Bis-exo-2-norbornylboron triflate for stereospecific enolization of 3,3,3-trifluoropropionates

Article abstract of DOI:10.1021/ol1016178

The first boron-mediated enolization - aldolization of 3,3,3- trifluoropropionates has been reported. The preparation and application of bis-exo-bicyclo[2.2.1]heptan-2-ylboron triflate as a superior reagent for diastereospecific enolization has also been described.

Full text of DOI:10.1021/ol1016178

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4474-4477
Bis-exo-2-norbornylboron Triflate for
Stereospecific Enolization of
3,3,3-Trifluoropropionates
P. Veeraraghavan Ramachandran,* Gowrisankar Parthasarathy, and
Pravin D. Gagare
Department of Chemistry, Purdue UniVersity, 560 OVal DriVe,
West Lafayette, Indiana 47907-2084
chandran@purdue.edu
Received July 13, 2010
ABSTRACT
The first boron-mediated enolization-aldolization of 3,3,3-trifluoropropionates has been reported. The preparation and application of bis-exo-
bicyclo[2.2.1]heptan-2-ylboron triflate as a superior reagent for diastereospecific enolization has also been described.
Altering the biological properties of organic molecules via
fluorine substitution has been an efficient strategy in the
design and development of effective drugs.1 This trend has
motivated synthetic chemists to develop novel methods to
stereo- and regioselectively place fluoroalkyl groups in
organic molecules.2 The stereocontrolled cross-aldol reaction
is a powerful synthetic tool. However, the metal enolates of
R-CF3 ketones often underwent defluorination, leading to the
formation of R,ꢀ-unsaturated difluorocarbonyls.3 Successful
reports of enolate preparation of a CF3-ketone involve either
DIBAL-H reduction of alkenyl phosphate4 or treatment with
TiCl4 in the presence of Et3N.3 The latter protocol requires
the addition of Ti(O-i-Pr)4 during the aldolization step, lest
the yield is very poor.
One of the hallmarks of the boron-mediated cross-aldol
reaction is the high level of stereocontrol,5 although the
enolborinates of fluorocarbonyls have rarely been described.6
The enolboration of esters remained relatively unexplored7
until Abiko and Masamune described the efficacy of dialky-
lboron triflates for the diastereoselective and substrate-
controlled enantioslective aldol reaction.8 An efficient reagent-
controlled enantioselective enolboration-aldolization of
propionates was executed by us to prepare the synthons of
the potent antitumor agent (-)-dictyostatin.9 As part of our
program on fluoroorganic synthesis via boranes,10 we were
(1) (a) Filler, R.; Saha, R. Future Med. Chem. 2009, 1, 777. (b) Ojima,
I. Fluorine in Medicinal Chemistry and Chemical Biology; Wiley-Blackwell:
West Sussex, U.K., 2009.
(5) Cowden, C. J.; Paterson, I. Org. React. (N.Y.) 1997, 51, 1.
(6) Kuroboshi, M.; Ishihara, T. Bull. Chem. Soc. Jpn. 1990, 63, 1191.
(7) (a) Corey, E. J.; Kim, S. S. J. Am. Chem. Soc. 1990, 112, 4976. (b)
Brown, H. C.; Ganesan, K. Tetrahedron Lett. 1992, 33, 3421. (c) Ganesan,
K.; Brown, H. C. J. Org. Chem. 1994, 59, 2336.
(2) (a) Cao, L. L.; Gao, B. L.; Ma, S. T.; Liu, Z. P. Curr. Org. Chem.
2010, 14, 889. (b) Cahard, D.; Xu, X.; Couve-Bonnaire, S.; Pannecoucke,
X. Chem. Soc. ReV. 2010, 39, 558. (c) Prakash, G. K. S.; Wang, F.; Stewart,
T.; Mathew, T.; Olah, G. A. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 4090.
(d) Uneyama, K.; Katagiri, T.; Amii, H. Acc. Chem. Res. 2008, 41, 817.
(3) Ito, Y.; Yamanaka, M.; Mikami, K. J. Am. Chem. Soc. 2004, 126,
13174.
(8) (a) Abiko, A.; Liu, J.-F.; Masamune, S. J. Org. Chem. 1996, 61,
2590. (b) Abiko, A. Acc. Chem. Res. 2004, 37, 387. (c) Inoue, T.; Liu,
J.-F.; Buske, D. C.; Abiko, A. J. Org. Chem. 2002, 67, 5250. (d) Abiko,
A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc. 1997, 119, 2586.
(9) Ramachandran, P. V.; Pratihar, D. Org. Lett. 2009, 11, 1467.
(10) Ramachandran, P. V.; Chatterjee, A. Org. Lett. 2008, 10, 1195.
(4) Ishihara, T.; Kuroboshi, M.; Yamaguchi, K.; Okada, Y. J. Org. Chem.
1990, 55, 3107.
10.1021/ol1016178  2010 American Chemical Society
Published on Web 09/17/2010

interested in the synthesis of dictyostatin wherein the C6-
methyl is swapped for a trifluoromethyl group.11 Conse-
quently, we examined the enolboration-aldolization of 3,3,3-
trifluoropropionates (1).12,13 Herein, we describe the develop-
ment of bis-exo-2-norbornylboron triflate as a reagent for
the facile, diastereospecific incorporation of anti-R-triflu-
oromethyl ꢀ-hydroxy moieties.
E-enolates and 1d and 3 for Z-enolates (Scheme 1).17 In
contrast with the nonfluorinated alkyl propionates,8a the syn-
Scheme 1. Optimization of Enolization Conditions Using 2 and 3
As a first step, we set out to optimize the conditions for
the diastereoselective enolboration to realize either the syn-
or anti-aldols from 3,3,3-trifluoropropionates. Accordingly,
we prepared the methyl (1a), ethyl (1b), isopropyl (1c), tert-
butyl (1d), benzyl (1e), and phenyl (1f) esters from 3,3,3-
trifluoropropionic acid14 and examined their enolboration
with di-n-butylboron triflate (n-Bu2BOTf, 2) in the presence
of diisopropylethylamine (conditions A) and dicyclohexyl-
boron triflate (Chx2BOTf, 3) in the presence of triethylamine
(conditions B).15 Upon aldolization of 4-fluorobenzaldehyde
(4a), the syn- and anti-aldols,16 respectively, were obtained
from these enolates (Table 1). On the basis of the aldol
aldols were obtained with lower diastereoselectivity, although
the anti-aldols were realized with relatively high selectivity.18
The effect of the alkyl groups of the dialkylboron triflates
was then examined19 to improve the diastereoselectivity for
the enolization and aldolization. 9-Borabicyclo[3.3.1]nonyl
trifluoromethanesulfonate (9-BBN-OTf, 6), a reagent with
lower steric requirements for the E-selective enolbora-
tion,17,19 was examined with the expectation of better
selectivity for the syn-aldols. Unexpectedly, enolization of
the syn-favoring ester 1a with 6 in the presence of i-Pr2NEt
decreased the selectivity to 57:43 (Scheme 2). An examina-
Table 1. Effect of R Group of Ester on Enolization with 2 and 3
aldol
no.
1
R
enol. conditionsa
5b
yieldc (%) syn/antid
Scheme 2. Enolboration-Aldolization with Reagents 6-8
1
2
3
4
5
6
7
8
9
1a Me
1a Me
1b Et
1b Et
1c iPr
1c iPr
1d tBu
1d tBu
1e Bn
A
B
A
B
A
B
A
B
A
B
A
B
5aa
5aa
5ab
5ab
5ac
5ac
5ad
5ad
5ae
5ae
5af
69
71
71
80
52
72
62
76
65
81
61
20
86:14
21:79
84:16
10:90
76:24
6:94
53:47
5:95
82:18
6:94
10 1e Bn
11 1f Ph
12 1f Ph
60:40
50:50
5af
a A: 2, i-Pr2NEt, -78 °C, 30 min, 0 °C, 40 min. B: 3, Et3N, -78 °C,
2 h. b The first letter refers to the aldehyde, and the second letter refers to
the ester. c Combined yield of syn and anti isomers. d Syn and anti ratios
were determined by 19F NMR spectroscopy.16
tion of the 19F NMR spectrum of the 9-BBN enolate revealed
an isomeric ratio of 53:47, which essentially corresponds to
the aldol stereoisomeric ratio. We are further investigating
this.
Since the C6-C7 relationship in C6-CF3-dictyostatin
is anti, we focused our attention on bulkier boron triflates
to achieve the maximum selectivity of anti-aldols.19 To
this end, we prepared two novel reagents, bis-exo-
bicyclo[2.2.1]heptan-2-ylboron triflate (bis-exo-2-nor-
bornylboron triflate, Nrb2BOTf, 7) and bis-exo-bicy-
clo[2.2.2]octan-2-ylboron triflate (Bco2BOTf, 8), from the
corresponding dialkylboranes. Upon enolization of the
anti-favoring ester 1d with both of these reagents (Scheme
2), followed by aldolization, the anti-aldols were obtained
exclusiVely, thus identifying 7 and 8 as superior reagents
for the Z-selective17 enolization of tert-butyl 3,3,3-
trifluoropropionate. Reagent 7 was chosen for further
studies due to the ready availability of norbornene.
stereochemistry, we deduce that the optimal conditions were
achieved with an ester-reagent combination of 1a and 2 for
(11) (a) Curran and co-workers have shown that the 6-methyl group
influences the potency of (-)-dictyostatin. Hence, the preparation of 6-CF3-
dictyostatin: (b) Raccor, B. S.; Vogt, A.; Sikorski, R. P.; Madiraju, C.;
Balachandran, R.; Montgomery, K.; Shin, Y.; Fukui, Y.; Jung, W.-H.;
Curran, D. P.; Day, B. W. Mol. Pharmacol. 2008, 73, 718.
(12) For the aldolization of 3,3,3-trifluoropropanamides via silyl enolates,
see: Shimada, T.; Yoshioka, M.; Konno, T.; Ishihara, T. Org. Lett. 2006,
8, 1129
.
(13) For the aldolization of 3,3,3-trifluoropropanamides via titanium
enolates, see: Franck, X.; Seon-Meniel, B.; Figadere, B. Angew. Chem.,
Int. Ed. 2006, 45, 5174
.
(14) Komata, T.; Akiba, S.; Hosoi, K.; Ogura, K. J. Fluorine Chem.
2008, 129, 35.
(15) The reagent-amine combination was selected on the basis of
Abiko’s study; see ref 8a.
Org. Lett., Vol. 12, No. 20, 2010
4475

With the above optimized conditions, the generality of our
process was examined with a selected series of aldehydes
with 2 (conditions A: i-Pr2NEt, -78 °C, 30 min, 0 °C, 40
min) and 7 (conditions C: Et3N, -78 °C, 2 h) and compared
with 3 (conditions B: Et3N, -78 °C, 2 h) (Table 2). The
the TBS ether and oxidized with DMP to the aldehyde (4i).
Ester 1d was converted to the Z-enolate with 7 and treated
with 4i to obtain the aldol 5id in 88% yield and g99%
selectivity. This hydroxy ester was protected as the TBS ether
and reduced with BH3·SMe2 to the corresponding alcohol 9.
This constitutes the synthesis of the racemic C5-C9
framework of our target (Scheme 3).
Table 2. Examination of Aldehydes for the Aldol Reaction
Scheme 3
.
Preparation of Racemic C5-C9 Framework of
6-CF3-dictyostatin
R′CHO
R′
aldol
no.
4
enol. conditionsa 5b yield,%c syn/antid
1
2
3
4
5
6
7
8
9
4a p-FC6H4
4a p-FC6H4
4a p-FC6H4
4b Ph
A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
5aa
5ad
5ad
5ba
5bd
5bd
5ca
5cd
5cd
5da
5dd
5dd
5ea
5ed
5ed
5fa
69
76
74
64
79
87
67
90
76
70
81
95
50
72
75
48
65
52
63
65
73
61
40
70
86:14
5:95
e1:g99
86:14
6:94
e1:g99
86:14
9:91
e1:g99
86:14
4:96
e1:g99
90:10
12:88
e1:g99
57:43
8:92
e1:g99
75:25
8:92
4b Ph
4b Ph
4c p-NO2 C6H4
4c p-NO2 C6H4
4c p-NO2 C6H4
10 4d p-MeO C6H4
11 4d p-MeO C6H4
12 4d p-MeO C6H4
13 4e E-PhCHdCH
14 4e E-PhCHdCH
15 4e E-PhCHdCH
16 4f n-Pr
In conclusion, our investigations concentrated on the
boron-mediated enolization of 3,3,3-trifluoromethylpropi-
onates, and we have described the first successful enolbora-
tion-aldolization of these fluoroesters. Contrary to the
17 4f n-Pr
5fd
18 4f n-Pr
5fd
19 4g i-Pr
5ga
5gd
5gd
5ha
5hd
5hd
20 4g i-Pr
21 4g i-Pr
e1:g99
54:46
9:91
22 4h t-Bu
23 4h t-Bu
(20) Typical Procedure for the Anti-Selective Aldol Reaction. Bis-
exo-2-norbornylborane (Nrb2BH) (2.5 mmol), prepared from norbornene
and BH3·SMe2, was transferred to an oven-dried 50 mL round-bottom
flask in a glove bag. Methylene chloride (5 mL) was added, and the
mixture was cooled to 0 °C, followed by the addition of trifluo-
romethanesulfonic acid (2.8 mmol). The reaction mixture was stirred at
ambient temperature for 1 h and cooled to -78 °C, and triethylamine
(3.6 mmol) was added dropwise via syringe, followed by the addition
of tert-butyl 3,3,3-trifluoropropionate (1 mmol). The resulting solution
was stirred at this temperature for 2 h. The aldehyde (1.5 mmol) in
methylene chloride (1 mL) was then added, dropwise, to the above
enolate solution and stirred for an additional 1 h, followed by stirring
at 0 °C for 1 h. The reaction was quenched by the addition of pH 7
buffer solution (2 mL). The mixture was diluted with MeOH (2 mL),
followed by the careful addition of 30% hydrogen peroxide (2 mL),
and stirred vigorously for 6-8 h. The reaction mixture was partitioned
between water (4 mL) and methylene chloride (20 mL), the aqueous
layer was extracted with methylene chloride, and the combined organics
were washed with brine (5 mL), dried (anhydrous Na2SO4), filtered,
concentrated, and purified by silica gel chromatography to obtain the
pure anti-aldol product. Typical Procedure for the Syn-Selective Aldol
Reaction. 3,3,3-Trifluoropropionates (1 mmol) and methylene chloride
(4 mL) were transferred to an oven-dried 50-mL round-bottom flask
under nitrogen. This solution was cooled to -78 °C, and a solution of
n-butylboron triflate in dichloromethane (2 mmol) was added, followed
by the dropwise addition of diisopropylethylamine (3 mmol). The
resulting solution was stirred at this temperature for 30 min and 0 °C at
40 min. The aldehyde (0.75 mmol) in methylene chloride (1 mL) was
added dropwise to the enolate solution. The reaction mixture was stirred
for 1 h at -78 °C and 1 h at 0 °C and quenched by addition of pH 7
buffer solution (2 mL). The mixture was diluted with MeOH (2 mL),
followed by the careful addition of 30% hydrogen peroxide (2 mL),
and stirred vigorously for 6-8 h. The reaction mixture was partitioned
between water (4 mL) and methylene chloride (20 mL). The aqueous
layer was extracted with methylene chloride, and the combined organics
were washed with brine (5 mL), dried (anhydrous Na2SO4), filtered,
concentrated, and purified by silica gel chromatography to obtain the
pure syn-aldol product.
24 4h t-Bu
e1:g99
a A: R ) Me, 2, i-Pr2NEt, -78 °C, 30 min, 0 °C, 40 min. B: R ) t-Bu,
3, Et3N, -78 °C, 2 h. C: R ) t-Bu, 7, Et3N, -78 °C, 2 h. b The first letter
refers to the aldehyde, and the second letter refers to the ester. c Combined
yield of syn and anti isomers. d Syn and anti ratios were determined by 19
F
NMR spectroscopy.16
diastereomeric excess (de) for syn-aldols with reagent 2 is
in the 72-80% range for aromatic aldehydes and lower for
aliphatic aldehydes. Reagent 3 provided anti-aldols in
76-92% de. The bulky reagent 7 provided anti-aldols
exclusively (g99%) for all classes of aldehydes examined,
thus confirming its control.
Pursuing our goal, we examined reagent 7 for the
preparation of the CF3-containing racemic substructure of
C6-CF3 dictyostatin. 1,3-Propanediol was monoprotected as
(16) (a) The diastereomer ratio (dr) was determined by 19F NMR
spectroscopy. (b) For the assignment of the syn and anti configuration, see:
Sakamoto, T.; Takahashi, K.; Yamazaki, T.; Kitazume, T. J. Org. Chem.
1999, 64, 9467.
(17) Note that the E-enolate for the esters is similar to the Z-enolate for
ketones.
(18) In comparison, the TiCl4-catalyzed aldol reaction of silicon enolates
(ref 12) and TMEDA-assisted aldol reaction of titanium enolates (ref 13)
of trifluoropropanamides provide syn-products selectively.
(19) Brown and co-workers have shown that decreased bulk on boron
favors syn-aldol and increased bulk favors anti-aldols for ketone
enolization-aldolization. Brown, H. C.; Ganesan, K.; Dhar, R. K. J. Org.
Chem. 1992, 57, 3767.
4476
Org. Lett., Vol. 12, No. 20, 2010

nonfluorinated propionates, the syn-aldols were obtained in
relatively lower de. The high de for the anti-aldols were
improved further by utilizing a bulkier reagent for enoliza-
tion. The preparation and application of bis-exo-2-norbornyl-
boron triflate as a superior reagent for diastereospecific
enolization has been described20 in conjunction with the
preparation of the critical subunit of C6-CF3-dictyostatin.
This process should find application in the efficient prepara-
tion of trifluoromethyl analogues of various pharmacologi-
cally active compounds bearing an R-methyl hydroxyl unit.
Further investigations are in progress to improve the syn-
selectivity and to develop a substrate- and reagent-controlled
enantioselective reaction.
Acknowledgment. We thank the Herbert C. Brown Center
for Borane Research for financial support of this project.
Supporting Information Available: Experimental details
and spectral data of compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL1016178
Org. Lett., Vol. 12, No. 20, 2010
4477