Diastereoselective synthesis of propargylic fluorides and its application in preparation of monofluorinated sugar

Article abstract of DOI:10.1016/j.tet.2010.04.078

An effective method to diastereoselectively synthesize enantioenriched propargylic fluorides was developed via S_NI type reaction of DAST participated dehydroxy-fluorination of diastereomeric propargylic alcohol cobaltcarbonyl complexes. A serious of propargylic fluorides can be prepared by this approach in good yields with moderate to high diastereoselectivities. To demonstrate the application of this approach in synthesis, monofluorinated sugar 12, an important and versatile building block, was prepared in an efficient manner.

Full text of DOI:10.1016/j.tet.2010.04.078

Tetrahedron 66 (2010) 5218e5228
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Diastereoselective synthesis of propargylic fluorides and its application in
preparation of monofluorinated sugar
*
Shilu Fan, Chun-Yang He, Xingang Zhang
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 March 2010
Received in revised form 19 April 2010
Accepted 20 April 2010
Available online 24 April 2010
An effective method to diastereoselectively synthesize enantioenriched propargylic fluorides was de-
veloped via SN1 type reaction of DAST participated dehydroxy-fluorination of diastereomeric propargylic
alcohol cobaltecarbonyl complexes. A serious of propargylic fluorides can be prepared by this approach
in good yields with moderate to high diastereoselectivities. To demonstrate the application of this ap-
proach in synthesis, monofluorinated sugar 12, an important and versatile building block, was prepared
in an efficient manner.
Keywords:
Propargylic fluorides
DAST
Ó 2010 Elsevier Ltd. All rights reserved.
Dicobalt octacarbonyl
Alkyne-cobalt carbonyl complex
Monofluorinated sugar
1. Introduction
Recently, an alternative approach to the synthesis of enantioen-
riched proparylic fluorides via SE20 fluorination of chiral allenylsi-
Although fluorinated compounds rarely exist in nature, they
have attracted considerable attention in life sciences. Because in-
corporation of fluorine atom(s) into an organic molecule usually
leads to profound changes in its physical, chemical, and biological
properties.1 This is probably due to the unique properties of the
fluorine atom and/or the carbonefluorine bond.2 Therefore, sub-
stitution of a hydrogen atom or a hydroxyl group in parent com-
pounds with the fluorine atom is now a common strategy in the
course of developing new drug candidates.1d,3 Among the fluori-
nated compounds, propargylic fluorides constitute a distinct class
of fluorinated compounds that can be used not only as the key
building blocks to access many organofluorinated molecules by
simple functional group manipulations,4 but also as the important
biological probes and inhibitors in life sciences.5 Indeed, many bi-
ologically active molecules, such as insecticides, herbicides, fluori-
nated Vitamin D, and prostanoid analogs, contain propargylic
fluorides motif.5 However, the synthetic methods for this class of
fluorinated compounds, especially asymmetrically synthetic
methods are still limited. The most commonly used method to
asymmetrically synthesize propargylic fluorides thus far is dehy-
droxy-fluorination of enantioenriched propargylic alcohols with
((diethylamino)sulfur trifluoride) (DAST) reported by Gree’s group.6
lanes with Selectfluor was developed by Gouverneur’s group.7 Very
recently, a high enantioselective synthesis of chiral terminal
propargylic fluorides was reported by Jørgensen’s group.8 Although
these attractive approaches have been developed, new methods to
facilitate the access of enantioenriched proparylic fluorides remain
highly desirable. Herein, we disclosed an effective method for
diastereoselective synthesis of enantioenriched propargylic
fluorides from diastereomeric propargylic alcohols via an SN1
reaction in high yields with moderate to high diastereoselectivities
(Scheme 1, Eq. 1) and its application in the synthesis of a mono-
fluorinated sugar.
2. Results and discussion
Our experiments were based on the fact that treatment of
compounds 1aeb or 2a with DAST only provided 7% to 34% yields of
the corresponding diastereomeric porpargylic fluorides (Scheme
1), and that cobalt-carbonyl moiety in alkyne-cobalt carbonyl
complex (Nicholas reaction9) could significantly stabilize the
a
carbocation. Thus, we envisioned that the stable chiral carboca-
tion intermediates induced by alkyne-cobalt carbonyl complex and
the chiral 1,3-dioxolane moiety of diastereomeric mixture of
propargylic alcohol 3 and 4, in which the reaction center is in ra-
cemic form, might provide a good platform to access enantioen-
riched propargylic fluorides in good yields. To the best of our
knowledge, the facial diastereoselectivity of intermolecular SN1
* Corresponding author. Tel.: þ86 21 54925333; fax: þ86 21 64166128; e-mail
address: xgzhang@mail.sioc.ac.cn (X. Zhang).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.078

S. Fan et al. / Tetrahedron 66 (2010) 5218e5228
5219
Scheme 1. Dehydroxy-fluorination of diastereomeric propargylic alcohols 1 and 2.
reactions on putative chiral carbocation intermediates has not been
extensively studied.10 Furthermore, the reaction can be easily
scaled up because propargylic alcohols 1 and 2 could be easily
obtained by addition of various of alkynes to readily available 4-O-
(Table 1, entries 4 and 5). Simple treatment of 7 with cerium (IV)
diammonium nitrate (CAN) to remove cobalt-carbonyl moiety
afforded final product 5 in good yields (72e90%, two steps from 3)
without erosion of dr value (Table 1). It should be mentioned that
the epimers anti-7 and syn-7 can be separated by flash silica gel
chromatography,14 and the subsequent treatment of anti-7 or syn-7
with CAN can provide optically pure anti-5 or syn-5 easily.
Encouraged by these results, we then investigated the reaction
to an expanded broad of substrates. Substrate 4a (anti/syn¼1:3), in
which the substituent benzyloxymethylene (BnOCH2) group at
position C1 was omited with respect to 3b, was first tested and
a high diastereoselectivity (anti/syn¼13:1) was achieved (Table 2,
entry 1). More results were summarized in Table 2. High yields and
benzyl-2,3-O-isopropylidene-L
-threose11 and 1-(R)-glyceraldehyde
acetonide,12 respectively. In addition, the resulting enantioenriched
propargylic fluorides 5 and 6 are versatile building blocks for many
unnatural monofluorinated sugars.13
Initially, a mixture of alkyne complexes 3a that was easily pre-
pared in high yield by treatment of propargylic alcohols 1a with
Co2(CO)8 (Scheme 2) was chosen as model substrates for this study.
A survey of a series of reaction conditions showed that treatment of
3a (anti/syn¼2:1) in CH2Cl2 (0.15 M) with 1.2 equiv of DAST at
Scheme 2. Preparation of propargylic alcohol cobaltecarbonyl complexes 3 and 4.
ꢀ78 ꢁC to room temperature afforded 7a in high yield, and anti-7a
was observed as the major product (anti/syn¼5:1) (Table 1, entry 1).
Interestingly, when a higher optically enriched anti-3a (anti/
syn¼6.5:1) was employed as the substrate, better diaster-
eoselectivity (anti/syn¼8:1) was provided (Table 1, entry 2). It was
noteworthy that a gram-scale reaction of anti-3a (anti/syn¼6.5:1,
1.3 g) provided 7a with even higher diastereoselectivity (anti/
syn¼9:1) (Table 1, entry 3). Further investigation of other substrates
showed that the alkyne complexes 3b and 3c also afforded prop-
argylic fluorides in good yields with moderate diastereoselectivities
diastereoselectivities (anti/syn) ranging from 5.1:1 to 17:1 (de-
termined by 19F NMR) were observed for all substrates 4. For all the
aliphatic alkynes, the diastereoselectivities depend on the steric
features of the substituents. The less hindered alkyl substituted
alkyne complexes provided good to high dr values (Table 2, entries
1e6), while bulky substrates afforded moderate diaster-
eoselectivities (Table 2, entries 7e9). Interestingly, the reaction of
compound 4c also provided higher selectivity (anti/syn¼7.6:1) than
its corresponding analogs 3a (anti/syn¼5:1). In the case of 4f, the
cyclopropyl substituted alkyne complex, the dr values were ranged

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S. Fan et al. / Tetrahedron 66 (2010) 5218e5228
Table 1
Table 2
Diastereoselective dehydroxy-fluorination of propargylic alcohol cobalt carbonyl
Diastereoselective dehydroxy-fluorination of propargylic alcohol cobaltecarbonyl
complexes 3 with DASTa
complexes 4 with DASTa
Entry
3, R (anti/syn)
7 (anti/syn)b
7 yield (%)c
5 yield (%)d
Entry
1
4, R (anti/syn)
8
8 yield
6 yield (%)d
(anti/syn)e
(anti/syn)b
(%)c
1
3a, CH2OPMB (2:1)
3a (6.5:1)
3a (6.5:1)
5:1
8:1
9:1
5.4:1
91
90
81
72
2
(82)
(73)
82
4a, CH2OBn (1:2.3)
13:1
100
88 (14:1) (anti-6a,
86 syn-6a, 82)f
87 (9:1)
3e
4
3b, CH2OBn (1.5:1)
81 (anti-5b,
2
3
4b, (CH2)2OBn (1:1.5)
4c, CH2OPMB (1:1)
8.1:1
7.6:1
99
(91)
95 syn-5b, 98)f
anti-6c, 80f;
syn-6c, 75f
87 (8.2:1)
84 (anti-5c,
5
3c,
(1.8:1)
5.4:1
87
92 syn-5c, 87)f
4
5
4d, (CH2)2OPMB (1:2.3)
4e, (CH2)7CH3 (1:1.2)
8.2:1
8.4:1
100
100
95 (9:1)
a
Unless otherwise noted, the reaction was carried out by using 3 (0.3 mmol,
1 equiv) and DAST (1.2 equiv) in a 0.15 M CH2Cl2 solution at ꢀ78 ꢁC to rt.
8.3:1
to 17:1
5.5:1
5.4:1
6:1
6
4f,
(1:1.5)
87
84 (8.3:1 to 17:1)
b
Determined by 19F NMR before column chromatography.
7
8
9
10
4g, CH2OTrt (1:1.3)
4h, t-Bu (1:1)
4i, Cyl (1:1)
100
100
96
87, (anti-6g, 96)f
83, (5:1)
94, (6:1)
d
c
NMR yield determined by 19F NMR using benzotrifluoride (BTF) as an internal
standard, yield in parentheses was isolated yield.
d
Overall yield, two steps from 3.
4j, TMS (1:1.6)
d
Trace
e
The reaction was carried out on a 1.3 g of scale at ꢀ90 ꢁC to ꢀ78 ꢁC to rt.
f
isolated yield from the reaction of anti-7 or syn-7, respectively.
11
12
4k, H (1:1.6)
4l, Ph (1:1.4)
7:1
89
94
9 84 (8:1)
from 8.3:1 to 17:1 (anti/syn) (Table 2, entry 6). Under the similar
conditions, compound 4j bearing a TMS failed to provide the
product (Table 2, entry 10), while the terminal alkyne complexes 4k
furnished the propargylic fluorides in good yield with dr 7:1 (anti/
syn) (Table 2, entry 11). For the aryl substituted alkyne complexes 4l
and 4m, the diastereoselectivties (anti/syn) ranged from 5.1:1 to
6.4:1 (Table 2, entries 12 and 13). Similarly, the enantioenriched
fluorinated complexes 8 can be separated by flash silica gel chro-
matography, which was treated by CAN to provide propargylic
fluorides 6 smoothly without erosion of the dr values. Due to the
low boil point of compound 6k, it was deprotected directly by
treatment with HCl to afford diol 9 in good yield (Table 2, entry 11).
Notably, the enantioenriched propargylic fluorides can be easily
accessed by one pot reaction (Scheme 3). Treatment of the mixture
of 2a with Co2(CO)8 at room temperature, followed by the reaction
with DAST at ꢀ78 ꢁC to rt, and subsequently with CAN afforded the
final product 6a in good yield (70% overall yield) with high dia-
stereoselectivity (anti/syn¼12:1). Transformation of anti-7a also
proved to be an efficient approach to access monofluorinated sugar
12 that can be used as an important and versatile building block to
prepare many other unnatural sugars for chemical biology study,
such as antibiotic.13d As depicted in Scheme 3, 10 was obtained in
86% yield by deprotection of cobalt-carbonyl moiety of anti-7a with
CAN, followed by treatment of the resulting propargylic fluorides
with DDQ. Alcohol 10 was selectively reduced with H2 in the
presence of Lindlar catalyst. The resulting Z-alkene was sub-
sequently oxidized with MnO2 to afford aldehyde 11, which was
then treated with HCl in MeOH to provide monofluorinated sugar
12 in 40% overall yield (three steps).
6.4:1
90 (syn-6l, 98;
anti-6l, 94)f
4m,
13
5.1:1
98
83 (anti-6m, 82)f
(1:1.2)
a
Reactions were carried out by using 4 (0.3 mmol, 1 equiv) and DAST (1.2 equiv)
in a 0.15 M CH2Cl2 solution at ꢀ78 ꢁC to rt.
b
Determined by 19F NMR before column chromatography.
c
NMR yield determined by 19F NMR using benzotrifluoride (BTF) as an internal
standard, yield in parentheses was isolated yield.
d
Overall yield, two steps from 4.
e
f
Determined by 19F NMR after column chromatography.
isolated yield from the reaction of anti-8 or syn-8, respectively.
corresponding syn-5b/anti-5b or syn-6a/anti-6a were provided, re-
spectively. 19F NMR shows that the chemical shifts of anti-5b
(ꢀ184.8 ppm) and anti-6a (ꢀ186.5 ppm) are at higher field than their
diastereoisomers syn-5b (ꢀ181.2 ppm) and syn-6a (ꢀ181.6 ppm). For
all of themajorfluorinated productsof5 or6 prepared byourmethod,
the chemical shifts of 19F NMR signals are at higher field than their
corresponding minor ones (see Supplementary data Table SI). Thus,
the major products were assigned to be anti-5 or anti-6. This config-
uration assignment was further confirmed by the X-ray crystallo-
graphic analysis of optically pure anti-5d16 and anti-6m16 (Fig. 1), in
which anti-5d was prepared from 10 through Mitsunobu reaction.
The enantioenriched anti-1b was synthesized by following
Mukaiyama’s procedure11 (Scheme 5, Eq.1) and syn-2awas obtained
by the reaction of 2a with Lipase AK Amano (Scheme 5, Eq. 2). After
careful separation by flash silica gel chromatography, the anti-2a0
can be provided in high dr value, which was subsequently depro-
tected by K2CO3 to afford anti-2a in 93% yield (Scheme 5, Eq. 3).
Since moderate to high diastereoselectivities of anti-propargylic
fluorides 5 and 6 were obtained from isomeric mixture of prop-
argylic alcohols 1 and 2, the possibility of the SN2 type reaction can
be ruled out. This was further confirmed by the reaction of enan-
tioenriched anti-2a and syn-2a (Scheme 6). Surprisingly, when
The absolute configurations of the propargylic fluorides were
established through the SN2 dehydroxy-fluorination of 1 and 2 with
DAST. As depicted in Scheme 4, four representative substrates anti/
syn-1 and anti/syn-2, whose configurations can be assigned
according to the literature,11,15 were chosen for this study.
When anti-1b (anti/syn¼14:1)/syn-1b (syn/anti¼2.3:1) or anti-2a
(anti/syn¼28:1)/syn-2a (anti/syn¼1:40) were treated with DAST, the

S. Fan et al. / Tetrahedron 66 (2010) 5218e5228
5221
Scheme 3. One pot reaction to prepare anti-6a from 2a and transformation of optically pure propargylic fluoride anti-7a to monofluorinated sugar 12.
Scheme 4. Dehydroxy-fluorination of enantioenriched anti-/syn-1b and anti-/syn-2a with DAST.

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S. Fan et al. / Tetrahedron 66 (2010) 5218e5228
Figure 1. X-ray crystal structure of compound anti-5d and anti-6m.
Scheme 5. Preparation of enantioenriched anti-1b and anti-/syn-2a.

S. Fan et al. / Tetrahedron 66 (2010) 5218e5228
5223
Scheme 6. Diastereoselective dehydroxy-fluorination of propargylic alcohols anti-2a and syn-2a with DAST.
enantioenriched cobaltecarbonyl complexes anti-4a derived from
anti-2a (anti/syn¼28:1) was treated with DAST at ꢀ78 ꢁC, a high
diastereoselectivity (anti/syn¼29:1) of anti-8a was obtained
(Scheme 6, Eq. 1). However, under the same conditions, the syn-4a
(anti/syn¼1:40) only provided moderate dr value (anti/syn¼4:1)
(Scheme 6, Eq. 2), suggesting that different cation transition states
are involved in the reaction, and the chiral 1,3-dioxolane moiety of
3 and 4 is a critical factor for the diastereoselectivities. The origins
of diastereoselectivities for 5 and 6 may be explained in Scheme 7.
When the cobaltecarbonyl complexes A were treated with DAST,
a cationic intermediate B was generated. It has been demonstrated
that the positive charge of this kind of cation may localize on car-
bon (carbocation) or cobalt (cobalt cation), in which the latter is
assumed to be the better representative of the charge distribution
in these complexes.17 Thus, the cobalt cation intermediates TSI and
TSII were employed to explain the diastereoselectivities. When
anti-A was treated with DAST at ꢀ78 ꢁC, the intermediate TSI was
generated. Because of the steric repulsion between cobalt-
ecarbonyl complex and BnOCH2 and/or Ha, TSI is a favored tran-
sition state. As a result, the addition of fluoride anion to TSI should
be from less hindered Re face to generate anti product. When TSII
was produced from syn-A, the diastereoselectivity of the fluorina-
tion depends on the isomerization rate between TSI and TSII. Since
the fluorination reaction was carried out at low temperature, the
isomerization of TSII to TSI was slow, and both additions of fluoride
anion to TSI from less hindered Re face and TSII from less hindered
Scheme 7. Mechanistic proposal on stereocontrol.

5224
S. Fan et al. / Tetrahedron 66 (2010) 5218e5228
Si face occurred, respectively. As a result, a moderate anti diaster-
eoselectivity was observed. Therefore, for the fluorination of iso-
meric mixture of propargylic alcohols cobaltecarbonyl complexes 7
and 8, the comprehensive results are anti as major products.
(%) 383 (MþꢀMe), 249, 91(100), 77, 65, 43. HRMS: calculated for
C23H24O4F (MþꢀMe): 383.1659; found: 383.1622.
4.3.2. (4R,5S)-4-((R)-4-(Benzyloxy)-1-fluorobut-2-ynyl)-5-(benzylox-
ymethyl)-2,2-dimethyl-1,3-dioxolane (syn-5b). 1H NMR (300 MHz,
3. Conclusion
CDCl3)
d
ppm 7.27e7.17 (m,10H), 5.21 (dd, J¼47.7, 5.4 Hz,1H), 4.51 (s,
2H), 4.48 (s, 2H), 4.18e4.14 (m, 1H), 4.07e4.00 (m, 3H), 3.64 (dd,
J¼10.8, 3.9 Hz, 1H), 3.56 (dd, J¼10.5, 6.0 Hz, 1H), 1.40 (s, 3H), 1.38 (s,
In summary, an effective method to diastereoselectively syn-
thesize propargylic fluorides via SN1 type of dehydroxy-fluorina-
tion of propargylic alcohols cobaltecarbonyl complexes with DAST
was developed. It was demonstrated that the dicobalt octacarbonyl
facilitated asymmetric SN1 type dehydroxy-fluorination between
the chiral cation intermediates and fluoride anion. The reaction
scope can be extended to a series of aliphatic and aromatic alkynes,
which provided an alternative approach to access propargylic
fluorides. In view of the biological application, the resulting enan-
tioenriched propargylic fluoride was further transformed into
monofluorinated sugar 12 in an efficient manner. Further applica-
tions of propargylic fluorides 5 and 6 in the synthesis of bioactive
molecules are under active investigation in our laboratory.
3H). 19F NMR (282 MHz, CDCl3):
d
ppm ꢀ181.2 (ddt, J¼47.7, 13.5,
5.9 Hz). IR (thin film): nmax 2989, 2934, 2864, 1728, 1641, 1455 cmꢀ1
.
MS (EI): m/z (%) 383 (MþꢀMe), 307, 249, 91 (100), 77, 65, 43.
4.3.3. (4S,5R)-4-(Benzyloxymethyl)-5-((S)-3-cyclopropyl-1-fluo-
20
roprop-2-ynyl)-2,2-dimethyl-1,3-dioxolane (anti-5c). [
a]
D
ꢀ8.72 (c
1.1, CH2Cl2). 1H NMR (300 MHz, CDCl3)
d
ppm 7.36e7.26 (m, 5H), 5.19
(dt, J¼48.9, 1.8 Hz, 1H), 4.62 (s, 2H), 4.34e4.28 (m, 1H), 4.05 (ddd,
J¼17.4, 7.5, 3.0 Hz, 1H), 3.73 (dd, J¼10.5, 3.9 Hz, 1H), 3.64 (dd, J¼10.5,
6.0 Hz, 1H), 1.46 (s, 3H), 1.44 (s, 3H), 1.24e1.18 (m, 1H), 0.82e0.65 (m,
4H). 19F NMR (282 MHz, CDCl3):
d
ppm ꢀ183.0 (ddd, J¼49.1, 18.3,
3.7 Hz).13C NMR (100 MHz, CDCl3):
d
ppm 137.9,128.4,127.64,127.60,
110.5, 94.8, 81.7 (d, J¼174.7 Hz), 78.9 (d, J¼23.1 Hz), 76.0 (d, J¼3.7 Hz),
73.5, 70.8, 68.5 (d, J¼25.3 Hz), 27.3, 26.5 (d, J¼2.2 Hz), 8.4, 8.35, ꢀ0.69,
ꢀ0.73. IR(thin film):nmax 2990, 2935, 2867, 2241,1497,1455 cmꢀ1. MS
(EI): m/z(%)303(MþꢀMe),221,197, 91(100), 43. HRMS:calculatedfor
C19H23O3F: 318.1631; found: 318.1622.
4. Experimental section
4.1. General procedure for the synthesis of propargylic
alcohol cobaltecarbonyl complexes 3 and 4
Dicobalt octacarbonyl (670 mg, 1.6 mmol, 1.2 equiv) was added
portionwise to a solution of propargylic alcohols 1 or 2 (1.6 mmol,
1.0 equiv) in THF (8 mL). The reaction mixture was stirred at room
temperature for 12 h and then concentrated. The residue was pu-
rified by column chromatography (petroleum ether/ethyl
acetate¼8:1) to give 3 or 4 as a red oil.
4.3.4. (4S,5R)-4-(Benzyloxymethyl)-5-((R)-3-cyclopropyl-1-fluo-
roprop-2-ynyl)-2,2-dimethyl-1,3-dioxolane
(300 MHz, CDCl3)
(syn-5c). 1H
NMR
d
ppm 7.37e7.29 (m, 5H), 5.10 (ddd, J¼48.9, 6.3,
1.8 Hz, 1H), 4.63 (d, J¼1.8 Hz, 2H), 4.23e4.17 (m, 1H), 4.09e4.00 (m,
1H), 3.75 (dd, J¼10.5, 2.7 Hz, 1H), 3.62 (dd, J¼10.5, 6.0 Hz, 1H). 19F
NMR (282 MHz, CDCl3):
d
ppm ꢀ176.8 (ddd, J¼53.1, 12.4, 4.2 Hz). IR
(thin film): nmax 2989, 2926, 2241, 1455 cmꢀ1. MS (EI): m/z (%) 303
(MþꢀMe), 221, 197, 91(100), 43.
4.2. General procedure for the synthesis of enantioenriched
propargylic fluorides cobaltecarbonyl complexes anti-7 and
anti-8
4.3.5. (4R)-4-(4-(Benzyloxy)-1-fluorobut-2-ynyl)-2,2-dimethyl-1,3-
dioxolane (6a). 1H NMR (300 MHz, CDCl3)
d ppm 7.34e7.29 (m, 5H),
To a solution of 3 or 4 (0.3 mmol,1 equiv) in dry CH2Cl2 (2 mL) was
5.11 (dd, J¼48.0, 5.1 Hz, 1H), 4.58 (s, 2H), 4.32e4.24 (m, 3H),
added dropwise DAST (50
m
L, 0.36 mmol) at ꢀ78 ꢁC under N2. After
4.14e4.05 (m, 2H), 1.45 (s, 3H), 1.37 (s, 3H). 19F NMR (282 MHz,
stirring for 6 h at ꢀ78 ꢁC, the reaction mixture was warmed to room
temperature and stirred overnight. The reaction mixture was diluted
with ethyl acetate, washed with H2O, brine, dried over Na2SO4, and
concentrated to give enantioenriched anti-7 or anti-8. If necessary, 7
or 8 could be further purified by flash silica gel chromatography.
CDCl3)
d
ppm ꢀ180.7 (ddt, J¼47.9, 12.1, 4.8 Hz, 0.07F), ꢀ186.1 (ddt,
J¼49.3, 16.4, 6.2 Hz, 0.93F). 13C NMR (75.4 MHz, CDCl3):
d ppm
137.0, 128.4, 128.0, 127.9, 110.5, 85.9 (d, J¼10.4 Hz), 81.5 (d,
J¼175.6 Hz), 80.2 (d, J¼25.2 Hz), 76.6 (d, J¼25.1 Hz), 71.6, 65.0 (d,
J¼3.3 Hz), 57.0 (d, J¼2.7 Hz), 26.2, 25.1.
4.3. General procedure for the synthesis of enantioenriched
propargylic fluorides anti-5 and anti-6
4.3.6. (R)-4-((S)-4-(Benzyloxy)-1-fluorobut-2-ynyl)-2,2-dimethyl-
20
1,3-dioxolane (anti-6a). [
(300 MHz, CDCl3)
1.5 Hz, 1H), 4.59 (s, 3H), 4.33e4.23 (m, 3H), 4.16e4.09 (m, 2H), 1.46
a
]
D
10.93 (c 1.48, CH2Cl2). 1H NMR
d
ppm 7.35e7.25 (m, 5H), 5.13 (ddd, J¼48.0, 4.2,
To a solution of 7 or 8 (0.3 mmol) in acetone (2 mL) was added
ceric ammonium nitrate (CAN) (660 mg, 1.2 mmol, 4 equiv) in por-
tions. After stirring for 15 min at room temperature, the reactionwas
concentrated. The residue was purified by silica gel chromatography
using petroleum ether/ethyl acetate as eluent to give 5 or 6.
(s, 3H), 1.38 (s, 3H). 19F NMR (282 MHz, CDCl3):
d
ppm ꢀ186.1 (d,
J¼48.3 Hz). 13C NMR (100 MHz, CDCl3):
d ppm 137.0, 128.4, 128.0,
127.96, 110.6, 85.9 (d, J¼13.7 Hz), 81.6 (d, J¼175.6 Hz), 80.2 (d,
J¼33.4 Hz), 76.6 (d, J¼25.1 Hz), 71.7, 65.0 (d, J¼4.3 Hz), 57.0 (d,
J¼3.6 Hz), 26.2, 25.2. IR (thin film): nmax 2987, 2936, 1714, 1523,
1455 cmꢀ1. MS (EI): m/z (%) 278 (Mþ), 157, 101 (100). HRMS: cal-
culated for C16H19O3F: 278.1318; found: 278.1311.
4.3.1. (4R,5S)-4-((S)-4-(Benzyloxy)-1-fluorobut-2-ynyl)-5-(benzylox-
20
ymethyl)-2,2-dimethyl-1,3-dioxolane (anti-5b). [
a
]
D
ꢀ5.16 (c 1.2,
CH2Cl2). 1H NMR (300 MHz, CDCl3)
d
ppm 7.33e7.26 (m, 10H), 5.21
(ddd, J¼48.0, 3.3,1.5 Hz,1H), 4.59 (s, 2H), 4.56 (s, 2H), 4.35e4.29 (m,
1H), 4.15 (d, J¼6.9 Hz, 2H), 4.10 (dd, J¼7.8, 3.3 Hz, 1H), 3.71 (dd,
J¼10.5, 3.6 Hz, 1H), 3.65 (dd, J¼10.8, 6.0 Hz, 1H), 1.46 (s, 3H), 1.45 (s,
4.3.7. (R)-4-((R)-4-(Benzyloxy)-1-fluorobut-2-ynyl)-2,2-dimethyl-
1,3-dioxolane (syn-6a). 1H NMR (300 MHz, CDCl3, 293 K, TMS):
7.36e7.30 (m, 5H), 5.10 (ddt, J¼48.6, 5.4, 1.5 Hz, 1H), 4.59 (s, 2H),
4.41e4.30 (m, 1H), 4.24 (dd, J¼6.3, 1.2 Hz, 1H), 4.16e4.10 (m, 1H),
3.94 (dd, J¼8.7, 6 Hz, 1H), 1.47 (s, 3H), 1.48 (s, 3H). 19F NMR
3H). 19F NMR (282 MHz, CDCl3)
d
ppm ꢀ184.8 (ddt, J¼48.0, 17.8,
6.2 Hz). 13C NMR (100 MHz, CDCl3)
d
ppm 137.7, 136.9, 128.4, 128.3,
128.0, 127.9, 127.9, 127.8, 127.6, 127.5, 110.6, 86.7 (d, J¼10.4 Hz), 81.5
(d, J¼176.2 Hz), 79.5 (d, J¼26.0 Hz), 78.6 (d, J¼23.0 Hz), 76.2 (d,
J¼3.7 Hz), 73.4, 71.7, 70.5, 56.9 (d, J¼3.0 Hz), 27.2, 26.5. IR (thin
film): nmax 3032, 2988, 2935, 2868, 1726, 1455 cmꢀ1. MS (EI): m/z
(282 MHz, CDCl3):
d
ppm ꢀ180.7 (ddt, J¼49.6, 12.1, 6.2 Hz).
4.3.8. (4R)-4-(5-(Benzyloxy)-1-fluoropent-2-ynyl)-2,2-dimethyl-1,3-
dioxolane (6b). 1H NMR (300 MHz, CDCl3)
ppm 7.40e7.25 (m, 5H),
d

S. Fan et al. / Tetrahedron 66 (2010) 5218e5228
5225
5.16e4.92 (dt, J¼48.9, 2.1 Hz, 1H), 4.54 (s, 2H), 4.30e4.19 (m, 1H),
4.12e4.03 (m, 2H), 3.59 (t, J¼6.6 Hz, 2H), 2.57 (m, 2H), 1.44 (s, 3H),
J¼49.5, 3.9, 1.8 Hz, 1H), 4.22 (ddd, J¼22.5, 10.5, 5.7 Hz, 1H),
4.11e4.02 (m, 2H), 1.44 (s, 3H), 1.37 (s, 3H), 1.28 (m, 1H), 0.85e0.70
1.37 (s, 3H). 19F NMR (282 MHz, CDCl3)
d
ppm ꢀ179.2 (dm,
(m, 4H). 19F NMR (282 MHz, CDCl3)
d
ppm ꢀ177.5 (dd, J¼51.4,
J¼49.6 Hz, 0.08F), ꢀ185.7 (ddt, J¼47.6, 15.5, 6.2 Hz). 13C NMR
14.1 Hz, 0.05F), ꢀ184.2 (ddd, J¼49.9, 16.1, 4.5 Hz, 0.95F). 13C NMR
(75.4 MHz, CDCl3)
d
ppm 137.8, 128.3, 127.7, 127.6, 110.4, 87.7 (d,
(100 MHz, CDCl3)
d
ppm 110.4, 94.1 (d, J¼15.0 Hz), 81.9 (d,
J¼10.5 Hz), 80.5 (d, J¼175.8 Hz), 77.0 (d, J¼24.6 Hz), 75.0 (d,
J¼25.1 Hz), 73.0, 67.7 (d, J¼2.9 Hz), 65.0 (d, J¼3.9 Hz), 26.2, 25.3,
20.2. IR (thin film): nmax 3032, 2989, 2930, 2241,1455 cmꢀ1. MS (EI):
m/z (%) 277 (MþꢀHþ), 101, 91 (100). HRMS: calculated for
C17H21O3F: 292.1475; found: 292.1476.
J¼174.9 Hz), 77.3, 76.9, 69.0 (d, J¼25.2 Hz), 64.9 (d, J¼3.8 Hz), 26.2,
25.3, 8.4, ꢀ0.1, ꢀ0.6. IR (thin film): nmax 2989, 2929, 2855,
2243 cmꢀ1. MS (EI): m/z (%) 197 (MþꢀHþ), 97 (100), 77, 61, 57, 51, 41.
HRMS: calculated for C11H15O2F: 198.1056; found: 198.1053.
4.3.14. (R)-4-((S)-1-Fluoro-4-(trityloxy)but-2-ynyl)-2,2-dimethyl-
4.3.9. (R)-4-((S)-1-Fluoro-4-(4-methoxybenzyloxy) but-2-ynyl)-2,2-
1,3-dioxolane (anti-6g). [
CDCl3):
ppm 7.46e7.21 (m, 15H), 5.09 (dt, J¼48.6, 2.1 Hz, 1H), 4.22
a]
20 9.2, (c 1.2, CH2Cl2). 1H NMR (300 MHz,
D
20
dimethyl-1,3-dioxolane (anti-6c). [
a
]
10.71 (c 1.24, CH2Cl2). 1H
d
D
NMR (300 MHz, CDCl3)
d
ppm 7.29 (d, J¼8.5 Hz, 2H), 6.90 (d,
(ddd, J¼17.1, 6.3, 4.5 Hz, 1H), 4.11e4.04 (m, 2H), 3.85 (d, J¼3.3 Hz,
J¼8.5 Hz, 2H), 5.14 (dd, J¼48.3, 4.5 Hz, 1H), 4.54 (s, 1H), 4.31 (ddd,
J¼15.3, 10.5, 5.1 Hz, 1H), 4.22 (dd, J¼6, 0.6 Hz, 1H), 4.17e4.07 (m,
2H), 3.82 (s, 3H), 1.47 (s, 3H), 1.39 (s, 3H). 19F NMR (282 MHz,
2H), 1.45 (s, 3H), 1.37 (s, 3H). 19F NMR (282 MHz, CDCl3):
d
d
ppm
ppm
ꢀ187.4 (ddt, J¼49.1, 16.1, 7.9 Hz). 13C NMR (75.4 MHz, CDCl3)
146.8, 143.2, 128.5, 127.95, 127.90, 127.89, 127.2, 110.6, 87.6, 86.8 (d,
J¼10.0 Hz), 82.0, 81.6 (d, J¼176.4 Hz), 76.6 (d, J¼8.4 Hz), 64.9 (d,
J¼3.8 Hz), 52.9 (d, J¼2.3 Hz), 29.7. 26.2. 25.3. IR (thin film): nmax
3060, 2988, 2927, 1491, 1449 cmꢀ1. MS (EI): m/z (%) 430 (Mþ), 415,
353, 243 (100), 183, 165, 105, 77, 43. HRMS: calculated for
C28H27O3F: 430.1944; found: 430.1939.
CDCl3):
(100 MHz, CDCl3)
d
ppm ꢀ185.8 (ddt, J¼48.2, 13.8, 5.9 Hz). 13C NMR
d ppm 159.4, 129.7, 129.0, 113.8, 110.5, 86.0 (d,
J¼9.5 Hz), 81.6 (d, J¼176.5 Hz), 80.1 (d, J¼25.3 Hz), 76.6 (d,
J¼24.6 Hz), 71.3, 65.0 (d, J¼4.0 Hz), 56.6, 55.2, 26.21, 25.17. IR (thin
film): nmax 2988, 2937, 1612, 1514, 1422, 1250, 1220, 1112, 1074, 846,
819 cmꢀ1. MS (EI): m/z (%) 308 (Mþ), 157, 136, 121 (100), 101. HRMS:
calculated for C17H21O4F: 308.1424; found: 308.1429.
4.3.15. (4R)-4-(1-Fluoro-4,4-dimethylpent-2-ynyl)-2,2-dimethyl-1,3-
dioxolane (6h). 1H NMR (300 MHz, CDCl3)
d
ppm 5.05 (dd, J¼49.5,
4.3.10. (R)-4-((R)-1-Fluoro-4-(4-methoxybenzyloxy)
but-2-ynyl)-
3.0 Hz, 0.85H), 4.96 (dd, J¼49.5, 7.5 Hz, 0.15H), 4.19 (m, 1H), 4.00
2,2-dimethyl-1,3-dioxolane (syn-6c). 1H NMR (300 MHz, CDCl3)
(dt, J¼16.8, 8.7 Hz, 2H), 1.38 (s, 3H), 1.31 (s, 3H), 1.16 (s, 9H). 19F NMR
d
ppm 7.27 (d, J¼8.1 Hz, 2H), 6.88 (d, J¼8.7 Hz, 2H), 5.09 (ddd,
(282 MHz, CDCl3)
d
ppm ꢀ177.6 (dd, J¼49.7, 8.8 Hz, 0.17F), ꢀ185.9
J¼48.6, 6.9, 1.2 Hz, 1H), 4.51 (s, 2H), 4.35 (m, 1H), 4.17 (d, J¼6.6 Hz,
2H), 4.12 (td, J¼8.7, 1.5 Hz, 1H), 3.94 (dd, J¼9.0, 6.0 Hz, 1H), 3.80 (s,
(dd, J¼48.9,19.2 Hz, 0.83F). 13C NMR (75.4 MHz, CDCl3)
d ppm 110.8,
110.4, 99.0 (d, J¼10.4 Hz), 81.7 (d, J¼174.2 Hz), 77.3, 72.2 (d,
J¼25.7 Hz), 65.7, 64.7 (d, J¼4.4 Hz), 30.9, 30.3, 29.7, 27.4, 26.6, 25.4,
25.3. IR (thin film): nmax 2990, 2935, 2242, 1383 cmꢀ1. MS (EI): m/z
(%) 183, 141, 101 (100), 91, 77, 73, 43, 41. HRMS: calculated for
C12H19O2F: 214.1369; found: 214.1373.
3H), 1.47 (s, 3H), 1.38 (s, 3H). 19F NMR (282 MHz, CDCl3):
d
d
ppm
ppm
ꢀ180.6 (ddt, J¼47.6, 11.3, 5.9 Hz). 13C NMR (100 MHz, CDCl3):
159.5, 129.7, 129.0, 113.8, 111.0, 86.3, 83.1 (d, J¼174.5 Hz), 79.6 (d,
J¼25.4 Hz), 76.7 (d, J¼23.1 Hz), 71.4, 65.5 (d, J¼4.6 Hz), 56.6 (d,
J¼2.9 Hz), 55.2, 26.5, 25.2. IR (thin film): nmax 2991, 2936, 1613,
1515 cmꢀ1. MS (EI): m/z (%) 308 (Mþ), 293, 157, 136, 121 (100).
HRMS: calculated for C17H21O4F: 308.1424; found: 308.1422.
4.3.16. (4R)-4-(3-Cyclohexyl-1-fluoroprop-2-ynyl)-2,2-dimethyl-1,3-
dioxolane (6i). 1H NMR (300 MHz, CDCl3)
d
ppm 5.10 (dm, J¼49.2 Hz,
0.86H), 5.02 (dm, J¼49.5 Hz, 0.14H), 4.30e4.18 (m,1H), 4.11e4.01 (m,
4.3.11. (4R)-4-(1-Fluoro-5-(4-methoxybenzyloxy)pent-2-ynyl)-2,2-
2H), 2.42 (m, 1H), 1.79e1.26 (m, 16H). 19F NMR (282 MHz, CDCl3)
dimethyl-1,3-dioxolane (6d). 1H NMR (300 MHz, CDCl3)
d
ppm 7.24
d
ppm ꢀ177.7 (dt, J¼50.5, 9.9 Hz, 0.16F), ꢀ185.6 (ddd, J¼49.7, 16.9,
(d, J¼8.5 Hz, 2H), 6.86 (d, J¼8.5 Hz, 2H), 5.06 (dt, J¼48.9, 2.1 Hz,1H),
4.45 (s, 1H), 4.25 (m, 1H), 4.12e4.02 (m, 2H), 3.78 (s, 3H), 3.54 (t,
J¼7.2 Hz, 2H), 2.55 (q, J¼3.9 Hz, 2H), 1.44 (s, 3H), 1.37 (s, 3H). 19F
5.3 Hz, 0.84F). 13C NMR (75.4 MHz, CDCl3)
d
ppm 110.6, 110.4, 95.0 (d,
J¼10.4 Hz), 81.8 (d, J¼173.4 Hz), 77.3, 73.7 (d, J¼24.6 Hz), 65.7 (d,
J¼3.8 Hz), 64.8 (d, J¼4.0 Hz), 32.1 (d, J¼2.0 Hz), 28.9 (d, J¼3.4 Hz),
26.6, 26.1, 25.7, 25.4, 25.3, 24.6. IR (thin film): nmax 2989, 2934, 2857,
2235,1451 cmꢀ1. MS (EI): m/z (%) 225 (MþꢀMe),183,101 (100), 91, 73,
43. HRMS: calculated for C14H21O2F: 240.1526; found: 240.1529.
NMR (282 MHz, CDCl3)
d
ppm ꢀ179.2 (dm, J¼49.9 Hz, 0.11F),
ꢀ185.8 (ddt, J¼50.8, 15.5, 6.5 Hz, 0.89F). 13C NMR (75.4 MHz, CDCl3)
d
ppm 159.3, 129.9, 129.3, 113.8, 110.4, 87.8 (d, J¼10.6 Hz), 81.8 (d,
J¼174.2 Hz), 76.8, 75.0 (d, J¼25.0 Hz), 72.6, 67.4 (d, J¼3.0 Hz), 65.0
(d, J¼4.0 Hz), 55.2, 30.3, 29.7, 26.5, 26.2, 25.3, 20.1. IR (thin film):
nmax 2989, 2936, 2866, 2241, 1614, 1587, 1515 cmꢀ1. MS (EI): m/z (%)
322 (Mþ), 307, 221, 189, 121 (100), 101, 43. HRMS: calculated for
C18H23O4 F: 322.1580; found: 322.1584.
4.3.17. (2R)-3-Fluoropent-4-yne-1,2-diol (9). To a solution of 8k
(0.3 mmol) in acetone (2 mL), was added CAN (660 mg, 1.2 mmol)
in portions. After stirring for 30 min at room temperature, the re-
action mixture was diluted with ethyl ether, washed with water,
brine, dried over Na2SO4, filtered, and concentrated at 0 ꢁC. The
residue was dissolved in methanol (2 mL) and H2O (0.2 mL), THF
(0.3 mL), concentrated HCl (eight drops) was added. After stirring
for 2 days at room temperature, the reaction mixture was diluted
with ethyl acetate, washed with water, brine, dried over Na2SO4,
filtered, and concentrated. The residue was purified by silica gel
chromatography (petroleum ether/ethyl acetate¼1:1) to give
product 9 (anti/syn¼8:1) (28 mg, 80% overall yield) as a light yellow
4.3.12. (4R)-4-(1-Fluoroundec-2-ynyl)-2,2-dimethyl-1,3-dioxolane
(6e). 1H NMR (300 MHz, CDCl3)
d
ppm 5.32 (dt, J¼49.5, 2.1 Hz, 0.9H),
4.99 (dt, J¼49.5 Hz, 0.1H), 4.28e4.17 (m, 1H), 4.11e4.01 (m, 2H), 2.22
(qd, J¼6.9, 2.1 Hz, 2H), 1.52e1.25 (m, 18H), 0.86 (t, J¼6.3 Hz, 3H). 19F
NMR (282 MHz, CDCl3)
d
ppm ꢀ178.2 (ddt, J¼49.6,12.4, 6.5 Hz, 0.1F),
ꢀ185.4 (ddt, J¼48.8, 16.6, 7.0 Hz, 0.9F). 13C NMR (75.4 MHz, CDCl3)
d
ppm 110.3, 91.0 (d, J¼5.2 Hz), 81.8 (d, J¼174.2 Hz), 77.0 (d,
J¼27.8 Hz), 73.8 (d, J¼12.5 Hz), 64.8 (d, J¼3.8 Hz), 31.8, 29.1, 29.0, 28.7,
26.1, 25.3, 22.6, 18.7, 14.0. IR (thin film): nmax 2930, 2858, 2238,
1381 cmꢀ1. MS (EI): m/z (%) 255 (MþꢀHþ), 205, 101 (100), 43, 41.
HRMS: calculated for C16H27O2F: 270.1995; found: 270.1996.
oil. 1H NMR (300 MHz, CDCl3):
d
ppm 5.17 (ddd, J¼47.7, 4.8, 2.1 Hz,
0.89H), 5.13 (ddd, J¼48.9, 6.6, 1.2 Hz, 0.11H), 4.00e3.75 (m, 3H),
2.79 (dd, J¼6.3,1.8 Hz,1H), 2.53 (br, 2H). 19F NMR (282 MHz, CDCl3):
d
ppm ꢀ187.8 (ddd, J¼46.8, 13.3, 4.5 Hz, 0.89F), ꢀ189.1 (ddd, J¼49.1,
14.1, 5.1 Hz, 0.11F). 13C NMR (100 MHz, CDCl3)
d ppm 82.7 (d,
4.3.13. (4R)-4-(-3-Cyclopropyl-1-fluoroprop-2-ynyl)-2,2-dimethyl-
J¼172.6 Hz), 78.8 (d, J¼10.8 Hz), 72.7, 72.5, 61.8 (d, J¼4.6 Hz). IR
1,3-dioxolane (6f). 1H NMR (300 MHz, CDCl3)
d ppm 5.02 (ddd,
(thin film): nmax 3298, 2924, 2852, 2127, 1463 cmꢀ1. MS (EI): m/z (%)

5226
S. Fan et al. / Tetrahedron 66 (2010) 5218e5228
118 (Mþ) 68, 61(100), 57, 43, 40. HRMS: calculated for C5H7O2F:
118.0430; found: 118.0428.
concentrated. The residue was purified by silica gel chromatogra-
phy (petroleum ether/ethyl acetate¼20:1) to give product anti-6a
(anti/syn¼12:1) (58 mg, 70% overall yield) as a light yellow oil.
4.3.18. (R)-4-((S)-1-Fluoro-3-phenylprop-2-ynyl)-2,2-dimethyl-1,3-
20
dioxolane (anti-6l). [
CDCl3)
a]
17.78 (c 1.6, CH2Cl2). 1H NMR (300 MHz,
4.4.1. (S)-4-((4R,5S)-5-(Benzyloxymethyl)-2,2-dimethyl-1,3-dioxo-
lan-4-yl)-4-fluorobut-2-yn-1-ol (10). anti-7a (2.56 g, 3.3 mmol) was
dissolved in acetone (25 mL), and ceric ammonium nitrate (7.2 g,
13.0 mmol) was added in portions. The mixture was stirred at room
temperature for 15 min and diluted with ethyl acetate, washed
with water, brine, dried over Na2SO4, filtered, and concentrated.
The resulting residue was dissolved in CH2Cl2 (14 mL), DDQ (0.74 g,
3.3 mmol) and H2O (2 mL) were added. The mixture was stirred at
room temperature overnight. The reaction was quenched with
water and extracted with ether. The combined organic layers were
washed with brine, dried over Na2SO4, filtered, and concentrated.
The residue was purified by silica gel column chromatography
D
d
ppm 7.48e7.25 (m, 5H), 5.32 (dd, J¼49.2, 4.8 Hz, 1H), 4.40
(m, 1H), 4.21e4.12 (m, 2H), 1.49 (s, 3H), 1.40 (s, 3H). 19F NMR
(282 MHz, CDCl3)
(100 MHz, CDCl3)
d
ppm ꢀ184.8 (dd, J¼49.1, 16.1 Hz). 13C NMR
ppm 131.9, 129.1, 128.3, 121.3 (d, J¼3.7 Hz),
d
110.6, 89.4 (d, J¼10.4 Hz), 83.0 (d, J¼1.3 Hz), 82.7 (d, J¼51.7 Hz),
82.2, 82.1 (d, J¼176.4 Hz), 76.8 (d, J¼24.6 Hz), 65.0 (d, J¼3.9 Hz),
26.2, 25.3. IR (thin film): nmax 2988, 2936, 2229, 1491 cmꢀ1. MS (EI):
m/z (%) 234 (Mþ), 219, 177, 159, 133, 101 (100), 43. HRMS: calculated
for C14H15O2F: 234.1056; found: 234.1055.
4.3.19. (R)-4-((R)-1-Fluoro-3-phenylprop-2-ynyl)-2,2-dimethyl-1,3-
20
dioxolane (syn-6l). [
CDCl3)
a
]
D
40.44 (c 1.2, CH2Cl2). 1H NMR (300 MHz,
(petroleum ether/ethyl acetate¼10:1) to give alcohol 10 (778 mg,
20
d
ppm 7.47e7.31 (m, 5H), 5.28 (dd, J¼48.9, 7.2 Hz, 1H), 4.45
88% yield) as a yellow oil. [
a
]
ꢀ7.48 (c 2.2, CH2Cl2). 1H NMR
D
(m, 1H), 4.19 (t, J¼9 Hz, 1H), 4.04 (dd, J¼9 Hz, J¼6 Hz, 1H), 1.50 (s,
(300 MHz, CDCl3):
d
7.35e7.29 (m, 5H), 5.25 (ddd, J¼48.6, 3.0,
3H), 1.41 (s, 3H). 19F NMR (282 MHz, CDCl3):
d
ppm ꢀ178.7 (dd,
1.2 Hz, 1H), 4.61 (s, 2H), 4.34e4.29 (m, 1H), 4.17 (dd, J¼6.6, Hz
J¼1.2 Hz, 2H), 4.10 (ddd, J¼17.7, 7.8, 3.3 Hz, 1H), 3.69 (dd, J¼22.8,
10.5 Hz, 1H), 3.68 (dd, J¼24.9, 10.5 Hz, 1H), 2.29 (s, 1H), 1.46 (s, 3H),
J¼49.1, 10.7 Hz). 13C NMR (100 MHz, CDCl3)
d
ppm 131.9, 131.9,
129.3, 128.4, 121.2 (d, J¼3.7 Hz), 111.0, 89.6 (d, J¼10.4 Hz), 83.7 (d,
J¼174.2 Hz), 81.9 (d, J¼24.6 Hz), 76.9 (d, J¼24.2 Hz), 65.7 (d,
J¼3.7 Hz), 26.6, 25.3.
1.44 (s, 3H). 19F NMR (282 MHz, CDCl3):
d
ppm ꢀ186.0 (ddt, J¼48.2,
ppm 137.7, 128.4, 127.7,
18.3, 5.6 Hz). 13C NMR (100 MHz, CDCl3):
d
110.7, 89.1 (d, J¼9.6 Hz), 81.3 (d, J¼175.2 Hz), 78.6 (d, J¼26.0 Hz),
78.5 (d, J¼22.3 Hz), 76.1 (d, J¼3.7 Hz), 73.5, 70.4, 50.5, 27.2, 26.4. IR
(thin film): nmax 3340, 3034, 2991, 1498, 1455, 1379 cmꢀ1. MS (EI):
m/z (%) 308 (Mþ), 293, 221, 187, 91 (100). HRMS: calculated for
C17H21O4F: 308.1424; found: 308.1427.
4.3.20. (4R)-4-(1-Fluoro-3-(6-methoxynaphthalen-2-yl)prop-2-
ynyl)-2,2-dimethyl-1,3-dioxolane (6m). 1H NMR (300 MHz, CDCl3):
d
ppm 7.90 (s, 1H), 7.67e7.63 (m, 2H), 7.44 (d, J¼8.1 Hz, 1H), 7.14 (d,
J¼9.0 Hz, 1H), 7.06 (s, 1H), 5.36 (dd, J¼49.2, 4.5 Hz, 1H), 4.45e4.37
(m, 1H), 4.19 (d, J¼6.0 Hz, 2H), 3.88 (s, 3H), 1.50 (s, 3H), 1.41 (s, 3H).
19F NMR (282 MHz, CDCl3):
d
ppm ꢀ179.1 (dd, J¼48.0, 10.2 Hz,
4.4.2. (S,Z)-4-((4R,5S)-5-(Benzyloxymethyl)-2,2-dimethyl-1,3-dioxo-
lan-4-yl)-4-fluorobut-2-enal (11). To a solution of 10 (400 mg,
1.28 mmol) in ethyl alcohol (20 mL) was added Lindlar catalyst
(88 mg) at room temperature. Then H2 was introduced into the
flask. The reaction was stirred with a H2-balloon for 4 h. The
Lindlar catalyst was filtered through a short Celite pad and the
filtrate was concentrated to give Z-alcohol. 1H NMR (300 MHz,
0.16F), ꢀ185.2 (dd, J¼50.3, 16.7 Hz, 0.84F). 13C NMR (75.4 MHz,
CDCl3):
d ppm 158.6, 134.5, 132.1, 129.3, 128.8, 128.7, 128.1, 126.8,
119.6, 116.1, 116.0, 110.6, 105.6, 90.0 (d, J¼10.5 Hz), 82.2 (d,
J¼175.5 Hz), 81.9 (d, J¼24.7 Hz), 77.0 (d, J¼24.7 Hz), 65.0 (d,
J¼3.8 Hz), 55.3, 26.3, 25.4. IR (thin film): nmax 2986, 2226, 1624,
1600, 1486 cmꢀ1. MS (EI): m/z (%) 314 (Mþ), 101 (100). HRMS: cal-
culated for C19H19O3F: 314.1318; found: 314.1320.
CDCl3)
d ppm 7.39e7.26 (m, 5H), 5.97 (m, 1H), 5.67 (m, 1H), 5.36
(dt, J¼47.1, 6.0 Hz, 1H), 4.60 (s, 1H), 4.19e4.14 (m, 3H), 3.97 (m, 1H),
4.3.21. (R)-4-((S)-1-Fluoro-3-(6-methoxynaphthalen-2-yl)prop-2-
3.72e3.60 (m, 2H), 2.23 (s, 1H), 1.437 (s, 3H), 1.432 (s, 3H). 19F NMR
20
ynyl)-2,2-dimethyl-1,3-dioxolane (anti-6m). Mp 88 ꢁC; [
a
]
9.8 (c
(282 MHz, CDCl3)
NMR (100.7 MHz, CDCl3)
d
ppm ꢀ184.4 (dt, J¼46.0 Hz, J¼12.7 Hz). 13C
D
0.15, CH2Cl2). 1H NMR (300 MHz, CDCl3)
d
ppm 7.92 (s, 1H), 7.68 (dd,
d
ppm 127.5, 134.9 (d, J¼10.4 Hz), 128.3,
J¼9.0 Hz, 2H), 7.45 (d, J¼8.1 Hz,1H), 7.16 (dd, J¼8.7, 2.1 Hz,1H), 7.10 (s,
1H), 5.36 (dd, J¼49.2, J¼4.5 Hz, 1H), 4.43 (ddd, J¼15.9, 10.5, 5.4 Hz,
1H), 4.19 (m, 2H), 3.91 (s, 3H), 1.51 (s, 3H), 1.41 (s, 3H). 19F NMR
127.6, 125.9 (d, J¼22.4 Hz), 110.1, 88.2 (d, J¼165.8 Hz), 78.1 (d,
J¼26.8 Hz), 77.4 (d, J¼3.0 Hz), 70.2, 58.4, 26.9, 26.5. IR (thin film):
nmax 3400, 2990, 2870, 1455 cmꢀ1. MS (EI): m/z (%) 310(Mþ), 295,
275, 221, 162, 91(100), 59, 43. HRMS: calculated for C17H23O4F:
310.1580; found: 310.1576.
(282 MHz, CDCl3):
(100 MHz, CDCl3):
d
ppm 185.1 (dd, J¼49.4, 17.2 Hz). 13C NMR
d
ppm 158.6,134.6,132.1 (d, J¼3.8 Hz),129.4,128.8
(d, J¼3.0 Hz), 128.2, 126.9, 119.6, 116.1 (d, J¼3.8 Hz), 110.6, 105.8, 90.1
(d, J¼10.6 Hz), 82.2 (d, J¼174.4 Hz), 82.0 (d, J¼25.1 Hz), 77.0 (d,
J¼25.1 Hz), 65.1(d, J¼3.7 Hz), 55.3, 26.3, 25.4. IR(thinfilm):nmax 2986,
2226, 1624, 1600, 1486 cmꢀ1. MS (EI): m/z (%) 314 (Mþ), 101 (100).
HRMS: calculated for C19H19O3F: 314.1318; found: 314.1321.
Z-alcohol was used to do the next step without purification. To
a solution of crude Z-alcohol in CH2Cl2 (20 mL) was added MnO2
(1.2 g, 13.8 mmol) at room temperature. After the reaction mixture
was stirred for 12 h, another 13.8 mmol of MnO2 was added, and
the reaction mixture was stirred for 24 h. The MnO2 was then fil-
tered and the filtrate was concentrated. The resulting residue was
purified with silica gel chromatography (petroleum ether/ethyl
acetate¼20:1) to give aldehyde 11 (300 mg, 75% yield two steps) as
4.4. One pot reaction to prepare anti-6a from propargylic
alcohol 2a
a light yellow oil. 1H NMR (300 MHz, CDCl3)
d ppm 9.98 (d,
To a solution of 2a (anti/syn¼1:2.3, 83 mg, 0.3 mmol) in CH2Cl2
(2 mL) was added Co2(CO)8 (114 mg, 0.33 mmol). After stirring at
room temperature for 12 h, the reaction mixture was cooled to
J¼6.9 Hz, 1H), 7.36e7.27 (m, 5H), 6.52 (ddd, J¼20.4, 11.7, 7.2 Hz, 1H),
6.11 (dd, J¼11.4, 6.9 Hz,1H), 5.73 (dt, J¼47.7, 6.3 Hz,1H), 4.59 (s, 2H),
4.21e4.07 (m, 2H), 3.64 (d, J¼4.5 Hz, 2H), 1.43 (s, 3H), 1.41 (s, 3H).
ꢀ78 ꢁC and DAST (50
mL, 0.36 mmol) was added. The resulting
19F NMR (282 MHz, CDCl3)
d
ppm ꢀ184.4 (ddd, J¼47.6, 19.5,
ppm 190.9 (d, J¼2.8 Hz),
mixture was stirred at ꢀ78 ꢁC for 9 h and warmed up to room
temperature naturally. Stirring continued for 12 h at room tem-
perature and then acetone (2 mL) was added, followed by addition
of CAN (660 mg, 1.2 mmol) in portions. After stirring for 30 min at
room temperature, the reaction mixture was diluted with ethyl
acetate, washed with water, brine, dried over Na2SO4, filtered, and
12.7 Hz). 13C NMR (75.4 MHz, CDCl3)
d
142.1 (d, J¼21.9 Hz), 137.5, 132.0 (d, J¼5.5 Hz), 128.4, 127.8, 127.7,
110.6, 89.0 (d, J¼172.8 Hz), 78.3 (d, J¼24.7 Hz), 77.4, 73.6, 70.0, 26.9,
26.6. IR (thin film): nmax 2990, 2867, 1686 cmꢀ1. MS (EI): m/z (%) 293
(MþꢀMe), 91(100). HRMS: calculated for C17H21O4F: 308.1424;
found: 308.1423.

S. Fan et al. / Tetrahedron 66 (2010) 5218e5228
5227
4.4.3. (1S)-2-(Benzyloxy)-1-((3S)-3-fluoro-6-methoxy-3,6-dihydro-
2H-pyran-2-yl)ethanol (12). To a solution of 13 (61 mg, 0.2 mmol) in
MeOH/THF/H2O (2 mL/0.3 mL/0.2 mL) was added concentrated HCl
eight drops. The resulting mixture was stirred at room temperature
for 30 h. Ethyl acetate was added, and the mixture was washed with
saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered, and
concentrated. The resulting residue was purified with silica gel
chromatography (petroleum ether/ethyl acetate¼8:1) to give 12
313, 253, 221, 179, 91(100), 77. HRMS: calculated for C23H25O5:
381.1702 (MꢀCH3); found: 381.1704 (MþꢀMe).
4.4.6. (R)-4-(Benzyloxy)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)but-
2-yn-1-ol (syn-2a) and (S)-4-(benzyloxy)-1-((R)-2,2-dimethyl-1,3-
dioxolan-4-yl)but-2-ynyl acetate (anti-2a0). The alcohol 2a (1.5 g,
5.4 mmol) was dissolved in hexane (10.5 mL) and 4 Å MS (1.89 g,
powdered) was added. Then Lipase AK Amano (950 mg) was added
all at once, followed by the addition of vinyl acetate (3.8 mL,
41.3 mmol). The solution was vigorously stirred at rt for 35 h,
after which time the mixture was filtered through Celite. The
volatiles were evaporated under reduced pressure. The residue
was purified by column chromatography (petroleum ether/ethyl
acetate¼100:1/50:1/20:1/5:1) yielded anti-2a0 and syn-2a0
1.34 g (78%) as a colorless oil and syn-2a (anti/syn¼1:40, de-
termined by HPLC) as a colorless oil 333 mg (22%).
(28 mg, 53%) as an oil. 1H NMR (300 MHz, CDCl3):
d ppm 7.36e7.26
(m, 5H), 6.06 (t, J¼11.7 Hz, 1H), 5.81 (dd, J¼10.2, 2.1 Hz, 1H), 5.24
(ddd, J¼48.9, 8.7, 0.9 Hz, 1H), 4.91 (s, 1H), 4.59 (s, 2H), 4.14 (m, 1H),
3.92 (td, J¼9.0, 1.5 Hz, 1H), 3.73e3.62 (m, 2H), 3.89 (s, 3H), 2.43 (br,
1H). 19F NMR (282 MHz, CDCl3):
d
ppm ꢀ196.9 (ddd, J¼48.0, 11.6,
5.6 Hz). 13C NMR (100 MHz, CDCl3):
d
ppm 137.8, 129.5, 129.3, 128.4,
127.7 (d, J¼11.1 Hz), 127.6, 95.4 (d, J¼2.3 Hz), 82.4 (d, J¼166.8 Hz),
73.4, 71.0, 68.0, 68.0 (d, J¼23.7 Hz), 56.2. IR (thin film): nmax 3460,
2980, 1455, 1394 cmꢀ1. MS (EI): m/z (%) 282 (Mþ), 91 (100), 43.
HRMS: calculated for C15H19O4F: 282.1267; found: 282.1270.
syn-2a: 1H NMR (300 MHz, CDCl3)
d ppm 7.39e7.26 (m, 5H), 4.58
(s, 2H), 4.49 (m, 0.1H), 4.37 (m, 0.9H), 4.24e4.16 (m, 3H), 4.12e4.04
(m,1.1H), 3.90 (dd, J¼8.7, 5.4 Hz, 0.9H), 2.42, and 2.40 (s, 2H),1.46 (s,
3H), 1.37 (s, 3H). IR (thin film): nmax 3393, 1722, 1455 cmꢀ1. MS (EI):
m/z (%) 275 (MþꢀHþ), 261 (MþꢀMe), 171, 128, 101(100). HRMS:
calculated for C16H20O4: 276.1362; found: 276.1353.
4.4.4. (S)-4-((4R,5S)-5-(Benzyloxymethyl)-2,2-dimethyl-1,3-dioxo-
lan-4-yl)-4-fluorobut-2-ynyl 4-nitrobenzoate (anti-5d). To a THF
solution (4 mL) of 10 (93 mg, 0.3 mmol), PPh3 (134 mg, 0.51 mmol)
and p-nitrobenzoic acid (96 mg, 0.57 mmol) was added DEAD
(90 mg, 0.51 mmol) at 0 ꢁC. After stirring for 30 min at same tem-
perature, the reaction mixture was concentrated. The residue was
purified by column chromatography (petroleum ether/ethyl
acetate¼20:1) to give anti-5d (137 mg, quantity) as awhite solid. Mp
anti-2a0: 1H NMR (300 MHz, CDCl3)
d ppm 7.35e7.30 (m, 5H),
5.56 (dt, J¼4.2, 1.8 Hz, 1H), 4.58 (s, 2H), 4.36e4.30 (m, 1H), 4.21 (d,
J¼1.8 Hz, 2H), 4.12 (dd, J¼8.7, 6.9 Hz, 1H), 3.99 (dd, J¼8.4, 6.0 Hz,
1H), 2.13 (s, 3H),1.45 (s, 3H),1.38 (s, 3H). 13C NMR (100 MHz, CDCl3)
ppm 169.5, 137.1, 128.4, 128.1, 127.9, 110.5, 82.8, 80.7, 76.3, 71.6, 65.6,
63.7, 57.1, 26.2, 25.2, 20.8. IR (thin film): nmax 2989, 1749, 1373,
1227 cmꢀ1. MS (EI): m/z (%) 303(MþꢀMe), 171, 101(100), 91. HRMS:
calculated for C18H22O5: 318.1467; found: 318.1472.
61 ꢁC; [
a
]
D
20 ꢀ6.94 (c 1.0, CH2Cl2). 1H NMR (300 MHz, CDCl3):
d ppm
8.29 (d, J¼8.7 Hz, 2H), 8.22 (d, J¼8.7 Hz, 2H), 7.38e7.28 (m, 5H), 5.31
(dd, J¼47.7,1.2 Hz,1H), 4.97 (d, J¼6.3 Hz, 2H), 4.60 (s,1H), 4.34e4.29
(m,1H), 4.17 (ddd, J¼16.5, 8.4, 3.6 Hz,1H), 3.72e3.69 (m, 2H),1.47 (s,
3H), 1.45 (s, 3H). 19F NMR (376 MHz, CDCl3):
d
ppm ꢀ185.4 (ddt,
4.4.7. (S)-4-(Benzyloxy)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)but-
2-yn-1-ol (anti-2a). To a solution of anti-2a0 (246 mg, 1.0 mmol) in
MeOH (3.5 mL) was added K2CO3 (161 mg, 1.2 mmol). After stirring
for 20 min, the reaction mixture was quenched with saturated NH4Cl,
extracted with ethyl acetate, washed with water, brine, dried over
Na2SO4, filtered, and concentrated. The residue was purified by col-
umn chromatography (petroleum ether/ethyl acetate¼10:1/6:1) to
give alcohol anti-2a (anti/syn¼28:1, determined by HPLC) as an oil
J¼48.6,16.9, 6.8 Hz). 13C NMR (100 MHz, CDCl3):
d ppm 163.8,150.8,
137.7, 134.5, 131.2, 130.9, 128.4, 127.8, 127.6, 123.6, 110.9, 83.9
(J¼9.9 Hz), 81.5 (J¼175.2 Hz), 80.6 (J¼25.9 Hz), 78.6 (J¼23.14 Hz),
76.1 (J¼4.4 Hz), 73.54, 70.46, 52.98, 27.25, 26.55. IR (KBr): nmax 3121,
2871, 1726, 1530 cmꢀ1. MS (EI): m/z (%) 457(Mþ), 442, 150, 91(100),
43. HRMS: calculated for C24H24NO7F: 457.1537; found: 457.1534.
4.4.5. (S)-4-(Benzyloxy)-1-((4R,5R)-5-(benzyloxymethyl)-2,2-di-
methyl-1,3-dioxolan-4-yl)but-2-yn-1-ol (anti-1b). A solution of n-
BuLi (1.6 M in hexanes, 3.0 mL, 4.8 mmol) was slowly added to
a solution of alkyne (0.76 mL, 5.2 mmol) in anhydrous THF (40 mL)
at ꢀ78 ꢁC. After the mixture was stirred at ꢀ78 ꢁC for 15 min,
a brown solution of Ti(O-i-Pr)4 and TiCl4 (1 M solution in DCM,
2.4 mL, 2.4 mmol) was added dropwise to the reaction mixture and
the resulting mixture was stirred at ꢀ78 ꢁC for 1.5 h. A solution of
aldehyde (1.0 g, 4.0 mmol) in anhydrous THF (30 mL) was then
added. The resulting mixture was stirred at ꢀ78 ꢁC for 2 h and then
slowly warmed to room temperature and stirred overnight. The
reaction was quenched by addition of phosphate buffer pH¼7
(200 mL) and filtered through a Celite plug. The filtrate was evap-
orated under reduced pressure to give a mixture of an oil and an
aqueous solution. Ether (200 mL) and water (100 mL) were added.
The organic phase was separated and washed with brine (100 mL),
dried over MgSO4, filtered, and concentrated to give a yellow oil.
The crude material was purified by column chromatography (pe-
troleum ether/ethyl acetate¼15:1/10:1) to give alcohol anti-1b
(anti/syn¼14:1) as an orange oil (1.28 g, 81%). 1H NMR (400 MHz,
(200 mg, 93%). 1H NMR (300 MHz, CDCl3)
d ppm 7.39e7.26 (m, 5H),
4.58 (s, 2H), 4.49 (m, 0.9H), 4.37 (m, 0.1H), 4.24e4.16 (m, 3H),
4.12e4.04 (m, 1.9H), 3.90 (dd, J¼8.7, 5.4 Hz, 0.1H), 2.42, and 2.40 (s,
2H),1.46 (s, 3H),1.37 (s, 3H). IR (thin film): nmax 3393,1722,1455 cmꢀ1
.
MS (EI): m/z (%) 275 (MþꢀHþ), 261 (MþꢀMe), 171, 128, 101(100).
HRMS: calculated for C16H20O4: 276.1362; found: 276.1353.
Acknowledgements
National Natural Science Foundation of China (20852003,
20902100, and 20832008), the Shanghai Rising-Star Program
(09QA1406900) and SIOC are greatly acknowledged for funding
this work. Professor Feng-Ling Qing was also greatly acknowledged
for help.
Supplementary data
Experimental information, characterization data of compounds
1 and 2, 1H and 13C NMR spectra of 5, 6, 10e12. Supplementary data
associated with this article can be found in online version at
doi:10.1016/j.tet.2010.04.078. This data include MOL files and
InChiKeys of the most important compounds described in this
article.
CDCl3, 293 K, TMS):
d ppm 7.35e7.27 (m, 10H), 4.60e4.55 (m, 5H),
4.28e4.13 (m, 3H), 4.01(d, J¼7.5, 4.2 Hz, 1H), 3.69 (d, J¼5.1 Hz, 2H),
2.36 (br, 1H), 1.45 (s, 3H), 1.44 (s, 3H). 13C NMR (100 MHz, CDCl3):
d
ppm 137.5, 137.0, 128.22, 128.20, 128.17, 127.8, 127.7, 127.6, 127.49,
References and notes
127.47, 109.8, 83.7, 82.3, 79.8, 76.5, 73.3, 71.4, 70.6, 62.2, 57.0, 26.8.
IR (thin film): nmax 3423, 3032, 2988, 2935, 2868, 1497, 1455, 1250,
1216, 1168, 908, 859, 745, 699 cmꢀ1. MS (EI): m/z (%) 381(MþꢀMe),
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