyl Es-
ter (Boc-P a l-P h e-OMe) (35). To a cooled (0 °C), stirred
solution of amino acid 24c (49 mg, 0.10 mmol), L-phenylalanine
methyl ester hydrochloride (32 mg, 0.15 mmol), and (benzo-
triazol-1-yloxy)tripyrrolidinophosphonium hexafluorophos-
phate (62 mg, 0.12 mmol) in anhydrous CH2Cl2 (0.5 mL) was
added N,N-diisopropylethylamine (52 µL, 0.30 mmol). The
solution was warmed to room temperature, stirred for an
additional 2 h, and then concentrated. The residue was
suspended with AcOEt (80 mL) and washed with H2O (2 × 10
mL). The organic phase was dried (Na2SO4), concentrated, and
eluted from a column of silica gel with 2:1 cyclohexane-AcOEt
to give dipeptide 35 (59 mg, 90%) as 1:1 mixture of conformers.
[R]D -23.5 (c 0.8, CHCl3). 1H NMR (DMSO-d6, 140 °C): δ 8.16
(s, 1 H, N′′H), 7.40-7.10 (m, 5 H, Ph), 5.85 (br d, 1 H, J ) 8.0
Hz, N′H), 4.66 (dd, 0.5 H, J 1′′,2′′a ) 6.5 Hz, J 1′′,2′′b ) 7.2 Hz,
H-1′′), 4.63 (dd, 0.5 H, J 1′′,2′′a ) 6.5 Hz, J 1′′,2′′b ) 7.2 Hz, H-1′′),
4.33 (ddd, 1 H, J 1′a,2′ ) 5.5 Hz, J 1′b,2′ ) 11.0 Hz, H-2′), 3.60 (s,
3 H, OCH3), 3.21 (dd, 1 H, J 1′a,1′b ) 14.0 Hz, H-1′a), 3.12 (dd,
1 H, J 2′′a,2′′b ) 13.8 Hz, H-2′′a), 3.04 (dd, 1 H, H-2′′b), 2.69 (dd,
1 H, H-1′b), 2.45 (s, 6 H, 2 CH3), 1.60 (s, 18 H, 2 t-Bu), 1.30 (s,
) 0.7 Hz, OCH3), 2.41 (s, 3 H, CH3), 2.24 (ddd, 1 H, J 1′a,2′
)
5.0 Hz, J 1′a,1′b ) 14.0 Hz, H-1′a), 2.08 (ddd, 1 H, J 1′b,2′ ) 8.0
Hz, H-1′b), 1.21 (t, 3 H, J ) 7.0 Hz, CH2CH3). 19F NMR: δ
-69.4. Anal. Calcd for C36H38F3N3O7 (681.70): C, 63.43; H,
5.62; F, 8.36; N, 6.16. Found: C, 63.41; H, 5.66; F, 8.38; N,
6.11.
(4S,2′S,2′′S)-1,3-Di-N-ben zyl-4-[2′-m eth oxyca r bon yl-2′-
(3′′,3′′,3′′-tr iflu or o-2′′-m eth oxy-2′′-ph en yl-pr opion ylam in o)-
et h yl]-6-m et h yl-2-oxo-1,2,3,4-t et r a h yd r op yr im id in e-5-
ca r boxylic Acid Eth yl Ester ((4S)-31 (S)-Mosh er Am id e).
Elution system: AcOEt. 1H NMR: δ 7.80-7.00 (m, 16 H, 3
Ph, NH), 5.34 and 4.72 (2 d, 2 H, J ) 16.5 Hz, PhCH2), 5.14
and 3.97 (2 d, 2 H, J ) 15.0 Hz, PhCH2), 4.79 (ddd, 1 H, J 1′a,2′
) 5.0 Hz, J 1′b,2′ ) 7.0 Hz, J 2′,NH ) 9.5 Hz, H-2′), 4.20 (dd, 1 H,
J 4,1′a ) 6.5 Hz, J 4,1′b ) 7.0 Hz, H-4), 4.10-3.95 (m, 2 H,
CH2CH3), 3.56 (s, 3 H, CO2CH3), 3.52 (q, 3 H, J ) 0.7 Hz,
OCH3), 2.38 (s, 3 H, CH3), 2.13 (ddd, 1 H, J 1′a,1′b ) 14.0 Hz,
H-1′a), 2.05 (ddd, 1 H, H-1′b), 1.12 (t, 3 H, J ) 7.0 Hz,
CH2CH3). 19F NMR: δ -69.2. Anal. Calcd for C36H38F3N3O7
(681.70): C, 63.43; H, 5.62; F, 8.36; N, 6.16. Found: C, 63.46;
H, 5.61; F, 8.38; N, 6.18.
3 H, t-Bu). MALDI-TOF MS: 656.4 (M+ + H), 679.0 (M+
+
Na), 695.4 (M+ + K). Anal. Calcd for C35H49N3O9 (655.78): C,
(2′S,2′′R)-4-[2′-Meth oxyca r bon yl-2′-(3′′,3′′,3′′-tr iflu or o-
2′′-m e t h oxy-2′′-p h e n yl-p r op ion yla m in o)-e t h yl]-2,6-d i-
m eth yl-p yr id in e-3,5-d ica r boxylic Acid Di-ter t-bu tyl Es-
ter (32 (R)-Mosh er Am id e). Elution system: 3:1 cyclohex-
64.10; H, 7.53; N, 6.41. Found: C, 64.15; H, 7.55; N, 6.48.
(2′S,2′′S,1′′′S)-4-[2′-(2′′-ter t-Bu t oxyca r b on yla m in o-3′′-
p h e n yl-p r op ion yla m in o)-2′-(1′′′-m e t h oxyca r b on yl-2′′′-
p h en yl-et h ylca r b a m oyl)-et h yl]-2,6-d im et h yl-p yr id in e-
3,5-d ica r boxylic Acid Di-ter t-bu tyl Ester (Boc-P h e-P a l-
P h e-OMe) (36). To a cooled (0 °C), stirred solution of dipeptide
35 (66 mg, 0.10 mmol) in CH2Cl2 (0.50 mL) was slowly added
a solution of TFA-CH2Cl2 (0.50-1.50 mL). Stirring was
continued at 0 °C for an additional 30 min, then the solution
was warmed to room temperature. After 30 min at room
temperature the solution was neutralized at 0 °C with
saturated aqueous Na2CO3 and extracted with CH2Cl2 (2 ×
50 mL). The combined organic phases were dried (Na2SO4) and
concentrated to give the corresponding free amine (47 mg,
∼85%), at least 95% by pure by NMR analysis, suitable for
the next step.
1
ane-AcOEt. [R]D -37.5 (c 0.8, CHCl3). H NMR: δ 8.21 (br d,
1 H, J 2′,NH ) 8.0 Hz, N′H), 7.60-7.50 and 7.42-7.36 (2 m, 5
H, Ph), 4.97 (ddd, 1 H, J 1′a,2′ ) 5.5 Hz, J 1′b,2′ ) 12.5 Hz, H-2′),
3.75 (s, 3 H, CO2CH3), 3.57 (dd, 1 H, J 1′a,1′b ) 14.0 Hz, H-1′a),
3.05 (q, 3 H, J ) 0.7 Hz, OCH3), 2.80 (dd, 1 H, H-1′b), 2.57 (s,
6 H, 2 CH3), 1.60 (s, 18 H, 2 t-Bu). 19F NMR: δ -70.2. Anal.
Calcd for C31H39F3N2O8 (624.65): C, 59.61; H, 6.29; N, 4.48.
Found: C, 59.69; H, 6.21; N, 4.43.
(2′S,2′′S)-4-[2′-Met h oxyca r b on yl-2′-(3′′,3′′,3′′-t r iflu or o-
2′′-m e t h oxy-2′′-p h e n yl-p r op ion yla m in o)-e t h yl]-2,6-d i-
m eth yl-p yr id in e-3,5-d ica r boxylic Acid Di-ter t-bu tyl Es-
ter (32 (S)-Mosh er Am id e). Elution system: 3:1 cyclohex-
1
ane-AcOEt. [R]D -28.2 (c 1.7, CHCl3). H NMR: δ 8.32 (br d,
1 H, J 2′,NH ) 8.0 Hz, N′H), 7.30-7.22 and 7.16-7.04 (2 m, 5
H, Ph), 5.00 (ddd, 1 H, J 1′a,2′ ) 5.5 Hz, J 1′b,2′ ) 13.0 Hz, H-2′),
3.80 (s, 3 H, CO2CH3), 3.57 (q, 3 H, J ) 0.7 Hz, OCH3), 3.54
(dd, 1 H, J 1′a,1′b ) 14.0 Hz, H-1′a), 2.72 (dd, 1 H, H-1′b), 2.41
(s, 6 H, 2 CH3), 1.62 (s, 18 H, 2 t-Bu). 19F NMR: δ -70.0. Anal.
Calcd for C31H39F3N2O8 (624.65): C, 59.61; H, 6.29; N, 4.48.
Found: C, 59.65; H, 6.29; N, 4.41.
(2′S,2′′R)-2-[2′-Meth oxyca r bon yl-2′-(3′′,3′′,3′′-tr iflu or o-
2′′-m eth oxy-2′′-p h en yl-p r op ion yla m in o)-eth yl]-6-m eth yl-
4-p h en yl-p yr id in e-3,5-d ica r boxylic Acid Di-ter t-bu tyl Es-
To a cooled (0 °C), stirred solution of the above free amine
(47 mg, ∼0.09 mmol), tert-butoxycarbonyl-L-phenylalanine (36
mg, 0.14 mmol), and (benzotriazol-1-yloxy)tripyrrolidinophos-
phonium hexafluorophosphate (84 mg, 0.16 mmol) in anhy-
drous CH2Cl2 (0.5 mL) was added N,N-diisopropylethylamine
(46 µL, 0.27 mmol). The solution was warmed to room
temperature, stirred for an additional 2 h, and then concen-
trated. The residue was suspended with AcOEt (80 mL) and
washed with saturated aqueous NaHCO3 (10 mL) and brine
(10 mL). The organic phase was dried (Na2SO4), concentrated,
6182 J . Org. Chem., Vol. 68, No. 16, 2003

Dihydropyrimidinyl and Pyridyl R-Amino Acids
and eluted from a column of silica gel with 2:1 cyclohexane-
AcOEt to give tripeptide 36 (66 mg, 82% from 35). [R]D -32.1
(c 1.9, CHCl3). 1H NMR (DMSO-d6, 120 °C): δ 7.60 (br d, 1 H,
J 2′,N”H ) 8.0 Hz, N′′H), 7.40-7.00 (m, 10 H, 2 Ph), 6.08 (br d,
1 H, J 2′′,NH ) 8.0 Hz, NHBoc), 4.64-4.52 (m, 2 H, H-2′′, H-1′′′),
4.14 (ddd, 1 H, J 1′a,2′ ) 5.5 Hz, J 1′b,2′ ) 8.5 Hz, H-2′), 3.59 (s, 3
H, OCH3), 3.24 (dd, 1 H, J 1′a,1′b ) 14.0 Hz, H-1′a), 3.06 (dd, 1
H, J 1′′′,2′′′a ) 6.5, J 2′′′a,2′′′b ) 14.0 Hz, H-2′′′a), 2.99 (dd, 1 H, J 1′′′,2′′′b
) 7.0 Hz, H-2′′′b), 2.86 (dd, 1 H, J 2′′,3′′a ≈ 0.5 Hz, J 3′′a,3′′b ) 13.5
Hz, H-3′′a), 2.82 (dd, 1 H, J 2′′,3′′b ) 4.0 Hz, H-3′′b), 2.72 (dd, 1
H, H-1′b), 2.50 (2 s, 6 H, 2 CH3), 1.60 (s, 18 H, 2 t-Bu), 1.30 (s,
reflections with I > 2σ(I)), S ) 1.045. All non-H atoms were
refined anisotropically; the N-H hydrogen atoms were re-
fined isotropically; all other hydrogens were included on
calculated positions, riding on their carrier atoms. A final
difference Fourier map showed no residual density outside
-0.17 and 0.16 Å-3. An ORTEP29 view of the molecule is shown
in Figure 3.
Ack n ow led gm en t. We thank the University of
Ferrara for financial support and Ajinomoto Co., Inc.
(Tokyo, J apan) for an unrestricted grant.
9 H, t-Bu). MALDI-TOF MS: 803.4 (M+ + H), 825.4 (M+
+
Su p p or tin g In for m a tion Ava ila ble: CIF file for com-
pound (4R)-11. This material is available free of charge via
the Internet at http://pubs.acs.org.
Na), 841.6 (M+ + K). Anal. Calcd for C44H58N4O10 (802.95): C,
65.82; H, 7.28; N, 6.98. Found: C, 65.89; H, 7.21; N, 6.92.
Cr ysta l d a ta for com p ou n d (4R)-11: C19H31N3O6, Mr )
397.47, colorless crystal (0.12 × 0.17 × 0.31 mm3), orthorhom-
bic, space group P212121 (no. 19) with a ) 5.8209(2) Å, b )
15.1688(4) Å, c ) 24.5767(9) Å, V ) 2170.0(1) Å3, Z ) 4, Dc )
1.217 g cm-3, 7282 reflections measured, 4361 indipendent,
Rint ) 0.041, (3.6 < θ < 27.5°, T ) 295 K, Mo KR radiation, λ
) 0.71073 Å) on a Nonius Kappa CCD diffractometer. The
structure was solved by direct methods (SIR97)27 and refined
on F2 (SHELXL-97).28 Refinement converged at a final wR2
value of 0.1047 (all reflections), R1 ) 0.0409 (for 3671
J O0342830
(27) Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.;
Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G.; Polidori, G.; Spagna,
R. J . Appl. Crystallogr. 1999, 32, 115.
(28) Sheldrick, G. M. SHELXL-97, Program for the Refinement for
Crystal Structures; University of Go¨ttingen: Go¨ttingen, Germany,
1997.
(29) Burnett, M. N.; J ohnson, C. K. ORTEP III; Oak Ridge National
Laboratory: Oak Ridge, TN, 1996; Report ORNL-6895.
J . Org. Chem, Vol. 68, No. 16, 2003 6183