Assembly of the TAN-1057 A/B heterocycle from a dehydroalanine precursor

Article abstract of DOI:10.1055/s-2000-8713

A tandem reaction process was used to form the tetrahydropyrimidinone core of the TAN-1057 A and B dipeptide antibiotics. Michael addition of ammonia to a dehydroalanine derivative, followed by intramolecular displacement of an S-methylisothiourea assembles the tetrahydropyrimidinone in one-step.

Full text of DOI:10.1055/s-2000-8713

SPECIAL TOPIC
2127
Assembly of the TAN-1057 A/B Heterocycle from a Dehydroalanine Precursor
Peishan Lin, A. Ganesan*1
Institute of Molecular and Cell Biology, National University of Singapore, 30 Medical Drive, Singapore 117609
Fax +44(2380)596805, E-mail: ganesan@soton.ac.uk
Received 30 July 2000
NH
NH2
Abstract: A tandem reaction process was used to form the tetrahy-
dropyrimidinone core of the TAN-1057 A and B dipeptide antibiot-
ics. Michael addition of ammonia to a dehydroalanine derivative,
followed by intramolecular displacement of an S-methylisothiourea
assembles the tetrahydropyrimidinone in one-step.
N
O
*
O
O
HN
N
H
O
NH2
H2N
H2N
N
N
H
Key words: amino acids, antibiotics, cyclizations, nucleophilic ad-
ditions, tandem reactions
TAN-1057 A *S
TAN-1057 B *R
NH
O
Over the last decade, combinatorial chemistry2 has devel-
oped into a powerful tool for the discovery of novel bio-
logically active compounds. For some time, we have been
interested in building combinatorial libraries around natu-
ral products, which are inherently disposed by evolution-
ary selection for the efficient display of chemical
information in 3-dimensional space. Such projects, how-
ever, dictate different constraints from classical total syn-
thesis, which is focused on reaching a single target
molecule. The generation of libraries in a practical man-
ner necessitates a sufficiently general and concise route,
ideally employing building blocks that are readily avail-
able with high diversity. Peptides meet these criteria far
more than any other natural products, but problems with
bioavailability and stability severely limit their use as
therapeutic agents. For these reasons, we have focused on
alkaloid natural products that are derived from peptides
but feature further transformations of the amide bonds or
side-chains to give more drug-like heterocycles. Previous-
ly, we have applied this concept to tetramic acids,3
fumitremorgins4 and fumiquinazolines.5
NH
H
*
N
H
N
NH
N
H
N
NH2
O
TAN-1057 C *R
TAN-1057 D *S
Figure Structures of TAN-1057 A-D
equilibration could be due to retro-Michael reaction and
readdition. This implies that the heterocycle is biogeneti-
cally derived by conjugate addition of a nitrogen nucleo-
phile to a dehydroalanine precursor, a reaction with
synthetic precedent.9 While our work was in progress, a
second synthesis10 of TAN-1057 A/B appeared in which
the Michael addition of guanidine to dehydroalanine was
attempted, but proved unsuccessful due to the formation
of a 2:1 adduct by further reaction of the initial product.
Our approach was based on formation of the tetrahydro-
pyrimidinone ring by a tandem reaction, in which Michael
addition of ammonia to a dehydroalanine would be fol-
lowed by the intramolecular displacement of an S-methyl-
isothiourea. The isothiourea thus serves as a latent
guanidine, and we had prior experience with such com-
pounds in a combinatorial solid-phase synthesis11 of un-
symmetrical guanidines. A suitable model for our strategy
was obtained by sequentially reacting p-nitrophenyl chlo-
roformate with 2-methoxybenzylamine and the free base
of S-methylisothiourea to afford 1 (Scheme 1), which was
condensed with Boc and Fmoc protected N-methyl L-
serine to give 2a and 2b respectively. Tosylation of the al-
cohol was accompanied by elimination to provide dehy-
droalanines 3a and 3b.
Here, we report preliminary results6 related to TAN-1057
(Figure), modified peptides recently isolated7 by workers
at Takeda from a culture of Flexibacter sp. PK-74 and
PK-176, which display potent antibiotic activity against
both Gram-positive and Gram-negative bacteria. Impor-
tantly, the compounds remain active against antibiotic-re-
sistant
strains,
including
methicillin-resistant
Staphylococcus aureus (MRSA). In an in vivo model with
MRSA infected mice, TAN-1057 A had an ED50 of 0.064
mg/kg, compared to 15.1 mg/kg for imipenem/cilastatin
or 3.4 mg/kg for vancomycin (currently the clinical anti-
biotic of last resort).
An elegant total synthesis of the TAN-1057 antibiotics
was achieved8 by the Williams group, in which the tet-
rahydropyrimidinone heterocycle was assembled from
chiral 2,3-diaminopropionic acid. The interconversion7a
of TAN-1057 A and B under basic conditions suggested
an alternative biomimetic disconnection to us, as the
A number of protocols were examined for the key reaction
of 3 with ammonia to yield tetrahydropyrimidinone 4
(Scheme 2). The best yield with 3a (39%) was obtained
using 1.5 molar equivalents of ammonia in methanol. Un-
der these conditions, product 4a precipitates from the re-
Synthesis 2000, No. 14, 2127–2130 ISSN 0039-7881 © Thieme Stuttgart · New York

2128
P. Lin, A. Ganesan
SPECIAL TOPIC
OMe
NH2
OMe
O
SMe
NH
OMe
O
SMe O
N N
Me
a
b
N
R
N
H
N
N
66%
H
H
H
OH
2a R=Boc, 88%
2b R=Fmoc, 98%
1
OMe
c
O
SMe O
Me
N
N
H
N
N
R
H
3a R=Boc, 74%
3b R=Fmoc, 72%
Reagents and conditions: (a) i. p-nitrophenyl chloroformate/(i-Pr)2NEt/CH2Cl2, ii. 2-methyl-2-thiopseudourea/Et3N; (b) R-N-methyl-L-serine/
DCC/HOBt/CH2Cl2; (c) p-TsCl/Et3N/DMAP/CH2Cl2
Scheme 1
action mixture. Concentration of the filtrate gave a residue synthesis, and further results will be reported in due
containing a mixture of byproducts including diamination course.
adducts which could not be fully characterized. With the
Fmoc protected dehydroalanine 3b, larger amounts of am-
monia were needed, and 4 molar equivalents yielded 43%
of 4b. Both 4a and 4b are suitable intermediates for fur-
Melting points were taken on a hot stage apparatus and are uncor-
rected. 1H and 13C NMR were recorded in CDCl3 at 400 MHz and
100MHz respectively. IR spectra were taken on KBr pellets. Low-
ther elaboration into TAN-1057 analogues. For example,
deprotection of 4b furnished 5, and the secondary amine
was then coupled with Fmoc-L-Ala-Cl to give the corre-
sponding dipeptide as a mixture of diastereomers in 30%
overall yield (unoptimized).
resolution mass spectra were obtained by atmospheric pressure ion-
ization, and high-resolution spectra (HRMS) by electrospray ion-
ization.
2-Methoxybenzylcarbonyl-S-methyl-2-thiopseudobiuret (1)
To a cooled (ice-bath) solution of 2-methoxybenzylamine (129 mL,
1 mmol) in CH2Cl2 (25 mL) under N2 was added pyridine (89 mL,
1.1 mmol) and p-nitrophenyl chloroformate (222 mg, 1.1 mmol).
The mixture was stirred at r.t. until completion, as monitored by
TLC (approximately 4 h). The solvent was then evaporated, the res-
idue dried in vacuo and redissolved in anhyd acetone (30 mL), fol-
lowed by the addition of S-methyl-2-thiopseudourea (99 mg, 1.1
mmol) and Et3N (153 mL, 1.1 mmol). After stirring at r.t. for one
In summary, we have demonstrated the formation of the
TAN-1057 A/B heterocycle by a tandem reaction initiated
by Michael addition to a dehydroalanine, thus avoiding
the use of more expensive unnatural amino acids. We are
currently investigating additional variants of this process
and adaptation of the conditions to solid-phase library
Me
N
OMe
O
HN
R
NH3, MeOH
3a, b
N
N
N
O
H
H
4a R=Boc, 39%
4b R=Fmoc, 43%
Me
NH
OMe
O
HN
piperidine, CH2Cl2
4b
N
N
N
O
H
H
59%
5
Scheme 2
Synthesis 2000, No. 14, 2127–2130 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Assembly of the TAN-1057 A/B Heterocycle from a Dehydroalanine Precursor
2129
day, the mixture was filtered, the filtrate concentrated, and chro-
matographed (eluting with hexanes and then 1:1 EtOAc/hexanes) to
give 167 mg (66%) of 1 as a white solid; mp 93-95 °C.
1H NMR: d = 2.39 (s, 3 H), 3.86 (s, 3 H), 4.41 (d, 2 H, J = 6.1 Hz),
5.80 (br s, 1 H), 6.88 (d, 1 H, J = 8.2 Hz), 6.93 (t, 1 H, J = 7.4 Hz),
7.24-7.32 (m, 2 H).
Dehydroalanine (3a)
To a cooled solution (ice-bath) of 2a (118 mg, 0.26 mmol) in
CH2Cl2 (3 mL) was added anhyd Et3N (108 mL, 0.78 mmol) and
DMAP (3.2 mg, 0.026 mmol), followed by the dropwise addition of
p-toluenesulfonyl chloride (62 mg, 0.31 mmol) in CH2Cl2 (1 mL).
After 2 h the mixture was warmed to r.t. and stirred for 1.5 d. The
solvent was then evaporated, and the residue chromatographed
(EtOAc/hexanes, 1:3 to 3:7) to give 84 mg (74%) of 3a as a white
foam; mp 145-146 ∞C.
13C NMR: d = 13.3, 39.6, 55.3, 110.2, 120.5, 126.9, 128.4, 129.2,
157.4, 163.0.
IR (KBr): n = 3289, 1723, 1626 cm-1.
HRMS: m/z calcd for (C11H15N3O2S + H) 254.0964, (C11H15N3O2S
+ Na) 276.0783; found (M + H) 254.0963, (M + Na) 276.0783.
1H NMR: d = 1.42 (s, 9 H), 2.34 (s, 3 H), 3.19 (s, 3 H), 3.86 (s, 3 H),
4.42 (d, 2 H, J = 6.1 Hz), 5.28 (s, 1 H), 5.69 (br s, 1 H), 6.07 (br s,
1 H), 6.87 (d, 1 H, J = 6.2 Hz), 6.92 (t, 1 H, J = 7.5 Hz), 7.25-7.34
(m, 2 H), 13.73 (br s, 1 H).
Anal. calcd for C11H15N3O2S: C, 52.15; H, 5.97; N, 16.59. Found:
C, 52.19; H, 6.05; N, 16.16.
Isothiourea (2a)
13C NMR: d = 14.3 (SCH3), 28.0 (Boc- CH3), 36.6 (NCH3), 39.8
(NCH2), 55.3 (OCH3), 81.9 (Boc-C-O), 110.3, 112.0 (CH2, alkene),
120.6, 126.1, 128.9, 129.5, 144.1 (Cquat, alkene), 157.5 (Cquat, guani-
dino), 161.6 (Cquat, ureido), 167.3 (Cquat, Boc-C=O and Cquat, Ser-
C=O).
To a mixture of N-tert-butoxycarbonyl-N-methyl-L-serine (339 mg,
1.55 mmol) and HOBt (199 mg, 1.48 mmol) in CH2Cl2 (50 mL) was
added 1 (356 mg, 1.41 mmol) and DCC (105 mg, 1.48 mmol) at 0-
5 °C. The resulting mixture was stirred for 20 h and filtered. The fil-
trate was concentrated, redissolved in a small amount of CH2Cl2,
cooled with an ice-bath, and the white precipitate filtered off. The
filtrate was washed (5% NaHCO3) and the combined organic layers
were collected, dried (Na2SO4), concentrated, and chromatographed
(EtOAc/hexanes, 0:100 to 1:1) to give 562 mg (88%) of 2a as a
white foam; [a]D25 +2.98 (c = 0.013, CHCl3).
1H NMR (mixture of rotamers): d = 1.38 and 1.51 (1:1) (s, 9 H), 2.29
(s, 3 H), 2.93 and 3.02 (s, 3 H), 3.84-3.86 (m, 2 H), 3.85 (s, 3 H),
4.15-4.17 (m, 1 H), 4.40 (d, 2 H, J = 5.8 Hz), 6.00 (br s, 1 H), 6.88
(d, 1 H, J = 8.2 Hz), 6.92 (t, 1 H, J = 7.5 Hz), 7.25-7.29 (m, 2 H),
13.75 (br s, 1 H).
Anal. calcd for C20H28N4O5S: C, 55.03; H, 6.47; N, 12.83. Found:
C, 55.12; H, 6.37; N, 12.87.
Dehydroalanine (3b)
To a cooled solution (ice-bath) of 2b (241mg, 0.42mmol) in CH2Cl2
(12mL) was added Et3N (145 mL, 1.05 mmol) and DMAP (5.1 mg,
0.042 mmol), followed by dropwise addition of p-toluenesulfonyl
chloride (101 mg, 0.5 mmol) in CH2Cl2 (6 mL). After 2 h, the mix-
ture was warmed to r.t. and stirred for 24 h. The solvent was evap-
orated, and the residue chromatographed (EtOAc/hexanes, 3:7 to
2:1) to give 168 mg (72%) of 3b as a white foam.
1H NMR (mixture of rotamers): d = 2.27 and 2.30 (s, 3 H), 3.23 and
3.26 (s, 3 H), 3.83 and 3.83 (s, 3 H), 4.38 (br s, 5 H), 5.52 (br s, 1
H), 5.97-6.05 (br s, 2 H), 6.84-6.88 (m, 2 H), 7.23-7.36 (m, 6 H),
7.52 (m, 2 H), 7.72-7.74 (m, 2 H).
13C NMR (mixture of rotamers): d = 14.2, 28.1 and 28.2 (1:1), 33.1
and 34.3, 39.7, 55.3, 60.7, 61.7 and 63.3, 81.0 and 81.5, 110.2,
120.5, 126.0, 128.9, 129.6, 157.4, 161.4, 166.2, 170.1.
HRMS: m/z calcd for (C20H30N4O6S + H) 455.1965, (C20H30N4O6S
+ Na) 477.1784; found (M + H) 455.1964, (M + Na) 477.1784.
13C NMR: d = 14.3, 39.9, 47.0, 55.3, 68.4, 110.2, 119.8, 120.5,
125.1, 125.9, 127.0, 127.6, 128.9, 129.5, 141.2, 143.8, 157.4, 161.7,
162.1, 167.3.
Anal. calcd for C20H30N4O6S: C, 52.85; H, 6.65; N, 12.33. Found:
C, 52.39; H, 6.62; N, 12.06.
MS: m/z (%) = 559 [M + 1]+, (40), 396 (25), 179 (100).
Isothiourea (2b)
HRMS: m/z calcd. for (C30H30N4O5S + H) 559.2016, (C30H30N4O5S
+ Na) 581.1835; found (M + H) 559.2015, (M + Na) 581.1834.
To a mixture of Fmoc-N-methyl-L-serine (118 mg, 0.35 mmol) and
HOBt (46.8 mg, 0.35 mmol) in CH2Cl2 (6 mL) were added 1 (81
mg, 0.32 mmol) and diisopropyl carbodiimide (54 mL, 0.35 mmol)
at 0-5 °C. The resulting mixture was stirred overnight, filtered, and
washed (5% aq NaHCO3 and brine). The combined organic layers
were dried (Na2SO4), concentrated, and chromatograped (EtOAc/
hexanes, 0:100 to 3:2) to give 180 mg (98%) of 2b as a white foam;
[a]D25 +16.6 (c = 0.005 M, CHCl3).
2-[N-(2’-Methoxybenzylcarbamoyl)amino]-5-(N’-methyl-N’-
tert-butoxycarbonylamino)-1,4,5,6-tetrahydropyrimidin-4-one
(4a)
To 3a (196 mg, 0.45 mmol) in MeOH (10 mL) was added a solution
of 2 M NH3 in MeOH (344 mL, 0.69 mmol). The mixture turned
cloudy after stirring for 8 h, and was kept for a further 12 h until
complete consumption of the starting material. During this period,
the amount of white precipitate increased gradually. The precipitate
was collected and dried to obtain 71 mg (39%) of 4a as a white sol-
id; mp 198-199 °C.
IR (KBr): n = 3422, 1701 cm-1.
1H NMR (mixture of rotamers): d = 2.31(s, 3 H), 2.96 and 3.10 (s,
3 H), 3.65-3.97 (m, 2 H), 3.78 (s, 3 H), 4.21 (d, 2 H, J = 5.9 Hz),
4.30-4.36 (m, 2 H), 4.44-4.51 and 4.72 (m, 1 H), 4.58-4.62 (m, 1
H), 5.95 (br s, 1 H), 6.73 (t, 1 H, J = 7.4 Hz), 6.78-6.95 (m, 2 H),
7.16-7.49 (m, 5 H), 7.65-7.77 (m, 4 H), 13.73 and 13.96 (major)
(s, 1 H).
13C and Dept135: d = 14.2 and 14.3 (SCH3), 33.3 (NCH3), 39.8
(NCH2), 47.3 (Fmoc-CH), 55.2 (OCH3), 60.4 and 60.7 (Ser-OCH2),
62.5 (Ser-CH), 68.4 (Fmoc-CH2O), 110.1, 119.9, 120.5, 125.3,
125.5, 127.1, 127.6, 128.8, 129.3, 141.2 (Cquat), 143.8 (Cquat), 144.3
(Cquat), 156.9 (Cquat), 157.3 (Cquat), 161.5 (Cquat), 166.4 (Cquat), 169.4
(Cquat).
IR 3449, 3229, 1699, 1608 cm-1.
1H NMR (mixture of rotamers): d = 1.39 and 1.45 (s, 9 H), 2.75 and
2.80 (s, 3 H), 3.51-3.70 (m, 2 H), 3.83 (s, 3 H), 4.41 (d, 2 H, J = 5.6
Hz), 4.51 and 4.92 (br t, 1 H), 6.84 (d, 1 H, J = 8.2 Hz), 6.89 (t, 1 H,
J = 7.4 Hz), 7.20-7.28 (m, 2 H), 9.62 (br s, 1 H), 10.34 (br s, 1 H).
13C NMR (mixture of rotamers): d = 28.3 (Boc), 32.0 and 32.5
(NCH3), 38.7 (NCH2), 39.5 and 39.9 (pyrimidinone-CH2), 53.1 and
54.5 (pyrimidinone-CH), 55.2 (OCH3), 80.3 and 80.7 (Boc-C-O),
110.1, 120.2, 126.5, 128.3, 128.5, 155.3 and 155.9 (Cquat, Boc-
C=O), 156.6 and 157.2 (Cquat, guanidino), 160.1 (Cquat, ureido),
176.6 and 176.8 (Cquat, pyrimidinone-C=O).
MS: m/z (%) = 577 [M + 1]+ (28), 414 (85), 324 (18), 180 (100), 146
(63).
Synthesis 2000, No. 14, 2127–2130 ISSN 0039-7881 © Thieme Stuttgart · New York

2130
P. Lin, A. Ganesan
SPECIAL TOPIC
Anal. calcd for C19H27N5O5: C, 56.28; H, 6.71; N, 17.27. Found: C,
56.55; H, 6.45; N, 17.23.
13C NMR: d = 35.0, 38.7, 42.4, 55.3, 56.5, 110.1, 120.3, 126.7,
128.2, 156.6, 157.1, 160.0, 179.5.
MS: m/z (%) = 306 [M + 1]+ (100).
2-[N-(2’-Methoxybenzylcarbamoyl)amino]-5-(N’-methyl-N’-
fluorenylmethylcarbonylamino)-1,4,5,6-tetrahydropyrimidin-
4-one (4b)
Acknowledgement
Dehydroalanine 3b (100 mg, 0.18 mmol) was dissolved in MeOH
(3 mL) followed by the addition of 2 M NH3 in MeOH (358 mL, 0.72
mmol). A white precipitate formed after stirring for 20 min. The re-
action mixture was kept at r.t. for a further 20 h until the complete
consumption of starting material and then filtered. The filtrate was
evaporated off, the residue combined with the precipitate, and chro-
matographed to give 41 mg (43%) of 4b as a white solid; mp 179-
180 °C.
This work was supported by grants from the National Science and
Technology Board of Singapore.
References
(1) Present address: Department of Chemistry, University of
Southampton, Southampton SO17 1BJ, United Kingdom.
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1997, 36, 2454.
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(6) Taken in part from the Ph. D. thesis of Peishan Lin, National
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(b) Katayama, N.; Fukusumi, S.; Funabashi, Y.; Iwahi, T.;
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11777.
IR (KBr): n = 3457, 3222, 1701, 1606 cm-1.
1H NMR (mixture of rotamers): d = 2.80 and 2.84 (s, 3 H), 2.99 (m,
1 H), 3.64 (m, 1 H), 3.80 and 3.82 (s, 3 H), 3.95-4.45 (m, 3 H), 4.41
(d, 2 H, J = 6.6 Hz), 4.67 and 4.96 (m, 1 H), 6.83-6.94 (m, 2 H),
7.19-7.48 (m, 7 H), 7.59-7.68 (m, 2 H), 7.77 (d, 1 H, J = 7.6 Hz),
9.57 (br s, 1 H), 10.04 and 10.46 (br s, 1 H).
13C NMR and Dept135 (mixture of rotamers): d = 31.9 (NCH3),
38.7 and 39.3 (Ser-CH2), 47.1 (Fmoc-CH), 53.8 (Ser-CH), 55.3
(OCH3), 66.5 (CH2), 67.9 (CH2), 110.2, 119.7, 119.9, 120.3, 124.3,
125.1, 126.4, 126.5, 127.0, 127.2, 127.6, 127.7, 128.4, 128.8, 141.2,
141.3, 143.7, 143.8, 155.9, 156.5, 156.7, 157.3, 159.6, 160.2, 175.7,
176.3.
MS: m/z (%) = 528 [M + 1]+ (30), 365 (5), 179 (5), 64 (100).
HRMS: m/z calcd. for (C29H29N5O5 + H) 528.2248, (C29H29N5O5 +
Na) 550.2067; found (M + H) 528.2247, (M + Na) 550.2044.
2-[N- (2’-Methoxybenzylcarbamoyl)amino]-5-N’-methyl-1,5,6-
trihydropyrimidin-4-one (5)
(b) Williams, R. M.; Yuan, C.; Lee, V. J.; Chamberland, S. J.
Antibiot. 1998, 51, 189.
Compound 4b (20 mg, 0.038 mmol) was dissolved in 20% piperi-
dine (1 mL) in anhyd CH2Cl2, and stirred at r.t. until the complete
deprotection of Fmoc group as monitored by TLC (1.5 h). The re-
sulting mixture was diluted with CH2Cl2, washed (H2O, brine), and
dried (Na2SO4). Filtration and concentration gave a residue, which
was chromatographed to give 6.8 mg (59%) of 5 as a semi-solid.
(9) Chol, D.; Kohn, H. Tetrahedron Lett. 1995, 36, 7371.
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N.; Es-Sayed, M.; de Meijere, A. Eur. J. Org. Chem. 1998,
777.
(11) Lin, P.; Ganesan, A. Tetrahedron Lett. 1998, 39, 9789.
1H NMR: d = 2.55 (s, 3 H), 3.15-3.19 (m, 2 H), 3.56-3.62 (m, 1
H), 3.73 (s, 3 H), 4.36 (d, 2 H, J = 5.7 Hz), 6.78 (d, 1 H, J = 8.12
Hz), 6.84 (t, 1 H, J = 7.36 Hz), 7.14 (d, 1 H, J = 7.2 Hz), 7.20 (t, 1
H, J = 9.71, Hz), 9.48 (br s, 1 H), 10.18 (br s, 1 H).
Article Identifier:
1437-210X,E;2000,0,14,2127,2130,ftx,en;C03300SS.pdf
Synthesis 2000, No. 14, 2127–2130 ISSN 0039-7881 © Thieme Stuttgart · New York