A double iodoetherification of σ-symmetric diene acetals for installing four stereogenic centers in a single operation: Short asymmetric total synthesis of rubrenolide

Article abstract of DOI:10.1002/anie.200461584

Tetrahydrofuran units with multiple chiral centers are formed in a highly diastereoselective manner through the one-pot double intramolecular haloetherification of σ-symmetric diene acetals (see scheme). The utility of the method was demonstrated by the s

Full text of DOI:10.1002/anie.200461584

Communications
Asymmetric Synthesis
Although there are several reports on the discrimination of
acyclic s-symmetric dienes by intramolecular halolactoniza-
tion,[2] no domino-type reaction has been reported. Further-
more, the reaction was applied to a short asymmetric
synthesis of rubrenolide.
The chiral diene acetals (2 and 3) with oxygen-containing
functional groups, such as hydroxy, ether, and ester groups,
were prepared as shown in Scheme 2: 1) reaction of (R,R)-
hydrobenzoin and dichloroacetic acid in the presence of NaH
is followed by the formation of the ester to afford 1;
2) reaction of allylmagnesium bromide with 1 leads to the
hydroxy diene acetal 2; and 3) protection of the tert-hydroxy
function of 2 by appropriate methods leads to 3. The chiral
A Double Iodoetherification of s-Symmetric
Diene Acetals for Installing Four Stereogenic
Centers in a Single Operation: Short Asymmetric
Total Synthesis of Rubrenolide**
Hiromichi Fujioka,* Yusuke Ohba, Hideki Hirose,
Kenichi Murai, and Yasuyuki Kita*
Many biologically active natural products contain multiple
chiral centers and occur in their optically active form, and
therefore the development of meth-
odologies that can lead to multiple
chiral centers is desirable in syn-
thetic organic chemistry. Recently,
we developed the intramolecular
haloetherification of chiral ene ace-
tals from (R,R)-hydrobenzoin in
which two new chiral centers are
formed at remote positions.[1] As an
extension of this remote asymmetric
induction method we studied the
reaction of acyclic s-symmetric
diene acetals, and found an unpre-
cedented double intramolecular hal-
oetherification leading to the for-
mation of four asymmetric centers
in a single operation (Scheme 1).
Scheme 2. Preparation of various acyclic diene acetals. TBS=tert-butyldimethyl silyl, TES=triethyl-
silyl, Tf=trifluoromethanesulfonate, TMS=trimethylsilyl.
diene acetals (5) with a hydrogen, phenyl, and methyl
substituent were prepared by acetalization of the diallyl
aldehyde 4 with (R,R)-hydrobenzoin.[3]
We first studied the reactivity of substrate 3c by treatment
with N-iodosuccinimide (NIS; 2.5 equivalents) and methanol
(5.0 equivalents) in acetontrile at À40–08C.[1] However, no
reaction occurred and the starting material 3c was recovered.
When the reaction was carried out at room temperature, the
product obtained resulted from the attack of the methanol on
the olefin in an intermolecular fashion. We then changed the
Scheme 1. Double intramolecular haloetherification of acyclic s-sym-
metric diene acetals leading to the formation of four asymmetric
centers.
nucleophile from methanol to water. The reaction proceeded
smoothly to give 6c (R = OTMS) as the major product in a
yield of 73%. Other stereoisomers were
obtained as a mixture in an approximate
yield of 10% (Scheme 3).
[*] Prof. Dr. H. Fujioka, Y. Ohba, H. Hirose, K. Murai, Prof. Dr. Y. Kita
Graduate School of Pharmaceutical Sciences
Osaka University
To our surprise, the hydroxy aldehyde
6c’ was not detected, which we predicted
from the occurrence of intermediate II.[4]
1-6, Yamadaoka, Suita, Osaka 565-0871 (Japan)
Fax: (+81)6-6879-8229
E-mail: fujioka@phs.osaka-u.ac.jp
kita@phs.osaka-u.ac.jp
Even the use of 0.5 equivalents of NIS did
not give 6c’ at all, and 3c and 6c were
obtained. The structure of 6c was deter-
mined as follows: The relationship of the
substituents on the five-membered ring was determined by
NOE interaction experiments between two protons (Ha and
Hb) and the methyl group of the trimethylsilyl (TMS)
functional group. The complete structure of the product,
including the absolute configuration of all of the asymmetric
[**] This work was supported by Grants-in-Aid for Scientific Research
[(S) and (C)] from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan. The authors gratefully thank Prof. B.
Zwanenburg and Dr. L. Thijs for the generous gift of the mixture of
natural rubrenolide and rubrynolide.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
734
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DOI: 10.1002/anie.200461584
Angew. Chem. Int. Ed. 2005, 44, 734 –737

Angewandte
Chemie
attacked at the iodomethyl group (b)
bearing the eight-membered acetal ring
(Scheme 5).
The utility of this domino-type reac-
tion was shown with a short asymmetric
synthesis of rubrenolide (Scheme 6).
Rubrenolide was isolated from the
Scheme 3. Domino-type intramolecular iodoetherification of 3c.
trunk wood of the Amazonian tree
Nectandra rubra of the Lauraceae
carbon centers, was unambiguously determined by X-ray
crystallographic analysis[5] of the dimethyl compound 7 by
radical reduction using 2,2’-azobis[2-(2-imidazolin-2-yl)pro-
pane] (VA-061)[6] of 6c (Scheme 4).
family. It has a remote asymmetric center in addition to a g-
lactone ring with two asymmetric centers.[7] Although one
asymmetric synthesis has already been reported,[8] we have
developed a shorter asymmetric synthesis. The intramolecular
iodoetherification of the diene acetal 5a, obtained by
acetalization of the aldehyde 4a with (R,R)-hydrobenzoin,
afforded 6 f in 62% yield. Although the mixture contained
18% of other stereoisomers, 6 f was readily purified by
column chromatography on silica gel (hexane/ethyl acetate =
20:1). Hydrolysis of 6 f by treatment with 2,3-dichloro-5,6-
[9]
dicyano-1,4-benzoquinone (DDQ)
followed by oxidation
Table 1: Intramolecular iodoetherification of various diene acetals.
Entry Diene acetal
t [h] Total yield [%] d.r.[a]
Major
product
1
2
3
4
5
6
7
8
9
2
–
–
12
1.5 82
3.5 58
3
3
decomp
decomp
38
–
–
3a (R=OAc)
3b (R=OMe)
3c (R=OTMS)
3d (R=OTES)
3e (R=OTBS)
5a (R=H)
n.d.[b]
8/1
Scheme 4. Radical reduction of 6c. VA-061=2,2’-azobis[2-(2-imidazo-
lin-2-yl)propane], EPHP=1-ethylpiperidine hypophosphite.
6c
6d
6e
11/1
11/1
3.5/1 6 f
2/1
1.5/1 6h
84
80
72
72
A mechanistic rationale is shown in Scheme 3. The
hemiacetal intermediate II was obtained via the oxonium
cation intermediate I. The hemiacetal structure of an eight-
membered ring usually opens to give the hydroxy aldehyde,
such as 6c’. However, in this case, another olefin unit is
present at the proper position. The second intramolecular
iodoetherification then occurred faster than the opening of
the eight-membered ring to give 6c in good yield.
5b (R=Ph)
5c (R=Me)
3
13
6g
[a] Major diastereomer/other diastereomers. [b] Not determined.
This unprecedented double intramolecular iodoetherifi-
cation proved to be a general reaction. That is, various diene
acetals 3b–e, which have an ether group next to the acetal
function, and 5a–c, which have a hydrogen, methyl, and
phenyl substituent next to the acetal function, respectively,
afforded the double intramolecular iodoetherification prod-
ucts 6c–h as major products in fair to good yields (Table 1).
Dreiding models and the X-ray crystal structure of 7 have
led to the proposed conformation of the oxocyclic compounds
6c–h. Their conformations show that the environments of the
two iodomethyl functions (a) and (b) are completely different
and that the iodomethyl group (b) bearing the eight-
membered acetal ring is less hindered, so we expected it to
be more reactive. We then examined this observation using
compound 6c. As expected, nucleophiles predominantly
Scheme 5. Regioselective nucleophilic addition to 6c.
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Communications
5.89 (1H, d, J = 4.5 Hz), 6.72–6.79 (4H, m),
7.04–7.19 ppm (6H, m); 13C NMR (75 MHz,
CDCl3) d = 6.3, 32.5, 35.4, 38.2, 65.3, 76.7, 77.4,
87.8, 127.0, 127.1, 127.8, 127.9, 128.0, 128.1,
128.3, 128.4, 128.5, 128.6, 128.7, 138.7, 139.4,
178.0 ppm; FAB-HRMS: calcd for C22H25O3I2:
m/z 590.9906 (M++H); found: 590.9875.
Received: August 9, 2004
Published online: December 21, 2004
Keywords: asymmetric synthesis · chiral
.
auxiliaries · domino reactions · natural
products · synthetic methods
[1] a) H. Fujioka, H. Kitagawa, Y. Nagatomi,
Y. Kita, J. Org. Chem. 1996, 61, 7309 –
7315; b) H. Fujioka, N. Matsunaga, H.
Kitagawa, Y. Nagatomi, Y. Kita, Tetrahe-
Scheme 6. Asymmetric total synthesis of rubrenolide.
with NaClO2 gave the lactone 10. Cleavage of the carbon–
oxygen bond of the hydrobenzoin unit by ammonium cerium
nitrate (CAN)[10] followed by treatment with K2CO3 afforded
the epoxide 11. The introduction of the alkenyl unit to the
epoxide by a copper-assisted Grignard reagent gave the
hydroxylactone 12. To our surprise, treatment of 12 with
K2CO3 caused recyclization of the lactone ring and epoxide
dron Lett. 1996, 37, 2245 – 2248.
[2] For asymmetric desymmetrization of acyclic s-symmetric dienes,
see a) S. Takano, C. Murakata, Y. Imamura, N. Tamura, K.
Ogasawara, Heterocycles 1981, 16, 1291 – 1294; b) T. Yokomatsu,
H. Iwasawa, S. Shibuya, J. Chem. Soc. Chem. Commun. 1992,
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Tanabe, M. Shiro, T. Taguchi, J. Chem. Soc. Chem. Commun.
1992, 1005 – 1007; e) O. Kitagawa, S. Momose, Y. Fushimi, T.
Taguchi, Tetrahedron Lett. 1999, 40, 8827 – 8831.
[3] Diallyl aldehyde 4a (R = H) and phenyl aldehyde 4b (R = Ph)
are known compounds (for 4a, see: B. B. Snider, B. R. Smith,
Tetrahedron 2002, 58, 25 – 34; for 4b, see: W. A. Nugent, J.
Feldman, J. C. Calabrese, J. Am. Chem. Soc.
formation to give the epoxide 13. Opening of the epoxy ring
[11]
of 13 by Bi(OTf)3
smoothly proceeded to give (+)-
rubrenolide. Optical rotation studies and 1H NMR,
13C NMR, and IR spectroscopic analysis of the product with
an authentic sample of (+)-rubrenolide were in good agree-
ment.[12]
1995, 117, 8992 – 8998). Diallylmethyl alde-
In conclusion, we have found unprecedented double
intramolecular haloetherifications of s-symmetric diene ace-
tals. The reactions proceed in a highly diastereoselective
manner to give tetrahydrofuran units with multiple chiral
centers in a one-pot operation. Furthermore, a short asym-
metric synthesis of (+)-rubrenolide was carried out as an
application of the methodology. Since tetrahydrofuran moi-
eties with multiple chiral centers are found in a large number
of biologically active natural products, this method could
prove to be a highly useful tool.
hyde (4c, R = Me) was prepared from the
known diallyl ester 15b (obtained by methyl-
ation of 15a; see above reference for 4a) first
by reduction of the ester and then oxidation
with pyridinium dichromate.
[4] In our previous work (Ref. [1]), alcohols were used as nucleo-
philes, whereas here the use of water instead afforded the
hydroxyaldehyde by intramolecular haloetherification followed
by opening of the eight-membered hemiacetal ring (coll = 2,4,6-
collidine, H. Fujioka, H. Kitagawa, Y. Kita, unpublished results).
Experimental Section
Intramolecular iodoetherification reaction of 5a: N-iodo-
succinimide (NIS; 351 mg, 1.6 mmol) was added to a
solution of 5a (100 mg, 0.31 mmol) in CH3CN (0.62 mL)
at À408C under nitrogen, and the mixture was stirred for
30 min at the same temperature. Water (0.028 mL,
1.6 mmol) was added to the resulting mixture, which was allowed to
warm to 08C over 40 min. A saturate aqueous Na2S2O3 solution was
added to the mixture, which was then extracted with diethyl ether.
The organic layer was washed with brine, dried over MgSO4, and
evaporated in vacuo. The residue was purified by column chroma-
tography on silica gel using hexane/ethyl acetate (20:1) to give 6 f
(114 mg, 0.19 mmol, 62%) and a diastereoiomeric mixture (33 mg,
0.056 mmol, 18%).
[5] CCDC-244868 contains the supplementary crystallo-graphic
data for this paper. These data can be obtained free of charge
from www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: (+ 44)1223-336-033; or e-mail:
deposit@ccdc.cam.ac.uk.
[6] a) Y. Kita, H. Namubu, N. G. Ramesh, G. Anilkumar, M.
Matsugi, Org. Lett. 2001, 3, 1157 – 1160; b) H. Namubu, G.
Anilkumar, M. Matsugi, Y. Kita, Tetrahedron 2003, 59, 77 – 85.
For the reduction of the radical using VA-061 in water including
its use for this transformation, see H. Namubu, A. H. Alinejad,
K. Hata, H. Fujioka, Y. Kita, Tetrahedron Lett., in press.
6 f: [a]2D4 + 65.4 (c = 1.1, CHCl3); IR (KBr): no OH, no CO;
1H NMR (300 MHz, CDCl3) d: 1.98–2.03 (2H, m), 2.10–2.23 (1H, m),
2.40–2.42 (2H, m), 3.00–3.07 (3H, m), 3.28 (1H, dd, J = 9.3, 4.5 Hz),
4.03–4.21 (2H, m), 4.32 (1H, d, J = 8.4 Hz), 4.44 (1H, d, J = 8.4 Hz),
736
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Chemie
[7] For isolation and structure elucidation, see: a) N. C. Franca,
O. R. Gottlieb, D. T. Coxon, W. D. Ollis, An. Acad. Bras. Cienc.
1971, 43, 123 – 235; b) N. C. Franca, O. R. Gottlieb, D. T. Coxon,
W. D. Ollis, J. Chem. Soc. Chem. Commun. 1972, 9, 514 – 515;
c) N. C. Franca, O. R. Gottlieb, D. T. Coxon, Phytochemistry
1977, 16, 257 – 262; for the total synthesis, see e) S. K. Taylor,
J. A. Hopkins, K. A. Spangenberg, D. W. McMillen, J. B. Grutz-
ner, J. Org. Chem. 1991, 56, 5951 – 5955.
[8] For the asymmetric total synthesis, see: a) T. Saito, L. Thijs, G.-J.
Ettema, B. Zwanenburg, Tetrahedron Lett. 1993, 34, 3589 – 3592;
b) L. Thijs, B. Zwanenburg, Tetrahedron 2004, 60, 5237 – 5252.
Although the wrong stereochemical structure of rubrenolide was
originally proposed, the correct one is reported by Zwanenburg
et al.
[9] J. M. G. Fernꢀndes, C. O. Mellet, A. M. Marꢁn, J. Fuentes,
Carbohydr. Res. 1995, 274, 263 – 268.
[10] W. S. Trahanovsky, L. B. Young, G. L. Brown, J. Org. Chem.
1967, 32, 3865 – 3868.
[11] Although the use of BiCl3 has been reported (I. Mohammad-
poor-Baltork, S. Tangestaninejad, H. Aliyan, V. Mirkhani, Synth.
Commun. 2000, 30, 2365 – 2374), Bi(OTf)3 was also effective.
[12] Authentic rubrenolide was obtained by separation of a mixture
donated by Prof. B. Zwanenburg and Dr. L. Thijs, according to
Ref. [8b]. The synthetic rubrenolide has a [a]2D5 value of + 20.5
(c = 0.29, CHCl3), while the [a]2D0 value of the authentic sample
(Ref. [7c]) is + 21.2 (CHCl3).
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