Trifluoroacetic anhydride promoted tandem conjugate addition of boronic acids/acetal ring opening

Article abstract of DOI:10.1021/ol300272j

A new stereoselective tandem reaction consisting of the metal-free conjugate addition of boronic acids followed by an intramolecular ring opening of a cyclic acetal has been disclosed. Optically pure polysubstituted tetrahydropyrans have been synthesized

Full text of DOI:10.1021/ol300272j

ORGANIC
LETTERS
2012
Vol. 14, No. 5
1187–1189
Trifluoroacetic Anhydride Promoted
Tandem Conjugate Addition of Boronic
Acids/Acetal Ring Opening†
ꢀ
Silvia Roscales and Aurelio G. Csaky*
´
Laboratorio de Sıntesis Organica, Unidad de Cartografıa Cerebral,
Instituto Pluridisciplinar, Universidad Complutense, 28040 Madrid, Spain
ꢀ
´
csaky@quim.ucm.es
Received November 24, 2011
ABSTRACT
A new stereoselective tandem reaction consisting of the metal-free conjugate addition of boronic acids followed by an intramolecular ring opening
of a cyclic acetal has been disclosed. Optically pure polysubstituted tetrahydropyrans have been synthesized diastereoselectively by this new
reaction. Two new CÀC bonds and up to three stereocenters are formed in a single step, allowing the generation of quaternary stereocenters.
The conjugate addition of carbon nucleophiles to electron-
deficient alkenes constitutes one of the most relevant syn-
thetic methods for CÀC bond formation.1 Among the dif-
ferent reagents that have been developed for this purpose,
boronic acids have attracted a great deal of attention due
to their low toxicity, thermal stability, and ample com-
patibility with functional groups that are normally labile
to other organometallic nucleophiles.2 Direct conjugate
addition of boronic acids is normally precluded by their
low nucleophilicity, and activation is normally required.
This has been achieved by transmetalation to transition
metals, mainly Rh and Pd, in catalytic cycles.3,4 Although
less common, promotion of the conjugate addition reac-
tion of boronic acids by organic molecules has also been
(4) For recent reviews on Pd-catalyzed reactions, see: (a) Yamamoto,
Y.; Nishikata, T.; Miyaura, N. J. Synth. Org. Chem. Jpn. 2006, 64, 1112.
(b) Gutnov, A. Eur. J. Org. Chem. 2008, 4547. (c) Yamamoto, Y.;
Nishikata, T.; Miyaura, N. Pure Appl. Chem. 2008, 80, 807. (d) Miyaura,
N. Synlett 2009, 2039.
†
ꢀ
Dedicated to Prof. Carmen Najera (Universidad de Alicante) in honor of
her 60th birthday.
(1) For recent reviews, see: (a) Carreira, E. M.; Kvaerno, L. In
Classics in Stereoselective Synthesis; Wiley-VCH: Weinheim, 2009; Chap-
ter 12, p 389. (b) Thaler, T.; Knochel, P. Angew. Chem., Int. Ed. 2009, 48,
645. (c) Jerphagnon, T.; M. Pizzuti, G.; Minnaard, A. J.; Feringa, B. L.
Chem. Soc. Rev. 2009, 38, 1039. (d) Hawner, C.; Alexakis, A. Chem.
Commun. 2010, 46, 7295.
(5) (a) Hara, S.; Hyuga, S.; Aoyama, M.; Sato, M.; Suzuki, A.
Tetrahedron Lett. 1990, 31, 247. (b) Hara, S.; Shudoh, H.; Ishimura,
S.; Suzuki, A. Bull. Chem. Soc. Jpn. 1998, 71, 2403.
(6) (a) Wu, T. R.; Chong, J. M. J. Am. Chem. Soc. 2005, 127, 3244.
(b) Wu, T. R.; Chong, J. M. J. Am. Chem. Soc. 2007, 129, 4908.
(c) Pellegrinet, S. C.; Goodman, J. M. J. Am. Chem. Soc. 2006, 128,
3116. (d) Paton, R. S.; Goodman, J. M.; Pellegrinet, S. C. J. Org. Chem.
2008, 73, 5078. (e) Kim, S.-G. Tetrahedron Lett. 2008, 49, 6148. (f) Lee, S.;
MacMillan, D.W. C. J. Am. Chem. Soc. 2007, 129, 15438. (g) Inokuma
T.; Takasu, K.; Sakaeda, T.; Takemoto, Y. Org. Lett. 2009, 11, 2425.
(h) Sugiura, M.; Tokudomi, M.; Nakajima, M. Chem. Commun. 2010,
46, 7799. (i) Lundy, B. J.; Jansone-Popova, S.; May, J. A. Org. Lett.
2011, 13, 4958.
(2) (a) Hall, D. G. In Boronic Acids; Hall, D. G., Ed.; Wiley-VCH:
Weinheim, 2005; Chapter 1, p 1. (b) Ishiyama, T.; Miyaura, N. In Boronic
Acids; Hall, D. G., Ed.: Wiley-VCH: Weinheim, 2005; Chapter 2, p 101.
(c) Miyaura, N. Bull. Chem. Soc. Jpn. 2008, 81, 1535. (d) Primas, N.;
Bouillon, A.; Rault, S. Tetrahedron 2010, 66, 8821. (e) Molander, G. A.;
Trice, S. L. J.; Dreher, S. D. J. Am. Chem. Soc. 2010, 132, 17701.
(3) For recent reviews on Rh-catalyzed reactions, see: (a) Fagnou,
K.; Lautens, M. Chem. Rev. 2003, 103, 169. (b) Hayashi, T.; Yamasaki,
K. Chem. Rev. 2003, 103, 2829. (c) Hayashi, T. Pure Appl. Chem. 2004,
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K.; Hayashi, T. In Modern Rhodium-Catalyzed Organic Reactions; Evans,
P. A., Ed.: Wiley-VCH: Weinheim, 2005; Chapter 3, p 55. (f) Yoshida, K.;
Hayashi, T. In Boronic Acids; Hall, D. G., Ed.; Wiley-VCH: Weinheim, 2005;
Chapter 4, p 171. (g) Edwards, H. J.; Hargrave, J. D.; Penrose, S. D.; Frost,
C. G. Chem. Soc. Rev. 2010, 39, 2093. (h) Hargrave, J. D.; Allen, J. C.;
Frost, C. G. Chem. Asian J. 2010, 5, 386. (i) Magano, J.; Dunetz, J. M.
Chem. Rev. 2011, 111, 2177.
(7) See for example: (a) Seiple, I. B.; Rodrıguez, R. A.; Gianastassio,
R.; Fujiwara, Y.; Sobel, A. L.; Baran, P. S. J. Am. Chem. Soc. 2010, 132,
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(d) Molander, G. A.; Colombel, V.; Braz, V. A. Org. Lett. 2011, 13, 1852.
€
(e) Luthy, M.; Darmency, V.; Renaud, P. Eur. J. Org. Chem. 2011, 547.
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M.; Baran, P. S. J. Am. Chem. Soc. 2011, 133, 3292 and references
therein.
r
10.1021/ol300272j
2012 American Chemical Society
Published on Web 02/16/2012

Table 1. Tandem Conjugate Addition/Acetal Ring Openinga
entry
1 (R1)
2
R2, R3
R4
3 (dr)b
yieldc (%)
1
1a (PhCHdCH)
2a
2a
2a
2a
2a
2a
2b
2b
2b
2c
2c
2c
2d
2a
Me, Me
Me, Me
Me, Me
Me, Me
Me, Me
Me, Me
-(CH2)5-
-(CH2)5-
-(CH2)5-
Me, Et
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Ph
3aa (>98:02)
3ba (>98:02)
3ca (>98:02)
3da (>98:02)
3ea (>98:02)
80
70
85
70
75
2
1b (biphenyl-CHdCH)
1c (p-F-C6H4CHdCH)
1d (p-Me-C6H4CHdCH)
1e (p-Cl-C6H4CHdCH)
1f (p-MeO-C6H4CHdCH)
1a (PhCHdCH)
3
4
5
6
7
3ab (>98:02)
3bb (>98:02)
3cb (>98:02)
3ac (90:10)d
3cc (95:05)d
3dc (90:10)d
75
75
75
80
65
75
8
1b (biphenyl-CHdCH)
1c (p-F-C6H4CHdCH)
1a (PhCHdCH)
9
10
11
12
13
14
1c (p-F-C6H4CHdCH)
1d (p-Me-C6H4CHdCH)
1a (PhCHdCH)
Me, Et
Me, Et
Me, Me
Me, Me
f
1g (Ph)
a Reaction conditions: 1 (1.25 equiv), 2 (1.0 equiv), (CF3CO)2O (3.0 equiv), CH2Cl2 (1.7 mL/mmol), rt, 18 h. b Determined by integration of the 1H
NMR spectra (CDCl3, 300 MHz) of the reaction crudes. c Isolated yield after column chromatography. d Diastereomers separated by column
chromatography. f 1f (4.0 equiv).
reported, either in stoichiometric5 or catalytic variants.6
Generation of radicals from boronic acids and their deri-
vatives has also been used to effect some 1,4-additions.7
Among the different types of conjugate addition reac-
tions, tandem processes are particularly attractive,8 as these
methods permit the construction of several CÀC bonds in a
one-pot process and the simultaneous generation of various
stereocenters without isolation of intermediates. We dis-
close herein a new stereoselective tandem reaction which
consists of the conjugate addition of boronic acids followed
by the intramolecular ring opening of acetals9 under metal-
free conditions (trifluoroacetic anhydride-promotion). Two
new CÀC bonds and up to three stereocenters are formed in
this single-step process, which allows the generation of
quaternary sterocenters. Optically pure polysubstituted tet-
rahydropyran rings are synthesized diastereoselectively.
These constitute important synthetic targets, as the
tetrahydropyran skeleton is found among a wide variety
of biologically relevant natural products and pharmaceu-
tically active ingredients. Consequently, considerable efforts
have been made in recent times toward the stereoselective
preparation of these compounds.10
The results of the conjugate addition of several boronic
acids 1 to compounds 2 are given in Table 1. The addition
of boronic acids 1aÀd to the isopropylidene acetal 2a in the
presence of trifluoroacetic anhydride afforded exclusively
the corresponding tetrahydropyrans in high yield and as a
single diastereomer (entries 1À5).
On the other hand, no reaction was observed when the
reaction was carried out with boronic acid 1f (entry 6).
Extensive protodeborylation of this electron-rich boronic
acid in the presence of the trifluoroacetic acid generated in
the process may account for this result.2 When the isopro-
pylidene acetal was replaced by a cyclohexylidene acetal
(compound 2b), tetrahydropyran formation also took
place in high yield and diastereoselectivity (entries 7À9).
We observed that this reaction was also of use for the
stereoselective generation of a quaternary stereocenter in a
highly efficient fashion (entries 10À12). For this purpose,
we chose compound 2c as starting material,11 with a very
small difference in the electronic or steric character of
R2 (Me) and R3 (Et). We found that these reactions took
place with good dr. Only two of all possible diastereomers
were generated, which only differed in the relative disposition
of R2 and R3. In particular, we noticed that the reaction of 2c
(8) For recent reviews, see: (a) Guo, H.-C. ; Ma, J.-A. Angew. Chem.,
€
Int. Ed. 2006, 45, 354. (b) Enders, D.; Grondal, C.; Huttl, M. R. M.
Angew. Chem., Int. Ed. 2007, 46, 1570. (c) Miura, T.; Murakami, M.
ꢀ
Chem. Commun. 2007, 217. (d) Toure, B. B.; Hall, D. G. Chem. Rev.
2009, 99, 4439. (e) Youn, S. W. Eur. J. Org. Chem. 2009, 2597. (f)
Fustero, S.; Sanchez-Rosello, M.; del Pozo, C. Pure Appl. Chem. 2010,
82, 669.
(9) See for example: (a) Carreira, E. M.; Kvaerno, L. In Classics in
Stereoselective Synthesis; Wiley-VCH: Weinheim, 2009; Chapter 6, p 187.
(b) Kobayashi, S.; Arai, K.; Yamakwa, T.; Chen, Y. -J.; Salter, M. M.;
Yamashita, Y. Adv. Synth. Catal. 2011, 353, 1927 and references therein.
(10) For recent leading references, see for example: (a) Jørgensen,
K. A. Angew. Chem., Int. Ed. 2000, 39, 3558 (review). (b) Yang, X. -F.;
Mague, J. T.; Li, C. -J. J. Org. Chem. 2001, 66, 739. (c) Haustedt, L. O.;
Hartung, I. V.; Hoffmann, H. M. R. Angew. Chem., Int. Ed. 2003, 42,
2711. (d) Clarke, P. A.; Santos, S. Eur. J. Org. Chem. 2006, 2045 (review).
(e) Trost, B. M.; Machacek, M. R.; Faulk, B. D. J. Am. Chem. Soc. 2006,
128, 6745. (f) Wang, L.; Li, P.; Menche, D. Angew. Chem., Int. Ed. 2010,
49, 9270. (g) Clarke, P. A. Tetrahedron 2011, 67, 4959(Editorial,
Symposium-in-Print) and references therein.
(11) Compound 2c was used as a 1:1 mixture of diastereomers,
epimers at carbon-2 of the [1,3]dioxolan-4-yl moiety.
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Org. Lett., Vol. 14, No. 5, 2012

with the electron-deficient boronic acid 1c gave the corre-
sponding tetrahydropyran 3cc (entry 11) with very high dr.
On the other hand, no reaction was observed for the
methyl ketone 2d (entry 13) under similar conditions. The
reaction of 2a with phenylboronic acid 1g (entry 14) led to
deprotection of the acetal group of the starting material
together with the conjugate addition product of 1f to the
latter (10% yield, 50:50 of epimers at the β-carbon).
A reaction mechanism which accounts for the formation
of compounds 3 and the observed stereochemistry is
proposed in Scheme 1. Reaction of (CF3CO)2O with the
boronic acid 1 may give a mono- or a diacylboronate12
intermediate A, where the Lewis acidity of the boron atom
is enhanced with respect to 1. Coordination of this
species13 with the γ-oxygen of 2 gives intermediate B.
The intramolecular delivery (syn-addition, vide infra) of
the R1 group will be facilitated by the lone pair on the
δ-oxygen, leading to intermediate C. Intramolecular ring-
closure finally accounts for the formation of compounds 3.
The stereochemistry has been found to depend on both the
substrate and reagent structures. In this reaction, we have
observed a highly selective trans relative disposition between
R1 and OH in the final cyclic product 3. This is consistent
with a substrate-controlled chelated syn conjugate addition
step, as depicted on intermediate B (Scheme 1).
The final cyclization can be envisioned by an approach
of the enolate to the sp2 carbon of the electrophilic moiety
in a chairlike transition state D. The pseudoequatorial
disposition of the substituents minimizes the steric interaction
between R1 and the enolate, affording a trans relative dis-
position of R1 and COPh in the tetrahydropyrans 3.
In the case of the reactions with 2c as starting material,11
the high dr in the generation of the quaternary stereocenter
can be understood by placement of the smallest substituent
(R2 = Me) in a pseudoaxial disposition.
Finally, it is also worth mentioning that formation of
ethers 4 via cross-coupling of the boronic acids with the
acetal function (Scheme 2) was not observed under these
reaction conditions.13
Scheme 1. Proposed Mechanism
Scheme 2. Formation of Ethers 4
In conclusion, we have disclosed an unprecedented tan-
dem process initiated by the conjugate addition of a boronic
acid under metal-free conditions that affords polysubsti-
tuted tetrahydropyran rings in high dr and permits the
formation of quaternary stereocenters. The reaction gener-
ates two CÀC bonds and up to three stereocenters in a one-
pot process. The corresponding tetrahydropyrans are pre-
pared enantioselectively, as the reactions are carried out
using enantiopure reactants easily derived from the chiral
pool. The functionalization present in these tetrahydropyr-
ans 3 can be further manipulated, thus adding synthetic
value to the process.
With regard to the stereochemistry, the conjugate addi-
tion of carbon nucleophiles to acyclic γ-alkoxysubstituted-
R,β-unsaturated carbonyl compounds to afford either the
syn or the anti products has been amply documented.14,15
Acknowledgment. S.R. is thankful to the government of
Spain and for FPU grant No. AP20090051. Project CTQ-
2010-16170 from the Spanish government (MICINN) and
GR35/10-A from UCM are gratefully acknowledged for
financial support. Prof. J. Plumet (Departamento de Quımica
(12) (a) Ishihara, K.; Ohara, S.; Yamamoto, H. J. Org. Chem. 1996,
61, 4196. (b) Arnold, K.; Davies, B.; Giles, R. L.; Grojean, C.; Smith,
G. E.; Whiting, A. Adv. Synth. Catal. 2006, 348, 813. (c) Al-Zoubi,
R. M.; Marion, O.; Hall, D. G. Angew. Chem., Int. Ed. 2008, 47, 2876.
(13) For the coordination of boronic acid derivatives with acetals, see:
(a) Mitchell, T. A.; Bode, J. W. J. Am. Chem. Soc. 2009, 131, 18057. (b) Vo,
C.-V. T.; Mitchell, A.; Bode, J. W. J. Am. Chem. Soc. 2011, 133, 14082.
(14) (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. (d) Kireev, A. S.; Manpadi, M.; Kornienko, A. J. Org.
Chem. 2006, 71, 2630 and references therein.
ꢀ
Organica, Facultad de Ciencias Quımicas, Universidad
Complutense de Madrid) is thanked for useful comments
and suggestions.
Supporting Information Available. Experimental pro-
cedures, characterization of all new compounds and
assignment of the stereochemistry. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(15) For the anti-selective conjugate addition of boronic acids to γ,δ-
oxygen-substituted R,β-enoates under Rh(I) catalysis, see: Segura, A.;
ꢀ
The authors declare no competing financial interest.
Csaky, A. G. Org. Lett. 2007, 9, 3667.
Org. Lett., Vol. 14, No. 5, 2012
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