Toward the total synthesis of methyl isosartortuoate: Construction of the backbone of the diene unit

Article abstract of DOI:10.1016/j.tetlet.2004.04.139

The backbone of diene precursor in the proposed biogenesis of methyl isosartortuoate through a Diels-Alder reaction has been constructed via dehydration to establish the conjugated system; and double cyclization by using Horner-Wittig-Emmons reaction and

Full text of DOI:10.1016/j.tetlet.2004.04.139

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5163–5166
Toward the total synthesis of methyl isosartortuoate: construction
of the backbone of the diene unit
Peng Liu and Xingxiang Xu*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
Received 25 February 2004; revised 15 April 2004; accepted 16 April 2004
Abstract—The backbone of diene precursor in the proposed biogenesis of methyl isosartortuoate through a Diels–Alder reaction has
been constructed via dehydration to establish the conjugated system; and double cyclization by using Horner–Wittig–Emmons
reaction and the chiral epoxy ring opening.
Ó 2004 Published by Elsevier Ltd.
Methyl isosartortuoate with a novel tetracyclic tetra-
terpenoid architecture was first isolated by Su et al. in
1986 from the marine Sarcophyton tortuosum Tixier-
Durivault.1 It has been hypothesized that a plausible
biogenesis would involve generation of the cyclohexane
ring by a Diels–Alder reaction of two cembrenes (the
dienophile 2 and diene 3, shown in Scheme 1).2 Even
though these cembrenes have not been isolated, the
structural complexity, in conjunction with the interest-
ing biogenic possibility, captured our attention.3 Herein,
we describe the synthesis of the immediate precursor to
the diene unit 3.
constructed via an asymmetric epoxidation followed by
intramolecular epoxy ring opening. A plausible route to
6
would involve the macrocyclization of alde-
hydophosphonoacetate 8 by an HWE reaction, which
was accessible from 9 by a sequence of transformations
as shown in Scheme 3.
According to this synthetic plan, alcohol 9 was prepared
from geraniol and efficiently converted into the alde-
hydophosphonoacetate 8 as outlined in Scheme 3. In
order to prepare the optically active alcohol 10, several
methods were explored.4 The conversion was success-
fully accomplished by Sharpless asymmetric epoxida-
tion5 and subsequent reductive rearrangement of the
2,3-epoxyl alcohols using PPh3, I2, and pyridine.6 Next
asymmetric epoxidation of 10 and protection of the
secondary hydroxyl group by ethyl vinyl ether afforded 12.
As shown in Scheme 2, the synthesis of the diene unit 3
of methyl isosartortuoate could be strategically trans-
formed into compound 4, which could be prepared by
dehydration of 5. The chiral THF ring 5 would be
O
O
O
OH
O
O
+
COOMe
O
O
O
OH
H
H
O
O
CO2Me
MOMO
H
H
HO
1
2
3
Scheme 1.
* Corresponding author. Fax: +86-21-64166128; e-mail: xuxx@mail.sioc.ac.cn
0040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.04.139

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P. Liu, X. Xu / Tetrahedron Letters 45 (2004) 5163–5166
O
OH
HO
HO
O
O
O
O
H
H
H
MOMO
MOMO
MOMO
4
5
3
COOEt
HO
O
O
EtOOC
O
P(O)(OEt)2
OH
O
MOMO
O
6
8
7
Scheme 2.
b
a
d
HO
O
OBn
OBn
OH
10
9
NC
f
OBn
OBn
R2O
OR1
OR
13 R1= EE, R2= H
14 R1= H, R2= H
15 R1= EE, R2= MOM
e
11 R= H
12 R= EE
c
i
g
NC
OBn
RO
OBn
O
O
O
O
16
17 R= H
h
18 R=TBS
j
COOEt
TBSO
OH
O
O
O
O
O
P(O)(OEt)2
19
8
i
Scheme 3. Reagents and conditions: (a) 4 A MS, L-(+)DIPT, Ti(OPr )4, TBHP, CH2Cl2, 92.1%; PPh3, I2, pyridine, H2O, CH3CN–Et2O (3:5), 87.3%.
ꢀ
i
ꢀ
(b) 4 A MS, L-(+)DIPT, Ti(OPr )4 TBHP, CH2Cl2. (c) Ethyl vinyl ether, PPTS, CH2Cl2, 97.5%. (d) NaCN, LiClO4, CH3CN, 92.1%. (e) PTS,
CH3OH, 95.6%. (f) Dimethoxylpropane, PPTS, CH2Cl2, 97.3%. (g) DIBAL-H, Toluene, )78 °C; NaBH4, CH3OH, 87.9% for two steps. (h) TBSCl,
DMAP, Et3N, CH2Cl2, 96.1%. (i) Li-naphthalenide, 0 °C, 98.3%. (j) Triphosgene, Et3N, 0 °C; (EtO)2P(O)CH2COOEt, tBuOH, DMSO, rt, 83.4% for
two steps; NH4F, CH3OH, 87.2%; Dess–Martin peroidinane, CH2Cl2, 93.6%.
Treatment of 12 with NaCN/LiClO4 in CH3CN pro-
vided the b-hydroxynitrile 13.7 However, reduction8 of
15 (R1 ¼ EE, R2 ¼ MOM) with DIBAL-H followed by
acid hydrolysis of the imine and its reduction with
NaBH4 just afforded the desired product in 33–65%
yield because of b-elimination. On the contrary, reduc-
tion of 16 was readily realized with DIBAL-H in toluene
at )78 °C followed by acid hydrolysis with silica gel in
CHCl3 for 1 min and reduction of the resulting product
to give 17 in 87.9% yield. After protecting the primary
hydroxy group with TBS and removing the Bn group,9
the resulting allylic alcohol was converted into the allylic
chloride.3b
The phosphonoacetates moiety was introduced via SN2
displacement of the allylic chloride by ethyl (diethoxy-
phosphoryl) acetate carbanion in DMSO (83.4% for two
steps).10 Removal of the TBS protecting group and oxi-
dation of the resulting primary alcohol with Dess–Martin
peroidinane gave the precursor 8 for macrocyclization.
The intramolecular HWE reaction has been used suc-
cessfully in various size of c-rings,11 however, there were
few examples for macrocylization of b-alkoxyl alde-
hydophonoacetate. Due to the possible b-elimination, a
variety of reaction conditions for macrocyclization were
screened. It was found that only the b-elimination

P. Liu, X. Xu / Tetrahedron Letters 45 (2004) 5163–5166
5165
c
b
a
HO
8
EtOOC
O
OH
O
OH
7
20
d
f
R2O
R1O
HO
RO
O
O
H
H
OH
MOMO
MOMO
MOMO
23 R= Ac
24 R= H
6
5
R1= H, R2= H
g
e
21 R1= Ac, R2= H
22 R1= Ac, R2= Ms
h
i
O
O
O
O
H
H
MOMO
MOMO
25
4
Scheme 4. Reagents and conditions: (a) NaH, 18-Crown-6, DME, 10–16 °C, 68.7%. (b) DIBAL-H, CH2Cl2, )78 °C, 98%; PTS, MeOH, reflux,
ꢀ
74.9%. (c) Ac2O, pyridine, rt, 99%; MOMCl, DIPEA, DMAP, Et3N, CH2Cl2, 91.7%; DIBAL-H, CH2Cl2, )78 °C, 90%. (d) 4 A MS, L-(+)DIPT,
Ti(OPri)4 TBHP, CH2Cl2, 95.5%. (e) Ac2O, pyridine, rt, 85.3%. (f) SOCl2, pyridine, DMAP, CH2Cl2, 62.8%. (g) K2CO3, CH3OH, rt, 96.7%. (h)
Dess–Martin peroidinane, CH2Cl2, 72.4%. (i) CH3Li, THF, )78 °C; Dess–Martin peroidinane, CH2Cl2, 69.5% for two steps.
product was obtained under the condition of DBU/LiCl
in CH3CN. Interestingly, the slow addition of 8 via a
syringe pump to a slurry of NaH (3 equiv) and 18-
Crown-6 (3 equiv) in DME at 10–16 °C was found to
afford the desired carbocyclic ester in 68.7% yield
(Z : E ¼ 7 : 1) and the b-elimination product in 18.4%
yield (Scheme 4).
product 25 with CH3Li in THF at )78 °C followed by
oxidation of the resulting alcohol afforded the unsatu-
rated ketone 4.15
In summary, an efficient asymmetric synthesis of 14-
membered backbone 4, required for the preparation of
the diene unit of methyl isosartortuoate, has been
accomplished by double cyclization. The synthesis is
highlightened by a successful HWE macrocyclization for
b-alkoxyl aldehydophonoacetate 8 to construct the 14-
membered carbocylic unsaturated ester 7 and dehydra-
tion of the Sharpless AE product 5 to prepare the
unsaturated ketone 4. Further studies toward the total
synthesis of methyl isosartortuoate are still ongoing in
our laboratory.
Having prepared the carbocyclic ester 7, we used
asymmetric epoxidation again to construct the chiral
disubstituted-tetrahydrofuran ring. Reduction of the
ester function and hydrolysis of isopropylidene ketal in
7 afforded the separable Z-triol and E-triol. After
selective protection of tertiary hydroxyl group by
MOMCl via a sequence of transformations, the epoxi-
dation of 6 followed by a Lewis acid-catalyzed ring
opening furnished 512 in 95.5% yield.
After selective acetylation of the primary hydroxyl
group of 5 to afford monoacetate 21, we set out to find a
suitable dehydration protocol. Several literature meth-
ods13 such as MsCl, pyridine,13a;b and phosphorus oxy-
chloride (POCl3)13c were studied. However, the former
gave the mesylated 21 while the latter did not react.
Gratifyingly, it was found that the traditional method of
reacting alcohol 21 with thionyl chloride/pyridine at
room temperature furnished alkene 23 in 62.8% yield.14
Removal of acetyl group with K2CO3 in CH3OH gave
the allylic alcohol 24. Oxidation of 24 with Dess–Martin
peroidinane and subsequent treatment of the aldehyde
References and notes
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5166
P. Liu, X. Xu / Tetrahedron Letters 45 (2004) 5163–5166
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3.58–3.57 (m, 3H), 3.37 (s, 3H), 2.43–2.37 (m, 2H), 2.30–
2.02 (m, 9H), 1.7–1.52 (m, 3H), 1.63 (s, 3H), 1.58 (s, 3H),
1.24 (s, 3H). 13C NMR (CDCl3, 75 MHz): 135.1, 134.3,
125.4, 119.4, 91.8, 88.5, 84.4, 81.3, 74.7, 64.5, 55.2, 40.9,
38.6, 38.1, 36.7, 27.1, 25.1, 16.7, 16.0. IR (neat): 3351,
2984, 2951, 2929, 2883, 2839, 1744, 1439, 1378, 1145, 1131,
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20
D
12. Compound 5: ½aŠ )75.0 (c 0.5, CH3OH); 1H NMR
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