Asymmetric synthesis of 6-(2′,3′,4′,5′, 6′-pentafluorophenyl)-δ-lactones via "allyl"boranes via "allyl" boranes: Application for the synthesis of fluorinated analog of key pharmacophore of statin drugs

Article abstract of DOI:10.1016/j.jfluchem.2004.01.005

Asymmetric "allyl"boration of pentafluorobenzaldehyde with various α-pinene based "allyl"boranes provides homoallylic alcohols in high de and ee; the alcohols have been converted into δ-lactones via acryloylation, ring-closing metathesis and hydrogenation

Full text of DOI:10.1016/j.jfluchem.2004.01.005

Journal of Fluorine Chemistry 125 (2004) 615–620
Asymmetric synthesis of 6-(20,30,40,50,60-pentafluorophenyl)-d-lactones
via ‘‘allyl’’boranes: application for the synthesis of fluorinated
analog of key pharmacophore of statin drugs
P. Veeraraghavan Ramachandran*, Kamlesh J. Padiya, Vivek Rauniyar,
M. Venkat Ram Reddy, 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 24 October 2003; received in revised form 31 December 2003; accepted 6 January 2004
Abstract
Asymmetric ‘‘allyl’’boration of pentafluorobenzaldehyde with various a-pinene based ‘‘allyl’’boranes provides homoallylic alcohols in high
de and ee; the alcohols have been converted into d-lactones via acryloylation, ring-closing metathesis and hydrogenation. Pentafluorophenyl
analog of key pharmacophore of statin drugs has been synthesized using diastereoselective epoxidation and regioselective reduction as key
steps.
# 2004 Elsevier B.V. All rights reserved.
Keywords: Pentafluorobenzaldehyde; a-Pinene; ‘‘Allyl’’boranes; Ring-closing metathesis; Hydrogenation; Epoxidation; Reduction
1. Introduction
pinocampheyl borane (1b) [9], (B)-(E)-crotyldiisopinocam-
pheylborane (1c) [9], and (B)-g-2-methoxy-ethoxymethoxy-
allyldiisopinocampheylborane (1d) [3a,10] (Fig. 1) and one
representative aldehyde pentafluoro-benzaldehyde, 2 for the
present study. ‘‘Allyl’’boration of 2 with 1a at À100 8C took
place smoothly and the homoallylic alcohol was isolated in
89%yieldand99%ee[6b]. Similarly, crotylboration of2 with
1b and 1c provided the corresponding homoallylic alcohols
3b and 3c in >95% de and 94 and 92% ee, respectively. The
de was ascertained based on 1H NMR analysis of the crude
product. To determine the ee, the alcohols were derivatized
as either p-nitrobenzoate or cinnamyl esters and analyzed
using HPLC on a chiralcel OD-H column.1 Alkoxyallyl-
boration with 1d furnished the homoallylic alcohol 3d in
>95% de and 95% ee. The alcohols 3a–d were esterified
with acryloyl chloride in the presence of triethyl amine to
yield the corresponding acrylates 4a–d; these acrylates
were subjected to ring-closing metathesis (For recent
reviews, see [11]) using Grubbs’ first-generation catalyst
5 (Fig. 2). The reaction was very sluggish, and afforded
very low yields of products and most of the starting
material was recovered. However, the reaction of acrylates
4a–d with Grubbs’ second-generation catalyst 6 took place
Lactones are extremely versatile synthetic intermediates
in organic synthesis [1]. The lactone moiety is an important
structural component present in many biologically active
natural products [2]. For the past few years, we have been
developing methods for the synthesis of lactone containing
natural and unnatural products [3]. Although there are
several procedures available in the literature [1] for the
synthesis of lactones, there have been only a few reports
on the asymmetric synthesis of fluorolactones [4]. In con-
tinuation of some of our projects involving preparation of
fluoroorganic molecules via organoboranes [5,6], we under-
took the synthesis of fluorolactones via tandem asymmetric
‘‘allyl’’boration ring closing metathesis strategy.
2. Results and discussion
‘‘Allyl’’boration using a-pinene derived boranes typically
provides high levels of diastereo- and enantioselectivities for
homoallylic alcohols [7]. We chose four ‘‘allyl’’boranes
B-allyldiisopinocampheylborane(1a)[8],(B)-(Z)-crotyldiiso-
* Corresponding author. Tel.: þ1-765-494-5303; fax: þ1-765-494-0239.
E-mail address: chandran@purdue.edu (P.V. Ramachandran).
1 Chiralcel OD-H(TM) is a Trademark of Chiral Technologies Inc. Exton,
PA.
0022-1139/$ – see front matter # 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2004.01.005

616
P.V. Ramachandran et al. / Journal of Fluorine Chemistry 125 (2004) 615–620
O
R1
O
(i) 1a-d,
O
OH
B
2
R2
O
-78oC to -100oC
H
(ii) NaOH, H2O2
Cl
C6F5
C6F5
C6F5
NEt3
R1 R2
R1 R2
3a-d
4a-d
2
1a, R1 = H, R2 = H
3a, R1 = H, R2 = H,
4a, R1 = H, R2 = H,
92% yld.
4b, R1 = Me, R2 = H,
80% yld.
4c, R1 = H, R2 = Me,
87% yld.
4d, R1 = OMEM, R2 = H,
65% yld.
1b, R1 = Me, R2 = H
1c, R1 = H, R2= Me
1d, R1 = OMEM, R2 = H
89% yld, 99% ee
3b, R1 = Me, R2 = H,
75% yld, >95%de, 94% ee
3c, R1 = H, R2 = Me,
72% yld, >95% de, 92% ee
3d, R1 = OMEM, R2 = H,
65% yld, >95%de, 95% ee
O
Fig. 1. Asymmetric allylborating agents.
O
PChx3
Ru
Mes
N
N Mes
Ph
O
O
Ph
Grubbs II Generation
Catalyst
H2
Pd
Cl
Cl
Cl
Ru
C6F5
C6F5
R1 R2
8a-d
Cl
R1 R2
7a-d
PChx3
PChx3
6
5
8a, R1 = H, R2 = H,
95% yld.
7a, R1 = H, R2 = H,
93% yld.
Fig. 2. Grubbs’ catalysts for ring-closing metathesis reaction.
8b, R1 = Me, R2 = H,
92% yld.
7b, R1 = Me, R2 = H,
96% yld.
8c, R1 = H, R2 = Me,
94% yld.
8d, R1 = OMEM, R2 = H,
89% yld.
7c, R1 = H, R2 = Me,
96% yld.
7d, R1 = OMEM, R2 = H,
90% yld.
smoothly to afford dihydropyranones 7a–d in excellent
yields. The saturated d-lactones 8a–d were obtained in
essentially quantitative yields upon hydrogenation of dihy-
dropyranones 7a–d using H2 and Pd–C (Scheme 1).
We envisaged that the dihydropyranones 7a–d would be
useful chiral synthons for organic synthesis. To demonstrate
the applicability, we undertook the synthesis of the key
pharmacophore of statin drugs. Statin drugs are commer-
cially available as prescription drugs for lowering choles-
terol. Some of the blockbuster drugs2 include Mevacor 9
[12],3 Zocor,4 Pravachol,5 Lipitor 10,6 Lescol,7 and the
recently introduced Crestor 11 [13]8 (Fig. 3). Studies have
shown that the key pharmacophore in all these drugs is the
b-hydroxy-d-lactone unit [14]. The generally beneficial
effects of the fluorine substitution in a drug molecule [15]
have persuaded us to prepare the fluoro-analog of the
b-hydroxy-d-lactone moiety. The dihydropyranone 7a upon
reaction with alkaline hydrogen peroxide afforded the epox-
ide 12 as an exlusive 1,3-trans isomer in 72% yield. The high
diastereoselectivity obtained during the epoxidation could
be explained based on the attack of the hydroperoxide ion
from the face opposite to the substituent at C5 leading to
the 1,3-trans isomer due to the favorable stereoelectronics
[16,17] (Fig. 4). The reduction of the epoxide 12 under
Miyashita conditions [18] using diphenyl diselenide and
sodium borohydride took place in a highly regioselective
Scheme 1.
F
O
O
O
O
Me
O
H
O
N
OH
OH
10
HN
Lipitor(R)
O
9
Mevacor(R)
(Atorvastatin)
(Lovastatin)
O
O
N
OH
O
S
N
N
O
F
11
Crestor(R)
(Rosuvastatin)
2 Statin drugs constituted ꢀ6% of the total annual sale of the top 200
drugs in 1999, worth $125 billion in the USA. Lipitor, $3.0b Zocor, $2.3b
Pravacol, $1.18b Mevacor, $389.5m and Lescol, $268.1m.
3 Mevacor(r) is a trademark of Merck & Co.
Fig. 3. Statin drugs.
H
4 Launched in the market (Merck & Co.) in 1988. FDA approved new
O
H
dose ranges for Zocor1 in 1998.
O
5 Pravachol is a trademark of Bristol–Myers Squibb. FDA approved in
1996.
C6F5
H
O
6 FDA approved in 1996, Lipitor1 is a trademark of Pifizer (Parke–
Davis).
H
O
7 Lescol is a trademark of Novartis Pharma AG.
8 Crestor1 is a trademark of Astra Zenica.
Fig. 4. Diastereomeric transition-state model for the epoxidation of
pyrones.

P.V. Ramachandran et al. / Journal of Fluorine Chemistry 125 (2004) 615–620
617
(m, 5C), 132.5, 119.5, 65.7, 41.2; 19F NMR: d (ppm)
(CDCl3) À81.15, À92.68, À99.55.
O
O
O
PhSeSePh, NaBH4
AcOH, EtOH
NaOH, H2O2
72%
O
O
O
O
C6F5
C6F5
C6F5
OH
84%
12
13
7a
4.1.2. Preparation of (1S, 2R)-2-methyl-
1-pentafluorophenyl-3-buten-1-ol, 3b
Scheme 2.
Potassiumtert-butoxide(5.6 ml,1.0 Msolution,5.6 mmol)
was dissolved in 10 ml THF at À78 8C and cis-2-butene
(1.2 ml, 12.9 mmol) was added. n-Butyl lithium (2.3 ml,
2.5 M solution, 5.7 mmol) was added and stirred for 20 min
at À45 8C. The reaction mixture was cooled to À78 8C and
(À)-B-methoxydiisopinocampheylborane [(À)-Ipc2BOMe]
(2.2 g, 6.9 mmol) dissolved in 5.0 ml THF was added and
stirred for 1 h. Aldehyde 2 (1.0 g, 5.2 mmol) was dissolved in
3.0 mlofTHF, cooledto–78 8Candtransferredtothe reaction
mixtureviaacanulaatÀ78 8Candstirredfor3 h.Thereaction
mixture was oxidized with 2.8 ml 3 M NaOH and 2.8 ml
30% H2O2 and stirred overnight. The reaction mixture was
worked up with ether and water. The organic layer was dried
over MgSO4, concentrated under vacuum and purified by
column chromatography (silica gel, 5:1, hexane:ethyl ether)
toobtain3b.1HNMR(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 (bs, 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): À80.2, À92.9,
À99.8; EI–MS: m/z 235 (M À OH)þ, 197 (100%); CI–MS:
m/z 253 (M þ H)þ, 235 [ðM þ H À H2OÞþ, 100%].
manner to provide the trans b-hydroxy-d-lactone 13 in 84%
yield (Scheme 2).
3. Conclusions
In conlusion, we have synthesized various fluorinated a-
pyrones and d-lactones in optically pure form using a-
pinene based asymmetric ‘‘allyl’’boranes. We have also
synthesized a fluorinated analog of the key pharmacophore
of statin drugs via diastereoselective epoxidation and regio-
selective reduction. Further work is in progress to synthesize
fluoroanalogs of various biologically active molecules using
this protocol.
4. Experimental
4.1. General experimental procedures
All operations were carried out under an inert atmosphere.
The 1H, 11B, and 13C NMR spectra were plotted on a Varian
Gemini-300 spectrometer with a Nalorac-Quad probe. Mass
spectra were recorded using a Hewlett-Packard 5989B mass
spectrometer/5890 series II gas chromatograph or a Finnigan
mass spectrometer model 4000. CI gas used was isobutane.
Enantiomeric excess (% ee) was measured using Dynamax
HPLC fitted with HPXL Solvent Delivery System and
Dynamax UV (l, 254 nm) detector. Chiral column used
was CHIRALCEL OD-H. All the chemicals were obtained
from Aldrich Chemical Company and used as received.
Tetrahydrofuran was distilled from benzophenone ketyl
prior to use.
4.1.3. Preparation of (1S, 2S)-2-methyl-
1-pentafluorophenyl-3-buten-1-ol, 3c
Procedure is same that of 3b except that trans-2-butene
1
was used instead of cis-2-butene. H NMR (300 MHz) d
(ppm): 5.75–5.88 (m, 1H), 5.17–5.38 (m, 2H), 4.72 (d,
J ¼ 4:89 Hz, 1H), 2.56–2.82 (m, 1H), 2.42 (bs, 1H), 0.92
(d, J ¼ 7:17 Hz, 3H); 13C NMR (75.5 MHz) d (ppm): 139.5,
136.0–146.6 (m, 5C), 118.1, 69.7, 44.3, 16.4; 19F NMR
(300 MHz) d (ppm): À80.0, À92.8, À99.7.
4.1.4. Preparation of (1R, 2R)-2-methoxyethoxymethoxy-
1-pentafluorophenyl-3-buten-1-ol, 3d
sec-Butyl lithium (19.3 mL, 23.2 mmol) was added drop-
wise to a well-stirred solution of allyloxymethoxyethoxy-
methane (3.5 g, 24.4 mmol) in 50 ml THF at À78 8C and
stirred for 0.5 h. (À) Ipc2BOMe ((À)(B)-methoxydiisopino-
campheylborane) (9.3 g, 29.3 mmol, 1.0 M solution in THF)
was added to the reaction mixture and stirred for 1 h at
À78 8C. BF3.Et2O (5.6 ml, 44.0 mmol) was added and the
reaction mixture was cooled to À100 8C. Pentafluoroben-
zaldehyde 2 (4.8 g, 24.4 mmol) dissolved in 10 ml THF was
cooled to À78 8C and was added dropwise to the reaction
mixture. It was stirred at À100 8C for 2 h and then warmed
to À78 8C and stirred overnight. The reaction mixture was
oxidized with 12.0 ml of 3.0 M sodium hydroxide and
12.0 ml of 30% hydrogen peroxide and stirred for 10 h at
room temperature. The product was extracted with Et2O,
washed with water, and dried over MgSO4. The crude
4.1.1. Preparation of (1S)-1-pentafluorophenyl-3-
buten-1-ol, 3a
Aldehyde 2 (1.6 g, 8.2 mmol) was added to a stirred
solution of (B)-allyldiisopinocampheylborane 1a (Ipc2BAll)
(19.6 ml of 0.5 M solution in Et2O-pentane) at À100 8C and
maintained at that temperature for 2 h. The reaction was
followed by 11B NMR spectroscopy (d 56). Upon comple-
tion, the mixture was oxidized with 3.6 ml of 3.0 M NaOH
and 3.6 ml of 30% H2O2, stirred for 4 h at room temperature
and extracted with Et2O. The organic layer was dried over
MgSO4, concentrated under vacuum, and purified by silica
gel column chromatography (hexanes: ethyl acetate, 4:1) to
1
obtain 3a. H NMR: d (ppm) (CDCl3): 5.67–5.81 (m, 1H),
5.08–5.18 (m, 3H), 2.72–2.82 (m, 1H), 2.55–2.64 (m, 1H),
2.39 (bs, 1H); 13C NMR: d (ppm) (CDCl3): 146.4–135.9

618
P.V. Ramachandran et al. / Journal of Fluorine Chemistry 125 (2004) 615–620
product was purified by silica gel column chromatography
(hexane:ethyl acetate, 1:1) to obtain the homoallylic alcohol
3d. 1H NMR (300 MHz) d (ppm): 5.48–5.60 (m, 1H),
5.16–5.26 (m, 2H), 5.00 (d, J ¼ 8:31 Hz, 1H), 4.79 (d,
J ¼ 7:14 Hz, 1H), 4.74 (d, J ¼ 7:14 Hz, 1H), 4.51 (t,
J ¼ 8:31 Hz, 1H), 4.18 (bs, 1H), 3.92 (ddd, J ¼ 3:25,
6.69, 11.12 Hz, 1H), 3.74 (ddd, J ¼ 3:03, 4.44, 11.22 Hz,
1H), 3.58–3.61 (m, 2H), 3.42 (s, 3H); 13C NMR (75.5 MHz)
d (ppm): 135.6–146.8 (m, 5C), 133.0, 120.9, 92.8, 80.1,
71.9, 68.5, 67.3, 58.8; 19F NMR (300 MHz) d (ppm): À79.4,
À92.5, À100.1; EI–MS: m/z 235 (M À OH)þ, 197 (100%);
CI-MS: m/z 253 ðM þ HÞþ, 235 [ðM þ H À H2OÞþ, 100%].
(0.08 g, 0.01 mmol) was added and heated for 3 h. After
the completion of reaction (TLC), solvent was evaporated
under vacuum and the crude product was purified by column
chromatography (silica gel, 3:2, hexane:ethyl acetate) to
obtain the lactenone 7a. 1H NMR: d (ppm) (CDCl3): 6.99–
7.05 (m, 1H), 6.17 (dd, J ¼ 2:76, 9.72 Hz, 1H), 5.79 (dd,
J ¼ 3:83, 12.95 Hz, 1H), 3.01–3.11 (m, 1H), 2.47–2.57 (m,
1H); 13C NMR: d (ppm) (CDCl3): 162.7, 144.8, 134.2–144.4
(m, 5C), 121.4, 69.7, 28.6; 19F NMR: d (ppm) (CDCl3):
À78.26, À89.21, À98.28; EI–MS: m/z 194, 68 (100%);
CI–MS: m/z 265 [ðM þ HÞþ, 100%].
4.1.9. (5R, 6S)-5-methyl-6-pentafluorophenyl-5,
6-dihydropyran-2-one, 7b
4.1.5. Preparation of (1S)-1-pentafluorophenyl-3-butenyl
prop-2-enoate, 4a
1
Procedure same as that of 7a. H NMR (300 MHz) d
Alcohol 3a (0.65 g, 2.7 mmol) was dissolved in CH2Cl2
(6.0 ml) and cooled to 0 8C. Acryloyl chloride (0.3 ml,
4.1 mmol) and triethylamine (0.9 ml, 6.8 mmol) were added
to it at 0 8C and stirred for 1 h at room temperature. After the
completion of the reaction as indicated by TLC, the reaction
mixture was filtered over magnesium sulphate pad and
purified by column chromatography (silica gel, 9:1, hexane:
(ppm): 7.06 (dd, J ¼ 6:06, 9.90 Hz, 1H), 6.10 (d, J ¼
8:85 Hz, 1H), 5.93 (d, J ¼ 3:96 Hz, 1H), 2.61–2.68 (m,
1H), 1.13 (d, J ¼ 7:13 Hz, 3H); 13C NMR (75.5 MHz)
d (ppm): 162.7, 150.8, 119.9, 74.5, 33.8, 12.7; EI–MS:
m/z 195, 82 [C5H6Oþ, 100%], 54; CI–MS: m/z 279
[ðM þ HÞþ, 100%]; HRMS–CI: 279.0435 (actual),
279.0445 (calcd.).
1
ethyl acetate) to obtain pure acrylate ester 4a. H NMR: d
(ppm) (CDCl3): 6.44 (dd, J ¼ 1:37, 17.26 Hz, 1H), 6.08–
6.18 (m, 2H), 5.89 (dd, J ¼ 1:38, 10.44 Hz, 1H), 5.63–5.77
(m, 1H), 5.08–5.15 (m, 2H), 2.83–2.93 (m, 1H), 2.65–2.75
(m, 1H); 13C NMR: d (ppm) (CDCl3): 165.0, 147.3–136.1
(m, 5C), 131.9, 131.6, 127.6, 119.4, 66.5, 37.8; 19F NMR: d
(ppm) (CDCl3): À79.21, À91.47, À99.32.
4.1.10. (5S, 6S)-5-methyl-6-pentafluorophenyl-5,
6-dihydropyran-2-one, 7c
Procedure same as that of 7a. H NMR (300 MHz) d
1
(ppm): 6.79 (dd, J ¼ 1:92, 9.84 Hz, 1H), 6.12 (dd, J ¼ 2:64,
9.81 Hz, 1H), 5.40 (d, J ¼ 11:79 Hz, 1H), 3.12–3.24 (m,
1H), 1.07 (d, J ¼ 7:41 Hz, 3H); 13C NMR (75.5 MHz) d
(ppm): 162.6, 136.4–147.2 (m, 5C), 151.2, 120.3, 75.5, 32.7,
15.3; 19F NMR (300 MHz) d (ppm): À77.5, À88.9, À98.2;
EI–MS: m/z 195, 82 [C5H6Oþ, 100%], 54; CI–MS: m/z
279 [ðM þ HÞþ, 100%]; HRMS–CI: 279.0435 (actual),
279.0445 (calcd.).
4.1.6. Preparation of (1S, 2S)-2-methyl-
1-pentafluorophenyl-3-butenyl prop-2-enoate, 4c
1
Procedure same as that of 4a. H NMR (300 MHz) d
(ppm): 6.43 (dd, J ¼ 1:47, 17.28 Hz, 1H), 6.10 (ddd,
J ¼ 1:50, 11.94, 17.28 Hz, 1H), 5.73–5.90 (m, 3H), 5.08–
5.17 (m, 2H), 2.86–2.99 (m, 1H), 0.96 (d, J ¼ 6:93 Hz, 3H);
13C NMR (75.5 MHz) d (ppm): 165.1, 136.1–146.6 (m, 5C),
138.6, 131.8, 127.6, 116.7, 70.4, 41.4, 16.0; 19F NMR
(300 MHz) d (ppm): À78.4, À91.5, À99.2.
4.1.11. (5R, 6R)-5-(2-methoxyethoxymethoxy)-
6-pentafluorophenyl-5, 6-dihydropyran-2-one, 7d
1
Procedure same as that of 7a. H NMR (300 MHz) d
(ppm): 7.16 (dd, J ¼ 5:46, 9.87 Hz, 1H), 6.27 (d,
J ¼ 9:93 Hz, 1H), 5.90 (d, J ¼ 3:51 Hz, 1H), 4.72 (d,
J ¼ 7:20 Hz, 1H), 4.52 (d, J ¼ 7:20 Hz, 1H), 4.26 (dd,
J ¼ 3:60, 5.43 Hz, 1H), 3.60–3.66 (m, 1H), 3.42–3.46 (m,
2H), 3.52 (s, 3H), 3.31–3.38 (m, 1H); 13C NMR (75.5 MHz)
d (ppm): 161.4, 142.9, 123.2, 94.8, 74.1, 71.3, 67.3, 66.7,
59.0; 19F NMR (75.5 MHz) d (ppm): À76.5, À90.1, À99.0;
EI–MS: m/z 323 (M-CH2OCH3), 263, 195, 89, 59
[CH3OCH2CH2þ, 100%]; CI–MS: m/z 369 [ðM þ HÞþ,
100%], 281, 263, 195, 172, 165, 105; HRMS–CI:
369.0753 (actual), 369.0761 (calcd).
4.1.7. Preparation of (1R, 2R)-2-(2-
methoxyethoxymethoxy)-1-pentafluorophenyl-3-butenyl
prop-2-enoate, 4d
1
Procedure same as that of 4a. H NMR (300 MHz) d
(ppm): 6.47 (dd, J ¼ 1:26, 17.25 Hz, 1H), 6.09–6.19 (m,
2H), 5.91 (dd, J ¼ 1.38, 10.44 Hz, 1H), 5.53–5.65 (m, 1H),
5.22–5.30 (m, 2H), 4.68–4.79 (m, 3H), 3.71–3.78 (m, 1H),
3.46–3.65 (m, 3H), 3.39 (s, 3H); 13C NMR (75.5 MHz) d
(ppm): 164.9, 137.8–146.8 (m, 5C), 132.2, 127.5, 121.7,
92.9, 76.7, 71.6, 68.8, 66.9, 59.0; 19F NMR (300 MHz) d
(ppm): À77.6, À90.6, À99.2.
4.1.12. Preparation of (6S)-6-pentafluorophenyl-
tetrahydropyran-2-one, 8a
4.1.8. Preparation of (6S)-6-pentafluorophenyl-5,
6-dihydropyran-2-one, 7a
Acrylate 4a (0.5 g, 1.9 mmol) was heated in toluene
(20.0 ml) at 80 8C. Grubbs’ second-generation catalyst
Dihydro-pyranone 7a (0.1 g, 0.5 mmol) was dissolved in
ethyl acetate (2.0 ml). 0.1 g 10% palladium over charcoal
was added and stirred under hydrogen atmosphere over-
night. The reaction mixture was filtered over silica gel; the

P.V. Ramachandran et al. / Journal of Fluorine Chemistry 125 (2004) 615–620
619
crude product was concentrated under vacuum and purified
by column chromatography (silica gel, hexanes:ethyl acet-
ate, (3:1)) to obtain saturated lactone 8a. 1H NMR
(300 MHz) d (ppm): 5.71 (dd, J ¼ 3:90, 10.71 Hz, 1H),
2.56–2.85 (m, 2H), 1.92–2.36 (m, 4H); 13C NMR
(75.5 MHz) d (ppm): 169.5, 135.6–147.5 (m, 5C), 72.7,
29.7, 27.6, 19.4; 19F NMR (300 MHz) d (ppm): À80.2,
À90.2, À98.6.
(0.234 g, 0.75 mmol) in ethanol at RT and cooled to 0 8C.
Acetic acid (0.12 ml) was then added, followed by the
addition 0.14 g (0.5 mmol) of 12 dissolved in 2 ml of
THF–ethanol (1:1) and stirred for 20 min. The product
was extracted with ethyl acetate, washed with brine, and
dried over MgSO4. Evaporation of the solvents, followed by
column chromatography over silica (ethyl acetate:hexane:
1
3:2 as eluent) provided the hydroxylactone 13. H NMR:
d (ppm) (CDCl3): 6.15 (dd, J ¼ 3:83, 11.67 Hz, 1H), 4.49–
4.62 (m, 1H), 2.75–2.83 (m, 3H), 2.30–2.39 (m, 1H),
2.13–2.18 (m, 1H); 13C NMR: d (ppm) (CDCl3): 169.0,
136.1–146.9 (m, 5C), 68.3, 62.7, 38.4, 34.2.
4.1.13. (5R, 6S)-5-methyl-6-pentafluorophenyl
tetrahydropyran-2-one, 8b
1
Procedure same as that of 8a. H NMR (300 MHz) d
(ppm): 5.86 (d, J ¼ 4:95 Hz, 1H), 2.58–2.84 (m, 2H), 2.39–
2.44 (m, 1H), 1.92–2.01 (m, 1H), 1.69–1.80 (m, 1H); 0.95 (d,
J ¼ 6:87 Hz, 3H); 13C NMR (75.5 MHz) d (ppm): 169.2,
134.6–146.4 (m, 5C), 77.1, 31.8, 28.8, 25.4, 14.7; 19F NMR
(300 MHz) d (ppm): À77.8, À90.4, À98.5; EI–MS: m/z 280
(M)þ, 208, 181, 56 [CH2CH2COþ, 100%]; CI–MS: m/z 281
[ðM þ HÞþ, 100%]; HRMS–EI: m/z 280.0521 (actual),
280.0523 (calcd).
Acknowledgements
Financial support from the Herbert C. Brown Center for
Borane Research [19] and Aldrich Chemical Company is
greatly acknowledged.
4.1.14. (5S, 6S)-5-Methyl-6-pentafluorophenyl
tetrahydropyran-2-one, 8c
Procedure same as that of 8a. H NMR (300 MHz) d
References
1
[1] I. Collins, J. Chem. Soc. Perkin Trans. 1 11 (1999) 1377.
[2] H.M.R. Hoffmann, J. Rabe, Angew. Chem. Int. Ed. Engl. 24 (1985)
94.
(ppm): 5.30 (d, J ¼ 10:92 Hz, 1H), 2.56–2.84 (m, 2H),
2.24–2.44 (m, 1H), 2.04–2.14 (m, 1H), 1.62–1.84 (m,
1H), 0.94 (d, J ¼ 6:36 Hz, 3H); 13C NMR (75.5 MHz) d
(ppm): 169.4, 136.2–146.6 (m, 5C), 78.3, 32.5, 29.9, 28.2,
16.8; 19F NMR (300 MHz) d (ppm): À79.5, À90.0, À98.6;
EI–MS: m/z 280 (M)þ, 56 (100%); CI–MS: m/z 281
[ðM þ HÞþ, 100%]; HRMS–EI: m/z 280.0514 (actual),
280.0523 (calcd).
[3] (a) P.V. Ramachandran, J.S. Chandra, M.V.R. Reddy, J. Org. Chem.
67 (2002) 7547;
(b) M.V.R. Reddy, A.J. Yucel, P.V. Ramachandran, J. Org. Chem. 66
(2001) 2512;
(c) M.V.R. Reddy, H.C. Brown, P.V. Ramachandran, J. Organometal.
Chem. 624 (2001) 239;
(d) M.V.R. Reddy, J.P. Rearick, N. Hoch, P.V. Ramachandran, Org.
Lett. 3 (2001) 19;
(e) P.V. Ramachadran, M.V.R. Reddy, H.C. Brown, Tetrahedron
Lett. 41 (1999) 583;
4.1.15. (3R, 4R, 6S) 4-pentafluorophenyl-3, 7-dioxa-
bicyclo [4.1.0] heptan-2-one, 12
(f) P.V. Ramachandran, M.V.R. Reddy, H.C. Brown, J. Ind. Chem.
Soc. (1999) 739.
a-Pyrone 7a (1.0 g, 3.9 mmol) in methanol was treated
with 1.33 ml (13.2 mmol) of H2O2 and 0.39 ml of 6 N NaOH
at 0 8C. The reaction mixture was stirred for 1 h, diluted with
Et2O and water, acidified with concentrated HCl, and
extracted with Et2O (3 ꢁ 50 ml). The organic layers were
concentrated under aspirator vacuum. pPTS was added to
the crude product and refluxed in toluene using a Dean–
Stark apparatus. The crude product was concentrated under
vacuum and purified by column chromatography (EtOA-
[4] (a) D. Seebach, P. Renaud, Helv. Chim. Acta 68 (1985) 2342;
(b) Y. Komatsu, F. Sasaki, S. Takei, T. Kitazume, J. Org. Chem. 63
(1998) 8058;
(c) P. Bravo, M. Frigerio, A. Melloni, W. Panzeri, C. Pesenti, F.
Viani, M. Zanda, Eur. J. Org. Chem. (2002) 1895.
[5] (a) P.V. Ramachandran, M.P. Jennings, Chem. Commun. (2002) 386;
(b) P.V. Ramachandran, M.P. Jennings, Org. Lett. 3 (2001) 3789;
(c) M.P. Jennings, E.A. Cork, P.V. Ramachandran, J. Org. Chem. 65
(2000) 8763;
(d) H.C. Brown, G.M. Chen, M.P. Jennings, P.V. Ramachandran,
Angew. Chem. Intl. Ed. Engl. 38 (1999) 2052;
(e) P.V. Ramachandran, M.P. Jennings, H.C. Brown, Org. Lett. 1
(1999) 1399.
1
c:hexane, 1:4) to obtain the epoxy lactone 12. H NMR
(300 MHz) d (ppm): 5.92 (dd, J ¼ 3:30, 12.30 Hz, 1H),
3.83–3.85 (m, 1H), 3.71–3.73 (m, 1H), 2.73 (dd, J ¼ 12:28,
14.95 Hz, 1H), 2.53 (dt, J ¼ 3:12, 14.95 Hz, 1H), 13C NMR
(75.5 MHz) d (ppm): 165.9, 136.4–144.4 (m, 5C), 77.3,
65.9, 51.9, 49.0, 28.2; 19F NMR (300 MHz) d (ppm):
À78.8, À88.8, À98.1.
[6] (a) Asymmetric fluoroorganic chemistry, in: P.V. Ramachandran
(Ed.), ACS Symposium Series 746, American Chemical Society,
Washington, DC, 1999;
(b) D.J.S. Kumar, S. Madhavan, P.V. Ramachandran, H.C. Brown,
Tetrahedron Asymm. 11 (2000) 4629.
[7] (a) P.V. Ramachandran, Aldrichim. Acta 35 (2002) 23;
(b) H.C. Brown, P.V. Ramachandran, J. Organomet. Chem. 500
(1995) 1.
4.1.16. (4R, 6S)-4-hydroxy-6-pentafluorophenyl-
tetrahydropyran-2-one, 13
Sodium boro-hydride (0.057 g, 1.5 mmol) was added, in
small portions, to a stirred solution of diphenyldiselenide
[8] H.C. Brown, P.K. Jadhav, J. Am. Chem. Soc. 105 (1983) 2092.
[9] (a) H.C. Brown, K.S. Bhat, J. Am. Chem. Soc. 108 (1986) 293;
(b) H.C. Brown, K.S. Bhat, J. Am. Chem. Soc. 108 (1986) 5919.

620
P.V. Ramachandran et al. / Journal of Fluorine Chemistry 125 (2004) 615–620
[10] (a) H.C. Brown, P.K. Jadhav, K.S. Bhat, J. Am. Chem. Soc. 110
(1988) 1535;
(h) R. Filler, Y. Kobayashi (Eds.), Biomedical Aspects of Fluorine
Chemistry, Elsevier Biomedical, Amsterdam, 1982;
(i) A.S. Kiselyov, L. Strekowski, Org. Prep. Proc. Int. 28 (1996)
289;
(b) P.V. Ramachandran, B. Prabhudas, D. Pratihar, J.S. Chandra,
M.V.R. Reddy, Tetrahedron Lett. 44 (2003) 3745.
[11] (a) R.H. Grubbs, S. Chang, Tetrahedron 54 (1998) 4413;
(b) A. Furstner, Angew. Chem. Int. Ed. 39 (2000) 3013;
(c) T.M. Trnka, R.H. Grubbs, Acc. Chem. Res. 34 (2001) 18.
[12] (a) A. Endo, M. Kuroda, Y. Tsujita, J. Antibiot. 29 (1976) 1346;
(b) A.G. Brown, T.C. Smale, T.J. King, R. Hasenkamp, R.H.
Thompson, J. Chem. Soc. Perkin Trans. 1 (1976) 1165;
(c) A.W. Alberts, T.C. Smale, Proc. Natl. Acad. Sci. U.S.A. 77
(1980) 3957;
(j) D.B. Harper, D. O’Hagan, Nat. Prod. Rep. (1994) 123;
(k) Synthesis and chemistry of agrochemicals III, in: D.R. Baker,
J.G. Fenyes, J.J. Steffens (Eds.), ACS Symposium Series 504,
American Chemical Society, Washington, DC, 1992
[16] (a) P. Deslongchamps, Stereo-Electron. Effects (1983) 209;
(b) C.H. Heathcock, E. Kleinman, E.S. Binley, J. Am. Chem. Soc.
100 (1978) 8036;
(c) H.O. House, W.F. Fischer Jr, J. Org. Chem. 33 (1968) 949;
(d) N.L. Allinger, C. K. Riew, Tetrahedron Lett. (1966) 1269.
[17] (a) R. Ballini, E. Marcantoni, M. Petrini, J. Chem. Soc. Perkin
Trans. 1 (1991) 490;
(d) P.R. Hebert, J.M. Gaziano, K.S. Chan, C.H. Hennekens, JAMA
278 (1997) 4.
[13] C.I. Carswell, G.L. Plosker, B. Jarvis, Drugs 62 (2002) 2075.
[14] (a) S.Y. Sit, R.A. Parker, I. Motoc, W. Han, N. Balasubramanian,
J.D. Catt, P.J. Brown, W.E. Harte, M.D. Thompson, J.J. Wright, J.
Med. Chem. 33 (1990) 2982;
(b) S. Takano, Y. Shimazaki, Y. Sekiguchi, K. Ogasawara, Synthesis
(1989) 539;
(c) J.M. Escudier, M. Baltas, L. Gorrichon, Tetrahedron Lett. 32
(1991) 5345;
(b) G.E. Stokker, W.F. Hoffman, A.W. Alberts, E.J. Cragoe, A.A.
Deana, J.L. Gilfillan, J.W. Huff, F.C. Novello, J.D. Purgh, R.L. Smith,
A.K. Willard, J. Med. Chem. 28 (1985) 347.
(d) J.M. Escudier, M. Baltas, L. Gorrichon, Tetrahedron 49 (1993)
5253;
[15] (a) V.A. Soloshonok (Ed.), EPC-Synthesis of Fluoroorganic Com-
pounds: Stereochemical Challenges and Biomedical Targets, John
Wiley, Chichester, West Sussex, UK, 1999;
(e) S. Hatakeyama, K. Satoh, S. Takano, Tetrahedron Lett. 34 (1993)
7425;
(f) M. Oizumi, M. Takahashi, K. Ogasiwara, Synlett 9 (1997)
1111;
(b) T. Kitazume, T. Yamazaki, Experimental Methods in Organic
Fluorine Chemistry, Gordon and Breach Science, Amsterdam, 1998;
(c) D.J. Burton, Z.-Y. Yang, W. Qiu, Chem. Rev. 96 (1996) 1641;
(d) I. Ojima, Chem. Rev. 88 (1988) 1011;
(g) S. Schabbert, R. Tiedemann, E. Schaumann, Liebigs Ann. Recl.
(1977) 879;
(h) G. Dujardin, S. Rossignol, E. Brown, Synthesis (1998)
763;
(e) For several recent reviews, see: Biomedical frontiers of fluorine
chemistry, in: I. Ojima, J.R. McCarthy, J.T. Welch (Eds.), ACS
Symposium Series 639, American Chemical Society, Washington,
DC, 1996;
(i) M. Miyazawa, E. Matsuoka, S. Sasaki, S. Oonuma, K.
Maruyama, M. Miyashita, Chem Lett. (1998) 109;
(j) K. Prasad, O. Repic, Tetrahedron Lett. 25 (1984) 3391;
(k) A.K. Ghosh, H. Lei, J. Org. Chem. 65 (2000) 4779.
[18] M. Miyashita, T. Suzuki, M. Hoshino, A. Yoshikoshi, Tetrahedron 53
(1997) 12469.
(f) J.T. Welch, Tetrahedron 43 (1987) 3123;
(g) Biochemistry involving carbon–fluorine bonds, in: R. Filler
(Ed.), ACS Symposium Series 28, American Chemical Society,
Washington, DC, 1976;
[19] Publication #35 from Herbert C. Brown Center for Borane Research.