Total synthesis and absolute configuration of the natural amino acid tetrahydrolathyrine

Article abstract of DOI:10.1021/jo900800x

(Chemical Equation Presented) The natural product tetrahydrolathyrine has been synthesized through an iminoiodane-mediated aziridination of a (2S)-allylglycinol derivative, which provided a 2:3 mixture of diastereoisomers. One of these diastereoisomers wa

Full text of DOI:10.1021/jo900800x

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Total Synthesis and Absolute Configuration of the Natural Amino Acid
Tetrahydrolathyrine
Meryem Benohoud,† Loic Leman,† Silvia H. Cardoso,‡ Pascal Retailleau,†
Philippe Dauban,† Josiane Thierry,*,† and Robert H. Dodd*,†
†Centre de Recherche de Gif-sur-Yvette, Institut de Chimie des Substances Naturelles, UPR 2301, CNRS,
‡
Avenue de la Terrasse, 91198 Gif-sur-Yvette, France, and Departamento de Quımica, Instituto de Ciencias
´
Exatas, Universidade Federal de Juiz de Fora, 36036-330 Juiz de Fora, MG, Brazil
^
robert.dodd@icsn.cnrs-gif.fr
Received April 20, 2009
The natural product tetrahydrolathyrine has been synthesized through an iminoiodane-mediated
aziridination of a (2S)-allylglycinol derivative, which provided a 2:3 mixture of diastereoisomers. One
of these diastereoisomers was converted to the natural product and the other to its C-4 epimer. The C-
4 configuration was established from NOESY NMR analysis and X-ray structure of compounds
derived from the non-natural diastereoisomer. Thus, tetrahydrolathyrine was shown to have the
(2S,4R) absolute configuration.
Introduction
tuberactinomycins N and O6 and chymostatin),7 epicapreomy-
cidine 9 (constituent of muraymycins),8 stendomycidine 10
(constituent of stendomycin),9 tuberactidine 11 (constituent
of tuberactinomycin A),10 and viomycidine 12 (constituent of
viomycin).11 Of these, tetrahydrolathyrine 1,1 lathyrine 22 and
enduracididine 412 have also been isolated from plants as free
amino acids.
Only the total synthesis of capreomycidine has been
reported,5b while a semisynthesis of tetrahydrolathyrine
from lathyrine has been described.1 Our own laboratory
has recently completed the synthesis of a protected form of
enduracididine 4.13 We report here the first total synthesis of
tetrahydrolathyrine, which moreover has allowed the deter-
mination of its absolute configuration.
Tetrahydrolathyrine, 3-(2-amino-1,4,5,6-tetrahydropyri-
midin-4-yl)-L-alanine (1), is a naturally occurring nonpro-
teinogenic amino acid isolated in 1979 from seeds of Loncho-
carpus costaricensis.1 Structurally, it has been described
as the product of partial reduction of the natural com-
pound lathyrine (β-(2-aminopyrimidin-4-yl)-L-alanine) 2
(Figure 1).1,2 However, its absolute configuration has not
yet been determined. Tetrahydrolathyrine, which can be
viewed as a constrained analogue of arginine 3, belongs to a
family of natural amino acids having the terminal guanidine
nitrogen atom linked to the methylene backbone (Figure 2).
Most of these amino acids are components of peptide
antibiotics isolated from extracts of microorganisms and in-
clude enduracididine 4 and alloenduracididine 5 (constituents
of enduracidin),3 β-hydroxyenduracididine 6 and β-hydroxyal-
loenduracididine 7 (constituents of (R-ε)-mannopeptimy-
cins),4 capreomycidine 8 (constituent of capreomycins,5a
(6) Ando, T.; Matsuura, K.; Izumi, R.; Noda, T.; Take, T.; Nagata, A.;
Abe, J. J. Antibiot. 1971, 24, 680–686.
(7) Umezawa, H.; Aoyagi, T.; Morishima, H.; Kunimoto, S.; Matsuzaki,
M.; Hamada, M.; Takeuchi, T. J. Antibiot. 1970, 23, 425–427.
(8) McDonald, L. A.; Barbieri, L. R.; Carter, G. T.; Lenoy, E.; Lotvin, J.;
Petersen, P. J.; Siegel, M. M.; Singh, G.; Williamson, R. T. J. Am. Chem. Soc.
2002, 124, 10260–10261.
(9) Bodanszky, M.; Muramatsu, I.; Bodanszky, A.; Lukin, M.; Doubler,
M. R. J. Antibiot. 1968, 21, 77–78.
(10) Nagata, A.; Ando, T.; Izumi, R.; Sakakibara, H.; Take, T.; Hayano,
K.; Abe, J. J. Antibiot. 1968, 21, 681–687.
(1) Fellows, L. E.; Bell, E. A.; Lee, T. S.; Janzen, D. H. Phytochemistry
1979, 18, 1333–1335.
(2) Bell, E. A.; Foster, R. G. Nature 1962, 194, 91–92.
(3) Horii, S.; Kameda, Y. J. Antibiot. 1968, 21, 665–667.
(4) He, H.; Williamson, R. T.; Shen, B.; Graziani, E. I.; Yang, H. Y.;
Sakya, S. M.; Petersen, P. J.; Carter, G. T. J. Am. Chem. Soc. 2002, 124,
9729–9736.
(5) (a) Herr, E. B.; Haney, M. E.; Pittenger, G. E.; Higgins, C. E. Proc.
Ind. Acad. Sci. 1960, 69, 134. For the synthesis of capreomycidine, see: (b)
DeMong, D. E.; Williams, R. M. J. Am. Chem. Soc. 2003, 125, 8561–8565.
(11) Buchi, G.; Raleigh, J. A. J. Org. Chem. 1971, 36, 873–877.
(12) Fellows, L. E.; Hider, R. C.; Bell, E. A. Phytochemistry 1977, 16,
1957–1959.
ꢀ
(13) Saniere, L.; Leman, L.; Bourguignon, J.-J.; Dauban, P.; Dodd, R. H.
Tetrahedron 2004, 60, 5889–5897.
DOI: 10.1021/jo900800x
r
Published on Web 07/02/2009
J. Org. Chem. 2009, 74, 5331–5336 5331
2009 American Chemical Society

Benohoud et al.
JOCArticle
SCHEME 1. Retrosynthetic Analysis
FIGURE 1. Tetrahydrolathyrine, lathyrine, and arginine.
SCHEME 2
FIGURE 2. Cyclic guanidine amino acid family.
Results and Discussion
Synthesis. The planned synthetic route, analogous to that
previously used by us for the preparation of the lower homo-
logue enduracididine,13 relied on an iminoiodane-mediated
copper-catalyzed aziridination of an allylglycine derivative as
the key step. Retrosynthetic analysis suggested that tetrahy-
drolathyrine1 couldbe obtained fromthe guanidine13, which
in turn could be constructed from the diamine 14. The latter
could be prepared by cyanide-promoted opening of the
aziridine 15 obtained through aziridination of a suitably
protected L-allyglycine derivative 16 (Scheme 1).
We first prepared the appropriate L-allylglycine starting
material. Very efficient enantioselective methods for the
synthesis of R-amino acids have been described indepen-
dently by Lygo14 and Corey15 using Cinchona-derived qua-
ternary ammonium salts as chiral catalysts. The allylglycine
substrate 18 was thus prepared on a multigram scale by
electrophilic alkylation of the Schiff base 17 with allyl
bromide using O-(9)-allyl-N-(9-anthracenylmethyl)cincho-
nidinium bromide as catalyst (10 mol %). After optimization
of the published conditions, product 18 was obtained in good
yield (90%) and with an excellent optical purity (>98% as
measured by HPLC). Aqueous acid treatment of crude Schiff
base 18 gave (S)-allylglycine tert-butyl ester, the amino
function of which was protected by a Boc group using Boc
anhydride and ZrCl4 catalysis as described by Sharma et al.,
giving 19 (Scheme 2).16
Special attention was given to the choice of carboxylic acid
and amine protecting groups since our previous studies
concerning the synthesis of enduracididine showed this issue
to be crucial.17 Simultaneous protection of the two function-
alities in the form of an oxazolidin-2-one was deemed a good
choice, the cyclic carbamate being considered sufficiently
electron-withdrawing to minimize copper sequestration dur-
ing the aziridination step and, moreover, limiting the possi-
bility of intramolecular aziridine ring opening by the
nitrogen atom.18,19 Thus, ester 19 was reduced by LiAlH4,
and the resulting N-Boc amino alcohol was treated with
SOCl220 to afford the desired (S)-allyloxazolidin-2-one 20 in
good yield and without loss of optical purity.
We have previously shown that the iminoiodane-mediated
aziridination of a wide range of olefins can be achieved using
ꢀ
(17) Leman, L.; Saniere, L.; Dauban, P.; Dodd, R. H. Arkivoc 2003, 126–
134.
(18) This side reaction was observed when the 2-amino function was
protected by a phenylfluorenyl group (PhF); see ref 13.
(19) Simultaneous protection of the two functionalities in the form of a
1,3-oxazoline was also effected. However, iminoiodane-mediated aziridina-
tion of the 4-allyl-1,3-oxazoline was not successful.
(14) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997, 38, 8595–8598.
(15) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414–
12415.
(16) Sharma, G. V. M.; Reddy, J. J.; Lakshmi, P. S.; Krishna, P. R.
Tetrahedron Lett. 2004, 45, 6963–6965.
(20) Matsunaga, H.; Ishizuka, T.; Kunieda, T. Tetrahedron 1997, 53,
1275–1294.
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SCHEME 3
SCHEME 4
amine on the terminal guanidine. Several attempts were
made using different fluoride ion sources (TASF or TBAF),
solvents (DMF, THF, MeCN), or temperatures (room tem-
perature, 50 °C, 90 °C), but all resulted in degradation
products. On the hypothesis that the guanidino protecting
groups did not survive these harsh conditions, it was decided
to replace the Ses protecting group by a more easily cleavable
Boc group earlier in the synthesis. Thus, treatment of the
sulfonamide 22 with Boc2O in the presence of a cata-
lytic amount of DMAP followed by reaction with fluoride
anion cleanly gave the N-Boc cyano derivative 26 in 71%
yield. At this stage, it was possible to separate the diaster-
eoisomers 26-A and 26-B by chromatography on silica gel
(Scheme 4).
Reduction of the cyano function of 26-A with PtO2 using
the same conditions as before afforded the intermediate
amine that was reacted directly with S-methyl N,N0-bis
(benzyloxycarbonyl)isothiourea under conditions described
by Izdebski26 to give the protected guanidine derivative 27-A
in 84% yield (Scheme 5). Treatment of this compound with
HCl in methanol for 16 h now allowed the cleavage of both
N-Boc protecting groups followed by cyclization to provide
the 2-aminotetrahydropyrimidine derivative 25-A in quanti-
tative yield.
a convenient one-pot procedure.21 Thus, using our opti-
mized conditions, mixing 1.0 equiv of olefin 20, 1.2 equiv
of iodosylbenzene (PhIdO), and 1.2 equiv of trimethylsily-
lethanesulfonamide (SesNH2) in the presence of 25 mol % of
Cu(CH3CN)4PF6 in acetonitrile at room temperature pro-
vided the desired N-Ses aziridine 21 in 45% yield (65% yield
based on recovered starting material) though with only
minimal diastereoselectivity (43:57 determined by HPLC)
(Scheme 3).22 At this stage, the two diastereoisomers could
not be separated.
Opening of the aziridine ring of 21 (as a mixture of
diastereoisomers) using cyanide anion was then investi-
gated.23 Careful control of the reaction conditions (KCN
in MeOH for 16 h at 30 °C) was required in order to minimize
the formation of the side product 23 resulting from intramo-
lecular opening of the oxazolidin-2-one 22. The cyano
derivative 22 was thus obtained as the unique product in
75% yield.
Activation of the cyclic carbamate of 25-A with Boc2O
followed by treatment with a catalytic amount of cesium
carbonate27 in methanol at room temperature afforded the
amino alcohol 28-A in 51% overall yield. Sharpless oxida-
tion28 of this primary alcohol 28-A provided the carboxylic
acid in 90% yield. In the final step of the synthesis, the amino
functionalities were regenerated by refluxing the product in 6
N HCl solution for 1 h, affording amino acid 29-A in 72%
yield for both steps. Treatment of 26-B in the same manner
gave the amino acid 29-B in comparable overall yield.
At this point, it remained to determine which diastereoi-
somer, 29-A or 29-B, corresponded to the natural amino acid
tetrahydrolathyrine. Comparison of the physical and spec-
tral data of compounds 29-A and 29-B with the data reported
by Fellows et al.1 for tetrahydrolathyrine and its epimer
clearly indicated that 29-B corresponded to the natural
product and 29-A to its C-4 epimer (see Experimental Sec-
tion).
The cyano group of 22 was hydrogenated under pressure
(3 bar) in MeOH/CHCl3 at room temperature using PtO2 as
catalyst to afford the intermediate amine as the hydrochlor-
ide salt in quantitative yield.24 The latter was reacted directly
with S-methyl N,N0-bis(benzyloxycarbonyl)isothiourea
25
using HgCl2 as catalyst to give the protected guanidine
derivative 24 in 64% yield. Unexpectedly and in contrast to
observations made during the synthesis of enduracididine,
removal of the Ses group of 24 with cesium fluoride in DMF
at 90 °C for 24 h failed to provide the 2-aminotetrahydro-
pyrimidine 25, which would result from the attack of the free
Absolute Configuration Determination. The solids ob-
tained by crystallization of 29-A and 1 were not suitable
for X-ray crystallography. Furthermore, because NMR
analysis of these flexible compounds did not allow their
absolute configuration at C-4 to be determined with cer-
tainty, a cyclic derivative, isolated unexpectedly in a parallel
ꢀ
(21) Dauban, P.; Saniere, L.; Tarrade, A.; Dodd, R. H. J. Am. Chem. Soc.
2001, 123, 7707–7708.
(22) No efforts were made to improve this step since in our previous study
of an allylglycine derivative aziridination, varying the solvents (benzene or
dichloromethane) or the reaction temperature resulted in no increase in the
yield of aziridine (see ref 17).
(23) Tanner, D.; He, H. M. Tetrahedron 1992, 48, 6079–6086.
(24) Duggan, M. E.; Naylor-Olsen, A. M.; Perkins, J. J.; Anderson, P. S.;
Chang, C. T-C.; Cook, J. J.; Gould, R. J.; Ihle, N. C.; Hartman, G. D.;
Lynch, J. J.; Lynch, R. J.; Manne, P. D.; Schaffer, L. W.; Smith, R. L. J. Med.
Chem. 1995, 38, 3332–3341.
(26) Gers, T.; Kunce, D.; Markowski, P.; Izdebski, J. Synthesis 2004, 37–
42.
(27) Ishizuka, T.; Kunieda, T. Tetrahedron Lett. 1987, 28, 4185–4188.
(28) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org.
Chem. 1981, 46, 3936–3938.
(25) Su, W. Synth. Commun. 1996, 26, 407–413.
J. Org. Chem. Vol. 74, No. 15, 2009 5333

Benohoud et al.
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SCHEME 5a
aYields obtained starting from diastereoisomer 26-B are indicated in brackets.
SCHEME 6
FIGURE 3. Absolute configuration of tetrahydrolathyrine and of
its C-4 epimer.
the natural nonproteinogenic amino acid tetrahydrolathyr-
ine 1 (= 29-B) and its diastereoisomer 29-A (Figure 3). The
(2S 4R) stereochemistry of the natural compound was
deduced from NOESY NMR studies of the cyclic derivative
31-A and confirmed by X-ray crystallography of compound
25-A.
study, proved much more amenable to NMR study. Thus,
treatment of 27-A with catalytic cesium carbonate in metha-
nol afforded the alcohol 30-A in which one Cbz group was
cleaved and the second underwent transesterification. Sharp-
less oxidation of 30-A then gave directly lactam 31-A, though
in low yield (Scheme 6). This cyclic compound has both
stereocenters incorporated on the ring. Irradiation of CH(3)
in a NOE experiment showed enhancements of the signals
for CH2(10), indicating that these protons are in proximity
and on the same side of the ring. As the C-3 stereocenter is
fixed (i.e., (S)), the C-5 stereocenter was assigned the (S)
configuration.
Final confirmation of the absolute configuration of dia-
stereoisomer A was obtained by X-ray crystallography of 25-
A which was shown to be (2S,4S) (see Supporting Informa-
tion). Since compound 25-A corresponds to the C-4 epimer
of 25-B, the direct precursor of tetrahydrolathyrine 1, it can
be concluded that the latter has the absolute configuration
(2S,4R).
Experimental Section
(4S)-4-[(1-[2-(Trimethylsilyl)ethanesulfonyl]-2-aziridinyl)me-
˚
thyl]-1,3-oxazolidin-2-one (21). To activated 3 A molecular
sieves (16 g) in freshly distilled MeCN (63 mL) were added
compound 20 (2.00 g, 15.73 mmol) and Cu(CH3CN)4PF6 (0.88
g, 3.93 mmol, 0.25 equiv). A mixture of SesNH2 (3.42 g, 18.88
mmol, 1.2 equiv) and iodosylbenzene (PhIO) (4.15 g, 18.88
mmol, 1.2 equiv) was then introduced in five portions over a
90 min period. The heterogeneous green reaction mixture was
stirred overnight at room temperature and then filtered through
a Celite pad, and the filtrate was concentrated in vacuo. The
residue was purified by column chromatography (silica gel,
heptane/AcOEt 2/1, 1/1, 1/4) to afford the N-(Ses)aziridine
derivative 21 (2.15 g, 45% yield) as an inseparable mixture of
diastereoisomers. 1H NMR (300 MHz, CDCl3) δ 0.09 (2s, 9H),
1.09-1.16 (m, 2H), 1.37-1.56 (m, 1H), 2.10-2.18 (m, 1H),
2.19-2.24 (m, 1H), 2.58 (d, 1H, J = 6.9 Hz), 2.65 (d, 1H, J = 6.9
Hz), 2.75-2.88 (m, 1H), 3.07-3.17 (m, 2H), 3.99-4.08 (m, 1H),
4.08-4.16 (m, 1H), 4.57 (q, 1H, J = 15.6 and 8.1 Hz), 6.06, 6.30
(2s, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ -2.0, 9.6, 9.7, 33.1,
33.4, 34.2, 35.5, 36.6, 36.8, 49.1, 50.8, 51.8, 69.5, 69.9, 158.9,
159.2 ppm. IR (neat) ν 3358, 2952, 1738, 1315, 1248, 1143,
In conclusion, using a one-pot iminoiodane-mediated
copper-catalyzed aziridination of an allyloxazolidinone de-
rivative, we have described herein the first total synthesis of
5334 J. Org. Chem. Vol. 74, No. 15, 2009

Benohoud et al.
JOCArticle
834 cm-1. HRMS calcd for C11H22N2O4SSiNa (M þ Naþ) m/z
329.0967, found 329.0955. Anal. Calcd for C11H22N2O4SSi: C
43.11, H 7.24, N 9.14. Found: C 42.85, H 7.23, N 8.94. HPLC
Hypercarb (150 ꢀ 4.6 mm), isocratic MeCN/H2O 30/70, 1 mL/
min, tR1 = 15.9 min (43%), tR2 = 16.9 min (57%).
Guanidino Compounds 27-A and 27-B. To a solution of the
cyano derivative 26-A (185 mg, 0.50 mmol) in a mixture of dry
10/1 MeOH/CHCl3 (c 0.15 M) was added PtO2 (29 mg, 0.25
mmol, 0.5 equiv). The mixture was stirred under H2 in a Parr
apparatus (3.0 bar) at rt for 6 h then filtered through a pad of
Celite and concentrated in vacuo to afford the amine in a
Cyano Derivative 22 and Pyrrolidine 23. To a solution of N-
(Ses)aziridine 21 (300 mg, 0.98 mmol) in dry MeOH (30 mL) at rt
under argon was added potassium cyanide (128 mg, 1.96 mmol,
2.0 equiv). The mixture was stirred at 30 °C for 16 h. The solvent
was removed under reduced pressure, and the mixture was
diluted with water and extracted with ethyl acetate (3 ꢀ ). The
combined organic extracts were dried (MgSO4) and concen-
trated in vacuo, and the residue was purified by column chro-
matography (silica gel, 5% MeOH/DCM) to afford the cyano
compound 22 (230 mg, 75% yield) as a mixture of diastereo-
isomers. 1H NMR (300 MHz, CDCl3) δ 0.06 (2s, 9H), 0.96-1.03
(m, 2H), 1.78-1.84 (m, 1H), 1.93-1.96 (m, 1H), 2.57-2.77 (m,
2H), 2.97-3.08 (m, 2H), 3.65-3.76 (m, 1H), 3.94-4.10 (m, 2H),
4.44-4.51 (m, 1H), 5.56 (bs, 1H), 5.97 (d, 1H, J = 11.4 Hz,)
ppm; 13C NMR (75 MHz, CDCl3) δ -1.9, 10.3, 10.6, 25.5, 25.7,
40.9, 41.4, 48.1, 48.5, 49.3, 50.1, 51.1, 51.3, 70.0, 70.4, 117.2,
117.6, 159.1, 160.5 ppm; IR (neat) ν 3264, 2954, 2250, 1737,
1415, 1312, 1249, 1138, 1021, 835 cm-1; HRMS calcd for
C12H23N3O4SSiNa m/z 356.1076 (M þ Naþ), found 356.1081.
HPLC Hypercarb (150 ꢀ 4.6 mm), isocratic MeCN/H2O 35/65,
1 mL/min tR1 = 8.2 min (42%), tR2 = 9.9 min (58%).
Further elution of the column with 20% MeOH/DCM
afforded compound 23 as a mixture of diastereoisomers. 1H
NMR (300 MHz, CDCl3) δ 0.05 (2s, 9H), 1.00-1.10 (m, 2H),
1.71-2.00 (m, 2H), 2.04-2.10 (m, 1H), 2.68-2.79 (m, 1H),
2.85-3.03 (m, 3H), 3.23-3.54 (m, 1H), 3.57-3.81 (m, 1H),
4.13-4.31 (m, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ -1.9,
10.1, 10.2, 25.0, 25.2, 40.2, 40.6, 47.5, 48.5, 50.5, 51.2, 54.8, 55.0,
56.5, 57.2, 117.5, 117.7 ppm; IR (neat) ν 3368, 2951, 2247, 1323,
1249, 1137, 1020, 832 cm-1; HRMS calcd for C11H24N3O2SSi
m/z 290.1359 (M þ Hþ), found 290.1349.
quantitative yield as the hydrochloride salt. [R]20 -14.6 (c
D
0.85, MeOH); 1H NMR (300 MHz, DMSO-d6) δ 1.38 (s, 9H),
1.47 (s, 9H), 1.62-1.83 (m, 4H), 2.76 (t, 2H, J = 7.5 Hz), 3.47-
3.59 (m, 1H), 4.09-4.19 (m, 1H), 4.22-4.26 (m, 1H), 4.32 (t, 1H,
J = 9.0 Hz), 6.95 (d, 1H, J = 9.0 Hz), 7.88 (s, 3H) ppm; 13C
NMR (125 MHz, DMSO-d6) δ 27.6, 28.2, 32.7, 36.1, 38.0, 44.3,
52.6, 66.0, 78.0, 82.5, 148.7, 151.6, 155.6 ppm.
To a solution of this amine (554 mg, 1.35 mmol) in dry DMF
(2.7 mL) were added S-methyl-N,N0-bis(benzyloxycarbonyl)
isothiourea (1.065 g, 2.97 mmol, 2.2 equiv) and DMAP (182
mg, 1.49 mmol, 1.1 equiv). The mixture was stirred for 4 h at rt
under argon. The mixture was diluted with ethyl acetate (20 mL)
and washed with 10% aqueous citric acid (3ꢀ), water (2ꢀ), and
brine (1ꢀ). The organic layer was dried (MgSO4) and concen-
trated in vacuo, and the residue was purified by column chro-
matography (silica gel, 1% MeOH in DCM) to afford the
guanidine derivative 27-A (774 mg, 84% yield). [R]20 -8.2 (c
D
0.92, CHCl3); 1H NMR (500 MHz, CDCl3) δ 1.42 (s, 9H), 1.54
(s, 9H), 1.62-1.68 (m, 1H), 1.69-1.75 (m, 1H), 1.77-1.81 (m,
1H), 1.92-1.97 (m, 1H), 3.30-3.35 (m, 1H), 3.62-3.68 (m, 2H),
4.13-4.16 (m, 1H), 4.24-4.28 (m, 1H), 4.33-4.37 (m, 1H), 4.73
(d, 1H, J = 5.0 Hz), 5.12 (s, 2H), 5.18 (s, 2H), 7.28-7.40 (m,
10H), 8.51 (s, 1H), 11.72 (s, 1H) ppm; 13C NMR (75 MHz,
CDCl3) δ 28.0, 28.3, 35.5, 37.6, 39.1, 45.0, 52.6, 66.7, 67.1, 68.2,
79.8, 83.9, 127.9, 128.1, 128.3, 128.6, 128.7, 128.8, 134.5, 136.7,
149.5, 151.9, 153.7, 156.0, 156.1, 163.6 ppm; HRMS calcd for
C34H45N5O10Na m/z 706.3064 (M þ Naþ), found 706.3045.
Compound 26-B was treated under the same conditions as 26-
A to first provide the corresponding amine. [R]20D þ22.9 (c 0.40,
MeOH); 1H NMR (500 MHz, DMSO-d6) δ 1.39 (s, 9H), 1.48 (s,
9H), 1.58-1.69 (m, 2H), 1.76-1.81 (m, 1H), 1.84-1.89 (m, 1H),
2.75 (t, 2H, J = 8.0 Hz), 3.50-3.56 (m, 1H), 4.12-4.14 (m, 1H),
4.18-4.22 (m, 1H), 4.35-4.38 (m, 1H), 6.96 (d, 1H, J = 9.0 Hz),
7.83 (s, 3H) ppm; 13C NMR (125 MHz, DMSO-d6) δ 27.6, 28.2,
32.4, 36.1, 38.0, 45.5, 53.2, 66.6, 78.1, 82.6, 148.7, 151.6, 155.6
ppm.
Cyano Compounds 26-A and 26-B. To a solution of the
mixture of diastereoisomers of the cyano derivative 22 (70 mg,
0.21 mmol) in freshly distilled MeCN (0.50 mL) at rt under
argon were added Boc2O (101 mg, 0.46 mmol, 2.2 equiv) and
DMAP (5 mg, 0.04 mmol, 0.2 equiv). The mixture was stirred at
rt under argon for 16 h. The solvent was removed under reduced
pressure, and the residue was purified by column chromatogra-
phy (silica gel, 2% MeOH/DCM) to afford the N-(Ses), N-(Boc)
derivative (94 mg, 84% yield) as an inseparable mixture of
diastereoisomers. To this mixture of diastereoisomers (93 mg,
0.17 mmol) was added a solution of 1 M TBAF in THF (0.51
mL, 0.51 mmol, 3 equiv). The mixture was stirred at rt under
argon for 16 h. The solvent was removed under reduced
pressure, and the residue was purified by column chromatogra-
phy (silica gel, heptane/AcOEt 1/1) to afford compounds 26A
and 26-B (51 mg, 71% yield) as a mixture of diastereoisomers
that could be separated by column chromatography (silica gel,
5% Et2O/DCM). Diastereoisomer 26-A eluted first. Diastereo-
isomer 26-A: [R]20D þ40.1 (c 0.50, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 1.43 (s, 9H), 1.55 (s, 9H), 1.82-1.91 (m, 1H), 2.15-
2.24 (m, 1H), 2.59-2.78 (m, 2H), 3.83-3.94 (m, 1H), 4.13 (dd,
1H, J = 9.1 and 2.5 Hz), 4.25-4.31 (m, 1H), 4.38 (t, 1H, J = 8.5
Hz), 4.90 (d, 1H, J = 9.0 Hz) ppm; 13C NMR (75 MHz, CDCl3)
δ 24.3, 27.9, 28.2, 37.3, 43.9, 52.1, 66.4, 80.7, 84.4, 116.6, 149.2,
This amine was then transformed into 27-B (64% yield
for both steps). [R]20D þ 31.5 (c 0.19, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 1.41 (s, 9H), 1.51 (s, 9H), 1.63-1.75
(m, 1H), 1.76-1.87 (m, 2H), 1.95-2.05 (m, 1H), 3.30-3.41
(m, 1H), 3.55-3.66 (m, 2H), 4.16-4.19 (m, 1H), 4.25-4.33
(m, 2H), 5.12 (s, 2H), 5.15 (d, 1H, J = 5.0 Hz), 5.19 (s, 2H),
7.28-7.40 (m, 10H), 8.49 (s, 1H), 11.69 (s, 1H) ppm; 13C NMR
(125 MHz, CDCl3) δ 27.9, 28.3, 34.4, 37.6, 39.4, 46.8, 54.0, 67.0,
67.2, 68.2, 79.8, 83.9, 127.9, 128.0, 128.4, 128.6, 128.7, 128.8,
134.5, 136.6, 149.3, 152.0, 153.6, 156.0, 156.2, 163.5 ppm;
HRMS calcd for C34H45N5O10Na m/z 706.3064 (MþNaþ),
found 706.3069.
Tetrahydropyrimidines 25-A and 25-B. To a solution of the
guanidine compound 27-A (146 mg, 0.21 mmol) in dry MeOH
(3.5 mL) was added HCl (3.5 mL of a 1.25 M solution in
MeOH). The mixture was stirred for 16 h at rt under argon,
the solvent was removed under reduced pressure, and the residue
was purified by chromatography (silica gel, 5% MeOH in
DCM) to furnish the pure product 25-A in quantitative yield
151.5, 155.1 ppm. Diastereoisomer 26-B: [R]20 þ26.4 (c 0.46,
D
1
CHCl3); H NMR (300 MHz, CDCl3) δ 1.42 (s, 9H), 1.53 (s,
(70 mg). [R]20 -3.9 (c 0.84, CHCl3); 1H NMR (300 MHz,
D
9H), 2.02-2.17 (m, 2H), 2.60-2.71 (m, 2H), 3.89-3.98 (m, 1H),
4.14-4.21 (m, 1H), 4.32-4.40 (m, 2H), 5.41 (d, 1H, J = 9.0 Hz)
ppm; 13C NMR (75 MHz, CDCl3) δ 23.8, 27.9, 28.2, 37.6, 45.7,
53.5, 67.0, 80.5, 84.4, 117.0, 149.2, 151.8, 154.9 ppm; HRMS
calcd for C17H27N3O6Na m/z 392.1798 (M þ Naþ), found
392.1805.
CDCl3) δ 1.51-1.65 (m, 2H), 1.86-1.96 (m, 1H), 2.01-2.06 (m,
1H), 3.38 (t, 2H, J = 5.7 Hz), 3.67-3.75 (m, 1H), 3.89-3.95 (m,
1H), 3.97-4.04 (m, 1H), 4.44 (t, 1H, J = 8.0 Hz), 4.95 (s, 2H),
5.09 (s, 2H), 7.33-7.35 (m, 5H), 7.50 (s, 1H), 8.78 (s, 1H) ppm;
13C NMR (75 MHz, CDCl3) δ 24.6, 37.0, 40.9, 46.5, 49.6, 66.9,
70.0, 128.0, 128.2, 128.3, 128.5, 128.6, 135.3, 153.6, 156.4,
J. Org. Chem. Vol. 74, No. 15, 2009 5335

Benohoud et al.
JOCArticle
159.8 ppm; HRMS calcd for C16H21N4O4 m/z 333.1563
(M þ Hþ), found 333.1557.
(1.2 mL), MeCN (1.2 mL), and H2O (1.8 mL) were added at rt
sodium metaperiodate (NaIO4) (39 mg, 0.18 mmol, 3.0 equiv)
and ruthenium trichloride hydrate (0.3 mg, 0.001 mmol, 0.022
equiv). The biphasic mixture was stirred vigorously for 3 h at rt.
DCM (1 mL) was added, and the phases were separated. The
aqueous phase was extracted with DCM ( ꢀ 3), and the
combined organic extracts were dried (MgSO4) and concen-
trated in vacuo. The crude product was purified by column
chromatography (silica gel, 5% MeOH/DCM) to afford the
The guanidino compound 27-B was treated in the same way as
27-A to provide 25-B in 78% yield. [R]20D -29.1 (c 0.75, CHCl3);
1H NMR (500 MHz, CDCl3) δ 1.66 (s, 1H), 1.72 (s, 2H), 1.94-
2.02 (m, 1H), 3.39 (s, 2H), 3.83-3.93 (m, 2H), 4.15 (s, 1H), 4.44-
4.48 (m, 1H), 4.93 (s, 1H), 5.16 (s, 2H), 7.30-7.34 (m, 5H), 7.50
(s, 1H), 8.94 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 24.8, 36.9,
40.9, 45.8, 48.9, 66.9, 70.2, 128.0, 128.2, 128.3, 128.5, 128.7,
135.0, 155.4, 156.9, 159.8; HRMS calcd for C16H21N4O4 m/z
333.1563 (M þ Hþ), found 333.1566.
corresponding N-Boc carboxylic acid (21 mg, 90% yield). [R]20
D
þ58.5 (c 0.11, CHCl3); 1H NMR (500 MHz, CDCl3) δ 1.47 (s,
9H), 1.86 (m, 1H), 1.93 (m, 1H), 2.10 (m, 1H), 2.43 (m, 1H),
3.02-3.14 (m, 2H), 3.78 (s, 1H), 4.27 (s, 1H), 5.12 (s, 2H), 6.18
(bs, 1H), 7.36-7.47 (m, 5H), 8.23 (s, 1H), 12.02 (bs, 1H) ppm;
13C NMR (75 MHz, CDCl3) δ 23.5, 28.7, 36.1, 36.3, 52.1, 67.9,
79.0, 127.9, 128.5, 128.7, 135.4, 151.9, 155.8, 156.2, 177.7 ppm;
HRMS calcd for C20H29N4O6 m/z 421.2087 (M þ Hþ), found
421.2076.
Tetrahydropyrimidines 28-A and 28-B. To a solution of 25-A
(43 mg, 0.13 mmol) in distilled MeCN (0.65 mL) were added at rt
under argon Boc2O (57 mg, 0.26 mmol, 2.0 equiv) and DMAP
(32 mg, 0.26 mmol, 2.0 equiv). The mixture was stirred at rt for
3 h. The solvent was removed under reduced pressure, and the
residue was purified by column chromatography (silica gel, 10%
MeOH in DCM) to afford the N-Boc carbamate derivative (41
1
mg, 73% yield). [R]20 -39.9 (c 1.00, CHCl3); H NMR (500
This product (11.4 mg, 0.027 mmol) was dissolved in 6 N HCl,
and the solution was refluxed for 1 h. The solvent was removed
by freeze-drying, and the residue was purified by chromatogra-
phy (C18, H2O/MeOH, 5% to 50%) affording compound 29-A
in 80% yield (5.6 mg). Mp: 256-258 °C (colorless solid, crystal-
lized from H2O/MeOH); [R]20D þ39.8 (c 0.20, H2O); 1H NMR
(500 MHz, D2O) δ 1.83-1.89 (m, 1H), 2.05-2.12 (m, 1H),
2.17-2.19 (m, 2H), 3.38-3.41 (m, 2H), 3.83-3.88 (m, 1H), 4.12
(t, 1H, J = 6.7 Hz) ppm; 13C NMR (75 MHz, D2O) δ 24.6, 36.0,
36.3, 45.8, 51.1, 154.4, 173.0 ppm; HRMS calcd for C7H15N4O2
m/z 187.1195 (M þ Hþ), found 187.1193.
D
MHz, CDCl3) δ 1.47 (s, 9H), 1.52-1.57 and 1.63-1.75 (m, 2H),
1.81-1.87 and 2.02-2.07 (m, 2H), 3.17-3.21 (m, 2H), 3.38-
3.43 (m, 1H), 3.88-3.90 (m, 1H), 4.23-4.26 (m, 1H), 4.29-4.34
(m, 1H), 5.00 (q, 2H, J= 10.0 Hz), 7.28-7.32 (m, 5H), 9.43 (s,
1H), 11.69 (s, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 25.6,
27.9, 36.3, 38.7, 44.5, 52.2, 66.2, 66.4, 84.1, 128.0, 128.2, 128.5,
137.2, 148.9, 151.9, 158.7, 163.0 ppm; HRMS calcd for
C21H28N4O6Na m/z 455.1907 (M þ Naþ), found 455.1905.
To a solution of this N-Boc-oxazolidinone derivative (40 mg,
0.09 mmol) in dry MeOH (0.5 mL) was added at rt cesium
carbonate (6 mg, 0.02 mmol, 0.2 equiv). The mixture was stirred
for 4 h, diluted with water, and extracted with ethyl acetate
(3 ꢀ ). The combined organic extracts were dried (MgSO4) and
concentrated in vacuo. The residue was purified by column
chromatography (silica gel, 2% MeOH/DCM) to afford the
The same sequence of reactions applied to compound 28-B
first provided the corresponding N-Boc carboxylic acid. [R]20
D
1
-8.2 (c 0.84, CHCl3); H NMR (500 MHz, CDCl3) δ 1.44 (s,
9H), 1.63-1.67 (m, 2H), 1.70-1.76 (m, 1H), 1.91-1.97 (m, 1H),
3.26-3.30 (m, 2H), 3.47-3.51 (m, 1H), 4.27 (s, 1H), 5.20 (s, 2H),
5.85 (bs, 1H), 7.36-7.47 (m, 5H) ppm; 13C NMR (75 MHz,
CDCl3) δ 24.9, 28.5, 36.3, 36.4, 52.8, 53.4, 67.5, 79.3, 127.7,
128.2, 128.5, 135.4, 151.5, 155.8, 156.3, 177.5 ppm; MS(ESIþ) m/
z 443.2 (M þ Naþ), 421.2 (M þ 2Hþ) and 321.2 ([M - Boc] þ
2Hþ).
amino alcohol 28-A (27 mg, 70% yield). [R]20 þ15.8 (c 0.97,
D
CHCl3); 1H NMR (500 MHz, CDCl3) δ 1.43 (s, 9H), 1.57-1.63
(m, 1H), 1.69-1.73 (m, 2H), 1.99-2.05 (m, 1H), 3.19-3.31 (m,
2H), 3.46-3.51 (m, 1H), 3.53-3.56 (m, 1H), 3.60-3.63 (m, 1H),
3.67-3.71 (m, 1H), 3.72-3.77 (m, 1H), 5.09 (m, 2H), 7.28-7.38
(m, 5H), 8.83 (s, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 25.9,
28.4, 37.3, 38.1, 46.3, 49.3, 64.8, 66.0, 79.6, 127.7, 127.9, 128.4,
137.5, 155.9, 158.4, 163.0 ppm; HRMS calcd for C20H30N4O5-
Na m/z 429.2114 (M þ Naþ), found 429.2120.
This product was then transformed into tetrahydrolathyrine
(1) (40% yield for both steps). Mp: 260 °C (colorless solid,
crystallized from H2O/MeOH) (lit.1 258-259 °C, crystallized
from H2O/Me2CO); [R]20 -20.0 (c 0.20, H2O) (lit.1 [R]25
D
D
The same sequence of reactions as above was applied to 25-B
to first afford the corresponding N-Boc derivative. [R]20D þ2.6
-18.9 (c 0.175, H2O)); 1H NMR (500 MHz, D2O) δ 1.65-
1.71 (m, 1H), 1.90-2.00 (m, 2H), 2.16-2.20 (m, 1H), 3.20-3.27
(m, 2H), 3.65-3.70 (m, 1H), 4.06-4.09 (m, 1H) ppm; 13C NMR
(75 MHz, D2O) δ 23.8, 35.1, 35.4, 44.5, 45.3, 154.5, 176.5 ppm;
HRMS calcd for C7H15N4O2 m/z 187.1195 (M þ Hþ), found
187.1199.
1
(c 0.82, CHCl3); H NMR (500 MHz, CDCl3) δ 1.55 (s, 9H),
1.59-1.64 and 1.77-1.83 (m, 2H), 1.87-1.93 and 1.96-2.00 (m,
2H), 3.22-3.24 (m, 2H), 3.51-3.54 (m, 1H), 3.95-3.97 (m, 1H),
4.29-4.39 (m, 2H), 5.09 (s, 2H), 7.28-7.38 (m, 5H), 9.16 (s, 1H),
11.69 (s, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 25.4, 28.0,
35.9, 40.6, 45.5, 52.5, 66.9, 67.6, 84.6, 128.0, 128.1, 128.2, 128.4,
128.6, 136.3, 150.1, 151.9, 158.5, 163.3 ppm.
Acknowledgment. This work was supported by CNRS
and by fellowships from ICSN to M.B. and L.L. and by a
grant from CAPES Brazil (S.H.C.). We are grateful to J.-F.
Gallard and M.-T. Martin for NOESY analysis of com-
pound 31-A and to Professor Mauro Vieira de Almeida
(University of Juiz de Fora) for many fruitful discussions.
This compound was then transformed into compound 28-B
1
(51% yield for both steps). [R]20 -21.7 (c 0.97, CHCl3); H
D
NMR (500 MHz, CDCl3) δ 1.44 (s, 9H), 1.62-1.67 (m, 2H),
1.70-1.76 (m, 1H), 1.91-2.05 (m, 1H), 3.26-3.30 (m, 2H),
3.47-3.51 (m, 1H), 3.60-3.63 (m, 1H), 3.67-3.71 (m, 1H),
3.72-3.77 (m, 1H), 5.09 (m, 2H), 7.28-7.38 (m, 5H), 8.82 (s, 1H)
ppm; 13C NMR (75 MHz, CDCl3) δ 26.0, 28.4, 36.7, 38.2, 46.1,
49.5, 64.5, 66.2, 79.7, 127.7, 127.9, 128.3, 137.4, 155.9, 158.4,
163.0 ppm; HRMS calcd for C20H31N4O5 m/z 407.2294 (M þ
Hþ), found 407.2295.
Supporting Information Available: General information.
Experimental procedures for 18, 19, 20, 24, 30-A, 31-A, and
1
SesNH2. H NMR and 13C NMR spectra of synthetic inter-
mediates of tetrahydrolathyrine 1 and the C-4 epimers. NOE
experiments on 31-A. ORTEP drawing of 25-A and X-ray data
of 25-A in CIF format. This material is available free of charge
via the Internet at http://pubs.acs.org.
(4S)-3-[2-Amino-1,4,5,6-tetrahydropyrimidin-4-yl]-L-alanine
Hydrochloride (29-A) and Tetrahydrolathyrine (1 = 29B). To a
solution of the amino alcohol 28-A (23 mg, 0.06 mmol) in CCl4
5336 J. Org. Chem. Vol. 74, No. 15, 2009