Stereoselective construction of halogenated quaternary stereogenic centers via catalytic asymmetric diels-alder reaction

Full text of DOI:10.1021/ja1018628

Published on Web 04/07/2010
Stereoselective Construction of Halogenated Quaternary Stereogenic Centers
via Catalytic Asymmetric Diels-Alder Reaction
Kazutaka Shibatomi,*,† Kentaro Futatsugi,‡ Fumito Kobayashi,† Seiji Iwasa,† and
Hisashi Yamamoto*,‡
Department of Materials Science, Toyohashi UniVersity of Technology, 1-1 Hibarigaoka, Tempaku-cho,
Toyohashi 441-8580, Japan, and Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue,
Chicago, Illinois 60637
Received March 5, 2010; E-mail: shiba@tutms.tut.ac.jp; yamamoto@uchicago.edu
Scheme 1. Stereoselective Construction of Halogenated Chiral
Stereoselective construction of halogenated chiral carbon centers
is an important synthetic task because chiral fluorinated compounds
are well-recognized as fascinating drug candidates1 and chiral
brominated compounds are useful synthetic intermediates for the
synthesis of a range of optically active molecules. Asymmetric
Diels-Alder reaction of halogenated olefins is an attractive
approach for the stereoselective formation of halogenated quaternary
stereogenic centers. However, to the best of our knowledge, only
one report on the enantioselective Diels-Alder reaction of fluo-
roolefins has been published, and this reaction yielded fluorinated
cycloadducts with up to 43% ee using a stoichiometric amount of
a chiral titanium(IV) mediator;2 however, significant efforts for this
class of reaction without asymmetric induction have been made.3,4
Additionally, in the case of bromoolefins, most of the successful
enantioselective Diels-Alder reactions have been observed only
when brominated enals are used as a dienophile.5 Last year,
Danishefsky reported an elegant method for the formation of trans-
fused bicyclic systems by the radical isomerization of a cis-fused
Diels-Alder adduct with a nitro function (the trans-DA paradigm).6
We assumed that brominated bicyclic Diels-Alder adducts derived
from R-bromo cyclic ketones could also be converted into trans-
fused bicyclic systems by their reductive alkylation involving an
inversion of the stereochemistry. In this paper, we describe the first
highly enantioselective Diels-Alder reactions of R-halogenated R,ꢀ-
unsaturated ketones; these reactions provide optically active cy-
clohexane derivatives with a halogenated quaternary stereogenic
center (Scheme 1). Furthermore, a brominated cycloadduct was
successfully converted to a trans-fused bicyclic system via reductive
alkylation. This process is applicable to the asymmetric synthesis
of natural steroid compounds.
Carbon Centers
Scheme 2. Lewis Acid-Activated Chiral Oxazaborolidine (OXB)
Scheme 3. Enantioselective Diels-Alder Reactions Catalyzed by
Lewis Acid-Activated Oxazaborolidine (OXB)
Our previous study revealed that Lewis acid-activated chiral
oxazaborolidine (OXB) 1 acts as an efficient catalyst in the
asymmetric Diels-Alder reaction (Scheme 2).7 Initially, we
examined the Diels-Alder reaction of 2-fluorohepten-1-en-3-one
(2) with cyclopentadiene (3a) in the presence of 10 mol % 1a. The
reaction proceeded smoothly at -78 °C to yield product 4a in 94%
ee with good exo selectivity8 (Scheme 3).9 In contrast, the
Diels-Alder reaction of ethyl vinyl ketone under the same
conditions yielded a nonfluorinated product with high endo
selectivity.7a This drastic difference in diastereoselectivity is in good
agreement with the results of a previous study on titanium(IV)-
mediated Diels-Alder reactions of R-fluoroenone.2,3c
catalyzed by a Brønsted acid-activated chiral OXB.10 Using this
approach, we examined the Diels-Alder reaction of fluoroenone
2 and the functionalized monosubstituted cyclopentadienes 3b-d
catalyzed by 1a. As Table 1 shows, all of the corresponding
products were obtained in good yields with excellent diastereo- and
enantioselectivity as single regioisomers (up to 94% ee; entries
We then used substituted cyclopentadienes as the diene. Recently,
we demonstrated the highly regio- and enantioselective Diels-Alder
reaction of 1- and 2-substituted cyclopentadienes (∼1:1 mixture)
† Toyohashi University of Technology.
‡ The University of Chicago.
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10.1021/ja1018628  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 5625–5627 5625

C O M M U N I C A T I O N S
Table 1. Enantioselective Diels-Alder Reaction of R-Fluoroenone
Table 2. Asymmetric Diels-Alder Reaction of R-Halo Cyclic
2a
Enonesa
a See the Supporting Information for details. b Isolated yield.
c Determined by chiral HPLC or GC analysis. d Both the relative and
absolute stereochemistry were confirmed by X-ray crystallographic
analysis. e After a single recrystallization. f Reaction was carried out at
-78 °C.
penten-1-one (7a) with 5b proceeded smoothly with high enanti-
oselectivity in the presence of 5 mol % catalyst to provide a
reasonable yield of the enantiomerically pure product 9a after a
single recrystallization (entry 1). The use of both 2-bromocyclo-
hexen-1-one (7b) and 2-chlorocyclopenten-1-one (7c) also yielded
the corresponding halogenated bicyclic adducts with excellent
regio-, diastereo-, and enantioselectivities (entries 2 and 3). Catalyst
1b with a 3,5-dimethoxyphenyl group was more reactive in the
reaction with the simple and less reactive diene 8 while maintaining
a high level of asymmetric induction (entries 4 and 5).
a See the Supporting Information for details. b Isolated yield.
c Determined by chiral HPLC or GC analysis. d Reaction carried out
with 30 mol % 1a. e Both the relative and absolute stereochemistry were
confirmed by X-ray crystallographic analysis of the corresponding oxime
(see the Supporting Information for details).
1-3).9 These reactions showed exo selectivity similar to that of
the reaction shown in Scheme 3. Subsequently, Dane’s diene (5b)
and its analogues 5a and 5c were also applied to the reaction with
2. All of the reactions proceeded smoothly in the presence of 30
mol % catalyst, providing tricyclic products in high yields with
excellent enantioselectivities as sole diastereoisomers (up to 94%
ee; entries 4-6).9 Thus, the present method enables the efficient
synthesis of fluorocyclohexane derivatives having a fluorinated
chiral quaternary stereogenic center with high optical purity.
Our next study focused on the enantioselective formation of
halogenated bicyclic Diels-Alder adducts using 2-halocycloalken-
1-ones.11 To our delight, catalyst 1a exhibited high reactivity toward
this class of substrates (Table 2). The reaction of 2-bromocyclo-
We then aimed to use the optically active brominated bicyclic
adducts for asymmetric syntheses of estrone and norgestrel,12 which
have a trans-fused CD ring system, with the trans-selective reductive
alkylation of 9a as a key step. However, the general trend of
diastereoselectivity in the alkylation of metal enolates favors
undesired cis alkylation via 1,2-asymmetric induction.13 We as-
sumed that the use of the enolate species generated from the bulky
aluminum reagent aluminum tris(2,6-diphenylphenoxide) (ATPH)14
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C O M M U N I C A T I O N S
Scheme 4. Formal Syntheses of Estrone and Norgestrel via
Trans-Selective Reductive Alkylation of 9aa
Supporting Information Available: Experimental procedures,
characterization of all new compounds, and crystallographic data (CIF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
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a Key: (a) ATPH (1.1 equiv), toluene, rt, 1 h; (b) MeLi (2.2 equiv), Et2O,
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and a suitable reductant might reverse the substrate-controlled
diastereoselectivity, leading to trans alkylation.
As shown in Scheme 4, the reductive alkylation was performed
by precomplexation of 1.1 equiv of ATPH with 9a and subsequent
sequential treatment with 2.2 equiv of methyllithium and trimethy-
loxonium tetrafluoroborate. The corresponding methyl adduct was
obtained in 74% yield with a trans/cis ratio of 85/15. In addition,
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procedure with triethyloxonium tetrafluoroborate as the alkylating
reagent. This reaction afforded a 63% yield of the ethyl adduct
with a trans/cis ratio of 84/16. Pure trans adducts 11a and 11b were
obtained after preparative HPLC. Finally, acid-mediated isomer-
ization of the double bond afforded two key intermediates: 12a
leading to the formation of (+)-estrone by a known two-step
sequence12f and 12b leading to the formation of norgestrel by a
known five-step sequence.12f
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In conclusion, the first highly enantioselective Diels-Alder
reactions of R-halo-R,ꢀ-unsaturated ketones with Lewis acid-
activated chiral OXB as a catalyst have been demonstrated. The
reaction of R-fluoroenones can be employed for the stereoselective
construction of fluorinated quaternary stereogenic centers. In this
study, a brominated cis-fused Diels-Alder adduct derived from
an R-bromo cyclic enone was successfully converted to a trans-
fused bicyclic system via reductive alkylation using the bulky
aluminum reagent ATPH. With this process, remarkably short
catalytic asymmetric syntheses of (+)-estrone and norgestrel have
been realized.
(13) We actually tried methylation of the lithium enolate generated from 9a
and lithium naphthalenide using methyl iodide. The reaction at-78 °C
afforded predominantly the cis product (trans/cis ) 3/97) in 56% yield.
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Chem., Int. Ed. 2004, 43, 994. (b) Takikawa, H.; Ishihara, K.; Saito, S.;
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Acknowledgment. This work was supported by NSF (CHE-
0717618) and a Grant-in-Aid for Young Scientists (B) (21750096)
from MEXT. The partial support from Asahi Glass Foundation is
also acknowledged. We are grateful to Dr. Ian Steele for X-ray
analysis.
Note Added after ASAP Publication. A typographical error in the
name of compound 7b was corrected in the text on April 21, 2010.
JA1018628
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