Tuning efficiency of the 4-exo-trig cyclization by the electronic effect: Ring closure of 3,3-difluoro-4-pentenyl carbon radicals and synthesis of a gem-difluorocyclobutane nucleoside

Article abstract of DOI:10.1039/c2cc35876j

4-exo-trig Cyclization reaction of a 4-pentenyl carbon radical containing the gem-difluoromethylene moiety adjacent to a radical accepting α,β-unsaturated ester was found to proceed efficiently to furnish a novel gem-difluorocyclobutane derivative. The cyclized product could be transformed into a gem-difluoromethylene analogue of oxetanocin T.

Full text of DOI:10.1039/c2cc35876j

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COMMUNICATION
Tuning efficiency of the 4-exo-trig cyclization by the electronic effect:
ring closure of 3,3-difluoro-4-pentenyl carbon radicals and synthesis
of a gem-difluorocyclobutane nucleosidew
Hiroki Kumamoto,*a Sachiko Kawahigashi,a Hiromi Wakabayashi,a Tomohiko Nakano,a
Tomoko Miyaike,a Yasuyuki Kitagawa,a Hiroshi Abe,b Mika Ito,b Kazuhiro Haraguchi,a
Jan Balzarini,c Masanori Babad and Hiromichi Tanakaa
Received 14th August 2012, Accepted 20th September 2012
DOI: 10.1039/c2cc35876j
4-exo-trig Cyclization reaction of a 4-pentenyl carbon radical
containing the gem-difluoromethylene moiety adjacent to a radical
accepting a,b-unsaturated ester was found to proceed efficiently to
furnish a novel gem-difluorocyclobutane derivative. The cyclized
product could be transformed into a gem-difluoromethylene analogue
of oxetanocin T.
Oxetanocin A (1)1 is a nucleoside antibiotic isolated from Bacillus
megaterium (Fig. 1). Due to the unique four-membered oxetanose
moiety conferring promising anti-viral properties,2 considerable
efforts have been devoted to the synthesis of 1, and its base- or
sugar-modified derivatives.3 Interestingly, the thymine analogue of
oxetanocin T 24 also exhibits anti-HIV activity. As a sugar-
Fig. 1 Structure of compounds 1–4.
modified derivative, cyclobutane nucleoside 35 has been synthe-
course of our synthetic studies of 4 by radical cyclization, we
sized and reported to possess promising anti-HBV activity. In
found that the electron-withdrawing effect of the fluorine atom
this context, we have envisaged that a novel nucleoside 4, in which
facilitates the 4-exo-trig cyclization. In this communication we
the oxetanose ring oxygen of 2 is replaced with a geminal-
report these results and their application to the synthesis of 4.
difluoromethylidene (CF2) group, would show promising antiviral
There are three possible 4-pentenyl carbon radicals shown as
activities, as the CF2 group has been suggested as an isopolar and
A–C leading to the gem-difluorocyclobutane structure via 4-exo-trig
isosteric substituent for oxygen.6
cyclization reaction (Fig. 2). Initially, 5a, which is a precursor of the
Intramolecular cyclization of carbon-centered radicals to
1,1-difluoro-4-pentenyl carbon radical A, was reacted with Bu3SnH
unsaturated bonds has been widely used for the construction of
in the presence of AIBN in refluxing toluene. This reaction gave
cyclopentanes or cyclohexanes via 5-exo, 6-exo or 6-endo-trig mode
target 6a in 29% yield (cis/trans = 3/1). However, a major product
according to Baldwin’s rule.7,8 In contrast, there have been only a
was the reduced product 7a (32%). 2,2-Difluoro-carbon-radical B
few examples of 4-exo-trig cyclization reactions of 4-pentenyl
carbon radicals leading to cyclobutane rings.9 Successful ring
closures have relied upon the gem-dialkyl effect.9,10 During the
generated from 5b failed to cyclize and gave a complex mixture.
a School of Pharmacy, Showa University, 1-5-8 Hatanodai,
Shinagawa-ku, Tokyo 142-8555, Japan.
E-mail: kumamoto@pharm.showa-u.ac.jp; Fax: +81-3-3784-8252;
Tel: +81-3-3784-8187
b Advanced Science Institute, NanomedicalEngineering Laboratory,
RIKEN, 2-1 Hirasawa, Wako-shi, Saitama 351-0198, Japan
c Rega Institute for Medical Research, Katholieke Universiteit Leuven,
Minderbroedersstraat 10, B-3000 Leuven, Belgium
d Division of Antiviral Chemotherapy, Center for Chronic Viral
Diseases, Graduate School of Medical and Dental Sciences,
Kagoshima University, Kagoshima 89-8544, Japan
w Electronic supplementary information (ESI) available: Experimental
procedures for all newly synthesized products. CCDC 895081. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c2cc35876j
Fig. 2 Plausible radical intermediates A–C and their model compounds.
Chem. Commun., 2012, 48, 10993–10995 10993
c
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Table 1 Radical reaction of 5c–5fa
Scheme 1 Preparation of radical precursor 13.
Entry Precursor Yield [%] of 6 (ratio; cis/trans) Yield [%] of 7
The ester 11 was then converted into the Weinreb amide 12 in
excellent yield (90% yield). DIBAL-H reduction of 12 and
subsequent Wittig reaction gave the desired substrate 13
[a mixture of three stereoisomers; ca. major-(E)-13 : minor-
(E)-13 : (Z)-13 = 1 : 0.22 : 0.14].
1
2
3
4
5c
5d
5e
5f
72 (2/1)
91 (2/1)c
—
12b
—
72
61
22d
a
Reaction was carried out in refluxing toluene using 2.0 equiv. of Bu3SnH
b
and 0.2 equiv. of AIBN (dropwise addition over 4 h). Compound 8 was
With the substrate 13 in hand, we next carried out the
radical cyclization and the results are summarized in Table 2.
As shown in entry 1, when 13 was reacted with Bu3SnH under
the conditions described in Table 1, the yield of the desired
difluorocyclobutane derivative 14 was unexpectedly decreased
to 38% yield (diastereomeric mixture: ca. 2 : 1). On the basis of
NOE experiments, the major isomer was found to be trans,-
trans-14 with the minor isomer being trans,cis-14, respectively
(see ESIw). To improve the yield of 14, the reaction was carried
out at ambient temperature using Et3B as an initiator under an
O2 atmosphere. As can be seen in entries 2 to 5, the longer the
duration time of the dropwise addition of Bu3SnH, the better
the isolated yield of 14 although the ratio of trans,trans-14/
trans,cis-14 was unchanged.14 The best result was obtained
when Bu3SnH was added dropwise over 24 h to give 14 in
78% yield (entry 5). No improvement was observed at ꢀ20 1C
due to the recovery of 13 (47%) (entry 6).
c
obtained in 7% yield. The ratio was calculated by the integration of
1HNMR. d The stereochemistries of 6f were not determined.
In contrast to these results, when 5c was subjected to the same
reaction conditions for the ring-closure of 5a, intramolecular
4-exo-trig cyclization of the resulting 3,3-difluoro-4-pentenyl
carbon radical C efficiently proceeded to give the target
difluorocyclobutane 6a in 72% yield (cis/trans = 2 : 1), along
with the reduction product 7c (12%) and diene 8 (7%)
(Table 1, entry 1). As shown in entry 2, TBS-protected 5d
gave 6d (cis/trans = 2 : 1) in 91% isolated yield. As can be
seen in entry 3, the simple alkene 5e lacking the electron-
withdrawing group gave reduced product 7e as a sole product
in 72% yield (entry 3). A similar result was obtained in the case
of the de-fluorinated analogue 5f (entry 4). These results
suggested that the efficiency of the 4-exo-trig cyclization was
dependent upon the electron density of the double bond
although the influence of the conformational change of each
radical intermediate cannot be ruled out. To validate our
assumption, SOMO and LUMO levels of the model inter-
mediates were calculated based on Natural Bind Orbital
(NBO) theory Table S1, see ESI.w As anticipated, the energy
level of LUMO of 5c0 having both two fluorine atoms and
unsaturated ester is lower than those of 5e0 and 5f0 lacking
ester or two fluorine atoms. By taking the nucleophilic character of
the carbon centered radical into consideration,11 it would be
reasonable that increasing electrophilicity of the radical-accepting
unsaturated bond by fluorine substituents and ester facilitated the
4-exo-trig cyclization.
Finally, conversion of 14 to the target 4 was performed
(Scheme 2). DIBAL-H reduction of an epimeric mixture of 14
and subsequent phenylselenylation of the resulting hydroxyethyl
derivative by using PhSeCN and Bu3P15 gave 15 in 97% yield
in two steps. The selenide 15 was converted to terminal olefin 16
Table 2 Radical cyclization of 13
After optimization of the substrate for the radical cyclization,
we have turned our attention to the synthesis of the difluoro-
methylene analogue 4 of oxetanocin T 2. For the synthesis of the
target molecule, we needed to prepare the radical precursor 13 and
the synthetic route is illustrated in Scheme 1. Initially, Weinreb
amide 912 was treated with Li-HMDS and subsequently BOMCl
in one pot to give the a-benzyloxymethylated product, which was
then reduced by DIBAL-H to furnish the aldehyde 10 in 47%
yield. Compound 10 was subjected to Reformatsky reaction
utilizing BrF2CCO2Et and activated zinc13 followed by silylation
of the resulting secondary alcohol to give 11 in 77% yield.
Temp Timea Yield [%] Ratiob (trans,trans/
Entry Solvent
(1C)
(h)
of 14
trans,cis)
1
2
3
4
5
6
Toluene 110c
Benzene rt
Benzene rt
Benzene rt
Benzene rt
Toluene ꢀ20
4
2
4
8
24
48
38
72
70
77
78
48d
2.0/1
2.7/1
2.7/1
2.6/1
2.6/1
3.0/1
a
b
Bu3SnH was dropwise added at an indicated time. The ratio
(trans,trans/trans,cis) was calculated by integration of 1HNMR.
d
AIBN was used as an initiator. Compound 13 was recovered in 47%.
c
c
10994 Chem. Commun., 2012, 48, 10993–10995
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It was found that the 4-exo-trig cyclization reaction of the 3,3-
difluoro-4-pentenyl carbon radical efficiently proceeded to furnish
the novel gem-difluorocyclobutane. The electron withdrawing effect
of the two fluorine atoms adjacent to the radical accepting double
bond accelerated the cyclization reaction. As a synthetic application
of this radical ring closure, the synthesis of difluoromethylene
oxetanocin T 4, a potential anti-viral agent, was achieved.
Anti-viral assay revealed that compound 4 did not show any
activity against HIV-1, VZV and HCMV.
The authors are grateful to Ms Y. Odanaka and S. S.
Matsubayashi (Center for Instrumental Analysis, Showa Univer-
sity) for technical assistance with NMR spectroscopy, MS and
elemental analysis. Financial support from the Japan Society
for the Promotion of Science (KAKENHI No. 21590123 to
K.H.) is gratefully acknowledged.
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 10993–10995 10995