Asymmetric syntheses of 8-oxabicyclo[3,2,1]octanes: A cationic cascade cyclization

Article abstract of DOI:10.1002/anie.201202699

High octane: A novel and practical syntheses of 8-oxabicyclo[3.2.1]octanes using a cationic cascade cyclization reaction has been developed (see scheme; TIPS=triisopropylsilyl). The diastereomer of the cyclization product isolated depends upon whether the acetal or aldehyde substrate is used. Copyright

Full text of DOI:10.1002/anie.201202699

Angewandte
Chemie
DOI: 10.1002/anie.201202699
Synthetic Methods
Asymmetric Syntheses of 8-Oxabicyclo[3,2,1]octanes: A Cationic
Cascade Cyclization**
Bin Li, Yu-Jun Zhao, Yin-Chang Lai, and Teck-Peng Loh*
8-Oxabicyclo[3.2.1]octane, or 8-oxatropane, is a common
structural motif featured in many classes of polycyclic natural
products (Figure 1), some of which show interesting biolog-
ical activities.[1–4] 8-Oxatropanes are also structural mimics of
the cycloaddition reaction also worked well using epoxy enol
silanes as the dienophile.[8] Another cycloaddition compo-
nent, allenamide, which was proposed by Hsung and co-
workers has also been applied in this reaction successfully.[9]
Recently, Wang and co-workers developed a Lewis acid
catalyzed intramolecular cycloaddition of alkynylcyclopropyl
ketones with carbonyls to build this skeleton.[10] In addition,
many metals such as rhodium(II),[11] platinum(II),[12]
gold(I),[13] and tungsten[14] catalyze the 1,3-dipolar cycloaddi-
tion of carbonyl ylides and have been shown to be effective in
constructing the 8-oxatropane scaffold. Despite the excellent
progress made thus far for the synthesis of 8-oxatropanes,
practical and asymmetric selective methods are still lack-
ing.[9c,12b,15] Herein, we report an efficient diastereoselective
and enantioselective synthesis of 8-oxabicyclo-[3.2.1]octane
through a cationic cascade reaction mediated by TiCl4.
Figure 1. Selected examples of natural products containing the
8-oxatropane core.
Previously, we have reported the syntheses of five- and
six-membered ring compounds using the Mukaiyama aldol/
Prins cascade reaction (Scheme 1a).[16] We hypothesized that
the same cascade reaction design could be also applied for the
assembly of seven-membered rings (Scheme 1b). With this
notion in mind, we treated a solution of the 1,4-cyclic acetal
1a and silyl enol ether 2a with 1.2 equivalents of TiCl4 in the
hope of getting either the seven-membered ring compound A
or B. Surprisingly, this reaction afforded the 8-oxatropane 3a
in 91% yield as a single isomer. No trace of side products,
such as those produced from a chlorine trapping of tert-butyl
cation (A) or a Friedel–Crafts reaction with the phenyl group
(B),[17] were observed. The structure of 3a was ascertained by
tropane alkaloids, and consequently there is an increasing
interest in their potential pharmaceutical use, particularly
against cocaine abuse.[5]
Compelled by the interesting biological activities of 8-
oxatropanes, many groups have embarked on the search for
new methodologies to construct this bicyclic structure. For
example, Molander and co-workers have reported a Lewis
acid promoted double allylation of 1, 4-dicarbonyl com-
pounds to construct 8-oxatropanes.[6] The same group later
reported the syntheses of 8-oxatropanes using a TiCl4-pro-
moted cycloaddition of a bis(trimethylsilyl enol ether) and
1,4-dicarbonyl compounds.[7] Chiu and co-workers found that
[*] Prof. T. P. Loh
Department of Chemistry
University of Science and Technology of China
Hefei, Anhui 230026 (China)
B. Li, Y. C. Lai, Prof. T. P. Loh
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University, Singapore 637616 (Singapore)
E-mail: teckpeng@ntu.edu.sg
Dr. Y. J. Zhao
Departments of Internal Medicine
University of Michigan, Ann Arbor, MI 48109 (USA)
[**] We gratefully acknowledge the Nanyang Technological University,
the Singapore Ministry of Education Academic Research Fund Tier 2
(MOE2010- T2-2-067), and Tier 2 MOE2011-T2-1-013 for financial
support.
Scheme 1. a) Previous work. b) Preliminary study for the work pre-
sented herein.[19] TBAF=tetra-n-butylammonium fluoride, TIPS=triiso-
propylsilyl.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201202699.
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Table 1: Cascade cyclization between various cyclic acetals and silyl enol
ether 2a.[a]
inference from the X-ray crystal data of its alcohol derivative
(3a’). Other Lewis acids such as, TiBr4, SnCl4, BF3·OEt2, and
Sc(OTf)3 were also tested, but TiCl4 gave the best results.
With the optimal reaction conditions in hand, fifteen 1,4-
cyclic acetal substrates were investigated to explore the
reaction scope and the results are summarized in Table 1.
Generally, the desired products were obtained in good yields
with excellent diastereoselectivities (entries 1–14). The ether
group (entries 5 and 6) was well tolerated in the reaction.
When an electron-donating group was introduced in the
phenyl group (1g), the 8-oxabicyclo[3.2.1]octane 3g was
obtained in high yield (entry 7), and there was still no Friedel–
Crafts reaction observed for the phenyl unit. It is notable that
isolated alkenes (entries 9 and 10) and an isolated alkyne
(entry 11) were also tolerated in this reaction, although the
yields were slightly compromised. In the case of terminal
alkenes, the disubstituted substrate (entry 12) exhibited
better reactivity than the monosubstituted substrate
(entry 12). For the cycloheptene substrate 1n (entry 14), the
reaction yield was moderate. In contrast, when a similar
cyclohexene substrate (1o) was tested, the alkene product 3o
was obtained instead of the desired 8-oxatropane (entry 15).
To further expand the scope of this reaction, the reactivity
of five different silyl enol ethers were screened (Table 2).
Generally, high yields and high diastereoselectivities were
obtained when the trisubstituted silyl enol ethers 2a–d were
used (entries 1–4). When the disubstituted silyl enol ether 2e
Table 2: Cascade cyclization between various silyl enol ethers and cyclic
acetal 1a.[a]
[a] Reaction conditions: TiCl4 solution (0.24 mL, 1.0m in CH2Cl2) was
added to a solution of 1 (0.2 mmol), 2 (0.3 mmol), and 4 ꢀ molecular
sieve (0.3 g) in anhydrous dichloromethane (2 mL) at À788C. [b] Yield of
isolated product. Bn=benzyl.
[a] Reaction conditions: see Table 1. [b] Yield of isolated product. [c] The
d.r. values were determined by 1H NMR analysis of the crude reaction
mixture.
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Table 4: Cascade cyclization between various aldehydes and silyl enol
was used, the yield remained high, but the diastereoselectivity
decreased (entry 5).
ether 2a.[a]
Encouraged by previous results, we further explored the
asymmetric version of this reaction using chiral acetals[18]
(Table 3). For chiral acetals (1a’, 1aa, and 1ab) derived
from the same aldehyde, the acetal 1a’ derived from (2R,3R)-
Table 3: Asymmetric cyclization between various chiral cyclic acetals and
silyl enol ether 2a.[a]
[a] Reaction conditions: see Table 1. [b] Yield of isolated product. [c] The
d.r. values were determined by 1H NMR spectroscopy.
The structures of compounds 5a–d were ascertained by
reference to an X-ray diffraction analysis of compound 5d’
(Figure 2), which was derived from desilylation of 5d.
Interestingly, the 2-alkyl and 3-hydroxy groups in 5d’ were
aligned syn to each other, and this is in sharp contrast to the
2,3-anti stereochemistry observed in products 3a–k when
cyclic acetals were used as substrates (see Scheme 1 and
Tables 1–3).
[a] Reaction conditions: see Table 1. [b] Yield of isolated product. [c] The
ee values were determined by chiral HPLC analysis.
In light of the above results, a reaction mechanism may be
proposed to rationalize the impact of the cyclic acetal or
aldehyde groups on the stereochemical outcome of the
cyclizations. As depicted in Scheme 2, the initial step involves
a Mukaiyama aldol reaction between the acetal or aldehyde
and the silyl enol ether C. Subsequently, the olefin attacks the
silylated oxocarbenium via a syn-clinal, closed-chain transi-
2,3-butanediol gave 3a with the highest enantioselectivity
(entry 3). Accordingly, acetals derived from (2R,3R)-2,3-
butanediol were adopted for further optimization of the
reaction. Generally, high ee values were obtained independ-
ent of the substitution on the olefin substrates (entries 3–7).
The absolute stereochemistry of the cyclization products was
confirmed by X-ray analysis of a derivative of the enantio-
merically enriched product 3h (entry 5 and see the Support-
ing Information).[19]
From a mechanistic standpoint, we compared the differ-
ence in reactivity between acetals and aldehydes (Table 4).
Surprisingly, another 8-oxabicyclo[3.2.1]octane diastereomer
product, 5a, was obtained in good yield (51%) with high
diastereoselectivity when aldehyde 4a was used as the
substrate (entry 1). The five other substrates, 4b–f, also gave
the bicyclic products in moderate to good yields (entries 2–6).
In contrast, the diastereoselectivity of 5 f, which comprises
a cycloheptene group, was negligible.
Figure 2. Determination of the relative stereochemistry of 5d’. Thermal
ellipsoids shown at 50% probability.[19]
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Received: April 7, 2012
Revised: May 24, 2012
Published online: && &&, &&&&
Keywords: aldol reaction · cyclization · heterocycles ·
.
synthetic methods · titanium
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tion state with four possible conformations (D–G). According
to our model, the transition-state conformation appears to be
critical for defining the relative stereochemistry at the 2- and
3-positions of 8-oxatropane. In the case when an acetal is the
substrate, the transition state D is favored with the R1 and
OTIPS groups adopting pseudoequatorial positions. As
a result, the anti-configured product 3 is produced. In
comparision, the conformation of transition state F was not
favored, presumably because of 1,3-diaxial repulsion of the
OTIPS/Me and OTIPS/OR groups. In contrast, when an
aldehyde is the substrate, the transition state has the
conformation E with the R1 and OTiCln groups taking
pseudo equatorial positions and the OTIPS group occupying
a pseudoaxial position, thereby resulting in the formation of
the cyclization product 5. Our data also suggest that the
transition state G is inactive.
In conclusion, we have developed a novel and practical
diastereoselective cationic cascade cyclization reaction for the
synthesis of 8-oxabicyclo[3.2.1]octanes, a common structural
motif present in many natural products. More importantly, the
stereochemical outcome of the 2,3-substituents can be readily
controlled through employing either an acetal or an aldehyde
as the reaction initiator. In addition, a highly enantioselective
reaction can also be achieved by using (2R,3R)-2,3-butane-
diol-derived chiral acetals as the substrate. Moreover, the
mild reaction conditions and its compatibility with substrates
containing multiple electron-rich functional groups, such as
olefins, alkynes, and substituted anisole also make the present
protocol attractive for organic synthesis. Additional studies
on the application of this method to the synthesis of
functionalized tropanes are currently in progress and the
results will be reported in due course.
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Communications
Synthetic Methods
B. Li, Y. J. Zhao, Y. C. Lai,
T. P. Loh*
&&&& — &&&&
Asymmetric Syntheses of 8-
Oxabicyclo[3,2,1]octanes: A Cationic
Cascade Cyclization
High octane: A novel and practical syn-
theses of 8-oxabicyclo[3.2.1]octanes
using a cationic cascade cyclization
reaction has been developed (see
scheme; TIPS=triisopropylsilyl). The
diastereomer of the cyclization product
isolated depends upon whether the acetal
or aldehyde substrate is used.
6
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Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!