Efficient conditions for conversion of 2-substituted furans into 4-oxygenated 2-enoic acids and its application to synthesis of (+)-aspicilin, (+)-patulolide a, and (-)-pyrenophorin

Article abstract of DOI:10.1021/jo980942a

2-Substituted furans 1a,b,c were found to be conveniently transformed into trans 4-oxo-2-enals 2a,b,c in 62-87% yields by using NBS/pyridine in THF-acetone-H₂O (<-15 °C then rt) or NBS/ NaHCO₃ in acetone-H₂O (<-15 °C then rt after addition of pyridine). Further oxidation of the enals 2a-c using NaClO₂ led to the trans 4-oxo-2-enoic acids 3a-c in good yields. With this transformation in mind, we designed syntheses of (+)-aspicilin, (+)-patulolide, and (-)-pyrenophorin. In the synthesis of (+)-aspicilin as shown in Schemes 1 and 2, the pivotal intermediate 6 was prepared from olefin 7 in which 2-furyl group is attached. The AD reaction of 7 secured the C(5) and C(6) stereochemistry of aspicilin, and the subsequent transformation using the protocol described above afforded the ester 6. Stereocontrolled reduction of 6 followed by deprotection and the Yamaguchi macrocyclization furnished (+)-aspicilin. For the synthesis of (+)-patulolide (Scheme 3) and (-)-pyrenophorin (Scheme 4), the intermediates are the furans 38 and 44, which were prepared easily by the classical methods using furyllithium 33. The furan ring oxidations proceeded as well, furnishing acids 40 and 46 in good yields, acetalization of which afforded the known intermediates 41 and 47, respectively.

Full text of DOI:10.1021/jo980942a

J . Org. Chem. 1998, 63, 7505-7515
7505
Efficien t Con d ition s for Con ver sion of 2-Su bstitu ted F u r a n s in to
4-Oxygen a ted 2-En oic Acid s a n d Its Ap p lica tion to Syn th esis of
(+)-Asp icilin , (+)-P a tu lolid e A, a n d (-)-P yr en op h or in
Yuichi Kobayashi,* Miwa Nakano, G. Biju Kumar, and Kiyonobu Kishihara
Department of Biomolecular Engineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku,
Yokohama 226-8501, J apan
Received May 19, 1998
2-Substituted furans 1a ,b,c were found to be conveniently transformed into trans 4-oxo-2-enals
2a ,b,c in 62-87% yields by using NBS/pyridine in THF-acetone-H2O (<-15 °C then rt) or NBS/
NaHCO3 in acetone-H2O (<-15 °C then rt after addition of pyridine). Further oxidation of the
enals 2a -c using NaClO2 led to the trans 4-oxo-2-enoic acids 3a -c in good yields. With this
transformation in mind, we designed syntheses of (+)-aspicilin, (+)-patulolide, and (-)-pyrenophorin.
In the synthesis of (+)-aspicilin as shown in Schemes 1 and 2, the pivotal intermediate 6 was
prepared from olefin 7 in which 2-furyl group is attached. The AD reaction of 7 secured the C(5)
and C(6) stereochemistry of aspicilin, and the subsequent transformation using the protocol
described above afforded the ester 6. Stereocontrolled reduction of 6 followed by deprotection and
the Yamaguchi macrocyclization furnished (+)-aspicilin. For the synthesis of (+)-patulolide (Scheme
3) and (-)-pyrenophorin (Scheme 4), the intermediates are the furans 38 and 44, which were
prepared easily by the classical methods using furyllithium 33. The furan ring oxidations proceeded
as well, furnishing acids 40 and 46 in good yields, acetalization of which afforded the known
intermediates 41 and 47, respectively.
In tr od u ction
a few applications of this methodology have been suc-
cessful. Among them, the further oxidation to trans
4-oxo-2-enoic acids published by Hase3c is attractive in
that the overall transformation (eq 1) constitutes a
method for synthesis of the natural products possessing
the 4-oxygenated 2-enoic acid structures, some of which
are shown in Figure 1.6
Oxidation of 2,5-disubstituted furans into functionally
rich trans 2-ene-1,4-diones has been intensively stud-
ied.1,2 Application of this oxidation to 2-substituted
furans provides trans 4-oxo-2-enals, which are important
intermediates in organic synthesis. To date, Br2 coupled
with subsequent hydrolysis under acidic conditions,3
PCC,2i,4 and J ones reagent5 have been utilized for this
transformation. However, these reagents are not com-
patible with functional groups which are frequently
present in synthetic intermediates. Such groups are
olefins, acid labile groups or protective groups, and/or
distal hydroxyl group(s). Moreover, inadequate or mod-
erate to low yields have been reported for some of the
2-substituted furans. Thus, it is not surprising that only
(1) Lipshutz, B. H. Chem. Rev. 1986, 86, 795-819.
2-Substituted furans are prepared easily and in large
quantity not only by the classical alkylation of furyl-
lithium with alkyl halides,7 but also by the modern
coupling reaction using the appropriate combination of
a furyl organometallic or halide and an alkenyl or aryl
halide or organometallic under a transition metal cata-
lyst.8,9 In addition, the furan ring is chemically stable
(2) Oxidation of 2,5-disubstituted furans: By Br2 followed by hy-
drolysis: (a) Levisalles, J . Bull. Soc. Chim. Fr. 1957, 997-1003. (b)
Lee, T. Tetrahedron Lett. 1979, 2297-2300. (c) J urczak, J .; Pikul, S.
Tetrahedron Lett. 1985, 26, 3039-3040. (d) Pikul, S.; Raczko, J .;
Ankner, K.; J urczak, J . J . Am. Chem. Soc. 1987, 109, 3981-3987. By
m-CPBA: (e) Williams, P. D.; LeGoff, E. J . Org. Chem. 1981, 46, 4143-
4147. (f) Williams, P. D.; LeGoff, E. Tetrahedron Lett. 1985, 26, 1367-
1370. (g) Cattalini, M.; Cossu, S.; Fabris, F.; De Lucchi, O. Synth.
Commun. 1996, 26, 637-647. By Collins reagent: (h) Birch, A. J .;
Keogh, K. S.; Mamdapur, V. R. Aust. J . Chem. 1973, 26, 2671-2674.
By PCC: (i) Piancatelli, G.; Scettri, A.; D’Auria, M. Tetrahedron 1980,
36, 661-663. (j) J urczak, J .; Pikul, S. Tetrahedron Lett. 1984, 25,
3107-3110. By NaClO: (k) Fitzpatrick, J . E.; Milner, D. J .; White, P.
Synth. Commun. 1982, 12, 489-494.
(6) (a) Boeckman, R. H., J r.; Goldstein, S. W. In The Total Synthesis
of Natural Products; ApSimon, J ., Ed.; Wiley: New York, 1988; Vol.
7, Chapter 1. (b) Asaoka, M.; Takei, H. J . Synth. Org. Chem. J pn. 1986,
44, 819-828.
(3) (a) MacLeod, J . K.; Bott, G.; Cable, J . Aust. J . Chem. 1977, 30,
2561-2564. (b) Hirsch, J . A.; Szur, A. J . J . Heterocycl. Chem. 1972, 9,
523-529. (c) Hase, T. A.; Nylund, E.-L. Tetrahedron Lett. 1979, 2633-
2636. (d) Gunn, B. P. Tetrahedron Lett. 1985, 26, 2869-2872. (e) Gunn,
B. P. Heterocycles 1985, 23, 3061-3067. (f) Yadav, J . S.; Krishna, P.
R.; Gurjar, M. K. Tetrahedron 1989, 45, 6263-6270.
(7) Bu¨chi, G.; Wu¨est, H. J . Org. Chem. 1966, 31, 977-978.
(8) Reviews: (a) Tsuji, J . Palladium Reagents and Catalysts;
Wiley: New York, 1995. (b) Knight, D. W. In Comprehensive Organic
Synthesis; Trost, B. M.; Fleming, I.; Pattenden, G., Eds.; Pergamon:
New York, 1991; Vol. 3, pp 481-520. (c) Miyaura, N.; Suzuki, A. Chem.
Rev. 1995, 95, 2457-2483.
(9) (a) Pelter, A.; Rowlands, M. Tetrahedron Lett. 1987, 28, 1203-
1206. (b) Pelter, A.; Rowlands, M.; Clements, G. Synthesis 1987, 51-
53. (c) Kang, S.-K.; Lee, H.-W.; J ang, S.-B.; Kim, T.-H.; Kim, J .-S.
Synth. Commun. 1996, 26, 4311-4318.
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42, 151-154.
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1989, 54, 911-914.
S0022-3263(98)00942-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/01/1998

7506 J . Org. Chem., Vol. 63, No. 21, 1998
Kobayashi et al.
Ta ble 1. Oxid a tion of F u r a n s 1a -c to Ald eh yd es 2a -ca
yield of
entry
furan
oxidant
base
2a -cb (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1b
1c
1c
NBS
NBS
NBS
NCS
NBS
NBS
NBS
NBS
pyridine
-
65
50
71
0
62
69
87
76
c
NaHCO3
pyridine
pyridine
NaHCO3
pyridine
NaHCO3
c
c
a
Reactions were carried out below -15 °C until the furan was
consumed completely (usually <2 h) and then at room temperature
b
for several hours. Further oxidation to the acids 3a -c: see the
text. c After the disappearance of 1 (checked by TLC), pyridine was
added to the mixture.
Resu lts a n d Discu ssion
P r elim in a r y Resu lts. To obtain more information,
the NBS oxidation was applied to furans 1a -c. As a
scavenger of HBr, a weak base17 such as pyridine and
NaHCO3 was examined, and the results are shown in
Table 1. Although oxidation was completed within 2 h
at <-15 °C, further reaction at room temperature for
several hours was indispensable for isomerization of the
initially produced cis 4-oxo-2-enals to the trans enals 2a -
c. Since the aldehydes 2a -c were found to be unstable,
especially under alkaline conditions,17 isolation and
purification by column chromatography on silica gel were
carried out as fast as possible. With regard to 1a ,
oxidation in the presence of pyridine did provide a better
yield of the aldehyde 2a (entries 1 and 2). Almost equal
efficiency was also obtained with NaHCO3 (entry 3),
where addition of pyridine after the oxidation accelerated
isomerization to trans enal 2a . The oxidation of 1a with
NCS was not successful (entry 4). Similarly, NBS/
F igu r e 1. Naturally occurring 4-oxygenated 2-enoic acid
derivatives.
under mild oxidative, weakly acidic, and basic conditions.
These properties are convenient for transformation of an
initially introduced simple substituent to a more com-
plicated one through carbon-carbon bond-forming reac-
tions and/or functional group conversions. Thus, finding
a mild reagent and conditions for oxidation of 2-substi-
tuted furans 1 into trans 4-oxo-2-enals 2 makes the
transformation depicted in eq 1 a more versatile and
general method for synthesis of 4-oxo-2-enoic acids 3 and
4-oxygenated 2-enoic acids.10
Recently, we had an occasion to study the oxidation of
furan 4 in the synthesis of brefeldin A. After our efforts
with the literature protocols using PCC in CH2Cl2,2i,4 and
Br2 in aqueous acetone2c or aqueous MeCN2d proved
fruitless, we found that NBS11 in THF-acetone-H2O (at
-20 °C, then rt) was effective for oxidation of 4 into trans
4-oxo-2-enal 5 (eq 2).12 Slightly acidic conditions (pH
5-6) and short reaction times (4 h) coupled with easy
(13) (a) Quinkert, G.; Heim, N.; Glenneberg, J .; Do¨ller, U.; Eichhorn,
M.; Billhardt, U.-M.; Schwarz, C.; Zimmermann, G.; Bats, J . W.;
Du¨rner, G. Helv. Chim. Acta 1988, 71, 1719-1794. (b) Quinkart, G.;
Fernholz, E.; Eckes, P.; Neumann, D.; Du¨rner, G. Helv. Chim. Acta
1989, 72, 1753-1786. (c) Quinkert, G.; Becker, H.; Du¨rner, G.
Tetrahedron Lett. 1991, 32, 7397-7400. (d) Oppolzer, W.; Radinov, R.
N.; De Brabander, J . Tetrahedron Lett. 1995, 36, 2607-2610. (e)
Enders, D.; Prokopenko, O. F. Liebigs Ann. 1995, 1185-1191. (f) Sinha,
S. C.; Keinan, E. J . Org. Chem. 1997, 62, 377-386.
(14) (a) Rodphaya, D.; Sekiguchi, J .; Yamada, Y. J . Antibiot. 1986,
39, 629-635. (b) Makita, A.; Yamada, Y.; Okada, H. J . Antibiot. 1986,
39, 1257-1262. (c) Mori, K.; Sakai, T. Liebigs Ann. Chem. 1988, 13-
17. (d) Ayyangar, N. R.; Chanda, B.; Wakharkar, R. D.; Kasar, R. A.
Synth. Commun. 1988, 18, 2103-2109. (e) Solladie´, G.; Gerber, C.
Synlett 1992, 449-450. (f) Yang, H.; Kuroda, H.; Miyashita, M.; Irie,
H. Chem. Pharm. Bull. 1992, 40, 1616-1618. (g) Bestmann, H. J .;
Kellermann, W.; Pecher, B. Synthesis 1993, 149-152. (h) Sharma, A.;
Sankaranarayanan, S.; Chattopadhyay, S. J . Org. Chem. 1996, 61,
1814-1816. (i) Kamezawa, M.; Kitamura, M.; Nagaoka, H.; Tachibana,
H.; Ohtani, T.; Naoshima, Y. Liebigs Ann. 1996, 167-170.
(15) (a) Gerlach, H.; Oertle, K.; Thalmann, A. Helv. Chim. Acta 1977,
60, 2860-2865. (b) Seuring, B.; Seebach, D. Liebigs Ann. Chem. 1978,
2044-2073. (c) Labadie, J . W.; Tueting, D.; Stille, J . K. J . Org. Chem.
1983, 48, 4634-4642. (d) Baldwin, J . E.; Adlington, R. M.; Ramchari-
tar, S. H. Synlett 1992, 875-877. (e) Machinaga, N.; Kibayashi, C.
Tetrahedron Lett. 1993, 34, 841-844. (f) Matsushita, Y.; Furusawa,
H.; Matsui, T.; Nakayama, M. Chem. Lett. 1994, 1083-1084. (g)
Nokami, J .; Taniguchi, T.; Gomyo, S.; Kakihara, T. Chem. Lett. 1994,
1103-1106. (h) Bonete, P.; Na´jera, C. J . Org. Chem. 1994, 59, 3202-
3209. (i) Barco, A.; Benetti, S.; De Risi, C.; Pollini, G. P.; Zanirato, V.
Tetrahedron 1995, 51, 7721-7726. (j) Hoffman, R. V.; Patonay, T.;
Nayyar, N. K.; Tao, J . Tetrahedron Lett. 1996, 37, 2381-2384, and
references therein.
handling seem to suit the present purpose. Thus, to test
the generality of this key oxidation and efficiency of the
overall furan-methodology, we have carried out the
asymmetric syntheses of (+)-aspicilin,13 (+)-patulolide
A,3f,14 and (-)-pyrenophorin.5,10c,14e,15 Herein we describe
full results of our experimentation.16
(10) Although the method using 2-alkoxyfuran originally published
by Takei is efficient, this approach suffers from inadequacy of a side
chain-manipulation(s) due to instability of alkoxyfuran: (a) Asaoka,
M.; Yanagida, N.; Ishibashi, K.; Takei, H. Tetrahedron Lett. 1981, 22,
4269-4270. (b) Asaoka, M.; Yanagida, N.; Takei, H. Tetrahedron Lett.
1980, 21, 4611-4614. (c) Asaoka, M.; Yanagida, N.; Sugimura, N.;
Takei, H. Bull. Chem. Soc. J pn. 1980, 53, 1061-1064. (d) Gunn, B.
P.; Brooks, D. W. J . Org. Chem. 1985, 50, 4417-4418.
(11) NBS has been used to convert furfuryl alcohols and related
compounds into 2H-pyran-3(6H)-ones: (a) Georgiadis, M. P.; Coula-
douros, E. A. J . Org. Chem. 1986, 51, 2725-2727. (b) Perron, F.;
Albizati, K. F. J . Org. Chem. 1989, 54, 2044-2047.
(12) Kobayashi, Y.; Watatani, K.; Kikori, Y.; Mizojiri, R. Tetrahedron
Lett. 1996, 37, 6125-6128.
(16) (a) Kobayashi, Y.; Kishihara, K.; Watatani, K. Tetrahedron Lett.
1996, 37, 4385-4388. (b) Kobayashi, Y.; Nakano, M.; Okui, H.
Tetrahedron Lett. 1997, 38, 8883-8886.
(17) For example, stirring a mixture of an ethereal solution of 2a
and 1 N NaOH (1:1) at room temperature only for 30 min resulted in
complete decomposition. To remove pyridine, organic extracts were
washed with dilute HCl or dilute CuSO4 solution in some cases.

4-Oxygenated 2-Enoic Acids from 2-Substituted Furans
J . Org. Chem., Vol. 63, No. 21, 1998 7507
Sch em e 1
silyl ether 17 (Scheme 2), on the other hand, hardly
proceeded, and 17 was recovered. We then investigated
path B, and this approach using 2-bromofuran (10) and
alkenylborane 11 (M ) B(Sia)2) was found to be success-
ful. The sequence to 7 and further transformation to (+)-
aspicilin is summarized in Scheme 2.
11-Bromo-1-undecene, prepared from commercially
available 10-undecen-1-ol (12), was transformed into the
corresponding Grignard reagent 14. Copper-catalyzed
epoxide ring-opening of (-)-propylene oxide ((S)-13)21 of
[R]20 ) -13 to -14 (neat) (cf. [R]20 ) +12 to +14 for
D
D
(R)-isomer of >97% ee) with 14 afforded alcohol 15 in
88% yield. Since accurate enantiomeric purity of (S)-13
was not given, 15 was transformed to the corresponding
1
MTPA ester, and >95% ee was ascertained by H NMR
spectroscopy. The alcohol 15 was also obtained from (R)-
29 of 98.8% ee by the epoxide ring-opening with 14
followed by reductive dechlorination with LiAlH4 quan-
titatively (eq 4). Compound 15 was transformed into
acetylene 17 in excellent yield by the standard method
through alcohol 16. To convert 17 into the key alkenyl-
pyridine and NBS/NaHCO3 oxidation of 1b,c furnished
the corresponding aldehydes 2b,c in good yields. The
aldehydes 2a -c thus prepared were converted to acids
3c,18
3a -c with NaClO2
respectively.
in 77%, 78%, and 70% yields,
Syn th esis of (+)-Asp icilin . Keeping in mind that the
furan ring is a chemically stable synthetic equivalent of
the 4-oxo-2-butenoic acid structure, we envisioned a
synthesis of (+)-aspicilin as shown in Scheme 1. The
pivotal intermediates are 4-oxo-2-enoate 6 and the al-
kenyl furan 7. Asymmetric dihydroxylation (AD) of 7
using AD-mix-â19 followed by the oxidative transforma-
tion of the furan ring should produce 6. Stereoselective
reduction of 6 and lactonization of the corresponding seco
acid would furnish (+)-aspicilin. To accomplish the
stereoselective reduction, chelation of a metal cation to
the oxygen at C(5) of 6 is a crucial requirement.
For preparation of 7, two sequences (paths A and B
depicted in Scheme 1) are feasible. Initially, path A was
examined. Preparation of the required iodide 9 was
attempted from the readily available acetylene 16 of
Scheme 2 (vide infra). Hydroalumination of 16 with
DIBALH (2.2 equiv) in hexane and the subsequent
iodination were carried out according to the procedure
for simple acetylenes.20 However, a substantially large
quantity of olefin 28 was coproduced with iodide 27 (eq
3). Slow addition of DIBALH to 16 in hexane at lower
temperatures or vice versa did not improve the situation.
These results indicate the reaction of DIBALH with the
hydroxyl group was competitive with the hydroalumina-
tion on the triple bond followed by proton transfer to give
an aluminum alkoxide of 28. Hydroalumination of the
metal 11 (Scheme 1) and to accomplish the reaction with
10 producing the key intermediate 7, we selected the
Suzuki reaction due to its convenience.8c,22 Hydrobora-
tion of 17 with (Sia)2BH in THF was carried out as usual
to produce alkenylborane 11 (M ) B(Sia)2). Subse-
quently, aqueous NaOH, 2-bromofuran (10), and Pd-
(PPh3)4 (5 mol %) were added to a THF solution of 11,
and the mixture was stirred for further 5 h under reflux
to afford 7 in 92% yield. 1H NMR (500 MHz) spectrum
of 7 confirmed the trans olefin geometry (J olefin ) 16 Hz),
and there was no production of the cis isomer or the
terminal olefin (deiodination product).
The Sharpless asymmetric dihydroxylation19 of 7 pro-
ceeded efficiently at room temperature overnight. Ex-
clusive production of one diastereoisomer was confirmed
1
by H NMR spectroscopy of the derived bis-MTPA ester
1
since the H NMR spectra of 18 and its diastereoisomer
32 shown in eq 5 (vide infra) were superimposed.
Absolute stereochemistry of the diol was tentatively
assigned as 18 based on the well-established empirical
rule and was confirmed upon completion of the synthesis.
It is worth mentioning that, while the high yield of 91%
was obtained with AD-mix-â, the classical osmium-
catalyzed dihydroxylation23 afforded the diol only in
moderate yield (50%). These results indicate that com-
petitive oxidation of the furan ring occurred under the
(18) (a) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27,
888-890. (b) Kraus, G. A.; Roth, B. J . Org. Chem. 1980, 45, 4825-
4830. (c) Kraus, G. A.; Taschner, M. J . J . Org. Chem. 1980, 45, 1175-
1176.
(19) (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G.
A.; Hartung, J .; J eong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-
M.; Xu, D.; Zhang, X.-L. J . Org. Chem. 1992, 57, 2768-2771. (b) Kolb,
H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94,
2483-2547.
(20) Zweifel, G.; Miller, J . A. In Organic Reactions; Dauben, W. G.,
Ed.; Wiley: New York, 1984; Vol. 32, pp 375-517.
(21) Purchased from Merck.
(22) Miyaura, N.; Yamada, K.; Suginome, H.; Suzuki, A. J . Am.
Chem. Soc. 1985, 107, 972-980.
(23) Schro¨der, M. Chem. Rev. 1980, 80, 187-213.

7508 J . Org. Chem., Vol. 63, No. 21, 1998
Kobayashi et al.
Sch em e 2a
a
Reagents and conditions: (a) (1) CBr4, PPh3 (100%), (2) Mg, THF; (b) 14, CuCN (0.05 equiv) (88%); (c) Br2; (d) NaNH2, NH3 (96% from
o
15); (e) TBDMSCl, imidazole, DMF (100%); (f) Sia2BH (2 equiv), THF, -10 C, 1 h then 10 (3 equiv), Pd(PPh3)4 (0.05 equiv), aq NaOH (1.5
equiv), reflux, 5 h (92%); (g) AD-mix-â, MeSO2NH2, 0 °C to room temperature (91%); (h) MOMCl, i-Pr2NEt, CH2Cl2, 30 oC (92% for 19,
84% for 23); (i) NBS (1.1 equiv), NaHCO3 (2 equiv), acetone/H2O (10:1), -15 °C, 15 min then furan (3 equiv), 30 min and C5H5N (2 equiv),
overnight (71%); (j) NaClO2 (5 equiv), Me2CdCHMe (15 equiv) (88%); (k) [2-Cl-C5H4NMe]I (3 equiv), MeOH (1.2 equiv), NEt3 (2.4 equiv)
(65%); (l) Zn(BH4)2, -78 °C to -40 °C, Et2O (90%); (m) NBS (1.1 equiv), DMSO/H2O (19:1) (79%); (n) LiOH, MeOH-H2O; (o) 2,4,6-
Cl3C6H2COCl, NEt3 then DMAP, toluene, reflux (53% from 24); (p) HS(CH2)2SH, BF3‚OEt2 (56%).
latter conditions as has been suggested.24 During our
investigation, the AD reaction of 2-(1-alkenyl)furans was
reported by Ogasawara.25 The alcohol 18 was protected
with MOMCl into the MOM ether 19 in high yield, and
the stage was set for the furan ring oxidation.
Oxidation of furan 19 with NBS was carried out under
the conditions mentioned above. Unfortunately, NBS/
pyridine afforded a mixture of the aldehyde 20 and the
bromofuran 30 in a ratio of 7:1.26 However, NBS/
NaHCO3 proceeded successfully to furnish the somewhat
According to the procedure of Nakata,28 reduction of 6
using excess Zn(BH4)2 was carried out in Et2O at -78 °C
to produce the alcohol 22 in 90% yield with >15:1
diastereoselectivity (determined by 1H NMR spectros-
copy). The structure of 22 with the C(4)-C(5) anti
stereochemistry was tentatively assigned on the basis of
literature analogy2d,29 and was confirmed at the stage of
aspicilin. Protection of alcohol 22 afforded the MOM
ether 23, which was transformed in good yield to the seco
acid 25 by deprotection of the TBDMS group with NBS30
followed by hydrolysis. With regard to the deprotection,
the use of Bu4NF in THF resulted in competitive elimi-
nation of the MOM group at the C(5) position to furnish
31 (R ) H, TBDMS). Finally, macrolactonization by the
Yamaguchi method31 furnished 26 (FAB mass, M+ + Na
unstable aldehyde 20 in 71% yield. Further oxidation
of 20 with NaClO2 furnished the acid 21 and the
subsequent esterification by using the Mukaiyama re-
agent27 afforded the key intermediate 6 in good yield.
) 483), which upon deprotection of the three MOM
groups with BF3‚OEt2 and HS(CH2)2SH13e,f afforded (+)-
aspicilin in 30% yield from 24 after chromatography on
silica gel. Physicochemical data of (+)-aspicilin thus
obtained were consistent with the reported values: 1H
(24) Oxidation of furans: Hartman, R. F.; Rose, S. D. J . Org. Chem.
1981, 46, 4340-4345.
(25) (a) Taniguchi, T.; Ohnishi, H.; Ogasawara, K. Chem. Commun.
1996, 1477-1478. (b) Taniguchi, T.; Nakamura, K.; Ogasawara, K.
Synlett 1996, 971-972. (c) Taniguchi, T.; Nakamura, K.; Ogasawara,
K. Synthesis 1997, 509-511.
NMR (300 MHz),13e,f optical rotation ([R]22 ) +37.5 (c
D
0.55, CHCl3); lit.13e [R]23 ) +37.7 (c 0.22, CHCl3), lit.13f
D
[R]D ) +38.5 (c 1.05, CHCl3)), and mp (152-155 °C
(recrystallized from hexane-ethyl acetate); lit. 154-156
°C;13c,f 150-152 °C13e).
(26) Formation of 30 is explained by considering the cation i where
the abstraction of Hb by pyridine is competitive with the desired
reaction (A) due to the steric hinderence by the MOM-oxy group.
(28) (a) Nakata, T.; Tani, Y.; Hatozaki, M.; Oishi, T. Chem. Pharm.
Bull. 1984, 32, 1411-1415. (b) Oishi, T.; Nakata, T. Acc. Chem. Res.
1984, 17, 338-344.
(29) Iida, H.; Yamazaki, N.; Kibayashi, C. J . Org. Chem. 1986, 51,
3769-3771 and references therein.
(30) Batten, R. J .; Dixon, A. J .; Taylor, R. J . K.; Newton, R. F.
Synthesis 1980, 234-236.
(31) Inanaga, J .; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. J pn. 1979, 52, 1989-1993.
(27) Saigo, K.; Usui, M.; Kikuchi, K.; Shimada, E.; Mukaiyama, T.
Bull. Chem. Soc. J pn. 1977, 50, 1863-1866.

4-Oxygenated 2-Enoic Acids from 2-Substituted Furans
Sch em e 3a
J . Org. Chem., Vol. 63, No. 21, 1998 7509
a
Reagents and conditions: (a) 33, THF, rt (95%); (b) LiBr, [(C8H17)3NMe]Cl (cat.), 100 °C (94%); (c) Mg, THF; (d) 36, CuCN (cat.), THF
(90%); (e) LiAlH4, THF, rt (93%); (f) NBS (1.5 equiv), pyridine (2 equiv), THF/acetone/H2O (5:4:2), -20 °C, 1 h then rt, 4 h (73%); (g)
NaClO2, 2-methyl-2-butene, t-BuOH/phosphate buffer (pH 3.6)/H2O (2:1:1) (87%); (h) HO(CH2)2OH, p-TsOH (cat.), C6H6 then LiOH, MeOH/
H2O (62%).
Sch em e 4a
As mentioned above, we established a highly stereo-
selective synthesis of (+)-aspicilin. Our route has the
advantages of flexibility and simplicity. Consequently,
stereoisomers and analogues with methylene chains of
different lengths will be synthesized with a similar effort
in a predictable way. For example, 17(R)-isomer of
aspicilin would be prepared simply by switching the
starting epoxide (S)-13 to the (R)-isomer, while the C(4)-
C(6) diastereoisomers by carrying out the AD reaction
with AD-mix-R, by preparing the cis isomer of 7 thereby
producing the C(5)-C(6) anti diol upon the AD reaction
with AD-mix-R or -â, and/or by nonchelation controlled
reduction of the 4-oxo-2-enoate producing the C(4)-C(5)
syn alcohol. In practice, dihydroxylation of 7 using AD-
mix-R resulted in exclusive production of 32 in good yield
a
Reagents and conditions: (a) TBDPSCl, imidazole, DMF
(eq 5). These flexibilities are indispensable for elucidat-
(100%); (b) DIBALH, THF, -50 to -15 °C, 3 h (91%); (c) I2, PPh3,
ing the biological function of aspicilin.
C6H6 (88%); (d) 33, THF, rt (94%); (e) NBS (1.2 equiv), pyridine (4
equiv), THF/acetone/H2O (5:4:2), -20 °C, 1 h then rt, 5 h (64%);
(f) NaClO2, 2-methyl-2-butene, t-BuOH/phosphate buffer (pH 3.6)/
H2O (2:1:1) (83%); (g) HO(CH2)2OH, p-TsOH (cat.), C6H6 then
LiOH, MeOH/H2O (8:1) (70%).
of 37 with LiAlH4 furnished the key intermediate 38 in
excellent yield.
Without protection of the hydroxyl group, the NBS/
pyridine oxidation was applied to furan 38 under the
conditions mentioned above. The reaction proceeded
successfully to furnish trans 4-oxo-2-enal 39 in 73% yield.
Oxidation of 39 with NaClO2 in the presence of 2-methyl-
2-butene18 furnished acid 40 in 87% yield. During these
conversions the hydroxyl group remained untouched.
Finally, protection of the carbonyl group at the C(4)
position and hydrolysis of the ethyl ester partially formed
during ketalization furnished the acid 41, whose 1H NMR
spectra were in accord with the data reported.14b
Syn th esis of (-)-P yr en op h or in . Previously, the
Mitsunobu reaction has been utilized for synthesis of (-)-
pyrenophorin from 47 with inversion of the hydroxyl
group at C(7).15a,e,f Consequently, the key intermediate
is furan 44, and the target compound is acid 47 as shown
in Scheme 4. Iodide 4334 was prepared from com-
mercially available 42 (86% ee)35 in 80% yield. Alkylation
of 43 with 2-furyllithium (33) afforded the key compound
Syn th esis of (+)-P a tu lolid e A. Since (+)-patulolide
A is synthesized from acid 41 by macrolactonization
followed by deprotection,14b,d we planned a synthesis of
acid 41 as shown in Scheme 3, where the key intermedi-
ate is the furan 38. Alkylation of 1-bromo-5-chloropen-
tane with 2-furyllithium (33) afforded the chloride 34 in
95% yield according to the procedure of Bu¨chi.7 Since
an attempt to prepare the Grignard reagent from 34
failed due to instability of the reagent under the condi-
tions we used (THF, reflux), 34 was converted to bromide
35 with LiBr (2 equiv) in the presence of [(C8H17)3NMe]-
1
Cl32 in 94% yield (97% conversion by H NMR), and the
Grignard reagent 36 was prepared successfully. Al-
though the direct precursor of alcohol 38 is apparently
(R)-propylene oxide33 on the basis of the above aspicilin
synthesis, we opted for (S)-epichlorohydrin (29) (98.9%
ee) due to its easier handling and availability. Thus,
reaction of (S)-29 with 36 under the copper catalyst
afforded 37 in 90% yield, and reductive dechlorination
(32) Loupy, A.; Pardo, C. Synth. Commun. 1988, 18, 1275-1281.
(33) Koppenhoefer, B.; Schurig, V. Organic Syntheses; Wiley: New
York, 1993; Coll. Vol. VIII; pp 434-441. This epoxide is available from
Merck.
(34) Snider, B. B.; Shi, Z. J . Am. Chem. Soc. 1994, 116, 549-557.
(35) Synthesis of enantiomerically pure 42: Noyori, R.; Ohkuma,
T.; Kitamura, M.; Takaya, H.; Sayo, N.; Kumobayashi, H.; Akutagawa,
S. J . Am. Chem. Soc. 1987, 109, 5856-5858.

7510 J . Org. Chem., Vol. 63, No. 21, 1998
Kobayashi et al.
CO3 followed by extraction with ethyl acetate and purification
by chromatography (hexane/Et2O): IR (neat) 1597, 1508, 729
cm-1; 1H NMR δ 1.15 and 1.28 (2d, J ) 7 and 7 Hz, 3 H), 1.46-
1.98 (m, 8 H), 2.63-2.89 (m, 2 H), 3.43-3.53 (m, 1 H), 3.70-
3.98 (m, 2 H), 4.62 and 4.72 (2m, 1 H), 5.96-6.02 (m, 1 H),
6.26-6.29 (m, 1 H), 7.29 (br s, 1 H). Anal. Calcd for
44 in good yield. The NBS oxidation of 44 under the
same conditions mentioned above afforded the enal 45
in 64% yield, which upon oxidation with NaClO2 (83%
yield) and subsequent ketalization furnished the inter-
mediate 47, whose 1H NMR spectrum was in good
agreement with the reported data.15c
C
13H20O3: C, 69.61; H, 8.99. Found: C, 69.44; H, 9.04.
7-(2-F u r yl)-1-m eth ylh ep tyl Aceta te (1c). A solution of
8-(2-furyl)-2-octanol (38) (305 mg, 1.55 mmol) (preparation: see
below), Ac2O (1 mL, 10 mmol), and pyridine (1.4 mL, 17 mmol)
was allowed to stand overnight at room temperature, and most
of volatile materials were removed by using a vacuum pump.
The residue was directly subjected to chromatography (hexane/
ethyl acetate) to afford the acetate 1c (359 mg, 97%): IR (neat)
1736, 1246, 729 cm-1; 1H NMR δ 1.19 (d, J ) 6 Hz, 3 H), 1.22-
1.70 (m, 10 H), 2.02 (s, 3 H), 2.59 (t, J ) 7 Hz, 2 H), 4.82-4.94
(m, 1 H), 5.98 (dq, J ) 3, 1 Hz, 1 H), 6.25 (dd, J ) 3, 2 Hz, 1
H), 7.28 (dd, J ) 2, 1 Hz, 1 H); 13C NMR δ 170.9, 156.6, 140.8,
110.2, 104.8, 71.0, 35.9, 29.17, 29.04, 27.96, 27.92, 25.3, 21.3,
19.9.
(2E)-7-P h en yl-4-oxo-2-h ep t en a l (2a ). (A) NBS/pyri-
dine: To a solution of 1a (218 mg, 1.17 mmol) and pyridine
(0.38 mL, 4.70 mmol) in THF-acetone-H2O (5:4:1, 6 mL) was
added NBS (250 mg, 1.40 mmol) dissolved in THF-acetone-
H2O (5:4:1, 2 mL) at -20 °C. The solution was stirred for 1 h
at -20 °C and 6 h at room temperature and then poured into
a mixture of ethyl acetate and aqueous Na2S2O3 with vigorous
stirring. The organic layer was separated, and the aqueous
layer was extracted with ethyl acetate. The combined organic
layers were dried over MgSO4 and concentrated. The residue
was purified by chromatography (hexane/ethyl acetate) to
afford 2a (153 mg, 65%).
(B) NBS/NaHCO3: To a mixture of 1a (100 mg, 0.538 mmol)
and NaHCO3 (90 mg, 1.08 mmol) in acetone-H2O (10:1, 2 mL)
was added NBS (105 mg, 0.591 mmol) dissolved in acetone-
H2O (10:1, 0.7 mL) at -15 °C. After 40 min at -15 °C, pyridine
(0.16 mL, 1.98 mmol) was added, the mixture was stirred
further 2 h at room temperature, and ethyl acetate was added.
The solution was washed with 1 N HCl, dried over MgSO4,
and concentrated to furnish the crude product, which was
purified by chromatography (hexane/ethyl acetate) to afford
2a (77 mg, 71%): IR (neat) 1730, 1695, 1248 cm-1; 1H NMR δ
2.01 (quintet, J ) 7 Hz, 2 H), 2.67 (t, J ) 7 Hz, 2 H), 2.70 (t,
J ) 7 Hz, 2 H), 6.73 (dd, J ) 16, 7 Hz, 1 H), 6.83 (d, J ) 16,
1 H), 7.15-7.33 (m, 5 H), 9.76 (d, J ) 7 Hz, 1 H); 13C NMR δ
200.0, 193.6, 144.9, 141.2, 137.4, 128.60, 128.58, 126.3, 40.2,
34.8, 24.9.
Con clu sion
In summary, we have shown the usefulness of the two-
step conversion of 2-substituted furans 1 into trans 4-oxo-
2-enoic acids 3. The pivotal NBS oxidation is carried out
under mild conditions and consequently, common func-
tional groups should be compatible. Actually, ester, THP,
siloxy, phenyl, and free hydroxyl groups were found to
be such groups. In addition, this furan methodology has
the advantages of easy preparation and chemical stability
of furans 1 under various conditions, which are conve-
nient for manipulation of the substituent as is demon-
strated in this manuscript. We are confident that when
4-oxygenated 2-enoic acids or their derivatives are re-
quired, an efficient method can immediately be devised
by taking into consideration the 2-substituted furans as
a synthetic equivalent of 4-oxo-2-enoic acids.
Exp er im en ta l Section
Gen er a l Meth od s. Infrared (IR) spectra are reported in
wave numbers (cm-1). Unless otherwise noted, 1H NMR (300
MHz) and 13C NMR (75 MHz) spectra were measured in CDCl3
using SiMe4 (δ ) 0 ppm) and the center line of CDCl3 triplet
(δ ) 77.1 ppm) as internal standards, respectively. The
following solvents were distilled before use: THF (from Na/
benzophenone), Et2O (from Na/benzophenone), and CH2Cl2
(from CaH2). N,N-Dimethylformamide (DMF) was dried over
CaH2. (S)-Propylene oxide (13) was purchased from Merck,
and (R)- and (S)-epichlorohydrins (29) were kindly offered by
Daiso, J apan. The phosphate buffer of pH 3.6 was prepared
by mixing Na2HPO4‚12H2O (2.31 g), citric acid (1.31 g), and
H2O (98.6 g). 2-Bromofuran (10) was prepared according to
the literature procedure.36 Routinely, organic extracts were
concentrated using a rotary evaporator, and residues were
purified by chromatography on silica gel.
2-(3-P h en ylp r op yl)fu r a n (1a ). To an ice-cold solution of
furan (4.12 mL, 57 mmol) and bipyridine (ca. 10 mg) in THF
(100 mL) was added n-BuLi (45 mL, 0.91 M in hexane, 41
mmol) dropwise. After being stirred for 1 h at 0-5 °C,
1-bromo-3-phenylpropane (4.75 mL, 6.27 g, 31.5 mmol) was
added to the solution. The brown solution was stirred over-
night at room temperature and poured into a mixture of
hexane and saturated NH4Cl with vigorous stirring. Hexane
layer was separated, and the aqueous layer was extracted with
hexane. The combined hexane solutions were dried over
MgSO4 and concentrated to give an oil, which was purified by
chromatography (hexane/ethyl acetate) followed by distillation
under reduced pressure to afford 1a (5.16 g, 88%): bp 113-
115 °C (2 Torr); IR (neat) 1599, 1506, 1496, 1454, 731, 700
cm-1; 1H NMR δ 1.97 (quintet, J ) 7 Hz, 2 H), 2.62-2.70 (m,
4 H), 5.99 (d, J ) 3 Hz, 1 H), 6.28 (dd, J ) 3, 2 Hz, 1 H), 7.15-
7.33 (m, 6 H); 13C NMR δ 156.2, 142.1, 141.0, 128.7, 128.5,
126.0, 110.2, 105.0, 35.2, 29.6, 27.4. Anal. Calcd for
(2E)-7-(Tet r a h yd r op yr a n yloxy)-4-oxo-2-oct en a l (2b ).
(A) Furan 1b (77 mg, 0.34 mmol) was oxidized by using NBS
(64 mg, 0.36 mmol) dissolved in THF-acetone-H2O (5:4:2, 1
mL) and pyridine (0.083 mL, 1.03 mmol) in THF-acetone-
H2O (5:4:2, 3 mL) at -20 °C for 1 h and then rt for 5 h to
furnish aldehyde 2b (51 mg, 62% yield) after a similar workup
as described above. (B) A mixture of 1b (100 mg, 0.45 mmol),
NBS (87 mg, 0.49 mmol), and NaHCO3 (75 mg, 0.89 mmol) in
acetone-H2O (10:1, total 2.7 mL) was stirred at -15 °C for
40 min and, after addition of pyridine (0.071 mL, 0.89 mmol),
at room temperature for 2.5 h. To this was added 0.5 N CuSO4
(2.5 mL), and the mixture was stirred vigorously for 15 min.
After separation of the phases, the organic layer was rinsed
again with 0.5 N CuSO4 (1 mL), washed with brine, dried over
MgSO4, and concentrated. The residue was purified by
chromatography (hexane/ethyl acetate) to afford 2b (73 mg,
69%): IR (neat) 1692, 1641 cm-1 1H NMR δ 1.15 and 1.25
;
(2d, J ) 6 and 6 Hz, 3 H), 1.40-1.98 (m, 8 H), 2.72-2.97 (m,
2 H), 3.39-3.52 (m, 1 H), 3.76-3.96 (m, 2 H), 4.53-4.61 (m, 1
H), 6.79 (dt, J ) 16, 7 Hz, 1 H), 6.89 (dd, J ) 16, 4 Hz, 1 H),
9.79 (d, J ) 7 Hz, 1 H).
(2E)-11-Acetoxy-4-oxo-2-d od ecen a l (2c). (A) According
to the procedure for the oxidation of 1b, furan 1c (30 mg, 0.125
mmol) was converted into 2c (28 mg, 87% yield) by using NBS
(29 mg, 0.16 mmol) dissolved in THF-acetone-H2O (5:4:2, 0.7
mL), pyridine (0.040 mL, 0.49 mmol), and THF-acetone-H2O
(5:4:2, 2 mL). (B) According to the procedure for the oxidation
of 1b, furan 1c (50 mg, 0.21 mmol) was converted into 2c (41
C
13H14O: C, 83.83; H, 7.58. Found: C, 83.62; H, 7.62.
2-(3-(Tetr a h yd r op yr a n yloxy)bu tyl)fu r a n (1b). By us-
ing a similar procedure for the preparation of 1a , furan (0.12
mL, 1.7 mmol), 1-iodo-3-(tetrahydropyranyloxy)butane37 (160
mg, 0.56 mmol) dissolved in THF (1 mL), n-BuLi (0.46 mL,
2.47 M solution in hexane, 1.13 mmol), and THF (3 mL)
afforded 1b (90 mg, 71%) after workup with saturated NaH-
(36) Keegstra, M. A.; Klomp, A. J . A.; Brandsma, L. Synth. Commun.
1990, 20, 3371-3374.
(37) Mori, K.; Tanida, K. Tetrahedron 1981, 37, 3221-3225.

4-Oxygenated 2-Enoic Acids from 2-Substituted Furans
J . Org. Chem., Vol. 63, No. 21, 1998 7511
mg, 76%) by using NBS (41 mg, 0.23 mmol), NaHCO3 (35 mg,
0.42 mmol), pyridine (0.033 mL, 0.23 mmol), and acetone-
H2O (10:1, total 1.5 mL): 1H NMR δ 1.20 (d, J ) 6 Hz, 3 H),
1.22-1.73 (m, 10 H), 2.03 (s, 3 H), 2.68 (t, J ) 6 Hz, 2 H),
4.83-4.96 (m, 1 H), 6.78 (dd, J ) 16, 7 Hz, 1 H), 6.88 (d, J )
16 Hz, 1 H), 9.79 (d, J ) 7 Hz, 1 H); 13C NMR δ 200.3, 193.7,
171.0, 145.1, 137.5, 70.9, 41.1, 35.8, 29.1, 28.9, 25.1, 23.4, 21.3,
19.9.
(2E)-7-P h en yl-4-oxo-2-h ep ten oic Acid (3a ). To a solu-
tion of the aldehyde 2a (358 mg, 1.77 mmol) and 2-methyl-2-
butene (1.87 mL, 17.7 mmol) in t-BuOH (23 mL), and the
phosphate buffer (pH 3.6, 11 mL) was added NaClO2 (226 mg,
purity 85%, 2.12 mmol) dissolved in H2O (11 mL), and the
resulting mixture was stirred for 2 h at room temperature.
Most of the solvents were removed by using a vacuum pump,
and ethyl acetate and brine were added to the residue. The
aqueous layer was acidified to pH ca. 4 by addition of 1 N HCl.
The organic layer was separated, and the aqueous layer was
extracted with ethyl acetate. The combined organic layers
were dried over MgSO4 and concentrated to leave an oil, which
was purified by chromatography (benzene/ethyl acetate/MeOH)
to give 3a (297 mg, 77%): IR (Nujol) 1672, 1624 cm-1; 1H NMR
δ 1.99 (quintet, J ) 7 Hz, 2 H), 2.660 (t, J ) 7 Hz, 2 H), 2.661
(t, J ) 7 Hz, 2 H), 6.64 (d, J ) 16 Hz, 1 H), 7.10 (d, J ) 16 Hz,
1 H), 7.14-7.33 (m, 5 H); 13C NMR δ 199.5, 170.5, 141.33,
141.27, 129.7, 128.6, 126.3, 40.8, 34.8, 24.9.
(2E)-7-(Tetr a h yd r op yr a n yloxy)-4-oxo-2-octen oic Acid
(3b). According to the above procedure, aldehyde 2b (29 mg,
0.12 mmol) was converted into acid 3b (24 mg, 78%) by using
NaClO2 (19 mg, purity 85%, 0.18 mmol) dissolved in H2O (0.3
mL), 2-methyl-2-butene (0.10 mL, 0.94 mmol), t-BuOH (1 mL),
and the phosphate buffer (pH 3.6, 0.3 mL): IR (CCl4) 1698,
1640 cm-1; 1H NMR δ 1.15 and 1.26 (2d, J ) 6 and 6 Hz, 3 H),
1.44-1.96 (m, 8 H), 2.72 and 2.84 (2t, J ) 7 and 7 Hz, 2 H),
3.42-3.55 (m, 1 H), 3.74-3.97 (m, 2 H), 4.58-4.64 (m, 1 H),
6.68 and 6.70 (2d, J ) 16 and 16 Hz, 1 H), 7.150 and 7.156
(2d, J ) 16 and 16 Hz, 1 H).
(2E)-11-Acetoxy-4-oxo-2-d od ecen oic Acid (3c). Accord-
ing to the above procedure, aldehyde 2c (23 mg, 0.090 mmol)
was oxidized to acid 3c (17 mg, 70%) by using NaClO2 (12 mg,
purity 85%, 0.11 mmol) dissolved in H2O (0.5 mL), 2-methyl-
2-butene (0.099 mL, 0.93 mmol), t-BuOH (1 mL), and the
phosphate buffer (pH 3.6, 0.5 mL). The following 1H NMR
spectrum (300 MHz) was identical with the reported3f data (90
MHz): 1H NMR δ 1.21 (d, J ) 6 Hz, 3 H), 1.2-1.7 (m, 10 H),
2.04 (s, 3 H), 2.65 (t, J ) 7 Hz, 2 H), 4.83-4.94 (m, 1 H), 6.68
(d, J ) 16 Hz, 1 H), 7.13 (d, J ) 16 Hz, 1 H).
ee: [R]20 ) +12 to +14) and CuCN (19 mg, 0.21 mmol) in
D
THF (5 mL) was added the above Grignard reagent 14 (19 mL,
0.34 M in THF, 6.5 mmol) between -55 to -60 °C over 40
min. The resulting mixture was stirred below -30 °C for 1 h,
warmed to 0 °C over 1 h, and then poured into a mixture of
ethyl acetate and saturated NH4Cl with vigorous stirring. After
separation of the phases, the aqueous phase was extracted
with ethyl acetate. The combined organic extracts were dried
over MgSO4 and concentrated to give a residue, which was
purified by chromatography (hexane/ethyl acetate) to afford
15 (803 mg, 88%). Since ee of the starting epoxide was not
given, 15 was transformed to the bis-MTPA ester by the
standard procedure39 [(1) (R)-(-)-MTPACl, pyridine/CHCl3 (1:
1), 0 °C to room temperature; (2) Me2N(CH2)3NH2] and ee was
determined to be >95%: [R]23D ) +5.2 (c 0.96, CHCl3); bp 120-
135 °C (1 Torr); IR (neat) 3338, 1641, 993, 908 cm-1; 1H NMR
δ 1.18 (d, J ) 6 Hz, 3 H), 1.22-1.52 (m, 19 H), 2.04 (q, J ) 7
Hz, 2 H), 3.73-3.88 (m, 1 H), 4.93 (d, J ) 10 Hz, 1 H), 5.00 (d,
J ) 17 Hz, 1 H), 5.82 (ddt, J ) 17, 10, 7 Hz, 1 H); 13C NMR δ
139.3, 114.2, 68.0, 39.3, 33.7, 29.60, 29.55, 29.52, 29.42, 29.1,
28.9, 25.7, 23.3. HRMS (CI) m/z calcd for C14H29O (M + H)+
213.2218, found 213.2222. Anal. Calcd for C14H28O: C, 79.18;
H, 13.29. Found: C, 79.18; H, 13.13.
(2S)-13-Tetr a d ecen -2-ol (15) fr om (R)-Ep ich lor oh yd r in
(29). To a mixture of (R)-epichlorohydrin (29) (463 mg, 5.0
mmol, 98.8% ee) and CuCN (22 mg, 0.25 mmol) in THF (5 mL)
at -50 °C was added slowly a THF solution of 14 (14 mL, 0.46
M, 6.44 mmol), which had been prepared from Mg (800 mg,
0.033 g-atom), 11-bromo-1-undecene (4.9 g, 21 mmol), 1,2-
dibromoethane (4 drops), and THF (total 40 mL) in a similar
manner described above. The mixture was stirred between
-20 and -30 °C for 1.5 h and poured into a mixture of
saturated NH4Cl and ethyl acetate with vigorous stirring.
Extraction and purification as mentioned above afforded (2R)-
1-chloro-13-tetradecen-2-ol (1.23 g, 100%): IR (neat) 3371,
1641, 993, 910 cm-1; 1H NMR δ 1.15-1.63 (m, 18 H), 2.04 (q,
J ) 7 Hz, 2 H), 2.30 (d, J ) 3 Hz, 1 H), 3.47 (dd, J ) 11, 7 Hz,
1 H), 3.63 (dd, J ) 11, 3 Hz, 1 H), 3.75-3.85 (m, 1 H), 4.93 (d,
J ) 10 Hz, 1 H), 5.00 (d, J ) 17 Hz, 1 H), 5.81 (ddt, J ) 17,
10, 7 Hz, 1 H); 13C NMR δ 139.4, 114.2, 71.5, 50.5, 34.2, 33.8,
29.52, 29.50, 29.46, 29.44, 29.1, 28.9, 25.5.
To an ice-cold solution of the above chloride (1.23 g, 5.0
mmol) in THF (15 mL) was added LiAlH4 (143 mg, 3.77 mmol)
portionwise. The mixture was stirred at room temperature
overnight and cooled to 0 °C. After sequential addition of ethyl
acetate (0.98 mL, 10 mmol), H2O (0.45 mL, 25 mmol), and NaF
(1.05 g, 25 mmol), the resulting mixture was stirred at room
temperature for 1 h and filtered through a pad of Celite with
ethyl acetate. The filtrate was concentrated, and the residue
was purified by chromatography (hexane/ethyl acetate) to
10-Un d ecen ylm a gn esiu m Br om id e (14). To an ice-cold
solution of alcohol 12 (14 mL, 70 mmol) and PPh3 (20.2 g, 77
mmol) in CH2Cl2 (100 mL) was added CBr4 (23.2 g, 70 mmol)
portionwise. The solution was stirred at the same temperature
for 1 h and concentrated to give a white solid. Hexane was
added to the solid, and the mixture was filtered through a pad
of silica gel with hexane. The filtrate was concentrated, and
the residue was distilled to afford 11-bromo-1-undecene (16.0
1
furnish the title alcohol 15 (1.05 g, 99%), H NMR spectrum
of which was identical with that obtained from (S)-propylene
oxide (13).
(2S)-13-Tetr a d ecyn -2-ol (16). To a solution of olefin 15
(2.12 g, 10 mmol) in CHCl3 (15 mL) was added bromine (0.52
mL, 10 mmol) slowly at -50 °C. After 15 min, the solution
was poured into a vigorously stirred aqueous Na2S2O3 with
Et2O. The organic layer was separated, and the aqueous layer
was extracted with Et2O twice. The combined organic layers
were concentrated to give the bromine-adduct, which was used
for the next reaction without further purification.
g, 100%): bp 89-90 °C (3 Torr); IR (neat) 1639, 993, 910 cm-1
;
1H NMR δ 1.23-1.51 (m, 12 H), 1.85 (quintet, J ) 7 Hz, 2 H),
2.04 (q, J ) 7 Hz, 2 H), 3.40 (t, J ) 7 Hz, 2 H), 4.93 (d, J ) 10
Hz, 1 H), 4.99 (d, J ) 17 Hz, 1 H), 5.81 (ddt, J ) 17, 10, 7 Hz,
1 H); 13C NMR δ 134.3, 109.2, 29.0, 28.7, 27.8, 24.3, 24.0, 23.8,
23.7, 23.1.
To a suspension of Mg (1.26 g, 0.052 g-atom) in THF (14
mL) was added 1,2-dibromoethane (5 drops) to activate Mg,
and a solution of the above bromide (8.63 g, 37.1 mmol) in THF
(20 mL) was added dropwise with a gentle heating. After the
addition, the mixture was refluxed for 30 min, cooled to room
temperature, and diluted with THF (74 mL). The resulting
supernatant was titrated to be 0.34 M of 10-undecenylmag-
nesium bromide (14).
To a suspension of NaNH2 in liquid NH3 (ca. 200 mL), which
had been prepared from sodium metal (1.6 g, 0.070 g-atom)
and a catalytic amount of Fe(NO3)3‚9H2O in NH3, was added
a solution of the above bromine-adduct in THF (8 mL) slowly.
The cooling bath was removed and stirring was continued.
After 1 h, a mixture of H2O-THF (ca. 1:1), saturated NH4Cl,
and Et2O were added successively, and the resulting mixture
was stirred overnight at room temperature. The product was
extracted with Et2O several times, and the combined ethereal
solutions were dried over MgSO4 and concentrated. The
(2S)-13-Tetr a d ecen -2-ol (15) fr om (S)-P r op ylen e Oxid e
(13).38 To a mixture of (S)-propylene oxide (13) (249 mg, 4.29
mmol) of [R]20 ) -13 to -14 (neat) (cf. (R)-isomer of >97%
D
(39) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543-2549.
(38) Reaction was carried out by T. Okui of our laboratory.

7512 J . Org. Chem., Vol. 63, No. 21, 1998
Kobayashi et al.
residue was purified by chromatography (hexane/ethyl acetate)
Anal. Calcd for C24H46O4Si: C, 67.55; H, 10.87. Found: C,
67.50; H, 10.79.
to afford acetylene 16 (2.01 g, 96% from 15): [R]22 ) +6.3 (c
D
0.94, CHCl3); IR (neat) 3360, 3311, 2117 cm-1; 1H NMR δ 1.19
(d, J ) 6 Hz, 3 H), 1.22-1.58 (m, 19 H), 1.94 (t, J ) 3 Hz, 1
H), 2.18 (dt, J ) 3, 7 Hz, 2 H), 3.72-3.86 (m, 1 H); 13C NMR
δ 84.9, 68.2, 68.1, 39.4, 29.60, 29.54, 29.48, 29.43, 29.1, 28.7,
28.5, 25.7, 23.4, 18.3. HRMS (CI) m/z calcd for C14H27O (M +
H)+ 211.2062, found 211.2059. Anal. Calcd for C14H26O: C,
79.94; H, 12.46. Found: C, 79.88; H, 12.42.
(1R,2S,13S)-13-[(ter t-Bu tyldim eth ylsilyl)oxy]-1-(2-fu r yl)-
1,2-tetr a d eca n ed iol (32). In a manner similar to the above
experiment, olefin 7 (32 mg, 0.080 mmol), AD-mix-R (113 mg),
MeSO2NH2 (8 mg, 0.08 mmol), t-BuOH (0.4 mL), and H2O (0.4
mL) afforded diol 32 (29 mg, 85%), whose 1H NMR was
identical with that of 18. No contamination of 18 in the
product 32 was confirmed by the method described above for
18.
(13S )-13-[(t er t -B u t y ld im e t h y ls ily l)o x y ]-1-t e t r a d e -
cyn e (17). A solution of alcohol 16 (2.01 g, 9.57 mmol),
TBDMSCl (1.73 g, 11.5 mmol), and imidazole (0.98 g, 14.4
mmol) in DMF (20 mL) was stirred overnight at room tem-
perature and poured into a mixture of hexane and saturated
NaHCO3. After being vigorously stirred at room temperature
for 30 min, the layers were separated, and the aqueous layer
was extracted with hexane twice. The combined hexane
solutions were dried over MgSO4 and concentrated to give an
oil, which was purified by chromatography (hexane/ethyl
(1S,2R,13S)-2-(13-[(ter t-Bu t yld im et h ylsilyl)oxy]-1,2-
bis(m eth oxym eth oxy)-1-tetr a d eca n yl)fu r a n (19). A solu-
tion of alcohol 18 (2.36 g, 5.52 mmol), MOMCl (1.68 mL, 22.1
mmol), and i-Pr2NEt (9.62 mL, 55.2 mmol) in CH2Cl2 (18 mL)
was stirred overnight between 25 and 30 °C and poured into
saturated NaHCO3. After vigorous stirring for 30 min, the
mixture was extracted with ethyl acetate twice. The combined
organic layers were dried over MgSO4 and concentrated to give
an oil, which was purified by chromatography (hexane/ethyl
acetate) to furnish the MOM ether 19 (2.62 g, 92%): [R]22
)
acetate) to afford the silyl ether 17 (3.12 g, 100%): [R]21
)
D
D
-39.3 (c 1.23, CHCl3); IR (neat) 1032, 835, 775 cm-1; 1H NMR
δ 0.03 (s, 6 H), 0.87 (s, 9 H), 1.10 (d, J ) 6 Hz, 3 H), 1.10-1.50
(m, 20 H), 3.35 (s, 3 H), 3.36 (s, 3 H), 3.68-3.80 (m, 1 H), 3.83-
3.92 (m, 1 H), 4.58 (d, J ) 7 Hz, 1 H), 4.59 (d, J ) 7 Hz, 1 H),
4.65 (d, J ) 7 Hz, 1 H), 4.68 (d, J ) 7 Hz, 1 H), 4.74 (d, J ) 7
Hz, 1 H), 6.31 (dd, J ) 3, 1 Hz, 1 H), 6.33 (dd, J ) 3, 2 Hz, 1
H), 7.38 (dd, J ) 2, 1 Hz, 1 H); 13C NMR δ 152.2, 142.5, 110.2,
109.1, 97.2, 94.5, 78.9, 73.9, 68.7, 55.7, 55.6, 39.7, 31.4, 29.65,
29.58, 29.52, 29.49, 29.45, 25.9, 25.7, 25.1, 23.8, 18.1, -4.5,
+8.2 (c 0.94, CHCl3); IR (neat) 3313, 2119, 835, 773 cm-1; H
NMR δ 0.04 (s, 6 H), 0.88 (s, 9 H), 1.11 (d, J ) 6 Hz, 3 H),
1.16-1.60 (m, 18 H), 1.94 (t, J ) 3 Hz, 1 H), 2.18 (dt, J ) 3,
7 Hz, 2 H), 3.70-3.82 (m, 1 H); 13C NMR δ 84.9, 68.7, 68.1,
39.8, 29.70, 29.63, 29.55, 29.49, 29.1, 28.8, 28.5, 25.9, 25.8, 23.8,
18.4, 18.2, -4.5, -4.8. HRMS (CI) m/z calcd for C20H41OSi
(M + H)+ 325.2927, found: 325.2918.
1
(1E,13S)-2-(13-[(ter t-Bu t yld im et h ylsilyl)oxy]-1-t et r a -
d ecen yl)fu r a n (7). To a solution of acetylene 17 (2.45 g, 7.56
mmol) in THF (8 mL) at -10 °C was added a solution of
Sia2BH in THF (30 mL), which had been prepared from BH3
(20 mL, 1 M in THF, 20 mmol) and 2-methyl-2-butene (20 mL,
2 M in THF, 40 mmol) at -10 °C for 2 h. After being stirred
at -10 °C for 1 h, 3 N NaOH (4 mL, 12 mmol), 2-bromofuran
(10) (3.34 g, 22.7 mmol), and Pd(PPh3)4 (440 mg, 0.38 mmol)
were added to the solution. The mixture was stirred under
reflux for 5 h. After being cooled to 0 °C, 3 N NaOH (25 mL,
75 mmol) and 35% H2O2 (7.5 mL) were added slowly. Vigorous
stirring was continued at room temperature for 2 h, and the
mixture was poured into saturated NH4Cl. The product was
extracted with hexane several times, and the combined
extracts were dried over MgSO4 and concentrated to leave the
residue, which was purified by chromatography (hexane/Et2O)
-4.8. Anal. Calcd for
C28H54O6Si: C, 65.33; H, 10.57.
Found: C, 65.31; H, 10.60.
(2E,5S,6R,17S)-17-[(ter t-Bu t yld im et h ylsilyl)oxy]-5,6-
bis(m eth oxym eth oxy)-4-oxo-2-octadecen al (20). To a mix-
ture of the MOM ether 19 (793 mg, 1.54 mmol) and NaHCO3
(258 mg, 3.08 mmol) in acetone-H2O (10:1, 3 mL) was added
NBS (304 mg, 1.69 mmol) dissolved in acetone-H2O (10:1, 1.5
mL) at -15 °C. The mixture was stirred for 40 min, and furan
(0.34 mL, 4.7 mmol) was added to quench excess NBS. After
30 min at -15 °C, pyridine (0.24 mL, 3.03 mmol) was added.
The mixture was stirred at room temperature overnight and
poured into the phosphate buffer (pH 3.6) with ethyl acetate.
The phases were separated, and the aqueous phase was
extracted with ethyl acetate. The combined organic phases
were dried over MgSO4 and concentrated to give the residue,
which was purified by chromatography (hexane/ethyl acetate)
to furnish aldehyde 20 (584 mg, 71%): IR (neat) 1697, 1032,
to furnish 7 (2.72 g, 92%): IR (neat) 960, 837, 777, 729 cm-1
;
1H NMR (500 MHz) δ 0.035 (s, 6 H), 0.89 (s, 9 H), 1.11 (d, J )
6 Hz, 3 H), 1.17-1.52 (m, 18 H), 2.12-2.21 (m, 2 H), 3.72-
3.81 (m, 1 H), 6.12 (d, J ) 3 Hz, 1 H), 6.16 (dt, J ) 16, 6 Hz,
1 H), 6.19 (d, J ) 16 Hz, 1 H), 6.33 (dd, J ) 3, 2 Hz, 1 H), 7.30
(d, J ) 2 Hz, 1 H); 13C NMR δ 153.6, 141.3, 136.5, 118.6, 111.2,
105.9, 68.8, 39.8, 32.8, 29.70, 29.65, 29.60, 29.5, 29.3, 29.2, 25.9,
25.8, 23.8, 18.2, -4.5, -4.8. HRMS (CI) m/z calcd for C24H45O2-
Si (M + H)+ 393.3189, found: 393.3195.
1
835, 775 cm-1; H NMR δ 0.03 (s, 6 H), 0.87 (s, 9 H), 1.10 (d,
J ) 6 Hz, 3 H), 1.12-1.76 (m, 20 H), 3.26 (s, 3 H), 3.37 (s, 3
H), 3.69-3.81 (m, 1 H), 3.87-3.95 (m, 1 H), 4.27 (d, J ) 3 Hz,
1 H), 4.57 (d, J ) 7 Hz, 1 H), 4.64 (d, J ) 7 Hz, 1 H), 4.70 (d,
J ) 7 Hz, 1 H), 4.72 (d, J ) 7 Hz, 1 H), 6.88 (dd, J ) 16, 8 Hz,
1 H), 7.38 (d, J ) 16 Hz, 1 H), 9.77 (d, J ) 8 Hz, 1 H). HRMS
(CI) m/z calcd for C24H55O7Si (M + H)+ 531.3717, found:
531.3718.
(1S,2R,13S)-13-[(ter t-Bu tyldim eth ylsilyl)oxy]-1-(2-fu r yl)-
1,2-tetr a d eca n ed iol (18).38 To an ice-cold mixture of olefin
7 (200 mg, 0.509 mmol), t-BuOH (2.6 mL), and H2O (2.6 mL)
were added MeSO2NH2 (48 mg, 0.50 mmol) and AD-mix-â
(0.713 g). The mixture was stirred overnight at room tem-
perature and diluted with brine. The product was extracted
with ethyl acetate several times. The combined organic
solutions were dried over MgSO4 and concentrated. The
residue was purified by chromatography (hexane/ethyl acetate)
to afford diol 18 (198 mg, 91%). Since all of the 1H NMR
signals were superimposed with those of the diastereomer 32
of eq 5 (vide infra), diastereomeric purity of 18 was determined
by comparison of 1H NMR signals of the corresponding bis-
MTPA esters, and no isomer was detected in each spectrum.
Met h yl (2E,5S,6R,17S)-17-[(ter t-Bu t yld im et h ylsilyl)-
oxy]-5,6-bis(m eth oxym eth oxy)-4-oxo-2-octadecen oate (6).
According to the procedure for the preparation of 3a , aldehyde
20 (173 mg, 0.326 mmol) was converted into the acid 21 (156
mg, 88%) by using NaClO2 (148 mg, purity 85%, 1.63 mmol)
in H2O (1 mL), 2-methyl-2-butene (0.52 mL, 4.9 mmol), t-BuOH
(2 mL), and the phosphate buffer (pH 3.6, 1 mL): IR (neat)
1699, 835, 775 cm-1 1H NMR δ 0.03 (s, 6 H), 0.87 (s, 9 H),
;
1.10 (d, J ) 6 Hz, 3 H), 1.12-1.72 (m, 20 H), 3.25 (s, 3 H),
3.35 (s, 3 H), 3.67-3.82 (m, 1 H), 3.87-3.97 (m, 1 H), 4.26 (d,
J ) 3 Hz, 1 H), 4.58 (d, J ) 7 Hz, 1 H), 4.64 (d, J ) 7 Hz, 1 H),
4.67 (d, J ) 7 Hz, 1 H), 4.71 (d, J ) 7 Hz, 1 H), 6.77 (d, J ) 16
Hz, 1 H), 7.53 (d, J ) 16 Hz, 1 H), 9.2 (br peak, 1 H).
Diol 18: [R]23 ) +10.8 (c 0.93, MeOH); IR (neat) 3369, 835,
To a solution of 2-chloro-1-methylpyridinium iodide (363 mg,
1.42 mmol) in CH2Cl2 (1.5 mL) was added a solution of acid
21 (259 mg, 0.474 mmol), MeOH (0.023 mL, 0.57 mmol), and
NEt3 (0.16 mL, 1.15 mmol) in CH2Cl2 (1.5 mL). The resulting
mixture was refluxed for 4 h, cooled to room temperature, and
concentrated. The residue was purified by chromatography
(hexane/ethyl acetate) to furnish the methyl ester 6 (172 mg,
D
1
773 cm-1; H NMR δ 0.03 (s, 6 H), 0.88 (s, 9 H), 1.10 (d, J )
6 Hz, 3 H), 1.12-1.52 (m, 20 H), 2.47 (br s, 1 H), 2.78 (br s, 1
H), 3.70-3.82 (m, 1 H), 3.82-3.92 (m, 1 H), 4.46 (t, J ) 6 Hz,
1 H), 6.31 (ddd, J ) 3.3, 0.9, 0.6 Hz, 1 H), 6.34 (dd, J ) 3.3,
1.8 Hz, 1 H), 7.38 (dd, J ) 1.8, 1.2 Hz, 1 H); 13C NMR δ 154.4,
142.4, 110.5, 107.8, 73.6, 71.2, 68.7, 39.8, 32.9, 29.69, 29.62,
29.57, 29.54, 29.51, 25.9, 25.8, 25.5, 23.8, 18.1, -4.5, -4.8.
65%): [R]22 ) -34.1 (c 0.82, CHCl3); IR (neat) 1732, 1703,
D

4-Oxygenated 2-Enoic Acids from 2-Substituted Furans
J . Org. Chem., Vol. 63, No. 21, 1998 7513
835, 775 cm-1; 1H NMR δ -0.01 (s, 6 H), 0.83 (s, 9 H), 1.06 (d,
J ) 6 Hz, 3 H), 1.08-1.70 (m, 20 H), 3.23 (s, 3 H), 3.33 (s, 3
H), 3.76 (s, 3 H), 3.65-3.79 (m, 1 H), 3.86 (dt, J ) 3, 7 Hz, 1
H), 4.20 (d, J ) 3 Hz, 1 H), 4.53 (d, J ) 7 Hz, 1 H), 4.59 (d, J
) 7 Hz, 1 H), 4.63 (d, J ) 7 Hz, 1 H), 4.67 (d, J ) 7 Hz, 1 H),
6.74 (d, J ) 16 Hz, 1 H), 7.46 (d, J ) 16 Hz, 1 H); 13C NMR δ
199.5, 166.0, 136.4, 130.6, 97.2, 96.1, 83.3, 78.1, 68.6, 56.5, 55.9,
52.2, 39.7, 30.5, 29.59, 29.52, 29.46, 29.43, 25.8, 25.7, 25.3, 23.7,
18.0, -4.6, -4.9. HRMS (CI) m/z calcd for C29H57O8Si (M +
H)+ 561.3823, found: 561.3817.
dried over MgSO4 and concentrated to furnish acid 25, which
was used for the next reaction without further purification:
IR (neat) 1716, 1658, 1032 cm-1; 1H NMR δ 1.19 (d, J ) 6 Hz,
3 H), 1.1-1.7 (m, 20 H), 3.38 (s, 3 H), 3.39 (s, 3 H), 3.40 (s, 3
H), 3.61-3.70 (m, 1 H), 3.72-3.89 (m, 2 H), 4.40-4.48 (m, 1
H), 4.63 (d, J ) 7 Hz, 1 H), 4.65 (d, J ) 7 Hz, 1 H), 4.67 (d, J
) 7 Hz, 1 H), 4.68 (d, J ) 7 Hz, 1 H), 4.74 (d, J ) 7 Hz, 2 H),
6.07 (dd, J ) 16, 1 Hz, 1 H), 7.07 (dd, J ) 16, 6 Hz, 1 H).
A solution of the above acid 25 and NEt3 (0.09 mL, 0.65
mmol) in THF (1 mL) was stirred at room temperature for 20
min, and then 2,4,6-trichlorobenzoyl chloride (0.05 mL, 0.19
mmol) in THF (0.5 mL) was added. Stirring was continued
at room temperature further 2 h, and the solution was diluted
with toluene (ca. 20 mL). The resultant white solid (triethyl-
amine hydrochloride) was removed by filtration through a pad
of Celite, and the filtrate was diluted further with toluene
(total 50 mL). The toluene solution thus obtained was added
over 3 h to a refluxing solution of DMAP (78 mg, 0.64 mmol)
dissolved in toluene (10 mL). After the addition, the solution
was cooled to room temperature, diluted with Et2O, washed
with 1 N HCl and saturated NaHCO3, and dried over MgSO4.
Concentration and purification by chromatography (hexane/
ethyl acetate) afforded lactone 26 (31 mg, 53% from 24): IR
Met h yl
(2E,4R,5R,6R,17S)-17-[(ter t-Bu t yld im et h yl-
silyl)oxy]-5,6-b is(m et h oxym et h oxy)-4-h yd r oxy-2-oct a -
d ecen oa t e (22). To a solution of ketone 6 (123 mg, 0.220
mmol) in Et2O (1 mL) was added an ethereal solution of
Zn(BH4)2 (4.8 mL, 0.138 M, 0.66 mmol) at -78 °C. The
mixture was gradually warmed to -40 °C over 1 h and poured
into brine. The resulting mixture was stirred at room tem-
perature for 1 h and then extracted with Et2O several times.
The combined ethereal solutions were dried over MgSO4 and
concentrated. The residue was purified by chromatography
(hexane/ethyl acetate) to furnish alcohol 22 (112 mg, 90%),
whose diastereomeric selectivity was determined to be >15:1
1
by H NMR spectroscopy of the crude product: [R]24 ) +9.6
D
(c 1.31, CHCl3); IR (neat) 3473, 1728, 1658, 835, 775 cm-1; 1H
NMR δ 0.04 (s, 6 H), 0.88 (s, 9 H), 1.10 (d, J ) 6 Hz, 3 H),
1.12-1.46 (m, 21 H), 3.41 (s, 6 H), 3.52-3.60 (m, 1 H), 3.74 (s,
3 H), 3.68-3.80 (m, 1 H), 4.02 (d, J ) 6 Hz, 1 H), 4.39-4.46
(m, 1 H), 4.66 (d, J ) 7 Hz, 1 H), 4.68 (d, J ) 7 Hz, 1 H), 4.70
(d, J ) 7 Hz, 1 H), 4.71 (d, J ) 7 Hz, 1 H), 6.19 (dd, J ) 16, 2
Hz, 1 H), 7.08 (dd, J ) 16, 4 Hz, 1 H); 13C NMR δ 167.0, 147.6,
121.5, 98.1, 97.2, 83.1, 78.7, 70.4, 68.6, 56.3, 56.1, 51.5, 39.7,
30.6, 29.63, 29.60, 29.54, 29.47, 25.8, 25.7, 25.3, 23.7, 18.0,
-4.6, -4.9. HRMS (CI) m/z calcd for C29H59O8Si (M + H)+
563.3979, found: 563.3979.
(neat) 1720, 1657, 920 cm-1 1H NMR δ 1.0-1.6 (m, 23 H),
;
3.35 (s, 3 H), 3.39 (s, 3 H), 3.40 (s, 3 H), 3.46-3.56 (m, 1 H),
3.86 (dd, J ) 7, 1.5 Hz, 1 H), 4.43 (d, J ) 8 Hz, 1H), 4.58 (d,
J ) 7 Hz, 1 H), 4.61 (d, J ) 7 Hz, 1 H), 4.63 (d, J ) 7 Hz, 1 H),
4.74 (d, J ) 7 Hz, 1 H), 4.78 (d, J ) 7 Hz, 1 H), 4.82 (d, J ) 7
Hz, 1 H), 4.90-5.10 (m, 1 H), 6.01 (d, J ) 16 Hz, 1 H), 6.95
(dd, J ) 16, 8 Hz, 1 H); 13C NMR δ 165.7, 143.4, 125.4, 97.7,
97.4, 93.9, 81.1, 77.8, 74.8, 70.8, 55.94, 55.87, 55.5, 35.3, 31.1,
28.11, 28.06, 27.4, 26.9, 26.6, 26.2, 25.4, 23.5, 20.4; FAB mass,
M+ + Na ) 483.
To an ice-cold solution of the MOM ether 26 (31 mg, 0.067
mmol) and 1,2-ethanedithiol (0.045 mL, 0.61 mmol) in CH2Cl2
(1 mL) was added BF3‚OEt2 (0.051 mL, 0.41 mmol), and the
solution was stirred at room temperature for 3 h. Saturated
NaHCO3 and ethyl acetate were added to the solution, and
the mixture was stirred for 10 min. The layers were separated,
and aqueous layer was extracted with ethyl acetate. The
combined extracts were dried over MgSO4 and concentrated.
The residue was purified by chromatography on silica gel with
a mixture of benzene and EtOH as an eluent to afford (+)-
aspicilin (12.3 mg, 56%): [R]22D ) +37.5 (c 0.55, CHCl3) (lit.13e
Met h yl
(2E,4R,5S,6R,17S)-17-[(ter t-Bu t yld im et h yl-
silyl)oxy]-4,5,6-t r is(m et h oxym et h oxy)-2-oct a d ecen oa t e
(23). According to the procedure for the preparation of 19,
alcohol 22 (58 mg, 0.102 mmol) was converted into 23 (52 mg,
84%) by using MOMCl (0.025 mL, 0.33 mmol), i-Pr2NEt (0.090
mL, 0.51 mmol), and CH2Cl2 (1 mL): [R]23 ) -7.1 (c 0.80,
D
1
CHCl3); IR (neat) 1730, 1660, 835, 775 cm-1; H NMR δ 0.03
(s, 6 H), 0.88 (s, 9 H), 1.10 (d, J ) 6 Hz, 3 H), 1.12-1.70 (m,
20 H), 3.37 (s, 3 H), 3.38 (s, 3 H), 3.40 (s, 3 H), 3.61-3.70 (m,
1 H), 3.74 (s, 3 H), 3.70-3.80 (m, 2 H), 4.36-4.41 (m, 1 H),
4.61 (d, J ) 7 Hz, 1 H), 4.63 (d, J ) 7 Hz, 1 H), 4.66 (d, J ) 7
Hz, 1 H), 4.68 (d, J ) 7 Hz, 1 H), 4.73 (d, J ) 7 Hz, 2 H), 6.07
(dd, J ) 16, 1 Hz, 1 H), 6.97 (dd, J ) 16, 7 Hz, 1 H); 13C NMR
δ 166.4, 145.3, 123.2, 97.5, 97.0, 94.9, 80.2, 78.0, 75.7, 68.6,
55.98, 55.79, 55.76, 51.5, 39.6, 31.3, 29.58, 29.51, 29.45, 25.8,
25.6, 25.3, 23.7, 18.0, -4.6, -4.9. HRMS (CI) m/z calcd for
[R]23 ) +37.7 (c 0.22, CHCl3); lit.13f [R]D ) +38.5 (c 1.05,
D
CHCl3)); mp 152-155 °C (recrystallized from hexane/ethyl
acetate) (lit.13c,f 154-156 °C; lit.13e 150-152 °C). The following
1H and 13C NMR spectra were identical with the reported13e,f
data: 1H NMR (CDCl3 + D2O) δ 1.08-1.60 (m, 23 H), 3.57 (t,
J ) 3 Hz, 1 H), 3.74 (dt, J ) 3, 7 Hz, 1 H), 4.52-4.60 (m, 1 H),
5.04 (sextet, J ) 6 Hz, 1 H), 6.12 (dd, J ) 16, 2 Hz, 1 H), 6.90
(dd, J ) 16, 5 Hz, 1 H); 13C NMR δ 165.9, 145.0, 123.2, 74.7,
73.5, 71.3, 70.0, 35.7, 31.9, 28.3, 27.7, 27.5, 27.2, 27.1, 26.3,
24.3, 23.5, 20.4.
C
27H53O9Si (M - C4H9)+ 549.3459, found: 549.3464.
Meth yl (2E,4R,5S,6R,17S)-4,5,6-Tr is(m eth oxym eth oxy)-
17-h yd r oxy-2-octa d ecen oa te (24). A solution of the silyl
ether 23 (100 mg, 0.165 mmol) and NBS (30 mg, 0.17 mmol)
in DMSO-H2O (19:1, 1.6 mL) was stirred at room temperature
overnight and poured into the phosphate buffer (pH 3.6). The
mixture was extracted with Et2O three times. The combined
ethereal solutions were dried over MgSO4 and concentrated.
The residue was purified by chromatography (benzene/ethyl
2-(5-Br om op en tyl)fu r a n (35). To an ice-cold solution of
furan (1.38 mL, 14 mmol) and bipyridine (ca. 10 mg) in THF
(20 mL) was added n-BuLi (8.44 mL, 1.35 M in hexane, 11.4
mmol) dropwise, and the brown solution was stirred at 0-5
°C for 1 h to generate 2-furyllithium (33). 1-Bromo-5-chloro-
pentane (0.50 mL, 704 mg, 3.80 mmol) was added to the
solution. After 14 h at room temperature, the solution was
poured into a mixture of hexane and saturated NH4Cl with
vigorous stirring. Hexane layer was separated, and the
aqueous layer was extracted with hexane. The combined
hexane solutions were dried over MgSO4 and concentrated to
give an oil, which was purified by chromatography (hexane/
Et2O) to afford 34 (621 mg, 95%): bp 95-100 °C (3 Torr); IR
acetate) to afford alcohol 24 (64 mg, 79%): [R]21 ) -6.0 (c
D
0.64, CHCl3); IR (neat) 3481, 1724, 1660, 1032 cm-1; 1H NMR
δ 1.18 (d, J ) 6 Hz, 3 H), 1.2-1.7 (m, 21 H), 3.37 (s, 3 H), 3.38
(s, 3 H), 3.40 (s, 3 H), 3.62-3.70 (m, 1 H), 3.74 (s, 3 H), 3.72-
3.82 (m, 2 H), 4.35-4.42 (m, 1 H), 4.62 (d, J ) 7 Hz, 1 H), 4.63
(d, J ) 7 Hz, 1 H), 4.66 (d, J ) 7 Hz, 1 H), 4.68 (d, J ) 7 Hz,
1 H), 4.73 (d, J ) 7 Hz, 2 H), 6.06 (d, J ) 16 Hz, 1 H), 6.98
(dd, J ) 16, 7 Hz, 1 H); 13C NMR δ 166.6, 145.3, 123.3, 97.6,
97.1, 94.9, 80.2, 78.1, 75.8, 68.2, 56.10, 55.91, 55.88, 51.6, 39.3,
31.3, 29.64, 29.58, 29.53, 29.48, 25.7, 25.3, 23.4. HRMS (CI)
m/z calcd for C25H49O9 (M + H)+ 493.3377, found: 493.3376.
(+)-Asp icilin . A mixture of ester 24 (56 mg, 0.114 mmol)
and LiOH‚H2O (36 mg, 0.86 mmol) in MeOH and H2O (6:1,
1.1 mL) was stirred at 40 °C overnight and diluted with the
phosphate buffer (pH 3.6). The product was extracted with
ethyl acetate several times. The combined organic layers were
1
(neat) 1597, 1508, 732 cm-1; H NMR δ 1.42-1.55 (m, 2 H),
1.62-1.73 (m, 2 H), 1.73-1.88 (m, 2 H), 2.63 (t, J ) 7 Hz, 2
H), 3.55 (t, J ) 6.5 Hz, 2 H), 5.99 (d, J ) 3.5 Hz, 1 H), 6.28
(dd, J ) 3.5, 2 Hz,1 H), 7.31 (d, J ) 2, 1 H); 13C NMR δ 155.8,
140.6, 109.9, 104.7, 44.7, 32.2, 27.7, 27.2, 26.3.
A mixture of 34 (5.45 g, 31.6 mmol), LiBr (5.48 g, 63.1
mmol), and trioctylmethylammonium chloride (640 mg, 1.6
mmol) was stirred at 100 °C for 2 days, cooled to room

7514 J . Org. Chem., Vol. 63, No. 21, 1998
Kobayashi et al.
temperature, and filtered through a pad of silica gel with
hexane. The filtrate was concentrated to give the bromide 35
(6.46 g, 97% conversion by 1H NMR, 94% yield), which was
distilled for the next reaction: bp 80-90 °C (1 Torr); IR (neat)
was separated and the aqueous layer was extracted with ethyl
acetate twice. The combined organic layers were dried over
MgSO4 and concentrated. The residue was purified by chro-
matography (benzene/ethyl acetate) to furnish the ketal acid
1
1600, 1510, 734 cm-1; H NMR δ 1.42-1.57 (m, 2 H), 1.59-
41 (20 mg, 62%): [R]26 ) -2.2 (c 0.6, CHCl3). The following
D
1.73 (m, 2 H), 1.82-1.97 (m, 2 H), 2.64 (t, J ) 7 Hz, 2 H), 3.41
(t, J ) 7 Hz, 2 H), 5.98 (d, J ) 3 Hz, 1 H), 6.28 (dd, J ) 3, 2
Hz, 1 H), 7.29 (d, J ) 2 Hz, 1 H).
(2R)-8-(2-F u r yl)-2-octa n ol (38). To a mixture of Mg (1.34
g, 0.055 g-atom) and THF (7 mL) was added 1,2-dibromoethane
(5 drops) to activate Mg, and a solution of 35 (4.0 g, 18.4 mmol)
in THF (10 mL) was added slowly to prepare the Grignard
reagent 36. After the addition, the solution was diluted with
THF (20 mL). The Grignard reagent 36 thus prepared was
used for the next reaction immediately.
1H NMR spectra of 41 were in good agreement with the
reported14b data: 1H NMR δ 1.18 (d, J ) 6 Hz, 3 H), 1.2-1.8
(m, 11 H), 3.75-3.84 (m, 1 H), 3.84-4.02 (m, 4 H), 6.08 (d, J
) 16 Hz, 1 H), 6.83 (d, J ) 16 Hz, 1 H).
(3S)-3-[(ter t-Bu tyldiph en ylsilyl)oxy]-1-iodobu tan e (43).
A solution of alcohol 42 (536 mg, 4.54 mmol, 86% ee deter-
mined by 1H NMR spectroscopy of the corresponding MTPA
ester), TBDPSCl (1.42 mL, 5.46 mmol), and imidazole (927 mg,
13.6 mmol) in DMF (7 mL) was stirred for 18 h at 53 °C, cooled
to room temperature, and poured into saturated NaHCO3 with
hexane. After 30 min of vigorous stirring, the organic layer
was separated, and the aqueous layer was extracted with
hexane. The combined organic layers were dried over MgSO4
and concentrated. The residue was purified by chromatogra-
phy (hexane/ethyl acetate) to afford methyl (3S)-3-[(tert-
butyldiphenylsilyl)oxy]butanoate (1.62 g, 100%): 1H NMR δ
1.04 (s, 9 H), 1.12 (d, J ) 6 Hz, 3 H), 2.39 (dd, J ) 15, 7 Hz,
1 H), 2.57 (dd, J ) 15, 7 Hz, 1 H), 3.59 (s, 3 H), 4.23-4.37 (m,
1 H), 7.32-7.48 (m, 6 H), 7.60-7.75 (m, 4 H).
According to the procedure for the preparation of 15, (S)-
(+)-epichlorohydrin (29) (2.17 mL, 27.7 mmol) of 98.9% ee, the
above Grignard reagent 36, CuCN (164 mg, 1.83 mmol), and
THF (36 mL) afforded 37 (3.83 g, 90%): IR (neat) 3390, 1597,
1
1508, 725 cm-1; H NMR δ 1.24-1.70 (m, 10 H), 2.14 (d, J )
5 Hz, 1 H), 2.61 (t, J ) 7.5 Hz, 2 H), 3.47 (dd, J ) 11, 7 Hz, 1
H), 3.64 (dd, J ) 11, 3 Hz, 1 H), 3.74-3.85 (m, 1 H), 5.97 (m,
1 H), 6.28 (m, 1 H), 7.29 (m, 1 H); 13C NMR δ 156.5, 140.7,
110.1, 104.7, 71.5, 50.6, 34.3, 29.3, 29.1, 28.0, 25.5.
Dechlorination of 37 (427 mg, 1.85 mmol) was carried out
using LiAlH4 (70 mg, 1.85 mmol) in THF (10 mL) at room
temperature overnight to afford the furan 38 (337 mg, 93%):
To a solution of the above product (1.30 g, 3.64 mmol) in
THF (15 mL) was added DIBALH (9.1 mL, 1 M in hexane, 9.1
mmol) at -70 °C dropwise. The solution was gradually
warmed to -15 °C over 3 h and, after being cooled again to
-40 °C, EtOH (2.14 mL, 36.4 mmol) was added slowly to
destroy excess hydride. After 15 min, the cooling bath was
removed, and the solution was poured into an ice-cold mixture
of hexane and 1 N HCl with vigorous stirring. The phases
were separated, and the aqueous phase was extracted with
hexane twice. The combined organic layers were washed with
saturated NaHCO3, dried over MgSO4, and concentrated. The
residue was purified by chromatography (hexane/ethyl acetate)
to afford (3S)-3-[(tert-butyldiphenylsilyl)oxy]-1-butanol (1.08
g, 91%), whose 1H and 13C NMR data were identical with those
reported.34
bp 100 °C (1 Torr); [R]23 ) -6.1 (c 0.94, CHCl3); IR (neat)
D
1
3400, 1632, 1539, 753 cm-1; H NMR δ 1.18 (d, J ) 6 Hz, 3
H), 1.25-1.53 (m, 9 H), 1.57-1.71 (m, 2 H), 2.61 (t, J ) 7.5
Hz, 2 H), 3.72-3.84 (m, 1 H), 5.97 (d, J ) 3 Hz, 1 H), 6.27 (dd,
J ) 3, 2 Hz, 1 H), 7.29 (d, J ) 2 Hz, 1 H); 13C NMR δ 156.6,
140.7, 110.1, 104.6, 68.2, 39.4, 29.4, 29.2, 28.06, 28.02, 25.7,
23.6. Anal. Calcd for C12H20O2: C, 73.42; H, 10.26. Found:
C, 73.10; H, 10.45.
(2E,11R)-11-Hyd r oxy-4-oxo-2-d od ecen oic Acid (40). To
a solution of the furan 38 (190 mg, 0.968 mmol) and pyridine
(0.16 mL, 1.93 mmol) in THF-acetone-H2O (5:4:2, 7 mL) was
added NBS (259 mg, 1.46 mmol) dissolved in THF-acetone-
H2O (5:4:2, 3 mL) at -20 °C. After being stirred at -20 °C
for 1 h and then at room temperature for 4 h, the solution
was poured into a mixture of ethyl acetate and aqueous
Na2S2O3 with vigorous stirring. The organic layer was sepa-
rated, and the aqueous layer was extracted with ethyl acetate.
The combined organic layers were dried over MgSO4 and
concentrated. The residue was purified by chromatography
(hexane/ethyl acetate) to give aldehyde 39 (150 mg, 73%): IR
To a solution of the above alcohol (291 mg, 0.886 mmol),
imidazole (147 mg, 2.16 mmol), and PPh3 (341 mg, 1.30 mmol)
in benzene (10 mL) was added iodine (440 mg, 1.73 mmol).
The resulting red brown solution was stirred at room temper-
ature for 1 h and poured into a mixture of aqueous Na2S2O3
and hexane with vigorous stirring. The hexane layer was
separated, and the aqueous layer was washed with hexane.
The combined organic layers were dried over MgSO4 and
concentrated. The residue was dissolved in THF (40 mL), and
aqueous 35% H2O2 (8.4 mL) was added to destroy PPh3
recovered. After being stirred at room temperature for 30 min,
brine and hexane were added to the mixture. The organic
layer was separated, and the aqueous layer was extracted with
hexane. The combined organic layers were dried over MgSO4
and concentrated to furnish the crude product, which was
purified by chromatography (hexane/Et2O) to give iodide 43
(neat) 3450, 1720 cm-1 1H NMR δ 1.19 (d, J ) 6 Hz, 3 H),
;
1.26-1.74 (m, 11 H), 2.70 (t, J ) 7 Hz, 2 H), 3.74-3.86 (m, 1
H), 6.78 (dd, J ) 16, 7 Hz, 1 H), 6.88 (d, J ) 16 Hz, 1 H), 9.79
(d, J ) 7 Hz, 1 H).
According to the procedure for preparation of 3a , a mixture
of 39 (299 mg, 1.41 mmol), NaClO2 (225 mg, purity 85%, 2.49
mmol), and 2-methyl-2-butene (1.5 mL, 14 mmol) in t-BuOH
(10 mL), the phosphate buffer (pH 3.6, 5 mL), and H2O (5 mL)
was stirred at room temperature for 1.5 h to furnish acid 40
(281 mg, 87%). IR and the following 1H NMR spectra of 40
were identical with the reported14h data: 1H NMR δ 1.20 (d, J
) 6 Hz, 3 H), 1.2-1.7 (m, 10 H), 2.65 (t, J ) 7 Hz, 2 H), 3.75-
3.90 (m, 1 H), 6.42 (br s, 2 H), 6.67 (d, J ) 16 Hz, 1 H), 7.14
(d, J ) 16 Hz, 1 H); 13C NMR δ 199.8, 169.1, 140.6, 130.1,
68.4, 41.5, 39.0, 29.2, 29.0, 25.4, 23.5, 23.2.
Eth ylen e Ketal of(2E,11R)-11-Hydr oxy-4-oxo-2-dodecen -
oic Acid (41). A solution of acid 40 (29 mg, 0.13 mmol), HC-
(OEt)3 (67 mg, 0.63 mmol), ethylene glycol (78 mg, 1.26 mmol),
and p-TsOH‚H2O (3 mg, 0.02 mmol) in benzene (1.5 mL) was
stirred at 35 °C overnight and then poured into a mixture of
ethyl acetate and brine. The ethyl acetate layer was sepa-
rated, and the aqueous layer was extracted with ethyl acetate
repeatedly. The combined organic layers were dried over
MgSO4 and concentrated to give a mixture of 41 and its ethyl
ester which, without separation, was treated with 2 N LiOH
(0.63 mL, 1.26 mmol) in MeOH (6 mL) at room temperature
overnight. The solution was acidified to pH 4 with 1 N HCl
and poured into brine with ethyl acetate. The organic layer
1
(337 mg, 88%), whose IR and H NMR data were identical with
those reported.34
(3S)-2-(3-[(ter t-Bu tyldiph en ylsilyl)oxy]bu tyl)fu r an (44).
According to the procedure for preparation of 34, iodide 43
(2.02 g, 4.59 mmol), furan (1.00 mL, 13.7 mmol), n-BuLi (6.19
mL, 1.48 M in hexane, 9.16 mmol), bipyridine (ca. 10 mg), and
THF (35 mL) afforded 44 (1.62 g, 94%): bp 135 °C (1 Torr); IR
(neat) 1596, 1509, 1430, 707 cm-1 1H NMR δ 1.06 (s, 9 H),
;
1.08 (d, J ) 6 Hz, 3 H), 1.69-1.90 (m, 2 H), 2.57-2.75 (m, 2
H), 3.85-3.97 (m, 1 H), 5.85 (br s, 1 H), 6.24 (br s, 1 H), 7.32-
7.47 (m, 7 H), 7.62-7.75 (m, 4 H); 13C NMR δ 156.3, 140.7,
135.99, 135.95, 134.9, 134.5, 129.6, 129.5, 127.6, 127.5, 110.1,
104.6, 69.0, 37.6, 27.2, 23.9, 23.2, 19.4. Anal. Calcd for
C
24H30O2Si: C, 76.14; H, 7.99. Found: C, 76.22; H, 8.25.
(2E,7S)-7-[(ter t-Bu tyldiph en ylsilyl)oxy]-4-oxo-2-octen o-
ic Acid (46). To a solution of the furan 44 (676 mg, 1.79
mmol) and pyridine (0.58 mL, 7.2 mmol) in THF-acetone-
H2O (5:4:2, 8 mL) was added NBS (383 mg, 2.15 mmol)
dissolved in THF-acetone-H2O (5:4:2, 2 mL) at -20 °C. The
solution was stirred for 1 h at -20 °C and then at room

4-Oxygenated 2-Enoic Acids from 2-Substituted Furans
J . Org. Chem., Vol. 63, No. 21, 1998 7515
temperature for 5 h and poured into a mixture of ethyl acetate
and aqueous Na2S2O3 with vigorous stirring. The organic layer
was separated, and the aqueous layer was extracted with ethyl
acetate. The combined organic layers were dried over MgSO4
and concentrated. The residue was purified by chromatogra-
phy (hexane/ethyl acetate) to afford aldehyde 45 (450 mg,
47 and its ethyl ester, which, without further purification, was
treated with 2 N LiOH (1.05 mL, 2.1 mmol) in MeOH (8 mL)
at room temperature overnight to furnish 47 (64 mg, 70%),
whose 1H NMR data was in good agreement with the reported15c
data: 1H NMR δ 1.04 (s, 9 H), 1.06 (d, J ) 6 Hz, 3 H), 1.41-
1.60 (m, 2 H), 1.62-1.90 (m, 2 H), 3.79-3.98 (m, 5 H), 6.04 (d,
J ) 16 Hz, 1 H), 6.79 (d, J ) 16 Hz, 1 H), 7.33-7.45 (m, 6 H),
7.64-7.70 (m, 4 H).
64%): IR (neat) 1695, 1112, 707 cm-1 1H NMR δ 1.05 (s, 9
;
H), 1.11 (d, J ) 6 Hz, 3 H), 1.65-1.89 (m, 2 H), 2.59-2.80 (m,
2 H), 3.88-4.01 (m, 1 H), 6.64 (dd, J ) 16, 7 Hz, 1 H), 6.74 (d,
J ) 16 Hz, 1 H), 7.31-7.47 (m, 6 H), 7.61-7.70 (m, 4 H), 9.73
(d, J ) 7 Hz, 1 H).
Ack n ow led gm en t. We gratefully acknowledge the
generous supply of (S)- and (R)-epichlorohydrin from
Daiso Co. Ltd. We thank Prof. Tadashi Eguchi and Dr.
Hiroshi Ikeda of this institute for the mass spectrum of
According to the procedure for preparation of 3a , a mixture
of 45 (342 mg, 0.867 mmol), NaClO2 (139 mg, purity 85%, 1.31
mmol), 2-methyl-2-butene (0.74 mL, 7.0 mmol) in t-BuOH (8
mL), the phosphate buffer (pH 3.6, 4 mL), and H2O (4 mL)
was stirred at room temperature for 1 h to give acid 46 (296
mg, 83%) after purification by chromatography (hexane/ethyl
acetate): IR (neat) 1701, 1111, 702 cm-1; 1H NMR δ 1.06 (s, 9
H), 1.10 (d, J ) 6 Hz, 3 H), 1.66-1.88 (m, 2 H), 2.55-2.78 (m,
2 H), 3.88-3.99 (m, 1 H), 6.57 (d, J ) 16 Hz, 1 H), 7.04 (d, J
) 16 Hz, 1 H), 7.34-7.48 (m, 6 H), 7.63-7.72 (m, 4 H).
Eth ylen e Keta l of (2E,7S)-7-[(ter t-Bu tyld ip h en ylsilyl)-
oxy]-4-oxo-2-octen oic Acid (47). According to the procedure
for preparation of 41, a solution of 46 (84 mg, 0.20 mmol),
HC(OEt)3 (113 mL, 1.03 mmol), p-TsOH‚H2O (5 mg, 0.03
mmol), and ethylene glycol (128 mg, 2.06 mmol) in benzene
(3.5 mL) was stirred at 35 °C overnight to afford a mixture of
1
26 and 500 MHz H NMR spectrum of 7, respectively.
We also thank Mr. Yasumasa Tashiro of Nippon Chemi-
phar for measuring the high resolution mass spectra.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds lacking elemental analyses (16 pages). This mate-
rial is contained in libraries on microfiche, immediately follows
this article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
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J O980942A