Asymmetric fluoroallylboration of aldehydes

Article abstract of DOI:10.1021/ol201551y

Contrary to previous reports, the homologation of benzyloxydifluorovinyllithium with bulky chiral iodomethylboronates readily provides a series of chiral γ,γ-difluoroallylboronates. Asymmetric fluoroallylboration of aldehydes with a 2-phenylbornane-2,3-diol-derived reagent provides gem-difluorinated homoallyl alcohols in good yields and 77-95% ee. Preparation of a chiral α-pyrone in >99% ee has also been described.

Full text of DOI:10.1021/ol201551y

ORGANIC
LETTERS
2011
Vol. 13, No. 15
4044–4047
Asymmetric Fluoroallylboration of
Aldehydes
P. Veeraraghavan Ramachandran,* Agnieszka Tafelska-Kaczmarek, and
Kaumba Sakavuyi
Herbert C. Brown Center for Borane Research, Department of Chemistry,
Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907-2084, United States
chandran@purdue.edu
Received June 9, 2011
ABSTRACT
Contrary to previous reports, the homologation of benzyloxydifluorovinyllithium with bulky chiral iodomethylboronates readily provides a series
of chiral γ,γ-difluoroallylboronates. Asymmetric fluoroallylboration of aldehydes with a 2-phenylbornane-2,3-diol-derived reagent provides gem-
difluorinated homoallyl alcohols in good yields and 77ꢀ95% ee. Preparation of a chiral R-pyrone in >99% ee has also been described.
Asymmetric allylboration is an important carbonꢀ
carbon bond-forming reaction for organic syntheses.1 Par-
tially fluorinated biologically active molecules are often
enhanced in their potency and bioavailability.2 As part of
our ongoing projects on fluoroorganic synthesis via
boranes,3 we had reported the preparation of chiral fluori-
nated homoallyl alcohols via the asymmetric allylboration
of fluoro aldehydes.4 We recently described the preparation
of a fluorinated allylborating agent, β-benzyloxy-γ,γ-difluor-
oallylboronate (1),5 for the synthesis of R-gem-difluorinated
homoallyl alcohols and dihydropyrones.6 In continuation,
we herein report the successful synthesis of chiral γ,γ-difluor-
oallylboronates and the subsequent allylboration of alde-
hydes for the preparation of highly enantioenriched gem-
difluorinated homoallyl alcohols7 and derivatives.
The simplest protocol envisioned to prepare the chiral
analogues of the difluoroallylboronate reagent was to
transesterify the isopropoxy groups with a chiral diol
(Scheme 1).8 On the basis of the success of the tartrate
esters in allylborations,9 diisopropyl tartrate (2a) was
(1) For reviews, see: (a) Ramachandran, P. V. Aldrichim. Acta 2002,
35, 23. (b) Brown, H. C.; Zaidlewicz, M. Organic Syntheses via Boranes:
Recent Developments; Aldrich Chemical Co.: Milwaukee, WI, 2001; Vol. 2.
(c) Roush, W. R. In Methods of Organic Chemistry, Houben-Weyl, 4th
ed.; Helmchen, G., Hoffman, R. W., Mulzer, J., Schaumann, E., Eds.; Georg
Thieme Verlag: Stuttgart, 1996; Supplement E 21, Vol. 3, p 1410.
(2) (a) Tozer, M. J.; Herpin, T. F. Tetrahedron 1996, 52, 8619. (b)
Schirlin, D.; Baltzer, S.; Altenburger, J. M.; Tarnus, C.; Remy, J. M.
Tetrahedron 1996, 52, 305. (c) Romanenko, V. D.; Kukhar, V. P. Chem.
Rev. 2006, 106, 3868. (d) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359.
(e) O’Hagan, D. J. Fluorine Chem. 2010, 131, 1071.
(6) Ramachandran, P. V.; Tafelska-Kaczmarek, A.; Sakavuyi, K.;
Chatterjee, A. Org. Lett. 2011, 13, 1302.
(7) For reports on the preparation of optically active gem-difluor-
ohomoallyl alcohols via enzymatic resolution, see: (a) Kirihara, M.;
Kawasaki, M.; Katsumata, H.; Kakuda, H.; Shiro, M.; Kawabata, S.
Tetrahedron: Asymmetry 2002, 13, 2283. (b) Itoh, T.; Kudo, K.; Tanaka,
N.; Sakabe, K.; Takagi, Y.; Kihara, H. Tetrahedron Lett. 2000, 41, 4591.
(c) You, Z.-W.; Jiang, Z.-X.; Wang, B.-L.; Qing, F.-L. J. Org. Chem.
2006, 71, 7261. (d) Itoh, T.; Kudo, K.; Yokota, K.; Tanaka, N.; Hayasa,
S.; Renou, M. Eur. J. Org. Chem. 2004, 406. (e) Kaneda, T.; Komura, S.;
Kitazume, T. J. Fluorine Chem. 2005, 126, 17.
(3) (a) Ramachandran, P. V.; Jennings, M. P.; Brown, H. C. Org.
Lett. 1999, 1, 1399. (b) Ramachandran, P. V.; Jennings, M. P. Org. Lett.
2001, 3, 3789. (c) Ramachandran, P. V.; Parthasarathy, G.; Gagare,
P. D. Org. Lett. 2010, 12, 4474.
(4) Kumar, D. J. S.; Madhavan, S.; Ramachandran, P. V.; Brown,
H. C. Tetrahedron: Asymmetry 2000, 11, 4629.
(5) (a) Ramachandran, P. V.; Chatterjee, A. Org. Lett. 2008, 10, 1195.
(b) Ramachandran, P. V.; Chatterjee, A. J. Fluorine Chem. 2009,
130, 144.
ꢀ
(8) (a) Nyzam, V.; Belaud, C.; Zammattio, F.; Villieras, J. Bull. Soc.
Chim. Fr. 1997, 134, 583. (b) Mears, R. J.; Sailes, H. E.; Watts, J. P.;
Whiting, A. J. Chem. Soc., Perkin Trans. 1 2000, 3250.
(9) (a) Roush, W. R.; Walts, A. E.; Hoong, L. K. J. Am. Chem. Soc.
1985, 107, 8186. (b) Roush, W. R.; Palkowitz, A. D.; Palmer, M. A. J. J.
Org. Chem. 1987, 52, 316. (c) Roush, W. R.; Hoong, L. K.; Palmer,
M. A. J.; Park, J. C. J. Org. Chem. 1990, 55, 4109. (d) Roush, W. R.;
Hoong, L. K.; Palmer, M. A. J.; Straub, J. A.; Palkowitz, A. D. J. Org.
Chem. 1990, 55, 4117.
r
10.1021/ol201551y
Published on Web 07/12/2011
2011 American Chemical Society

result suggests that the ease of homologation of 4b is
attributable to the benzyloxy group on the vinyl moiety.
Further examination of this phenomenon is necessary.
Allylboration of benzaldehyde (5a), monitored by 11B
NMR spectroscopy (disappearance of peak at δ 33.5 ppm
and appearance of the peak at δ 22.5 ppm), proceeded to
completion within 12 h. An oxidative workup provided the
chiral difluorinated homoallyl alcohol 6a in 68% isolated
yield as an oil. Determination of the enantiomeric purity
using gas chromatographic (GC) analysis on a CP-Chir-
asil-Dex CB column revealed an ee of 93% in the S-isomer
(vide infra).
Scheme 1. Failed Trans-Esterification of Difluoroallylboronate
The constitutional isomer of the bornanediol chiral
auxiliary 2c (Figure 1) was also converted to the iodo-
methylboronate 4c and allylboronate 3c as before.
Allylboration of benzaldehyde furnished 42% of the
fluorinated homoallyl alcohol 6a in 27% ee in the R-
isomer.
treated with 1 in tetrahydrofuran (THF) at room tempera-
ture (rt) for 4 h. However, there was no evidence of any
transesterification even under reflux for 4 h. Changing the
solvents also did not facilitate the reaction. Contrary to the
report by Kennedy and Hall, transesterification with the
(þ)-camphor-derived 2-phenylbornane-2,3-diol 2b10 also
met with the same fate.11
We then opted to prepare the chiral allylboronate via
the homologation12 of benzyloxydifluorovinyllithium (de-
rived from trifluoroethanol)5a using the camphor diol
iodomethylboronate 4b reported previously.11,13 Hall had
reported the failed homologation of a vinylcuprate using
4b.11 Roush also had reported the failed homologation of
silylvinylcuprate and silylvinyllithium employing 4b.13
However, we were interested in understanding the effect,
if any, of the fluorine atoms or the benzyloxy group of the
benzyloxydifluorovinyllithium on the homologation.
To our delight, the transesterification of diisopropyl
iodomethylboronate14 with 2b followed by homologation
of benzyloxydifluorovinyllithium in THF (Scheme 2) af-
forded the necessary reagent 3b. To delineate the effect of
the fluorine and benzyloxy groups on the success of the
homologation reaction, we examined the preparation of
the parent γ,γ-difluoroallylboronate reagent (3b0). Treat-
ment of 2,2-difluorovinyllithium15 (prepared by the reac-
tion of 1,1-difluoroethylene and sec-butyllithium) with 4b
provided a very low yield (e20%) of 3b0 (Scheme 2). This
Figure 1. Camphor-derived chiral auxiliaries.
Clearly, the presence of the phenyl group adjacent to
the bridgehead methyl group is important in achieving
high ee. With the hope of improving the enantioselectivity
in the asymmetric fluoroallylboration, novel bornanediols
were prepared substituting the phenyl group in 2b with a
3,5-dimethylphenyl (2d) and 2-naphthyl (2e) groups
(Figure 1).16 These were then converted to the chiral
iodomethylboronates 4d and 4e, respectively, and even-
tually transformed to the corresponding fluoroallylborat-
ing agents 3d and 3e, respectively. Upon allylboration of
benzaldehyde, the use of 3d provided 6a in 50% yield and
90% ee, whereas 3e provided a 53% yield and 79% ee for the
homoallyl alcohol. The results are summarized in Table 1.
We had previously reported a rapid fluoroallylbora-
tion in pentane with an achiral reagent.5a This prompted
us to study the effect of solvents on the asymmetric
Scheme 2. Preparation and Reaction of Chiral Difluoroallyl-
boronate
(10) Herold, T.; Schrott, U.; Hoffmann, R. W. Chem. Ber 1981, 114,
359.
(11) Kennedy, J. W. J.; Hall, D. G. J. Org. Chem. 2004, 69, 4412.
(12) Wuts, P. G. M.; Thompson, P. A.; Callen, G. R. J. Org. Chem.
1983, 48, 5398.
(13) Lira, R.; Roush, W. R. Org. Lett. 2007, 9, 4315.
(14) Soundararajan, R.; Li, G.; Brown, H. C. J. Org. Chem. 1996, 61,
100.
(15) Sauvetre, R.; Normant, J. F. Tetrahedron Lett. 1981, 22, 957.
(16) Lachance, H.; St-Onge, M.; Hall, D. G. J. Org. Chem. 2005, 70,
4180.
(17) Reist, E. J.; Bartuska, V. J.; Goodman, L. J. Org. Chem. 1964,
29, 3725.
(18) See the Supporting Information for the ORTEP diagram of 7.
Org. Lett., Vol. 13, No. 15, 2011
4045

Scheme 3. Stereochemical Correlation of 7 and 9
fluoroallylboration. Benzaldehyde was reacted with 3b in
pentane, THF, and CH2Cl2. The reagent is only sparingly
soluble in pentane, and the reaction in CH2Cl2 provided a
slightly better yield and ee for 6a than in THF (Table 1).
The formation of (S)-7 can be rationalized by the
transition-state model depicted in Figure 2.11,20 It is note-
worthy that the two fluorine atoms in the reagent have no
influence in the stereochemical outcome of the reaction.21
Table 1. Asymmetric Difluoroallylboration of Benzaldehyde
(5a): Optimization of Reagent and Conditionsa
homoallyl alcohol 6a
entry
reagent 3
solvent
yieldb (%)
eec (%)
isomer
1
2
3
4
5
6
3b
3b
3b
3c
3d
3e
CH2Cl2
THF
68
93
92
Sd
S
62
e
pentane
CH2Cl2
CH2Cl2
CH2Cl2
42
50
53
27
90
79
Rf
S
Figure 2. Transition-state model for the formation of 6a.
S
a Reactions were carried out at rt with 1.5 equiv of crude reagent for
12 h. b Isolated yields of pure products. c Determined by GC analysis on a
CP-Chirasil-Dex CB column. d On the basis of X-ray crystallographic
analysis of 7 derived from 6a and stereochemical correlation (Scheme 3).
e No reaction due to the poor solubility of the reagent in pentane. f On the
basis of GC analysis.
With the standardized conditions for achieving the
optimal ee in hand, we probed the generality of reagent
3bwitha seriesof aldehydesofvarying stericand electronic
environments (Table 2). Strongly electron-withdrawing
groups and steric demands affected the ee. Substitution
of benzaldehyde at the o-, m-, and p-positions with an
electron-donating methoxy group (5bꢀd) did not have any
significant impact on the ee of the product alcohol. How-
ever, p-tolualdehyde (5e) provided an improved yield
(79%) and 92% ee for the alcohol. Halogens, such as
chlorine and fluorine in the para-position (5h and 5g,
respectively) also did not affect the ee. A p-CF3 group
(5f) decreased the ee slightly (88%), whereas a p-NO2
group (5i) substantially lowered the ee to 78%. A decrease
in ee was also observed when both the ortho-positions were
blocked with methyl groups (5j). 1-Naphthaldehyde (5k)
and an R,β-unsaturated aldehyde, cinnamaldehyde (5l),
afforded the alcohol in 89% and 93% ee, respectively.
Hydrocinnamaldehyde (5m), a representative aliphatic
aldehyde, also gave the product in 92% ee. Cyclohexane-
carboxaldehyde (5n) increased the ee to 95%, and further
increasing the bulk to a tert-butyl group [pivalaldehyde
(5o)] decreased the ee to 78% (as that of 5j). The yields
were in the range of 45ꢀ79%, with the bulky aldehydes
providing lowest yields. We believe that we have obtained
The stereochemistry of the homoallyl alcohol 6a, ob-
tained from 3dꢀe, is the same as that obtained from 3b,
as determined by the GC analysis (vide supra). X-ray crys-
tallographic analysis of the corresponding β-hydroxy ke-
tone (3,3-difluoro-4-hydroxy-4-phenylbutan-2-one, 7), ob-
tained via debenzylation of 6a with sodium in liquid
ammonia,5a,17 revealed it to be the S-isomer.18 This was
further confirmed by converting (S)-7 to (R,S)-8 as shown
in Scheme 3 and comparing its optical rotation with that of
(S,R)-8, prepared from the homoallylic alcohol (R)-97a of
known configuration.19
(19) (R)-9 was prepared as described in ref 7a. For the preparation of
8, see the Supporting Information.
ꢀ
(20) (a) Chataigner, I.; Lebreton, J.; Zammattio, F.; Villieras, J.
Tetrahedron Lett. 1997, 38, 3719. (b) Mitra, S.; Gurrala, S. R.; Coleman,
R. S. J. Org. Chem. 2007, 72, 8724.
(21) Compared to the R-homoallyl alcohol from the allylboration of
benzaldehyde with the parent nonfluorinated allylborating agent,21a the
S-isomer for the difluorinated homoallyl alcohol is an artifact of the
CahnꢀIngold Prelog rules.21b (a) Lachance, H.; Lu, X.; Gravel, M.;
Hall, D. G. J. Am. Chem. Soc. 2003, 125, 10160. (b) Cahn, R. S.; Ingold,
C.; Prelog, V. Angew. Chem., Int. Ed. 1966, 5, 385.
4046
Org. Lett., Vol. 13, No. 15, 2011

column (see the Supporting Information for details). The
targeted chiral R-pyrone 13 was prepared in 77% yield by
alkaline hydrolysis, followed by cyclization under Yama-
guchi conditions. GC analysis using a CP-Chirasil-Dex CB
column revealed an ee of >99%.
Table 2. Asymmetric Difluoroallylboration of Aldehydes with
3ba
Scheme 4. Preparation of Chiral R-Pyrone 13
In conclusion, we have herein reported the first success-
ful preparation of chiral difluoroallylboronates, and have
demonstrated their application for the difluoroallylbora-
tion of a series of aromatic and aliphatic aldehydes, yield-
ing R-gem-difluorohomoallyl alcohols in good yields and
77ꢀ95% ee. A representative example of the benzyloxy-
substituted difluorohomoallyl alcohol was converted to
the corresponding chiral R-pyrone in >99% ee. Further
applications of these fluorinated chiral building blocks will
be reported in due course.
a Reactions were carried out in dichloromethane at rt with 1.5 equiv
of crude reagent for 12 h. b Isolated yield of pure product. c Determined
by GC analysis on a CP-Chirasil-Dex CB column. d Determined by
HPLC analysis on a Chiralcel OD-H column. e Determined by HPLC
analysis of the p-nitrobenzoyl derivative on a Chiralcel OD-H column.
the S-isomer in all of the cases, on the basis of the
confirmed configuration of 6a.
Acknowledgment. Financial support from the Herbert
C. Brown Center for Borane Research is gratefully
acknowledged.
Having achieved the chiral difluoroallylboration of
aldehydes, we demonstrated the application of this proto-
col for the preparation of chiral R-pyrones by following the
sequence of reactions that we had reported recently
(Scheme 4).6 Thus, (S)-7 (96% ee) was protected as the
TBS ether 10 and converted to the protected δ-hydroxy
olefinic ester 11 via a Z-stereospecific StillꢀGennari olefi-
nation in 77% yield, as a single isomer without loss of
optical activity. Deprotection of the TBS ether 11 with
Supporting Information Available. Experimental details
and spectral data of compounds. The X-ray crystallo-
graphic data for 7 has been deposited with the Cambridge
Crystallographic Data Center. This data (CCDC 832344)
can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif. This material is available free of charge via
the Internet at http://pubs.acs.org
HF pyridine gave the δ-hydroxy ester 12 in 96% ee,
confirmed by HPLC analysis using a Chiralcel OD-H
3
Org. Lett., Vol. 13, No. 15, 2011
4047