A short and efficient synthesis of (+)-prelactone B

Article abstract of DOI:10.1016/j.tetasy.2003.10.032

The asymmetric total synthesis of (+)-prelactone B, a biologically important natural β-hydroxy-δ-lactone derivative that contains a 2,3-trans-dialkylpyran ring system, is described. This approach involves the use of a very efficient oxazolidinone-mediated anti-aldol reaction, and a diastereoselective coupling between a ketene silyl acetal with an aldehyde followed by lactonization.

Full text of DOI:10.1016/j.tetasy.2003.10.032

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 147–150
A short and efficient synthesis of (+)-prelactone Bq
*
ꢀ
Luiz C. Dias, Leonardo J. Steil and Valeria de A. Vasconcelos
ꢀ
Instituto de Quımica, Universidade Estadual de Campinas, UNICAMP, C.P. 6154, 13084-971 Campinas, SP, Brazil
Received 19 September 2003; accepted 22 October 2003
Abstract—The asymmetric total synthesis of (+)-prelactone B, a biologically important natural b-hydroxy-d-lactone derivative that
contains a 2,3-trans-dialkylpyran ring system, is described. This approach involves the use of a very efficient oxazolidinone-mediated
anti-aldol reaction, and a diastereoselective coupling between a ketene silyl acetal with an aldehyde followed by lactonization.
ꢀ 2003 Elsevier Ltd. All rights reserved.
1. Introduction
(+)-prelactone B 2 may give access to the other prelact-
ones as well as to additional derivatives with potential
relevance to biological studies.12;13
The prelactones 1–4 constitute an important class of
highly functionalized chiral d-lactones isolated from
various polyketide macrolide producing microorganisms
(Fig. 1).1–6 Prelactone B 2, a b-hydroxy d-lactone that
contains a 2,3-trans-dialkylpyran ring system is a bio-
logically important natural pyranone derivative, isolated
from bafilomycin producing Streptomyces griseus (strain
2599 ana 18) by Zeek and Bindseil in 1993.1 The dis-
covery of these molecules supports the widely accepted
hypothesis of the step by step functionalization of
growing polyketide chains in the biosynthesis of mac-
rolides.7–11
2. Results and discussion
Our approach began with a highly selective anti-aldol
reaction between oxazolidinone (+)-5 and methacrolein
to give (+)-6 in 77% yield and 15:1 diastereoselectivity
(Scheme 1).14 The aldol adduct (+)-6 was smoothly
hydrogenated to give b-hydroxyimide (+)-7 in 99% iso-
lated yield after silica gel column chromatography.14
In order to prepare the corresponding aldehyde, the
attempted conversion of (+)-7 into the corresponding
Weinreb amide under standard conditions resulted in
To date, four syntheses of prelactone B 2 have been
described.6;9;10 An efficient and flexible enantioselective
synthesis of prelactone B 2 is essential for providing
further material for biological studies, along with access
to novel analogues. The approach herein described for
Figure 1.
q This paper is dedicated to the Brazilian Chemical Society (SBQ).
* Corresponding author. Tel.: +55-019-3788-3021; fax: +55-019-3788-
3023; e-mail: ldias@iqm.unicamp.br
Scheme 1.
0957-4166/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.10.032

148
L. C. Dias et al. / Tetrahedron: Asymmetry 15 (2004) 147–150
significant amounts of nucleophilic attack on the oxa-
zolidinone carbonyl.
4. Experimental section
4.1. (4S)-3-[(2R,3S)-3-Hydroxy-2,4-dimethylpent-4-
enoyl]-4-benzyl-1,3-oxazolidin-2-one 614b
This problem was circumvented by the protection of the
–OH function as its TBS ether followed by the reductive
removal of the chiral auxiliary in (+)-7 with LiBH4 and
water in Et2O (recovery of the oxazolidinone auxiliary
was nearly quantitative in this reaction) to give the
primary alcohol ())-8 in 79% yield for the two-step
sequence (Scheme 1).15 Finally, a Swern oxidation
cleanly provided the anti-substituted aldehyde ())-9.16
This unpurified aldehyde was directly subjected to a
BF3ÆOEt2 promoted aldol reaction with the ketene silyl
acetal 10 to give the aldol adduct ())-11 in 75% yield and
with >95:5 diastereoselectivity (Scheme 2).17;18 This
result is readily accommodated by the merged a,b-stereo-
induction model A (Scheme 2), which predicts the
preferential formation of the Felkin/1,3-anti product
diastereomer through an aldehyde re-face attack.17 The
carbonyl facial bias of anti-substituted aldehydes are
highly predictable, since factors, which govern both 1,2-
and 1,3-asymmetric induction mutually reinforce the
nucleophilic addition to the Felkin aldehyde diastereo-
face.17 Removal of the secondary TBS protecting group
in ())-11 followed by lactonization was accomplished by
treatment of ester ())-11 with HCl/THF/H2O at rt for
48 h to give (+)-prelactone B (2) in 77% overall yield
(Scheme 2).6–10;19
Oxazolidinone (+)-5 (2.32 g, 10.0 mmol) was treated
with MgCl2 (96 mg, 1.0mmol), NaSbF 6 (780mg,
3.0mmol), triethylamine (2.80mL, 20.0mmol), meth-
acrolein (1.24 mL, 12.0mmol), and chlorotrimethyl-
silane (1.82 mL, 15.0mmol) in 20mL of ethyl acetate at
25 ꢁC for 30h. The yellow slurry was pushed through a
plug of silica gel (10cm · 10cm) with diethyl ether
(350mL). The ether solution was concentrated in vacuo,
and 20mL of methanol added along with 4 drops of
trifluoroacetic acid. This was stirred at 25 ꢁC for 30min
and then concentrated to a pale yellow oil. This oil was
purified by flash chromatography (10cm · 20cm) (10–
15% acetone in hexanes) to give 2.33 g of (+)-6 as a
22
D
colorless oil (77%). Rf 0.26 (25% EtOAc/hexane); ½aꢀ
+57.6 (c 1.46, CH2Cl2); IR (thin film) 3500, 3069, 3029,
2978, 2936, 2881, 1778, 1698, 1650, 1604, 1498, 1461,
1454, 1386, 1351, 1291, 1251, 1211, 1109, 1014, 971,
1
908 cmꢁ1; H NMR (300 MHz, CDCl3) 7.38–7.24 (m,
5H), 5.03 (br s, 1H), 4.98 (t, 1H, J 1.6 Hz), 4.71 (dddd,
1H, J 10.7, 6.8, 3.4, 3.4 Hz), 4.27–4.10 (m, 4H), 3.31 (dd,
1H, J 13.4, 3.2 Hz), 2.83 (d, 1H, J 5.9 Hz), 2.79 (dd, 1H,
J 13.6, 9.7 Hz), 1.82 (s, 3H), 1.16 (d, 3H, J 6.6 Hz); 13C
NMR (75 MHz, CDCl3) 176.4, 153.6, 144.6, 135.1,
129.4, 128.8, 127.2, 114.0, 79.2, 66.1, 55.6, 40.5, 37.9,
17.2, 14.9; HRMS calcd for C17H21NO4: 303.1471,
found: 303.1470.
4.2. (4S)-3-[(2R,3R)-2,4-Dimethyl-3-hydroxy-1-oxo-
1-pentyl]-4-phenylmethyl-2-oxazolidinone 714c
After two vacuum/H2 cycles to remove air from the
reaction flask, a stirred solution of 3.14 g (10.3 mmol) of
the anti-substituted b-hydroxyimide (+)-6 and 10% Pd/C
(25 mg) in 15 mL of MeOH, was hydrogenated at 1 atm
and room temperature for 2 h. The reaction mixture was
filtered (Celite), and the filtrate concentrated. Purifica-
tion by flash chromatography (15% EtOAc in hexane)
gave 3.04 g (10.0 mmol, 97%) of (+)-7 as a white crys-
talline solid. Rf 0.22 (25% EtOAc/hexane); mp 63–64 ꢁC;
22
½aꢀ +61 (c 0.46, CH2Cl2); IR (thin film) 3700–3500 (br),
Scheme 2.
D
3015, 2895, 2890, 1785, 1690, 1455, 1385 cmꢁ1; 1H NMR
(500 MHz, CDCl3) 7.37–7.23 (m, 5H), 4.23–4.14 (m,
3H), 4.06 (apparent quint, 1H, J 7.0Hz), 3.51 (m, 3H),
3.34 (dd, 1H, J 13.4, 3.3 Hz), 2.76 (dd, 1H, J 13.4,
9.7 Hz), 2.68 (d, 1H, J 8.5 Hz), 1.84 (m, 1H), 1.21 (d, 3H,
J 6.9 Hz), 1.01 (d, 3H, J 6.9 Hz), 0.97 (d, 3H, J 6.7 Hz);
13C NMR (125 MHz, CDCl3) 177.4, 153.7, 135.3, 129.4,
128.9, 127.8, 79.5, 66.0, 55.6, 40.4, 37.8, 30.7, 19.9, 15.7,
14.9; HRMS calcd for C17H23NO4: 305.1627, found:
305.1621.
3. Conclusions
The spectroscopic and physical data (1H and 13C NMR,
20
IR, ½aꢀ , Rf ) for 2 were identical in all respects to the
D
published data.6–10;19 The synthesis required seven steps
from oxazolidinone (+)-5 and produced the desired
product in 33% overall yield, which compared very well
with other published routes. As the anti-aldol reaction
works with high diastereoselectivities for a,b-unsatu-
rated aldehydes, this approach can be used also for the
preparation of analogues of prelactone B containing a
double bond on the side chain. As a result, the route to
(+)-prelactone B 2 presented here is, in principle, readily
applicable for the preparation of additional analogues
with potential relevance to biological studies.19
4.3. (4S)-3-[(2R,3R)-2,4-Dimethyl-3-tert-butyldimethyl-
silyloxy-1-oxo-1-pentyl]-4-phenylmethyl-2-oxazolidinone
To a solution of 2.62 g (8.61 mmol) of the b-hydroxy-
imide (+)-7 in 35 mL of THF at 0 ꢁC was added 1.12 mL

L. C. Dias et al. / Tetrahedron: Asymmetry 15 (2004) 147–150
149
(10.36 mmol) of 2,6-lutidine and 2.17 mL (9.45 mmol) of
tert-butyldimethylsilyl trifluoromethanesulfonate. After
15 min at 0 ꢁC, the reaction was quenched by the addi-
tion of 7 mL of MeOH. After an additional 5 min the
reaction was washed with 35 mL of aqueous NaHSO4
followed by 35 mL of saturated aqueous NaHCO3. The
organic layer was dried over Na2SO4 and concentrated
in vacuo yielding 3.33 g (92%) of the pure material,
which was carried on without further purification. Rf
0.46 (25% EtOAc/hexane); 1H NMR (300 MHz, CDCl3)
7.20–7.40 (m, 5H), 4.60–4.75 (m, 1H), 4.00–4.20 (m,
1H), 3.45 (dd, 1H, J 13.2 and 3.3 Hz), 2.64 (dd, 1H, J
13.2 and 10.3 Hz), 1.82 (dqq, 1H, J 7.0, 6.6, and 2.2 Hz),
1.18 (d, 3H, J 6.6 Hz), 0.98 (d, 3H, J 7.0Hz), 0.96 (d,
3H, J 6.6 Hz), 0.91 (s, 9H), 0.13 (s, 3H), 0.11 (s, 3H); 13C
NMR (75 MHz, CDCl3) 175.9, 153.5, 136.0, 129.8,
129.4, 127.7, 76.8, 66.5, 56.2, 44.4, 39.0, 31.7, 26.8, 21.3,
19.1, 17.4, 14.1, )3.2, )3.8; HRMS calcd for
C23H37NO4Si: 419.2492, found: 419.2488.
addition of 30mL of saturated aqueous NH 4Cl. The
mixture was allowed to warm to room temperature and
then diluted with 50mL of CH 2Cl2 and 50mL of satu-
rated aqueous NH4Cl. The layers were separated and
the aqueous phase extracted with two 30mL portions of
CH2Cl2. The combined organic extracts were washed
with 50mL of brine, dried over anhydrous Na 2SO4, and
concentrated in vacuo. A 1H NMR spectrum of the
unpurified aldehyde proved to be very clean. Purifica-
tion by silica gel column chromatography (50% CH2Cl2
in hexane) provided 1.17 g (4.79 mmol, 95%) of aldehyde
22
D
(thin film) 2957, 2856, 1720, 1470, 1390, 1260, 1037,
())-9 as a colorless liquid. ½aꢀ )35.1 (c 0.6, CHCl3); IR
1
835 cmꢁ1; H NMR (500 MHz, CDCl3) 9.78 (d, 1H, J
2.4 Hz), 3.67 (dd, 1H, J 5.0and 4.0Hz), 2.52 (m, 1H),
1.84 (m, 1H), 1.11 (d, 3H, J 7.0Hz), 0.92 (d, 3H, J
6.7 Hz), 0.90 (d, 3H, J 6.9 Hz), 0.89 (s, 9H), 0.07 (s, 3H),
0.06 (s, 3H); 13C NMR (125 MHz, CDCl3) 204.9, 79.1,
49.9, 32.8, 25.9, 18.8, 18.3, 12.1, )4.1, )4.3. This mate-
rial proved to be very unstable for obtaining a high
resolution mass spectral analysis.
4.4. (2S,3R)-2,4-Dimethyl-3-[(tert-butyldimethylsilyl)-
oxy]pentan-1-ol 86;14d
4.6. tert-Butyl (3R,4S,5R)-5-[(tert-butyldimethylsilyl)-
oxy]-3-hydroxy-4,6-dimethylheptanoate 116
To a solution of 2.70g (6.43 mmol) of the anti-TBS
protected b-hydroxyimide and 0.13 mL (7.06 mmol) of
H2O in 75 mL of Et2O at 0 ꢁC was slowly added 3.6 mL
(7.2 mmol) of a 2.0M solution of LiBH 4 in THF (gas
evolution). After stirring for 1 h at 0 ꢁC, the reaction was
quenched by the addition of 45 mL of 1.0M aqueous
sodium potassium tartrate and stirred for an additional
20min. The mixture was then diluted with 100mL of
CH2Cl2 and 50mL of 1.0M aqueous sodium potassium
tartrate. The layers were separated and the aqueous
layer extracted with two 50mL portions of CH 2Cl2. The
combined organic extracts were washed with 100 mL of
brine, dried over anhydrous Na2SO4, and concentrated
in vacuo to produce a residue, which was purified by
silica gel column chromatography (15% EtOAc/hexane)
Boron trifluoride etherate (0.24 mL, 1.95 mmol) was
added dropwise to a solution of 1.21 g of the enolsilane
10 (6.0mmol) and the aldehyde ( ))-9 (0.48 g, 1.95 mmol)
in 50mL of CH 2Cl2 at )78 ꢁC. The reaction was stirred
for 1 h, quenched at )78 ꢁC via the addition of 50mL of
saturated aqueous NaHCO3, and then warmed to
ambient temperature. The mixture was diluted with
50mL of CH 2Cl2 and washed with 25 mL of saturated
aqueous NaHCO3. The aqueous washing was extracted
once with 25 mL of CH2Cl2. The combined organic
layers were dried over anhydrous Na2SO4, concentrated
in vacuo, and purified by chromatography to give 0.52 g
22
of ester ())-11 (1.46 mmol, 75% yield). ½aꢀ )5.1 (c 0.7,
D
CHCl3); Rf 0.35 (10% EtOAc/hexane); 1H NMR
(500 MHz, CDCl3) 4.50(m, 1H), 3.50(m, 1H), 2.49 (dd,
1H, J 15.4, 8.1 Hz), 2.27 (dd, 1H, J 15.4, 5.9 Hz), 1.95
to give 1.37 g (86%) of alcohol ())-8 as a colorless oil.
22
D
½aꢀ )7.8 (c 0.9, CH2Cl2); Rf 0.46 (25% EtOAc/hexane);
1H NMR (300 MHz, CDCl3) 3.69 (ddd, 1H, J 10.9, 6.0,
and 4.4 Hz), 3.59 (ddd, 1H, J 10.9, 5.8, and 5.5 Hz), 3.44
(dd, 1H, J 5.1 and 4.8 Hz), 2.65 (dd, 1H, J 6.0and
5.5 Hz), 1.80–2.00 (m, 2H), 0.99 (d, 3H, J 7.0Hz), 0.95
(d, 1H, J 6.6 Hz), 0.94 (s, 9H), 0.93 (d, 3H, J 7.0Hz),
0.13 (s, 3H), 0.10 (s, 3H); 13C NMR (125 MHz, CDCl3)
82.9, 66.6, 37.5, 33.7, 26.7, 19.6, 19.1, 18.9, 17.2, )3.3;
HRMS calcd for C13H30O2Si: 246.2015, found:
246.1997.
(m, 1H), 1.70(m, 1H), 1.46 (s, 9H), .099 (d, 3H,
J
7.0Hz), 0.95 (d, 3H, J 7.0Hz), 0.93 (d, 3H, J 6.6 Hz),
0.92 (s, 9H), 0.13 (s, 3H), 0.10 (s, 3H); 13C NMR
(125 MHz, CDCl3) 171.4, 105.2, 82.7, 80.6, 67.5, 41.3,
38.3, 32.2, 28.2, 26.3, 19.9, 18.9, 18.5, 11.9, )3.5, )3.6;
HRMS calcd for C19H40O4Si: 360.2696, found:
360.2689.
4.7. (+)-Prelactone B, (3R,4S,5R)-3-hydroxy-4,6-
dimethyl-heptanoic acid-d-lactone 26–10
4.5. (2R,3R)-2,4-Dimethyl-3-[(tert-butyldimethylsilyl)-
oxy]pentanal 917a
To a solution of ester 11 (0.50 g, 1.38 mmol) in 10 mL of
THF was added 2 mL of water. To the resulting solution
was added dropwise 1 mL of concentrated HCl after
which the mixture was stirred at rt for 48 h. The reaction
mixture was then concentrated in vacuo, and purified by
silica gel column chromatography (EtOAc/hexanes, 1:1)
to give 0.182 g (1.06 mmol, 77%) of (+)-prelactone B as a
To a solution of 0.69 mL (7.74 mmol) of oxalylchloride
in 30mL of CH 2Cl2 at )78 ꢁC was added 1.14 mL
(15.66 mmol) of DMSO (gas evolution). After 10min, a
solution of 1.24 g (5.04 mmol) of the alcohol 8 in 20mL
of CH2Cl2 was added. The cloudy white mixture was
stirred for 15 min after which 3.9 mL (26.2 mmol) of
triethylamine was added. The reaction mixture was
stirred at )78 ꢁC for 40min and then quenched by the
white solid. Rf 0.11 (50% EtOAc/hexane); mp 97–98 ꢁC;
22
½aꢀ +39.1 (c 0.6, MeOH); IR (Nujol) 3466, 2360, 2341,
D

150
L. C. Dias et al. / Tetrahedron: Asymmetry 15 (2004) 147–150
1
1722, 998 cmꢁ1; H NMR (500 MHz, CDCl3) 3.75 (m,
2H), 2.90(dd, 1H, J 17.2, 5.8 Hz), 2.60(br s, 1H), 2.46
(dd, 1H, J 17.2, 7.9 Hz), 1.97 (dsept, 1H, J 6.9, 2.1 Hz),
1.73 (ddq, 1H, J 10.4, 8.2, 6.7 Hz), 1.07 (d, 3H, J
6.8 Hz), 1.05 (d, 3H, J 6.7 Hz), 0.91 (d, 3H, J 6.8 Hz);
13C NMR (125 MHz, CDCl3) 171.2, 86.2, 69.8, 39.0,
38.9, 28.9, 20.0, 14.0, 13.6; HRMS calcd for C9H16O3:
172.1099, found: 172.1107.
Chakraborty, T. K.; Tapadar, S. Tetrahedron Lett. 2003,
44, 2541.
10. As this work was about to be submitted, a very short
synthesis of ())-prelactone B appeared: Pihko, P. M.;
€
Erkkila, A. Tetrahedron Lett. 2003, 44, 7607.
11. Yamashita, Y.; Saito, S.; Ishitani, H.; Kobayashi, S. J. Am.
Chem. Soc. 2003, 125, 3793.
12. (a) Dias, L. C.; de Oliveira, L. G.; de Sousa, M. A. Org.
Lett. 2003, 5, 265; (b) Dias, L. C.; de Oliveira, L. G. Org.
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15. Treatment of aldol adduct (+)-7 with LiBH4, MeOH in
THF led to epimerization of the aldol adduct, with a
mixture of both syn and anti diols being obtained.
16. Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
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Acknowledgements
We are grateful to FAEP-UNICAMP, FAPESP, and
CNPq (Brazil) for financial support. We also thank
Prof. Carol H. Collins, from IQ-UNICAMP, for helpful
suggestions about English grammar and style.
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18. The diastereomeric ratio for compound ())-11 was deter-
mined by 1H (500 MHz) and 13C NMR (125 MHz)
spectroscopic analysis of the crude product mixture.
19. After submission of this manuscript, two other syntheses
7. Chakraborty, T. K.; Tapadar, S. Tetrahedron Lett. 2001,
42, 1375.
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ꢀ €
of prelactone B appeared: (a) Csaky, A. G.; Mba, M.;
9. (a) Fournier, L.; Gaudel-Siri, A.; Kocienski, P. J.; Pons, J.
M. Synlett 2003, 107; (b) Fournier, L.; Gaudel-Siri, A.;
Kocienski, P. J.; Pons, J. M. Synlett 2003, 584; (c)
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