Enantiodivergent syntheses of γ-substituted butenolides with tertiary and quaternary asymmetric centers

Article abstract of DOI:10.1016/S0040-4039(02)02711-9

Continuous nucleophilic addition with several organometallic reagents to tricyclic lactone (-)-1 proceeded diastereoselectively. Newly generated tertiary and quaternary asymmetric centers were controlled by the order in which the nucleophilic reagents were added. Using this methodology, enantiodivergent syntheses of several γ-substituted butenolides with tertiary and quaternary asymmetric centers were established from a single chiral material.

Full text of DOI:10.1016/S0040-4039(02)02711-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 745–749
Enantiodivergent syntheses of g-substituted butenolides with
tertiary and quaternary asymmetric centers
Katsufumi Suzuki and Kohei Inomata*
Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
Received 18 October 2002; revised 13 November 2002; accepted 22 November 2002
Abstract—Continuous nucleophilic addition with several organometallic reagents to tricyclic lactone (−)-1 proceeded diastereose-
lectively. Newly generated tertiary and quaternary asymmetric centers were controlled by the order in which the nucleophilic
reagents were added. Using this methodology, enantiodivergent syntheses of several g-substituted butenolides with tertiary and
quaternary asymmetric centers were established from a single chiral material. © 2003 Elsevier Science Ltd. All rights reserved.
Chiral g-substituted butenolides 2 are known to be useful
synthons for the enantiocontrolled construction of a
variety of biologically active natural and unnatural
compounds.1 Therefore, chiral synthesis of g-substituted
butenolides has been an ongoing challenge for
researchers attempting the organic synthesis of certain
substances.2,3 We have recently reported the enantiodi-
vergent synthesis of (+)- and (−)-trans-quercus lactones
3 from (+)-1 as a single chiral material via continuous
diastereoselective nucleophilic addition.4 We have found
that (+)-1 is the synthetic equivalent of both enantiomers
of chiral g-butyl-substituted butenolide 2a (Scheme 1).
We report here an application of this methodology to
synthesize both enantiomers of several chiral g-substi-
tuted butenolides 2 with tertiary and quaternary asym-
metric centers from a single chiral material 1 (Scheme 1).5
Scheme 1.
Keywords: chiral synthesis; chiral building block; nucleophilic addition; lactones; butenolides.
* Corresponding author. Tel.: +81(22)234-4181; fax: +81(22)275-2013; e-mail: inomata@tohoku-pharm.ac.jp
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02711-9

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K. Suzuki, K. Inomata / Tetrahedron Letters 44 (2003) 745–749
In the present study optically pure tricyclic lactone
(−)-1, prepared from dicyclopentadiene by our estab-
lished method,6 was allowed to react with the first
organometallic reagent (R1M), and then continuously
reacted with the second organometallic reagents (R2M)
in the same flask to furnish diastereomeric diols 6 and
7 (Scheme 2). The results of this continuous nucleo-
philic addition are summarized in Table 1. In the case
of using diisobutylaluminum hydride (DIBAL) as the
first nucleophilic reagent (R1M) and using some
organometallic reagents as the second nucleophilic
reagents (R2M) in tetrahydrofuran (THF), diastereose-
lective nucleophilic addition proceeded preferentially to
yield diol 6 with some alkyl and aryl substitutions, and
to selectively construct a tertiary asymmetric center
(entries 1, 2, 6, and 8). In comparison with entries 1 and
2, a higher yield and higher diastereoselectivity of diols
ride (nBuMgCl) was used as R2M. These results sug-
gested that it was suitable for the reaction to use
Grignard reagent as R2M. For this reason, we demon-
strated the use of some other Grignard reagents as R2M
(entries 6 and 8). We then inverted the newly generated
asymmetric center in the order in which the nucleo-
philic reagents were added. In THF, lactone (−)-1
reacted with stoichiometric amounts of nbutyllithium
(nBuLi) as R1M to avoid dialkylation,7 and continu-
ously reacted with DIBAL or L-Selectride as R2M. In
these cases, a lower yield and lower diastereoselectivity
of diols 6b, 7b were observed (entries 3 and 4). When
toluene was used as a solvent, a drastic improvement in
this reaction was observed.8 Entry 5 shows that diol 6b
was obtained in 78% yield as an almost single product,
and that the inversion of the newly generated tertiary
asymmetric center succeeded. Although a similar result
was obtained in the case of the methyl group (entry 7),
n
6a and 7a were observed, when butylmagnesium chlo-
Scheme 2.
Table 1. Continuous nucleophilic addition to lactone (−)-1
Entry
Solvent
R1M
R2M
Products
Yielda (%)
Ratiob 6:7
6 and 7
1
2
3
4
5
6
7
8
THF
THF
THF
THF
DIBAL
DIBAL
nBuLi
nBuLi
nBuLi
DIBAL
MeLi
nBuLi
a: R1=H, R2=nBuc
a: R1=H, R2=nBu
b: R1=nBu, R2=H
b: R1=nBu, R2=H
b: R1=nBu, R2=H
c: R1=H, R2=Me
d: R1=Me, R2=H
e: R1=H, R2=Phd
f: R1=Ph, R2=H
g: R1=nBu, R2=Me
h: R1=Me, R2=nBu
i: R1=Me, R2=Ph
j: R1=Ph, R2=Me
k: R1=nBu, R2=Ph
l: R1=Ph, R2=nBu
46
81
38
26
78
82
77
83
25
60
56
68
84
44
69
71:29
\99:1
52:48
67:33
\99:1
93:7
nBuMgCl
DIBAL
L-Selectride
L-Selectride
MeMgBr
L-Selectride
PhMgBr
L-Selectride
MeMgBr
nBuMgCl
PhMgBr
Toluene
THF
Toluene
THF
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
94:6
94:6
DIBAL
PhLi
9
60:40
\99:1
\99:1
\99:1
\99:1
\99:1
\99:1
10
11
12
13
14
15
nBuLi
MeLi
MeLi
PhLi
MeMgBr
PhMgBr
nBuLi
PhLi
nBuMgCl
a Isolated yield.
b The ratios 6:7 have been determined on the 1H NMR spectra at 270 MHz of crude products by integration of the signals due to the bridgehead
protons or the oxymethine protons.
c nButyl.
d Phenyl.

K. Suzuki, K. Inomata / Tetrahedron Letters 44 (2003) 745–749
747
sion to lactone 8. We believe that the diastereoselectiv-
ity in these reactions can be explained as follows. First,
nucleophilic addition of R1M to (−)-1 gives the corre-
sponding acetal derivative 4, which is equilibrated to
the metal-chelated intermediate 5. Next,asecond nucleo-
phile (R2M) approaches from the outside of the
chelated ring to give a single stereoisomer. Thus, the
newly generated asymmetric center is controlled selec-
tively by the order in which the nucleophilic reagents
are added (Scheme 2). We cannot, however, explain the
lower selectivity in entry 9 (Table 1), though the reac-
tion could possibly have proceeded through an acyclic
intermediate.
,
Scheme 3. Reagents and conditions: (i) cat. TPAP, NMO, 4 A
molecular sieves, CH2Cl2, rt; (ii) ODCB, reflux.
Table 2. Studies of the oxidation of diol 6
Entry
Substrate
Product 8
Yielda (%)
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
6g
6h
6i
8a: R1=H, R2=nBu
8b: R1=nBu, R2=H
8c: R1=H, R2=Me
8d: R1=Me, R2=H
8e: R1=H, R2=Ph
8f: R1=Ph, R2=H
8g: R1=nBu, R2=Me
8h: R1=Me, R2=nBu
8i: R1=Me, R2=Ph
8j: R1=Ph, R2=Me
8k: R1=nBu, R2=Ph
8l: R1=Ph, R2=nBu
66
61
57
45
65
48
41
45
37
40
42
45
As shown in Scheme 3 and Table 2, oxidation of diol 6
with a catalytic amount of tetrapropylammonium per-
ruthenate (TPAP)10 in the presence of 4-methylmorpho-
line N-oxide (NMO) gave the corresponding lactones
8,11 respectively, in 37–66% yield (Scheme 3, Table 2).
Nuclear Overhauser effect (NOE) experiments were
carried out for all of the lactones 8 because strong NOE
was observed between the proton of the R1 group and
the olefinic proton in the bicyclo[2.2.1]heptene ring, and
it was confirmed that the stereochemistry of the newly
generated asymmetric centers, as shown in Scheme 3
and Table 2, was correct. A retro-Diels–Alder reaction
of lactone 8 in refluxing o-dichlorobenzene (ODCB)
yielded both enantiomers of corresponding g-substi-
tuted butenolides 2 (Scheme 3, Table 3).12 The absolute
configurations of butenolides 2a–e were assigned by
comparison of their optical rotations with those
reported previously.13–17 Of these butenolides, com-
pound 2b is also known as b-angelica lactone, which is
a key intermediate in the syntheses of some natural
products such as (+)-blastmycinone,18 (−)-saprathin,19
and (+)-himbacine.20 Because butenolide 2f has never
been reported,21 the absolute configuration was deter-
9
10
11
12
6j
6k
6l
a Isolated yield.
lower selectivity and yield were observed in the case of
the phenyl group (entry 9). We next demonstrated
similar construction of a quaternary asymmetric center
(entries 10–15). In all cases, the reactions proceeded to
furnish diol 6 diastereoselectively with 44–84% yield,
and to construct quaternary asymmetric centers includ-
ing alkyl and aryl moieties.9 All of the diastereomeric
diol 7 products were readily separated by silica gel
column chromatography either directly or after conver-
Table 3. Studies of the retro-Diels–Alder reaction of lactone 8
b
Entry
Substrate
Product 2
Yielda (%)
[h]D (c)
eec (%)
1
2
3
4
5
6
7
8
8a
8b
8c
8d
8e
8f
8g
8h
8i
(+)-2a: R1=H, R2=nBu
(−)-2a: R1=nBu, R2=H
(+)-2b: R1=H, R2=Me
(−)-2b: R1=Me, R2=H
(+)-2c: R1=H, R2=Ph
(−)-2c: R1=Ph, R2=H
(−)-2d: R1=nBu, R2=Me
(+)-2d: R1=Me, R2=nBu
(+)-2e: R1=Me, R2=Ph
(−)-2e: R1=Ph, R2=Me
(+)-2f: R1=nBu, R2=Ph
(−)-2f: R1=Ph, R2=nBu
84
85
61
52
19
12
85
77
92
83
90
80
+100.8 (1.0)
−100.4 (1.2)d
+117.0 (1.3)e
−114.0 (0.8)f
+277.2 (0.8)g
−276.7 (0.7)
−19.1 (0.7)
\98
\98
\98
\98
\98
\98
\98
\98
\98
\98
\98
\98
+19.2 (1.2)h
+274.4 (1.2)i
−274.3 (1.3)j
+163.1 (1.0)
−161.4 (0.9)
9
10
11
12
8j
8k
8l
a Isolated yield.
b Measured in CHCl3 at room temperature.
c Determined by HPLC with a chiral stationary phase (Chiralcel OD, eluent: 2-propanol-hexane).
d lit.13a −101.0.
e lit.14e +93.8 (c 0.5).
f lit.14b −107 (c 1.6).
g lit.15b +304 (c 1.0).
h lit.16b (29% ee) +4.6 (c 1.42).
i lit.17b +275.6 (c 1.0).
j lit.17a (91% ee) −248.3 (c 5.0).

748
K. Suzuki, K. Inomata / Tetrahedron Letters 44 (2003) 745–749
Scheme 4.
mined based on their connection with the structures of
the starting diastereomeric lactones 8k and 8l. Entries 5
and 6 in Table 3 show that there was a lower yield in
the retro-Diels–Alder reaction. In these cases, b,g-
unsaturated lactone 9 was also obtained in 8% yield
with butenolide 2c (Scheme 4). These results suggest the
possibility of the racemization of 2 through a retro-
Diels–Alder reaction. We therefore determined the
enantiomeric excess (ee) of 2 by HPLC with a chiral
stationary phase. Fortunately, all of the butenolides 2
existed in >98% ee. Thus, serious racemization had not
occurred under these reaction conditions.22
Ghera, E.; Hassner, A. Tetrahedron Lett. 2000, 41, 5583–
5587; (c) Braun, M.; Rahematpura, J.; Bu¨hne, C.; Paulitz,
T. C. Synlett 2000, 1070–1072; (d) D’Oca, M. G. M.;
Pilli, R. A.; Vencato, I. Tetrahedron Lett. 2000, 41,
9709–9712; (e) Ma, S.; Wu, S. Chem. Commun. 2001,
441–442; (f) Ma, S.; Shi, Z.; Wu, S. Tetrahedron: Asym-
metry 2001, 12, 193–195; (g) Rudler, H.; Parlier, A.;
Certal, V.; Frison, J.-C. Tetrahedron Lett. 2001, 42, 5235–
5237; (h) Honzumi, M.; Ogasawara, K. Tetrahedron Lett.
2002, 43, 1047–1049.
4. Suzuki, K.; Shoji, M.; Kobayashi, E.; Inomata, K. Tetra-
hedron: Asymmetry 2001, 12, 2789–2792.
5. Preliminary results of this work were presented at The
122nd Annual Meeting of the Pharmaceutical Society of
Japan, Chiba, Japan, March 26–28, 2002. See abstracts
vol. 2, p 39.
6. Suzuki, K.; Inomata, K. Synthesis 2002, 1819–1822.
7. In our preliminary results, when Grignard reagents were
used as R1M, undesirable dialkylated products were pref-
erentially yielded.
In conclusion, we have established enantiodivergent
syntheses of both enantiomers of several g-substituted
butenolides with tertiary and quarternary asymmetric
centers from tricyclic lactone (−)-1 as a single chiral
material. This result means that these chiral butenolides
can also be synthesized from enantiomeric lactone (+)-1
by the same methods described above. Therefore, lac-
tone 1 can be used enantiodivergently and enantiocon-
vergently as a synthetic equivalent of both enantiomers
of g-substituted butenolides 2. We have just begun to
investigate exploitation of lactone 1 as a chiral buteno-
lide equivalent for the synthesis of pharmacologically
important natural and unnatural compounds.
8. A solvent effect similar to that of nucleophilic addition to
lactone derivatives has been reported, see: Bessieres, B.;
Morin, C. Synlett 2000, 1691–1693.
9. Typical procedure of continuous nucleophilic addition: to
a stirred solution of lactone (−)-1 (100 mg, 0.67 mmol) in
anhydrous toluene (2 mL) was added phenyllithium (0.88
M in cyclohexane–diethyl ether, 0.9 mL, 0.77 mmol) at
−78°C. After the mixture was stirred at the same temper-
ature for 2 h, methylmagnesium bromide (0.93 M in
THF, 2.9 mL, 2.67 mmol) was added, and the mixture
was stirred for 11 h at the same temperature. Then, satd
aq. NH4Cl (3 mL) was added to quench the reaction. The
mixture was extracted with AcOEt (5 mL×3), washed
with satd aq. NaHCO3 (10 mL), brine (10 mL), and was
dried (MgSO4) and evaporated under reduced pressure.
The residue was chromatographed on silica gel (benzene/
AcOEt=2/1) to give 6j (137 mg, 84%) as a colorless oil.
10. Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P.
Synthesis 1994, 639–666.
Acknowledgements
We would like to thank Professor K. Ogasawara,
Tohoku University, Sendai, Japan, and Dr. K. Kawa-
mura, Nisshin Flour Milling Co. Ltd, Tokyo, Japan,
for their many useful suggestions. We would also like
to thank the Japan Association of Chemistry and Nis-
shin Flour Milling Co. LTD, Tokyo, Japan, for their
financial support (to K.I.).
11. Bloch, R.; Brillet, C. Synlett 1991, 829–830.
12. Similar synthesis of butenolides via the retro-Diels–Alder
reaction, see: Corbera, J.; Font, J.; Monsalvatje, M.;
Ortun˜o, R. M.; Sa´nchez-Ferrando, F. J. Org. Chem.
1988, 53, 4393–4395. See also Refs. 13a and 16a.
13. For examples of chiral syntheses of 2a, see: (a) Bloch, R.;
Gilbert, L. J. Org. Chem. 1987, 52, 4603–4605; (b) Taka-
hata, H.; Uchida, Y.; Momose, T. J. Org. Chem. 1995,
60, 5628–5633; (c) Harcken, C.; Bru¨ckner, R. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2750–2752; (d) Tsuboi, S.;
Sakamoto, J.; Yamashita, H.; Sakai, T.; Utaka, M. J.
Org. Chem. 1998, 63, 1102–1108.
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tuted butenolides, see: (a) Martin, S. F.; Lopez, O. D.
Tetrahedron Lett. 1999, 40, 8949–8953; (b) Nakache, P.;

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1
21. Data for (+)-2f: colorless oil. IR (film): w=1767 cm−1. H
NMR (270 MHz, CDCl3) l 0.85 (t, J=6.9 Hz, 3H),
1.16–1.34 (m, 4H), 1.91–2.01 (m, 1H), 2.09–2.20 (m, 1H),
6.05 (d, J=5.6 Hz, 1H), 7.07–7.42 (m, 5H), 7.62 (d,
J=5.6 Hz, 1H). 13C NMR (270 MHz, CDCl3) l 13.8,
22.6, 25.7, 39.4, 91.5, 119.6, 124.7, 127.9, 128.6, 138.8,
159.3, 172.1. EI MS: m/z 216 (M+), 159 (100%). HRMS:
calcd for C14H16O2 216.1150. Found: 216.1158.
22. In Ref. 4, we reported that ee values of (+)- and (−)-2a
were 90–92% because of a partial racemizaton occurring
under these reaction conditions. After the publication, we
determined the ee of starting lactone 1. Because the
lactone 1 we used in Ref. 4 existed in 90% ee, no
racemization occurred through the retro-Diels–Alder
reaction. In this report, lactone 1 with >98% ee, which
was synthesized by the method in Ref. 6, was used as a
starting material.
17. For examples of chiral syntheses of 2e, see: (a) Musierow-