Enantioselective bromolactonization of conjugated (2)-enynes

Article abstract of DOI:10.1021/ja100173w

"Chemical equation presented" A catalytic enantioselective syn-1,4-bromolactonization of conjugated (Z)-enynes was reported. Diastereomeric ratios >20:1 and up to 99% enantiomeric excesses were observed. Di-, tri-, and tetra-substituted bromoallenes were prepared together with lactone heterocycles efficiently and stereoselectively. Preliminary investigations suggest that the chiral catalyst may serve as a bifunctional reagent by interacting with both a carboxylic acid nucleophile and NBS electrophile.

Full text of DOI:10.1021/ja100173w

Published on Web 03/01/2010
Enantioselective Bromolactonization of Conjugated (Z)-Enynes
Wei Zhang,† Suqing Zheng,† Na Liu,† Jenny B. Werness,‡ Ilia A. Guzei,‡ and Weiping Tang*,†
School of Pharmacy and Department of Chemistry, UniVersity of Wisconsin, Madison, Wisconsin 53705
Received January 8, 2010; E-mail: wtang@pharmacy.wisc.edu
Table 1. Screening of Catalysts and Conditionsa
Halogen promoted addition of nucleophiles to alkenes represents
one of the most fundamental reactions in chemistry and is widely
used in organic synthesis for the stereoselective introduction of
functional groups.1 However, the catalytic enantioselective addition
of halogen and nucleophile to unactivated alkenes remains elusive
despite recent impressive progress in asymmetric catalysis. A few
highly enantioselective reactions were developed for the halocy-
clization of alkenes promoted by chiral electrophiles comprising
halonium cations.2-4 Up to 93% ee was obtained for iodocyclization
of γ-hydroxy-cis-alkenes using Salen-Co or Salen-Cr catalysts.2,3
Iodocyclization of polyprenoids with up to 99% ee was achieved
with a stoichiometric amount of chiral phosphoramidites.4 Among
entry
catalyst
ee %b
all halocyclizations, halolactonization is arguably the most versatile
since the resulting lactone can be easily elaborated.5 Although there
have been several examples of enantioselective halolactonization,
low enantioselectivity was generally observed prior to our study.6
We recently discovered a DABCO-catalyzed highly diastereo-
selective enyne bromolactonization reaction.7 Unlike the well-
known anti-1,2-bromolactonization of alkenes, syn-1,4-bromolac-
tonization of enynes occurred in the presence of DABCO catalyst.
Herein, we report a bifunctional catalyst promoted highly enanti-
oselective bromolactonization of conjugated (Z)-enynes for the
preparation of versatile bromoallenes8 and lactone heterocycles with
high optical purity.
1
2
3
4
5
6
7
8
3a, (9R), R ) H
3b, (9R), R ) Me
-58
0
3c, (9R), R ) triphenylsilyl
3d, (9R), R ) Bn
5
21
24
-6
30
0
70
75
10
80
NR
-13
10
19
89
80
3e, (9R), R ) 1-naphthyl
3f, (9S), R ) H
4a, (9S), R ) Ph
4b, (9R), R ) Ph
9
5a, (9S), R1 ) H, X ) O, R2 ) 3,5-(CF3)2C6H3
5b, (9S), R1 ) H, X ) O, R2 ) Ts
5c, (9R), R1 ) H, X ) O, R2 ) Ts
5d, (9S), R1 ) OMe, X ) O, R2 ) Ts
5e, (9S), R1 ) H, X ) S, R2 ) 3,5-(CF3)2C6H3
5f, (9R), R1) H, X ) S, R2 ) 3,5-(CF3)2C6H3
5g, (9S), R1 ) H, X ) O, R2 ) Ph
5h, (9S), R1 ) H, X ) O, R2 ) t-Bu
5d
10
11
12
13
14
15
16
Our initial studies revealed that 20 mol % of cinchonidine 3a,9
which has a bridgehead nitrogen similar to DABCO, could induce
moderate ee for product 2a from cis-enyne 1a and still retain high
diastereoselectivity (dr > 20:1) (entry 1, Table 1).10 The ee’s
dropped significantly with 9-alkoxy, 9-siloxy, and 9-epimeric
cinchonidines (entries 2-6), suggesting that the 9-hydroxyl group
of 3a plays an important role for the induction of enantioselectivity
and is likely served as a hydrogen bond donor rather than an
acceptor.
17c d
,
18c
5d (10 mol %)
a Conditions: To a solution of enyne 1 and catalyst (20 mol %) in
CHCl3 was added NBS, and the solution was stirred at rt unless noted
otherwise. b Products with negative enantiomeric excess (ee) have ent-2a
as the major isomer. c Solvent is ClCH2CH2Cl. d 72% isolated yield.
1,2-dichloroethane gave the highest isolated yield and ee (entry
17).10 When the catalyst loading was decreased to 10 mol %, the
ee dropped from 89% to 80% (entry 18).
We then converted the 9-hydroxyl group to amide, urea, and
thiourea, which are strong hydrogen bond donors (entries 7-16).11
Amides 4a and 4b provided low enantioselectivity (entries 7 and
8). Catalysts with a urea group improved the enantioselectivity
significantly (entries 9, 10, and 12).12 Notably, ureas 5b and 5d,
which are first reported here, performed better than known catalyst
5a.12 It is also interesting to note that urea 5b with a 9S
configuration performed much better than its 9-epimer 5c. This is
opposite to the trend observed for catalyst 3, where the 9R
configuration performed better than 9S (3a versus 3f). Surprisingly,
thiourea catalyst 5e with the 9S configuration was not able to
catalyze the reaction (entry 13). Full conversions and comparable
rates were observed for most catalysts in Table 1 except 5e. Urea
catalyst 5d was then chosen for further optimization in different
solvents. Of the solvents surveyed, including chloroform, methylene
chloride, 1,2-dichloroethane, toluene, ethyl acetate, and acetonitrile,
It has been proposed that halogenation reagents could be activated
by chiral nucleophilic promoters4 or Lewis acids.13 In the case of
catalyst 5d, either the quinuclidine nitrogen or urea group may
activate NBS via formation of a new electrophilic brominating
species or hydrogen bonding respectively. When we premixed NBS
(1.2 equiv) and 5d (20 mol %) in ClCH2CH2Cl and stirred for
20 min before the addition of acid 1a, the ee of product 2a dropped
from 89% to 54% without significant change of the yield. A
longer premixing time (4 h) further deteriorated the ee to 26%.
The reaction between NBS and catalyst 5d appeared to be an
undesired pathway. Although other mechanisms cannot be ruled
out at present, activation of NBS by hydrogen bonding with urea
and/or protonated amine is more consistent with the above results
and data in Table 1.
We then explored the scope of the catalytic enantioselective
enyne bromolactonization (Table 2). High enantioselectivity was
generally observed for cis-enynes with various terminal substituents
† School of Pharmacy.
‡ Department of Chemistry.
9
3664 J. AM. CHEM. SOC. 2010, 132, 3664–3665
10.1021/ja100173w  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of the Enantioselective Enyne Bromolactonizationa
The relative stereochemistry of the products and the absolute
stereochemistry of the bromoallenes were assigned based on our
previous study7 and Lowe’s rule for allenes respectively.14 The
X-ray structure of lactone 2n further confirmed our assignment.15
In summary, we have developed a bifunctional catalyst promoted
highly enantioselective bromolactonization of (Z)-enynes.16 We
anticipate that further investigation of this class of bifunctional
catalysts would lead to novel entries for other halogen promoted
enantioselective reactions.
Acknowledgment. I.A.G. performed X-ray crystallography. We
thank the University of Wisconsin and the donors of the Petroleum
Research Fund (48092-G1) for funding.
Supporting Information Available: Experimental procedures and
characterization data for the new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
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JA100173W
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