Solid phase synthesis of enantiomerically pure polyhydroxyvalerolactams

Article abstract of DOI:10.1016/S0040-4039(00)02146-8

A general method for the solid phase synthesis of type 2 3,4,5-trihydroxypiperidin-2-ones is described. Amination of D-ribonolactone 4 was accomplished using a Mitsunobu reaction, and type 7 aminolactone underwent direct lactamisation upon treatment with NaOAc. For the solid phase synthesis, the aminoacid was anchored directly to a TentaGel resin, and the lactamisation step was concomitant with the cleavage from the resin.

Full text of DOI:10.1016/S0040-4039(00)02146-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 871–873
Solid phase synthesis of enantiomerically pure
polyhydroxyvalerolactams
Jordi Piro´,a Mario Rubiralta,a Ernest Giraltb and Anna Dieza,*
aLaboratori de Qu´ımica Orga`nica, Facultat de Farma`cia, Universitat de Barcelona, 08028-Barcelona, Spain
bDepartament de Qu´ımica Orga`nica, Facultat de Qu´ımica, Universitat de Barcelona, 08028-Barcelona, Spain
Received 23 October 2000; accepted 21 November 2000
Abstract—A general method for the solid phase synthesis of type 2 3,4,5-trihydroxypiperidin-2-ones is described. Amination of
D-ribonolactone 4 was accomplished using a Mitsunobu reaction, and type 7 aminolactone underwent direct lactamisation upon
treatment with NaOAc. For the solid phase synthesis, the aminoacid was anchored directly to a TentaGel® resin, and the
lactamisation step was concomitant with the cleavage from the resin. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
minal carboxyl of the aminoacid moiety to a TentaGel®
resin,5 perform the condensation with D-ribonolactone
4, and lactamise. Since lactamisation is performed using
NaOAc/MeOH, the cleavage of the molecule from the
resin would be concomitant with the cyclisation,6 and
no linker would be necessary.7 However, the reaction
conditions of some transformations had to be adapted
to make them compatible with the solid support, and
the reaction sequence was first established in solution.
We recently reported the synthesis of pseudodipeptide 1
as a conformationally restricted Ser-Leu surrogate (Fig.
1),1 in which a protected derivative of compound 2
(R=iBu) was obtained as an intermediate. Since poly-
hydroxylated lactams have been reported as having
interesting biological activities, such as glycosidase
inhibitors,2 cancer cell metastasis inhibitors,3 and anti-
inflammatories,4 we considered the possibility of syn-
thesising a small collection of 3,4,5-trihydroxypipe-
ridin-2-ones 2, whose activity may be modulated by the
side chain functionalisation of the aminoacid moiety.
2. Results and discussion
First, we explored the possibility of aminating ribono-
lactone 4 using a Mitsunobu reaction, which is mild
and suitable for solid phase synthesis.8 This was satis-
factorily achieved by N-alkylation of the sulphonamide
derived from Leu (5) with 4 in the presence of DEAD
and PPh3, followed by cleavage of the arylsulfone
group of compound 69 with PhSH (Scheme 1).10 Treat-
For this purpose, we envisaged to apply the lactamisa-
tion strategy that we had established1 to a solid phase
synthesis in which the lactams would be released in the
last step. In this way, we could perform their synthesis
in parallel and obtain the products with a high degree
of purity. Our strategy consisted of anchoring the ter-
iBu
CO2tBu
R
CO2
NH
R
CO2Me
O
HO
O
N
O
O
N
+
O
S O
OBn
H2N
NO2
O
O
HO
OH
OH
OH
2
1
3
4
{Ser-Leu}-OtBu
Figure 1.
Keywords: hydroxypiperidines; azasugars; hydroxylactams; solid phase synthesis.
* Corresponding author. Tel.: +34-934035849; fax: +34-934034539; e-mail: adiez@farmacia.far.ub.es
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02146-8

872
J. Piro´ et al. / Tetrahedron Letters 42 (2001) 871–873
iBu
CO2Me
O
iBu
CO2Me
O
iBu
CO2Me
O
CO2Me
CO2Me
NH2
Leu-OMe
N
HN
(iii)
N
(NO2)oC6H4O2S
(ii)
(i)
(iv)
NH
O
O
O
S O
HO
8a
O
NO2
O
O
O
O
O
5
6
7
Scheme 1. Reagents and conditions: i) Et3N (1.5 equiv.), o-NBSCl (1.5 equiv.), CH2Cl2, room temperature, 1.5 h (72%); ii) 4 (1.5
equiv.), PPh3 (1.5 equiv.), DEAD (1.5 equiv.), CH2Cl2, 0°C, 5 min, room temperature, 12 h (80%); iii) PhSH (1.1 equiv.), K2CO3
(3 equiv.), DMF (87%); iv) NaOAc (5 equiv.), MeOH, reflux, 15 h (96%).
ment of the resulting secondary amine 711 with NaOAc/
MeOH yielded the expected lactam 8.12
pounds 3a–c.15 The formation of the primary amines 11
and the sulphonamides 3 was confirmed by a positive
and a negative ninhydrine test, respectively. Condensa-
tion of 3a–c with 4, followed by cleavage of the arylsul-
fone using PhSH, led to the secondary amines 13a–c,
which gave a positive chloranyl test. Subsequent lac-
tamisation using NaOAc in MeOH resulted in the
target lactams 8a–c. After removal of the resin, the
MeOH solvent was replaced by CH2Cl2 and the prod-
ucts filtered to yield 8a–c in pure form.
For the solid phase synthesis we followed Sieber’s13 and
Liskamp’s method6 since the TentaGel® resin also
swells conveniently in MeOH, which was necessary for
an efficient lactamisation/cleavage step. The reaction
sequence was applied in parallel to obtain the Leu (8a),
Val (8b), and Phe (8c) derivatives (Scheme 2).
Anchoring of the Fmoc protected aminoacids to the
TentaGel® resin was achieved using DIC/DMAP/HOBt
and repeating the process 4 times to obtain compounds
10a–c in >95% yield.14 After capping with Ac2O, the
Fmoc group was cleaved to obtain amines 11a–c. Stan-
dard sulfonation of the amines gave the expected com-
Finally, hydrolysis of the acetal function of lactams
8a–c using PPTS in MeOH yielded 3,4,5-trihydroxyp-
iperidin-2-ones 2a–c (Scheme 3), which were identified
by their analytical data.16
O
1. 4 x (i), (ii)
2. (iii), (iv)
1. (v), (iv)
2. (vi)
O
R
R
(vii), (iv), (vi)
O
O
HO
NH2
NHFmoc
9
10a-c
11a-c
TentaGel® resin
a R = iBu
b R = iPr
O
O
O
R
R
c R = Bn
O
O
O
(NO2)oC6H4O2S-N
HN
O
O
O
(viii), (ix)
(x), (iv), (xi)
(xii), (xiii)
8a-c
3a-c
O
O
O
12a-c
13a-c
Scheme 2. Reagents and conditions: i) Fmoc-Leu, Fmoc-Val, or Fmoc-Phe (5 equiv.), DIC (5 equiv.), DMAP (0.1 equiv.), HOBt
(5 equiv.), DMF/CH2Cl2 (1:9, 6 ml/g of resin), 4 h, room temperature; ii) rinsing with CH2Cl2/MeOH/Et2O (3 times each); iii)
Ac2O (1 equiv.), pyridine (2 equiv.), DMF (6 ml/g of resin), 1 h, room temperature; iv) rinsing with DMF/MeOH/Et2O (3 times
each); v) 3×20% piperidine–DMF (v/v, 6 ml/g of resin, 5–10–10 min), room temperature; vi) ninhydrine test; vii) Et3N (5 equiv.),
o-NBSCl (5 equiv.), DMF (6 ml/g of resin), room temperature, 1.5 h; viii) 4 (5 equiv.), PPh3 (5 equiv.), DEAD (5 equiv.), THF
(6 ml/g of resin), 0°C, 10 min, room temperature 12 h; ix) rinsing with THF/MeOH/Et2O; x) PhSH (1.5 equiv.), K2CO3 (2 equiv.),
DMF (6 ml/g of resin), room temperature, 40 min.; xi) chloranyl test; xii) NaOAc (5 equiv.), MeOH, reflux, 24 h; xiii) 1. filtration,
2. evaporation of the MeOH, 3. solution in CH2Cl2, 4. filtration, 5. evaporation of the solvent (40% total for 8a; 27% total for
8b, and 37% total for 8c).
CO2Me
O
CO2Me
O
CO2Me
O
PPTS (1 equivalent)
MeOH, reflux, 48 h
N
N
N
8a-c
HO
HO
HO
OH
OH
OH
OH
OH
OH
2c (80%)
2a (75%)
2b (68%)
Scheme 3.

J. Piro´ et al. / Tetrahedron Letters 42 (2001) 871–873
873
Acknowledgements
10. Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett.
1995, 36, 6373–6374.
11. Lactone 7: [h]D=−42 (c=1.10, CHCl3); IR (CHCl3) 3300
(NH), 1785 (CO), 1736 (CO) cm−1. 1H NMR (CDCl3, 300
This work has been supported by grants PB97-0976
(MEC, Spain), 2FD97-0293 (MEC and EU), HF1999-
0068 (MEC), and grant 1999SGR-00077 (CIRIT, Gen-
eralitat de Catalunya). We also thank the CIRIT for a
PhD grant given to J.P.
MHz):
l 0.90 and 0.92 (2d, J=7 Hz, 3H each,
CH(CH3)2), 1.39 and 1.47 (2s, 3H each, C(CH3)2), 1.41–
1.44 (m, 2H, CH2CH), 1.64–1.72 (m, 1H, CH(CH3)2),
2.48 (dd, J=13 and 2 Hz, 1H, H-5), 3.22 (dd, J=8 and
7 Hz, NCH), 3.26 (dd, J=13 and 3 Hz, H-5), 3.72 (s, 3H,
CO2CH3), 4.61 (dd, J=3 and 2 Hz, 1H, H-4), 4.65 (d,
J=6 Hz, 1H, H-3), 4.82 (d, J=6 Hz, 1H, H-2). 13C
NMR (CDCl3, 75 MHz): l 21.7 and 22.8 (CH(CH3)2),
24.9 ((CH3)2CH), 25.5 and 26.7 (C(CH3)2), 42.5
(CH2CH), 48.6 (C5), 51.8 (CO2CH3), 60.8 (NCH), 75.6
(C2), 79.4 (C3), 82.8 (C4), 113.1 (C(CH3)2), 174.2 (CO),
175.1 (CO). Anal. Calcd for C15H25NO6: C, 57.13; H,
7.99; N, 4.44. Found: C, 56.72; H, 7.86; N, 4.39.
References
1. Piro´, J.; Rubiralta, M.; Giralt, E.; Diez, A. Tetrahedron
Lett. 1999, 40, 4865–4868.
2. Fleet, G. W. J.; Ramsden, N. G.; Dwek, R. A.;
Rademacher, T. W.; Fellows, L. E.; Nash, R. J.; Green,
D. St. C.; Winchester, B. J. Chem. Soc., Chem. Commun.
1988, 483–485.
3. (a) Tsuruoka, T.; Nakabayashi, S.; Fukuyasu, H.; Ishii,
Y.; Tsuruoka, T.; Yamamoto, H.; Inouye, S.; Kondo, S.
EP 328111 A2, 1989;; (b) Fleet, G. W. J.; Ramsden, N.
G.; Witty, D. R. Tetrahedron 1990, 45, 319–326.
4. Tsuruoka, T.; Yuda, Y.; Nakabayashi, A.; Katano, K.;
Sezaki, M.; Kondo, S. JP 63216867 A2, 1988.
5. NovaSyn® TG hydroxy resin, loading=0.27 mmol/g.
Novabiochem (ref. No. 01-64-0096).
12. Lactam 8a: [h]D=+5 (c=1.02, CHCl3); IR (CHCl3) 3400
1
(br, OH), 1742 (CO), 1650 (CO) cm−1. H NMR (CDCl3,
300 MHz): l 0.94 and 0.96 (2d, J=3 Hz, 3H each,
CH(CH3)2), 1.41 and 1.52 (2s, 3H each, C(CH3)2),1.55–
1.75 (m, 3H, CH2CH(CH3)2), 2.60 (br s, 1H, OH), 3.23
(dd, J=12 and 4 Hz, 1H, H-6), 3.37 (dd, J=12 and 9 Hz,
1H, H-6), 3.70 (s, 3H, CO2CH3), 4.10–4..15 (m, 1H, H-5),
4.56–4.63 (m, 2H, H-3 and H-4), 5.3 (dd, J=10 and 6 Hz,
1H, NCH). 13C NMR (CDCl3, 75 MHz): l 21.3 and 23.2
(CH(CH3)2), 24.8 (CH(CH3)2), 24.8 and 26.0 (C(CH3)2),
37.5 (CH2CH), 43.7 (C6), 52.3 (CO2CH3), 53.9 (NCH),
65.7 (C5), 74.4 and 74.8 (C3 and C4), 110.8 (C(CH3)2),
166.7 and 171.9 (CO). Anal. Calcd for C15H25NO6: C,
57.13; H, 7.99; N, 4.44. Found: C, 57.28; H, 7.90; N,
4.46.
6. Reichwein, J. F.; Liskamp, R. M. J. Tetrahedron Lett.
1998, 39, 1243–1246.
7. (a) Forns, P.; Fields, G. B. In Practical Solid-Phase
Synthesis. A Book Companion; Kates, S. A.; Albericio, F.,
Eds. Solid Support. M. Dekker: New York, 2000; (b)
Obrecht, D.; Villalgordo, J. M. In Solid-Supported Com-
binatorial and Parallel Synthesis of Small-Molecular-
Weight Compound Libraries Solid Support. Pergamon:
Oxford, 1998.
8. For a review, see: Booth, S.; Hermkens, P. H. H.; Otten-
heijm, H. C. J.; Rees, D. C., Tetrahedron, 1998, 54,
15385–15443.
13. Sieber, P. Tetrahedron Lett. 1987, 28, 6147–6150.
14. Ma, Y.; Souveaux, E. Biopolymers 1989, 28, 965–973.
15. The synthesis of compound 3a was described by a slightly
different method in Ref. 6.
16. Lactam 2a: [h]D=+11 (c=1.20, CHCl3); IR (CHCl3)
3450 (br, OH), 1740 (CO), 1648 (CO) cm−1 1H NMR
.
9. Lactone 6: [h]D=+40 (c=1.15, CHCl3); IR (CHCl3) 1793
(CO), 1743 (CO), 1547 (NO2) cm−1 1H NMR (CDCl3,
.
(CDCl3, 300 MHz): l 0.95 (d, J=7 Hz, 6H, CH(CH3)2),
1.48–1.61 (m, 1H, CH(CH3)2),1.67–1.83 (m, 2H,
CH2CH), 2.95 (br s, 1H, OH), 3.26 (br s, 1H, OH), 3.35
(dd, J=12 and 8 Hz, 1H, H-6), 3.45 (dd, J=12 and 6 Hz,
1H, H-6), 3.72 (s, 3H, CO2CH3), 4.01 (br s, 1H, OH),
4.09 (d, J=3 Hz, 1H, H-3), 4.12–4.22 (m, 1H, H-5), 4.37
(t, J=3 Hz, 1H, H-4), 5.23 (dd, J=10 and 5 Hz, 1H,
NCH); ). 13C NMR (CDCl3, 75 MHz): l 21.3 and 23.3
(CH(CH3)2), 24.6 (CH(CH3)2), 37.0 (CH2CH), 46.4 (C6),
52.4 (CO2CH3), 54.5 (NCH), 64.7 (C5), 68.9 (C4), 69.2
(C3), 170.5 and 171.6 (CO). Anal. Calcd for C12H21NO6:
C, 52.35; H, 7.69; N, 5.09. Found: C, 52.39; H, 7.57; N,
4.62. Lactams 2b and 2c show similar characteristic data.
Lactam 2b: [h]D=−36 (c=1, CHCl3). Lactam 2c: [h]D=−
33 (c=1, CHCl3).
300 MHz): l 0.75 and 0.88 (2d, J=7 Hz, 3H each,
(CH3)2CH), 1.41 and 1.48 (2s, 3H each, (CH3)2C), 1.49–
1.60 (m, 1H, (CH3)2CH), 1.74–1.84 (m, 2H, CH2), 3.56
(dd, J=16 and 7 Hz, 1H, H-5), 3.71 (s, 3H, CO2CH3),
3.75 (dd, J=16 and 7 Hz, 1H, H-5%), 4.43 (dd, J=7 and
6 Hz, 1H, NCH), 4.83–4.87(m, 2H, H-3 and H-4), 4.85
(br s, 1H, H-2), 7.68 (dd, J=7 and 2 Hz, 1H, Ar-H3),
7.70–7.79 (m, 2H, Ar-H4 and Ar-H5), 8.09 (dd, J=6 and
3 Hz, 1H, Ar-H6). 13C NMR (CDCl3, 75 MHz): l 21.5
and 22.3 ((CH3)2CH), 24.4 ((CH3)2CH), 25.6 and 26.7
((CH3)2C), 38.3 (CH2), 46.3 (C5), 52.7 (CO2CH3), 58.0
(NCH), 74.1 (C2), 77.3 (C3), 79.9 (C4), 113.8 ((CH3)2C),
124.3 (Ar-C3), 131.5 (Ar-C6), 131.8 and 134.3 ( Ar-C2,
Ar-C4 and Ar-C5), 147.8 (Ar-C1), 171.1 and 173.4 (CO).
.
.