A stereocontrolled access to ring-fused piperidines through a formal [2+2+2] process

Article abstract of DOI:10.1021/ol061914e

(Chemical Equation Presented) A formal [2+2+2] process has been devised that allows the stereocontrolled formation of ring-fused piperidines from allylsilanes possessing an oxime moiety. The cascade involves an intermolecular radical addition of an α-iodoacetate onto an allylsilane double bond, which is followed by a 5-exo-trig cyclization onto an oxime and is completed by the formation of the amide bond by nucleophilic attack of the amine onto the ester function.

Full text of DOI:10.1021/ol061914e

ORGANIC
LETTERS
2006
Vol. 8, No. 21
4871-4874
A Stereocontrolled Access to
Ring-Fused Piperidines through a
Formal [2+2+2] Process
Edouard Godineau, Christian Scha1fer, and Yannick Landais*
UniVersity Bordeaux-I, Laboratoire de Chimie Organique et Organome´tallique, 351,
Cours de la Libe´ration, 33405 Talence Cedex, France
y.landais@lcoo.u-bordeaux1.fr
Received August 2, 2006
ABSTRACT
A formal [2
+
2
+
2] process has been devised that allows the stereocontrolled formation of ring-fused piperidines from allylsilanes possessing
-iodoacetate onto an allylsilane double bond, which is
an oxime moiety. The cascade involves an intermolecular radical addition of an
r
followed by a 5-exo-trig cyclization onto an oxime and is completed by the formation of the amide bond by nucleophilic attack of the amine
onto the ester function.
The piperidine substructure can be found in numerous natural
products and is also present in a wide range of biologically
relevant targets currently under preclinical and clinical tests.1
We envisioned that 2,3-ring-fused piperidines could be
elaborated through a simple strategy based on a formal
[2+2+2] process, in which two bonds of the piperidine ring
would be formed through radical reactions, the last one being
the result of an ionic nucleophilic process (Scheme 1). The
followed by the formation of the second C-C bond through
a rapid 5- or 6-exo-trig cyclization of the resulting radical
onto an oxime. Pioneering studies by Bartlett, Hart, and Naito
have shown that such cyclizations are usually faster than
those involving simple olefins.2 The resulting alkoxyaminyl
radical would then cyclize to produce the corresponding six-
membered ring lactam in a “one-pot” operation. Three new
stereogenic centers could also be created and stereochemistry
would be controlled by a resident allylic substituent.
Precedents from our laboratory3 have shown that an allylic
silicon group is particularly well suited in this context as it
leads to improved reaction rate during intermolecular addition
of electrophilic radical species onto olefins and efficiently
controls the stereochemical outcome of the whole transfor-
mation, leading to high levels of 1,2- and 1,5-diastereocon-
trol. Its synthetic utility is also enhanced by the possible
Scheme 1. Formal Radical-Ionic [2+2+2] Cascade for the
Stereocontrolled Synthesis of Ring-Fused Piperidines
(2) (a) Hart, D. J.; Seely, F. L. J. Am. Chem. Soc. 1988, 110, 1631-
1633. (b) Bartlett, P. A.; Mc Laren, K. L.; Ring, P. C. J. Am. Chem. Soc.
1988, 110, 1633-1634. (c) Miyabe, H.; Ueda, M.; Naito, T. Synlett 2004,
1140-1157. (d) Ueda, M.; Miyabe, H.; Sugino, H.; Miyata, O.; Naito, T.
Angew. Chem., Int. Ed. 2005, 44, 6190-6193. (e) Miyabe, H.; Ueda, M.;
Fujii, K.; Nishimura, A.; Naito, T. J. Org. Chem. 2003, 68, 5618-5626.
(3) (a) James, P.; Landais, Y. Org. Lett. 2004, 6, 325-328. (b) James,
P.; Felpin, F.-X.; Schenk, K.; Landais, Y. J. Org. Chem. 2005, 70, 7985-
7995. (c) James, P.; Schenk, K.; Landais, Y. J. Org. Chem. 2006, 71, 3630-
3633.
first C-C bond would thus be generated through an
intermolecular addition of a radical species onto an olefin,
(1) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 23, 3679-3681.
10.1021/ol061914e CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/16/2006

C-Si bond oxidation,4 thus allowing the introduction of an
additional hydroxy group. We report in this Letter our prelim-
inary results on this straightforward approach to ring-fused
piperidines using a cascade of radical and ionic processes.
Reetz-Yamamoto titanium-mediated allylation of 7 with
3-TBS-protected hydroxy propanal led to the â-hydroxysilane
8 as a unique diastereomer in moderate yield. Acetylation
of the secondary alcohol followed by desilylation of the
primary alcohol led to 9, which was oxidized (DMP) and
subsequently transformed into oxime 10 (E/Z mixture). In
parallel, homologation of aldehyde 11 through a Wittig
reaction, followed by hydrolysis of the resulting enol ether
into the corresponding aldehyde led finally to oxime 12 in
good overall yield.
Several allylsilane-oximes were thus prepared from the
corresponding aldehydes, available from dienes having an
allylsilane moiety (Scheme 2). Access to the aldehyde
Scheme 2. Preparation of Oximes 2 and 6
Our preliminary investigations started with the cyclization
of simple olefin 13 devoid of an allylic substituent, using
ethyl iodoacetate (2 equiv) and Et3B as an initiator (4 equiv)
(Scheme 4). Addition, then cyclization occurred smoothly
Scheme 4. Two-Pot Preparation of Lactams 15a-c
function involved a regioselective dihydroxylation of one of
the double bonds of 1 and 4, followed by oxidation of the
resulting diol. Use of Sharpless chiral ligands allowed good
regiocontrol during the dihydroxylation step, with the di-
substituted olefin reacting faster than that of the allylsilane.
This strategy thus afforded useful aldehydes having an
allylsilane moiety in generally good yields. Oximes 2 and 6
(E/Z mixture) were then at hand by simply reacting the crude
aldehyde with methylhydroxylamine hydrochloride in the
presence of a base.
but provided the monocyclic compound 14a in 80% yield
as an 8:2 mixture of cis/trans diastereomers, without traces
of the desired lactamized product. Complete lactamization
was finally observed with conditions A or B, leading to 15a
in reasonable overall yield. This protocol was then extended
to allylsilanes 2 and 10. It was anticipated that addition of
R-halo esters to allylsilanes might bring in additional
problems such as halogen atom transfer.5 Addition of an
R-iodoacetate onto an allylsilane under radical conditions
may thus be followed by a fast iodine atom transfer,
generating a â-iodosilane known to â-eliminate spontane-
ously even under mild conditions to produce the correspond-
ing olefin.6 When the reaction was applied to allylsilane 2,
the corresponding cyclopentane 14b (not shown) was,
however, produced in a very satisfying 95:5 ratio of cis/
trans isomers (84%), demonstrating that iodine transfer was
probably slow as compared to cyclization,7 and that the
Allylsilane 10 was prepared starting from phenyldimethyl-
allylsilane 7 through the route depicted below (Scheme 3).
Scheme 3. Preparation of Oximes 10 and 12
(4) (a) Fleming, I. Chemtracts: Org. Chem. 1996, 1-64. (b) Landais,
Y.; Jones, G. Tetrahedron 1996, 52, 7599-7662.
(5) Rate constants for 5-exo-trig cyclizations onto oximes and iodine atom
transfer from R-iodoacetate have been estimated: k ≈ 3 × 107 and k ≈
107 M‚s-1, respectively. Fallis, A. G.; Brinza, I. M. Tetrahedron 1997, 53,
17543-17594.
(6) (a) Porter, N. A.; Zhang, G.; Reed, A. D. Tetrahedron Lett. 2000,
41, 5773-5777. (b) Guindon, Y.; Gue´rin, G.; Chabot, C.; Ogilvie, W. J.
Am. Chem. Soc. 1996, 118, 12528-12535.
4872
Org. Lett., Vol. 8, No. 21, 2006

silicon group controlled efficiently the stereochemistry of
the two stereogenic centers.3 Attempted purification of the
crude mixture onto silica gel led to 45% of the cis-cyclo-
pentane 14b, along with 37% of the desired lactam 15b.8 A
similar observation was made with allylsilane 10. Direct
lactamization on the crude reaction mixture, using conditions
A or B, finally led to 15b and 15c in good overall yield.
Interestingly, when using tert-butyliodoacetate, 14d-e were
isolated in good yield (74% and 78%) and were resistant to
further lactamization on silica gel.
process was generally high yielding with allylsilanes, and
the reaction conditions tolerate various functional groups,
including â-silyl acetates (10) which are prone to Peterson
elimination under Lewis acidic conditions.
We also found that introduction of electron-withdrawing
substituents R to the ester function of the radical precursor
allowed the formation of lactams in a single-pot operation
(Scheme 5). In this case, the presence of the phenyl ester
These preliminary results were encouraging and showed
that the silicon group led to an excellent transfer of chirality
during the 5-exo-trig cyclization. However, a stepwise
formation of the fused bicyclo[4.3.0] system was not yet
satisfying and our next efforts focused toward a one-pot
process. It was finally found that simply introducing a better
leaving group on the ester function allowed the two steps to
be performed in a single-pot operation. By using phen-
yliodoacetate9 as the radical precursor, lactams were thus
obtained in one pot, in excellent yield and high stereoselec-
tivity under mild conditions (Table 1). A high level of
Scheme 5. Addition of Bromodifluoroacetate to Allylsilanes
group is not required, and 20 and 21 are formed from 2 and
10, respectively, in reasonable yields and high diastereocon-
trol (>95:5). To our knowledge this is the first successful
intermolecular radical addition of R,R-difluoroacetate to
olefins.11
The study was also extended to precursors possessing a
ketoxime function. In contrast with the results above, addition
of ethyl iodoacetate (2 equiv) to allylsilane 22 (Supporting
Information) led to monocyclized product 23 in which two
fragments of acetate had been incorporated, the reaction
proceeding with high yield and complete diastereocontrol
(Scheme 6). Interestingly when the reaction was repeated
Table 1. One-Pot Preparation of Lactams 15-19
Scheme 6. Addition of Ethyl Iodoacetate to Ketoximes
entry olefin Et3B (equiv) product
cis/transa
76:24
>95:5
>95:5
>90:10
>95:5
85:13.5:1.5c
>95:5
yield (%)b
1
2
3
4
5
6
7
13
2
10
6
12
16
17
2
3
3
3
3
6
6
15a
15b
15c
15d
15e
18
69
76
78
61
85
51
47
with ethyl xanthate,12 the same product was formed, albeit
in lower yield, indicating that the formation of the R-amino
ester moiety occurred probably through a radical process.
This result is also noteworthy as it shows that 5-exo-trig
cyclization on a disubstituted sp2 center is still favored
relative to iodine-atom transfer.13
A tentative rationalization of the observed cascade is
proposed below (Figure 1). The electrophilic radical species
I is formed by abstraction of halogen from the R-haloester
precursor. This then adds selectively onto the olefin to
generate the radical intermediate II. This step is probably
fast with electron-rich allylsilanes to form stabilized â-silyl
19
a Ratio estimated from 1H NMR of the crude reaction mixture. b Isolated
yield. c Ratio estimated through GC.
stereocontrol was obtained with bulky substituents in the
allylic position. Complete 1,2- and 1,5-stereocontrol was thus
observed with allylic PhMe2Si and t-Bu groups at -20 °C
(entries 2-5 and 7, Table 1). The reaction was found to be
more sluggish with precursors having an alkyl group in the
allylic position (6 equiv of Et3B are required in this case,
entries 6 and 7) and less efficient in terms of yield.10 The
(10) Polar effects are likely at the origin of these differences in reactivity
between allylsilanes and their alkylated analogues.3
(11) Itoh, T.; Sakabe, K.; Kudo, K.; Ohara, H.; Takagi, Y.; Kihara, H.;
Zagatti, P.; Renou, M. J. Org. Chem. 1999, 64, 252-265.
(12) Tournier, L.; Zard, S. Z. Tetrahedron Lett. 2005, 46, 455-459.
(13) Analogous 5-exo-trig cyclizations on trisubstituted olefins are known
to be slower than addition on disubstituted olefins.
(7) Iodine-atom transfer followed by regeneration of the â-silyl radical
under the reaction conditions (Et3B) may not be completely ruled out.
(8) It is noteworthy that 14a requires forcing conditions to lactamize
and does not cyclize on silica as compared to silicon analogues.
(9) Phenyliodoacetate was prepared from phenol in two steps (Supporting
Information).
Org. Lett., Vol. 8, No. 21, 2006
4873

recombine with I to provide bis-addition product VI.
Experiments aiming at trapping intermediate III (R′′ ) Et)
with more persistent benzyl radicals led to the corresponding
benzyl-protected aminoxide in low yield, indicating that
N-alkylation to form 23 occurred most likely through a
recombination of two radical species (I and III) and not
through an ionic pathway.12,14
In conclusion, we reported here a “one-pot” stereocon-
trolled elaboration of five-membered-ring fused piperidines
through a new formal [2+2+2] process, involving a cascade
of radical and ionic transformations. The bicyclic systems
thus obtained may be elaborated further, for instance through
oxidation of the C-Si bond.15 This strategy should find
applications in the synthesis of a number of natural products
of biological interest. Work along these lines is in progress
in our laboratory.
Acknowledgment. We gratefully acknowledge the CNRS,
MENRT (grant to E.G.), the Institut Universitaire de France,
and COST-D28 for financial support. We also thank Prof S.
Zard (Ecole Polytechnique, Palaiseau) for fruitful discussions
and Prof. J.-C. Quirion (University of Rouen) for a generous
gift of ethyl bromodifluoroacetate.
Figure 1. Tentative mechanistic rationale of the cascade.
radical II. This rapidly cyclizes through a 5-exo-trig process,
providing the alkoxyaminyl radical III. When R′′ is a
hydrogen, III likely reacts with Et3B to regenerate an ethyl
radical and boron amide IV, which cyclizes through an ionic
process to form the bicyclic lactam V. Activation of the ester
function through precoordination with BEt2 may occur,
accelerating the process. However, the nature of the leaving
OR group on the ester is crucial for this step as demonstrated
by the rapid lactamization observed when R ) OPh as
compared with R ) OEt. When R′′ is not a hydrogen, steric
hindrance around the alkoxyaminyl radical probably prevents
the formation of IV and provides III with enhanced kinetic
stability. The latter thus possesses enough lifetime to
Supporting Information Available: Detailed experi-
mental procedures and spectral and analytical data for all
precursors and cyclized products. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL061914E
(14) When 22 was treated with a mixture of ethyl iodoacetate and benzyl
iodide, under radical conditions (Et3B/O2), a mixture of 23 and a
monocyclized product having a NBn(OMe) group were formed in various
amounts depending on the iodide ratio.
(15) This was demonstrated with the oxidation of compound 15b, using
Fleming buffered conditions4 (KBr, AcONa, AcOOH; 82% yield).
4874
Org. Lett., Vol. 8, No. 21, 2006