Palladium-catalyzed intramolecular allylic alkylation reaction in marine natural product synthesis: Enantioselective synthesis of (+)-methyl pederate, a key intermediate in syntheses of mycalamides

Article abstract of DOI:10.1021/jo9805246

A novel preparation of (+)-methyl pederate (4), a key intermediate in syntheses of mycalamides (1), marine natural products from a New Zeland sponge of the genus Mycale, is described. The key step involves palladium- catalyzed intramolecular allylic alkylation of the carbonate 21, derived from (+)-(4R,5R,E)-5-(tert-butyldimethylsiloxy)-4-methyl-2-hexenol (13), yielding lactones 5 in 87% yield. Demethoxycarbonylation of the cyclization products 5 and further functional group transformations led to (+)-methyl pederate (4).

Full text of DOI:10.1021/jo9805246

J . Org. Chem. 1998, 63, 5895-5902
5895
P a lla d iu m -Ca ta lyzed In tr a m olecu la r Allylic Alk yla tion Rea ction in
Ma r in e Na tu r a l P r od u ct Syn th esis: En a n tioselective Syn th esis of
(+)-Meth yl P ed er a te, a Key In ter m ed ia te in Syn th eses of
Myca la m id es
Masahiro Toyota,* Masako Hirota, Youichi Nishikawa, Keiichiro Fukumoto, and
Masataka Ihara*
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, J apan
Received March 19, 1998
A novel preparation of (+)-methyl pederate (4), a key intermediate in syntheses of mycalamides
(1), marine natural products from a New Zealand sponge of the genus Mycale, is described. The
key step involves palladium-catalyzed intramolecular allylic alkylation of the carbonate 21, derived
from (+)-(4R,5R,E)-5-(tert-butyldimethylsiloxy)-4-methyl-2-hexenol (13), yielding lactones 5 in 87%
yield. Demethoxycarbonylation of the cyclization products 5 and further functional group
transformations led to (+)-methyl pederate (4).
In tr od u ction
Mycalamides A (1a )1 and B (1b)2 are strong antiviral
and antitumor compounds isolated from a New Zealand
marine sponge Mycale species. Furthermore, mycala-
mides (1) are recently reported to exhibit immunosup-
pressive activity via inhibition of T cell activation.3 Each
contains a trioxabicyclo[4.4.0]decane ring system and
N-acyl aminal unit at C10. Because of their unique
structures and pharmacological activities, mycalamides
(1) and their relatives [theopederins A-E (2)4 and on-
namide A (3)5] are attractive candidates for total syn-
theses.6
In our first contribution to this area, we herein describe
an enantioselective preparation of (+)-methyl pederate
(4), a possible key intermediate to mycalamides (1), based
upon a palladium-catalyzed intramolecular allylic alky-
lation reaction.7
(1) Perry, N. B.; Blunt, J . W.; Munro, M. H. G. J . Am. Chem. Soc.
1988, 110, 4850-4851.
(2) Perry, N. B.; Blunt, J . W.; Munro, M. H. G.; Thompson, A. M. J .
Org. Chem. 1990, 55, 223-227.
(3) Galvin, F.; Freeman, G. J .; Razi-Wolf, Z.; Bennacerraf, B.; Nadler,
L.; Reiser, H. Eur. J . Immunol. 1993, 23, 283-286.
(4) Fusetani, N.; Sugawara, T.; Matsunaga, S. J . Org. Chem. 1992,
57, 3828-3832.
(5) Sakemi, S.; Ichiba, T.; Kohmoto, S.; Saucy, G. J . Am. Chem. Soc.
1988, 110, 4852-4853.
(6) Total syntheses of mycalamides A and B and onnamide A: (a)
Hong, C. Y.; Kishi, Y. J . Org. Chem. 1990, 55, 4242-4245. (b) Idem J .
Am. Chem. Soc. 1991, 113, 9693-9694. (c) Nakata, T.; Matsukura, H.;
J ian, D.; Nagashima, H. Tetrahedron Lett. 1994, 35, 8229-8232.
Related synthetic studies: (d) Tsuzuki, K.; Watanabe, T.; Yanagiya,
M.; Matsumoto, T. Tetrahedron Lett. 1976, 4745-4748. (e) Adams, M.
A.; Duggan, A. J .; Smolanoff, J .; Meinwald, J . J . Am. Chem. Soc. 1979,
101, 5364-5370. (f) Nakata, T.; Nagao, S.; Mori, N.; Oishi, T.
Tetrahedron Lett. 1985, 26, 6461-6464. (g) Nakata, T.; Nagao, S.;
Oishi, T. Ibid. 1985, 26, 6465-6468. (h) Matsuda, F.; Tomiyoshi, N.;
Yanagiya, M.; Mastumoto, T. Tetrahedron 1988, 44, 7063-7080. (i)
Kocienski, P.; J arowicki, K.; Marczak, S. Synthesis 1991, 1191-1200.
(j) Roush, W. R.; Marron, T. G. Tetrahedron Lett. 1993, 34, 5421-5424.
(k) Hoffmann, R. W.; Schlapbach, A. Ibid. 1993, 34, 7903-7906. (l)
Marron, T. G.; Roush, W. R. Ibid. 1995, 36, 1581-1584. (m) Hoffmann,
R. W.; Breitfelder, S.; Schlapbach, A. Helv. Chim. Acta 1996, 79, 346-
352. (n) Kocienski, P.; Raubo, P.; Davis, J . K.; Boyle, F. T.; Davies, D.
E.; Richter, A. J . Chem. Soc., Perkin Trans. 1 1996, 1797-1808. (o)
Roush, W. R.; Marron, T. G.; Pfeifer, L. A. J . Org. Chem. 1997, 62,
474-478.
S0022-3263(98)00524-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/30/1998

5896 J . Org. Chem., Vol. 63, No. 17, 1998
Toyota et al.
Sch em e 1
Sch em e 2
Syn th etic P la n . For synthesizing (+)-methyl peder-
ate (4) in an enantioselective manner, the novel synthetic
strategy depicted in Scheme 1 was designed, employing
a palladium-catalyzed intramolecular allylic alkylation.
Namely, when the regioselective (6-exo-trig) cyclization
of the allylic alcohol derivative 6 obtained from the chiral
aldehyde 7 occurs, the vinyl δ-lactones 5 can be produced.
Demethoxycarbonylation, followed by coupling reaction
with a glycolic acid derivative, would furnish the methyl
pederate skeleton, transformable into 4.
Resu lts a n d Discu ssion
stereoisomers 11 and 12 was difficult at this stage, it was
found that the desired major isomer was easily separated
as the corresponding allylic alcohol 13 after DIBALH
reduction. Therefore, the mixture of homoallylic alcohols
11 and 12 was subjected to protection (tert-butyldimeth-
ylsilyl trifluoromethanesulfonate, 2,6-lutidine, CH2Cl2, 0
°C) followed by DIBALH reduction (95%). A route that
could provide material suitable for the subsequent key
step was now available.
P r ep a r a tion of (4R,5R,E)-5-(ter t-bu tyld im eth yl-
siloxy)-4-m eth yl-2-h exen ol (13). (A) Rou te via P a l-
la d iu m -Ca ta lyzed Hyd r ogen olysis. To synthesize the
requisite carbonate 21 for the key step (21 f 5), a
palladium-catalyzed regio- and stereoselective hydro-
genolysis8 route was first adopted (Scheme 2). Tiglic
alcohol (8)9b was subjected to the Sharpless asymmetric
epoxidation9 (cumene hydroperoxide, (-)-diisopropyl tar-
trate, titanium(IV) isopropoxide, 3 Å molecular sieves,
CH2Cl2, -70 °C) to afford the 2,3-epoxy alcohol 9 with
92% ee, determined by using the Mosher ester analysis.10
After oxidation of 9 with tetrapropylammonium perru-
thenate in the presence of 4-methylmorpholine N-oxide,11
the efficient construction of the (E)-olefin 10 (E:Z ) 16:
1) was achieved by utilization of the Masamune-Roush
procedure.12 Palladium-catalyzed hydrogenolysis8 of the
resulting (E)-alkenyloxirane 10 was conducted with the
tris(dibenzylideneacetone)dipalladium(0)-chloroform ad-
duct [(dba)3Pd2‚CHCl3] in the presence of Bu3P-HCO2H-
Et3N in 1,4-dioxane to provide the alcohol 11 as the major
isomer in a 16:1 mixture. Although separation of the
(B) R ou t e via Ald ol R ea ct ion . It was considered
that the requisite allylic alcohol 13 could be formed in a
more efficient manner via chemoselective reduction of the
thiol ester 17 (Scheme 3). Two stereogenic centers on
15 were constructed through a diastereoselective aldol
addition of the boron enolate derived from the (4S,5R)-
norephedrine-based chiral carboximide 1413 with acetal-
dehyde (>98% de by 1H NMR analysis). For excising the
imide auxiliary of 15, several procedures were surveyed,
including transamination14 to the N-methoxy-N-methy-
lamide, transesterification13 with lithium benzyloxide,
and LiAlH4 reduction.13 Typically, these reactions were
capricious and less selective when performed on a large
scale. To alleviate this bottleneck, an alternative solution
was sought. Removal of the oxazolidinone auxiliary was
readily achieved (99%) by using Damon’s reported lithio
mercaptide procedure.15 Following protection of 16, the
resulting thiol ester 17 was efficiently reduced to the
(7) A part of the present work has been published as a preliminary
communication: Toyota, M.; Nishikawa, Y.; Fukumoto, K. Heterocycles
1998, 47, 675-678.
(8) Oshima, M.; Yamazaki, H.; Shimizu, I.; Nisar, M.; Tsuji, J . J .
Am. Chem. Soc. 1989, 111, 6280-6287.
(9) (a) Katsuki, T.; Sharpless, K. B. J . Am. Chem. Soc. 1980, 102,
5974-5976. (b) Martin, T.; Rodrigues, C. M.; Martin, S. V. Tetrahe-
dron: Asymmetry 1995, 6, 1151-1164.
(10) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543-2549.
(13) Evans, D. A.; Robert, L. D.; Shih, T. L.; Takacs, J . M.; Zahler,
R. J . Am. Chem. Soc. 1990, 112, 5290-5313.
(14) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977,
4171-4173.
(15) Damon, R. E.; Coppola, G. M. Tetrahedron Lett. 1990, 31, 2849-
2852.
(11) Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639-666.
(12) Blanchette, M. A.; Choy, W.; Davis, J . T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,
2183-2186.

Enantioselective Synthesis of (+)-Methyl Pederate
J . Org. Chem., Vol. 63, No. 17, 1998 5897
Sch em e 3
Sch em e 4
Ta ble 1. Con d ition s a n d Yield s of P d -Ca ta lyzed
Cycliza tion Rea ction of Com p ou n d 21
temp time yield
entry
catalyst
Pd(Ph3P)4
ligand solvent
(°C)
(h)
(%)
19
low
1a
2a
3
4
5
dppe
THF
THF
THF
reflux
reflux
3
7
(dba)3Pd2‚CHCl3 dppe
(dba)3Pd2‚CHCl3 Ph3P
reflux 0.5 25
33
MeCN reflux 6.5 48
DMSO 90 70
DMF
DMF
b
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Bu3P
Ph3P
Ph3P
Ph3P
Ph3P
MeCN reflux
1
b
b
b
b
6
5
7
45
90
7.5 66
6.5 87
8c
a
b
aldehyde 7 by Fukuyama’s hydrosilylation method16
using 10% palladium-charcoal. When 7 was subjected
to the standard conditions for Masamune-Roush olefi-
nation,12 the only obtainable product was 18. It should
be noted that the (Z)-olefin was not detected by 1H NMR
analysis. After reduction of 18 with DIBALH, the alcohol
13 was obtained in quantitative yield.
NaH (1 equiv) was added. All reactions were carried out by
using Pd(OAc)2 (10 mol %) and PPh3 (40 mol %). c The reaction
was conducted in a sealed tube.
dramatically by varying the reaction conditions. In the
first set of reactions Pd(0) was utilized as a catalyst. In
contrast to entry 1, (dba)3Pd2‚CHCl3 did not effect the
cyclization (entry 2). The yield of this lactonization
improved upon using a catalytic amount of Pd(OAc)2 with
phosphine ligand (entries 4 and 5). For evaluation of the
effect of solvent, we performed the same reaction by
employing DMSO, in which the cyclized products 5 were
obtained in 70% yield (entry 6). At higher temperatures,
this reaction proceeds smoothly, providing the desired
compounds 5 (entries 7 and 8). From these results, we
could conclude that the selective δ-lactone formation has
been governed by the several factors including solvent
and palladium catalyst. In addition, the yield is highly
dependent upon the polarity of the solvent.
Syn th esis of (+)-Meth yl P ed er a te. Having found
conditions for the preparation of 5, the stage was now
set for the completion of the synthesis. After demethoxy-
carbonylation (76%) of 5, the corresponding lactone was
generated as a 3:1 mixture of diastereomers. The non-
stereoselectivity of the cyclization was of little conse-
quence, since both of the diastereomers could be con-
verted efficiently to the bicyclic lactone 22 using Nakata’s
procedure.6g Namely, the above lactone was subjected
to ozonolysis (O3, MeOH, -78 °C; Me2S), followed by
acidic treatment (concd HCl, CH2Cl2), to afford 22 in 97%
yield for two steps. After transformation of 22 into the
thioacetal 23, coupling reaction6e of O-(2-methoxy-2-
propyl)glycolate with 23 in the presence of LDA, carried
out between -78 °C and -15 °C, produced the coupled
products, which were allowed to react in succession with
trimethyl orthoformate and MeOH in the presence of 10-
camphorsulfonic acid, and benzoyl chloride to furnish the
P alladiu m -Catalyzed In tr am olecu lar Allylic Alky-
la tion Rea ction s Lea d in g to δ-La cton es. With a
route to multigram quantities of 13 firmly in hand, our
synthetic elaboration was next focused on the δ-lactone
formation of the allyl ether 21. Attempts to control the
ring size of the products in palladium-catalyzed intramo-
lecular allylic alkylation processes have been reported.17
However, the lack of examples18 of their applications to
the synthesis of complex natural products may, in part,
be due to the relatively low product yields. We have
carried out extensive studies on the palladium-catalyzed
intramolecular lactonization of the allylic alcohol deriva-
tive 21. Conversion of the alcohol 13 to the carbonate
21 was achieved via the reaction sequence summarized
in Scheme 4. Namely, carbonate formation (98%) of 13
followed by deprotection of the TBDMS group of 19 with
Bu4NF provided the alcohol 20, which was subjected to
esterification with malonic acid monomethyl ester in the
presence of DMAP and [1-(3-(dimethylamino)propyl)]-3-
ethylcarbodiimide hydrochloride (WSC) to give 21. The
representative results, summarized in Table 1, show that
the outcome of the lactonization reaction can be altered
(16) Fukuyama, T.; Lin, S.-C.; Li, L. J . Am. Chem. Soc. 1990, 112,
7050-7051.
(17) Recent Reviews: (a) Heumann, A.; Reglier, M. Tetrahedron
1995, 51, 975-1015. (b) Frost, C. G.; Howarth, J .; Williams, J . M. J .
Tetrahedron: Asymmetry 1992, 3, 1089-1122, and references therein.
(18) (a) Takahashi, T.; Kataoka, H.; Tsuji, J . J . Am. Chem. Soc. 1983,
105, 147-149. (b) Trost, B. M.; Verhoeven, T. R. J . Am. Chem. Soc.
1980, 102, 4743-4763.

5898 J . Org. Chem., Vol. 63, No. 17, 1998
Toyota et al.
Sch em e 5
of (+)-methyl pederate (4) and (+)-methyl epi-pederate
(26). The latter could be recycled to a mixture of 4 and
26 (5:1, respectively) by Collins oxidation and reduction
with NaBH4.6d The spectral properties (1H NMR, IR) of
synthetic (+)-methyl pederate (4), [R]22 +131.16 (CH2-
D
Cl2) [lit.6o [R]23 +115 (CH2Cl2)], were identical in all
D
respects to those provided by Dr. Nakata.
Exp er im en ta l Section
Gen er a l. Unless otherwise noted, all reactions were per-
formed in oven-dried glassware, sealed with a rubber septum
under an atmosphere of argon. Anhydrous tetrahydrofuran
(THF) and dichloromethane (CH2Cl2) were purchased from
Kanto Chemical Co., Inc. Pyridine, toluene, triethylsilane (Et3-
SiH), diisopropylamine (i-Pr2NH), boron trifluoride diethyl
etherate (BF3‚Et2O), 1,4-dioxane, and triethylamine (Et3N)
were distilled from CaH2. Hexamethylphosphoramide (HMPA)
and dimethyl sulfoxide (DMSO) were distilled from CaH2
under reduced pressure. N,N-Dimethylformamide (DMF) was
distilled under argon from CaSO4. Acetone (Me2CO) and
methanol (MeOH) were distilled under argon immediately
prior to use. Unless otherwise mentioned, materials were
obtained from commercial suppliers and used without further
purification. Organic extracts were dried by being stirred over
anhydrous MgSO4, filtered through Celite, and concentrated
under reduced pressure with the aid of a rotary evaporator.
Flash chromatography was carried out using Merck 60 (230-
400 mesh) or Cica 60 (spherical/40-100 µm) silica gel. Reac-
tions and chromatography fractions were analyzed employing
precoated silica gel 60 F254 plates (Merck). Compounds were
visualized using a ultraviolet lamp (254 nm) and/or by staining
with p-anisaldehyde (in EtOH), phosphomolybdic acid (in
EtOH), or ammonium molybdate (in 10% H2SO4). IR spectra
were recorded as films on NaCl plates unless otherwise noted.
1H NMR spectra were measured as CDCl3 solutions at 300
MHz. Chemical shifts are expressed in ppm downfield from
internal tetramethylsilane or relative internal CHCl3.
values are in hertz.
J
(+)-(2R,3R)-2,3-E p oxy-2-m et h yl-1-b u t en ol (9). To a
stirred solution of (E)-2-methyl-2-butenol (8)9b (1.00 g, 11.6
mmol) and diisopropyl D-tartrate (342 mg, 1.46 mmol) in CH2-
Cl2 (60 mL) at -25 °C was added 3 Å molecular sieves (9.32 g,
powdered), and then the mixture was again stirred at -25 °C
for 0.5 h. After slow addition of Ti(Oi-Pr)4 (0.310 mL, 1.22
mmol) at -25 °C, the resulting mixture was stirred at the same
temperature for 0.5 h, and cumene hydroperoxide (4.10 mL,
80%, 22.0 mmol) was added dropwise at -78 °C. The mixture
was again stirred at -70 °C for 13 h. The mixture was
quenched by addition of a solution of Bu3P (2.40 mL, 9.76
mmol) and citric acid (170 mg, 0.810 mmol) in a 1:9 mixture
of Me2CO and Et2O (20 mL) at -78 °C and then allowed to
warm to room temperature. After 20 min of stirring at room
temperature, the solution was filtered through Celite. The
filtrate was concentrated to leave an oil, which was chromato-
graphed. Elution with a 1:2 mixture of hexanes-EtOAc gave
9 (802 mg, 68%) as a colorless oil. [R]22 +17.4 (c 0.690, CH2-
D
Cl2). IR 3450 cm-1
.
1H NMR δ 1.28 (3H, s), 1.32 (3H, d, J )
5.5), 2.00 (1H, dd, J ) 8.2 and 4.7), 3.17 (1H, q, J ) 5.5), 3.57
(1H, dd, J ) 12.4 and 8.2) and 3.70 (1H, dd, J ) 12.4 and 4.7).
13C NMR (75.4 MHz) δ 13.4, 13.8, 55.9, 61.1 and 65.4.
(-)-Ben zyl (4R,5R,E)-4,5-Ep oxy-4-m eth yl-2-h exen oa te
(10). To a stirred solution of 9 (115 mg, 1.13 mmol) in MeCN
(5 mL) were added 4 Å molecular sieves (565 mg, powdered),
4-methylmorpholine N-oxide (198 mg, 1.70 mmol), and Pr4-
NRuO4 (19.8 mg, 97%, 56.4 µmol) at room temperature, and
then the resulting suspension was again stirred at room
temperature for 1 h. After filtration through Celite, the filtrate
was concentrated to afford the aldehyde, which was im-
mediately used in subsequent Masamune-Roush olefination
without further purification.
benzoate 24 as a 1:1 mixture of epimers. Subsequent
conversion to 25 was accomplished in 79% overall yield
through dethioacetalization and reduction with NaBH4
(Scheme 5).
Application of Grieco’s o-nitrophenylselenenylation
method19 to 25 produced the selenide, which was treated
with 30% hydrogen peroxide to give the corresponding
exo-olefin. Finally, hydrolysis of the benzoate moiety
with NaOMe yielded an easily separable 13:12 mixture
To a slurry of LiCl (57.5 mg, 1.36 mmol) in MeCN (2 mL)
were added dropwise a solution of diethyl [(benzyloxycarbonyl)-
methyl]phosphonate (389 mg, 1.36 mmol) at room tempera-
(19) (a) Sharpless, K. B.; Young, M. W. J . Org. Chem. 1975, 40, 947-
949. (b) Grieco, P. A.; Gilman, S.; Nishizawa, M. J . Org. Chem. 1976,
41, 1485-1486.

Enantioselective Synthesis of (+)-Methyl Pederate
J . Org. Chem., Vol. 63, No. 17, 1998 5899
ture, followed after 5 min by a solution of the above aldehyde
in MeCN (5 mL) at 0 °C. After 1 h of stirring at 0 °C, the
solvent was removed by reduced pressure to furnish the
residue, which was diluted with Et2O. The ethereal layer was
washed with H2O and saturated NaCl, dried, filtered, and
evaporated to leave an oil, which was chromatographed.
Elution with an 8:1 mixture of hexanes-EtOAc afforded a 16:1
lized from Et2O-hexane to provide 15 (2.34 g, 57%) as colorless
prisms, mp 116-118 °C, judged by 1H NMR spectroscopy to
consist of >98% one diastereomer: [R]24 -30.0 (c 0.151,
D
1
CHCl3). IR 3350, 1780, and 1680 cm-1; H NMR δ 0.90 (3H,
d, J ) 7.0), 1.22 (3H, d, J ) 6.6), 1.25 (3H, d, J ) 7.0), 2.93
(1H, br d, J ) 3.0), 3.76 (1H, dq, J ) 6.6 and 3.0), 4.15-4.25
(1H, m), 4.81 (1H, dq, J ) 7.2 and 6.6), 5.69 (1H, d, J ) 7.2),
and 7.20-7.45 (5H, m). Anal. Calcd for C15H19NO4: C, 64.96;
H, 6.90; N, 5.05. Found: C, 64.87; H, 6.83; N, 5.04.
mixture of (E)- and (Z)-10 (139 mg, 53% for two steps) as a
1
colorless oil. [R]22 -28.5 (c 0.108, CHCl3). IR 1720 cm-1. H
D
NMR δ 1.35 (2.82H, d, J ) 5.0), 1.36 (0.18H, d, J ) 5.0), 1.42
(2.82H, s), 1.43 (0.18H, s), 5.86 (0.06H, d, J ) 11.0), 6.05
(0.94H, d, J ) 15.0), 6.41 (0.06H, d, J ) 11.0) and 6.80 (0.94H,
d, J ) 15.0). HRMS calcd for C14H16O2 (M+ - 16) 216.1149,
found 216.1152.
(+)-S-Eth yl (2S,3R)-3-Hyd r oxy-2-m eth ylbu ta n eth ioa te
(16). To a -78 °C solution of ethanethiol (53 µL, 0.720 mmol)
in THF (5 mL) was added dropwise BuLi (0.347 mL, 10 wt %
in hexane, 0.542 mmol), and then the solution was stirred at
the same temperature for 10 min. To this was slowly added
a solution of 15 (100 mg, 0.361 mmol) at -78 °C, and the
mixture was again stirred at the same temperature for 0.5 h.
The mixture was quenched with saturated NH4Cl at 0 °C, and
then the resulting mixture was extracted with EtOAc. The
organic layer was washed in succession with saturated CuSO4,
H2O, saturated NaHCO3, H2O, and saturated NaCl, dried,
filtered, and evaporated to leave an oil, which was chromato-
graphed. Elution with a 2:1 mixture of hexanes-EtOAc
furnished the thiol ester 16 (58.0 mg, 99%) as a colorless oil,
together with (4S,5R)-norephedrine-2-oxazolidinone (53.0 mg,
(+)-Ben zyl (4R,5R,E)-5-Hyd r oxy-4-m eth yl-2-h exen oa te
(11). To a stirred solution of (dba)3Pd2‚CHCl3 (7.4 mg, 7.2
µmol) in 1,4-dioxane (1 mL) was added Bu3P (1.8 µL, 7.2 µmol)
at room temperature. After being stirred at room temperature
for 5 min, Et3N (67 µL, 0.48 mmol) and a solution of HCO2H
(45 µL, 1.2 mmol) in 1,4-dioxane (2 mL) were added at room
temperature, and then the resulting mixture was stirred at
the same temperature for 5 min. To this was slowly added a
solution of 10 (55.5 mg, 0.239 mmol) in 1,4-dioxane (2 mL) at
room temperature, and the mixture was continued to stir at
room temperature for 9.5 h. The reaction mixture was
subjected to short column chromatography, and the solvent
was removed to yield an oil, which was chromatographed.
Elution with a 1:1 mixture of hexanes-EtOAc furnished a 16:1
100%). 16: [R]26 + 14.5 (c 0.123, CHCl3). IR 3400 and 1680
D
cm-1; H NMR δ 1.18 (3H, d, J ) 6.2), 1.22 (3H, d, J ) 4.4),
1
1.26 (3H, t, J ) 7.3), 2.39 (1H, d, J ) 3.6), 2.63 (1H, dt, J )
4.4 and 3.7), 2.89 (2H, q, J ) 7.3) and 4.09 (1H, ddq, J ) 6.2,
3.7 and 3.6). Anal. Calcd for C7H14O2S: C, 51.82; H, 8.70; S,
19.76. Found: C, 52.03; H, 8.59; S, 19.80.
mixture of 11 and 12 (49.8 mg, 89%) as a colorless oil. [R]22
D
+21.6 (c 0.098, CHCl3). IR 3450 and 1715 cm-1
.
1H NMR δ
1.07 (0.18H, d, J ) 6.5), 1.11 (2.82H, d, J ) 6.5), 1.16 (2.82H,
d, J ) 6.0), 1.18 (0.18H, d, J ) 6.0), 5.87 (0.06H, dd, J ) 15.0
and 1.0), 5.92 (0.94H, dd, J ) 15.0 and 1.0), 6.99 (0.06H, dd,
J ) 15.0 and 7.5) and 7.00 (0.94H, dd, J ) 15.0 and 7.5).
HRMS calcd for C14H18O3 (M+) 234.1255, found 234.1195.
(-)-(4S,5R)-4-Meth yl-5-p h en yl-3-p r op a n oyl-1,3-oxa zo-
lid in -2-on e (14). To a stirred solution of (4S,5R)-norephe-
drine-2-oxazolidinone13 (16.9 g, 95.2 mmol) in THF (100 mL)
at -78 °C was added dropwise BuLi (63.8 mL, 10 wt % in
hexane, 99.6 mmol), and then the resulting solution was
stirred at -78 °C for 1 h. After slow addition of propionyl
chloride (9.97 mL, 112 mmol) at -78 °C, the mixture was
allowed to warm to 0 °C and maintained at the same temper-
ature for an additional 1.5 h. The mixture was quenched with
1 Μ K2CO3 (100 mL) at 0 °C and diluted with EtOAc. The
organic layer was washed with saturated NaCl, dried, filtered,
and evaporated to leave an oil, which was chromatographed.
Elution with a 2:1 mixture of hexanes-EtOAc yielded 14 (22.1
g, 100%) as a colorless oil. Ku¨gelrohr distillation (110 °C/0.1
(+)-S-E t h yl
(2S,3R)-3-(ter t-Bu t yld im et h ylsiloxy)-2-
m eth ylbu ta n eth ioa te (17). To a stirred solution of 16 (13.9
mg, 85.8 µmol) in DMF (2 mL) were added TBDMSCl (15.6
mg, 0.103 mmol) and imidazole (11.6 mg, 0.172 mmol) at room
temperature, and then the mixture was stirred at the same
temperature for 10 h. The mixture was diluted with Et2O,
and the ethereal layer was washed with H2O, saturated NaCl,
dried, filtered, and evaporated to provide an oil, which was
chromatographed. Elution with a 5:1 mixture of hexanes-
EtOAc afforded 17 (23.8 mg, 100%) as a colorless oil. [R]25
D
+2.25 (c 0.203, CHCl3). IR 1680 cm-1; H NMR δ 0.04 (3H,
1
s), 0.05 (3H, s), 0.85 (9H, s), 1.15 (3H, d, J ) 6.2), 1.18 (3H, d,
J ) 7.0), 1.23 (3H, t, J ) 7.3), 2.58 (1H, dt, J ) 7.0 and 7.0),
2.84 (2H, q, J ) 7.3), and 4.02 (1H, dq, J ) 7.0, 6.2). Anal.
Calcd for C13H28O2SSi: C, 56.47; H, 10.21; S, 11.59. Found:
C, 56.63; H, 10.14; S, 11.62.
(+)-Eth yl (4R,5R,E)-5-(ter t-Bu tyldim eth ylsiloxy)-4-m eth -
yl-2-h exen oa te (18). To a stirred solution of 17 (2.00 g, 7.25
mmol) in Me2CO (20 mL) was added 10% Pd-C (44 mg). After
being stirred for 10 min, Et3SiH (3.47 mL, 21.7 mmol) was
slowly added at 0 °C, and the reaction solution was again
stirred for 5 min at 0 °C and for 10 min at room temperature.
The catalyst was filtered off and washed with Me2CO. Con-
centration of the combined filtrate and washings gave an oil,
which was chromatographed. Elution with a 20:1 mixture of
hexanes-EtOAc afforded the aldehyde 7 (1.57 g, 100%) as a
colorless oil. IR 2850 and 1730 cm-1; 1H NMR δ 0.03 (3H, s),
0.05 (3H, s), 0.85 (9H, s), 1.05 (3H, d, J ) 7.1), 1.16 (3H, d, J
) 6.7), 2.36 (1H, ddq, J ) 7.1, 4.9 and 1.1), 4.24 (1H, dq, J )
6.7 and 4.9), and 9.74 (1H, q, J ) 1.1).
mmHg) gave the pure 14. [R]25 -51.8 (c 0.690, CHCl3). IR
D
1700 cm-1; H NMR δ 0.89 (3H, d, J ) 6.8), 1.22 (3H, t, J )
1
7.5), 2.92 (2H, q, J ) 7.5), 4.78 (1H, dq, J ) 7.8 and 6.8), 5.68
(1H, d, J ) 7.2) and 7.34 (5H, s). Anal. Calcd for C13H15NO3:
C, 66.94; H, 6.48; N, 6.00. Found: C, 66.70; H, 6.57; N, 5.95.
(-)-(4S,5R,2′S,3′R)-3-(3-Hyd r oxy-2-m eth ylbu ta n oyl)-4-
m et h yl-5-p h en yl-1,3-oxa zolid in -2-on e (15). To a stirred
solution of 14 (3.43 g, 14.7 mmol) in CH2Cl2 (20 mL) at -78
°C was slowly added Bu2BOTf (16.9 mL, 1 M in CH2Cl2, 16.9
mmol), followed after 10 min by Et3N (2.67 mL, 19.2 mmol).
The resulting mixture was stirred at -78 °C for 0.5 h and at
0 °C for 1 h. Upon cooling to -78 °C, freshly distilled
acetaldehyde (1.51 mL, 29.4 mmol) was slowly added at -78
°C, and the mixture was stirred for 0.5 h at the same
temperature and then warmed to 0 °C for 0.5 h. The reaction
was quenched by addition of 0.25 M KH2PO4 (25 mL) and then
allowed to warm to room temperature. To this were slowly
added MeOH (50 mL) and 30% H2O2 (22.5 mL) in MeOH (67.5
mL) at room temperature, and the resulting solution was again
stirred at the same temperature for 45 min. After removal of
the solvent, 10% NaHCO3 (70 mL) was added, and then the
solution was extracted with EtOAc. The organic layer was
washed with saturated NaCl, dried, filtered, and evaporated
to furnish an oil, which was chromatographed. Elution with
a 1:2 mixture of hexanes-EtOAc gave rise to 15 (3.27 g, 80%)
as a colorless powder. The solid thus obtained was recrystal-
To a slurry of LiCl (873 mg, 20.6 mmol) in MeCN (4 mL)
were slowly added diethyl [(ethoxycarbonyl)methyl]phospho-
nate (4.09 mL, 20.6 mmol) and DBU (1.98 mL, 13.3 mmol) at
room temperature and then a solution of the above aldehyde
in MeCN (12 mL) at 0 °C. After being stirred at 0 °C for 1 h,
the mixture was allowed to warm to room temperature and
diluted with Et2O. The ethereal layer was washed with H2O,
saturated NaCl, dried, filtered, and evaporated to afford 18
(1.60 g, 94%) as a colorless oil. [R]26 +13.2 (c 0.207, CHCl3).
D
IR 1710 and 1650 cm-1; H NMR δ 0.04 (3H, s), 0.05 (3H, s),
1
0.89 (9H, s), 1.04 (3H, d, J ) 6.6), 1.09 (3H, d, J ) 6.2), 1.29
(3H, t, J ) 7.1), 2.25-2.37 (1H, m), 3.74 (1H, dq, J ) 6.2 and
6.0), 4.12 (2H, q, J ) 7.1), 5.80 (1H, dd, J ) 15.8 and 1.1), and
6.96 (1H, dd, J ) 15.8 and 7.9). Anal. Calcd for C15H30O3Si:
C, 62.89; H, 10.55. Found: C, 62.68; H, 10.53.

5900 J . Org. Chem., Vol. 63, No. 17, 1998
Toyota et al.
(+)-(4R,5R,E)-5-(ter t-Bu tyld im eth ylsiloxy)-4-m eth yl-2-
h exen ol (13). (A): To a stirred solution of the mixture 11
and 12 (68.0 mg, 0.291 mmol) in CH2Cl2 (2 mL) were added
dropwise 2,6-lutidine (68.0 µL, 0.580 mmol) and TBDMSOTf
(80.0 µL, 0.350 mmol) at 0 °C, and then the mixture was stirred
at 0 °C for 3 h. The mixture was quenched by additions of
saturated NaHCO3 and saturated KHSO4, and the resulting
solution was extracted with Et2O. The ethereal layer was
dried, filtered, and evaporated to give an oil, which was
chromatographed. Elution with a 20:1 mixture of hexanes-
Ku¨gelrohr distillation (103 °C/6 mmHg) furnished the pure 20.
[R]25D +27.3 (c 0.107, CHCl3). IR 3400 and 1750 cm-1; 1H NMR
δ 1.04 (3H, d, J ) 7.0), 1.14 (3H, d, J ) 6.6), 1.65 (1H, br s),
2.27 (1H, br dq, J ) 7.0 and 6.2), 3.70 (1H, dq, 6.6 and 6.2),
3.79 (3H, s), 4.61 (2H, d, J ) 6.3), 5.64 (1H, ddt, J ) 15.6, 6.3
and 0.7), and 5.79 (1H, br dd, J ) 15.6 and 7.5). HRMS calcd
for C7H12O (M+ - 76) 112.0888, found 112.0866. Anal. Calcd
for C9H16O4: C, 57.44; H, 8.57. Found: C, 57.21; H, 8.58.
(+)-(4R ,5R ,E )-5-(Me t h oxym a lon yl)-4-m e t h yl-2-h e x-
en yl Meth yl Ca r bon a te (21). To a solution of 20 (489 mg,
2.60 mmol), monomethyl malonate (430 mg, 3.64 mmol), and
DMAP (444 mg, 3.64 mmol) in CH2Cl2 (20 mL) was added
dropwise a solution of WSC (697 mg, 3.64 mmol) in CH2Cl2
(20 mL) at 0 °C, and then the resulting solution, after 10 min,
was allowed to warm to room temperature. The mixture was
again stirred at the same temperature for 24 h. After removal
of the solvent, the residue was diluted with Et2O. The ethereal
layer was washed with H2O, saturated NaCl, dried, filtered,
and evaporated to give an oil, which was chromatographed.
Elution with a 3:1 mixture of hexanes-EtOAc provided 21 (659
mg, 88%), together with the starting material (47.1 mg).
Ku¨gelrohr distillation (108 °C/4 mmHg) gave the pure 21.
EtOAc provided the TBDMS ethers (89.0 mg, 88%) as a
1
colorless oil. [R]22 +15.0 (c 0.415, CHCl3). IR 1720 cm-1. H
D
NMR δ 0.03 (3H, s), 0.04 (3H, s), 0.88 (9H, s), 1.03 (3H, d, J )
6.9), 1.08 (3H, d, J ) 6.3), 5.85 (0.06H, dd, J ) 15.0 and 1.0),
5.86 (0.94H, dd, J ) 15.0 and 1.0), 6.99 (0.06H, dd, J ) 15.0
and 7.5), and 7.03 (0.94H, dd, J ) 15.0 and 7.5). HRMS calcd
for C16H23O3Si (M+ - 57) 291.1415, found 291.1404.
To a -78 °C solution of the above material (89.0 mg, 0.256
mmol) in CH2Cl2 (3 mL) was slowly added DIBALH (0.57 mL,
0.96 M in hexane, 0.547 mmol), and the mixture was again
stirred at -78 °C for 1 h. The mixture was quenched by
addition of MeOH (0.3 mL) and 0.5 M sodium potassium
tartrate (3 mL), and then the resulting solution was stirred
at room temperature for 12 h. The mixture was extracted with
CH2Cl2, and the organic layer was dried, filtered, and evapo-
rated to afford an oil, which was chromatographed. Elution
with a 4:1 mixture of hexanes-EtOAc gave rise to 13 (59.7
[R]25 +23.9 (c 0.129, CHCl3). IR 1750, 1740, and 1730 cm-1
;
D
1H NMR δ 1.03 (3H, d, J ) 7.0), 1.18 (3H, d, J ) 6.6), 2.46
(1H, dq, J ) 7.0 and 6.4), 3.38 (2H, s), 3.75 (3H, s), 3.79 (3H,
s), 4.60 (2H, d, J ) 5.5), 4.87 (1H, dq, J ) 6.6 and 6.4) and
5.59-5.77 (2H, m). HRMS calcd for C11H17O4 (M+ - 75)
213.1126, found 213.1109. Anal. Calcd for C13H20O7: C, 54.16;
H, 6.99. Found: C, 53.99; H, 6.77.
mg, 95%) as a colorless oil: [R]26 +11.6 (c 0.20, CHCl3). IR
D
3350 and 1650 cm-1; 1H NMR δ 0.01 (3H, s), 0.02 (3H, s), 0.86
(9H, s), 0.96 (3H, d, J ) 7.0), 1.04 (3H, d, J ) 6.2), 1.56 (1H,
br t, J ) 4.4), 2.19 (1H, dq, J ) 7.0 and 6.5), 3.62 (1H, dq, J )
6.5 and 6.2), 4.11 (2H, br t, J ) 4.4), and 5.58-5.65 (2H, m).
Anal. Calcd for C13H28O2Si: C, 63.88; H, 11.54. Found: C,
63.83; H, 11.52.
(+)-(4R,5R)-4,5-Dim eth yl-2-(m eth oxyca r bon yl)-3-vin yl-
p en ta n olid e (5). En tr y 1: To a slurry of NaH (3.8 mg, 60%,
95 µmol, washed three times with hexanes) in THF (0.5 mL)
was slowly added a solution of 21 (27.1 mg, 94.1 µmol) in THF
(0.5 mL) at 0 °C, and the resulting mixture was stirred at 0
°C for 15 min and then at room temperature for 0.5 h. This
solution was slowly added via cannula to a solution of
Pd(Ph3P)4 (5.4 mg, 4.7 µmol) and bis(diphenylphosphino)-
ethane (dppe) (3.7 mg, 9.4 µmol) in THF (1 mL) under reflux,
and then the mixture was again heated under reflux for 3 h,
cooled to room temperature, and diluted with Et2O. The
organic layer was washed with H2O, saturated NaCl, dried,
filtered, and evaporated to leave an oil, which was chromato-
graphed. Elution with a 3:1 mixture of hexanes-EtOAc gave
5 (3.70 mg, 19%) as a colorless oil. Ku¨gelrohr distillation (140
°C/5 mmHg) afforded 5 as a mixture of four diastereomers.
(B): To a -78 °C solution of 18 (4.70 g, 16.4 mmol) in THF
(60 mL) was added dropwise DIBALH (36.3 mL, 0.95 M in
hexane, 34.5 mmol), and then the solution was stirred at the
same temperature for 1 h. To this were added H2O (36 mL),
Et2O (50 mL) and hexanes (50 mL) at -78 °C, and the
resulting mixture was allowed to warm to room temperature.
After 9 h of stirring at room temperature, Celite and MgSO4
were added at 0 °C. The insoluble solid was filtered off and
washed with Et2O. Concentration of the combined filtrates
and washings left an oil, which was chromatographed. Elution
with a 6:1 mixture of hexanes-EtOAc provided 13 (4.07 g,
100%) as a colorless oil. Characteristics are identical to those
synthesized previously.
[R]22 + 50.6 (c 0.119, CHCl3). IR 1750, 1745, and 1720 cm-1
;
D
1H NMR δ 0.85 (0.27H, d, J ) 7.0), 0.90 (1.96H, d, J ) 7.0),
0.98 (0.21H, d, J ) 7.0), 0.99 (0.56H, d, J ) 7.0), 1.31, 1.34,
1.36, and 1.37 (totally 3H, each d, each J ) 6.6), 1.91-2.05
(1H, m), 3.08-3.18 (1H, m), 3.40 (0.33H, d, J ) 11.0), 3.48
(0.67H, d, J ) 11.0), 3.77 (3H, s), 4.58 (0.33H, dq, J ) 6.6 and
2.2), 4.71 (0.67H, dq, J ) 6.6 and 2.2), 5.10-5.22 (2H, m), and
5.76 (1H, ddd, J ) 16.0, 10.0 and 6.8). HRMS calcd for
(+)-(4R,5R,E)-5-(ter t-Bu tyld im eth ylsiloxy)-4-m eth yl-2-
h exen yl Meth yl Ca r bon a te (19). To a stirred solution of
13 (4.00 g, 16.3 mmol) in CH2Cl2 (150 mL) were added slowly
methyl chloroformate (1.64 mL, 21.2 mmol) and pyridine (1.58
mL, 19.5 mmol) at 0 °C, and the mixture was again stirred at
the same temperature for 1 h. The mixture was quenched by
addition of H2O, and the resulting solution was extracted with
Et2O. The ethereal layer was dried, filtered, and evaporated
to yield an oil, which was chromatographed. Elution with a
15:1 mixture of hexanes-EtOAc furnished the carbonate 19
(4.84 g, 98%) as a colorless oil. Ku¨gelrohr distillation (86 °C/4
C
C
11H16O4 (M+) 212.1048, found 212.1039. Anal. Calcd for
11H16O4: C, 62.25; H, 7.60. Found: C, 62.28; H, 7.60.
En tr y 2: To a stirred suspension of NaH (5.2 mg, 60%,
0.130 mmol, washed three times with hexanes) in THF (0.3
mL) was added dropwise a solution of 21 (34.0 mg, 0.118 mmol)
in THF (0.5 mL) at room temperature, and then the mixture
was stirred for 40 min. To a stirred solution of dppe (9.4 mg,
24 µmol) in THF (0.3 mL) was added (dba)3Pd2‚CHCl3 (6.1 mg,
5.9 µmol) at room temperature, and the resulting mixture was
again stirred for 20 min. To this was slowly added at room
temperature the carbanion solution described above, and then
the mixture was stirred at room temperature for 7 h. TLC
analysis showed that 5 were generated along with numerous
byproducts.
mmHg) provided the pure 19. [R]24 +13.2 (c 0.155, CHCl3).
D
IR 1750 cm-1; H NMR δ 0.01 (3H, s), 0.02 (3H, s), 0.86 (9H,
1
s), 0.96 (3H, d, J ) 6.5), 1.03 (3H, d, J ) 6.5), 2.18 (1H, ddq,
J ) 7.0, 7.0 and 6.5), 3.62 (1H, dq, J ) 7.0 and 6.5), 3.75 (3H,
s), 4.56 (2H, br t, J ) 6.0), 5.55 (1H, ddt, J ) 15.0, 6.6 and
0.7), and 5.77 (1H, ddt, J ) 15.0, 7.0 and 1.0). HRMS calcd
for C13H27OSi (M+ - 75) 227.1832, found 227.1866. Anal.
Calcd for C15H30O4Si: C, 59.56; H, 10.00. Found: C, 59.42;
H, 10.20.
(+)-(4R,5R,E)-5-H yd r oxy-4-m et h yl-2-h exen yl Met h yl
Ca r bon a te (20). To a stirred solution of 19 (251 mg, 0.831
mmol) in THF (5 mL) was slowly added Bu4NF (0.481 mL, 1
M in THF, 1.66 mmol) at room temperature, and the mixture
was stirred at room temperature for 20 h and then at 30 °C
for 1 h. After removal of the solvent, the residue was
chromatographed. Elution with a 2:1 mixture of hexanes-
EtOAc gave rise to 20 (123 mg, 79%) as a colorless oil.
En tr y 3: To a stirred solution of Ph3P (2.0 mg, 7.6 µmol)
in THF (0.5 mL) was added (dba)3Pd2‚CHCl3 (1.0 mg, 0.97
µmol) at room temperature, and then the mixture was stirred
at room temperature for 10 min. After slow addition of a
solution of 21 (27.1 mg, 94.1 µmol) in THF (0.5 mL) at room
temperature, the resulting solution was again stirred at the
same temperature for 3.5 h, and then heated under reflux for
0.5 h. After removal of a precipitate through Celite, the filtrate

Enantioselective Synthesis of (+)-Methyl Pederate
J . Org. Chem., Vol. 63, No. 17, 1998 5901
was concentrated to provide an oil. Purification in the same
way furnished 5 (4.9 mg, 25%).
mL, 1.24 mmol) and BF3‚Et2O (0.15 mL, 1.03 mmol) at 0 °C,
and then the mixture was stirred at the same temperature
for 0.5 h. After removal of a portion of the solvent, the residue
was chromatographed. Elution with a 2:1 mixture provided
23 (241 mg, 100%) as a colorless powder. Recrystallization of
the above material from Et2O-heptane furnished 23 (171 mg,
72%) as colorless prisms, mp 150-151 °C. [R]22D -18.3 (c 0.77,
En tr y 4: To a solution of 21 (34.3 mg, 0.119 mmol) in MeCN
(2 mL) were added Pd(OAc)2 (2.70 mg, 11.0 mmol) and Bu3P
(11.9 µL, 48.0 µmol) at room temperature, and then the
mixture was heated under reflux for 1 h. Workup in the same
way gave rise to 5 (8.40 mg, 33%).
En tr y 5: To a solution of 21 (33.6 mg, 0.117 mmol) in MeCN
(2 mL) were added Pd(OAc)2 (2.60 mg, 11.0 µmol) and Ph3P
(11.5 mg, 43.9 µmol) at room temperature, and the mixture
was heated under reflux for 6.5 h. Workup in the usual way
provided 5 (11.8 mg, 48%).
1
CHCl3). IR 1710 cm-1; H NMR δ 0.89 (3H, d, J ) 7.1), 1.35
(3H, d, J ) 6.6), 2.12-2.21 (2H, m), 2.26 (1H, dd, J ) 17.6
and 12.0), 2.91 (1H, ddd, J ) 17.6, 6.3 and 0.8), 3.18-3.28
(4H, m), 4.34 (1H, d, J ) 9.9) and 4.48 (1H, dq, J ) 6.6 and
2.2). HRMS calcd for
C
10H16O2S2 (M+) 232.0591, found
En tr y 6: To a solution of 21 (772 mg, 2.68 mmol) in DMSO
(1 mL) were added Pd(OAc)2 (65.4 mg, 0.268 mmol) and Ph3P
(280 mg, 1.07 mmol) at room temperature, and then the
mixture was heated at 90 °C for 5 h. The mixture was cooled
to room temperature and then diluted with Et2O. The ethereal
layer was washed with H2O and saturated NaCl, dried,
filtered, and evaporated to leave an oil. Purification in the
same way furnished 5 (395 mg, 70%).
En tr y 7: To a solution of 21 (20.6 mg, 71.5 µmol) in DMSO
(1 mL) were added Pd(OAc)2 (1.70 mg, 6.97 µmol) and Ph3P
(7.50 mg, 28.6 µmol) at room temperature, and the mixture
was heated at 45 °C for 7.5 h. Workup in the same way gave
5 (10.1 mg, 66%).
232.0564. Anal. Calcd for C10H16O2S2: C, 51.69; H, 6.94; S,
27.60. Found: C, 51.63; H, 6.99; S, 27.72.
(+)-Meth yl (2R,4R,5R,6R)-[5,6-Dim eth yl-4-(1,3-dith iolan -
2-yl)-2-m et h oxyt et r a h yd r op yr a n yl]-2-O-b en zoylglyco-
la te (24). To a -78 °C solution of LDA, prepared from
i-Pr2NH (0.109 mL, 0.776 mmol) and BuLi (0.497 mL, 10 wt
% in hexanes, 0.776 mmol), in THF (5 mL) was slowly added
a solution of methyl O-(2-methoxy-2-propyl)glycolate6a (125 mg,
0.776 mmol) in THF (5 mL), and the mixture was stirred at
-78 °C for 10 min and then at 0 °C for 15 min. To this was
slowly added a solution of 23 (100 mg, 0.431 mmol) in THF (5
mL) at -78 °C, and the resulting solution was again stirred
at -78 °C for 2 h and at 0 °C for 0.5 h. The mixture was
quenched by dropwise addition of EtOH (0.5 mL) at 0 °C and
allowed to warm to room temperature. The resulting solution
was diluted with Et2O and H2O and separated. The aqueous
layer was extracted with Et2O, and the combined ethereal
layers were washed with H2O, saturated NaCl, dried over K2-
CO3, filtered, and evaporated to leave a residue (273 mg),
which without purification was used in the subsequent step.
To a solution of the above compound in CH2Cl2 (1 mL) were
added MeOH (1 mL), trimethyl orthoformate (0.5 mL, 4.57
mmol), and 10-camphorsulfonic acid (48 mg, 0.216 mmol), and
the resulting solution was stirred at room temperature for 1
h. After addition of NaHCO3, the mixture was extracted with
Et2O. The organic layer was washed with saturated NaCl,
dried (K2CO3), filtered, and evaporated to an oil, which was
used in the next step without purification. [R]23D +43.3 (c 0.09,
CHCl3). IR 3340 and 1740 cm-1; 1H NMR δ 0.71 (1.5H, d, J )
7.0), 0.88 (1.5H, d, J ) 7.0), 1.16 (1.5H, d, J ) 6.8), 1.18 (1.5H,
d, J ) 6.8), 1.54-1.62 (1H, m), 1.73 (1H, dd, J ) 12.0 and
11.9), 1.83-2.14 (2H, m), 3.29 (1.5H, s), 3.33 (1.5H, s), 3.82
(3H, s), 3.83-3.91 (1H, m), 4.27 (0.5H, d, J ) 10.2), 4.30 (0.5H,
d, J ) 10.2), 4.32 (0.5H, d, J ) 6.4) and 4.38 (0.5H, d, J )
4.5). HRMS calcd for C14H24O5S2 (M+ - 32) 304.0802, found
304.0815.
En tr y 8: A mixture of 21 (29.7 mg, 0.103 mmol), Pd(OAc)2
(2.50 mg, 10.3 µmol), and Ph3P (10.7 mg, 4.12 µmol) in DMF
(1 mL) was heated at 90 °C in a sealed tube for 6.5 h. Workup
in the same way provided 5 (18.9 mg, 87%).
(-)-(1R,2R,6R,7R)-6,7-Dim eth yl-3-oxo-2,8-d ioxa bicyclo-
[3.3.0]octa n e (22). To a solution of 5 (390 mg, 1.84 mmol) in
DMF (20 mL) was added LiI (493 mg, 3.68 mmol) at room
temperature, and the solution was heated under reflux for 5
h. The reaction was cooled to room temperature and then
quenched by addition of H2O. The resulting mixture was
extracted with Et2O. The ethereal layer was dried, filtered,
and evaporated to yield an oil, which was chromatographed.
Elution with a 4:1 mixture of hexanes-EtOAc gave a 3:1
mixture of the corresponding lactones (215 mg, 76%) as a
colorless oil. [R]22 +48.07 (c 0.03, CHCl3). IR 1740, 1640
D
cm-1; H NMR δ 0.85 (2H, d, J ) 7.1), 0.99 (1H, d, J ) 7.1),
1
1.31 (1H, d, J ) 6.6), 1.34 (2H, d, J ) 6.6), 1.80-1.98 (1H, m),
2.36-2.48 (1.2H, m), 2.56-2.68 (1H, m), 2.72-2.83 (0.8H, m),
4.52-4.62 (1H, m), 5.03-5.19 (2H, m), 5.73 (0.33H, ddd, J )
16.8, 10.1 and 5.6), and 5.80 (0.67H, ddd, J ) 16.8, 10.1 and
5.6). HRMS calcd for C9H14O2 (M+) 154.0933, found 154.0989.
Through a stirred solution of the above material (181 mg,
1.17 mmol) in MeOH (10 mL) at -78 °C was passed a stream
of O3. When the reaction mixture maintained a blue color for
15 min, the stream of ozone was replaced by nitrogen and the
solution was stirred until the color dissipated. To the resulting
clear reaction mixture was added Me2S (0.40 mL, 5.86 mmol)
at -78 °C, and the solution was allowed to warm to room
temperature. After being stirred for 1 h at room temperature,
the solvent was removed under reduced pressure to leave a
residue (ca. 250 mg), which was taken up in CH2Cl2 (15 mL).
To this was slowly added concd HCl (2 mL) at room temper-
ature, and the mixture was again stirred at the same tem-
perature for 15 h. The mixture was neutralized with saturated
NaHCO3 at 0 °C, and then the resulting solution was extracted
with Et2O. The ethereal layer was washed with saturated
NaCl, dried, filtered, and evaporated to afford a solid, which
was chromatographed. Elution with a 1:1 mixture of hex-
anes-EtOAc gave 22 (168 mg, 92% for two steps) as a powder.
Recrystallization from Et2O furnished 22 as prisms, mp 58-
To a solution of the above alcohol (231 mg) and DMAP (0.5
mg, 4.10 µmol) in pyridine (1 mL) was slowly added benzoyl
chloride (75.2 µL, 647 µmol) at 0 °C, and the solution was
stirred at 0 °C for 15 min and at room temperature for 8 h.
The mixture was quenched by addition of saturated KHSO4
at 0 °C, and the mixture was extracted with Et2O. The
ethereal layer was washed with saturated NaCl, dried, filtered,
and evaporated to give an oil, which was chromatographed.
Elution with a 6:1 mixture of hexanes-EtOAc provided a 1:1
mixture of 24 (185 mg, 97% for three steps) as a colorless oil.
[R]24D +34.2 (c 0.07, CHCl3). IR 1760 and 1730 cm-1; 1H NMR
δ 0.75 (1.5H, d, J ) 7.5), 0.90 (1.5H, d, J ) 7.5), 1.15 (1.5H, d,
J ) 7.5), 1.20 (1.5H, d, J ) 7.5), 1.80-2.22 (3H, m), 2.40-
2.60 (1H, m), 3.18-3.22 (4H, m), 3.23 (1.5H, s), 3.40 (1.5H, s),
3.78 (1.5H, s), 3.82 (1.5H, s), 3.82-3.90 (1H, m), 4.32 (0.5H,
d, J ) 7.5), 4.38 (0.5H, d, J ) 7.5), 5.30 (0.5H, s), 5.39 (0.5H,
s), 7.40-7.48 (2H, m), 7.50-7.64 (1H, m), 8.00-8.12 (2H, m).
59 °C. [R]19 -10.5 (c 0.05, CHCl3). IR 1780 cm-1; 1H NMR δ
HRMS calcd for
408.1081.
C
21H28O6S2 (M+ - 32) 408.1064, found
D
0.97 (3H, d, J ) 7.0), 1.23 (3H, d, J ) 6.2), 2.10 (1H, ddt, J )
7.0, 5.0 and 2.0), 2.45 (1H, dd, J ) 17.6 and 3.3), 2.75-2.83
(1H, m), 2.88 (1H, dd, J ) 17.6 and 10.5), 4.33 (1H, dq, J )
6.2 and 5.0), and 6.06 (1H, d, J ) 5.1). HRMS calcd for
C8H13O3 (M+ + 1) 157.0864, found 157.0877. Anal. Calcd for
C8H12O3: C, 61.52; H, 7.74. Found: C, 61.52; H, 7.71.
(-)-(3R,4R,5R)-4,5-Dim eth yl-3-(1,3-d ith iola n -2-yl)p en -
ta n olid e (23). To a solution of 22 (161 mg, 1.03 mmol) in
CH2Cl2 (10 mL) were added dropwise 1,2-ethanedithiol (0.104
(+)-Meth yl (2R,4R,5R,6R)-[5,6-Dim eth yl-4-(h yd r oxy-
m et h yl)-2-m et h oxyt et r a h yd r op yr a n yl]-2-O-b en zoylgly-
cola te (25). A mixture of 24 (50.8 mg, 0.115 mmol), HgO (37.6
mg, 0.173 mmol), and HgCl2 (62.6 mg, 0.230 mmol) in a
mixture of MeCN (0.8 mL) and H2O (0.2 mL) was heated at
62 °C for 3 h. The mixture was cooled to room temperature
and then diluted with Et2O. The resulting mixture was
filtered through Celite. The filtrate was separated, and the

5902 J . Org. Chem., Vol. 63, No. 17, 1998
Toyota et al.
organic layer was washed in succession with 5 M NH4OAc,
H2O, saturated NaHCO3, H2O, and saturated NaCl, dried,
filtered, and evaporated to yield the aldehyde (63.2 mg), which
was immediately used in the subsequent reaction without
purification. IR 2725, 1760, 1740, and 1730 cm-1; 1H NMR δ
0.75 (1.5H, d, J ) 7.0), 0.89 (1.5H, d, J ) 7.0), 1.11 (1.5H, d,
J ) 7.0), 1.16 (1.5H, d, J ) 6.8), 1.76-2.24 (3H, m), 2.50-
2.68 (1H, m), 3.29 (1.5H, s), 3.44 (1.5H, s), 3.80 (1.5H, s), 3.81
(1.5H, s), 3.92-4.08 (1H, m), 5.38 (0.5H, s), 5.43 (0.5H, s),
7.40-7.48 (2H, m), 7.56-7.64 (1H, m), 7.98-8.12 (2H, m) and
9.69 (1H, s).
anes-EtOAc-Et3N afforded a 1:1 mixture of the olefin (26.9
mg, 60% for two steps) as a colorless oil. [R]25 +73.4 (c 0.27,
D
CHCl3). IR 1760 and 1740 cm-1; 1H NMR δ 0.95 (1.5H, d, J )
7.0), 1.11 (1.5H, d, J ) 7.7), 1.14 (1.5H, d, J ) 6.2), 1.16 (1.5H,
d, J ) 7.0), 2.14 (0.5H, d, J ) 13.9), 2.18-2.29 (1H, m), 2.46
(0.5H, d, J ) 14.7), 2.91 (0.5H, ddd, J ) 14.6, 2.5 and 1.6),
3.05 (0.5H, ddd, J ) 13.9, 3.3 and 1.7), 3.27 (1.5H, s), 3.40
(1.5H, s), 3.81 (3H, s), 3.86-3.96 (1H, m), 4.74 (0.5H, dd, J )
2.2 and 2.2), 4.80 (0.5H, dd, J ) 2.2, 2.2), 4.87 (1H, br s), 5.36
(0.5H, s), 5.43 (0.5H, s), 7.38-7.50 (2H, m), 7.52-7.64 (1H,
m), 8.00-8.12 (2H, m). HRMS calcd for C11H15O3 (M+ - 153)
195.1020, found 195.1017.
To a 0 °C solution of the above aldehyde in MeOH (1 mL)
was added NaBH4 (4.30 mg, 0.115 mmol) in several portions,
and then the mixture was again stirred at 0 °C for 0.5 h. To
this was added saturated NH4Cl (4 mL) at 0 °C, and the
solvent was removed under reduced pressure. The resulting
solution was extracted with Et2O, and the ethereal layer was
washed with H2O and saturated NaCl, dried, filtered, and
evaporated to afford an oil, which was chromatographed.
Elution with a 1:1 mixture of hexanes-EtOAc furnished 25
as a 1:1 mixture (33.4 mg, 79% for two steps) as a colorless
To a 0 °C solution of the above benzoate (26.9 mg, 77.0 µmol)
in MeOH (4 mL) was slowly added a solution of NaOMe (8.4
mg, 155 µmol) in MeOH (1 mL), and the mixture was again
stirred at 0 °C for 10 min, and then at room temperature for
1 h. After removal of the solvent, the residue was diluted with
Et2O. The ethereal layer was washed with H2O, dried, filtered,
and evaporated to afford an oil, which was chromatographed.
Elution with a 6:1:0.07 mixture of hexanes-EtOAc-Et3N
provided (+)-methyl pederate (4) (9.3 mg, 50%) as a colorless
oil. [R]22 + 131.16 (c 0.09, CH2Cl2) [lit.6o [R]23 +115 (c 0.30,
oil. [R]25 +63.4 (c 0.31, CHCl3). IR 3500, 1750, and 1730
D
D
D
cm-1
;
1H NMR δ 0.71 (1.5H, d, J ) 7.0), 0.88 (1.5H, d, J )
CH2Cl2)]. IR 3400 and 1740 cm-1; 1H NMR δ 0.94 (3H, d, J )
7.0), 1.16 (3H, d, J ) 6.2), 2.22 (1H, br dq, J ) 7.0 and 2.7),
2.31 (1H, dt, J ) 14.0 and 2.0), 2.37 (1H, d, J ) 14.0), 2.90
(1H, d, J ) 5.6), 3.30 (3H, s), 3.84 (3H, s), 3.92 (1H, dq, J )
6.2 and 2.7), 4.36 (1H, d, J ) 5.5), 4.73 (1H, dd, J ) 2.0 and
1.1) and 4.83 (1H, dd, J ) 2.0 and 0.8). HRMS calcd for
C11H15O3 (M+ - 49) 195.1020, found 195.1013. Further elution
gave (+)-methyl epi-pederate (26) (8.5 mg, 45%). Recrystal-
lization from Et2O of 26 gave rise to prisms, mp 68-69 °C.
7.0), 1.14 (1.5H, d, J ) 5.5), 1.16 (1.5H, d, J ) 5.5), 1.34-1.48
(1H, m), 1.72-1.82 (2.5H, m), 1.92 (0.5H, dd, J ) 3.5 and 3.5),
2.21-2.34 (1H, m), 3.28 (1.5H, s), 3.42 (1.5H, s), 3.56 (2H, dd,
J ) 7.0 and 7.0), 3.79 (1.5H, s), 3.79 (1.5H, s), 3.86-3.96 (1H,
m), 5.32 (0.5H, s), 5.38 (0.5H, s), 7.44-7.50 (2H, m), 7.56-
7.63 (1H, m) and 8.04-8.10 (2H, m). HRMS calcd for C18H23O6
(M+ - 31) 355.1493, found 355.1499.
(+)-Meth yl P ed er a te (4). To a stirred solution of 25 (18.2
mg, 0.130 mmol) and 2-nitrophenyl selenocyanate (44.8 mg,
0.200 mmol) in THF (2 mL) at 0 °C was slowly added Bu3P
(49.0 µL, 0.200 mmol), and the mixture was again stirred at 0
°C for 10 min and then at room temperature for 8 h. The
mixture was subjected to column chromatography on Florisil.
Elution with a 5:1 mixture of hexanes-EtOAc produced the
selenide (229 mg), a colorless oil, together with a small portion
of inseparable impurities. IR 1750 and 1730 cm-1; 1H NMR δ
0.76 (1.5H, d, J ) 7.0), 0.94 (1.5H, d, J ) 6.6), 1.16 (1.5H, d,
J ) 6.6), 1.17 (1.5H, d, J ) 6.6), 1.75-2.16 (3H, m), 2.36-
2.50 (1H, m), 2.80-3.00 (2H, m), 3.26 (1.5H, s), 3.40 (1.5H, s),
3.80 (1.5H, s), 3.81 (1.5H, s), 3.84-3.92 (1H, m), 5.33 (0.5H,
s), 5.38 (0.5H, s), 7.28-7.62 (6H, m), 7.86-8.08 (2H, m) and
8.24-8.40 (1H, m). HRMS calcd for C25H29NO8Se 551.1057,
found 551.1099.
To a 0 °C solution of the above selenide in THF (2 mL) was
added dropwise 30% H2O2 (0.170 mL, 1.50 mmol), and the
resulting mixture was again stirred at 0 °C for 1 h and then
at room temperature for 10 min. After addition of H2O and
Et2O, the organic layer was washed with 10% Na2CO3 and
H2O, dried, filtered, and evaporated to give an oil, which was
chromatographed. Elution with a 6:1:0.07 mixture of hex-
[R]24 +87.15 (c 0.070, CHCl3). IR 3400 and 1740 cm-1 1H
;
D
NMR δ 1.02 (3H, d, J ) 7.0), 1.17 (3H, d, J ) 6.6), 1.92 (1H,
d, J ) 14.3), 2.21 (1H, br dq, J ) 7.0 and 2.5), 2.78-2.80 (2H,
m), 3.34 (3H, s), 3.82 (3H, s), 3.92 (1H, dq, J ) 6.6 and 2.5),
4.43 (1H, d, J ) 4.4), 4.70 (1H, dd, J ) 2.2 and 2.1) and 4.84
(1H, t, J ) 2.0). HRMS calcd for C10H16O4 (M+ - 44) 200.1048,
found 200.1034. Anal. Calcd for C12H20O5: C, 59.00; H, 8.25.
Found: C, 59.38; H, 8.05.
Ack n ow led gm en t. We are very grateful to Dr.
Tadashi Nakata (Riken), for sending us copies of the
spectral data of (+)-methyl pederate (4).
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra
(300 MHz) for compounds 9, 10, 11, 24, 25, and 4 (6 pages).
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