Stereoselective conjugate addition of aryl- And alkenylboronic acids to acyclic γ,δ-oxygen-substituted α,β-enoates

Article abstract of DOI:10.1021/ol7016033

The substrate-controlled Rh¹-catalyzed conjugate addition of aryl- and alkenylboronic acids to α,β-unsaturated esters which bear γ- and δ-oxygen substituents takes place in a highly anti diastereoselective fashion either when using γ-hydroxyl u

Full text of DOI:10.1021/ol7016033

ORGANIC
LETTERS
2007
Vol. 9, No. 18
3667-3670
Stereoselective Conjugate Addition of
Aryl- and Alkenylboronic Acids to
Acyclic
r,â
γ,δ-Oxygen-Substituted
-Enoates†
Amaya Segura and Aurelio G. Csa´ky2*
Departamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, UniVersidad Complutense,
28040-Madrid, Spain
csaky@quim.ucm.es
Received July 9, 2007
ABSTRACT
The substrate-controlled RhI-catalyzed conjugate addition of aryl- and alkenylboronic acids to
-oxygen substituents takes place in a highly anti diastereoselective fashion either when using
when the -oxygen substituent is protected with a nonbulky group. The -oxygen substituent plays a role in the stereoselectivity of the
r
,
â
-unsaturated esters which bear
γ- and
δ
γ-hydroxyl unprotected starting materials or
γ
δ
reaction, and better results are obtained when this OH-group is protected.
The conjugate addition of organometallic reagents to unsat-
urated carbonyl compounds is one of the main synthetic
methods for C-C bond formation. Among the different
procedures reported, the reaction of aryl- and alkenylboronic
acids under RhI catalysis, the Hayashi-Miyaura reaction,1
has become increasingly popular.2 The RhI-catalyzed con-
jugate addition reaction of organoboronic acids to electron-
deficient alkenes can be carried out in water-containing
solvents, is widely functional-group tolerant, and is compat-
ible with the presence of unprotected OH and NH groups,
which together with the catalytic use of the transition metal
and the low toxicity of boron compounds makes this
procedure very attractive from an environmental standpoint.
In addition, aryl- and alkenylboronic acids can be con-
veniently prepared by a variety of methods.3
Control of the stereoselectivity is crucial in the develop-
ment of new synthetic methods. In the RhI-catalyzed
conjugate addition reactions of organoboronic acids and their
derivatives, this has been achieved by using a variety of chiral
ligands attached to the transition metal.2,4 In contrast, the
substrate-controlled stereoselectivity of this reaction has been
scarcely explored,5,6 in particular with regard to conforma-
tionally flexible acyclic substrates.
† Dedicated to Prof. Vicente Gotor (Universidad de Oviedo) in honor of
his 60th birthday.
(1) First report: Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics
1997, 16, 4229.
(2) Reviews: (a) Hayashi, T. Synlett 2001, 879. (b) Fagnou, K.; Lautens,
M. Chem. ReV. 2003, 103, 169. (c) Hayashi, T.; Yamasaki, K. Chem. ReV.
2003, 103, 2829. (d) Hayashi, T. Pure Appl. Chem. 2004, 76, 465. (e)
Hayashi, T. Bull. Chem. Soc. Jpn. 2004, 77, 13. (f) Yoshida, K.; Hayashi,
T. In Modern Rhodium-Catalyzed Organic Reactions; Evans, P. A., Ed.;
Wiley-VCH: Weinheim, Germany, 2005; Chapter 3, p 55.
(3) For recent leading references on the synthesis of boronic acids and
derivatives, see: (a) Kalinin, A. V.; Scherer, S.; Snieckus, V. Angew. Chem.,
Int. Ed. 2003, 42, 3399. (b) Zhu, W.; Ma, D. Org. Lett. 2006, 8, 261. (c)
Stefani, H. E.; Cellab, R.; Vieira, A. S. Tetrahedron 2007, 63, 3623. (d)
Murphy, J. M.; Tzschucke, C. C.; Hartwig, J. F. Org. Lett. 2007, 9, 757
and references cited therein.
(4) Kurihara, K.; Sugishita, N.; Oshita, K.; Piao, D.; Yamamoto, Y.;
Miyaura, N. J. Organomet. Chem. 2007, 692, 428 and references cited
therein.
10.1021/ol7016033 CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/31/2007

We report herein the stereoselective RhI-catalyzed conju-
gate addition of aryl- and alkenylboronic acids to the R,â-
unsaturated esters 1-5, which bear a γ-oxygen substituent
(Figure 1).
Table 1. Addition of RB(OH)2 to Esters 1 and 2a
product
entry
substrate
R
(de, %; yield, %)b,c
1
2
3
4
5
6
1
1
1
2
2
2
C4H6
p-F-C4H6
(E)-PhCHdCH
C4H6
p-F-C4H6
6a (>98; 90)
6b (>98; 85)
6c (>98; 90)
6a (>98; 90)
6b (>98; 85)
6c (>98; 85)
(E)-PhCHdCH
a Reactions carried out at room temperature with 0.2 mmol of esters
1-2, 2.0 equiv of RB(OH)2, and 1.0 equiv of Et3N with 5 mol % of RhI
with respect to 1-2 in 0.5 mL of dioxane-H2O (10:1). b Diastereomeric
excesses determined by integration of the 1H NMR signals of the reaction
crudes. c Yield of the isolated product after column chromatography on silica
gel.
Figure 1. γ,δ-Oxygen-substituted R,â-enoates 1-5.
These types of compounds have been traditionally con-
sidered as poor substrates for conjugate addition reactions,
as oxygen at the γ-position makes the â-carbon less
electrophilic than ordinary R,â-unsaturated esters.7 Addition-
ally, in comparison with ketones, linear R,â-unsaturated
esters are known to be less reactive toward the RhI-catalyzed
conjugate addition reactions of organoboronic acids.2 We
have chosen for our study the γ,δ-oxygen-substituted R,â-
enoates 1-5, which are easily prepared from D-glyceralde-
hyde acetonide. Substrates 1 and 2 have been used as starting
materials for the conjugate addition of arylcuprate reagents,
and the products of these reactions are valuable intermediates
in the synthesis of natural and pharmaceutical products.8
Compounds 3 and 4, with free OH groups, constitute
interesting substrates for the evaluation of the stereoselective
bias of the RhI-catalyzed conjugate addition of organoboronic
acids, as OH-free compounds are often not compatible with
traditional methods for conjugate addition reactions, such
as organocuprate chemistry.6,9
In all cases we observed high conversion of the starting
materials and exclusive formation of the anti reaction product
6. We also found that compound 2, which differed from 1
in the geometry of the CdC bond, afforded similar results
(Table 1, entries 4-6).
Compound 3, with an unprotected γ-hydroxyl group, did
also react (Scheme 2) with aryl- and alkenylboronic acids
to afford, in this case, the trans-lactones 7 (Table 2, entries
1-5).
Scheme 2. Addition of RB(OH)2 to Esters 3-5
At first (Scheme 1) we examined the reaction of compound
1 with several organoboronic acids using [(cod)RhCl]2 as
Scheme 1. Addition of RB(OH)2 to Esters 1 and 2
We observed that yields with Et3N were inferior to those
obtained in the corresponding reactions of compounds 1 and
2. However, the use of Ba(OH)2 afforded high yields of
lactones 7, resulting from the in situ cyclization of the
corresponding anti open-chain adducts, which were not
isolated.
In a similar fashion, compound 4, with both γ- and
δ-hydroxyl groups unprotected (Scheme 2), afforded the
catalyst in dioxane-H2O (10:1) as solvent and in the
presence of a base, conditions which are known to be
efficient for transmetalation from boron to rhodium and
subsequent conjugate addition reaction to R,â-unsaturated
esters (Table 1, entries 1-3).
(8) See for example: (a) Hanessian, S.; Ma, J.; Wang, W. Tetrahedron
Lett. 1999, 40, 4627. (b) Reichard, G. A.; Ball, Z. T.; Aslanian, R.; Anthes,
J. C.; Shiha, N.-Y.; Piwinskia, J. J. Bioorg. Med. Chem. Lett. 2000, 10,
2329. (c) Han, G.; Hruby, V. J. Tetrahedron Lett. 2001, 42, 4281. (d)
Manpadi, M.; Kornienko, A. Tetrahedron Lett. 2005, 46, 4433. (e) Kireev,
A. S.; Nadein, O. N.; Agustin, V. J.; Bush, N. E.; Evidente, A.; Manpadi,
M.; Ogasawara, M. A.; Rastogi, S. K.; Rogelj, S.; Shors, S. T.; Kornienko,
A. J. Org. Chem. 2006, 71, 5694.
(9) For other OH-free directed conjugate additions of RMgX and RLi
reagents to open-chain systems, see: (a) Fleming, F. F.; Wang, Q.; Steward,
O. W. J. Org. Chem. 2003, 68, 4235. (b) Fleming, F. F.; Wang, Q. Chem.
ReV. 2003, 103, 2035. (c) Fleming, F. F.; Zhang, Z.; Wang, Q.; Steward,
O. W. Angew. Chem., Int. Ed. 2004, 43, 1126. (d) Reyes, E.; Vicario, J. L.;
Carrillo, L.; Bad´ıa, D.; Uria, U.; Iza, A. J. Org. Chem. 2006, 71, 7763.
(5) (a) Ramnauth, J.; Poulin, O.; Bratovanov, S. S.; Rakhit, S.; Madd-
aford, S. P. Org. Lett. 2001, 3, 2571. (b) Chen, Q.; Kuriyama, M.; Soeta,
T.; Hao, X.; Yamada, K.; Tomioka, K. Org. Lett. 2005, 7, 4439.
(6) For conjugate additions of R-RhI reagents to γ-OH-substituted cyclic
enones, see: de la Herra´n, G.; Mba, M.; Murcia, M. C.; Plumet, J.; Csa´ky¨,
A. G. Org. Lett. 2005, 7, 1669.
(7) Leonard, J.; Mohialdin, S.; Reed, D.; Ryan, G.; Swain, P. A.
Tetrahedron 1995, 51, 12843.
3668
Org. Lett., Vol. 9, No. 18, 2007

additions of RLi and RMgX reagents or lithium diallyl-
cuprates produce the syn adducts with high selectivity. On
the other hand, the additions of alkyl-, alkenyl-, and
arylcuprates are mainly anti-selective. This has been inter-
preted by nonchelation-controlled models, due to the lower
chelation ability of organocopper in comparison with RLi
or RMgX reagents. Most of these models explain the
diastereoselection on the basis of the steric and electronic
interactions which develop upon metal-olefin π-complex
formation or simple nucleophilic addition of the RM species.
It has also been noted that these types of additions are less
diastereoselective with (Z)-esters than with (E)-esters, and
models have been developed to account for this observation.
The RhI-catalyzed conjugate addition reaction of organo-
boronic acids to the acetal-protected esters (E)-1 and (Z)-2
was found to be highly anti-selective, irrespective of the
double bond geometry. The reaction with the γ-OH-δ-OTBS
protected ester 3 was also highly anti-selective, while the
addition to the γ-OH-δ-OH ester 4 was slightly less
stereoselective, although the anti isomer was also predomi-
nant. On the other hand, no diastereoselectivity was observed
with the γ-OTBS-δ-OTBS ester 5.
Table 2. Addition of RB(OH)2 to Esters 3-5a
Therefore, the predominance of the anti-products in these
reactions may be understood assuming that diastereoselection
takes place upon formation of the oxo-π-allyl-RhI intermedi-
ate, which may be the rate-limiting step of the catalytic cycle
(Scheme 3),2 and that there is no chelation between the metal
moiety and the OR1 group in this case.11,12
a Reactions carried out at room temperature with 0.2 mmol of esters
3-5, 2.0 equiv of RB(OH)2, and 1.0 equiv of base with 5 mol % of RhI
with respect to 3-5 in 0.5 mL of dioxane-H2O (10:1). b Diastereomeric
excesses determined by integration of the 1H NMR signals of the reaction
crudes. c Yield of the isolated product after column chromatography on silica
gel. d Reaction carried out in dioxane-H2O (10:0.5). e Reaction carried out
in dioxane-H2O (8:2).
Scheme 3. Proposed Stereochemical Course
trans-lactones 8 as the major reaction products (Table 2,
entries 6-14). However, the free δ-hydroxyl group influ-
enced the stereochemical outcome of the RhI-catalyzed
conjugate addition reaction, as the stereoselectivity was lower
than when using compounds 1-3 as starting materials. As
evidenced for the reaction with PhB(OH)2, Ba(OH)2 (entry
6) afforded good yield and diastereoselective excess. Similar
results were observed when using LiOH (entry 7), but the
use of K3PO4 resulted in lower stereoselectivity (entry 8).
We also observed an influence of the water content of the
reaction medium in the stereoselectivity when using Ba(OH)2
(entries 9 and 10).
Last, we carried out the RhI-catalyzed conjugate addition
reaction of PhB(OH)2 to compound 5, with both γ- and
δ-hydroxyl groups protected as bulky TBS-derivatives
(Scheme 2). However, a 1:1 mixture of diastereomers 9a
was obtained in this case (Table 2, entry 15).
Both transition state models minimize steric interactions
of the metal moiety with both the OR1 and CH2OR2 groups.13
Model I, leading to the anti adducts, is sterically destabilized
by an A1,3-interaction of the R-H with OR,1 while model II,
leading to the syn adducts, is sterically destabilized by an
A1,3-interaction of the R-H with CH2OR.2 However, model
I is energetically more favorable than II, as the nucleophile
The stereochemical outcome of conjugate addition reac-
tions of organometallic reagents to γ-alkoxy-R,â-enoates has
been addressed by several groups. The diastereoselectivity
has been found to be dependent on both the substrate and
reagent structures. In a broad sense,10 chelation-controlled
(11) This is to be compared with the additions of vinyl-RhI species to
γ-OH-substituted cyclic enones, which may take place under chelation or
nonchelation control, and similar additions of Ar-RhI species, which take
place under nonchelation control. See ref 6.
(12) For OH-directed stereoselectivity in Rh-catalyzed hydrogenation
reactions, see: Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993,
93, 1307 and references cited therein.
(13) Similar models have been used to interpret the addition reactions
of other nucleophiles to γ-hydroxy-substituted R,â-unsaturated esters. See:
Kireev, A. S.; Manpadi, M.; Kornienko, A. J. Org. Chem. 2006, 71, 2630
and references cited therein.
(10) See: (a) Roush, W. R.; Michaelides, M. R.; Tai, D. F.; Lesur, B.
M.; Chong, W. K. M.; Harris, D. J. J. Am. Chem. Soc. 1989, 111, 2984. (b)
Yamamoto, Y.; Chounan, Y.; Nishii, S.; Ibuka, T.; Kitahara, H. J. Am.
Chem. Soc. 1992, 114, 7652. (c) Mengel, A.; Reiser, O. Chem. ReV. 1999,
99, 1191.
Org. Lett., Vol. 9, No. 18, 2007
3669

enters antiperiplanar to the lowest σ*-lying orbital of the
γ-C-X groups (X ) H, OR,1 CH2OR2), which is the γ-C-
OR1 bond, as compared with II, where the nucleophile enters
antiperiplanar to the γ-C-CH2OR2 bond.
Thus, the high anti selectivity observed for esters 1 and 3
is the consequence of the combination of a relatively small
R1 group (1, R1 ) CH2-O-acetal; 3, R1 ) H), which
minimizes the steric interaction present in I, with a relatively
bulky R2 group (1, R2 ) CH2-O-acetal; 3, R2 ) TBS), which
increases the steric interaction present in II. Stereoselectivity
is eroded in ester 4, as the size of R2 is smaller (3, R2 ) H),
and completely vanishes in 5, as the size of R1 is larger (5,
R1 ) TBS).
With regard to the Z-ester 2, the high anti selectivity may
be understood on the basis of prior Z-E isomerization, which
may take place upon complexation of the metal with the
double bond. A competition experiment with an equimo-
lecular mixture of 1, 2, and PhB(OH)2 showed the exclusive
formation of 6a (50% yield) together with unreacted 1 and
2 in 20:80 ratio. This shows that the (Z)-ester 2 reacts slower
than the (E)-ester 1, in agreement with the Z-E isomerization
hypothesis.13
In conclusion, the RhI-catalyzed conjugate addition reac-
tion of organoboronic acids to acyclic γ,δ-oxygen-substituted
R,â-unsaturated esters takes place in a highly diastereo-
selective fashion to afford the anti reaction products, either
when using γ-hydroxyl unprotected starting materials or
when the γ-oxygen substituent is protected with a nonbulky
group. The δ-oxygen substituent plays a role in the stereo-
selectivity of the reaction, and better results are obtained
when this OH-group is protected.
Acknowledgment. We thank Prof. Plumet (UCM) for
valuable discussions about the paper. UCM-CAM Regional
Plan Projects CCG06-UCM/SAL-1058 and Project CTQ2006-
15279-C03-00 are gratefully acknowledged for financial
support.
Supporting Information Available: Preparative methods,
spectra of compounds 6-9, and procedures for the stereo-
chemical assignment of the reaction products. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL7016033
3670
Org. Lett., Vol. 9, No. 18, 2007