A general synthetic approach for the synthesis of β-hydroxy-δ-lactones: asymmetric total synthesis of prelactones and epi-prelactones V and E

Article abstract of DOI:10.1016/j.tetlet.2007.11.080

A general synthetic approach for the synthesis of prelactones and epi-prelactones V and E has been reported using an Evans' aldol reaction as the key step.

Full text of DOI:10.1016/j.tetlet.2007.11.080

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 919–922
A general synthetic approach for the synthesis of
b-hydroxy-d-lactones: asymmetric total synthesis
of prelactones and epi-prelactones V and EI
Gowravaram Sabitha,* P. Padmaja, K. Bhaskar Reddy and J. S. Yadav
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 15 June 2007; revised 3 November 2007; accepted 14 November 2007
Available online 19 November 2007
Abstract—A general synthetic approach for the synthesis of prelactones and epi-prelactones V and E has been reported using an
Evans’ aldol reaction as the key step.
Ó 2007 Published by Elsevier Ltd.
b-Hydroxy-d-lactones represent an important structural
motif present in a large number of organic natural pro-
ducts1 such as mevinolin and compactin,2a phomo-
lactone2b and massoialactone.2c Prelactones 1–7 isolated
from bafilomycin-producing microorganisms and vari-
ous polyketide macrolide producing microorganisms
belong to this class of compounds.3 These lactones exhibit
properties such as ATPase inhibition and antibacterial,
antifungal and immunosuppressive activities.2a,b,4 The
discovery of these molecules supports the widely
accepted hypothesis of step-by-step functionalization of
a growing polyketide chain in the biosynthesis of macro-
lides.5 Furthermore, highly functionalized chiral d-lac-
tones have attracted considerable attention in recent
years due to their importance as building blocks in nat-
ural product synthesis.6 Although there are many meth-
ods reported for the synthesis of prelactones, very few
are known for epi-prelactones.7 Therefore, an efficient
and flexible approach for the enantioselective synthesis
of prelactones and epi-prelactones is essential. Herein,
we report a general route for the synthesis of prelactones
and epi-prelactones V and E, 3–6. The approach
described here also gives access to the other prelactones
as well as to additional derivatives with potential rele-
vance in biological studies (Fig. 1).
OH
O
OH
O
OH
O
OH
O
O
O
O
O
epi-Prelactone V
Prelactone C
Prelactone V
Prelactone B
2
1
4
3
OH
O
OH
O
OH
O
O
O
O
3,5-Dimethyl-6-ethyl-
4-hydroxylactone
epi-Prelactone E
Prelactone E
6
5
7
Figure 1.
The Evans’ asymmetric aldol reaction8 was chosen as
the key step for the synthesis of these molecules. Thus,
aldol reaction of aldehyde 9 with (4R)-N-propionyl-4-
benzyloxazolidinone 8 using dibutylboron triflate and
triethylamine in DCM at ꢀ78 °C for 30 min provided
the syn aldol product 10 in 82% yield as a single diaste-
reomer. The chiral auxiliary was removed by transami-
dation to afford Weinreb amide 11. Amide 11 was
subjected to a Grignard reaction with MeMgI to afford
keto compound 12, which on stereoselective reduction
with tetramethylammonium triacetoxyborohydride9
provided the 1,3-anti diol 13 (98:2 dr). The diol 13 was
protected as acetonide 14 and its structure confirmed
by 13C NMR spectral studies.
Keywords: b-Hydroxy-d-lactones; Prelactones; Evans’ aldol.
q IICT Communication No. 070535.
*
After reductive debenzylation of compound 14, the alco-
hol was oxidized to the corresponding acid via a two
Corresponding author. Tel./fax: +91 40 27160512; e-mail:
sabitha@iictnet.org
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.11.080

920
G. Sabitha et al. / Tetrahedron Letters 49 (2008) 919–922
step process; firstly to an aldehyde using IBX in DMSO
and then by perchlorite oxidation to the acid, which was
converted into methyl ester 15 on treatment with diazo-
methane in ether (52% over four steps). Exposure of
compound 15 to AcOH/H2O (4:1) at room temperature
for 2 h resulted in acetonide cleavage and subsequent
cyclization furnished the target prelactone V, 3 (Scheme
1).
the corresponding acetonide 18. The chemical shifts of
the acetonide were observed at 98.7 and 19.7 ppm, in
agreement with values commonly observed for a syn
diol.10 Debenzylation, IBX oxidation, conversion into
the acid and treatment with diazomethane as described
in Scheme 1 afforded ester 19. Treatment of compound
19 with AcOH/H2O (4:1) at rt afforded epi-prelactone
V, 4 in 88% yield (Scheme 2).
For the synthesis of epi-prelactone V, Weinreb amide 11
was treated with DIBAL-H to afford the aldehyde 16.
Grignard reaction of 16 with excess MeMgI in ether at
ꢀ15 °C for 30 min afforded the 1,3-syn diol 17 in 85%
yield. The syn stereochemical relationship of diol 17
was verified by analysis of the 13C NMR spectrum of
For the synthesis of prelactone E, the Weinreb amide 11
was treated with ethyl magnesium bromide to afford
ketone 20 in 78% yield. Stereoselective reduction of
the keto group using tetramethylammonium tri-
acetoxyborohidride9 afforded 1,3-anti diol 21 (98:2 dr)
in 82% yield. After acetonide protection, the same
O
O
OH
10
O
OH
11
O
O
Bu2BOTf, Et3N, CH2Cl2,
°
-78 C, 30 min,
NH(OMe)Me.HCl
N
N
OBn
OBn
O
N
O
Me3Al, DCE
MeO
BnO
O
82%
0
°
9
0 C to -15 C, 1 h, 90%
8
Ph
Ph
OH
OH
13
O
OH
12
MeMgI, Et2O
rt, 30 min, 76%
(Me)4NBH(OAc)3
2, 2- DMP, DCM
PPTS, 1 h, 95%
OBn
OBn
10 h, -10 0C to rt
85%
OH
a) Pd/C, 1 h
AcOH : H2O
4:1
b) IBX, DCM,
O
O
O
O
O
DMSO, 2 h.
OBn
OMe
rt, 2 h, 88%
c) Na2HPO4. 2H2O,
NaClO2, 30 min
O
O
14
15
Prelactone V
d) CH2N
2, Et2O
3
30 min, overall yield 52%
Scheme 1.
O
OH
OH OH
DIBAL-H, DCM
-78 OC, 2 h, 90%
MeMgI, Et2O
2, 2- DMP, DCM
11
OBn
OBn
-15 OC, 30 min
85%
PPTS, 1 h
95%
17
16
96:4
OH
a) Pd/C, 1 h
b) IBX, DCM,
DMSO, 2 h.
O
O
O
AcOH : H2O
4:1
O
O
OMe
OBn
18
rt, 2 h, 88%
c) Na2HPO4. 2H2O,
NaClO2, 30 min
d) CH2N
2,Et2O
30 min, overall yield 52%
O
O
19
epi-prelactone V
4
Scheme 2.
OH OH
O
OH
EtMgBr, dry THF
30 min, 78%
2, 2- DMP, DCM
PPTS, 1 h, 94%
(Me)4NBH(OAc)3
11
OBn
OBn
10 h, 0 0C to rt
8.5:1.5 de, 82%
20
a) Pd/C, 1 h
21
OH
b) IBX, DCM,
DMSO, 2 h.
AcOH : H2O
4:1
O
O
O
O
O
c) Na2HPO4. 2H2O,
NaClO2, 30 min
OMe
rt, 2 h, 90%
OBn
O
O
Et2O
d) CH2N2,
30 min, overall yield 55%
Prelactone E
23
22
5
Scheme 3.

G. Sabitha et al. / Tetrahedron Letters 49 (2008) 919–922
921
OH OH
O
O
2, 2- DMP, DCM
PPTS, 1 h, 95%
EtMgBr, dry
30 min, 90%
16
OBn
OBn
25
24
96 : 4
OH
a) Pd/C, 1 h
b) IBX, DCM,
DMSO, 2 h.
AcOH : H2O
4:1
O
O
O
OMe
c) Na2HPO4. 2H2O,
NaClO2, 30 min
rt, 2 h, 90%
O
O
d) CH2N
2,Et2O
epi-Prelactone E
30 min, overall yield 55%
26
6
Scheme 4.
Asymmetric Synthesis; Morrison, J. D., Scott, J. W.,
Eds.; Academic Press: New York, 1984; 4, pp 1–226.
7. (a) Jung Kim, S.; Young Kang, H.; Sherman, D. H.
Synthesis 2001, 12, 1790–1793; (b) Tapadar, S.; Chakr-
aborty, T. K. Tetrahedron Lett. 2001, 42, 1375–1377; (c)
Yamashita, Y.; Saito, S.; Ishitani, H.; Kobayashi, S. J.
Am. Chem. Soc. 2003, 125, 3793–3798; (d) Csaky, A. G.;
Mba, M.; Plumet, J. Synlett 2003, 13, 2092–2094; (e)
Enders, D.; Hass, M. Synlett 2003, 14, 2182–2184; (f)
Chakraborty, T. K.; Tapadar, S. Tetrahedron Lett. 2003,
44, 2541–2543; (g) Pihko, P. M.; Erkkila, A. Tetrahedron
Lett. 2003, 44, 7607–7609; (h) Aggarwal, V. K.; Bae, I.;
Yoon Lee, H. Tetrahedron 2004, 60, 9725–9733; (i) Yadav,
J. S.; Bhaskar Reddy, K.; Sabitha, G. Tetrahedron Lett.
2004, 45, 6475–6476; (j) Miyazawa, M.; Narantsetseg, M.;
Yokoyama, H.; Yamaguchi, S.; Hirai, Y. Heterocycles
2004, 63, 1017–1021; (k) Dias, L. C.; Steil, L. J.;
Vasconcelos, V. A. Tetrahedron: Asymmetry 2004, 15,
147–150; (l) Yadav, J. S.; Sridhar Reddy, M.; Prasad, A.
R. Tetrahedron Lett. 2005, 46, 2133–2136; (m) Salaskar,
A. A.; Mayekar, N. V.; Sharma, A.; Nayak, S. K.;
Chatopadhyaya, A.; Chattopadhyay, S. Synthesis 2005,
16, 2777–2781; (n) Sellars, J. D.; Steel, P. G. Org. Biomol.
Chem. 2006, 4, 3223–3224; (o) Chandrasekhar, S.; Ramb-
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Tetrahedron Lett. 2001, 42, 8463–8465.
sequence of reactions as described in Scheme 1, afforded
ester 23. Exposure of 23 to AcOH/H2O (4:1) at rt
furnished prelactone E, 5 in 90% yield (Scheme 3).
The synthesis of epi-prelactone E began with the inter-
mediate aldehyde 16. Accordingly, Grignard reaction
of 16 with excess EtMgBr in dry THF at ꢀ15 °C for
30 min afforded the 1,3-syn diol 24 in 90% yield. The
syn stereochemical relationship of diol 24 was verified
by analysis of the 13C NMR spectrum of the corre-
sponding acetonide 25. The chemical shifts of the aceto-
nide were observed at 98.7 and 19.6 ppm, in agreement
with values commonly observed for a syn diol.10 Deben-
zylation, IBX oxidation, conversion into the acid, and
treatment with diazomethane as before afforded ester
26. Reaction of 26 with AcOH/H2O (4:1) at rt afforded
epi-prelactone E, 6 (Scheme 4).
In conclusion, we have accomplished the stereoselective
synthesis of prelactones V, E and epi-prelactones V, E
using an Evans’ aldol reaction as the key step. The
methodology presented here is general and should allow
access to novel analogues of the prelactones.
8. (a) Evans, D. A. Aldrichim. Acta 1982, 15, 23; (b) Evans,
D. A.; Bartoli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
References and notes
1
2127–2129; (c) Spectral data: prelactone V (3): H NMR
(CDCl3, 300 MHz): d 3.93 (dt, J = 5.7, 7.2 Hz, 1H), 3.75
(dq, J = 6.2, 10.1 Hz, 1H), 2.9 (dd, J = 5.6, 16.6 Hz, 1H),
2.42 (dd, J = 7.2, 16.6 Hz, 1H), 1.98 (br, 1H, OH), 1.58
(ddq, J = 10.2, 7.2, 6.8 Hz, 1H), 1.38 (d, J = 6.2 Hz, 3H),
1.09 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 75 MHz):
170.5, 79.0, 69.6. 43.3, 39.0, 19.5, 13.7; EIMS: m/z 144
(M+); IR (neat): 3435, 2980, 2932, 1730, 1383, 1267, 1095,
1. Bindseil, K. U.; Zeeck, A. Helv. Chem. Acta 1993, 76, 150–
157, and references cited therein.
2. (a) Endo, J. A. J. Med. Chem. 1985, 28, 401–405; (b)
Honda, T.; Kametani, T.; Kanai, K.; Tatsuzaki, Y.;
Tsubuki, M. J. Chem. Soc., Perkin Trans. 1 1990, 1733–
1737; (c) Cavil, G. W. K.; Clark, D. V.; White field, F. B.
Aust. J. Chem. 1968, 21, 2819–2823.
3. (a) Boddien, C.; Gerber Nolte, J.; Zeeck, A. Liebigs Ann.
1996, 9, 1381–1384; (b) Cortes, J.; Wiesmann, K. E. H.;
Roberts, G. A.; Brown, M. J. B.; Staunton, J.; Leadlan, P.
F. Science 1995, 268, 1487–1489; (c) Esumi, T.; Fukay-
ama, H.; Oribe, R.; Kawazoe, K.; Iwabuchi, Y.; Irie, H.;
Hatakayama, S. Tetrahedron Lett. 1997, 38, 4823–4828;
(d) Hanefeld, U.; Hooper, A. M.; Stauntons, J. Synthesis
1999, 401–403.
4. (a) Argoudelis, A. D.; Zieserl, J. F. Tetrahedron Lett.
1966, 18, 1969; (b) Laurence, B. R. J. Chem. Soc., Chem.
Commun. 1982, 59.
5. O’ Hagen, D. In The Polyketide Metabolites., E. D.; Ellis
Horwood: New York, 1991; 116–137.
6. (a) Warmerdam, E.; Tranoy, I.; Renoux, B.; Gesson, J. P.
Tetrahedron Lett. 1998, 39, 8077–8080; (b) Hanessian, S.
Total Synthesis of Natural Products: The Chiron Approach;
Pergamon Press: Oxford, 1983; (c) Scott, J. W. In
25
1046, 979 cmꢀ1; ½aꢁD +31.5 (c 0.98, MeOH), [Reported7l
value: +32.8 (c 0.98, MeOH)]; epi-prelactone V (4): 1H
NMR (CDCl3, 300 MHz): 4.92 (qd, J = 3.7, 7.3, 1H), 4.07
(q, J = 4.4 Hz, 1H), 2.83 (dd, J = 5.1, 18.3 Hz, 1H), 2.53
(dd, J = 2.9, 18.3 Hz, 1H), 1.93 (m, 1H), 2.24 (br, 1H,
OH), 1.34 (d, J = 6.5 Hz, 3H), 0.98 (d, J = 7.3 Hz, 3H);
13C NMR (CDCl3, 75 MHz): 171.0, 74.9, 68.3, 38.2, 35.9,
17.6, 10.1; LCMS: 167 [M+Na]; IR (neat): 3424, 2924,
25
1714, 1458, 1381, 1078, 965 cmꢀ1; ½aꢁD ꢀ80.6 (c 1.3,
CHCl3), [Reported7o value: ꢀ81.8 (c 1.3, CHCl3)]; Prel-
actone E (5): 1H NMR: (CDCl3, 300 MHz): d 3.70–3.88
(m, 2H), 2.88 (dd, J = 6.0, 17.3 Hz, 1H), 2.48 (dd, J = 7.5,
16.6 Hz, 1H), 1.85 (m, 1H), 1.53–1.76 (m, 2H), 1.08 (d,
3H, J = 6.8 Hz), 1.03 (t, J = 7.5 Hz, 3H), 1.26 (br, 1H,
OH); 13C NMR (CDCl3, 75 MHz): 171.1, 83.5, 69.6, 40.4,
38.9, 25.7, 13.7, 8.7; LCMS: 181.1 [M+Na]; IR (neat):
25
3426, 2970, 1728, 1379, 1252, 1099, 950 cmꢀ1; ½aꢁD þ 40:4

922
G. Sabitha et al. / Tetrahedron Letters 49 (2008) 919–922
(c 8 mg/ml in Et2O), [Reported7p value: +41.9 (c 8 mg/ml
ꢀ17.8 (c 1, CHCl3); Prelactone E acetonide (22): 1H NMR
(CDCl3, MHz): 7.21–7.33 (m, 5H), 4.46 (s, 2H), 3.95–4.04
(m, 1H), 3.47–3.53 (t, J = 6.0 Hz, 2H), 3.05–3.14 (m, 1H),
1.40–1.68 (m, 5H), 1.37 (s, 6H), 0.89–0.97 (t, J = 6.8 Hz,
3H), 0.79–0.85 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3,
75 MHz): 138.3, 128.9, 128.3, 128.1, 100.6, 77.4, 73.6, 67.8,
65.8, 40.1, 31.6, 27.4, 24.2, 25.1, 12.4, 10.9; LCMS: 315
[M+Na]; IR (neat): 3429, 2928, 1641, 1457, 1380, 1271,
in Et2O)]; epi-prelactone E (6): 1H NMR (CDCl3, 300 MHz):
d 4.59 (tt, J = 3.0, 5.2 Hz, 1H), 4.01 (m, 1H), 2.76 (dd,
J = 5.2, 18.1 Hz, 1H), 2.49 (dd, J = 2.2, 18.1 Hz, 1H), 1.93
(m, 1H), 1.78 (m, 1H), 1.42–1.67 (m, 1H), 1.04 (t,
J = 7.5 Hz, 3H), 0.94 (d, J = 7.5 Hz, 3H), 1.25 (br, 1H,
OH); 13C NMR(CDCl3, 75 MHz): 170.1, 79.2, 68.8, 48.2,
37.1, 25.0, 10.2, 10.1; LCMS: 181.0 [M+Na]; IR: 3426,
25
25
2926, 1728, 1461, 1379, 1252, 1099, 950 cmꢀ1; ½aꢁD +4.3 [c
1109, 1072, 969, 884 cmꢀ1; ½aꢁD ꢀ21 (c 1, CHCl3); epi-
0.5, CHCl3]; prelactone V acetonide (14): 1H NMR
(CDCl3, 200 MHz): 7.14–7.42 (m, 5H), 4.46 (s, 2H),
3.98–4.14 (m, 2H), 3.44–3.58 (m, 2H), 1.48–1.85 (m, 3H),
1.4 (s, 3H), 1.34 (s, 3H), 1.24 (d, J = 6.4 Hz, 3H), 0.91 (d,
J = 6.4 Hz, 3H); 13C NMR (CDCl3, 75 MHz): 137.6,
128.6, 127.4, 127.2, 100.2, 71.6, 68.4, 68.1, 66.2, 35.2, 33.4,
25.6, 24.3, 18.3, 4.2; LCMS: 301 [M+Na]; IR (neat): 3412,
Prelactone E acetonide (25): 1H NMR (CDCl3, 200 MHz):
7.23–7.36 (m, 5H), 4.49 (AB quartet, J = 12.5 Hz, 2H),
4.0–4.12 (m, 1H), 3.67–3.80 (m, 1H), 3.41–3.59 (m, 2H),
1.43–1.89 (m, 5H), 1.39 (s, 3H), 1.35 (s, 3H), 0.76–0.96 (m,
6H); 13C NMR (CDCl3, 150 MHz): 138.5, 128.3, 127.6,
127.4, 98.7, 74.8, 73.0, 70.0, 66.7, 34.3, 33.4, 29.9, 25.5,
19.6, 9.6, 4.5; LCMS: 315 [M+Na]; IR (neat): 3443, 2965,
2984, 2842, 1634, 1462, 1370, 1265, 1112, 930, 828 cmꢀ1
epi-prelactone
acetonide (18): 1H NMR (CDCl3,
;
2858, 1624, 1456, 1380, 1260, 1106, 1037, 970, 737 cmꢀ1
;
25
V
½aꢁD ꢀ16 (c 1, CHCl3).
200 MHz): 7.19–7.44 (m, 5H), 4.50 (s, 2H), 4.0–4.17 (m,
2H), 3.46–3.61 (m, 2H), 1.50–1.92 (m, 3H), 1.42 (s, 3H),
1.37 (s, 3H), 1.12 (d, J = 6.2 Hz, 3H), 0.87 (d, J = 6.2 Hz,
3H); 13C NMR (CDCl3, 75 MHz): 138.5, 128.3, 127.6,
127.5, 98.7, 73.0, 69.9, 68.9, 66.7, 36.1, 33.3, 30.0, 19.7,
18.8, 4.4; LCMS: 301 (M+Na); IR (neat): 3420, 2976,
9. (a) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am.
Chem. Soc. 1988, 110, 3560–3578; (b) Evans, D. A.; Ng, H.
P.; Clark, J. S.; Rieger, D. L. Tetrahedron 1992, 48,
2127.
10. (a) Rychnovsky, S.-D.; Roger, B.; Yang, G. J. Org. Chem.
1993, 58, 3511–3515; (b) Evans, D. A.; Rieger, D. L.;
Gage, J. R. Tetrahedron Lett. 1990, 31, 7099–7103.
25
2868, 1622, 1455, 1177, 1263, 1105, 909, 739 cmꢀ1; ½aꢁD