An expeditious enantioselective total synthesis of valilactone

Article abstract of DOI:10.1021/jo060844m

The title compound was synthesized through an expeditious route using Crimmins aldolization to establish the two key stereogenic centers and a hydroxyl group activation (HGA) protocol to construct the anti α,β-disubstituted β-lactone from the corresponding syn aldol.

Full text of DOI:10.1021/jo060844m

An Expeditious Enantioselective Total Synthesis of Valilactone
Yikang Wu* and Ya-Ping Sun
State Key Laboratory of Bio-organic & Natural Products Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
yikangwu@mail.sioc.ac.cn
ReceiVed April 21, 2006
The title compound was synthesized through an expeditious route using Crimmins aldolization to establish
the two key stereogenic centers and a hydroxyl group activation (HGA) protocol to construct the anti
R,â-disubstituted â-lactone from the corresponding syn aldol.
Introduction
Obesity, which is always associated with increased risk of
hypertension and heart disease,1 is now broadly recognized as
a new global health problem.2 One of the so far established
means to fight obesity is to inhibit pancreas lipase, an enzyme
responsible for absorption of fat. Many naturally occurring
â-lactones possess potent lipase inhibition activity, among them
lipstatin after saturation of the carbon-carbon double bonds
by hydrogenation has already been successfully developed into
a drug (tetrahydrolipstatin 1, marketed under the name of Orlistat
or Xenical. For the structures, see Figure 1).
Valilactone (2) was isolated from the MG 147-CF2 strain of
Streptomyces by Kitahara and co-workers in 1987,3 with a
structure closely related to that of 1. Although to most
researchers it is usually only known as a potent esterase
inhibitor, valilactone in fact was also tested on pancreas lipase.
The IC50 value for lipase inhibition was reported to be 0.00014
µg/mL (0.35 nM)sabout 3 orders of magnitude lower than that4
of 1 (IC50 ) 0.36 µM)! However, the striking lipase inhibition
activity of 2 was somehow completely ignored by the scientific
community. While numerous studies5 of 1 were performed since
the 1980s, only one investgation on valilactone was documented
in the literature.6
FIGURE 1. The structures of tetrahydrolipstatin and valilactone.
the outstanding biological activity of valilactone, we believe
that valilactone deserves further studies. Here in this article we
wish to report an expedient enantioselective total synthesis of
natural valilactone, which exploited a lactonization through
(5) See the following for example: (a) Bodkin, J. A.; Humphries, E. J.;
McLeod, M. D. Tetrahedron Lett. 2003, 44, 2869-2872. (b) Ghosh, A.
K.; Fidanze, S. Org. Lett. 2000, 2, 2405-2407. (c) Parson, P. J.; Cowell,
J. K. Synlett 2000, 107-109. (d) Dirat, O.; Kouklovsky, C.; Langlois, Y.
Org. Lett. 1999, 1, 753-755. (e) Ghosh, A. K.; Liu, C. Chem. Commun.
1999, 1743-1744. (f) Paterson, I.; Doughty, V. A. Tetrahedron Lett. 1999,
40, 393-394 (g) Giese, B.; Roth, M. J. Braz. Chem. Soc. 1996, 7, 243-
246. (h) Hanessian, S.; Tehim, A.; Chen, P. J. Org. Chem. 1993, 58, 7768-
7781. (i) Fleming, I.; Lawrence, N. J. J. Chem. Soc., Perkin Trans. 1 1998,
2670-2686. (j) Pons, J.-M.; Pommier, A.; Lerpiniere, J.; Kocienski, P. J.
Chem. Soc., Perkin Trans. 1 1993, 1549-1551. (k) Chadha, N. K.; Tang,
P. C.; Courtney, L. F.; Cook, C. M.; Wovkulich, P. M.; Uskokovic, M. R.
J. Org. Chem. 1991, 56, 4714-4718. (l) Fleming, I.; Lawrence, N. J.
Tetrahedron Lett. 1990, 31, 3645-3648. (m) Barbier, P.; Schneider, F. J.
Org. Chem. 1988, 53, 1218-1221. (n) Barbier, P.; Schneider, F.; Widmer,
U. HelV. Chim. Acta 1987, 70, 1412-1418. For a closely related compound
panclicin, see the following: (o) Yang, H.-W.; Zhao, C.; Romo, D.
Tetrahedron 1997, 53, 16471-16488. See also a simplified analogue: (p)
Cardani, S.; De Toma, C.; Gennari, C.; Scolastico, C. Tetrahedron 1992,
48, 5557-5564. (q) Thadani, A. N.; Batey, R. A. Tetrahedron Lett. 2003,
44, 8051-8055. (r) Pommier, A.; Pons, J.-M. Synthesis 1991, 1294-1300.
(s) Polkowska, J.; Lukaszewicz, E.; Kiegiel, J.; Jurczak, J. Tetrahedron
Lett. 2004, 45, 3873-3875.
It is not clear why this happened. However, judging from
the importance of developing new potent antiobesity agents and
(1) Mark, A. L.; Correia, M. L.; Rahmouni, K.; Haynes, W. G. Clin.
Exp. Hypertens. 2004, 26, 629-636.
(2) Scaglione, R.; Argano, C.; Di Chiara, T.; Licata, G. Expert ReV.
CardioVasc. Ther. 2004, 2, 203-212.
(3) Kitahara, M.; Asano, M.; Naganawa, H.; Maeda, K.; Hamada, M.;
Aoyagi, T.; Umezawa, H.; Iitaka, Y.; Nakamura, H. J. Antibiot. 1987, 40,
1647-1650.
(6) (a) Bate, R. W.; Fernandez-Moro, R.; Ley, S. V. Tetrahedron Lett.
1991, 32, 2651-2654. (b) Bate, R. W.; Fernandez-Moro, R.; Ley, S. V.
Tetrahedron 1991, 47, 9929-9938.
(4) Weibel, E. K.; Hadvary, P.; Hochuli, E.; Kupfer, E.; Lengsfeld, H.
J. Antibiot. 1987, 40, 1081-1085.
10.1021/jo060844m CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/28/2006
5748
J. Org. Chem. 2006, 71, 5748-5751

Total Synthesis of Valilactone
SCHEME 1
FIGURE 2. Retrosynthetic analyses of formation of the â-lactone ring,
which may be constructed from either the “anti aldols” through
carboxylic group activation (CGA) or the “syn aldols” through hydroxyl
group activation (HGA).
hydroxyl group activation (HGA7) with readily accessible
enantiopure syn aldol as the precursor.
Results and Discussion
Essentially all the bio-active â-lactones so far known are R,â-
disubstitued, with the two substituents on the 2-oxetanone ring
trans to each other. The bioactivity of these compounds is
dependent critically not only on the presence of an intact
â-lactone ring but also on the absolute configurations of the
stereogenic centers on the lactone ring. Therefore, construction
of the trans disubstitued â-lactone moiety is one of the key issues
in the synthesis of these compounds.
In principle, trans â-lactones can be derived from either anti
aldols through carboxylic group activation7 (CGA) or from syn
aldols through HGA (cf. Figure 2). In practice, however, HGA
is much less common than CGA, although syn aldols are readily
attainable in enantiopure forms via, for instance, Evans8 or
Crimmins9 aldolization.
From the outset of this work we planned to make use of
enantiopure syn aldols as the chirality source of the stereogenic
centers of the â-lactone moiety. As shown in Scheme 1, the
synthesis started with a TiCl4-mediated asymmetric aldol
condensation9 between 3 and 4,10 which afforded the syn aldol
5 as the only detectable product in 78% yield (along with 16%
of recovered starting 3). The chiral auxiliary11a in 5 was then
nondestructively removed11b-c with concurrent protection of the
carboxylic group as a benzyl ester. The resulting 6 was treated
with I2 in the presence12 of NaHCO3 to give ketone 7 in 87%
yield.
than -40 °C, but the diasteoemeric selectivity (22:1) was the
same as that obtained at -40 °C in Ghosh’s5b synthesis of 1.
The diastereomers were separated on silica gel, and the remote
hydroxyl group (δ to the carbonyl group) in 8 was then
selectively protected5b with TIPSOTf ((i-Pr)3SiOSO2CF3) at 0
°C, leaving the â OH as the only open site for further
transformation.
The key â-lactone functionality was constructed through a
three step sequence, which was first introduced by Lenz14a in
the synthesis of 4-methyl-oxetan-2-one (a much less hindered
â-lactone with no substituent on the R-carbon and only one small
methyl group on the â-carbon): (1) converting the hydroxyl
group into a good leaving group by treatment with MsCl/NEt3,
(2) cleaving the benzyl group by hydrogenolysis under neutral
conditions to release a free carboxylic group without affecting
the liable â-OMs functionality, and (3) treating the newly
generated carboxylic acid with a base to initiate an intramo-
lecular SN2 reaction, yielding a â-lactone ring with concurrent
configuration inversion at the â carbon. It should be noted that
in sharp contrast to the facile conversions observed in the
successful literature cases,14,15 the ring-closure of the R,â-dialkyl
substituted substrates was often very tricky when the substituents
Generation of the 1,3-anti diol motif and the subsequent
selective protection of the remote hydroxyl group were done in
a manner similar to that in Ghosh’s5b synthesis of 1. The
substrate chirality induced asymmetric reduction with Me4NBH-
(OAc)313 was performed at -15 °C, which was more convenient
(7) Mulzer, J.; Bruntrup, G.; Chucholowski, A., Angew. Chem., Int. Ed.
Engl. 1979, 18, 622-623.
(8) (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
103, 2127-2129. (b) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi,
F. J. Am. Chem. Soc. 1990, 113, 1047-1049.
(9) (a) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc.
1997, 119, 7883-7884. (b) Crimmins, M. T.; Chaudhary, K. Org. Lett.
2000, 2, 775-777. (c) Crimmins, M. T.; King, B. W.; Tabet, E. A.;
Chaudhary, K. J. Org. Chem. 2001, 66, 894-902.
(10) Woessner, W. D.; Ellison, R. A. Tetrahedron Lett. 1972, 3735-
3738.
(11) (a) For a very convenient procedure for synthesizing such auxiliaries,
see Wu, Y.-K.; Yang, Y.-Q.; Hu, Q. J. Org. Chem. 2004, 69, 3990-3992.
(b) Wu, Y.-K.; Sun, Y.-P.; Yang, Y.-Q.; Hu, Q.; Zhang, Q. J. Org. Chem.
2004, 69, 6141-6144. (c) Su, D.-W.; Wang, Y.-C.; Yan, T.-H. Tetrahedron
Lett. 1999, 40, 4197-4198.
(12) Nicolaou, K. C.; Bunnage, M. E.; McGarry, D. G.; Shi, S.; Somers,
P. K.; Wallace, P. A.; Chu, X.-J.; Agrios, K. A.; Gunzner, J. L.; Yang, Z.
Chem.sEur. J. 1999, 5, 599-617.
(13) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560-3578.
(14) (a) Zhang, Y.; Gross, R. A.; Lenz, R. W. Macromolecules 1990,
23, 3206-3212. (b) De Angilis, F.; De Fusco, E.; Desiderio, P.; Giannessi,
F.; Pibrizio, F.; Tinti, M. O. Eur. J. Org. Chem. 1999, 2705-2707. (c)
Bernabei, I.; Castagnani, R.; De Angelis, F.; De Fusco, E.; Giannessi, F.;
Misiti, D.; Muck, S.; Scafetta, N.; Tinti, M. O. Chem.sEur. J. 1996, 2,
826-831. (d) Sato, T.; Kawara, T.; Nishizawa, A.; Fujisawa, T. Tetrahedron
Lett. 1980, 21, 3377-3380. See also another related case with inversion at
the â position: (e) Griesbeck, A.; Seebach, D. HelV. Chim. Acta 1987, 70,
1320-1325.
(15) Wu, Y.-K.; Sun, Y.-P. Chem. Commun. 2005, 1906-1908.
J. Org. Chem, Vol. 71, No. 15, 2006 5749

Wu and Sun
SCHEME 2
SCHEME 3
TABLE 1. Representative Results of the Lactonization Exploiting
the â-Leaving/Inversion Protocol (cf. Scheme 2)a
entry substituent
R/R′
conditions
resultsb
Removal of the protecting group R′ (which was expected to
reduce the bulkiness of the chain) did not lead to any descernible
improvement (entries 8 and 9). On the contrary, it facilitated
generation of the undesired product 14. It seemed that the
functionality on the substituent might also have an influence
on the reaction path (path a or b, Scheme 2), at least to some
extent.
After numerous failures we were pleased to find that
powdered K2CO3 in dry THF could revert the product ratio,
yielding the anticipated lactone 13 as the main product (entry
10). This gratifying result allowed us to resume the synthesis
along the initially designed route after the long halt.
Cleavage of the TIPS protecting group was first attempted
with the classic Bu4NF in THF. The product was a rather
complicated mixture. Addition of some AcOH to the reaction
system as Ghosh et al.5b did in their synthesis of 1 led to 15 as
the only product. However, the reaction could not go to
completion. Some starting 13a always remained. Then we tried
HF‚Py. The initial runs were performed in commercially
available THF. The best yield we obtained was around 80%.
Later, by chance we attempted dry THF as the reaction solvent
and found that the yield of the desilylation could be raised to
92% (Scheme 3).
1
2
11
Ms/TIPS DBU/THF/15 °C/1 h
A
B
B
B
B
B
C
A
D
E
12a
12a
12a
12a
12a
12a
12b
12c
11
Ts/Bn
Ts/Bn
Ts/Bn
Ts/Bn
Ts/Bn
Ts/Bn
Ts/H
NaOH/DMSO/14 °C/1.5 hc
Cs2CO3/Et2O-H2O/0 °C/18 h
Cs2CO3/THF/0 °C/4 h
NaOHd/THF/10 °C/5 h
NaHCO3/MeOH/0 °C/2 h
DBU/THF/15 °C /8 h
3
4
5
6
7
8
DBU/THF/0 °C/1 h
DBU/THF/0 °C/0.16 h
9
Ms/H
10
Ms/TIPS K2CO3/THF/19 °C/12 h
a The reactions were run by mixing the reactants at a lower temperature
than those listed in the table and then by stirring at the stated temperature
(the ambient temperature) for the stated time. b (A) The product mixture
contained mainly 14a and traces of the starting acid. (B) The product mixture
contained mainly the unreacted starting acid and a small amount of 14b.
(C) All starting acid was consumed, yielding a ca. 33:67 mixture of 13b/
14c. (D) All the starting 12c was converted into 14c. (E) 13a and 14a were
isolated in 71% and 25% yield, respectively. c Containging about 30% (v/
v) of H2O. d In the presence of 1 M equiv (with respect to NaOH) of 18-
crown-6.
were not small simple alkyl groups. In the synthesis of nocar-
diolactone,16 a compound with two very long alkyl chain on
the lactone ring, we already noticed that the existing protocols
(Na2CO3 or NaHCO3 in a H2O-Et2O or H2O-CHCl3 biphasic
medium) was applicable to only very simple/nonhindered sub-
strates and developed a DBU-based procedure. In this work,
we encountered similar difficulty again in the lactonization. It
appeared that lactonization via HGA in general was far not “a
solved problem” as those elegant literature examples seemingly
implied.14 The undesired product in most runs was the decar-
boxylation-elimination16 compound alkene 14 (Scheme 2),
which shared a common carboxylate intermediate with the
lactone 13.
Using the â-mesyloxy acid 11 or the closely related analogues
12a-c, we tested a range of conditions. Some representative
results are listed in Table 1. From these data it can be seen that
the undesired decarboxylation-elimination product 14 was often
easier to form than 13 (entries 1-6). Such products were not
reported in those literature14 cases, suggesting that changes in,
for instance, the size of the substituents and the substitution
pattern (â-monosubstituted or R,â-disubstituted) may signifi-
cantly vary the predominating reaction path.
At this point the only remaining task was to connect an (S)-
N-formylvaline moiety to the hydroxyl group in compound 15.
In the previous synthesis6 by Ley and co-workers, such a
transformation was achieved in three steps. To improve the
overall efficiency of the synthesis, in this work we tried to avoid
use of any protecting group on the amino group so that the task
could be fulfilled in one step. After many tries, we finally
succeeded in directly combining the known (S)-N-formylvaline17
(16) with 15 in the presence of DCC/DMAP,18 affording the
end product valilactone 2 in 88% yield. The physical and
spectroscopic data of 2 synthesized in this work were in good
1
consistence19 with those reported by Ley,6b and the H NMR
spectrum looked essentially the same as that3 published by
Kitahara.
In summary we have completed an expeditious enantiose-
lective total synthesis of natural valilactone, a potent lipase
inhibitor. Two of the three stereogenic centers in the target
molecule were initially constructed through chiral auxiliary
induced asymmetric aldolization under the conditions of Crim-
mins. The third stereogenic center was established via a substrate
It is interesting to note that even the best set of conditions
(DBU/THF) developed in our synthesis of nocardiolactone failed
to give satisfactory results here, although the expected lactone
did form in low yield (entry 7).
(17) Muramatsu, I.; Murakami, M.; Yoneda, T.; Hagitani, A. Bull. Chem.
Soc. Jpn. 1965, 38, 244-246.
(18) Sakiyama, F.; Witkop, B. J. Org. Chem. 1965, 30, 1905-1907.
(16) (a) Sun, Y.-P.; Wu, Y.-K. Synlett 2005, 1477-1479. (b) Sun, Y.-
P.; Wu, Y.-K. Synlett 2006, 1132 (erratum).
5750 J. Org. Chem., Vol. 71, No. 15, 2006

Total Synthesis of Valilactone
Lactonization of 11 (Leading to 13a and 14a). A mixture of
11 (60 mg, 0.115 mmol) and powdered K2CO3 (21 mg, 0.15 mmol)
in dry THF (12 mL) was stirred at the ambient temperature (ca. 19
ïC) for 12 h. The reaction mixture was then diluted with diethyl
ether (50 mL), washed with water and brine (10 mL each), and
dried over Na2SO4. After removal of the solvent, the residue was
chromatographed on silica gel (12:1 n-hexane/Et2O) to give 13a
as a colorless oil (35 mg, 0.083 mmol, 71% yield) along with alkene
14a (12 mg, 0.031 mmol, 25% yield). Data for 13a: [R]21D -20.9°
(c 1.05, CHCl3). 1H NMR (300 MHz, CDCl3): δ 4.48 (dt, J ) 4.1,
6.3 Hz, 1H), 4.16-3.92 (m, 1H), 3.26 (dt, J ) 4.1, 7.5 Hz, 1H),
2.09-1.94 (m, 2H), 1.82-1.71 (m, 2H), 1.58-1.11 (m, 16H),
1.10-0.99 (m, 21H), 0.88 (br t, J ) 5.8 Hz, 6H). FT-IR (film):
2931, 2866, 1826, 1464, 1381, 1122, 882 cm-1. EI-MS m/z (%):
383 (4.0), 339 (19.7), 335 (31.3), 283 (29.3), 257 (62.6), 215
(100.0), 131 (33.5), 103 (25.9), 75 (36.5), 57 (77.0), 43 (27.3). ESI-
chirality induced asymmetric reduction. The syn aldol derived
from aldolization was eventually transformed into a trans R,â-
disubstituted â-lactone via a hydroxyl group activation. Because
of the predeterminable absolute configuration of the newly
formed chiral centers, broad functional compatibility and low
cost of the auxiliary/reagents (TiCl4/TMEDA), syn aldols are
chiral building blocks of great potential in both laboratory and
industry. However, up to now direct use of syn aldols in the
synthesis of the anti â-lactones represented by valilactone and
tetrahydrolipstatin has been impossible because of the lack of
a feasible HGA protocol. The present work illustrates the first
successful HGA-based approach to synthesis of this class of
lipase inhibiting â-lactones and may provide a solid basis for
further exploration on lactonization through HGA.
HRMS: calcd for C25H51O3Si ([M + H]+), 427.3602; found,
Experimental Section
1
427.3617. Data for 14a: [R]25 -6.5° (c 0.45, CHCl3). H NMR
D
Synthesis of Compound 5. TiCl4 (0.44 mL, 3.99 mmol) was
added dropwise to a solution of 3 (1.061 g, 3.32 mmol) in dry
CH2Cl2 (16 mL) stirred at 0 ïC under N2. After 10 min, dry TMEDA
(1.65 mL, 8.3 mmol) was added dropwise. The dark solution was
(300 MHz, CDCl3): δ 5.44-5.40 (m, 2H), 3.85-3.75 (m, 1H),
2.27-2.17 (m, 2H), 2.10-1.93 (m, 2H), 1.57-1.19 (m, 19H), 1.06
(s, 18H), 0.88 (t, J ) 6.6 Hz, 6H). FT-IR (film): 2927, 2866, 1464,
1106, 883, 677 cm-1. EI-MS m/z: 381 (0.58), 339 (84.8), 297 (25.4),
257 (66.1), 215 (42.0), 131 (100), 103 (65.7), 75 (66.4), 43 (48.4).
Anal. Calcd for C24H50OSi: C, 75.31; H, 13.17. Found: C, 75.41;
H, 13.22.
ï
then stirred at 0 C for 0.5 h before the aldehyde 4 (1.540 g, 6.64
mmol) was introduced dropwise. Stirring was continued at the same
temperature for 2 h. Aqueous NH4Cl (30 mL) was introduced,
followed by diethyl ether (300 mL). The phases were separated,
and the organic phase was washed in turn with aqueous NH4Cl
(50 mL × 2) and water and dried over Na2SO4. Removal of the
solvents and the drying agent left an oily residue, which was
chromatographed (9:1 to 3:1 n-hexane/EtOAc) on silica gel to give
Synthesis of Valilactone (2). A mixture of N-formal-L-valine
(28 mg, 0.19 mmol), DCC (39 mg, 0.19 mmol), and DMAP (3
mg, 0.025 mmol) in dry CH2Cl2 (0.5 mL) was stirred at the ambient
temperature for 10 min before a solution of 15 (34 mg, 0.126 mmol)
in dry CH2Cl2 (0.5 mL) was introduced dropwise. The mixture was
then stirred at the ambient temperature for 21 h before being diluted
with diethyl ether, washed with water and brine, and dried over
Na2SO4. After removal of the solvent, the residue was chromato-
graphed on silica gel (1:1 n-hexane/EtOAc) to give 2 as a white
solid (44 mg, 0.111 mmol, 88% yield). Mp: 55-56 °C (lit.6b 55-
56 °C). [R]21D -33.7° (c 0.12, CHCl3) (lit.6b [R]23D -33.6° (c 0.7,
CHCl3)). 1H NMR (300 MHz, CDCl3):20 δ 8.27 (s, 1H), 6.05 (d, J
) 8.7 Hz, 1H), 5.06-4.98 (m, 1H), 4.63 (dd, J ) 4.8, 8.7 Hz,
1H), 4.29 (dt, J ) 4.3, 8.6 Hz, 1H), 3.22 (dt, J ) 4.1, 7.8 Hz, 1H),
2.30-2.10 (m, 2H), 2.04-1.96 (m, 1H), 1.84-1.50 (m, 4H), 1.42-
1.20 (m, 14H), 0.99 (d, J ) 7.0 Hz, 3H), 0.90 (d, J ) 6.9 Hz, 3H),
0.90-0.85 (m, 6H). FT-IR (film) 3330, 2958, 2926, 2857, 1821,
1736, 1686, 1459, 1193, 1122, 1012 cm-1. ESI-MS m/z: 398.3
([M + H]+). ESI-HRMS: calcd for C22H39NO5Na ([M + Na]+),
420.2720; found, 420.2719.
5 as a pale yellow sticky oil (1.422 g, 78%): [R]24 +31.3° (c
D
1.05, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.38-7.23 (m, 5H),
5.14 (dt, J ) 4.4, 7.0 Hz, 1H), 4.99 (ddd, J ) 3.6, 6.5, 9.9 Hz,
1H), 4.33-4.29 (m, 3H), 3.58 (s, 1H), 3.31 (dd, J ) 3.0, 13.2 Hz,
1H), 3.07-2.92 (m, 2H), 2.78-2.70 (m, 3H), 2.45 (dd, J ) 9.3,
15.1 Hz, 1H), 2.07-1.86 (m, 5H), 1.73-1.31 (m, 16H), 0.91 (t, J
) 7.4 Hz, 3H), 0.88 (t, J ) 7.2 Hz, 3H). FT-IR (film): 3439, 2928,
2857, 1694, 1455, 1365, 1320, 1193, 702 cm-1. ESI-MS m/z: 574.0
([M + Na]+). ESI-HRMS: calcd for C29H45NO3S3Na ([M +
Na]+), 574.2454; found, 574.2457.
Synthesis of Compound 8. Me4NBH(OAc)3 (386 mg, 1.47
mmol) was added to dry CH3CN (0.9 mL) and glacial acetic acid
(0.9 mL). The mixture was stirred at the ambient temperature for
0.5 h to give a solution. The solution was cooled to -15 °C and a
solution of 7 (69 mg, 0.184 mmol) in dry CH3CN (0.9 mL) was
added dropwise. The mixture was stirred at -15 °C until TLC
showed disappearance of the starting material (ca. 3 h). To the
reaction mixture were added 0.5 N potassium sodium tartrate (3
mL) and diethyl ether (200 mL), followed by solid Na2CO3 (1.67
g, 15.75 mmol). The phases were separated, and the aqueous phase
was back extracted with diethyl ether (30 mL × 4) after being
adjusted to pH 8 with NaHCO3. The combined organic phases were
washed with water and brine and dried over Na2SO4. The solvent
was removed by rotary evaporation, and the residue was chromato-
graphed on silica gel (2:1 n-hexane/EtOAc) to give 8 as a colorless
Acknowledgment. This work has been supported by the
National Natural Science Foundation of China (Grants 20025207,
20272071, 20372075, and 20321202), the Chinese Academy
of Sciences (“Knowledge Innovation” project, Grant KGCX2-
SW-209), and the Major State Basic Research Development
Program (Grant G2000077502).
Supporting Information Available: General remarks on Ex-
perimental Section, procedures for synthesis of 3, 6, 7, 9-11, 15,
1
oil (67 mg, 97% yield): [R]26 -1.7° (c 1.20, CHCl3). H NMR
(300 MHz, CDCl3): δ 7.37-D7.26 (m, 5H), 5.15 (s, 2H), 4.20-
3.98 (m, 1H), 3.95-3.83 (m, 1H), 3.16 (d, J ) 4.7 Hz, 1H), 2.53
(q, J ) 6.8 Hz, 1H), 2.11 (s, 1H), 1.72-1.57 (m, 4H), 1.51-1.24
(m, 16H), 0.86 (t, J ) 7.1 Hz, 6H). FT-IR (film): 3402, 2926,
2857, 1732, 1456, 1379, 1160, 697 cm-1. ESI-MS m/z: 379.1 ([M
+ H]+). ESI-HRMS: calcd for C23H38O4Na ([M + Na]+),
401.2662; found, 401.2666.
1
1
and H NMR spectra of 3, 5, 7-11, 13a, 2, and the H NMR
spectrum (copied from the literature for comparison) of natural
valilactone in pdf format. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO060844M
(20) It perhaps should be mentioned that in the 1H NMR spectrum of
both natural valilactone (ref 3) and the 2 synthesized in this work there
existed some weak signals at around δ 8.01 and 3.92 (conformational
isomer?), which are not included in data listing because their integrals are
too small. These signals did not change after repeated chromatographic
purification. They were not listed in the ref 6b but presumably also existed
because the authors claimed their valilactone was identical in all aspects to
Kitahara’s.
(19) There was a typographical error in the 1H NMR data in ref 6b: the
signal at δ 3.22 (1H, dt, 8.0, 4.1 Hz, H-2) should be 3.22 (1H, dt, 4.1, 8.0
Hz, H-2), because the smaller J value stemmed from the coupling between
H-2 and H-3 (the two protons at the â-lactone ring), which is around 4 Hz
when the two protons are trans to each other. Otherwise our data for 2
agreed well with those in ref 6b.
J. Org. Chem, Vol. 71, No. 15, 2006 5751