Pd(II)-Catalyzed Aminofluorination of Alkenes in Total Synthesis 6-(R)-Fluoroswainsonine and 5-(R)-Fluorofebrifugine

Article abstract of DOI:10.1021/acs.orglett.6b00030

The total syntheses of two fluorinated alkaloids, 6-(R)-fluoroswainsonine and 5-(R)-fluorofebrifugine, are described. Both encompass (4aS,7R,8aR)-7-fluoro-5-tosylhexahydro-4H-[1,3]dioxino[5,4-b]pyridine as a key synthon which is obtained through a further

Full text of DOI:10.1021/acs.orglett.6b00030

Letter
pubs.acs.org/OrgLett
Pd(II)-Catalyzed Aminofluorination of Alkenes in Total Synthesis
6‑(R)‑Fluoroswainsonine and 5‑(R)‑Fluorofebrifugine
Liang Wu, Pinhong Chen,* and Guosheng Liu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Road, Shanghai, China, 200032
S
* Supporting Information
ABSTRACT: The total syntheses of two fluorinated alkaloids, 6-(R)-fluoroswainsonine and 5-(R)-fluorofebrifugine, are
described. Both encompass (4aS,7R,8aR)-7-fluoro-5-tosylhexahydro-4H-[1,3]dioxino[5,4-b]pyridine as a key synthon which is
obtained through a further optimized palladium-catalyzed aminofluorination of alkenes with high diastereoselectivity. 6-(R)-
Fluoroswainsonine is synthesized from the key synthon in 14 steps, and 5-(R)-fluorofebrifugine requires a sequential 15-step
transformation.
Swainsonine is an anticancer alkaloid with potential to treat
glioma and gastric carcinoma, and it also exhibits potential in its
use as an adjuvant for anticancer drugs.6 Febrifugine, which is a
quinazolinone alkaloid first isolated from the Chinese herb
Dichroa febrifuga, possesses antimalarial properties.7 Both have
attracted much attention in a synthetic sense due to their
special bioactivities.8,9 It is reported that the involvement of a
vicinal fluorine atom to an amine could decrease its basicity,10
resulting in increased biological activity,11 and lipophilicity.12
We envisioned the specified introducing fluorine atom into
these bioactive compounds, such as at the C5 position of
Febrifugine and the C6 position of Swainsonine, might
modulate their bioactivities. These two fluorinated natural
products have a similar 3-fluorinated piperidine core structure
and could be derived from the same synthon. Furthermore, we
envisioned that our previously reported intramolecular amino-
fluorination of alkenes might be a good method to selectively
build this synthon (Scheme 1). Herein, we report the total
synthesis of fluorinated swainsonine and febrifugine with highly
selective aminofluorination as the key reaction.
ntroduction of fluorine into organic moleculars could
1
Idramatically improve their druggability. For instance, the
introduction of fluorine into pipemidic acid could dramatically
enhance antibacterial potency, named as norfloxacin.2 Similar
improvement was observed with capecitabine as a drug for
breast and colorectal cancers3 and ezetimibe for coronary heart
disease.4 Furthermore, the hydrolytic stability of 7-F-PGI2
(prostacyclin) at pH 7.4 is prolonged from 10 min to more
than one month (Figure 1).5 Additional effort has been
dedicated to the discovery of fluorinated bioactive compounds,
some of which have been launched by pharmaceutical
companies.
In 2009, our group developed a Pd-catalyzed intermolecular
aminofluorination of alkenes, which provided a variety of
fluorinated piperidines.13 Later, further studies were surveyed
to provide other types of fluorinated heterocycles.14 Based on
our previous endo-cyclized aminofluorination reaction, we
Received: January 5, 2016
Figure 1. Representative fluorinated drugs.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00030
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Letter
Scheme 1. Retrosynthetic Analysis
Table 1. Further Screening of Aminofluorination Reaction
Conditions
a
b
entry
R, R
I(III) reagent
yield (%) (dr)
1
C(CH3)2 (1a)
PhI(OPiv)2 (2.0 equiv)
PhI(OPiv)2 (2.0 equiv)
PhI(OPiv)2 (2.0 equiv)
PhI(OPiv)2 (2.0 equiv)
PhI(OAc)2 (2.0 equiv)
PhI(O2CCF3)2 (2.0 equiv)
PhI(O2CPh)2 (2.0 equiv)
PhI(OPiv)2 (2.0 equiv)
PhI(OPiv)2 (1.5 equiv)
PhI(OPiv)2 (1.5 equiv)
trace
2
CO (1b)
37 (77:23)
0
speculated that chiral substrates 1a−1d might be good
substrates to test the aminofluorination, which might deliver
the expected synthon for the next total synthesis. According to
literature procedure, the ketone 4 could be obtained through
sequential protection of L-serine with tosyl chloride followed by
the allylation reaction in 69% yield over two steps (Scheme
2).15 The reduction of ketone 4 with LiBH4 afforded the
3
CH3, CH3 (1c)
4
CH2 (1d)
51 (84:16)
22 (74:26)
17 (79:21)
33 (80:20)
58 (91:9)
68 (93:7)
67 (93:7)
5
1d
1d
1d
1d
1d
1d
6
7
c
8
cd
,
9
cde
, ,
10
a
Scheme 2. Preparation of Alkene Substrates 1a−1d
Reaction conditions: 1 (0.1 mmol), Pd(OAc)2 (0.01 mmol), I(III)
reagent (2 equiv), AgF (5 equiv), MgSO4 (50 mg) in CH3CN (0.5
b
mL) at rt. 19F NMR yield with trifluorotoluene as an internal
c
standard; the data in parentheses are the dr ratios. Toluene as solvent.
d
e
Isolated yield. 2 mmol scale.
The structure of 2d was confirmed by X-ray determination,
which showed that the fluorine atom is trans to the 3-hydroxyl
group (Figure 2).
desired diol 5 as a major product in 87% yield with moderate
diastereoselectivity (dr 5:1), while another reduction system
such as NaBH4 with or without a Lewis acid as activator gave
the desired diol 5 in slightly lower yield and poor
diastereoselectivity, and the use of L-Selectride changed the
diastereoselectivity affording the diastereoisomer of 5 as the
major product (dr 1:7). Finally, substrates 1a−1d were
obtained through the corresponding protection processes (see
Supporting Information).
These substrates were initially tested with the previously
reported aminofluorination reaction conditions in CH3CN.13
As shown in Table 1, substrate 1a gave only trace desired
product 2a, in which the isopropylidene ketal protected 1,2-diol
moiety was not compatible with the strong oxidation conditions
resulting in the decomposition of substrate (entry 1). Then,
when the protection group was changed to a carbonyl group,
the reaction of substrate 1b gave the desired product 2b in 37%
yield, but with moderate diastereoselectivity (dr = 77:23, entry
2). For the simple dimethyl-protected 1c, the reaction also
failed to afford the target product (entry 3). When the diol was
protected with the most stable acetal group, excitingly, the
reaction of 1d provided product 2d in 51% yield with good
diastereoselectivity (dr = 84:16, entry 4). Further screening of
iodine(III) oxidants, such as PhI(OAc)2, PhI(O2CCF3)2, and
PhI(O2CPh)2, showed that these oxidants could also deliver
product 2d, but less effectively than PhI(OPiv)2 (entries 5−7).
The screening of palladium catalysts indicated that Pd(OAc)2
was the best. Finally, when the solvent was switched from
acetonitrile to toluene, both the yield and diastereoselectivity
were significantly improved, and the best result was obtained in
the case of PhI(OPiv)2 (1.5 equiv) with a diluted solution (0.1
M) to give 2d in 68% yield with a 93:7 dr ratio (entries 8−9).16
The reaction could also be carried out on 2 mmol scale without
a significant drop in yield and diastereoselectivity (entry 10).
Figure 2. XRD of aminofluorination product 2d.
With the fluorinated piperidine synthon 2d in hand, the
methylene deprotection of 2d was carried out to release the
diols. We found that compound 2d was not compatible to the
commonly used conditions, such as BCl3, HCl, NaI/SiCl4, and
AcCl/ZnCl. In contrast, treatment of 2d with PTSA in acetic
anhydride at 110 °C, followed by the hydrolysis in ammonia
solution, afforded the free diol 6 in 92% yield.17 Then, the
primary alcohol of 6 was selectively protected with a silyl group,
followed by the secondary hydroxyl group protection with a
benzyl group. Removing the silyl group with TBAF afforded
compound 7 in overall 60% yield over three steps (Scheme 3).
Next, the primary hydroxyl group was converted to a vinyl
group through a subsequent Swern oxidation and Wittig
reaction, and compound 8 was obtained in 75% yield.
Excitingly, when the tosyl group was removed with sodium in
naphthalene, the carbon−fluorine bond remained intact. The
crude amine was reacted with allyl chloroformate to give the
allyl carbamate, which underwent allylic amination under the
B
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(OsO4/NMO) to give the dihydroxylation product, which
reacted with Ts-imidazole to give the ring-closure product 14 in
74% yield over two steps. After nucleophilic attack by the
quinazolin-4-one anion, the main skeleton of fluorinated
febrifugine was obtained. After the final oxidation of the
secondary alcohol with Dess-Martin reagent22 and removal of
Boc and benzyl protection groups by HCl, the target
fluorinated ferbrifugine was obtained in 51% overall yield
over three steps. The optical rotation of 5-(R)-fluorofebrifugine
([α]D20 −47.0; c 0.18, D2O) is opposite that of (+)-febrifugine
Scheme 3. Synthesis of 6-(R)-Fluoroswainsonine
23
25
([α]D + 12.8; c 0.8, H2O).
In conclusion, we have reported the first total synthesis of
two fluorinated alkaloids, 6-(R)-fluoroswainsonine and 5-(R)-
fluorofebrifugine. Both encompass the (4aS,7R,8aR)-7-fluoro-5-
tosylhexahydro-4H-[1,3]dioxino[5,4-b]pyridine as a key syn-
thon, which was obtained through an optimized amino-
fluorination of alkenes with high regio- and diastereoselectivity.
ASSOCIATED CONTENT
* Supporting Information
■
S
catalysis of Pd(PPh3)4 to give the diene 9 in overall 61% yield
over three steps.18 For the following intramolecular ring-closing
metathesis, the Grubbs II catalyst exhibited better reactivity
than Grubbs I. Due to the presence of a basic amine, additions
of a Lewis acid and Bronsted acid were beneficial to improve
the yield. Combination of the Grubbs II catalyst with Ti(OiPr)4
could afford the indolizidine 10 in 71% yield.19 Finally, the
sequential cis-dihydroxylation of 10 using AD-mix-α with
methanesulfonamide and protection with acetonide generated
compound 11 in 58% yield with a 6.3:1 dr ratio.20 After column
purification, the pure cis-11 was treated by concentrated HCl (6
N) to remove the ketal and benzyl protection groups. Finally,
after neutralization with a base, fluorinated swainsonine was
obtained in 92% yield. The optical rotation of synthetic 6-(R)-
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00030.
The detailed experimental procedures, spectral data of
new compounds (PDF)
Crystallographic data for 2d (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: gliu@mail.sioc.ac.cn.
*E-mail: pinhongchen@sioc.ac.cn.
Notes
20
The authors declare no competing financial interest.
fluoroswainsonine ([α]D +81.0; c 0.21, D2O) is opposite to
21
25
(−)-swainsonine ([α]D −89.3; c 1, H2O).
ACKNOWLEDGMENTS
Next, we turned to synthesize 5-(R)-fluoroferifugine from
key synthon 7 (Scheme 4). First, the sequential process was
■
We are grateful for financial support from the National Basic
Research Program of China (973-2015CB856600) and the
National Nature Science Foundation of China (21225210,
21202185, 21421091, and 21472217).
Scheme 4. Synthesis of 5-(R)-Fluorofebrifugine
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