Synthetic studies on the dienophile unit of methyl isosartortuoate. Part 2: SmI2-mediated 14-membered carbocyclization

Article abstract of DOI:10.1016/S0040-4039(02)02603-5

The dienophile unit of methyl isosartortuoate has been synthesized. The 14-membered carbocycle was constructed by a SmI₂-mediated intramolecular Reformatsky reaction. The introduction of the oxo group at the γ-position of the α,β-unsaturated ester was achieved by rearrangement of an β,γ-epoxy ester.

Full text of DOI:10.1016/S0040-4039(02)02603-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 489–491
Synthetic studies on the dienophile unit of methyl
isosartortuoate. Part 2: SmI2-mediated 14-membered
carbocyclization
Zhangyong Hong and Xingxiang Xu*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
Received 26 September 2002; revised 7 November 2002; accepted 15 November 2002
Abstract—The dienophile unit of methyl isosartortuoate has been synthesized. The 14-membered carbocycle was constructed by
a SmI2-mediated intramolecular Reformatsky reaction. The introduction of the oxo group at the g-position of the a,b-unsaturated
ester was achieved by rearrangement of an b,g-epoxy ester. © 2002 Elsevier Science Ltd. All rights reserved.
In our previous letter,1 we outlined our synthetic strat-
egy and described the synthesis of the acyclic precursor
2 of the dienophile unit 1 of methyl isosartortuoate
(Fig. 1). Herein we would like to report the construc-
tion of the 14-membered carbocycle and the elabora-
tion of the dienophile 1.
A number of methods have been developed for macro-
carbocyclization,2 among which the SmI2-promoted
intramolecular Reformatsky reaction reported by
Inanaga in 19913 is particularly attractive. It was
thought that the distinct properties of samarium such
as its large ionic radius, flexible coordination, and high
oxophilicity would play an important role in facilitating
the cyclisation. Thus, we chose to investigate its
efficiency in the carbocyclization of the acyclic precur-
sor 2. a-Bromoester-v-aldehyde 4 was initially prepared
as outlined in Scheme 1.
Scheme 1. Reagents and conditions: (a) LDA, THF, TMSCl,
Et3N, −78°C; then NBS, rt, 90%; (b) Amberlyst 15, acetone,
H2O, 90%; (c) SmI2, THF, 0°C, 1 mmol/2 h; (d) MsCl, Et3N,
CH2Cl2, rt; (e) DBU, toluene, reflux, 10 h, 60% for three
steps.
Figure 1.
Keywords: methyl isosartortuoate; dienophile unit; b,g-epoxy ester
Treatment of ester 2 with LDA/TMSCl/Et3N followed
by bromination with NBS gave the a-bromoester 3 in
90% yield. Hydrolysis of the acetal group4 afforded the
rearrangement; SmI2-mediated; carbocyclization.
* Corresponding author. Fax: +86-21-64166128; e-mail: xuxx@
pub.sioc.ac.cn
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02603-5

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Z. Hong, X. Xu / Tetrahedron Letters 44 (2003) 489–491
required a-bromoester-v-aldehyde 4. In the presence of
an excess of SmI2, the cyclization of 4 proceeded
smoothly at 0°C to yield a multi-product isomeric
mixture, which was mesylated and treated with DBU to
give three chromatographically separable products
(ꢀ1:2:1) in 60% overall yield. The two less polar prod-
ucts were characterized as the a,b-unsaturated esters 6a
and 6b5 possessing a cis-cycloalkene differing in
configuration at the C-9 protected hydroxyl group. The
structure of the more polar component, 7a, was deter-
mined to be a rearranged product of 6a (see also
Scheme 3).
failed to realize this conversion, it was converted into
the useful compound 11a by repeated oxidation and
reduction cycles.12
The final task was to form the dienophile structural
unit. Obviously, it was necessary to remove or change
the benzyl groups. Hydrogenation of compound 10
which possesses a bulky TBS group gave the corre-
sponding saturated product. However, to our delight,
hydrogenation of 8 with Pd(OH)2/MeOH/EtOAc at rt
afforded the desired compound 12 (Scheme 4). Experi-
ments showed that 12 was unstable due to the presence
of the epoxide and free hydroxy groups, and was also
unable to undergo the basic rearrangement. Hence, the
two free hydroxy groups needed to be reprotected.
After several protecting groups had been exhausted, the
ethoxyethyl ether (EE) and the trimethylsilyl (TMS)
groups proved to be the protecting groups of choice,
and compounds 13a and 13b were obtained in 75% and
70% yield respectively. The EE-protected compound
13a could be smoothly rearranged to 14a with
CH3ONa/CH3OH and was further oxidized with Dess–
Martin periodinane13 to give ketone 16a. But deprotec-
tion of 14a or 16a under acidic conditions gave a
complicated mixture. For the TMS-protected com-
pound 13b, since the TMS group was labile to the
original rearrangement conditions (CH3OH/CH3ONa),
milder basic conditions were examined. Fortunately,
the rearrangement could be realized by treating 13b
with DBU in refluxing toluene and the desired com-
pound 14b was obtained in 90% yield. Deprotection of
14b with NH4F/MeOH14 gave the triol 15 quantita-
tively. To our disappointment, 15 could not be oxidized
directly to the corresponding trione. However, after
Dess–Martin periodinane oxidation of 14b, we obtained
the desired compound 16b15 which is the bis-TMS-pro-
tected form of dienophile unit 1.
After the successful macrocyclization, we focused our
attention on the introduction of the oxo-substitutent at
the g-position of the a,b-unsaturated ester 6. Direct
allylic oxidation using CrO3 or SeO2,7 or allylic
6
bromination8 of compound 6 proved to be unsuccess-
ful. As an alternative, the rearrangement under basic
conditions of an b,g-epoxy ester offered a different
approach.9 Compound 7a was thus treated with
MCPBA at rt to yield the b,g-epoxy ester 8 in 70% yield
(Scheme 2). Under basic conditions, compound 8
smoothly rearranged to the g-hydroxy-a,b-unsaturated
ester 9. An improved result was obtained when the
CH3OH/CH3ONa system was applied and 9 was
obtained in 70% yield. The oxo group at the g-position
of the a,b-unsaturated ester had now been successfully
introduced.
Based on the above results, and to take advantage of
the isomers 6, it was important to isomerize the double
bond of the a,b-unsaturated esters 6 to give the corre-
sponding b,g-isomers. In general, this transformation
can be achieved by treating a,b-unsaturated esters with
bases. When epimers 6a and 6b were treated with DBU
in toluene at reflux (Scheme 3), epimer 6a afforded the
desired b,g-unsaturated ester 7a in a ratio of 2.5:3
(7a:6a). However this isomerization failed for 6b.10 This
phenomenon reflects a subtle relationship between reac-
tion properties and the conformations of large rings.
For this reason, the C-9 configuration was determined
in the acyclic precursor (the details have been presented
in the previous letter1), as S in 6a and 7a.
In summary, a SmI2-promoted 14-membered carbocy-
clization has been accomplished and the bis-TMS-pro-
tected compound 16b has been synthesized, which is a
dienophile for a total synthesis of methyl isosartor-
tuoate. The synthesis of the natural product is still on
going in this laboratory.
With respect to 6b, the corresponding acyclic precursor
11b was selected for inversion of the configuration
(Scheme 3). Although Mitsunobu conditions or direct
SN2 substitution of the mesylate derivative11 of 11b
Scheme 2. Reagents and conditions: (a) mCPBA, CH2Cl2,
25°C, 70%; (b) CH3OH, CH3ONa, 70%; (c) TBSCl, DMAP,
CH2Cl2, Et3N, rt, 90%.
Scheme 3.

Z. Hong, X. Xu / Tetrahedron Letters 44 (2003) 489–491
491
1
91 (100.0); H NMR (300 MHz, CDCl3): l 7.30 (m, 10H,
ArH), 6.88 (dd, 1H, J=9.6 Hz, 6.6 Hz, vinyl H), 4.51 (m,
4H), 3.77 (m, 1H, OCH), 3.74 (s, 3H, OCH3), 3.54 (m,
1H, OCH), 2.87, 2.39 (ABX System, 2H, J=13.6 Hz, 8.7
Hz, 4.5 Hz, allylic H), 2.25 (m, 1H), 1.99 (m, 3H), 1.74
(m, 2H), 1.48 (m, 4H), 1.32 (m, 4H), 1.13 (m, 2H), 0.90
(m, 12H, 4 CH3); 13C NMR (CDCl3): l 168.6, 144.5,
139.6, 139.3, 130.3, 128.1 (2), 128.0 (2), 127.7, 127.6,
127.4 (2), 127.1, 127.0, 80.9, 72.5, 71.0 (2), 51.5, 44.5,
34.2, 33.5, 33.3, 32.0, 31.8, 30.9, 30.7, 27.0, 23.5, 22.7,
20.7, 20.6, 20.5, 17.2; HRMS (EI) calcd for C35H50O4
[M]+: 534.3709; found: 534.3706.
For 5b: IR (film) 2954, 2871, 1718, 1455, 1068 cm−1
;
ESI-MS (m/z, %) 535.5 (M+H+, 60.0); H NMR (300 Hz,
CDCl3): l 7.30 (m, 10H, ArH), 6.90 (m, 1H, vinyl H),
4.64 (m, 1H, CH2Ph), 4.34 (m, 3H, CH2Ph), 3.67 (s, 3H,
OCH3), 3.60 (m, 2H, OCH), 2.77 (m, 1H, allylic H), 2.25
(m, 1H, allylic H), 2.10 (m, 2H), 1.90 (m, 2H), 1.70 (m,
2H), 1.40–1.10 (m, 10H), 0.88 (m, 12H, 4 CH3).
6. Mehta, G.; Reoldy, D. S. Synlett 1997, 612.
7. Bestmann, H. J.; Schober, R. Angew. Chem., Int. Ed.
Engl. 1985, 24, 791.
1
8. Beccalli, E. M.; Majon, L.; Marchesini, A. J. Org. Chem.
1981, 46, 222.
9. (a) Larcheveque, M. Synthesis 1983, 297; (b) Cory, R.
M.; Ritchie, B. M.; Shrier, A. M. Tetrahedron Lett. 1990,
31, 6789.
10. Other deconjugation methods such as LDA/TMSCl/HCl
or photo rearrangement were tried, but did not isomerize
the double bond of 6. See: (a) Danishefsky, S. J.; Armis-
tead, D. M.; Wincott, F. E.; Selnick, H. G.; Hungate, R.
J. Am. Chem. Soc. 1987, 109, 8117; (b) Hanessian, S.;
Dube, D.; Hodges, P. J. J. Am. Chem. Soc. 1987, 109,
7063; (c) Mortezaei, R.; Awandi, D.; Henin, F.; Muzart,
J.; Pete, J. P. J. Am. Chem. Soc. 1988, 110, 4824.
11. (a) Corey, E. J.; Nicolaou, K. C.; Shibasaki, M.;
Machida, Y. Tetrahedron Lett. 1975, 37, 3183; (b) Yan-
kee, E. W.; Cooper, E. L. J. Am. Chem. Soc. 1974, 96,
5876.
Scheme 4. Reagents and conditions: (a) Pd(OH)2, CH3OH,
EtOAc, H2, 70%; (b) for 13a, ethyl vinyl ether, PPTS,
CH2Cl2, rt, 30 min, 75%; for 13b, TMSCl, Et3N, DMAP,
CH2Cl2;, rt, 1 h, 70%; (c) for 14a, CH3ONa, CH3OH, rt, 4 h,
70%; for 14b, DBU, toluene, reflux, 10 h, 90%; (d) NH4F,
CH3OH, 25°C, 9 h, quantitatively; (e) Dess–Martin periodi-
nane, Py, CH2Cl2, 80%.
Acknowledgements
This work was supported by the Chinese Academy of
Sciences and the National Natural Science Foundation
of China.
12. Selective reduction of the ketone with NaBH4–CeCl3,
LiAlH(OR)3, DIBALH, or other reagents failed to
improve the ratio of 11a.
13. (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991,
113, 7277; (b) Ireland, R. E.; Liu, L. J. Org. Chem. 1993,
58, 2899.
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15. Physical and spectroscopic data for 16b: IR (film) 2958,
1726, 1691, 1437, 1251, 1078, 840 cm−1; ESI-MS (m/z, %)
3. (a) Inanaga, J.; Yokoyama, Y.; Handa, Y.; Yamaguchi,
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method has been applied in the total synthesis of taxol.
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Nishimura, T.; Ohkawa, N.; Sakoh, H.; Nishimura, K.;
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4. Coppola, G. M. Synthesis 1984, 12, 1021.
5. Physical and spectroscopic data. For 5a: [h]2D0=−1.6 (c
1.25, CHCl3); EI-MS (m/z, %) 535 (M++1, 0.2), 427 (2.4),
1
513.5 (M+H+, 5.0), 535.5 (M+Na+, 22.0); H NMR (300
MHz, CDCl3): l 7.03 (s, 1H, vinyl H), 4.08 (m, 1H), 3.78
(s, 3H, OCH3), 3.67 (m, 1H), 3.27 (m, 1H), 2.66 (m, 1H),
2.50 (m, 2H), 2.24 (m, 1H), 1.71 (m, 2H), 1.55 (m, 1H),
1.21–1.39 (m, 7H), 1.18 (m, 1H), 1.00 (d, 3H, J=6.9 Hz,
CH3), 0.87 (d, 3H, J=6.9 Hz, CH3), 0.82 (d, 3H, J=6.9
Hz, CH3), 0.76 (d, 3H, J=7.2 Hz, CH3), 0.12 (s, 9H, 3
CH3), 0.09 (s, 9H, 3 CH3); HRMS (EI) calcd for
C27H52O5Si2: 512.3354; found: 512.3343.