First total synthesis of a new sesquiterpenoid natural product, (±)-3-(2,4-dihydroxybenzoyl)-4,5-dimethyl-5-(4,8-dimethyl-3(E),7(E)- nonadien-1-yl)tetrahydro-2-furanone

Article abstract of DOI:10.1016/S0040-4039(03)00146-1

An efficient and stereodefined process is described for the first preparation of a new prenyl-benzoylfuranone type sesquiterpenoid, (±)-3-(2,4-dihydroxybenzoyl)-4,5-dimethyl-5-(4,8-dimethyl-3(E),7(E)- nonadien-1-yl)tetrahydro-2-furanone. The synthetic str

Full text of DOI:10.1016/S0040-4039(03)00146-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1775–1777
First total synthesis of a new sesquiterpenoid natural
product, ( )-3-(2,4-dihydroxybenzoyl)-4,5-dimethyl-5-
(4,8-dimethyl-3(E),7(E)-nonadien-1-yl)tetrahydro-2-furanone
Hidemi Yoda,* Kazuhide Maruyama and Kunihiko Takabe
Department of Molecular Science, Faculty of Engineering, Shizuoka University, Johoku 3-5-1, Hamamatsu 432-8561, Japan
Received 16 December 2002; revised 9 January 2003; accepted 10 January 2003
Abstract—An efficient and stereodefined process is described for the first preparation of a new prenyl-benzoylfuranone type
sesquiterpenoid, ( )-3-(2,4-dihydroxybenzoyl)-4,5-dimethyl-5-(4,8-dimethyl-3(E),7(E)-nonadien-1-yl)tetrahydro-2-furanone. The
synthetic strategy is based on nucleophilic addition of organometallic reagents to the functionalized ketoamides elaborated from
dihydroxyacetone dimer for the stereoselective construction of the key quaternary carbon center in the target compound. © 2003
Elsevier Science Ltd. All rights reserved.
3-(2,4-Dihydroxybenzoyl)-4,5-dimethyl-5-(4,8-dimethyl-
3(E),7(E)-nonadien-1-yl)tetrahydro-2-furanone (1)
penoid derivatives possessing contiguous three stereo-
genic centers along with a quaternary carbon in the
lactone ring after structural characterization by the
same group based on comprehensive spectral analysis.
Since the synthesis of this type of compounds poses
interesting and often unsolved problems of stereocon-
trol, no report has appeared to date despite those
pharmacological activities and attractive structural fea-
tures. The central feature of this communication is to
report the details of the first and expeditious route from
dihydroxyacetone dimer for the stereoselective con-
struction of the tetrasubstituted lactone ring with
a quaternary carbon center and the total synthesis
together with two structurally related furanyl-substi-
tuted compounds, 2 and 3, was isolated in 1999 by
Kojima and co-workers1 from the roots of Ferula fer-
ulioides (Steud.) Korovin (Umbelliferae), which grows
in Bulgan Somon of Hovd City, Mongolia (Fig. 1).
Closely related new sesquiterpene phenylpropanoids,
pallidones, were also isolated in 2000 from the roots of
Ferula pallida (Umbelliferae).2 These natural products
have been used as a traditional medicine for the treat-
ment of spasm1 for a long time and were revealed to be
a new class of prenyl-benzoylfuranone type sesquiter-
Figure 1.
Keywords: sesquiterpenoid; benzoylfuranone; nucleophilic addition; terpene lactone; dihydroxyacetone.
* Corresponding author. Tel.: +81 53 478 1150; fax: +81 53 478 1150; e-mail: tchyoda@ipc.shizuoka.ac.jp
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00146-1

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H. Yoda et al. / Tetrahedron Letters 44 (2003) 1775–1777
of
( )-3-(2,4-dihydroxybenzoyl)-4,5-dimethyl-5-(4,8-
stereoselectivity (12a:13a=87:13, determined by HPLC)
(Scheme 2). After investigation with three types of
mono-protected amide alcohols 6, a surprising enhance-
ment in stereoselectivity was finally observed upon
dimethyl-3(E),7(E)-nonadien-1-yl)tetrahydro-2-furan-
one natural product (1).
As shown in Scheme 1, the protected mono-terpene
lactones 5, key starting compounds for the synthesis of
these terpenoids, were easily prepared from dihydroxy-
acetone dimer 4 according to our reported procedure.3
Aminolysis of 5 with Me2NH opened the lactone ring
to give amide alcohols 6 in high yields. Initial experi-
ments have been performed with 6a in expectation of
the stereoselective construction of the quaternary car-
bon center. Swern oxidation of 6a followed by the
nucleophilic addition of methyl- or pentenyl Grignard
reagent in situ gave the amide alcohol 7 and 8,4 as a
predominant product,5 respectively. After oxidation
with PCC, we were delighted to find that the second
alternating Grignard addition to the ketone intermedi-
employing
butyldiphenylsilyl) group, leading to the desired isomer
12c as the single product (determined by HPLC and 13
6c
with
the
largest
TBDPS(t-
C
NMR analysis). Cyclization of 12c under mild condi-
tions gave the trisubstituted lactone 14 in 76% yield
without silyl-deprotection. 14 thus obtained was
effected by coupling reaction with 2,4-dimethoxyben-
zaldehyde in the presence of LiHMDS at low tempera-
ture to produce the 3,4-trans-adduct 15 alone,9
including the almost equivalent of stereoisomers at the
benzyl position4 (determined by 13C NMR). Then, 15
was submitted to PCC oxidation again followed by
deprotection with Bu4NF to provide the lactone alcohol
16 in moderate yield. Whereas the deoxygenation reac-
tion of the primary alcohol in 16 with phenylchloro-
thionoformate10 or thiocarbonyldiimidazole11 gave
inseparable mixtures, use of Et3B–Bu3SnH12 in the pres-
ence of O2 at 0°C after bromination of the hydroxyl
group with CBr4–PPh3 dramatically changed the results
and brought about the desired deoxygenated product
17 in satisfactory yield. Finally, 17 was subjected to
deprotection with Me3SiI to complete the total synthe-
sis of ( )-1. The spectral data of synthesized 1 were
completely identical with those of the reported natural
compound.1
6
ates in the presence of CeCl3 could effect these reac-
tions to afford the desired products 9a and 9b in a
reverse stereoselective manner7 at the quaternary center
(the former; 9a:9b=92:8 and the latter; 9a:9b=7:93,
determined by HPLC). These compounds were
smoothly cyclized to the corresponding trisubstituted
lactones 10a and 10b, respectively. Stereochemical
results thus obtained can be easily explained in terms of
the thermodynamically more stable Cram’s non-chela-
tion transition model.4
With the above stereochemical outcome in hand, we
turned our attention to the total synthesis of ( )-1. To
begin with, successive treatment of 6a with Swern oxi-
dation reagents, homogeranylmagnesium bromide elab-
orated from geraniol in six steps,8 and PCC, followed
by the addition of the second methylmagnesium bro-
mide as described above afforded the amide alcohol 12a
through 11a as a predominant product with moderate
In summary, this work constitutes the first synthesis of
the naturally occurring prenyl-benzoylfuranone type of
sesquiterpenoid through stereoselective construction of
the tetrasubstituted lactones containing a quaternary
carbon center from mono-terpene lactones and verifies
the structure proposed in the literature for this
compound.
Scheme 1. Reagents and conditions: (a) Me2NH, THF; 86% (6a); 90% (6b); 92% (6c); (b) (i) (COCl)2, DMSO, THF, then Et3N,
−78 to −45°C; (ii) methylmagnesium bromide, THF, 0°C; 62% (7) (two steps); pentenylmagnesium bromide, THF, 0°C; 54% (8)
(two steps); (c) (i) PCC, CH2Cl2; (ii) pentenylmagnesium bromide, THF, CeCl3, −78°C; 53% (9a) (two steps); methylmagnesium
bromide, THF, CeCl3, −78°C; 43% (9b) (two steps); (d) p-TsOH, benzene, 50°C; 77% (10a); 68% (10b).

H. Yoda et al. / Tetrahedron Letters 44 (2003) 1775–1777
1777
Scheme 2. Reagents and conditions: (a) (i) (COCl)2, DMSO, THF, then Et3N, −78 to −45°C; (ii) homogeranylmagnesium bromide,
THF, 0°C; 48% (11a); 50% (11b); quant. (11c) (two steps, respectively); (b) (i) PCC, CH2Cl2; (ii) methylmagnesium bromide, THF,
CeCl3, −78°C; 50% (12a); 70% (12b); 76% (12c) (two steps, respectively); (c) p-TsOH, benzene, 50°C; 76%; (d) LiHMDS,
2,4-dimethoxybenzaldehyde, THF, −78°C; quant.; (e) (i) PCC, CH2Cl2; (ii) TBAF, THF; 40% (two steps); (f) (i) CBr4, PPh3,
CH2Cl2; 62%; (ii) Et3B, Bu3SnH, O2, CH2Cl2; 66%; (g) Me3SiI, CHCl3, −20°C; 88%.
Acknowledgements
4. Yoda, H.; Kimura, K.; Takabe, K. Synlett 2001, 400–
402.
This work was supported in part by a Grant-in-Aid
(No. 13640530) for Scientific Research from Japan
Society for the Promotion of Science.
5. The ratio of these two diastereomers was not determined.
6. Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima,
T.; Kamiya, Y. J. Am. Chem. Soc. 1989, 111, 4392–4398.
7. The relative stereochemistry was unambiguously deter-
mined based on its spectral data of synthetic 1.
8. (a) Trost, B. M.; Miller, C. H. J. Am. Chem. Soc. 1975,
97, 7182–7183; (b) Mandai, T.; Hara, K.; Nakajima, T.;
Kawada, M.; Otera, J. Tetrahedron Lett. 1983, 24, 4993–
4996.
9. The trans-structure was ascertained after completion of
the total synthesis of 1 based on its spectral data.
10. Sharma, R.; Marquez, V. E. Synth. Commun. 1994, 24,
1937–1945.
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