A concise synthesis of (±)-methylenolactocin and the formal synthesis of (±)-phaseolinic acid

Article abstract of DOI:10.1016/S0040-4039(01)00492-0

(±)-Methylenolactocin was prepared in five steps involving an indium-mediated allylation reaction as the key step.

Full text of DOI:10.1016/S0040-4039(01)00492-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3511–3514
A concise synthesis of (±)-methylenolactocin and the formal
synthesis of (±)-phaseolinic acid
Teck-Peng Loh* and Pek-Ling Lye
Department of Chemistry, The National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore
Received 2 February 2001; revised 9 March 2001; accepted 21 March 2001
Abstract—(±)-Methylenolactocin was prepared in five steps involving an indium-mediated allylation reaction as the key step.
©
2001 Elsevier Science Ltd. All rights reserved.
6
a–d
a-Methylene-b-butyrolactone is an integral building
We envisaged that the indium-mediated allylation
of
1
block of many bioactive natural products. Among
bromide 4 with hexanal would provide an efficient and
practical route to 3, a key intermediate for the synthesis
of (±)-methylenolactocin 1 and (±)-phaseolinic acid 2
(Scheme 1).
them, methylenolactocin 1 has attracted the most atten-
tion because of its interesting anti-tumour activity and
its unusual structure with high functionality and stereo-
2
chemistry. Accordingly, many approaches to the total
3a–c,4a–e
synthesis of this compound have been reported.
(Z)-Allylic bromide 4a was prepared in two steps from
methyl acrylate. Baylis–Hillman reaction involving the
coupling of methyl glyoxylate with methyl acrylate in
dioxane gave alcohol 5 in 52% yield. Subsequent brom-
However, most of the reported syntheses involved long
and difficult steps which rendered them impractical.
Therefore, a concise approach to the synthesis of 1 is
well-sought after. In this paper, we report an efficient
and practical method for the synthesis of (±)-
methylenolactocin 1 and (±)-phaseolinic acid 2, a
ination of 5 with PBr in ether proceeded smoothly to
3
afford both (Z)-4a and (E)-4b allylic bromides in 90%
overall yield. Both isomers can be easily separated
through flash column chromatography and the product
5
metabolite of the fungus Macrophomina phaseolina.
Scheme 1.
Scheme 2.
*
0
Corresponding author. Fax: (65)-7791691; e-mail: chmlohtp@nus.edu.sg
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00492-0

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T.-P. Loh, P.-L. Lye / Tetrahedron Letters 42 (2001) 3511–3514
ratio is 95:5 [(Z)-4a:(E)-4b]. The stereochemistries of
both stereoisomers were determined using NOE spec-
troscopy (Scheme 2).
troscopy, where the ring cyclized product 6a was deter-
mined as a trans-substituted lactone and thus the
cyclized product from the anti isomer. The homoallylic
alcohol 6b was determined to be the syn isomer based
on the NOESY studies of lactone 11 obtained from 6b
after treatment with TFA (Fig. 1).
With the bromide (Z)-4a in hand, we proceeded to
investigate the indium-mediated allylation with hexanal.
Although organoindium chemistry, together with ring-
closure olefin metathesis has been applied to achieve the
synthesis of the a-methylene lactone moiety, the
indium-mediated allylation reaction involving bromide
With these optimized conditions, the reactions of allylic
bromide (Z)-4a with four other different aldehydes
were investigated. The results are shown in Table 2.
(
Z)-4a proved to be more difficult than we had
7
expected. Initial attempts using classical indium-medi-
ated allylation reaction conditions in water consis-
tently afforded the undesired diester 6c as the major
product with only a trace amount of the desired
product (Table 1, entry 1). Therefore, attempts were
carried out to optimize the yield of 6a and 6b in the
indium-mediated allylation reaction of allylic bromide
All reactions proceeded smoothly to afford the desired
products in moderate to excellent yields. Except for the
reaction with 3-methoxybenzaldehyde (entry 4), all
other reactions gave low stereoselectivities.
6
With the product 6 obtained from hexanal, we
embarked on the total synthesis of (±)-methylenolac-
tocin 1 (Scheme 3).
(
Z)-4a with hexanal. The results are shown in Table 1.
With water as the solvent, most of the allyllic bromide
Z)-4a was converted to the undesired diester 6c (entry
). In an aqueous medium (H O/THF), the desired
Both the isomers, 6a and 6b, can be easily separated
through flash column chromatography and converted
to (±)-methylenolactocin 1. In the presence of TFA, 6b
was cyclized to the cis-b,g-substituted 11 in 79% yield.
Acid hydrolysis of 6a and 11 with 6N HCl afforded 1 in
(
1
2
product was obtained but in poor yield (entry 2). Even
when the reaction was carried out in pH 7 buffer
solution, the undesired 6c was still obtained in signifi-
cant amounts (entry 3). Attempts using dry THF
showed a similar result (entry 4). Fortunately, when the
reaction was performed neat, the desired product was
obtained as a mixture of two isomers (6a:6b 40:45) in a
combined yield of 85% (entry 5).
8
70% yield, whereas 11 underwent epimerization. The
relative stereochemistry of both lactones 6a and 11 was
confirmed by NOESY spectroscopy and the reported
1
13
8,9
H and C NMR data.
In addition, the target
molecule 1 obtained is identical to the natural product
1
13
10
by H and C NMR. On the other hand, 11 can lead
to a formal synthesis of (±)-phaseolinic acid via a
stereoselective hydrogenation using thiophenol, fol-
lowed by the removal of the sulfide group with Na–
Interestingly, the anti isomer cyclized under the reaction
conditions to afford 6a. The stereochemistries for both
11
6a and 6b were determined through NOESY spec-
Hg.
Table 1. Optimization of allylation reaction of allylbromide (Z)-4a with hexanal
Conditionsa
% Yield (6a+6b) (6a:6b:6c)
b
c
Entry
1
2
3
4
5
H O
THF:H O (1:1)
THF:H O:buffer pH 7.0 (1:1:2)
Dry THF
Neat
Mainly 6c
2
8 (20:20:60)
60 (36:36:28)
60 (40:40:20)
85 (40:45:15)
2
2
a
All reactions were performed at room temperature for 3 days.
Overall purified yield for 6a and 6b.
b
c
Product ratios (6a:6b:6c) were determined based on 1H NMR analysis.
Figure 1.

T.-P. Loh, P.-L. Lye / Tetrahedron Letters 42 (2001) 3511–3514
Table 2. Allylation reaction with four different aldehydes
3513
Aldehydea
Ratio a:b
b
Total yield (a+b%)
c
Entry
1
2
3
4
Nonyl aldehyde
Cyclohexanecarboxaldehyde
Benzaldehyde
(7a:7b) (53:47)
(8a:8b) (64:36)
(9a:9b) (35:65)
(10a:10b) (15:85)
34d
95
77
3-Methoxybenzaldehyde
60
a
All reactions were performed under neat conditions at room temperature for 3 days.
Product ratios (a:b) were determined based on isolated yields.
Overall purified yield for a and b.
b
c
d
Reaction not optimized.
1
13
Scheme 3. The H and C NMR data for compounds 6a, 11 and 1 are given in Ref. 12.
In conclusion, we have developed a short and efficient
route for the synthesis of (±)-methylenolactocin 1.
Especially noteworthy is that both the diastereomers
obtained from indium-mediated allylation of allylic
3. (a) Heathcock, C. H.; Graham, S. L.; Pirrung, M. C.;
Plavac, F.; White, C. T. In J. ApSimon: The Total
Synthesis of Natural Products, Vol. 5: The Total Synthesis
of Sesquiterpenes 1970–1979; Wiley: New York, 1983; (b)
Grieco, P. A.; Ohfune, Y.; Majetich, G. F. J. Org. Chem.
1983, 48, 360; (c) Tanaka, A.; Yamashita, K. Agric. Biol.
Chem. 1980, 44, 199 and references cited therein.
(
Z)-4a with hexanal can be converted to (±)-1 in just
five steps.
Furthermore, this method allows easy access to a wide
variety of analogues. The synthesis and biological eval-
uation of various analogues are currently in progress.
4. (a) Saicic, R. N.; Zard, S. Z. Chem. Commun. 1996, 1631;
(b) Takahata, H.; Uchida, Y.; Momose, T. J. Org. Chem.
1995, 60, 5628; (c) Vaupel, A.; Knochel, P. Tetrahedron
Lett. 1995, 26, 231; (d) Honda, T.; Kimura, N. J. Chem.
Soc., Chem. Commun. 1994, 77; (e) de Azevedo, M. B.
M.; Murta, M. M.; Greene, A. E. J. Org. Chem. 1992, 57,
Acknowledgements
4567 and references cited therein.
5. Mahato, S. B.; Siddiqui, K. I. A.; Bhattacharya, G.;
Ghosai, T. J. Nat. Prod. 1987, 50, 245.
This research was assisted financially by grants from
the National University of Singapore.
6
. (a) Paquette, L. A. In Green Chemistry, Frontiers in
Benign Chemical Syntheses and Processes; Anantas, P.;
Williamson, T. C., Eds.; Oxford University Press: New
York, 1998; (b) Li, C. J.; Chan, T. H. Tetrahedron Lett.
1999, 55, 11149; (c) Araki, S.; Shimizu, T.; Johar, P. S. J.
Org. Chem. 1991, 56, 2538; (d) Loh, T. P.; Diana, S. C.
H.; Sim, K. Y. Synlett 1996, 263; (e) Loh, T. P.; Cao, G.
Q.; Pei, J. Tetrahedron Lett. 1998, 39, 1457.
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52.8, 78.9, 125.0, 133.0, 168.2, 169.6. Compound 11: H
NMR (300 MHz): l 0.88–0.90 (m, 3H), 1.29–1.31 (m,
6H), 1.55–1.64 (m, 2H), 3.75 (s, 3H), 4.00 (d, J=7.6 Hz,
1H), 4.58–4.65 (m, 1H), 5.82 (d, J=2.4 Hz, 1H), 6.40 (d,
J=2.4 Hz, 1H); 13C NMR (75.4 MHz): l 13.8, 22.3, 25.1,
31.2, 31.4, 49.0, 52.2, 78.1, 124.9, 133.6, 168.8, 169.3.
6
1
0. Park, B. K.; Nakagawa, M.; Hirota, A.; Nakayama, M.
J. Antibiot. 1988, 6, 751.
1
1
1. Zhang, Z.; Lu, X. Tetrahedron: Asymmetry 1996, 7, 1923.
2. H and C NMR data for compound 6a: H NMR (300
MHz): l 0.85–0.89 (m, 3H), 1.30–1.33 (m, 6H), 1.68–1.76
1
13
1
1
Compound 1: H NMR (300 MHz): l 0.88–0.91 (m, 3H),
1.25–1.33 (m, 6H), 1.70–1.74 (m, 2H), 3.61 (m, 1H),
(
1
m, 2H), 3.58 (m, 1H), 3.80 (s, 3H), 4.79 (q, J=6.4 Hz,
4.78–4.82 (m, 1H), 6.00 (d, J=2.8 Hz, 1H), 6.44 (d,
J=2.8 Hz, 1H); C NMR (75.4 MHz): l 13.9, 22.3, 24.3,
H), 5.91 (d, J=2.4 Hz, 1H), 6.40 (d, J=2.4 Hz, 1H); 13
C
13
NMR (75.4 MHz): l 13.8, 22.3, 24.3, 29.6, 35.6, 49.7,
31.2, 35.6, 49.6, 79.0, 125.4, 132.7, 168.2, 172.8.
.
.