Stereoselective synthesis of belactosin C and its derivatives using a catalytic proline catalyzed crossed-aldol reaction

Article abstract of DOI:10.1016/j.tetlet.2007.01.059

A highly practical and concise stereoselective total synthesis of belactosin C and synthetic variants was achieved using an S-proline catalyzed crossed-aldol reaction as the key step.

Full text of DOI:10.1016/j.tetlet.2007.01.059

Tetrahedron Letters 48 (2007) 1707–1709
Stereoselective synthesis of belactosin C and its derivatives using
a catalytic proline catalyzed crossed-aldol reactionI
G. Kumaraswamy* and B. Markondaiah
Organic Division III, Fine Chemicals Laboratory, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 29 November 2006; revised 21 December 2006; accepted 10 January 2007
Available online 14 January 2007
Abstract—A highly practical and concise stereoselective total synthesis of belactosin C and synthetic variants was achieved using an
S-proline catalyzed crossed-aldol reaction as the key step.
Ó 2007 Elsevier Ltd. All rights reserved.
Many natural products possessing the 2-oxetanone
(b-lactone) moiety exhibit biological activity such as anti-
biotic, antitumour and antiobesity.1 Prominent natural
molecules bearing a 2-oxetanone ring include anisatin,
a potent vegetal poison and the antibiotic 1233A.2 A sig-
nificant number of natural 2-oxetanones with interesting
biological activity have been identified and synthesized.3
Recent additions to this family are belactosins A and C
(Fig. 1) which inhibit the 20s proteasome in vitro
(IC50 = 0.4 lM, chymotrypsin-like activity) in a yeast
based assay of Streptomycin metabolites.4
O
Antitumor activity
O
O
CO2H
O
O
H
N
H2N
N
H
O
O
belactosin C
O
R
CO2Bn
H
N
a
b
R = CH3
R = H
c R = H (3R,4S)
CbzHN
N
H
1
Figure 1.
The basic structure of the belactosins consists of a trans-
b-lactone moiety attached to an ornithine–alanine ami-
no acid dipeptide unit. Degradation studies suggested
that the b-lactone moiety is responsible for the antipro-
liferative activity. Two total syntheses of belactosins A
and C and their analogues have been previously re-
ported.5 Recently, we developed a stereocontrolled route
to belactosin C via an Oppolzer aldol reaction as the key
step using a sultam chiral auxiliary.6 Despite these
synthetic methods, there is still a need for an alternative
efficient synthetic route for belactosin C and new
derivatives in order to further investigate b-lactones
and their efficacy towards cancer and other diseases
(Fig. 1). We envisioned that belactosin C could be read-
ily accessed by an S-proline catalyzed crossed-aldol
reaction to install the two stereocentres of the trans-b-
lactone in a highly diastereo and enantioselective
manner.7 The retrosynthetic approach to belactosin C
and derivatives are shown in Scheme 1.
In this Letter we report a concise and a highly stereo-
selective synthetic route to belactosin C wherein the chiral-
ity is derived from catalytic S-proline. Our synthesis
began with a 10 mol % S-proline catalyzed crossed-aldol
reaction between 3-(S)-methylvaleraldehyde 6a, derived
from L-isoleucine 8 and glyceraldehyde acetonide 7,8
which in turn was prepared from D-mannitol. After ini-
tial trials, the reaction was carried out with 10 mol % of
S-proline and 1 equiv of 6a and 2 equiv of 7 in dry DMF
at 4 °C, stirring for 48 h led to aldol product 5a. Due to
the capricious nature of 5a,9 it was subjected to oxida-
tion using sodium chlorite and sodium dihydrogen
orthophosphate. The resulting b-hydroxy acid was
lactonized with bis(2-oxo-3-oxazolidinyl)phosphinic
chloride (BOPCl) to give b-lactone acetonide 4a in
46% overall yield from 6a.
Keywords: S-Proline; Belactosin C; b-Lactone; Ornithine–alanine;
Proliferative activity.
q IICT Communication No. 061225.
*
Corresponding author. Tel.: +91 40 27193275; fax: +91 40
27160387; e-mail addresses: gkswamy@iictnet.org; gkswamy_iict@
yahoo.co.in
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.059

1708
G. Kumaraswamy, B. Markondaiah / Tetrahedron Letters 48 (2007) 1707–1709
O
a R = CH3
O
CO2Bn
O
H
N
CbzHN
b
c
R = H
R = H (3R,4S)
N
H
O
O
R
1a
O
O
O
CO2Bn
O
.
CbzHN
NH2 HCl
HO
O
+
O
N
H
O
R
R
3a
4a
2
O
O
OH
R
O
H
+
H
O
H
O
O
O
R
6a
7
5a
Scheme 1.
O
O
O
R
O
i
ii
iii, iv
OH
OMe
OH
H
NH2
10
8
9
6a
O
OH
O
O
O
ix, x
viii
vi, vii
O
v
H
O
O
O
HO
O
R
O
R
HO
R
11a
ref.
4a
5a
O
O
xi
O
CO2Bn
O
6
H
N
Belactosin C
HO
CbzHN
N
H
O
R
O
R
1a
3a
Scheme 2. Reagents and conditions: (i) NaNO2, HBr, 0 °C–rt, 12 h; Zn, H2SO4, 0 °C–rt, 12 h (65% yield); (ii) dry MeOH, H2SO4, reflux, 12 h (70%
yield); (iii) LiAlH4, Et2O, rt, 3 h; (iv) PCC, DCM, rt, 1 h (59% yield over two steps); (v) 7, S-proline (10 mol %), DMF, addition of 6a via syringe
pump over 24 h; then 48 h, 4 °C; (vi) NaClO2, 20% NaH2PO4Æ2H2O, t-BuOH, 0 °C–rt, 4 h; (vii) BOPCl, Et3N, DCM, 23 °C, 1 h (46% overall yield
from 6a); (viii) 1 N HCl:THF (1:1) 0 °C–rt, 3 h (95% yield); (ix) NaIO4, 1,4-dioxane:H2O (1:2), 20 °C, 3 h; (x) NaClO2, 20% NaH2PO4Æ2H2O,
t-BuOH, 0 °C–rt, 4 h (83% yield over two steps); and (xi) 2, DCC, HOBt, EtOAc:H2O (1:1) rt, 1 h (50% yield).
b-Lactone acetonide 4a was subjected to hydrolysis with
1 N HCl:THF (1:1) at 0 °C to rt, for 4 h to give b-lac-
tone diol 11a in 95% yield. Diol 11a was subjected to
oxidative cleavage using sodium metaperiodate in 1,4-
dioxane:H2O (1:2) to give a crude aldehyde which was
further oxidized with chlorite/dihydrogen orthophos-
phate to afford b-lactone carboxylic acid 3a in an 83%
yield over the two steps.10 b-Lactone carboxylic acid
3a was coupled with dipeptide 211 which resulted cleanly
in fully protected belactosin C 1a in an 18% overall yield
from aldol 5a, (Scheme 2).
installed with inexpensive reagents. Application of this
novel methodology to synthesize various substituted b-
lactones in order to study their activity profiles is
under progress.
Acknowledgements
We are grateful to Dr. J. S. Yadav, Director, IICT, for
his constant encouragement. Financial assistance from
DST, New Delhi (Grant No. SR/SI/OC-39/2002) is
gratefully acknowledged. Thanks are also due to
Dr. T. K. Chakraborthy for his support. B.M. is
thankful to the UGC (New Delhi) for awarding the
fellowship.
Belactosin C derivative 1b was synthesized using valeral-
dehyde 6b (R = H) and glyceraldehyde acetonide 7
followed by the same sequence of steps as used in
Scheme 2 in an overall yield of 20%. In the same way,
diastereomer 1c12 was prepared using R-proline instead
of S-proline in an overall yield of 19%. The analytical
data of 1a and 1b were in full agreement with the
reported data.6
Supplementary data
Experimental procedures, spectral data and copies of
spectra for compounds 1c, 3c and 4a–c can be found
in the Supplementary data. Supplementary data associ-
ated with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2007.01.059.
In conclusion, we have developed a catalytic route for
the total synthesis of belactosin C and derivatives.
Significantly, the chirality of the b-lactone moiety was

G. Kumaraswamy, B. Markondaiah / Tetrahedron Letters 48 (2007) 1707–1709
1709
reomer formed during the S-proline catalyzed aldol
reaction was removed in the subsequent purification of
4a; (b) The diastereo and enantioselectivity of aldol
product 5a was determined on the basis of b-lactone
carboxylic acids 3a and 3b reported in our previous
work.6 The optical rotation of compound 3c, was
similar in magnitude but opposite in sign to that of 3b
References and notes
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5751; (d) Hanessian, S.; Tehim, A.; Chen, P. J. Org. Chem.
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K.; Sridhar Reddy, M.; Prasad, A. R. Tetrahedron Lett.
2006, 47, 4393–4395.
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Mizukami, T. J. Antibiot. 2000, 53, 81–83.
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511; (b) Larionov, O. V.; de Meijere, A. Org. Lett. 2004, 6,
2153–2156.
6. Kumaraswamy, G.; Padmaja, M.; Markondaiah, B.;
Nivedita, J.; Sridhar, B.; Uday kiran, M. J. Org. Chem.
2006, 71, 337–340.
7. (a) Pihko, P. M.; Erkkila, A. Tetrahedron Lett. 2003, 44,
7607–7609; (b) Storer, I. R.; MacMillan, D. W. C.
Tetrahedron 2004, 60, 7705–7714; (c) Northup, A. B.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798–
6799; (d) Zhao, G. L.; Liao, W. W.; Cordova, A.
Tetrahedron Lett. 2006, 47, 4929–4932.
8. Aldehydes containing an a-methine carbon (CHR3) adja-
cent to the carbonyl do not under go homo-dimerization
when exposed to the catalyst as the kinetic inaccessibility
of the a-methine proton and thermodynamic instability of
the corresponding enamine effectively prohibit nucleophile
formation.
9. b-Hydroxyaldehydes such as 5a were reported to undergo
oligomerization, elimination and other decomposition
reactions. For recent documented examples, see: (a)
Chemler, S. R.; Roush, W. R. J. Org. Chem. 2003, 68,
1319–1333; (b) Lautens, M.; Stammers, T. A. Synthesis
2002, 1933–2012.
25
25
ð½aꢀD +13.8 (c 0.05, CHCl3); lit.6 ð½aꢀD ꢁ10.5 (c 1,
CHCl3).
11. For the preparation of dipeptide unit 2, see Ref. 6.
25
12. Selected data: Compound 1c: ½aꢀD ꢁ11.5 (c 0.0125,
CHCl3); 1H NMR (200 MHz, CDCl3) d: 7.27–7.30 (m,
10H), 5.67 (d, J = 8.0 Hz, NH), 5.12 (d, J = 8.0 Hz, 2H),
5.03 (s, 2H), 4.50–4.60 (m, 1H), 4.43–4.49 (m, 1H), 4.42
(d, J = 4.4 Hz, 1H), 3.40–3.50 (m, 1H), 3.20–3.29 (m,
1H), 2.95–3.08 (m, 1H), 1.66–1.82 (m, 4H), 1.36–1.41 (m,
4H), 1.35 (d, J = 6.8 Hz, 3H), 0.94 (t, J = 7.3 Hz, 3H);
13C NMR (75 MHz) d: 172.3, 171.5, 169.5, 167.9, 156.0,
136.1, 135.0, 128.6, 128.5, 128.4, 128.3, 128.1, 127.9, 72.8,
67.3, 67.0, 57.4, 51.7, 51.1, 38.4, 29.9, 29.1, 25.1, 19.8,
18.3, 13.4; IR (KBr): 3316, 2933, 1825, 1731, 1652, 1534,
1447, 1238, 1178, 1072, 905, 738, 661. MS (LC): m/z 590
25
[M+Na]+. Compound 4a: ½aꢀD ꢁ28.6 (c 0.025, CHCl3);
1H NMR (300 MHz, CDCl3) d: 4.23 (ddd, J = 2.2, 6.8,
9.0 Hz, 1H), 4.19 (dd, J = 2.2, 3.7 Hz, 1H), 4.08 (dd,
J = 6.8, 8.3 Hz, 1H), 3.87 (dd, J = 6.8, 8.3 Hz, 1H), 3.49
(dd, J = 3.7, 8.3 Hz, 1H), 1.85–1.95 (m, 1H), 1.58–1.70
(m, 1H), 1.41 (s, 3H), 1.37 (s, 3H), 1.23–1.33 (m, 1H),
1.00 (d, J = 6.8 Hz, 3H), 0.95 (t, J = 7.5 Hz, 3H); 13C
NMR (75 MHz): d 170.0, 110.2, 74.8, 73.0, 65.0, 57.9,
33.3, 26.7, 25.7, 25.4, 16.5, 10.9; IR (KBr): 2962, 2875,
1828, 1460, 1378, 1214, 1114, 1066, 895; MS (LC): m/z
25
251 [M+Na]+. Compound 11a: ½aꢀD ꢁ38.5 (c 0.05,
CHCl3); 1H NMR (300 MHz, CDCl3) d: 4.33 (dd,
J = 3.9, 8.1 Hz, 1H), 3.68–3.80 (m, 3H), 3.53 (dd,
J = 4.3, 8.3 Hz, 1H), 2.94 (br s, 1H), 2.30 (br s, 1H),
1.89–1.99 (m, 1H), 1.60–1.70 (m, 1H), 1.20–1.33 (m, 1H),
1.05 (d, J = 6.6 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H); IR
(KBr): 3382, 2963, 1813, 1459, 1293, 1114, 1014, 877. MS
(LC): m/z 211 [M+Na]+.
10. (a) Efforts to estimate the level of diastereoselectivity of
5a were not successful. Presumably, the minor diaste-