A facile synthesis of highly substituted five-membered rings: Mukaiyama-aldol-oxonoium-ene (MAOE) domino reaction

Article abstract of DOI:10.1002/asia.201000884

In the presence of TiBr₄, an efficient and practical method has been developed for the Mukaiyama-aldol-oxonoium-ene reaction of acetals with silyl enol ether. The desired products were obtained in good yields and excellent diastereoselectivitie

Full text of DOI:10.1002/asia.201000884

COMMUNICATION
DOI: 10.1002/asia.201000884
A Facile Synthesis of Highly Substituted Five-Membered Rings: Mukaiyama-
Aldol-Oxonoium-Ene (MAOE) Domino Reaction
Hao Li and Teck-Peng Loh*[a]
Dedicated to Professor Eun Lee on the occasion of his retirement and 65th birthday
À
The construction of C C bonds in an efficient and practi-
cal manner is one of the most-challenging tasks in organic
synthesis.[1] Domino, cascade, and tandem reactions are
À
useful methods for forming one or more carbon carbon
bonds in a one-pot process.[2] More recently, we have report-
ed that cascade reactions involving a Mukaiyama-Aldol–
Prins (MAP) reaction provides an efficient entry into func-
tionalized five-membered rings with high diastereo- and
enantioselectivity (Scheme 1).[3]
Scheme 2. Grayanotoxins I–IV.
rings that have structural features similar to those in
Scheme 2. We envisaged that the domino reaction involving
disubstituted acetal 1 and silyl enol ether 2 would proceed
Scheme 1. Mukaiyma-Aldol-Prins (MAP) reaction.
In connection with our interest in the synthesis of graya-
notoxin natural products (Scheme 2),[4] we are interested in
the development of strategies to obtaining five-membered
[a] Dr. H. Li, Prof. Dr. T.-P. Loh
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
Singapore 637371 (Singapore)
Fax : (+65)6791-1961
E-mail: teckpeng@ntu.edu.sg
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201000884.
Scheme 3. Proposed hypothesis for the Mukaiyama-aldol-oxonoium-ene
(MAOE) domino reaction.
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Chem. Asian J. 2011, 6, 1948 – 1951

through
a
Mukaiyama-aldol–oxonoium–ene (MAOE)
domino reaction to afford the desired five-membered ring
(4) through two sequential oxocarbenium intermediates (I
and II; Scheme 3). Herein, we report a highly diastereo- and
enantioselective domino Mukaiyama-aldol–oxonoium–ene
(MAOE) reaction, furnishing functionalized five-membered
ring system with the generation of up to three stereogenic
centers in a one-pot manner.[5–7]
Initial studies were carried out using dialkyl-substituted
acetal 1a with dimethyl-substituted silyl enol ether 2a in the
presence of TiBr4 in dichloromethane at À788C (employing
reaction conditions identical to our previously reported
MAP reaction).[3] After column chromatography on silica
Scheme 4. Origin of the stereoselectivity.
Table 1. MAOE reactions using 1,1-disubstituted acetals.[a]
gel, our desired product 4aa was obtained in high
yield and excellent selectivity (Table 1, entry 1). It
is noteworthy that upon scaling the reaction up to
100 mmol, we observed no loss in yield and diaste-
reoselectivity for this domino process. Variation of
the silyl enol ether (2b and 2c) afforded similar re-
sults (Table 1, entries 2–3). Besides acylic acetal (di-
methyl substituted 1a), cyclic acetals such as cyclo-
hexenyl substituted acetal 1b was also employed in
the domino process (Table 1, entries 4–6). Gratify-
ingly, the MAOE domino reactions proceeded
smoothly and gave the desired products in high
yields with excellent diastereoselectivities.
Entry Silyl enol ether
Acetal[b]
Product
Yield [%][c] d.r.[d]
1
70
75
>99:1
>99:1
2a
1a
4aa
2
TLC and crude 1H and 13C NMR spectroscopic
analysis showed that there was no alkene function-
ality in the product. However, after column chro-
matography on silica gel, or leaving the product to
stand in CDCl3 overnight, the desired products
were obtained. On the basis of this phenomenon,
the domino reaction proceeded to generate MAP
product 3aa (Scheme 4) which underwent a HBr
elimination to MAOE product 4aa on purification
by column chromatography on silica gel.
We believe that the observed high diastereoselec-
tivity can be attributed to a disfavorable steric re-
pulsion between the bulky triisopropylsilyl (TIPS)
group and the substituents on the pendant double
bond (i.e., the steric interaction depicted in inter-
mediate I; Scheme 4). If the reaction proceeded via
the favored conformation, II, it would yield the
five-membered intermediate 3aa, which then under-
went elimination to afford the observed diastereo-
mer 4aa.
2b
1a
4ab
3
81
86
>99:1
>99:1
2c
1a
1b
4ac
4ba
4
2a
5
85
80
>99:1
2b
1b
4bb
Adhering to the strategy we reported earlier,[3]
optically pure dioxane acetal 5 was applied to the
MAOE domino process in the hope of developing
an asymmetric version.[8] The results are summar-
ized in Table 2. Gratifyingly, the domino reactions
proceeded in good yields and diastereoselectivities
to give products 6 and 7 after column chromatogra-
6
>99:1
2c
1b
4bc
[a] Mukaiyama-aldol–oxonoium–ene reactions were performed using TiBr4 (2 equiv),
acetal (1 equiv), and silyl enol ether (1.2 equiv) under a N2 atmosphere. [b] Disubsti-
tuted acetals were prepared by Wittig reactions. [c] Yield of isolated product. [d] Dia-
stereomeric ratios were determined by H and 13C NMR spectroscopy.
1
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1949

H. Li and T.-P. Loh
COMMUNICATION
Table 2. MAOE reactions using chial acetals.[a]
tion provides an easy route to con-
structing five-membered ring systems
in a one-pot manner in high yields
and with excellent diastereoselectivi-
ties. In all cases, the products were
obtained as single isomers. Asymmet-
ric version with a chiral acetal pro-
vided the products in high asymmet-
ric induction. This new methodology
provides
method for the synthesis of polyfunc-
tionalized cyclopentane building
blocks. Investigations into the appli-
cation of the MAOE domino reac-
tion for the total synthesis of natural
products are underway.
a
simple and practical
Entry
1
Silyl enol ether
Acetal
Product
Yield [%][b]
d.r.[c]
68
85:15
2a
5a
6aa
2
3
4
71
75
69
84:16
85:15
Experimental Section
General Procedure for the Domino Reaction
Between a Silyl Enol Ether and an Acetal
(Table 1, Entry 1)
2b
5a
6ab
To a 25 mL round-bottomed flask was added
CH2Cl2 (10 mL) and TiBr4 (0.36 g, 1 mmol,
2 equiv) at À788C. The silyl enol ether
(0.14 g, 0.6 mmol, 1.2 equiv) and acetal
(0.072 g, 0.5 mmol, 1 equiv, predissolved in
2 mL of CH2Cl2) were added sequentially to
the reaction system. The reaction was stirred
vigorously at the same temperature for
30 min. After the reaction had proceeded to
completion, it was quenched with saturated
sodium bicarbonate (2 mL) at À788C and ex-
tracted with CH2Cl2 (3x10 mL), washed with
brine, dried over anhydrous sodium sulfate,
filtered, and concentrated under reduced
pressure to give the crude product. The crude
product was purified using column chroma-
tography on silica gel (ethyl acetate/hexanes)
to give the pure product as colorless oil
(0.12 g, 70% yield).
2c
2a
5a
5b
6ac
6ba
84:16
84:16
5
6
86
75
2b
5b
6bb
Acknowledgements
87:13
We gratefully acknowledge Nanyang Techno-
logical University and the Ministry of Educa-
tion (No. M45110000) for funding this re-
search.
2c
5b
6bc
[a] Mukaiyama-aldol–oxonoium–ene reactions were performed using TiBr4 (2 equiv), acetal (1 equiv),
and silyl enol ether (1.2 equiv) under N2 atmosphere. [b] Yield of isolated product. [c] Diastereomeric
Keywords: domino reactions · five-
membered rings · Mukaiyama-aldol
1
ratios were determined by H and 13C NMR spectroscopy.
reaction
reaction
· natural products · ene
phy. Following a sequence of chemical transformations on
the final product, we were able to determine the relative
and absolute stereochemistry of the cyclopentane ring (for
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In summary, we have developed a highly stereoselective
Mukaiyama-aldol–oxonoium–ene (MAOE) domino reaction
from readily accessible starting materials. This domino reac-
1950
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Chem. Asian J. 2011, 6, 1948 – 1951

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Received: December 9, 2010
Published online: March 16, 2011
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www.chemasianj.org
1951