Catalytic enantioselective radical cyclization via regiodivergent epoxide opening

Article abstract of DOI:10.1021/ja105023y

A catalytic enantio- and diastereoselective radical cyclization using a regiodivergent epoxide opening (REO) for radical generation is described. It is demonstrated for the first time that the diastereoselectivity of cyclizations of acyclic radicals can be controlled catalytically. Building blocks for important applications in stereoselective synthesis are readily accessed.

Full text of DOI:10.1021/ja105023y

Published on Web 08/05/2010
Catalytic Enantioselective Radical Cyclization via Regiodivergent Epoxide
Opening
Andreas Gansa¨uer,* Lei Shi, and Matthias Otte
Kekule´-Institut fu¨r Organische Chemie und Biochemie der UniVersita¨t Bonn, Gerhard Domagk Strasse 1,
53121 Bonn, Germany
Received May 11, 2010; E-mail: andreas.gansaeuer@uni-bonn.de
Table 1. REO Cyclization of 1 Catalyzed by 10 mol % Cp2TiCl2 or
Abstract: A catalytic enantio- and diastereoselective radical
cyclization using a regiodivergent epoxide opening (REO) for
radical generation is described. It is demonstrated for the first
time that the diastereoselectivity of cyclizations of acyclic radicals
can be controlled catalytically. Building blocks for important
applications in stereoselective synthesis are readily accessed.
4 in the Presence of Mn, 1,4-C6H8, and 2,4,6-Collidinde*HCl
entry
cat., substrate, era
2, yield, er
3, yield, trans:cis, er (trans)
1
2
3
4
5
6
7
Cp2TiCl2, 1a, 50:50 2a, 31%, 50:50
3a, 9%, 66:34, 50:50
4, 1a, 50:50
4, 1a, 93:7
ent-4, 1a, 93:7
2a, 36%, 12.5:87.5 3a, 30%, 91:9, 94:6
2a, 15%, ND
2a, 56%, >99:<1
3a, 68%, 91:9, >99:<1
3a, 2%, ND, ND
3b, 11%, 68:32, 50:50
3b, 34%, 91:9, 3:97
3b, 68%, 91:9, >99:<1
Cp2TiCl2, 1b, 50:50 2b, 40%, 50:50
ent-4, 1b, 50:50
4, 1b, 93:7
2b, 42%, 84:16
2b, 14%, ND
Because of their high versatility, selectivity, and compatibility
with densely functionalized substrates, radical cyclizations are
frequently employed in the synthesis of complex molecules.1
Unfortunately, enantioselective cyclizations allowing highly selec-
tive access to important structures are still rare.2
The reported cyclizations are based on Lewis acid chelation of
the substrates, such as ꢀ-dicarbonyl compounds2a,b or hydroxamate
esters,2c to obtain cyclic radicals under chain conditions. Our
concept employs enantioselective radical generation via titanocene-
catalyzed regiodivergent epoxide opening (REO) and catalyst-
controlled diastereoselectivity of the 5-exo cyclization of an acyclic
radical (Scheme 1).3,4
a (2S,3R):(2R,3S).
Sharpless epoxides 1. Moreover, no precedent for the ability of 4
or any other titanocene to induce high 1,2-induction in radical
cyclizations was available.
Alkynes were chosen as radical acceptors in our model substrates
1 because the exocyclic olefin present in the products 3 can be
exploited for further stereoselective transformations with a large
degree of flexibility. The reactions of 1 with Cp2TiCl2 and 4 are
summarized in Table 1.
Cp2TiCl2 (entries 1 and 5) is not an attractive catalyst, as the
yields of the products are bad, 1 is opened to the undesired 2
preferentially (3-4:1), and the induction of diastereoselectivity by
the C5H5 ligands is too low (∼2:1). REOs with 4 are highly
enantioselective with the TBDPS group (97:3 in 3b; 94:6 in 3a).
Enantiomerically enriched substrates (entries 3 and 7) lead to 3a
and 3b in even higher selectivity. Complex 4 induces a 91:9
diastereoselectivity of the cyclization (Scheme 2). The alkyne
renders both transition states methylenecyclopentane-like rather than
cyclohexane-like as in the Beckwith-Houk model.8 In TStrans,
steric interactions between the alkyne, CH2OPG, and O[Ti] groups
are minimized. In TScis, there is an unfavorable interaction between
the CH2OPG and O[Ti] groups. This is especially relevant for the
menthyl-substituted ligands of 4. The pseudoaxial orientation of
the CH2OPG group is supported by the higher diastereoselectivities
with substituted alkynes (Table 2). Similar trans selectivities in
substrate-controlled radical cyclizations to give methylenecyclo-
pentanes have been reported.8c
The pivotal radicals are generated under catalytic conditions5b-e
that are based on the stoichiometric reaction of RajanBabu and
Nugent.5a As the catalyst we investigated Kagan’s complex (4).6
Although 4 can exert high reagent control in enantio- or regiose-
lective epoxide openings,3,7 it was not clear if this would also be
the case for the sterically and electronically biased silylated
Scheme 1. Concept of Enantioselective Radical Cyclization after
Regiodivergent Epoxide Opening (REO)
The flexibility of our approach is highlighted by the transforma-
tion of 3b into either 5a or 5c (Scheme 3). 5a can be obtained
from 3b by hydrogenation with Crabtree’s catalyst.9 5c can be
synthesized using the same methodology from 3b after inversion
of the protection pattern in a two-step sequence.
Scheme 2. Origin of the Diastereoselectivity of the Cyclization
9
11858 J. AM. CHEM. SOC. 2010, 132, 11858–11859
10.1021/ja105023y  2010 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Stereoselective Directed Hydrogenations with 3b
inductions of the O[Ti] group and the CH2OPG radical substituent
in cyclohexane-like transition structures according to the Beckwith-
Houk rules.8
Scheme 4. REO Cyclizations with Acrylate Acceptors
Table 2. REO Cyclization of 6a-f Catalyzed by 4
In summary, we have devised enantioselective catalytic radical
cyclizations for the stereodivergent synthesis of cyclopentanols.
Acknowledgment. We thank the Alexander von Humboldt-
Stiftung (Forschungsstipendium to L.S.) and the SFB 813 (“Chem-
istry at Spin Centers”) for financial support.
Supporting Information Available: Experimental details and
compound characterization, including NOE studies. This material is
available free of charge via the Internet at http://pubs.acs.org.
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entry
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6a, 93:7b
6b, 50:50b
6b, 93:7b
6c, 50:50b
6c, 93:7b
6d, 50:50b
6d, 91:9b
6e, 50:50c
6e, 93:7b
6f, 50:50c
6f, 84:16b
7a, 38%, 88.5:11.5
7a, 14%, ND
7b, 36%, 85:15
7b, 22%, ND
7c, 47%, 85.5:14.5
7c, 31%, ND
7d, 46%, 88:12
7d, 24%, ND
7e, 44%, 18:82
7e, 11%, ND
7f, 46%, 26:74
7f, 24%, ND
8a, 38%, 97:3
8a, 67%, >99:<1
8b, 25%, 97.5:2.5
8b, 58%, 99:1
8c, 33%, 97.5:2.5
8c, 51%, 98:2
8d, 36%, 97.5:2.5
8d, 56%, >99:<1
8e, 37%, 4:96
8e, 68%, >99:<1
8f, 40%, 1.5:98.5
8f, 55%, 99:1
9
10
11
12
a (2S,3R):(2R,3S). b cat ) 4. c cat ) ent-4. d Determined by chiral
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The high enantioselectivities of the reactions of all of the racemic
substrates (>97:3 except for 96:4 with 6e; Table 2) underlines the
efficiency of the REO of silylated Sharpless epoxides. The use of
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induced diastereoselectivity of the cyclizations was good (91:9,
8a-c) to excellent (97:3, 8d-f). From 8a-f, compounds 9a-f
were prepared as single isomers by hydrogenation. Both the cis
and trans isomers are useful for the synthesis of products with
interesting biological or olfactory properties, such as deoxypros-
taglandins10 or dihydrojasmonates, respectively.11 Finally, it was
established that alkenes are inferior to alkynes as radical acceptors
(Scheme 4). While the enantioselectivity is excellent, the diaste-
reoselectivity of the cyclization is too low because of the opposing
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