Diastereospecific fluorination of substituted azepanes

Article abstract of DOI:10.1016/j.tet.2012.10.078

Fluorination of bioactive compounds is an important step in drug discovery and development. Fluorination has been extensively studied in acyclic systems, carbocycles, and fused heterocycles. However, there is no report on fluorination of azepanes. As azep

Full text of DOI:10.1016/j.tet.2012.10.078

Tetrahedron xxx (2012) 1e9
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Diastereospecific fluorination of substituted azepanes
*
Alpesh Ramanlal Patel, Fei Liu
Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, NSW 2109, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Fluorination of bioactive compounds is an important step in drug discovery and development. Fluori-
nation has been extensively studied in acyclic systems, carbocycles, and fused heterocycles. However,
there is no report on fluorination of azepanes. As azepanes are components of many biologically active
substances and natural products. We herein present the first fluorination examples of substituted aze-
panes. Fluoroazepanes were prepared by deoxyfluorination diastereospecifically in excellent yields. The
absolute configuration at the fluorination site was unambiguously assigned by 2D NMR spectroscopy.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 28 August 2012
Received in revised form 11 October 2012
Accepted 29 October 2012
Available online xxx
Keywords:
Hydroboration
Deoxyfluorination
Azepanes
Neighboring group effect
Diastereospecificity
1. Introduction
minor groove binding agents (MGBLs).12 The added flexibility of
a seven membered ring allows functional groups (for instance hy-
Fluorine is virtually absent in bioactive natural molecules.
However, 20% of all drugs approved and 3 of the top 10 best selling
drugs in 2011 contain fluorine atom(s).1 In general, more than 1/5th
of all pharmaceuticals and 1/3rd of agrochemicals have at least one
fluorine atom.2 Because fluorine is the most electronegative atom,
is small and forms very strong CeF bonds, hydrogen replacement
by its bioisosteric fluorine in compounds can lead to profound
changes in their physical, chemical, and biological properties.2d,3
For example, the fluorine gauche effect is known to influence the
conformation of molecules as a complex function of steric, elec-
trostatic, and stereoelectronic contributors.4 Thus, fluorination re-
actions continue to be of interest to organic, medicinal, and agro
chemists as evidenced by a growing number of publications in this
area.5 In particular, fluorinated building blocks represent the most
efficient entry into diverse structures of fluorinated compounds.1
Herein, we report the first examples of fluorinated azepanes as
new building blocks for diversity generation.
droxyl groups) to adopt a variety of H-bonding positions for protein
binding.13 Unfortunately, despite the important role of azepanes in
bioactive molecules14 and the large potential of fluorinated aze-
panes in diversity-oriented bioactivity discovery, their preparation
has not been reported.
We chose a substituted tetrahydroazepine 7 as our starting
model for investigation. The 1,2-trans-benzyloxyazido substitution
motif in 7 can be easily reduced to 1,2-trans-hydroxylamino motif
found in many bioactive natural products.15 The 3-aminoazepane
motif is also seen in antitumor cis-platin analogs16 and somato-
statin mimics.17 Therefore fluorinated azepane building blocks from
7 will have wide utility in diversity-oriented synthesis of fluori-
nated bioactive leads. Many approaches, such as substitution of
oxygen with fluorine(s) in carbonyls and replacement of amides
with vinyl fluoride18 have been achieved successfully. Replacement
of a hydroxyl group with fluorine has also gained increasing pop-
ularity recently, and an increasing number of natural products and
bioactive molecules have been synthesized using deoxyfluorina-
tion.19 This strategy was therefore investigated in this study.
The most commonly used nucleophilic fluorinating agents for
substituting hydroxyl group with fluorine are diethylaminosulfur
trifluoride (DAST),20 bis(2-methoxyethyl)aminosulfur trifluoride
(DeoxofluorÒ),21 Fluorinox, 2,2-difluoro-1,3-dimethyl-imidazoli-
dine (DFI),22 and perfluoro-1-butanesulfonyl fluoride (PBSF).23
However, DFI and PBSF being milder reagents require harsher re-
action conditions and longer reaction times than DAST and
DeoxofluorÒ. So, we focused our attention on fluorination using
Substituted azepane rings are prevalent in many bioactive nat-
ural compounds.6 Recently, polysubstituted azepane rings and re-
lated compounds (iminocyclitols or iminosugars) have attracted
considerable attention of medicinal chemists and biologists as they
have demonstrated great potential7 as glycosidase inhibitors and
antidiabetics,8 anticancer,9 antivirals10 including HIV,11 and DNA
* Corresponding author. Tel.: þ61 2 9850 8312; fax: þ61 2 9850 8313; e-mail
address: fei.liu@mq.edu.au (F. Liu).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.10.078
Please cite this article in press as: Patel, A. R.; Liu, F., Tetrahedron (2012), http://dx.doi.org/10.1016/j.tet.2012.10.078

2
A.R. Patel, F. Liu / Tetrahedron xxx (2012) 1e9
DAST and DeoxofluorÒ. The general reactivity trend in nucleophilic
deoxyfluorination reactions follows the SN2 pathway with in-
version of stereochemistry at the participating stereo-center.
However, there are some reports of racemization mainly due to
SN1 competition.19a,19b Fluorination reactions of fused heterocycles
have been reported before19d,19e with SN2 outcomes. The stereo-
chemical outcomes of deoxyfluorination of substituted azepanes
were thus investigated, and we report here deoxyfluorination
with retention of stereochemistry due to neighboring group
participation.
Scheme 2. 8a and 9a: R1¼OH, R2, R3, R4¼H; 8b and 9b: R2¼OH, R1, R3, R4¼H; 8c and
9c: R3¼OH, R1, R2, R4¼H; 8d and 9d: R4¼OH, R1, R2, R3¼H.
pattern observed is significantly different from the mono-
substituted azepine reported previously (diastereoselectivity: 2:1
at C4; cis:trans to C3 substitution; and regioselectivity: C4 to C5 at
3:1) by Trost et al.26 The observed difference in selectivity may
potentially be due to the O-benzyl directing group (at C4) here
instead of N-Cbz (at C3) used by Trost.
2. Results and discussion
2.1. Synthesis of tetrahydroazepine 7
Our investigation started with the preparation of the hydrox-
yazepanes for use in deoxyfluorination. Disubstituted azepine 7 was
synthesized first as the precursor to hydroxyazepanes. The concise
Detailed analysis of 1H, 13C, and 2D NMR (HSQC, HMBC, COSY,
and NOESY) enabled us to unambiguously elucidate the structures
of compounds 8aed (Supplementary data).
six-step protocol (Scheme 1) by Furstner and Thiel24 was adopted,
€
starting from divinylcarbinol 1. Sharpless epoxidation of 1 was
performed as described previously25 and furnished epoxide 2 in
excellent optical purity and yield. O-Benzylationwas achieved using
benzyl bromidebeforeregioselectiveopeningof theoxiraneringof 3
with allylamine to provide diene 4 in 88% yield over two steps. tert-
Butyloxycarbonyl (Boc) protection of the secondary amine readily
provided diene 5, which served as the precursor for the following
ring closing metathesis. Metathesis reaction of 5 was performed by
refluxing 0.02 M solution of diene 5 in CH2Cl2 in the presence of
Grubbs catalyst (5þ3 mol %) to afford the desired cycloalkene 6 in
86% yield. Secondary alcohol functionality of 6 was subsequently
converted into an azido group with (PhO)2P(O)N3, diethyl azodi-
carboxylate, and triphenylphosphine (PPh3) in THF at room tem-
perature to provide 7 in an overall yield of 54% in six steps.
The key correlations of 8c and 8d are shown in Fig 1 as a rep-
resentative for the absolute configuration assignment. In 8c,
HMBC and HSQC couplings with C10
(dc 71.7 ppm) and C4 (dc
78.7 ppm), respectively, identified H4 at 3.37 ppm. H4 further
showed COSY correlations with H5a (dH 1.74 ppm) and H5b (dH
2.30 ppm), both of which showed correlations to H6
(dH
3.97 ppm). Moreover, H4 showed NOE to H6 in its NOESY spectra.
However, in 8d H6 (dH 4.14 ppm) did not show any detectable NOE
to H4 (dH 3.80 ppm), but showed strong NOE to H3 (dH 3.70 ppm).
Thus, the absolute configuration assignments at C6 in 8c and 8d
were confirmed to be S and R, respectively. The same process
enabled the assignment at C5 in 8a and 8b to be R and S, re-
spectively. The stereochemistry was further confirmed by N-Boc
deprotection using neat TFA to furnish compounds 9aed in
quantitative yields (Scheme 2). In the absence of geometric iso-
mers (cis and trans) of the N-Boc group, the assignments of 9aed
were secured by 2D NMR spectroscopy and confirmed the as-
signment of 8aed (Supplementary data).
COSY
H4
H3
COSY
H4
H3
Ph
Ph
N3
N3
O
H5b
H5a
O
H5b
H5a
4
4
5
5
(S)
(R)
Scheme 1. Synthesis of tetrahydroazepine 7. Reagents and conditions: (a) (D)-(ꢁ)-DIPT,
cumene hydroperoxide, Ti(OiPr)4, CH2Cl2, ꢁ35 ꢀC, 83%, >99% ee; (b) NaH, BnBr, THF,14 h,
rt, 93%; (c) Allylamine (neat), 40 h, 70 ꢀC, 95%; (d) Boc2O, Et3N, CH2Cl2, 16 h, rt, 96%; (e)
Grubbs catalyst, CH2Cl2, 42 h, 86%; (f) PPh3, DEAD, (PhO)2P(O)N3, THF, 2 h, rt, 89%.
COSY
COSY
COSY
COSY
H6
H6
OH
OH
8c
8d
2.2. Hydroborationeoxidation of tetrahydroazepine 7
Fig. 1. Key 2D NMR correlations for compound 8c and 8d.
Tetrahydroazepine 7 then underwent hydroboration (Scheme 2)
with borane dimethylsulfide (BH3$SMe2) as the boronating agent in
THF at 25 ꢀC to furnish hydroxyazepanes 8aed in 98% overall yield
with 2:1 regioselectivity. The mixture of compounds 8aed was
separated by reverse phase HPLC using acetonitrile:water:tri-
fluoroacetic acid (TFA) (from 30:70:0.1 to 60:40:0.1 over 85 min;
flow rate: 8.8 mL/min) as a mobile phase to give 8a (1%), 8b (36%),
8c (32%), and 8d (28%) as colorless oils. The hydroboration exhibi-
ted a mild level of regioselectivity (8aþ8b:8cþ8d at 38:62) and
a moderate level of diastereofacial selectivity (8aþ8c:8bþ8d at
30:70). It is noteworthy that the diastereoselectivity (1:37 at C5;
cis:trans to C4 substitution) and regioselectivity (C5 to C6 at 1:1.63)
2.3. Optimization of hydroboration of 7
While hydroboration of 7 using BH3$SMe2 furnished an excellent
overall yield of 8aed, reaction conditions were investigated to ex-
amine the regio- and diastereoselectivity of this reaction (Table 1).
The conventional condition with borane tetrahydrofuran complex
(Table 1, entry 2) gave excellent yield but unsurprisingly, poor dia-
stereoselectivity. On the other hand 9-BBN (Table 1, entry 6) fur-
nished excellent diastereoselectivity but poor yield even after reflux
for 48 h. BH3$NMe3 after reflux for 48 h (Table 1, entry 4) gave
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A.R. Patel, F. Liu / Tetrahedron xxx (2012) 1e9
3
Table 1
the course of the reaction can be tuned by a catalytic additive.
Transition metal-catalyzed addition of CatBH/PinBH to alkenes
and alkynes has shown remarkable chemo-,29 regio-,27,30 dia-
stereo-,27,30,31 and enantioselectivities for acyclic, carbocyclic, and
heterocyclic substrates.28a,32 We employed different metaleligand
combinations for hydroboration of azepine 7 to examine their
Screening of different hydroborating agentsa
Entry
Conditions
Yieldb (%)
Ratioc
8a
8b
8c
8d
1
2
3
4
BH3$DMS, 25 ꢀC, 14 h
BH3$THF, 25 ꢀC, 14 h
BH3$NMe3, 25 ꢀC, 24 h
BH3$NMe3, 66 ꢀC, 48 h
BH3$NMe3, 101 ꢀC, 48 h
BH3$NMe3, 110 ꢀC, 48 h
9-BBN, 25 ꢀC, 24 h
9-BBN, 66 ꢀC, 48 h
CatBH, 25 ꢀC, 24 h
98
81
0
20
0
0
0
12
0
42
0
1
0
0
0
0
0
0
0
0
0
0
0
0
0
37
34
0
49
0
0
0
1
0
37
0
1
0
0
33
31
0
0
0
0
0
0
0
27
0
51
0
29
35
0
51
0
0
0
99
0
36
0
effects on diastereoselectivity. [Rh(COD)2Cl]2,33 Ir(COD)(PCy3)(Py)
33b
PF6,34 Rh(COD)(DPPB) BF4,33b and Rh(COD)(PPh3)BF4
have
5a
6a
7
demonstrated excellent selectivity in styrene hydroboration and
were thus investigated in the hydroboration of 7. In the case of
CatBH, [Rh(COD)2Cl]2, and Ir(COD)(PCy3)(Py)PF6 furnished
a regioselectivity ratio of (C6:C5) of 13.3:1 in moderate yields
(Table 3, entries 1e2). Ir(COD)(PCy3)(Py)PF6 under reflux resulted
in higher yield but lower (8:1) regioselectivity (Table 3, entry 3).
In the case of PinBH, Rh(COD)(DPPB)BF4, and Rh(COD)(PPh3)BF4
furnished 10:1 regioselectivity and moderate yields. Recently, Lata
and Crudden28b have reported the use of Lewis acid additives,
such as Sc(OTf)3 and tris(pentafluorophenyl) borone (FAB) for Rh
catalyzed hydroboration of acyclic olefins. Sc(OTf)3 and FAB were
therefore employed with Rh(COD)(DPPB)BF4 and DCE as solvent.
In the case with Sc(OTf)3, 7 was recovered (Table 3, entry 6) while
FAB alone furnished 10:1 regioselectivity in good yield with
heating (Table 3, entry 8). The best diastereoselectivity (8d:8aec)
obtained in our study (Table 3, entries 1e8) with Rh and Ir cata-
lysts is 2.2:1. Noh et al.35 have reported excellent enantio- and
regioselectivity with the use of ligands (R)-DTMB-Segphos and
(S,S,R,R)-Tangphos in copper(I)-catalyzed hydroboration of sty-
8
9
10
11d
12d
13
14
CatBH, 66 ꢀC, 48 h
CatBH, 25 ꢀC, 24 h
CatBH, 66 ꢀC, 48 h
14
0
0
48
0
0
PinBH, 25 ꢀC, 24 h
PinBH, 66 ꢀC, 48 h
0
a
All the reactions were carried out in THF except entry 5 (in dioxane) and 6 (in
toluene).
b
c
Isolated yield of 8 after column chromatography; unreacted 7 was recovered.
Ratio was calculated on the basis of HPLC traces.
10 mol % (PPh3)3RhCl was used.
d
diastereofacial selectivity but poor yield. Utilization of dioxane and
toluene as solvents for BH3$NMe3 condition gave only starting ma-
terial 7 back. More stable hydroborating agents, such as CatBH and
PinBH were also employed. As anticipated, at room temperature
only starting materials were recovered. However, refluxing in THF
after 48 h with CatBH (Table 1, entry 10) furnished a mixture of di-
astereomers 8bed in low yield but no improvement in
diastereoselectivity.
The addition of rhodium catalyst (Table 1, entry 12) improved
regioselectivity, which was consistent with prior studies by Evans
et al.27 but the yield remained low. In the case of PinBH, only
starting azepine 7 was recovered (Table 1, entries 13, 14).
With BH3$SMe2 as the hydroborating agent, solvents were
screened for optimization (Table 2). In non-polar solvents, such as
benzene, diethyl ether, chloroform, methylene chloride, and di-
oxane under reflux for 48 h, only starting materials were re-
covered. However, toluene (Table 2, entry 2) furnished 8bed in 19%
yield with no significant change in diastereoselectivity to that of
THF (Table 2, entry 1). DCE resulted in excellent yields (Table 2,
entries 3) with significantly different regioselectivity (C6:C5 at
20:1) compared to 1.63:1 in the case of THF. In acetonitrile, only 7
was recovered (Table 2, entry 4). Overall polar aprotic solvents,
such as THF and DCE are the best for this hydroboration reaction,
which is in accordance with previous reports on diverse range of
substrates, such as styrene, acyclic, carbocyclic, and heterocyclic
olefins.28
rene and b-substituted vinyl arenes. We investigated these ligands
for CuCl catalyzed hydroboration of azepine 7 with PinBH in tol-
uene. (R)-DTMB-Segphos furnished 8bed in 78% yield with 11.5 to
1 regioselectivity (C6:C5) at 70 ꢀC in toluene (Table 3, entry 10)
while (S,S,R,R)-Tangphos demonstrated 24:1 regioselectivity and
82% yield (Table 3, entry 12). Solvent effects were investigated for
this copper-(S,S,R,R)-Tangphos catalyzed condition. THF, DCE and
CHCl3 did not result in better yield or selectivity. It is noteworthy
that although transition metal catalyzed hydroboration has been
extensively studied, reports on complex heterocyclic substrates
are rare. To our best knowledge, this is the first study of transition
metal catalyzed hydroboration of a substituted azepane ring.
2.4. Deoxyfluorination of azepanes 8bed
Compounds 8bed were subjected to fluorination reactions
(Scheme 3) inthe presence ofDASTorDeoxofluorÒ inDCM at 25 ꢀCto
provide fluoroazepanes 10bed, respectively (Table 4, entries 3, 13,
and 15). The stereochemical assignments of C5 and C6 in 10bed
were secured by 2D NMR experiments. Furthermore, 10bed were
Boc deprotected to give 11bed (Scheme 3) to further confirm the
stereochemistry at C5 and C6 without cis/trans isomerism due to the
Boc group.
Table 2
Solvent effects in hydroboration of 7a
Fluorination using nucleophilic agents, such as DAST is expected
to give inversion of stereochemistry at the participating chiral
carbon center.36 However, in our case retention of stereochemistry
at C5 and C6 of 10bed was observed as revealed by 2D NMR data
(Supplementary data).
Retention of stereochemistry in such fluorination cases is possi-
ble with the assistance of neighboring group participation.37 In the
case of cyclitol derivatives, there are a few reports for retention of
stereochemistry explained by double inversion through participa-
tion of adjacent 2-methoxyethoxymethyl,37a benzyl,37e methoxy37d
groups containing nucleophilic centers or bromomethyl37d via bro-
mine anchimeric assistance. Electron rich nitrogen or sulfur con-
taining heterocyclic substrates also demonstrates retention of
stereochemistry through formation of aziridinium or episulfonium
intermediates.37c,38 For example, retention of stereochemistry in
fluorination of benzyl protected piperidine 12 by hydroxy
Entry
Conditions
Yieldb (%)
Ratioc
8a
8b
8c
8d
1
2
3
4
THF, 25 ꢀC, 14 h
98
19
98
0
1
0
0
0
37
35
5
33
30
40
0
29
35
55
0
Toluene, 110 ꢀC, 48 h
DCE, 25 ꢀC, 14 h
MeCN, 82 ꢀC, 48 h
0
a
All reactions were carried out using BH3$SMe2 as hydroborating agent.
Isolated yield of 8aed after column chromatography; unreacted
b
7
was
recovered.
c
Ratio was calculated on the basis of HPLC traces.
Stabilized boranes, such as CatBH and PinBH with less Lewis-
acidity, offer an advantage of better functional group tolerance
and ease for storage and handling. However, hydroboration with
stabilized boranes usually requires catalytic activation. As such
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4
A.R. Patel, F. Liu / Tetrahedron xxx (2012) 1e9
Table 3
Catalyst screening in hydroboration of 7a
Entry
Conditions
Yielda (%)
Ratiob
8a
8b
8c
8d
1
2
3
4
5
6
7
8
CatBH, 1 mol % [Rh(COD)2Cl]2, THF, 25 ꢀC, 24 h
43
38
72(70)
40
41
0
36
67(63)
26
78(72)
53
82(80)
86
0
14
60
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
7
7
11
9
9
0
12
9
5
8
4
4
7
0
18
9
52
24
27
33
32
0
21
24
49
38
31
31
35
0
41
69
62
58
59
0
67
67
46
54
65
65
58
0
CatBH, 5 mol % Ir(COD)(PCy3)(Py)PF6, THF, 25 ꢀC, 24 h
CatBH, 5 mol % Ir(COD)(PCy3)(Py)PF6, THF, 66 ꢀC, 14 h
PinBH, 1 mol % Rh(COD)(PPh3)BF4, DCE, 25 ꢀC, 24 h
PinBH, 1 mol % Rh(COD)(DPPB)BF4, DCE, 25 ꢀC, 24 h
PinBH, 1 mol % Rh(COD)(DPPB)BF4, 2 mol % Sc(OTf)3, DCE, 25 ꢀC, 24 h
PinBH, 1 mol % Rh(COD)(DPPB)BF4, 2 mol % FAB, DCE, 25 ꢀC, 24 h
PinBH, 1 mol % Rh(COD)(DPPB)BF4, 2 mol % FAB, DCE, 70 ꢀC, 14 h
PinBH, 3 mol % CuCl, 3.3 mol % Segphos, 6 mol % NaOtBu, toluene, 25 ꢀC, 24 h
PinBH, 3 mol % CuCl, 3.3 mol % Segphos, 6 mol % NaOtBu, toluene, 70 ꢀC, 14 h
PinBH, 3 mol % CuCl, 3.3 mol % Tangphos, 6 mol % NaOtBu, toluene, 25 ꢀC, 24 h
PinBH, 3 mol % CuCl, 3.3 mol % Tangphos, 6 mol % NaOtBu, toluene, 70 ꢀC, 14 h
PinBH, 3 mol % CuCl, 3.3 mol % Tangphos, 6 mol % NaOtBu, toluene, 110 ꢀC, 14 h
PinBH, 3 mol % CuCl, 3.3 mol % Tangphos, 6 mol % NaOtBu, CHCl3, 61 ꢀC, 14 h
PinBH, 3 mol % CuCl, 3.3 mol % Tangphos, 6 mol % NaOtBu, DCE, 70 ꢀC, 14 h
PinBH, 3 mol % CuCl, 3.3 mol % Tangphos, 6 mol % NaOtBu, THF, 66 ꢀC, 14 h
9
10
11
12
13
14
15
16
40
36
42
55
The entries in bold indicate the most optimal reactions conditions.
a
1.5 equiv CatBH or PinBH were used; % conversion based on crude 1H NMR; number in parentheses is isolated yield of 8aed after column chromatography; unreacted 7
was recovered.
b
Ratio was calculated on the basis of HPLC traces.
replacement was conferred via an aziridinium intermediate38
(Scheme 4, Eq. 1) to give 13. This neighboring group effect from an
electron rich nitrogen center by aziridinium formation is not possi-
ble in ourazepanes 8bed, given the presence of the N-Boc protecting
group.
In the case of 8bed, the retention of stereochemistry can best
be explained by the neighboring group effect of the carbamate
oxygen (Scheme 4, Eq. 2) via formation of a five (8ced) or six (8b)
membered ring. This would be in accordance with prior examples
Scheme 3. 8b: R1¼OH, R2, R3¼H; 8c: R2¼OH, R1, R3¼H; 8d: R3¼OH, R1, R2¼H; 10b and
11b: R1¼F, R2, R3¼H; 10c and 11c: R2¼F, R1, R3¼H; 10d and 11d: R3¼F, R1, R2¼H.
Table 4
Deoxyfluorination of compounds 8bed
Entry
Fluorinating agent
Substrate
Producta
Solvent
CH2Cl2
Temperature (ꢀC)
Time (h)
6.5
Yield (%)b
1
DAST
ꢁ78
92
2
3
4
5
6
7
8
9
DAST
DAST
DAST
DAST
8c
8c
8c
8c
8c
8c
8c
8c
8c
8c
8c
10c
10c
10c
10c
10c
10c
10c
10c
10c
10c
10c
CH2Cl2
0
25
25
25
25
ꢁ78
0
25
25
25
25
6.5
3.5
14
14
14
6.5
6.5
1.5
14
14
14
89
CH2Cl2
Toluene
CHCl3
n-Pentane
CH2Cl2
>99(97)
48c
5
90
94
DAST
DeoxofluorÒ
DeoxofluorÒ
DeoxofluorÒ
DeoxofluorÒ
DeoxofluorÒ
DeoxofluorÒ
CH2Cl2
96
CH2Cl2
Toluene
CHCl3
>99(98)
76c
91
10
11
12
n-Pentane
88
13
DAST
CH2Cl2
25
3.5
96(95)
14
15
16
DeoxofluorÒ
DAST
8b
8d
10b
10d
CH2Cl2
CH2Cl2
CH2Cl2
25
25
25
1.5
4
>99(97)
97(95)
DeoxofluorÒ
1.5
>99(97)
The entries in bold indicate the most optimal reactions conditions.
a
Only one diastereomer was formed.
Yield was calculated on the basis of HPLC traces; number in parentheses represents isolated yield.
Diastereomeric ratio (10c:10d) was 98:2.
b
c
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A.R. Patel, F. Liu / Tetrahedron xxx (2012) 1e9
5
slight racemization (98:2) was observed in the case of toluene with
DAST and DeoxofluorÒ (Table 4, entries 4 and 10).
3. Conclusion
In conclusion, we report here the first practical and efficient
diastereospecific fluorination of substituted azepanes in two steps
with an overall yield of>95% from a starting tetrahydroazepine 7.
The approach of deoxyfluorination using DAST or DeoxofluorÒ gave
diastereospecific fluorination with retention of stereochemistry,
most likely by neighboring group participation from a carbamate.
As fluorinated azepanes are important pharmacophores, these
fluorinated azepanes should serve as new fluorinated building
blocks in drug discovery.
4. Experimental section
4.1. General
Scheme 4. (1) Neighboring group effect via an aziridinium intermediate; (2) retention
of stereochemistry in deoxyfluorination; (3) inversion of stereochemistry in 6 via SN2
pathway.
All reactions were conducted under N2 atmosphere. Unless oth-
erwise specified, all reagents were purchased from SigmaeAldrich
and used without further purification. CH2Cl2 was obtained from
a solvent purification system (Innovative Technology SPS400) and
of amide oxygen participation.37b Sekar et al.39 investigated the
effect of nitrogen protecting groups for chlorination reaction using
PPh3 and N-chorosuccinimide (NCS), which also follows a SN2
pathway. Their study showed that protecting groups like phenyl,
substituted phenyl, and amide exhibit neighboring group partici-
pation resulting in retention of stereochemistry from double in-
version. However, in their system protecting groups, such as N-
tosyl or Cbz did not show any neighboring group effect and in-
version of stereochemistry was observed. In their study, the sub-
strate used was 2-hydroxy cyclohexylamine, which is quite
different from the azepanes here. To test if ring rigidity may in-
fluence such neighboring group participation, alcohol 6 was sub-
jected to deoxyfluorination using DeoxofluorÒ in DCM. Compared
to 8c, 6 may undergo deoxyfluorination with retention of stereo-
chemistry, given that the hydroxyl group is equal distance to the
carbamate group as is the case of 8c. However, due to the presence
of the double bond between C5 and C6, the seven-membered ring
in 6 is more rigid. The resulting fluoroazepane 14 from 6 was ob-
tained in excellent yield with inversion of stereochemistry
(Scheme 4, Eq. 3). It is also noteworthy that alcohol 6 undergoes
inversion of stereochemistry to form tetrahydroazepine 7 under
mitsunobu conditions following an SN2 pathway (Scheme 4, Eq. 3).
Thus, in spite of being at equicarbon distance to the nitrogen
center, the center of substitution in 6 (C3) and 8bed (C5 or C6)
presented different neighboring group effects potentially because
of the rigidity of 6 compared to 8bed. This suggests that retention
of stereochemistry in 8bed deoxyfluorination is dependent on ring
rigidity. To the best of our knowledge, this is the first example of
carbamate oxygen neighboring group effect for retention of ste-
reochemistry in deoxyfluorination. Given this neighboring group
effect, the yields and diastereomeric ratios under other fluorina-
tion conditions were examined using 8bed (Table 4). The deoxy-
fluorination at lower temperatures resulted in longer reaction
times as expected (Table 4, entries 1e3). The diastereospecific
conversion was maintained in all cases while different solvents
only affected yields. As DeoxofluorÒ21,40 is considered a better
fluorinating agent than DAST in terms of thermal stability40b and
reactivity,40e deoxyfluorination of 8bed was also examined using
DeoxofluorÒ (Table 4, entries 7e12, 14, and 16). The yields of
fluorination observed in these cases were slightly better than those
of DAST.
ꢀ
stored over MS 4 A beads. Ethyl acetate and petroleum ether were
distilled before use and the later refers to the fraction collected be-
tween 60 ꢀC and 80 ꢀC. THF and toluene were distilled from
ꢀ
NaebenzophenoneandstoredoverMS4 A beads. CHCl3 wasdistilled
ꢀ
from CaCl2 and stored over MS 4 A beads in the dark. Anhydrous n-
pentanewasobtainedfromSigmaeAldrichandusedwithoutfurther
purification. 1H NMR spectra were recorded at 25 ꢀC on either
aBrukerDRX600KorDPX400NMRSpectrometerandarereportedin
parts per million using the specified solvent as the internal standard
(CDCl3 at 7.26 ppm). 13C NMR spectra are reported in ppm using the
specified solvent as the internal standard (CDCl3 at 77.16 ppm).
4.2. (2S,3R)-1,2-Epoxy-4-penten-3-ol (2)
ꢀ
A crushed 4 A molecular sieves (400 mg) in CH2Cl2 (12 mL) was
cooled to ꢁ35 ꢀC. Pre-cooled (ꢁ35 ꢀC) titanium tetraisopropoxide
(350
m
L, 1.19 mmol) and (R,R)-(ꢁ)-diisopropyl tartrate (330
mL,
1.55 mmol) were added drop wise via syringe. Pre-cooled (ꢁ35 ꢀC)
divinylcarbinol (1.00 g, 11.9 mmol) and cumene hydroperoxide
(3.50 mL, 23.8 mmol) were added drop wise via glass syringe after
30 min. The reaction mixture was allowed to stir at ꢁ35 ꢀC for
36 h. Aqueous saturated Na2SO4 (1 mL) was added after warming
up to room temperature and the mixture was diluted with Et2O
(10 mL). The mixture was then stirred at ambient temperature for
3 h, the resulting slurry was vacuum filtered through a pad of
Celite and the resulting yellow solution was concentrated under
vacuum at 0 ꢀC to furnish the crude residue, which was subjected
to flash chromatography (petroleum ether/EtOAc, 4/1 then 100%
Et2O) to give 2 (990 mg, 83%) as a colorless oil with optical rotation
and 1H NMR spectral data matching those reported previously.25
½
a 2D0
ꢂ
ꢁ50 (c 0.73, CHCl3). 1H NMR (CDCl3, 400 MHz):
d 5.90e5.83
(m, 1H), 5.39 (br d, J¼17.3 Hz, 1H), 5.26 (d, J¼10.5 Hz, 1H), 4.34 (br
s, 1H), 3.09 (dd, J¼6.4, 3.0 Hz, 1H), 2.84e2.74 (m, 2H), 2.08 (br,
s, 1H).
4.3. (S)-2-((R)-1-Benzyloxy-allyl)-oxirane (3)
NaH (260 mg, 10.9 mmol) was added slowly to a solution of
epoxyalcohol 2 (990 mg, 9.90 mmol) and (n-Bu)4NI (370 mg,
990 mmol) in THF (22 mL). Benzyl bromide (3.39 g, 19.8 mmol) was
Significant differences in yields however were observed in tol-
uene and CHCl3 where DeoxofluorÒ compared to DAST led to much
better yields (Table 4, entries 4, 5, 10, and 11). On the other hand,
added drop wise via syringe after 5 min and the resulting sus-
pension was stirred at ambient temperature for 14 h. The reaction
was quenched by drop wise addition of aqueous saturated NaHCO3
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6
A.R. Patel, F. Liu / Tetrahedron xxx (2012) 1e9
(10 mL) and the aqueous layer was extracted with Et2O (2ꢃ20 mL).
The combined organic phases were dried (Na2SO4) before solvent
was evaporated to get the residue, which was purified by flash
chromatography (petroleum ether/EtOAc, 9/1) to give 3 (1.75 g,
93%) as a colorless oil with optical rotation and 1H NMR spectral
(95.8 mg, 300
(258 L, 1.20 mmol) in dry THF (7.5 mL) under N2 atmosphere at
25 ꢀC, diethyl azodicarboxylate (DEAD, 189
L, 1.20 mmol) was
mmol), PPh3 (314 mg, 1.20 mmol), and (PhO)2P(O)N3
m
m
added drop wise via syringe and the resulting mixture was stirred
at same temperature until the completion of reaction (monitored
by TLC, 4.5 h). The residue obtained by evaporation of reaction
mixture under reduced pressure was suspended in EtOAc (15 mL),
followed by filtration through a short pad of silica. The filtrate was
washed with aqueous 2 N HCl (15 mL), brine (15 mL), and dried
over MgSO4. The solvent was evaporated, and the crude was puri-
fied by flash chromatography (pentane/tert-butylmethylether, 20/
1) to afford compound 7 (91.3 mg, 89%) as a pale yellow syrup with
optical rotation and 1H NMR spectral data matching those reported
data matching those reported previously.24
½
a 2D0
7.34e7.24 (m, 5H), 5.88e5.77
ꢂ
ꢁ31.6 (c 1.4,
CHCl3); 1H NMR (CDCl3, 400 MHz):
d
(m, 1H), 5.38e5.31 (m, 2 H), 4.63 (d, J¼12.0 Hz, 1H), 4.47 (d,
J¼12.0 Hz, 1H), 3.80 (dd, J¼7.3, 4.2 Hz, 1H), 3.10e3.06 (m, 1H), 2.76
(dd, J¼5.2, 4.0 Hz, 1H), 2.67 (dd, J¼5.2, 2.6 Hz, 1H).
4.4. (2S,3R)-1-Allylamino-3-benzyloxy-pent-4-en-2-ol (4)
An epoxide 3 (790 mg, 4.15 mmol) was refluxed in freshly dis-
tilled allylamine (6.25 mL, 83.0 mmol) for 40 h. Excess allylamine
was removed under reduced pressure. The remaining pale yellow
oil was amine 4 (980 mg, 95%) with optical rotation and 1H NMR
spectral data matching those reported previously24 and was pure
enough to be used in the next step without further purification.
previously.24
d
½
a 2D0
ꢂ
þ38 (c 8.8, CHCl3); 1H NMR (CDCl3, 400 MHz):
7.39e7.20 (m, 5H), 5.74 (br s, 2H), 4.68e4.55 (m, 2H), 4.25e4.23
(m, 2H), 3.90e3.49 (m, 4H), 1.47 (s, 9H).
4.8. General procedure for hydroborationeoxidation
½
a 2D0
ꢂ
ꢁ36.6 (c 2.0, CHCl3); 1H NMR (CDCl3, 400 MHz):
d
7.35e7.22
Borane dimethylsulfide (BH3$SMe2)
2 M solution in THF
(m, 5H), 5.96e5.75 (m, 2H), 5.36e5.31 (m, 2H), 5.18e5.02 (m, 2H),
4.59 (d, J¼11.8 Hz, 1H), 4.35 (d, J¼11.8 Hz, 1H), 3.82e3.73 (m, 2H),
3.30e3.22 (m, 2H), 3.14 (br s, 2H), 2.77 (dd, J¼12.3, 3.7 Hz, 1H),
2.70e2.63 (m, 1H).
(78.0 L, 156 mol) was added drop wise via syringe to a well
m
m
stirred solution of olefin 7 (50.0 mg, 145 mmol) in dry THF (150 mL)
under N2 atmosphere at 25 ꢀC. The reaction mixture was allowed to
stir at same temperature for 14 h before the addition of EtOH
(900 mL), 6 N NaOH (600 mL), and 30% H2O2 (300 mL). The mixture
4.5. (2S,3R)-Allyl-(3-benzyloxy-2-hydroxy-pent-4-enyl)-car-
bamic acid-tert-butyl ester (5)
was heated at 50 ꢀC for 1 h to ensure complete oxidation. The
aqueous layer was saturated with K2CO3 to effect the separation of
the organic layer. The aqueous layer was then washed with EtOAc
(2ꢃ2 mL) and the combined organic layers were dried over MgSO4
before evaporation to furnish the crude residue. The crude was
subjected to flash chromatography (petroleum ether/EtOAc, 3/1) to
give a mixture of diastereomers 8aed (51.6 mg, 98%). The mixture
was then chromatographed on a Phenomenex Gemini C18 column
(150ꢃ21.20 mm) eluting with MeCN/water/TFA (from 30:70:0.1 to
60:40:0.1 over 85 min; flow rate: 8.80 mL/min; retention time 44.4,
42.0, 37.2, and 40.7 min for 8a, 8b, 8c, and 8d, respectively) to give
Di-tert-butyl dicarbonate (48.8 mg, 220
was added to a mixture of amine 4 (49.5 mg, 200
(39.0 L, 280
mol) in CH2Cl2 (2 mL) at 0 ꢀC and the resulting
mmol) in CH2Cl2 (2 mL)
mmol) and Et3N
m
m
mixture was stirred at ambient temperature for 2 h. The reaction
mixture was quenched by addition of water (2 mL) before the ex-
traction of the aqueous phase with EtOAc (2ꢃ5 mL). Successive
washing of the combined organic layers with aqueous 2 N HCl
(5 mL) and brine (5 mL) followed by drying (Na2SO4), evaporation
of the solvents and flash chromatography of the residue (petroleum
ether/EtOAc, 6/1) gave compound 5 (66.8 mg, 96%) as a colorless oil
with optical rotation and 1H NMR spectral data matching those
8a (500
mg, 1%), 8b (19.1 mg, 36%), 8c (17.0 mg, 32%), and 8d
(15.0 mg, 28%) as colorless oils in a ratio of 1:37:33:29. It is note-
worthy that 8aed were observed to have rotamers because of N-
Boc group.
reported previously.24
400 MHz):
½
a 2D0
ꢂ
ꢁ28.8 (c 2.0, CHCl3); 1H NMR (CDCl3,
d
7.34e7.23 (m, 5H), 5.89e5.68 (m, 2H), 5.39e5.29 (m,
2H), 5.12e5.02 (m, 2H), 4.62 (d, J¼12.0 Hz, 1H), 4.35 (d, J¼12.0 Hz,
4.8.1. (3R,4S,5R)-3-Azido-4-benzyloxy-5-hydroxyazepane-1-
1H), 3.88e3.67 (m, 4H), 3.41e3.35 (m, 2H), 1.42 (s, 9H).
carboxylic acid-tert-butyl ester (8a). ½a D20
ꢁ53 (c 0.9, CH2Cl2); IR (film)
ꢂ
nmax (cmꢁ1): 3600e3100 (br), 2977, 2930, 2361, 2104, 1684, 1416,
4.6. (3S,4R)-4-Benzyloxy-3-hydroxy-2,3,4,7-
1157, 1088, 1045; 1H NMR (600 MHz, CDCl3)
d 7.41e7.35 (m, 5H),
tetrahydroazepine-1-carboxylic acid-tert-butyl ester (6)
5.09e5.08 (t, J¼10.4 Hz, 1H), 4.69e4.67 (t, J¼10.6 Hz, 1H), 4.12e4.05
(m, 1H), 3.99e3.80 (m, 2H), 3.60e3.54 (m, 1H), 3.45e3.36 (m, 1H),
3.23e3.09 (m, 2H), 2.16e2.05 (m, 1H),1.92e1.80 (m, 1H),1.46 (s, 9H);
Grubbs catalyst (generation I) (11.6 mg, 14.1
added to a solution of diene 5 (98.0 mg, 280
(30 mL). The reaction mixture was refluxed for 20 h when addi-
tional Grubbs catalyst (7.00 mg, 8.50 mol, 3 mol %) was added and
mmol, 5 mol %) was
mmol) in CH2Cl2
13C NMR (150 MHz, CDCl3)
d 155.1, 137.7, 128.9, 128.5, 128.4, 90.6,
80.6, 76.4, 71.1, 60.6, 48.1, 42.1, 30.3, 28.5; HRMS (ESI): [MþH]þ, m/z
m
calcd for C18H27N4O4 363.2039, found 363.2034.
solution was refluxed for additional 22 h. Solvent was then evap-
orated and the residue was subjected to flash chromatography
(petroleum ether/EtOAc, 5/1 to 2/1) to provide tetrahydroazepine 6
(77.8 mg, 86%) as a yellow oil with optical rotation and 1H NMR
4.8.2. (3R,4S,5S)-3-Azido-4-benzyloxy-5-hydroxyazepane-1-
carboxylic acid-tert-butyl ester (8b). ½a D20
þ51.2 (c 0.8, CH2Cl2); IR
ꢂ
(film) nmax (cmꢁ1): 3600e3100 (br), 2977, 2930, 2361, 2105, 1684,
spectral data matching those reported previously.24
½
a 2D0
ꢂ
ꢁ78 (c 1.5,
1416, 1157, 1088, 1045; 1H NMR (600 MHz, CDCl3)
d 7.41e7.36 (m, 5H),
CHCl3); 1H NMR (CDCl3, 400 MHz):
d
7.38e7.27 (m, 5H), 5.79e5.65
5.00e4.96 (dd, J¼11.0, 4.6 Hz, 1H), 4.67e4.63 (t, J¼10.6 Hz, 1H),
3.80e3.51 (m, 4H), 3.28e3.12 (m, 2H), 3.10e2.96 (m, 1H), 2.48 (br s,
1H), 2.13e2.04 (m, 1H), 1.85e1.72 (m, 1H), 1.48 (s, 9H); 13C NMR
(m, 2H), 4.74e4.61 (m, 1H), 4.58e4.46 (m, 1H), 4.45e4.10 (m, 3H),
4.03e3.90 (m, 1H), 3.82e3.63 (m, 1H), 3.31e3.11 (m, 1H), 2.51 (br s,
1H), 1.41 (s, 9H).
(150 MHz, CDCl3)
d 154.9, 137.6, 128.9, 128.5, 128.4, 87.9, 80.9, 75.9,
70.7, 64.8, 45.0, 42.2, 30.6, 28.5; HRMS (ESI): [MþH]þ, m/z calcd for
4.7. (3R,4R)-3-Azido-4-benzyloxy-2,3,4,7-tetrahydroazepine-
1-carboxylic acid-tert-butyl ester (7)
C18H27N4O4 363.2039, found 363.2046.
4.8.3. (3R,4R,6S)-3-Azido-4-benzyloxy-6-hydroxyazepane-1-
To a well stirred solution of (3S,4R)-4-benzyloxy-3-hydroxy-
carboxylic acid-tert-butyl ester (8c). ½a D20
ꢁ49.2 (c 0.8, CH2Cl2); IR
ꢂ
2,3,4,7-tetrahydroazepine-1-carboxylic acid-tert-butyl ester
6
(film) nmax (cmꢁ1): 3600e3100 (br), 2977, 2930, 2361, 2105, 1684,
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A.R. Patel, F. Liu / Tetrahedron xxx (2012) 1e9
7
1416, 1157, 1088, 1045; 1H NMR (600 MHz, CDCl3)
d
7.40e7.34 (m,
d 137.1,128.8,128.4,128.1, 75.5, 72.2, 63.6, 60.8, 54.1, 47.6, 34.2; HRMS
5H), 4.68e4.56 (m, 2H), 4.0e3.94 (m, 1H), 3.87e3.78 (m, 1H),
3.69e3.61 (m, 2H), 3.37 (t, J¼9.0 Hz, 1H), 3.30 (dd, J¼14.9, 5.9 Hz,
1H), 2.90 (q, J¼14.9, 8.8 Hz, 1H), 2.54 (br s, 1H), 2.34e2.28 (dd,
J¼14.8, 5.0 Hz, 1H), 1.79e1.71 (m, 1H), 1.48 (s, 9H); 13C NMR
(ESI): [MþH]þ, m/z calcd for C13H19N4O2 263.1508, found 263.1509.
4.10. General procedure for deoxyfluorination of 10
(150 MHz, CDCl3)
d
156.5, 137.2, 128.6, 128.1, 128.0, 81.2, 78.7, 71.7,
A
solution of bis(2-methoxyethyl)aminosulfur trifluoride
68.3, 64.5, 54.9, 49.7, 37.0, 28.3; HRMS (ESI): [MþH]þ, m/z calcd for
(DeoxofluorÒ) (13.4 mg, 60.7
fluoride (DAST) (9.80 mg, 60.7
mmol) or diethylaminosulfur tri-
C
18H27N4O4 363.2039, found 363.2044.
m
mol) in dry DCM (100 L) was
m
added drop wise via a syringe to a well stirred solution of 8c
(20.0 mg, 55.2 mol) in dry DCM (100 L) under N2 atmosphere at
4.8.4. (3R,4R,6R)-3-Azido-4-benzyloxy-6-hydroxyazepane-1-
m
m
carboxylic acid-tert-butyl ester (8d). ½a D20
ꢂ
þ48.8 (c 0.8, CH2Cl2); IR
25 ꢀC. The reaction mixture was allowed to stir at the same tem-
perature until the completion of reaction (monitored by TLC). The
reaction mixture was quenched by ice cooled water before the
crude was extracted with EtOAc and washed with water and brine.
The organic phase was evaporated under reduced pressure after
drying over MgSO4 to give the crude product, which was subjected
to flash chromatography (petroleum ether/EtOAc, 9/1) to give 10c
(19.5 mg, 97%, using DAST; 19.7 mg, 98%, using DeoxofluorÒ) as
colorless oil.
(film) nmax (cmꢁ1): 3600e3100 (br), 2977, 2930, 2361, 2105, 1684,
1416, 1157, 1088, 1045; 1H NMR (600 MHz, CDCl3)
d 7.38e7.33 (m,
5H), 4.64e4.52 (m, 2H), 4.21e4.12 (m, 1H), 3.82e3.68 (m, 4H),
3.44e3.33 (m, 2H), 2.08e1.98 (m, 1H), 1.87 (br s, 1H), 1.48 (s, 9H);
13C NMR (150 MHz, CDCl3)
d 157.2, 137.8, 128.7, 128.1, 128.0, 81.2,
76.1, 71.9, 68.1, 64.9, 55.4, 49.0, 34.6, 28.4; HRMS (ESI): [MþH]þ, m/z
calcd for C18H27N4O4 363.2039, found 363.2032.
4.9. Typical procedure for Boc deprotection of 8
4.10.1. (3R,4S,5S)-3-Azido-4-benzyloxy-5-fluoroazepane-1-carboxylic
acid-tert-butyl ester (10b). Colorless oil, yield 95% (DAST), 97%
(3R,4R,6R)-3-Azido-4-benzyloxy-6-hydroxyazepane-1-carboxylic
acid-tert-butyl ester 8d (9.60 mg, 26.5
m
mol) was dissolved in TFA
(DeoxofluorÒ); Rf (petroleum ether/EtOAc, 9/1) 0.5; ½a 2D0
þ55.9 (c 1.0,
ꢂ
(500
m
L) at 25 ꢀC. The solution was allowed to stir for 5 min
CH2Cl2); IR (film) nmax (cmꢁ1): 2362, 2342, 2109, 1716, 1698, 1541,
before TFA was vacuum evaporated. The reaction flask was
kept under high vacuum (0.005 Torr, 25 ꢀC) for 3 h to remove
traces of TFA, and the colorless oil obtained was characterized as
(3R,4R,6R)-3-azido-4-benzyloxy-azepane-6-ol 9d (6.80 mg, 98%).
1522,1474,1457,1418; 1H NMR (600 MHz, CDCl3)
d 7.41e7.28 (m, 5H),
4.83e4.60 (m, 3H), 3.97e3.84 (m, 1H), 3.80e3.47 (m, 3H), 3.25e3.11
(m, 1H), 3.01e2.87 (m, 1H), 2.23e1.99 (m, 2H), 1.46 (s, 9H); 13C NMR
(150 MHz, CDCl3)
d 155.1, 137.6, 128.6, 128.5, 128.2, 93.6 (d,
1JCF¼173.1 Hz), 85.2 (d, 2JCF¼21.2 Hz), 80.9, 75.2, 63.7 (d, 3JCF¼6.2 Hz),
45.0, 40.9 (d, 3JCF¼11.4 Hz), 29.7 (d, 2JCF¼22.4 Hz), 28.5; HRMS (ESI):
[MþH]þ, m/z calcd for C18H26FN4O3 365.1989, found 365.2002.
4.9.1. (3R,4S,5R)-3-Azido-4-benzyloxyazepane-5-ol (9a). Colorless
oil, yield 97%; ½a D20
ꢂ
ꢁ57.6 (c 1.0, CH2Cl2); IR (film) nmax (cmꢁ1): 3587,
2341, 1698, 1683, 1636, 1558, 1199, 1132; 1H NMR (600 MHz, CDCl3)
d
7.40e7.31 (m, 5H), 4.77 (d, J¼11.5 Hz, 1H), 4.64 (d, J¼11.5 Hz, 1H),
4.10.2. (3R,4R,6S)-3-Azido-4-benzyloxy-6-fluoroazepane-1-carboxylic
4.33 (q, J¼4.3 Hz, 1H), 4.14 (t, J¼6.8 Hz, 1H), 3.83 (t, J¼5.0 Hz, 1H),
acid-tert-butyl ester (10c). Rf (petroleum ether/EtOAc, 9/1) 0.51; ½a D20
ꢂ
3.56e3.47 (m, 3H), 3.22e3.15 (m, 1H), 2.30e2.22 (m, 1H), 2.13e2.04
ꢁ54.1 (c 1.0, CH2Cl2); IR (film) nmax (cmꢁ1): 2361, 2341, 2109, 1716,
(m, 1H); 13C NMR (150 MHz, CDCl3)
d
137.0, 128.9, 128.6, 128.2, 84.9,
1541, 1521, 1473, 1456, 1418; 1H NMR (600 MHz, CDCl3)
d
7.39e7.34
73.8, 70.1, 56.6, 47.0, 42.1, 25.7; HRMS (ESI): [MþH]þ, m/z calcd for
(m, 5H), 4.93e4.78 (d, JHF¼54.0 Hz, 1H), 4.73 (t, J¼11.7 Hz, 1H),
1
C
13H19N4O2 263.1508, found 263.1505.
4.60e4.50 (m, 1H), 3.95e3.88 (m, 1H), 3.78e3.38 (m, 5H), 2.40e2.27
(m, 1H), 2.16e1.98 (m, 1H), 1.48 (s, 9H); 13C NMR (150 MHz, CDCl3)
1
4.9.2. (3R,4S,5S)-3-Azido-4-benzyloxyazepane-5-ol (9b). Colorless
d
155.1, 137.5, 128.7, 128.2, 88.3 (d, JCF¼171.0 Hz), 81.0, 77.3, 71.7,
oil, yield 97%; ½a D20
ꢂ
þ56.4 (c 1.0, CH2Cl2); IR (film) nmax (cmꢁ1): 3587,
64.7, 50.8 (d, 2JCF¼34.5 Hz), 48.4, 33.1 (d, 2JCF¼21.0 Hz), 28.4; HRMS
2341, 1698, 1683, 1636, 1558, 1456, 1199, 1132; 1H NMR (600 MHz,
(ESI): [MþH]þ, m/z calcd for C18H26FN4O3 365.1989, found 365.1996.
CDCl3)
d
7.40e7.31 (m, 5H), 4.67 (q, J¼21.4, 8.2 Hz, 2H), 4.19e4.13 (q,
J¼3 Hz, 1H), 3.98e3.93 (m, 1H), 3.71 (t, J¼8.2 Hz, 1H), 3.51e3.42 (m,
1H), 3.33e3.20 (m, 2H), 3.18e3.09 (m, 1H), 2.80 (br s, 1H),
2.25e2.18(m, 1H), 2.07e1.99 (m, 1H); 13C NMR (150 MHz, CDCl3)
4.10.3. (3R,4R,6R)-3-Azido-4-benzyloxy-6-fluoroazepane-1-
carboxylic acid-tert-butyl ester (10d). Rf (petroleum ether/EtOAc, 9/
1) 0.45; ½a 2D0
þ53.4 (c 0.9, CH2Cl2); colorless oil, yield 95% (DAST),
ꢂ
d
137.0,128.9,128.6,128.2, 82.4, 73.5, 69.3, 60.3, 44.1, 41.4, 25.6;HRMS
97% (DeoxofluorÒ); IR (film) nmax (cmꢁ1): 2361, 2341, 2109, 1716,
(ESI): [MþH]þ, m/z calcd for C13H19N4O2 263.1508, found 263.1503.
1541, 1521, 1473, 1456, 1418; 1H NMR (600 MHz, CDCl3)
d 7.40e7.34
(m, 5H), 5.13e5.00 (d, 1JHF¼48.7 Hz, 1H), 4.62 (s, 2H), 4.15e4.04 (m,
1H), 3.81e3.68 (m, 2H), 3.63e3.57 (m, 1H), 3.32e3.23 (m, 1H),
2.99e2.93 (m, 1H), 2.49e2.42 (m, 1H), 1.85e1.73 (m, 1H), 1.48 (s,
4.9.3. (3R,4R,6S)-3-Azido-4-benzyloxyazepane-6-ol (9c). Colorless
oil, yield 98%; ½a D20
ꢂ
ꢁ55.4 (c 0.9, CH2Cl2); IR (film) nmax (cmꢁ1):
3587, 2341, 1698, 1683, 1636, 1558, 1456, 1199, 1132; 1H NMR
9H); 13C NMR (150 MHz, CDCl3)
d 154.9, 137.6, 128.7, 128.3, 128.2,
2
(600 MHz, CDCl3)
d
7.40e7.29 (m, 5H), 4.70 (d, J¼11.5 Hz, 1H), 4.53
88.5 (d, 1JCF¼169.7 Hz), 81.1, 77.2, 72.4, 65.1, 51.2 (d, JCF¼25.9 Hz),
(d, J¼11.5 Hz, 1H), 4.21 (br s, 1H), 4.14e4.09 (m, 1H), 3.83 (m, 1H),
3.51 (dd, J¼14.2, 3.9 Hz, 1H), 3.43 (dd, J¼13.8, 5.2 Hz, 1H), 3.10 (d,
J¼13.0 Hz, 1H), 3.04 (dd, J¼14.2, 5.9 Hz, 1H), 2.26 (dt, J¼15.7, 5.9 Hz,
47.8, 33.1 (d, 2JCF¼20.1 Hz), 28.4; HRMS (ESI): [MþH]þ, m/z calcd for
C18H26FN4O3 365.1989, found 365.1994.
1H), 2.12 (dt, J¼15.7, 3.7 Hz, 1H); 13C NMR (150 MHz, CDCl3)
d
137.0,
4.11. General procedure for Boc deprotection
10b (9.60 mg, 26.3 mol) was dissolved in TFA (500 m
L) at 25 ꢀC.
128.8,128.5,128.3, 77.4, 72.0, 64.6, 61.0, 51.6, 47.2, 34.0; HRMS (ESI):
[MþH]þ, m/z calcd for C13H19N4O2 263.1508, found 263.1507.
m
The solution was allowed to stir for 5 min before TFA was vacuum
evaporated. The reaction flask was kept under high vacuum
(0.005 Torr, 25 ꢀC) for 3 h to remove traces of TFA, and the colorless
oily residue obtained was characterized as 11b (9.20 mg, 98%).
4.9.4. (3R,4R,6R)-3-Azido-4-benzyloxyazepane-6-ol (9d). ½a D20
þ53.6
ꢂ
(c 1.0, CH2Cl2); IR (film) nmax (cmꢁ1): 3587, 2341, 1698, 1683, 1636,
1558, 1456, 1199, 1132; 1H NMR (600 MHz, CDCl3)
d 7.39e7.36 (m,
5H), 5.00e4.96 (m, 1H), 4.67e4.63 (m, 1H), 3.79e3.51 (m, 4H),
3.26e3.13 (m, 2H), 3.08e2.97 (m, 1H), 2.48 (br s, 1H), 2.12e2.05 (m,
1H), 1.72e1.84 (br m, 1H), 1.48 (s, 9H); 13C NMR (150 MHz, CDCl3)
4.11.1. (3R,4S,5S)-3-Azido-4-benzyloxy-5-fluoroazepane (11b). ½a D20
ꢂ
þ60.6 (c 0.8, CH2Cl2); IR (film) nmax (cmꢁ1): 2362, 2341, 2112, 1716,
Please cite this article in press as: Patel, A. R.; Liu, F., Tetrahedron (2012), http://dx.doi.org/10.1016/j.tet.2012.10.078

8
A.R. Patel, F. Liu / Tetrahedron xxx (2012) 1e9
1698, 1684, 1671, 1558, 1541, 1521, 1456, 1199; 1H NMR (600 MHz,
4. (a) Craig, N. C.; Chen, A.; Suh, K. H.; Klee, S.; Mellau, G. C.; Winnewisser, B. P.;
Winnewisser, M. J. Am. Chem. Soc. 1997, 119, 4789; (b) Leroux, F.; Jeschke, P.;
Schlosser, M. Chem. Rev. 2005, 105, 827; (c) Muller, N. J. Pharm. Sci. 1986, 75, 987;
(d) Myers, A. G.; Barbay, J. K.; Zhong, B. J. Am. Chem. Soc. 2001,123, 7207;(e) Purser,
S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320; (f)
Buissonneaud, D. Y.; van Mourik, T.; O’Hagan, D. Tetrahedron 2010, 66, 2196.
5. (a) Lal, G. S.; Pez, G. P.; Syvret, R. G. Chem. Rev. 1996, 96, 1737; (b) Prakash, G. K.
S.; Yudin, A. K. Chem. Rev. 1997, 97, 757; (c) Umemoto, T. Chem. Rev. 1996, 96,
1757; (d) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359; (e) Singh, R. P.; Shreeve,
J. M. Tetrahedron 2000, 56, 7613; (f) Taylor, S. D.; Kotoris, C. C.; Hum, G. Tetra-
hedron 1999, 55, 12431; (g) Ametamey, S. M.; Honer, M.; Schubiger, P. A. Chem.
Rev. 2008, 108, 1501.
1
CDCl3)
d
7.41e7.30 (m, 5H), 4.88 (d, JHF¼45.2 Hz, 1H), 4.72 (q,
J¼14.8, 11.4 Hz, 2H), 4.04 (t, J¼7.7 Hz, 1H), 3.84e3.78 (m, 1H),
3.39e3.08 (m, 4H), 2.35e2.22 (m, 2H); 13C NMR (150 MHz, CDCl3)
1
d
136.5, 128.8, 128.6, 128.3, 90.6 (d, JCF¼177.0 Hz), 82.2 (d,
2JCF¼25.5 Hz), 73.6, 59.9 (d, 3JCF¼3.0 Hz), 44.7, 40.0 (d, 3JCF¼9.0 Hz),
26.1 (d, JCF¼22.5 Hz); HRMS (ESI): [MþH]þ, m/z calcd for
2
C
13H18FN4O 265.1465, found 265.1463.
4.11.2. (3R,4R,6S)-3-Azido-4-benzyloxy-6-fluoroazepane (11c). ½a D20
ꢂ
ꢁ~
ꢁ
6. (a) Nunez-Villanueva, D.; Bonache, M. A.; Infantes, L.; García-Lopez, M. T.; Martín-
þ59.9 (c 1.0, CH2Cl2); IR (film) nmax (cmꢁ1): 2361, 2341, 2111, 1716,
ꢁ
~
Martínez, M.; Gonzalez-Muniz, R. J. Org. Chem. 2011, 76, 6592; (b) Jacobi, P. A.; Lee,
K. J. Am. Chem. Soc. 2000, 122, 4295; (c) Wipf, P.; Spencer, S. R. J. Am. Chem. Soc.
2005,127, 225; (d) Boeckman, R. K.; Clark, T. J.; Shook, B. C. Org. Lett. 2002, 4, 2109;
(e) Zhu, L.; Lauchli, R.; Loo, M.; Shea, K. J. Org. Lett. 2007, 9, 2269; (f) Smith, A. B., III;
Cho, Y. S.; Pettit, G. R.; Hirschmann, R. Tetrahedron 2003, 59, 6991.
1684, 1671, 1558, 1541, 1521, 1456, 1199; 1H NMR (600 MHz, CDCl3)
d
7.41e7.30 (m, 5H), 5.08 (d, 1JHF¼44.0 Hz, 1H), 4.76 (d, J¼11.6 Hz,
1H), 4.52 (d, J¼11.6 Hz, 1H), 4.12 (br s, 1H), 3.96 (br s, 1H), 3.67e3.58
(m, 2H), 3.56e3.44 (m, 1H), 3.42e3.33 (m, 1H), 2.54e2.44 (m, 1H),
€
7. (a) Stutz, A. E. Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond;
Wiley-VCH: Weinheim, 1999; (b) Martin, O. R.; Compain, P. Iminosugars: From
Synthesis to Therapeutic Applications; Wiley-VCH: Weinheim, 2007; (c) Asano, N.
In Glycoscience: Chemistry and Chemical Biology; Fraser-Reid, B. O., Tatsuta, K.,
2.42e2.30 (m, 1H); 13C NMR (150 MHz, CDCl3)
d 136.6, 128.9, 128.6,
128.2, 87.5 (d, 1JCF¼173.1 Hz), 74.9, 71.9, 60.1, 49.5 (d, 2JCF¼27.4 Hz),
ꢁ
2
Thiem, J., Cote, G. L., Flitsch, S., Ito, Y., Kondo, H., Nishimura, S.-i., Yu, B., Eds.;
48.2, 31.6 (d, JCF¼20.8 Hz); HRMS (ESI): [MþH]þ, m/z calcd for
Springer: Heidelberg, 2008.
8. (a) Painter, G. F.; Eldridge, P. J.; Falshaw, A. Bioorg. Med. Chem. 2004, 12, 225; (b)
C
13H18FN4O 265.1465, found 265.1471.
ꢁ
ꢁ
~
Luo, B.; Marcelo, F.; Desire, J.; Zhang, Y.; Sollogoub, M.; Kato, A.; Adachi, I.; Canada,
ꢁ
ꢁ
4.11.3. (3R,4R,6R)-3-Azido-4-benzyloxy-6-fluoroazepane (11d). ½a D20
ꢂ
F. J.; Jimenez-Barbero, J.; Bleriot, Y. J. Carbohydr. Chem. 2011, 30, 641; (c) Liu, P. S. J.
Org. Chem. 1987, 52, 4717; (d) Jacob, G. S. Curr. Opin. Struct. Biol. 1995, 5, 605.
9. (a) Zitzmann, N.; Mehta, A. S.; Carrouee, S.; Butters, T. D.; Platt, F. M.; McCauley, J.;
þ58.7 (c 0.9, CH2Cl2); IR (film) nmax (cmꢁ1): 2362, 2341, 2112, 1698,
ꢁ
1684, 1671, 1558, 1541, 1521, 1456, 1199; 1H NMR (600 MHz, CDCl3)
Blumberg, B. S.; Dwek, R. A.; Block, T. M. Proc. Natl. Acad. Sci. U.S.A.1999, 96,11878;
(b) Nishimura, Y. Curr. Top. Med. Chem. 2003, 3, 575; (c) Fiaux, H.; Popowycz, F.;
1
d
7.41e7.30 (m, 5H), 5.04 (d, JHF¼46.4 Hz, 1H), 4.63 (q, J¼11.6,
€
Favre, S.; Schutz, C.; Vogel, P.; Gerber-Lemaire, S.; Juillerat-Jeanneret, L. J. Med.
6.0 Hz, 2H), 4.00e3.93 (m, 1H), 3.93e3.87 (m, 1H), 3.54e3.28 (m,
3H), 3.19e3.12 (q, J¼14.4, 6.9 Hz, 1H), 2.54e2.46 (m, 1H), 2.34e2.23
Chem. 2005, 48, 4237.
10. (a) Laver, W. G.; Bischofberger, N.; Webster, R. G. Sci. Am. 1999, 280, 78; (b) Wu,
S.-F.; Lee, C.-J.; Liao, C.-L.; Dwek, R. A.; Zitzmann, N.; Lin, Y.-L. J. Virol. 2002, 76,
3596; (c) Block, T. M.; Jordan, R. Antiviral Chem. Chemother. 2002, 12, 317; (d)
(m, 1H); 13C NMR (150 MHz, CDCl3)
d 137.0, 128.8, 128.5, 128.2, 85.8
1
3
(d, JCF¼171.7 Hz), 75.4 (d, JCF¼9.0 Hz), 72.4, 61.7, 50.9 (d,
2JCF¼26.6 Hz), 46.4, 31.9 (d, 2JCF¼21.5 Hz); HRMS (ESI): [MþH]þ, m/z
calcd for C13H18FN4O 265.1465, found 265.1469.
€
Greimel, P.; Spreitz, J.; Stutz, A. E. Curr. Top. Med. Chem. 2003, 3, 513; (e) Nash, R.
J.; Carroll, M.W.; Watson, A.A.; Fleet, G.W.J.; Horn, G. Vol. WO 2007010266,
2007.
11. (a) Sinnott, M. L. Chem. Rev. 1990, 90, 1171; (b) Groopman, J. E. Rev. Infect. Dis.
1990, 12, 908; (c) Robina, I.; Moreno-Vargas, A. J.; Carmona, A. T.; Vogel, P. Curr.
Drug Metab. 2004, 5, 329.
4.12. (3R,4R)-4-Benzyloxy-3-fluoro-2,3,4,7-
12. (a) Johnson, H. A.; Thomas, N. R. Bioorg. Med. Chem. Lett. 2002, 12, 237; (b)
Xuereb, H.; Maletic, M.; Gildersleeve, J.; Pelczer, I.; Kahne, D. J. Am. Chem. Soc.
2000, 122, 1883.
tetrahydroazepine-1-carboxylic acid-tert-butyl (14)
½
a 2D0
ꢂ
þ29.3 (c 1.7, CHCl3); IR (film) nmax (cmꢁ1): 2360, 2345, 2111,
13. Andreana, P. R.; Sanders, T.; Janczuk, A.; Warrick, J. I.; Wang, P. G. Tetrahedron
1715, 1699, 1651, 1541, 1522, 1474, 1457, 1418; 1H NMR (600 MHz,
Lett. 2002, 43, 6525.
14. Lee, S. J.; Beak, P. J. Am. Chem. Soc. 2006, 128, 2178 and references therein.
15. Kulanthaivel, P.; Hallock, Y. F.; Boros, C.; Hamilton, S. M.; Janzen, W. P.; Ballas, L.
M.; Loomis, C. R.; Jiang, J. B.; Katz, B. J. Am. Chem. Soc. 1993, 115, 6452.
16. Rezler, E. M.; Fenton, R. R.; Esdale, W. J.; McKeage, M. J.; Russell, P. J.; Hambley,
T. W. J. Med. Chem. 1997, 40, 3508.
17. Damour, D.; Barreau, M.; Blanchard, J.-C.; Burgevin, M.-C.; Doble, A.; Herman, F.;
Pantel, G.; James-Surcouf, E.; Vuilhorgne, M.; Mignani, S.; Poitout, L.; Merrer, Y.
L.; Depezay, J.-C. Bioorg. Med. Chem. Lett. 1996, 6, 1667.
CDCl3)
d 7.38e7.29 (m, 5H), 5.89e5.73 (m, 2H), 5.04 (d,
1JHF¼66.1 Hz, 1H), 4.91 (d, J¼11.9, 1H), 4.64 (q, J¼17.5, 11.6 Hz, 1H),
4.04e3.35 (m, 4H), 2.70e2.53 (m, 1H), 1.46 (s, 9H); 13C NMR
(150 MHz, CDCl3)
d 154.9, 136.7, 128.7, 128.2, 128.0, 126.8, 123.6,
112.2 (d, 1JCF¼219.0 Hz), 80.0, 71.5, 43.5, 41.5 (d, 2JCF¼17.3 Hz), 40.3
2
(d, JCF¼21.8 Hz), 28.6; HRMS (ESI): [MþNa]þ, m/z calcd for
18. Furuya, T.; Kutruff, C. A.; Ritter, T. Curr. Opin. Drug Discovery Dev. 2008, 11, 803.
19. (a) Bio, M. M.; Waters, M.; Javadi, G.; Song, Z. J.; Zhang, F.; Thomas, D. Synthesis
C
18H24FNO3Na 344.1638, found 344.1646.
ꢁ
€ €
2008, 891; (b) Kiss, L.; Forro, E.; Fustero, S.; Fulop, F. Eur. J. Org. Chem. 2011,
Acknowledgements
ꢁ
4993; (c) Nemoto, H.; Nishiyama, T.; Akai, S. Org. Lett. 2011, 13, 2714; (d) Cedron,
J. C.; Estevez-Braun, A.; Ravelo, A. n. G.; Gutierrez, D.; Flores, N.; Bucio, M. A.;
Perez-Hernandez, N.; Joseph-Nathan, P. Org. Lett. 2009, 11, 1491; (e) Xia, Y.;
Chackalamannil, S.; Greenlee, W. J.; Jayne, C.; Neustadt, B.; Stamford, A.;
Vaccaro, H.; Xu, X.; Baker, H.; O’Neill, K.; Woods, M.; Hawes, B.; Kowalski, T.
Bioorg. Med. Chem. Lett. 2011, 21, 3290.
ꢁ
ꢁ
ꢁ
ꢁ
This research was being supported by an iMQRES scholarship to
ARP from Macquarie University. We thank Peter Karuso for assist-
ing with 2D NMR spectroscopy.
20. Middleton, W. J. J. Org. Chem. 1975, 40, 574.
21. Lal, G. S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M.; Cheng, H. J. Org. Chem. 1999,
64, 7048.
Supplementary data
22. Hayashi, H.; Sonoda, H.; Fukumura, K.; Nagata, T. Chem. Commun. 2002, 1618.
23. Yin, J.; Zarkowsky, D. S.; Thomas, D. W.; Zhao, M. M.; Huffman, M. A. Org. Lett.
2004, 6, 1465.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2012.10.078.
€
24. Furstner, A.; Thiel, O. R. J. Org. Chem. 2000, 65, 1738.
25. Romero, A.; Wong, C.-H. J. Org. Chem. 2000, 65, 8264.
26. Trost, B. M.; Fandrick, D. R.; Brodmann, T.; Stiles, D. T. Angew. Chem., Int. Ed.
2007, 46, 6123.
References and notes
27. Evans, D. A.; Fu, G. C.; Hoveyda, A. H. J. Am. Chem. Soc. 1988, 110, 6917.
28. (a) Beletskaya, I.; Pelter, A. Tetrahedron 1997, 53, 4957; (b) Lata, C. J.; Crudden,
C. M. J. Am. Chem. Soc. 2010, 132, 131.
29. Mannig, D.; Noth, H. Angew. Chem., Int. Ed. Engl. 1985, 24, 878.
30. (a) Westcott, S. A.; Blom, H. P.; Marder, T. B.; Baker, R. T. J. Am. Chem. Soc.1992,114,
8863; (b) Evans, D. A.; Fu, G. C.; Hoveyda, A. H. J. Am. Chem. Soc. 1992, 114, 6671.
31. (a) Burgess, K.; Cassidy, J.; Ohlmeyer, M. J. J. Org. Chem.1991, 56,1020; (b) Burgess,
K.; Ohlmeyer, M. J. J. Org. Chem. 1991, 56, 1027; (c) Burgess, K.; Ohlmeyer, M. J.
Tetrahedron Lett. 1989, 30, 395.
1. Ritter, S. K. Chem. Eng. News 2012, 90, 10.
2. (a) Begue, J.-P.; Bonnet-Delpon, D. J. Fluorine Chem. 2006, 127, 992; (b) Isanbor,
ꢁ
ꢁ
C.; O’Hagan, D. J. Fluorine Chem. 2006, 127, 303; (c) Kirk, K. L. J. Fluorine Chem.
€
€
€
2006, 127, 1013; (d) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
€
€
3. (a)Bohm,H.-J.; Banner, D.;Bendels,S.;Kansy, M.;Kuhn, B.;Muller, K.;Obst-Sander,
U.;Stahl,M.ChemBioChem2004, 5, 637;(b)Gerebtzoff,G.;Li-Blatter, X.;Fischer, H.;
Frentzel, A.; Seelig, A. ChemBioChem 2004, 5, 676; (c) Jeschke, P. ChemBioChem
2004, 5, 570; (d) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305; (e) Lipinski, C. A.;
Lombardo, F.; Dominy, B. W.; Feeney, P. J. Adv. Drug Delivery Rev.1997, 23, 3; (f) Park,
B. K.; Kitteringham, N. R.; O’Neill, P. M. Annu. Rev. Pharmacol. Toxicol. 2001, 41, 443;
32. (a) Crudden, C. M.; Edwards, D. Eur. J. Org. Chem. 2003, 2003, 4695; (b) Harder,
S.; Spielmann, J. J. Organomet. Chem. 2012, 698, 7; (c) Burgess, K.; Ohlmeyer, M.
J. Chem. Rev. 1991, 91, 1179.
€
(g) Paulini, R.; Muller, K.; Diederich, F. Angew. Chem., Int. Ed. 2005, 44, 1788; (h)
Smart, B. E. J. Fluorine Chem. 2001, 109, 3.
Please cite this article in press as: Patel, A. R.; Liu, F., Tetrahedron (2012), http://dx.doi.org/10.1016/j.tet.2012.10.078

A.R. Patel, F. Liu / Tetrahedron xxx (2012) 1e9
9
33. (a) Murata, M.; Watanabe, S.; Masuda, Y. Tetrahedron Lett. 1999, 40, 2585; (b)
Hayashi, T.; Matsumoto, Y.; lto, Y. Tetrahedron: Asymmetry 1991, 2, 601.
34. (a) Evans, D. A.; Fu, G. C. J. Am. Chem. Soc. 1991, 113, 4042; (b) Brinkman, J. A.;
Nguyen, T. T.; Sowa, J. R. Org. Lett. 2000, 2, 981; (c) Knorr, J. R.; Merola, J. S.
Organometallics 1990, 9, 3008.
Chiang, Y.-c. P.; Beattie, T. R. Carbohydr. Res. 1993, 249, 259; (e) Ballereau, S.;
Guedat, P.; Spiess, B.; Rehnberg, N.; Schlewer, G. Tetrahedron Lett. 1995, 36,
7449; (f) Jeong, L. S.; Lee, J. E.; Kim, H. O.; Chun, M. W. Arch. Pharm. Res. 1998,
ꢁ
21, 338.
ꢁ
38. Dechamps, I.; Gomez Pardo, D.; Cossy, J. Eur. J. Org. Chem. 2007, 4224.
35. (a) Noh, D.; Yoon, S. K.; Won, J.; Lee, J. Y.; Yun, J. Chem.dAsian J. 2011, 6, 1967;
(b) Noh, D.; Chea, H.; Ju, J.; Yun, J. Angew. Chem., Int. Ed. 2009, 48, 6062.
36. Leroy, J.; Hebert, E.; Wakselman, C. J. Org. Chem. 1979, 44, 3406.
37. (a) Carless, H. A. J.; Busia, K. Carbohydr. Res. 1992, 234, 207; (b) Jenkins, C. L.;
Lin, G.; Duo, J.; Rapolu, D.; Guzei, I. A.; Raines, R. T.; Krow, G. R. J. Org. Chem.
2004, 69, 8565; (c) Yoshimura, Y.; Endo, M.; Kitano, K.; Yamada, K.; Sakata, S.;
Miura, S.; Machida, H. Nucleosides Nucleotides 1999, 18, 815; (d) Yang, S. S.;
39. Jaseer, E. A.; Naidu, A. B.; Kumar, S. S.; Rao, R. K.; Thakur, K. G.; Sekar, G. Chem.
Commun. 2007, 867.
40. (a) Lal, G.S.; Pez, G.P. US Patent 6,080,886, 2000. (b) Lal, G. S.; Pez, G. P.; Pesaresi,
R. J.; Prozonic, F. M. Chem. Commun. 1999, 215; (c) Singh, R. P.; Chakraborty, D.;
Shreeve, J. M. J. Fluorine Chem. 2001, 111, 153; (d) Lal, G. S.; Lobach, E.; Evans, A. J.
Org. Chem. 2000, 65, 4830; (e) Singh, R. P.; Majumder, U.; Shreeve, J. M. J. Org.
Chem. 2001, 66, 6263.
Please cite this article in press as: Patel, A. R.; Liu, F., Tetrahedron (2012), http://dx.doi.org/10.1016/j.tet.2012.10.078