Asymmetric synthesis of γ-perfluoroalkyl(aryl) butyrolactones via organoboranes

Article abstract of DOI:10.1016/j.tetlet.2003.11.050

Asymmetric 'allyl'boration of fluorinated aldehydes with α-pinene-based 'allyl' boranes provides the corresponding homoallylic alcohols in high ee and de, which upon hydroboration, followed by oxidation with TPAP/NMO furnish γ-perfluoroalkyl(aryl)-γ-butyr

Full text of DOI:10.1016/j.tetlet.2003.11.050

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1015–1017
Asymmetric synthesis of c-perfluoroalkyl(aryl) butyrolactones
via organoboranes
P. Veeraraghavan Ramachandran,* Kamlesh J. Padiya, Vivek Rauniyar,
M. Venkat Ram Reddy and Herbert C. Brown
Department of Chemistry, Herbert C. Brown Center for Borane Research, Purdue University, 560 Oval Drive,
West Lafayette, IN 47907-2084, USA
Received 28 October 2003; accepted 12 November 2003
Abstract—Asymmetric ꢀallylꢁboration of fluorinated aldehydes with a-pinene-based ꢀallylꢁ boranes provides the corresponding
homoallylic alcohols in high ee and de, which upon hydroboration, followed by oxidation with TPAP/NMO furnish c-perflu-
oroalkyl(aryl)-c-butyrolactones.
Ó 2003 Elsevier Ltd. All rights reserved.
Lactones are important synthons in organic chemistry.1
They are also present in a large number of natural
O
B
OH
products.2 The unique properties of fluoroorganic mole-
2
RF
H
cules in biological and medicinal chemistry3;4 inspired us
to synthesize fluorine-containing lactones. We have re-
cently reported several asymmetric syntheses of chiral
lactones via organoboranes.5 Even though several syn-
theses of lactones are available in the literature,1 there
have been only scarce reports of the syntheses of fluoro-
analogs.6
RF
1a
2, RF = C6F5
3, RF = CF3
NaOH, H2O2
4a: RF = C6F5,
89% yld., 99% ee
5a: RF = CF3,
50% yld., 98% ee
Scheme 1.
Although we have reported on the unique nature of the
asymmetric reduction of fluoroketones,3a and hydro-
boration of fluoro-olefins,7 asymmetric allylboration
of fluoroaldehydes8 with (B)-allyldiisopinocampheyl-
borane (1a),9 did not reveal any surprises. For example,
allylboration of two representative fluorinated aldehydes
pentafluorobenzaldehyde (2) and trifluoroacetaldehyde
(3) with reagent 1a was relatively straightforward at
)100 °C providing the products 4a and 5a in 99% and
98% ee, respectively (Scheme 1).
The success of the allylboration of fluoroaldehydes,
coupled with the possibility of the formation of func-
tionalized fluorinated lactones, persuaded us to under-
take the asymmetric crotyl- and alkoxylallylboration as
well with (B)-(Z)-crotyldiisopinocampheylborane (1b),10
(B)-(E)-crotyldiisopinocampheylborane (1c),10 and (B)-
c-2-methoxyethoxymethoxyallyldiisopinocampheyl-
borane (1d).11 We envisaged that the homoallylic alco-
hols obtained in high ee and de can be converted to the
diols via hydroboration–oxidation, followed by further
oxidation of the primary alcohols should provide
c-lactones. The secondary alcohol at the a-carbon to a
perfluoroalkyl(aryl) group is deactivated and should not
undergo oxidation to ketones. Herein we discuss the
successful synthesis of c-fluoroalkyl(aryl) b-substituted
c-lactones via allylboration, hydroboration, and oxida-
tion.
Keywords: a-Pinene; Allylboration; Homoallylic alcohol; Hydrobora-
tion; Fluorolactones.
* Corresponding author. Tel.: +1-765-4945303; fax: +1-765-4940239;
e-mail: chandran@purdue.edu
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.050

1016
P. V. Ramachandran et al. / Tetrahedron Letters 45 (2004) 1015–1017
with 1d afforded the product alcohol 5b in 75% yield,
>95% de, and 96% ee (Scheme 2).
OMe
M
B
R1
R2
B
2
R1
R2
.
BF3 Et2O
2
After achieving excellent diastereo- and enantioselec-
tivities in the allylboration, we proceeded with the
conversion of these homoallylic alcohols into diols via
hydroboration–oxidation. To obtain the optimum yield
of the diols, a model study was performed on 4a with
several boranes, such as BH3ÆTHF, 9-BBN, dichloro-
borane, and dicyclohexylborane. Dicyclohexylborane 6
gave the best results in terms of yield and regioselectivity
and was chosen as the hydroborating agent for the
present study. All of the homoallylic alcohols 4a–d and
5a–b underwent hydroboration with 6 and the diols 7a–
d and 8a–b were obtained in very good yields15 following
an alkaline hydrogen peroxide oxidation. The oxidation
of the 1° alcohol in 7a–d and 8a–b with several oxidizing
agents, such as PCC, PDC, Jones reagent, etc., resulted
in poor to moderate yields of the product lactones.16
However, oxidation of the diols 7a–d and 8a–b using
TPAP/NMO17 converted these diols into the corre-
sponding c-lactones 9a–d18 and 10a–b in good yields
(Scheme 3). This oxidizing system developed by Ley is
very mild, typically provides good yields, and is appli-
cable to sensitive substrates as well.19 Thus, a combi-
nation of allylboration, hydroboration, and Leyꢁs
oxidation provides an excellent procedure for the prep-
aration of c-lactones, particularly sensitive fluorinated
lactones.
"Ate" complex
CF3CHO
OH
C
6F5CHO
OH
F3C
F5C6
R2 R1
R2 R1
4b, R1 = Me, R2 =H
75% yld. >95% de, 94% ee
4c, R1 = H, R2 = Me
72% yld. >95% de, 92% ee
4d, R1 = H, R2 = OMEM
65% yld. >95% de, 95% ee
5b, R1 = H, R2 = OMEM
75% yld. >95% de, 96% ee
Scheme 2.
The reaction of 2 with all of the other three ꢀallylꢁ borane
reagents 1b, 1c, and 1d took place smoothly and the
product homoallylic alcohols 4b,12 4c, and 4d were
obtained in excellent de and ee. The de was determined
1
based on H NMR analysis of the crude product mix-
ture and the ee of the pure sample was ascertained using
an HPLC on a Chiralcel OD-H column. The reaction of
fluoral 3 with all the three reagents 1b–d posed an
interesting challenge. ꢀAllylꢁboration of 3 with 1b–d re-
sulted in the polymerization of fluoral even at )100 °C.
Unlike 1a, the higher order allylboranes 1b–d have to be
generated in situ at low temperature due to the boro-
tropic shift.10;11 They remain as ꢀateꢁ complexes and
1.33 equiv of BF3ÆEt2O is added to liberate the tri-
alkylborane13 (Scheme 2). We rationalized that the
strong Lewis acid, BF3ÆEt2O, initiated the polymeriza-
tion. In an attempt to arrest the polymerization of 3, the
reaction was carried out directly with ꢀateꢁ complex.14
However, the expected homoallylic alcohols from
reagents 1b and 1c could not be obtained in pure form
and in reliable yields. Fortunately, alkoxyallylboration
In conclusion, we have studied allylboration of fluoro-
aldehydes with various a-pinene-based ꢀallylꢁ boranes
and obtained homoallylic alcohols in excellent ee and
de. In the case of fluoral, alkoxyallylboration has been
achieved via the reaction of ꢀateꢁ complex to provide the
product in good yield. We have converted these alcohols
to fluorinated c-lactones in two steps via hydroboration,
followed by oxidation. Further work is in progress
toward the application of this methodology for the
synthesis of fluoro-analogs of biologically active mole-
cules containing c-lactones.
O
OH
BH
OH
2
O
OH
TPAP
NMO
RF
6
RF
R2 R1
R2 R1
R1
RF
NaOH, H2O2
R2
4 a-d
5 a,b
7 a-d
8 a,b
9 a-d
10 a,b
9a, RF = C6F5, R1 = H,
R2 = H, 64%
7a, RF = C6F5, R1 = H,
R2 = H, 79%
9b, RF = C6F5, R1 = Me,
R2 = H, 75%
7b, RF = C6F5, R1 = Me,
R2 = H, 84%
9c, RF = C6F5, R1 = H,
R2 = Me, 72%
7c, RF = C6F5, R1 = H,
R2 = Me, 85%
9d, RF = C6F5, R1 = OMEM,
R2 = H, 75%
7d, RF = C6F5, R1 = OMEM,
R2 = H, 72%
10a, RF = CF3, R1 = H,
R2 = H, 61%
8a, RF = CF3, R1 = H,
R2 = H, 71%
10b, RF = CF3, R1 = OMEM,
R2 = H, 68%
8b, RF = CF3, R1 = OMEM,
R2 = H, 82%
Scheme 3.

P. V. Ramachandran et al. / Tetrahedron Letters 45 (2004) 1015–1017
1017
2003, 44, 3745; (b) Ramachandran, P. V.; Chandra, J. S.;
Reddy, M. V. R. J. Org. Chem. 2002, 67, 7547.
12. (1R,2S)-2-Methyl-1-pentafluorophenyl-but-3-en-1-ol, 4b:
1H NMR (300 MHz) d (ppm): 5.45–5.58 (m, 1H), 4.91–
5.03 (m, 2H), 4.76 (d, J ¼ 4:86 Hz, 1H), 2.56–2.82 (m, 1H),
2.45 (br s, 1H), 1.12 (d, J ¼ 7:20 Hz, 3H); 13C
NMR (75.5 MHz) d (ppm): 138.3, 136.1–146.2 (m, 5C),
117.0, 70.5, 44.8, 16.9; 19F NMR (300 MHz) d (ppm):
)80.2, )92.9, )99.8; EI-MS: m=z 235 (M)OH)þ, 197
(100%); CI-MS: m=z 253 (M+H)þ, 235 [(M+H)H2O)þ,
100%].
Acknowledgements
Financial support from the Herbert C. Brown Center
for Borane Research20 and the Aldrich Chemical Com-
pany is greatfully acknowledged.
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