Rh-catalyzed addition of β-carbonyl pinacol alkylboronates to aldehydes: Asymmetric synthesis of γ-butyrolactones

Article abstract of DOI:10.1021/ol401468v

The rhodium-catalyzed 1,2-addition of chiral benzylic secondary alkylboronic esters with a coordinating carbonyl group to aldehydes was demonstrated with high levels of enantiospecificity. Pinacol boronic ester derivatives can be employed directly for the addition in the presence of KHF₂ without the use of corresponding trifluoroborate salts where retention of the configuration was observed. Enantiomerically enriched β,γ-diaryl-substituted γ-butyrolactones were synthesized in good yields.

Full text of DOI:10.1021/ol401468v

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Rh-catalyzed Addition of β‑Carbonyl
Pinacol Alkylboronates to Aldehydes:
Asymmetric Synthesis of γ‑Butyrolactones
Changwan Zhang and Jaesook Yun*
Department of Chemistry and Institute of Basic Science, Sungkyunkwan University,
Suwon 440-746, Korea
jaesook@skku.edu
Received May 24, 2013
ABSTRACT
The rhodium-catalyzed 1,2-addition of chiral benzylic secondary alkylboronic esters with a coordinating carbonyl group to aldehydes was
demonstrated with high levels of enantiospecificity. Pinacol boronic ester derivatives can be employed directly for the addition in the presence
of KHF2 without the use of corresponding trifluoroborate salts where retention of the configuration was observed. Enantiomerically enriched
β,γ-diaryl-substituted γ-butyrolactones were synthesized in good yields.
The rhodium-catalyzed addition of organoboron com-
pounds to Michael acceptors or carbonyl compounds has
been established as an efficient and reliable tool for
carbonÀcarbon bond formation since it was first reported
by Miyaura and co-workers.1 Excellent results using boro-
nic acids or potassium organotrifluoroborates have been
reported in the 1,4-addition and 1,2-addition.2 However,
most of the reactions are limited to aryl- or alkenylboron
derivatives that have sp2-hybridized carbon centers. While
much attention has recently been focused on transition
metal-catalyzed stereospecific reactions at stereogenic sp3
carbon centers,3 the use of alkylboron derivatives in this
type of rhodium-catalyzed reaction has been less widely
reported. For example, notable advances in the Suzuki-
Miyaura cross coupling of alkylboron derivatives have
recently been reported.4
The use of alkylboron derivatives in the rhodium-
catalyzed addition reaction is interesting but challenging
due to difficulties involved such as slow transmetalation
and side reactions resulting from β-hydride elimination
and protodeboronation. Despite these obstacles, Aggarwal
and co-workers recently reported the first stereospecific
1,2-addition of potassium alkyl trifluoroborate salts to
aldehydes in a highly stereoretentive manner.5 Encouraged
by their report, we thought that β-borylated carbonyl
compounds would be interesting molecules to investigate
(1) (a) Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997,
16, 4229–4231. (b) Sakai, M.; Ueda, M.; Miyaura, N. Angew. Chem., Int.
Ed. 1998, 37, 3279–3281. A recent review: (c) Tian, P.; Dong, H. Q.; Lin,
G. Q. ACS Catal. 2012, 2, 95–119.
(2) (a) Batey, R. A.; Thadani, A. N.; Smil, D. V. Org. Lett. 1999, 1,
1683–1686. (b) Yoshida, K.; Ogasawara, M.; Hayashi, T. J. Org. Chem.
2003, 68, 1901–1905. (c) Defieber, C.; Paquin, J.-F.; Serna, S.; Carreira,
E. M. Org. Lett. 2004, 6, 3873–3876. (d) Pucheault, M.; Darses, S.;
Genet, J.-P. Chem. Commun. 2005, 4714–4716. (e) Shintani, R.; Inoue,
M.; Hayashi, T. Angew. Chem., Int. Ed. 2006, 45, 3353–3356. (f) Brak,
K.; Ellman, J. A. J. Org. Chem. 2010, 75, 3147–3150.
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J. Am. Chem. Soc. 2009, 131, 5024–5025. (b) Ohmura, T.; Awano, T.;
Suginome, M. J. Am. Chem. Soc. 2010, 132, 13191–13193. (c) Sandrock,
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(b) Saito, B.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 6694–6695. (c) Dai,
X.; Strotman, N. A.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 3302–3303.
(d) Lu, Z.; Wilsily, A.; Fu, G. C. J. Am. Chem. Soc. 2011, 133, 8154–
8157. (e) Caeiro, J.;Sestelo, J. P.;Sarandeses, L. A.Chem.ÀEur. J. 2008, 14,
741–746. (f) Hatanaka, Y.; Hiyama, T. J. Am. Chem. Soc. 1990, 112, 7793–
7794. (g) Labadie, J. W.; Stille, J. K. J. Am. Chem. Soc. 1983, 105, 6129–
6137. (h) Goli, M.; He, A.; Falck, J. R. Org. Lett. 2011, 13, 344–346.
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R.; Hall, D. G. Nat. Chem. 2011, 3, 894–899.
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6292.
r
10.1021/ol401468v
XXXX American Chemical Society

Table 1. Optimization of the 1,2-Addition Reaction of Boronic
Esters (1) and Trifluoroborate Salts (2)a
Scheme 1
for the Rh-catalyzed addition in view of the stereochemical
effect. In the Suzuki-Miyaura coupling, β-borylated carbonyl
compounds were reported to display an intriguing stereo-
chemical inversion by the coordinating carbonyl group, as
opposed to the usual retention of configuration.4b,c Herein,
we investigated the rhodium-catalyzed 1,2-addition of chiral
alkylboronic esters to aldehydes that produce γ-butyrolac-
tones after cyclization of the resulting adducts (Scheme 1).
Our initial investigation involved carrying out the reac-
tion of boronic esters (1a, 1b) with p-nitrobenzaldehyde.
The enantiomerically enriched boronic esters were easily
prepared by following a developed protocol for the asym-
metric conjugate boration of R,β-unsaturated carbonyl
compounds6 while the corresponding trifluoroborate salts
(2) were prepared by following procedures reported in the
literature.7 Reactions of 1 and 2 were carried out in the
presence of 5 mol % [RhCl(cod)]2 in 1,4-dioxane and H2O
(7:1) at 80 °C, followed by an acid treatment (Table 1).
With pinacol boronic ester 1a itself, no substantial conver-
sion was observed under the reaction conditions (entry 1).
When the reaction was carried out in the presence of CsF
as an additive, both the yield and es8 (∼70%) increased
(entry 2), but significant racemization was still observed.
Furthermore, in the absence of water, the yield signifi-
cantly decreased as well as the es value, indicating the
importance of water in this addition (entry 3).
dr
sub-
additive
(equiv)
yield
(3-cis:
(%)b 3-trans)c
esd (%) of es (%) of
entry strate
3-cis
3-trans
1
1a
No rxn
2
1a CsF (2)
1a CsF (2)
2a
77
29
82
1.2:1 (3a)
1.2:1 (3a)
1.2:1 (3a)
1.2:1 (3a)
1.5:1 (3b)
1.5:1 (3b)
68
19
98
98
98
98
77
1
3e
4
97
97
94
94
5f
6
7f
1a KHF2 (1.2) 80
2b 87
1b KHF2 (1.2) 85
a 5 mol % [RhCl(cod)]2 (0.01 mmol) and 1.5 equiv of 1 or 2
(0.3 mmol) relative to p-nitrobenzaldehyde (0.2 mmol) were stirred in
1,4-dioxane and H2O (7:1, 2 mL) at 80 °C for 24 h. b Isolated yield of 3-cis
and 3-trans. c The diastereomeric ratio (dr) was determined by HPLC
analysis or by 1H NMR analysis. d Enantiospecificity. e Anhydrous
1,4-dioxane was used. f 5 mol % [RhCl(cod)]2 (0.01 mmol), 1.2 equiv of
p-nitrobenzaldehyde (0.24 mmol) relative to 1a or 2a (0.2 mmol) were used.
of the trifluoroborate salts, we evaluated different addi-
tives in the hopes of identifying more effective additives
than CsF in the reaction of the pinacol boronic esters.
When KHF2 was employed in the reaction, the desired
reaction took place with a high efficiency. After further
optimization of the reaction conditions, we demon-
strated that the use of 1.2 equiv of p-nitrobenzaldehyde
and 1.2 equiv of KHF2, relative to the pinacol boronic
esters, led to results comparable to the reactions using
excess trifluoroborate salts, generating products in good
yields with high es values (compare entries 5 and 7 vs 4
and 6). Again, the addition products were produced
without stereoinversion.
Diastereoselection of the addition was not high, and a
slight preference for the cis product was obtained as
indicated by the diastereomeric ratios of the 3-cis and
3-trans products (1.2À1.5:1), which did not vary much
under the different conditions. The exact boron species
that participates in the reaction remains unclear. Only a
few studies of the use of KHF2 salt in combination with
arylboronic acids (sp2CÀB) have been reported10 so far,
while no examples have been reported on the use of the salt
Then, we changed the boronic esters to trifluoroborate
salts (2a, 2b), expecting a more efficient transmetalation.
The addition products were obtained in good yields with
high es values (entries 4 and 6). Most interestingly, the chiral
center was completely retained9 and no stereoinversion was
observed. To eliminate the preparation and isolation steps
(6) (a) Mun, S.; Lee, J.-E.; Yun, J. Org. Lett. 2006, 8, 4887–4889. (b)
Lee, J.-E.; Yun, J. Angew. Chem., Int. Ed. 2008, 47, 145–147. (c) Sim,
H.-S.; Feng, X.; Yun, J. Chem.ÀEur. J. 2009, 15, 1939–1943. (d) Feng,
X.; Yun, J. Chem. Commun. 2009, 6577–6579. (e) Chen, I.-H.; Yin, L.;
Itano, W.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131,
11664–11665. (f) Feng, X.; Yun, J. Chem.ÀEur. J. 2010, 16, 13609–
13612.
(7) (a) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf,
M. R. J. Org. Chem. 1995, 60, 3020–3027. (b) Batey, R. A.; Thadani,
A. N.; Smil, D. V. Tetrahedron Lett. 1999, 40, 4289–4292. (c) Cazorla, C.;
Metay, E.; Lemaire, M. Tetrahedron 2011, 67, 8615–8621.
(8) The enantiospecificity calculated using the following equation [% es =
(ee of product/ee of starting material) Â 100] indicates the degree of
conservation of the enantiomeric purity over the course of the reactions:
Denmark, S. E.; Vogler, T. Chem.ÀEur. J. 2009, 15, 11737–11745. Also
see ref 4b.
(9) The absolute configurations of the addition products (3a-cis and
3a-trans) were determined by comparing optical rotation data reported
in the literature (see Scheme 2). In addition, hydrogenation of 3f-cis and
3f-trans gave (S)-5a, confirming the retention of the configuration of the
original stereogenic center. The other products in Table 2 were assigned
by analogy.
(10) (a) Wang, Z.-Q.; Feng, C.-G.; Zhang, S.-S.; Xu, M.-H.; Lin,
G.-Q. Angew. Chem., Int. Ed. 2010, 49, 5780–5783. (b) Yang, H.-Y.; Xu,
M.-H. Chem. Commun. 2010, 46, 9223–9225.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. 1,2-Addition of the Pinacol Boronic Esters (1) to
Aldehydes
Scheme 2. Derivatization of 3a-cis and 3a-trans Lactones
yield
(%)a
drb (3-cis:3-
3-cis
(er)c
3-trans
(er)c
entry
1
R2
trans)
1
2
1a 3-NO2 69
1a 2-NO2 73
1.5:1 (3c)
1.4:1 (3d)
1.5:1 (3e)
1.3:1 (3f)
1.4:1 (3g)
1:1 (3a)
93:7
93.5:6.5
92:8
a slightly decreased yield was obtained (entry 4). β-Cyano
alkylboronate (1c) was a reactive substrate as well, yielding
γ-butyrolactones with a high enantiospecificity but with a
lower yield than the corresponding ester derivative (entry 6).
The reaction of benzylic boronate (1e) with an electron-
withdrawing aryl substituent was less selective and afforded
products with decreased enantiospecificities (entry 9). How-
ever, a simple secondary alkylboron compound was inactive
in the addition (entry 10).
In this rhodium-catalyzed reaction, the boronate esters
play the role of homoenolate equivalents12 and their
original configuration is retained throughout the reaction.
If the current addition takes place by a similar mechanism
tothe additions of arylboronicacids toelectrophiles, where
transmetalation of an organic group from boron to rho-
dium is involved, a retentive transmetalation event still
occurs in the rhodium catalysis even in the presence of an
intramolecularly coordinating carbonyl group to the bo-
ron center.13 This is in contrast to the palladium-catalyzed
Suzuki-Miyaura coupling via stereoinvertive transmetala-
tion due to intramolecular coordination of the β-carbonyl
group.
90:10
3
1a 4-CN
1a
1b 4-CN
77
50
80
92.5:7.5 92.5:7.5
4
H
90:10
89:11
95:5
91:9
89:11
94:6
5
6
1c 4-NO2 45
1d 4-NO2 82
1d 4-CF3 76
1e 4-NO2 56
7
1.4:1 (3h)
1.2:1 (3i)
1.2:1 (3j)
93:7
91.5:8.5
90:10
85:15
8
91.9
9
87:13
10
1f 4-NO2
n.fd
a Isolated yield of 3-cis and 3-trans. b The diastereomeric ratio (dr)
was determined by 1H NMR. c The enantiomeric ratio (er) was deter-
mined by chiral HPLC analysis. d Not formed. 1f and protodeboronated
byproduct were only detected.
with pinacol boronic esters in the rhodium-catalyzed
addition. While in situ generation of organotrifluoroborate11
may be possible, the involvement of intermediate boron
species with fluoride coordination cannot be ruled out in
the reaction.
With the optimized reaction conditions using KHF2 as
an additive, reactions of a range of different pinacol
boronic esters and aldehydes were carried out (Table 2).
Most of the reactions directly produced cyclized lactones
as the major product after the first step, but the reaction
mixture was further treated with an acid for the complete
cyclization of acyclic γ-hydroxy esters. Benzylic boron
derivatives were reactive in this addition, and electron-
donating substituents are allowed on the aromatic ring. A
range of chiral β,γ-diarylsubstituted γ-butyrolactones
could be synthesized by applying this protocol. In general,
the addition was most successful for activated aldehydes
possessing an electron withdrawing substituent, resulting
in a good addition yield and high es values (>96%).
Sterically encumbered 2-nitrobenzaldehyde was a suitable
substrate as well, producing the 1,2-addition products in
good yield (entry 2). Particularly noteworthy is that the less
activated simple benzaldehyde resulted in adducts with
high enantiospecificities (es values of 91 and 93%) although
Chiral γ-butyrolactones are important structures found
in many natural and biologically active compounds.14 For
additional applications of the resulting products, func-
tional group transformations were carried out. When the
nitro group of the 3a-cis and 3a-trans products were
subjected to reduction, interestingly, both diastereomers
resulted in 4a-trans as a single diastereomer through
epimerization of the cis-isomer (Scheme 2).15 Removal
(12) (a) DiMauro, E.; Fry, A. J. Tetrahedron Lett. 1999, 40, 7945–
7949. (b) Otsubo, K.; Inanaga, J.; Yamaguchi, M. Tetrahedron Lett.
1986, 27, 5763–5764. (c) Hoppe, D. Angew. Chem., Int. Ed. Engl. 1984,
23, 932–948. (e) Burstein, C.; Glorius, F. Angew. Chem., Int. Ed. 2004,
43, 6205–6208. (f) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem.
Soc. 2004, 126, 14370–14371.
(13) For an alternative mechanism without transmetalation to rho-
dium, see ref 5.
(14) (a) Brown, H. C.; Kulkarni, S. V.; Racherla, U. S. J. Org. Chem.
1994, 59, 365–369. (b) Kitson, R. R. A.; Millemaggi, A.; Taylor, R. J. K.
Angew. Chem., Int. Ed. 2009, 48, 9426–9451. (c) Ward, R. S. Nat. Prod.
Rep. 1997, 14, 43–74.
(11) Recent reviews of organotrifluoroborates: (a) Stefani, H. A.;
Cella, R.; Vieira, A. S. Tetrahedron 2007, 63, 3623–3658. (b) Molander,
G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275–286. (c) Molander, G. A.;
Canturk, B. Angew. Chem., Int. Ed. 2009, 48, 9240–9261.
(15) The reduction of isolated 3a-cis also gave 4a-trans as a single
product with a yield of ∼60%, which indicates the epimerization of the
carbinol center during the reaction.
Org. Lett., Vol. XX, No. XX, XXXX
C

of the amino group produced 3f without erosion of the
initial ee value16 and hydrogenation of 3f produced 5a, the
absolute configuration of which was verified by compar-
ison with literature data.17
In summary, we showed that rhodium-catalyzed 1,2-
addition of chiral alkylboronic esters with a β-coordinat-
ing carbonyl group toaldehydes efficiently takes placewith
a high level of stereoretention. The direct use of organo-
boronic esters in the presence of KHF2 is convenient
and economical, as it obviates extra preparation and
isolation steps of the corresponding organofluoroborate
salts with a large excess of KHF2. This current method
offers an interesting homoenolate pathway to chiral
γ-butyrolactones.
Acknowledgment. This research was supported by the
Samsung Research Fund, Sungkyunkwan University
(2008) and by the BasicScience ResearchProgramthrough
the National Research Foundation of Korea (NRF)
funded by the Ministry of Education, Science and Tech-
nology (NRF-20110009533).
Supporting Information Available. Experimental pro-
cedures and chracterization of the products. This material
is available free of charge via the Internet at http://pubs.
acs.org.
(16) Chang, C.-J.; Fang, J.-M.; Liao, L.-F. J. Org. Chem. 1993, 58,
1754–1761.
(17) Pippel, D. J.; Curtis, M. D.; Du, H.; Beak, P. J. Org. Chem. 1998,
63, 2–3.
The authors declare no competing financial interest.
D
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