A diastereoselective synthesis of the tetrahydropyridazinone core of 2-oxo-1,6-diazobicyclo[4.3.0]nonane-9-carboxylate-based peptidomimetics starting from (S)-phenylalanine

Article abstract of DOI:10.1016/S0040-4039(03)00882-7

A diastereoseletvive synthesis of a peptidic tetrahydropyridazinone 10 from (S)-phenylalanine is reported. This derivative was then converted to the bicyclic peptidomimetic 11, an important class of β-strand mimetic.

Full text of DOI:10.1016/S0040-4039(03)00882-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4227–4230
A diastereoselective synthesis of the tetrahydropyridazinone core
of 2-oxo-1,6-diazobicyclo[4.3.0]nonane-9-carboxylate-based
peptidomimetics starting from (S)-phenylalanine
James Gardiner and Andrew D. Abell*
Department of Chemistry, University of Canterbury, Christchurch, New Zealand
Received 27 February 2003; revised 25 March 2003; accepted 4 April 2003
Abstract—A diastereoseletvive synthesis of a peptidic tetrahydropyridazinone 10 from (S)-phenylalanine is reported. This
derivative was then converted to the bicyclic peptidomimetic 11, an important class of b-strand mimetic. © 2003 Elsevier Science
Ltd. All rights reserved.
The phenylalanine-based tetrahydropyridazinone ring
To date, key tetrahydropyridazinones of type 1 have
only been synthesised as racemic mixtures.2–4 The mix-
tures are then subjected to a regioselective 1,3-dipolar
cycloaddition to give the racemic bicyclic pepti-
domimetics 2.2–4 A final extension of the peptide chain
yields mixtures of diastereoisomeric b-strand mimetics
that can be separated by HPLC.2 This basic methodol-
ogy has also recently been extended to the solid phase
to provide access to small libraries of b-strand mimetics
as mixtures of isomers. In this paper we present a
system 1 is a synthetic precursor of 2-oxo-1,6-diazobi-
cyclo[4.3.0]nonane-9-carboxylate
dipeptidomimetic
scaffolds 2 that are found in extended b-strand mimet-
ics and other bioactives.1–4 For example, bicycles 2 have
been incorporated into peptide sequences to give
extended b-strand mimetics of type 3 that inhibit serine
proteases, including thrombin.2–4 The idea of constrain-
ing a putative inhibitor molecule into an extended
conformation in this way is an important and generic
approach to protease inhibitor design.5
diastereoseletvive synthesis of
a
peptidic tetra-
hydropyridazinone ring system of type 1 from (S)-
phenylalanine (see compound 10). This derivative was
then converted to the bicyclic peptidomimetic 11 in
what is the first enantioselective synthesis of this impor-
tant class of b-strand mimetic.
The key to our synthesis is the use of chiral oxazolidi-
none chemistry pioneered by Seebach,6 to generate the
key a,a-dialkylated amino acid 7 (Scheme 1) which was
then taken through the sequence shown in Scheme 2 to
give 11. The N-benzoyl protecting group was chosen
for ease of access of the starting oxazolidinone 5;
however, it should be noted that Cbz-protected oxazo-
lidinones of this type (albeit with the ring substituents
syn) can also be prepared.7,8
A preliminary report3 suggests that the selectivity dis-
played by compounds of type 3, for one protease over
another, is influenced by the nature of the substituents
(Ar and X) on the 2-oxo-1,6-diazobicyclo[4.3.0]nonane-
9-carboxylate core. The recent screening of a library of
such compounds against a range of serine proteases
supports this observation with the identification of a
number of potent and selective inhibitors.4
The starting phenyloxazolidinone 5 was prepared in
three steps from (S)-phenylalanine as previously
described.8 Deprotonation of 5 at C-4 with LiHMDS
and alkylation of the resulting anion with allyl bromide
gave the alkylated oxazolidinone 69 as a single isomer
by 1H NMR and in excellent yield.10 Subsequent
hydrolysis of the oxazolidinone ring with NaOH in
* Corresponding author. Tel.: 64-3-3642818; fax: 64-3-3642110;
e-mail: a.abell@chem.canterbury.ac.nz
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00882-7

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J. Gardiner, A. D. Abell / Tetrahedron Letters 44 (2003) 4227–4230
preparation of 2 (P=Boc),2 gave variable results in our
hands. However, reduction of (−)-9 with sodium
methanol, followed by the addition of an excess of
diazomethane gave optically active (−)-711 in excellent
overall yield.12 The oxazolidinone 5 and the a,a-dialky-
lated amino acid 7 have been used previously by us to
cyanoborohydride
gave
the
desired
tetra-
hydropyridazinone (−)-1015 cleanly and in good yield
(Scheme 2). We decided to establish the enantiomeric
purity of the key intermediate (−)-7, and hence subse-
quent derivatives, by reduction to the alcohol 12a and
subsequent reaction with (S)- and (R)-methoxy-a-trifl-
uoromethylphenyl acetyl chlorides16 (Scheme 2). An
analysis of the product MTPA esters from these two
construct
a
1,2,3,6-tetrahydropyridine-based pepti-
domimetic, the absolute configuration of which was
determined by X-ray crystallography.13
With an adequate supply of (−)-7 in hand we set about
synthesising (Scheme 2) the heterocyclic core of the
dipeptidomimetic in a similar manner to that previously
reported for racemic 2.2 Ozonolysis of the olefin gave
the corresponding aldehyde (−)-8,14 which upon reflux-
ing for 3 days with hydrazine in THF, gave the cyclic
hydrazone (−)-914 in good yield. Hydrogenation of (−)-
9 over Adam’s catalyst (PtO2), as reported for the
1
reactions by H NMR revealed a diastereomeric excess
of >95%. This is a key finding since it also establishes
the enantiomeric purity of 5, which has found use
elsewhere.
Finally, treatment of (−)-10 with formaldehyde and
subsequent heating with an excess of ethyl acrylate gave
rise to a 1,3 dipolar cycloaddition as reported2 for the
preparation of 2 (P=Boc). Purification of this product
by chromatography gave the desired bicyclic template
1114 in modest yield. The absolute configuration of 11
was assigned as shown on the basis of the previously
determined absolute configuration of 5 and also the
relative configuration of 2 as reported by Takahashi
and Kahn.2–4 This is consistent with the assignment of
relative configuration to related compounds.1,17
In conclusion, we have presented the first enantioselec-
tive synthesis of the phenylalanine-based tetra-
hydropyridazinone 10, and its conversion to the
2-oxo-1,6-diazobicyclo[4.3.0]nonane-9-carboxylate di-
peptido-mimetic scaffold 11, an important component
of extended b-strand mimetics. The nature and absolute
configuration of the starting amino acid can be varied
to give a versatile and potentially general method for
the preparation of compounds of type 1. In addition,
the enantiomeric purity of the key intermediate 7, and
hence previously reported 5,7,8 has been shown to be
>95%.
Scheme 1. Reagents and conditions: (i) NaOH, then PhCHO,
DCM, reflux, then PhCOCl, DCM, −20°C, then 0°C for 3
days; (ii) LiHMDS, −78°C, THF, allyl bromide; (iii) NaOH/
MeOH, reflux, followed by CH2N2.
Acknowledgements
The work was supported by a Royal Society of New
Zealand Marsden grant.
References
1. For
a
review in this area, see: Hanessian, S.;
McNaughton-Smith, G.; Lombart, H.-G.; Lubell, W. D.
Tetrahedron 1997, 53, 12789.
2. Boatman, P. D.; Ogbu, C. O.; Eguchi, M.; Kim, H.-O.;
Nakanishi, H.; Cao, B.; Shea, J. P.; Kahn, M. J. Med.
Chem. 1999, 42, 1367.
3. Fuchi, N.; Doi, T.; Harada, T.; Urban, J.; Cao, B.; Kahn,
M.; Takahashi, T. Tetrahedron Lett. 2001, 42, 1305.
4. Fuchi, N.; Doi, T.; Cao, B.; Kahn, M.; Takahashi, T.
Synlett 2002, 285.
5. Tyndall, J. D. A.; Fairlie, D. P. Curr. Med. Chem. 2001,
8, 893.
Scheme 2. Reagents and conditions: (i) O3, CH2Cl2/MeOH
(3:1), −78°C; (ii) hydrazine, reflux, 2 days; (iii) NaB(CN)H3,
MeOH/HCl, 0°C–rt, 18 h; (iv) CH2O, reflux, ethyl acrylate;
(v) LiBH4, DCM; (vi) DMAP, Et3N and (S)- or (R)-MTP-Cl,
10 min, rt.

J. Gardiner, A. D. Abell / Tetrahedron Letters 44 (2003) 4227–4230
4229
6. Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 2708.
135.1, 136.1, 166.7, 173.2. FTIR (KBr) 3414, 2953, 1738,
1666, 1603, 1580, 1516, 1487, 1448 cm−1. m/z calcd for
C20H21NO3 323.1521, found 323.1525. [h]D=−56.8° (c
1.0, CHCl3).
7. Williams, R. M. In Synthesis of Optically Active h-Amino
Acids; Organic Chemistry Series, Vol. 7; Baldwin, J.;
Magnus, P. D., Eds.; Pergamon Press: Oxford, 1989.
8. (a) Abell, A. D.; Edwards, R. A.; Oldham, M. D. J.
Chem. Soc., Perkin Trans. 1 1997, 1655; (b) Abell, A. D.;
Taylor, J. M.; Oldham, M. D. J. Chem. Soc., Perkin
Trans. 1 1996, 1299.
12. It should be noted that while this sequence gives rise to
the (R)-enantiomer the methodology lends itself equally
well to the synthesis of the corresponding (S) isomer.
This can be achieved by either starting with an (R)-amino
acid or alternatively using a syn oxazolidinone, methods
for the preparation of which are known (see Refs. 7 and
8).
9. To a solution of oxazolidinone 5 (2.11 g, 5.91 mmol, 1
equiv.) in dry THF (15 mL) cooled to −78°C under argon
was added LiHMDS (6.501 mL of 1 M solution in
THF/hexanes, 6.5 mmol, 1.1 equiv.). The solution was
stirred at −78°C for 7 min whereupon allyl bromide
(0.768 mL, 8.87 mmol, 1.5 equiv.) was added and the
mixture stirred at −78°C for 2 h before being allowed to
warm to room temperature overnight. Saturated aqueous
NH4Cl solution (20 mL) was added and the solution
extracted with ether (3×20 mL). The ether extracts were
combined, dried over Na2SO4 and the solvent removed to
give (−)-6 as a white solid. Recrystallisation from ether
13. Abell, A. D.; Gardiner, J.; Phillips, A. J.; Robinson, W.
T. Tetrahedron Lett. 1998, 39, 9563.
14. Prepared using the method described in Ref. 2.
1
Compound 8: H NMR (CDCl3): l 3.06 (d, J=13.7 Hz,
1H, CHaCHO), 3.23 (d, J=18.1 Hz, 1H, PhCHa), 3.79 (s,
3H, OMe), 3.91 (d, J=13.7 Hz, 1H, CHbCHO), 4.29 (d,
J=18.1 Hz, 1H, PhCHb), 7.00 (m, 2H, PhH), 7.16 (d,
J=6.8 Hz, 1H, NH), 7.21 (m, 3H, PhH), 7.40 (t, J=7.3
Hz, 2H, PhH), 7.49 (t, J=7.3 Hz, 1H, PhH), 7.65 (d,
J=7.3 Hz, 2H, PhH), 9.67 (s, 1H, CHO). 13C NMR
(CDCl3): l 40.6, 48.4, 52.7, 61.4, 126.7, 127.1, 128.1,
128.4, 129.5, 131.5, 134.4, 134.5, 166.9, 172.1, 198.7.
FTIR (KBr) 3406, 3032, 2955, 1744, 1659, 1601, 1582,
1516, 1489 cm−1. m/z (ES) calcd for C18H17KN3O2 (M+
K) 348.1212, found 348.1220. [h]D=−83.6° (c 1.0,
CHCl3).
1
gave white needles (2.342 g, 93%). H NMR (500 MHz,
CDCl3):
l
2.82 (dd, J=13.7 and 5.4 Hz, 1H,
CHaCHꢀCH2), 3.45 (d, J=13.7 Hz, 1H, CHaPh), 3.59
(dd, J=13.7 and 10.1 Hz, 1H, CHbCHꢀCH2), 4.09 (d,
J=13.7 Hz, 1H, PhCHb), 5.50 (m, 4H, CHꢀCH2 and
PhH), 5.98 (m, 1H, CHꢀCH2), 6.03 (s, 1H, H2), 6.66 (t,
J=7.8 Hz, 2H, PhH), 6.77 (d, J=7.3 Hz, 2H, PhH), 6.95
(t, J=7.3 Hz, 1H, PhH), 7.02 (t, J=7.5 Hz, 2H, PhH),
7.14 (t, J=7.5 Hz, 1H, PhH), 7.38–7.45 (m, 5H, PhH).
13C NMR (CDCl3): l 39.7, 41.6, 69.8, 91.0, 122.2, 125.2,
127.4, 127.6, 127.8, 128.2, 129.0, 129.1, 129.1, 130.8,
131.3, 135.0, 136.2, 136.6, 169.9, 173.3. FTIR (KBr) 3026,
1792, 1653 cm−1. m/z (EI) calcd for C26H23NO3 397.1678,
found 397.1672. [h]D=−2.9° (c 1.0, CHCl3). Mp 141–
143°C.
1
Compound 9: H NMR (CDCl3): l 2.90 (d, J=18.2 Hz,
1H, CHaCH), 3.04 (d, J=13.7 Hz, 1H, PhCHa), 3.58 (d,
J=13.7 Hz, 1H, PhCHb), 3.90 (dd, J=4.6 and 18.2 Hz,
1H, CHbCH), 7.07 (m, 2H, PhH), 7.19 (s, 1H, CHꢀN),
7.21–7.26 (m, 4H, PhCONH and PhH), 7.42 (t, J=7.6
Hz, 2H, PhH), 7.51 (t, J=7.3 Hz, 1H, PhH), 7.70 (d,
J=7.8 Hz, 2H, PhH), 8.79 (brs, 1H, NꢀNH). 13C NMR
(CDCl3): l 34.1, 39.0, 56.3, 126.9, 127.3, 128.2, 128.5,
130.0, 131.8, 134.1, 134.4, 145.6, 167.1, 167.2. FTIR
(KBr) 3387, 3229, 3125, 2878, 1686, 1647, 1601, 1582,
1516, 1489 cm−1. m/z (ES) calcd for C18H17N3O2 (M+1)
308.1399, found 308.1395. [h]D=−128.4° (c 1.0, CHCl3).
Mp 189–192°C.
10. Note that the C-4 configuration of 5 has been inverted in
this sequence.
11. To a solution of (−)-6 (2.3 g, 5.79 mmol, 1 equiv.)
dissolved in methanol (30 mL) under argon was added
NaOH (11.587 mL of 1 M aqueous solution, 11.59 mmol,
2 equiv.). The solution was refluxed under argon for 1 h.
The solution was then cooled and concentrated under
reduced pressure. The residue was taken up in water (10
mL) and acidified to pH 2 with 10% aqueous HCl. The
aqueous solution was extracted with ether (3×20 mL) and
the combined ether extracts washed with brine (2×20
mL), dried over Na2SO4 and filtered. The resulting solu-
tion was then cooled to 0°C and an ethereal solution of
diazomethane added until the bright yellow colour per-
sisted over an extended period. The solution was stirred
at rt for 2 h whereupon the reaction was quenched with
the addition of a few drops of acetic acid. The solvent
was removed to give (−)-7 as a colourless oil (1.864 g,
99%). 1H NMR (500 MHz, CDCl3): l 2.72 (dd, J=7.3
Hz, 1H, CHaCHꢀCH2), 3.21 (d, J=13.7 Hz, 1H,
PhCHa), 3.60 (dd, J=7.3 Hz, 1H, CHbCHꢀCH2), 3.83 (s,
3H, OMe), 3.95 (d, J=13.7 Hz, 1H, PhCHb), 5.10 (m,
2H, CHꢀCH2), 5.65 (m, 1H, CHꢀCH2), 6.93 (br s, 1H,
NH), 7.19 (m, 2H, PhH), 7.41 (m, 3H, PhH), 7.41 (t,
J=7.3 Hz, 2H, PhH), 7.49 (t, J=7.3 Hz, PhH), 7.68 (m,
2H, PhH). 13C NMR (CDCl3): l 39.3, 40.1, 52.6, 66.2,
119.1, 126.6, 126.8, 128.1, 128.4, 129.5, 131.3, 132.1,
1
Compound 11: H NMR (CDCl3): l 1.28 (t, J=7.3 Hz,
3H, CO2CH2CH3), 2.25 (m, 1H, CHaCHCO2Et), 2.55 (m,
2H, CHbCHCO2Et and CCHaCH2N), 3.00 (ddd, J=6.3,
9.3 and 18.6 Hz, 1H, CHaCH2CHCO2Et), 3.04 (m, 3H,
CCHbCH2N and CCH2CH2N), 3.21 (m, 1H,
CHbCH2CHCO2Et), 3.57 (d, J=13.2 Hz, 1H, PhCHa),
3.68 (d, J=13.2 Hz, 1H, PhCHb), 4.22 (q, J=7.3 Hz, 2H,
CO2CH2CH3), 4.60 (dd, J=2.6 and 9.0 Hz, 1H,
CHCO2CH2CH3), 7.05 (m, 2H, PhH and NH), 7.20 (m,
3H, PhH), 7.38 (m, 3H, PhH), 7.47 (t, J=7.3 Hz, 1H,
PhH), 7.72 (d, J=7.3 Hz, 2H, PhH). 13C NMR (CDCl3):
l 14.1, 28.9, 34.0, 41.2, 52.1, 54.3, 57.5, 59.5, 61.8, 126.9,
127.0, 128.1, 128.4, 130.0, 131.4, 134.8, 136.5, 165.5,
166.7, 170.2. FTIR (KBr) 2939, 1736, 1649 cm−1. m/z
(ES) calcd for C24H27N3O4 (M+1) 422.2080, found
422.2075.
15. A small crystal of methyl orange was added to a solution
of the hydrazone (−)-9 (1.55 g, 5.05 mmol) dissolved in
methanol (40 mL) at 0°C. The solution turned yellow.
Drops of 2N aqueous HCl in MeOH were added until the
solution turned red. NaBH3CN (330 mg, 5.3 mmol, 1.05
equiv.) was added slowly. Whenever the colour of the
reaction mixture started to turn yellow during addition,

4230
J. Gardiner, A. D. Abell / Tetrahedron Letters 44 (2003) 4227–4230
drops of 2N aqueous HCl in MeOH were added immedi-
(brs, 1H, NH), 7.23 (s, 1H, NH), 7.26 (m, 2H, PhH),
7.31–7.35 (m, 3H, PhH), 7.42 (t, J=7.5 Hz, 2H, PhH),
7.50 (m, 1H, PhH), 7.20 (d, J=8.3 Hz, 2H, PhH). 13C
NMR (CDCl3): l 34.4, 43.6, 44.5, 57.7, 127.0, 127.3,
128.3, 128.5, 130.3, 131.6, 133.8, 134.8, 166.8, 173.2.
FTIR (KBr) 3248, 3063, 2936, 1649, 1638, 1580, 1508,
1483 cm−1. m/z (ES) calcd for C18H19N3O2 (M+1)
310.1556, found 310.1549. [h]D=−25.7° (c 1.0, CHCl3).
16. Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95,
512.
ately to restore to red colour. The reaction was stirred at
0°C for 3 h then allowed to warm to room temperature
overnight. The solvent was removed under reduced pres-
sure, the red residue taken up in ethyl acetate and washed
with saturated aqueous NaHCO3 (2×20 mL), water (2×20
mL) and dried over MgSO4. The solvent was removed to
give the product as a white foam. Purification by radial
chromatography eluting with 1:3 ethyl acetate/petroleum
ether gave (−)-10 as a sticky white solid (1.135 g, 73%).
1H NMR (CDCl3): l 2.51 (m, 2H, CH2N), 2.83 (m, 1H,
CHaCH2N), 3.15 (m, 1H, CHbCH2N), 3.19 (d, J=13.2
Hz, 1H, PhCHa), 3.53 (d, J=13.2 Hz, 1H, PhCHb), 6.99
17. Attwood, M. R.; Hassall, C. H.; Krohn, A.; Lawton,
G.; Redshaw, S. J. Chem. Soc., Perkin Trans. 1 1986,
1011.