Efficient enantioselective synthesis of piperidines through catalytic asymmetric ring-opening/cross-metathesis reactions

Article abstract of DOI:10.1002/anie.200605130

Mo the better! Chiral Mo complexes promote highly efficient asymmetric ring-opening/cross-metathesis reactions that afford functionalized piperidines in high E:Z selectivity and enantiomeric purity (see scheme for example; TBS = tert-butyldimethylsilyl).

Full text of DOI:10.1002/anie.200605130

Communications
DOI: 10.1002/anie.200605130
Asymmetric Catalysis
Efficient Enantioselective Synthesis of Piperidines through Catalytic
Asymmetric Ring-Opening/Cross-Metathesis Reactions**
G. Alex Cortez, Richard R. Schrock, and Amir H. Hoveyda*
The remarkable influence of catalytic olefin metathesis is due
to the availability of Mo- and Ru-based catalysts.[1] One
notable (and fortunate) aspect of these two classes of
initiating alkylidenes and carbenes is that they are comple-
mentary in regards to functional-group tolerance.[2] Unlike
Mo alkylidenes, Ru carbenes promote transformations of
substrates that bear a hydroxyl group; Mo-based systems, on
the other hand, often retain their high activity in the presence
of unhindered tertiary amines.[1,2] Herein, we report a method
for catalytic asymmetric ring-opening/cross-metathesis
(AROM/CM)[3] of unsaturated azabicycles; functionalized
piperidines are formed in up to 98% ee and with greater than
98% E selectivity. With a fewexceptions, high reactivity is
observed only with Mo complexes. The present studies put
forth the first catalytic AROM/CM protocol for enantiose-
lective synthesis of N-containing heterocycles.[4]
During the past several years, we have introduced chiral
Ru-[5] (e.g., 1–2; Scheme 1) and Mo-based (e.g., 3–6) com-
plexes[2] that promote asymmetric ring-closing metathesis
(ARCM)[6,7] and ring-opening metathesis (AROM).[8] In
connection with catalytic AROM/CM, the majority of studies
have involved reactions of meso norbornenes that deliver
enantiomerically enriched cyclopentanes.[3,8] One of the more
noteworthy applications of these chiral complexes, however,
relates to enantioselective synthesis of piperidines, compo-
nents of numerous biologically active compounds.[9] We have
reported a catalytic AROM/CM protocol that yields func-
tionalized pyrans in high enantiomeric purity (up to 98% ee;
> 98% E selectivity in all cases).[8c] To promote enantiose-
lective reactions of the oxabicycles, we utilized Ru-based
chiral complexes (1–2), which, however, often do not promote
Scheme 1. Chiral Mo- and Ru-based complexes used for various
enantioselective olefin metathesis reactions. Ar=2,4,6-iPr3C6H2,
Mes=2,4,6-Me3C6H2.
reactions of N-containing substrates (see belowfor exam-
ples).
[*] G. A. Cortez, Prof. A. H. Hoveyda
Department of Chemistry
Merkert Chemistry Center
Boston College
We first examined the ability of Ru and Mo complexes in
initiating AROM/CM of azabicycle 7 and styrene (Table 1).
Since a number of biologically active agents[10] contain 2,6-
disubstituted N-methylpiperidines, we examined reactions
that afford this type of heterocyclic structure.[11] The results
summarized in Table 1 illustrate that, presumably due to
Lewis basic N!Ru chelation, Ru carbenes 1–2 are ineffective
(< 2% conversion). Even the parent achiral non-phosphine
Ru carbene,[12] which typically exhibits higher activity (vs. 1
and 2) delivers 50% conversion to 8 after 12 h.[13] Only with
two chiral Mo alkylidenes, dimethylphenylimido 3b (Table 1,
entry 5) and adamantylimido 6[14] (Table 1, entry 10), catalytic
AROM/CM proceeds efficiently (> 98% conv.). Whereas the
reaction with arylimido 3b generates rac-8, AROM/CM
involving complex 6 leads to the desired trisubstituted
Chestnut Hill, MA 02467 (USA)
Fax: ( +1)617-552-1442
E-mail: amir.hoveyda@bc.edu
Prof. R. R. Schrock
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
[**] This research was financially supported by the NIH (GM-59426 to
R.R.S. and A.H.H.) and the NSF (CHE-0213009 to A.H.H.). G.A.C. is
grateful for a Pfizer and a NIH predoctoral fellowship (F31 GM-
73556). We thank E. S. Sattely, D. G. Gillingham, and Dr. Carl A.
Baxter for helpful discussions.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Initial screening of chiral Ru and Mo complexes.[a]
Table 2: Catalytic enantioselective synthesis of N-methylpiperidines
promoted by chiral Mo complex 6.[a]
Entry Product
Conv. [%][b] Yield [%][c] ee [%][d]
1
2
>98
>98
95
92
94
89
[b]
Entry
Chiral complexConv. [%]
8:9[b]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
1a
2a
2b
3a
3b
3c
4a
4b
5
<2
<2
<2
<2
>98
<2
<2
<2
<2
>98
–
–
–
–
–
–
–
–
3
>98
88
64
>20:1
–
–
–
–
2:1
<2%
–
–
–
–
94
4
5
6
>98
>98
>98
86
91
86
88
98
96
6
[a] Reactions carried out under N2. [b] Conversion and product ratios
determined by analysis of 400-MHz 1H NMR spectra of unpurified
products; >98% E selectivity in all cases. [c] Determined by chiral HPLC
analysis; see the Supporting Information for details.
piperidine in 94% ee along with about 30% of the homodi-
mer 9 (see belowfor optimal conditions for minimal
formation of 9).[15] It should be noted that in the absence of
a cross partner, azabicycle 7 is polymerized (228C, C6H6,
30 min). This finding points to the favorable reaction of the
propagating alkylidene with styrene (vs. another azabicyclic
substrate molecule) to afford Mo benzylidenes, which cleanly
initiate a subsequent catalytic cycle.[7a]
7
8
>98
>98
90
64
85
80
Chiral adamantylimido complex 6 promotes AROM/CM
of a range of unsaturated N-Me-azabicycles in 64–95% yield
and 64–98% ee (Table 2). Several points regarding the data in
Table 2 are worthy of note: 1) To minimize formation of
product-derived homodimer (see 9, Table 1), reactions were
carried out with 10 equivalents of cross partner (vs. two equi-
valents in Table 1); transformations proceed to greater than
98% conversion within one hour (vs. 12 h in Table 1),
affording the desired products without detectable amounts
of the by-product (< 2% by 1H NMR analysis). Thus, as
shown in entry 1 of Table 2, piperidine 8 is isolated in 95%
yield and 94% ee. 2) Mo-catalyzed AROM/CM of different
cross partners takes place with varying enantioselectivities,
depending on their steric and electronic attributes. Catalytic
AROM/CM with electron-rich p-methoxystyrene (Table 2,
entry 2) proceeds in 89% ee (92% yield), whereas reaction of
electron-deficient p-trifluoromethylstyrene (entry 3) is less
enantioselective (64% ee and 88% yield). Although initial
studies indicate that the electron-deficient olefin reacts at a
lower rate (e.g., > 90% conv. for p-methoxystyrene vs. 54%
conv. for p-trifluorostyrene with two equivalents of cross
partner after 4 h), a precise mechanistic rationale regarding
this selectivity trend, which is in contrast to AROM/CM of
[a] Reactions carried out in the presence of 5 mol% 6, 10 equiv of styrene
(2 equiv for entry 8), in C6H6 for 1 h, at 228C and under N2.
[b] Determined by analysis of 400-MHz H NMR spectra of unpurified
product mixtures. [c] Yields of isolated product after silica gel chroma-
tography; >98% E selectivity in all cases. [d] Determined by chiral HPLC
analysis; see the Supporting Information for details.
1
meso norbornenes[7a] and thus unexpected, is unclear at the
present time. As illustrated in entries 4–5 of Table 2, sterically
more hindered styrenes, including o-methylstyrene, readily
undergo highly enantioslective catalytic AROCM/CM.
The derived unsaturated azabicycle bearing a benzyl ether
substituent (vs. an OTBS group; Table 2, entry 6), and the
diastereomeric silyl ether (leading to 15), undergo reaction
with equally high efficiency and enantioselectivity. Mo-
catalyzed AROM/CM furnishes access to 2,6-disubstituted
piperidine 16 in 80% ee and 64% yield of isolated product
(Table 2, entry 8).
Chiral complex 6 promotes AROM/CM of unsaturated
azabicycles that bear carbamate groups, including the popular
and easily removable N-Cbz unit (Table 3). Cbz-protected
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Table 3: Catalytic enantioselective synthesis of carbamate-protected
piperidines promoted by chiral Mo complex 6 and Ru complex 1a.[a]
carried out in the absence of solvent for high conversion
(<10% conv. otherwise), deliver 22 and 23 in 90% and
94% ee and 70% and 66% yield, respectively. Unlike
AROM/CM of oxabicycles,[5b] reactions are significantly less
efficient with Ru carbene 2a[5b] (30% conv. and 42% ee for 22
and 40% conv. and 56% ee for 23). The higher reactivity of
unsubstituted azabicycles with chiral carbene 1a may be due
to reduced steric repulsion involved with transformations of
substrates lacking a siloxy or alkoxy substituent.[16]
One important point regarding the AROM/CM reactions
described above is whether such transformations are rever-
sible, since azabicycles are less strained than the previously
examined norbornenes.[7a] Our investigations indicate that
Mo-catalyzed reactions in Table 2 (N-methyl-substituted
substrates) are under kinetic control. For instance, subjection
of pure 14 (Table 2, entry 6; 96% ee) to the reaction
conditions (5 mol% 6, 10 equiv styrene, C6H6, 228C, 12 h)
furnishes less than 2% of the corresponding meso azabicycle
and leads to recovery of piperidine in 96% ee. In contrast,
certain reactions shown in Table 3 can, at least to a limited
extent, be reversible. For example, subjection of pure 20
(85% ee) to the reaction conditions leads to the formation of
about 20% of the corresponding meso Cbz carbamate; Cbz-
protected piperidine is recovered in 85% ee. Such reversi-
bility accounts for incomplete conversions, shown in Table 3.
A similar observation is made with Cbz amide 22 in the
presence of Ru carbene 1a: the achiral substrate is isolated in
15% yield after 24 h (10 mol% 1a, 20 equiv styrene, neat,
228C) along with recovered 22 (82% ee).
Another noteworthy issue relates to reactions of aliphatic
cross partners. As has been noted previously,[8b] the relatively
rapid rate of homodimerization of non-aromatic olefins
results in the formation of the exceptionally reactive[8a]
methylidene complex, which often promotes less selective
reactions [e.g., 24 in 66% ee and 43% yield, Eq. (1)]. As the
example in Equation (1) illustrates, reaction of the Mo
alkylidene intermediate derived from AROM may proceed
through a metallacyclobutane that affords an achiral divinyl-
piperidene (e.g., 25). Moreover, the well-established ability of
aliphatic alkenes to undergo cross-metathesis (e.g., the
homodimerization mentioned above) faster than styrenyl
alkenes leads to reaction of the desired chiral products (e.g.,
24) with another equivalent of a cross partner and the
Entry Product
Chiral
Conv.
t
Yield ee
complex; [%][b] [h] [%][c] [%][d]
mol%
1
2
3
4
5
6; 10
6; 10
6; 10
6; 10
6; 10
>98 12 93
70 12 65
>98 12 92
85 24 80
70 24 60
90
80
86
85
80
6
7
6; 10
83 24 80
91 24 70
82
1a; 10
ꢁ90[e]
8
9
6; 5
78 24 72
90 24 66
90
1a; 10
ꢁ94[e]
[a] Reactions carried out with 10 equiv of styrene in C6H6 for entries 1–6
and 8, and 20 equiv of styrene without solvent for entries 7 and 9; all
reactions performed at 228C, under N2. [b] Determined by analysis of 400-
MHz 1H NMR spectra of unpurified product mixtures. [c] Yields of
isolated product after silica gel chromatography; >98% E selectivity in all
cases. [d] Determined by chiral HPLC analysis; see the Supporting
Information for details. [e] The negative ee values indicate that the specific
isomers shown in Scheme 1 for 1a and 6 afford opposite product
enantiomers. Cbz=benzyloxycarbonyl.
piperidines 17–20 and 22
(Table 3, entries 1–4 and 6) can
be synthesized in 65–93% yield
and 80–90% ee. Similarly, ethyl
carbamates 21 and 23 (entries 5
and 8) are generated in 80% and
90% ee, respectively (60 and 72% yields of isolated product).
Ru carbenes 1–2,[5] as well as the parent achiral complex, do
not readily initiate the AROM/CM reactions shown in
Table 3 (ꢀ 20% conv. in 24 h). There are two exceptions:
the transformations shown in entries 7 and 9, involving an
unsaturated azabicycle that lacks a C4 substituent, proceed to
greater than 90% conversion (24 h) in the presence of
10 mol% 1a. These Ru-catalyzed processes, which must be
generation of a nonchiral piperidine (e.g., 26). Such compli-
cations with aliphatic substrates are endemic to olefin
metathesis[8b,17] and not particular to this class of catalysts.[8c]
The above considerations suggest that future research must
focus on designing catalytic transformations involving non-
styrenyl cross partners that are more immune to homodime-
rization.[18]
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The unsaturated side chains at the C2 and C6 atoms of
piperidines provide opportunities for functionalization of
enantiomerically enriched N-containing heterocyles; note-
worthy examples are provided in Scheme 2. The phenyl-
substituted allylic amine of 8 is cleaved with Na/NH3 (15 min,
ꢁ788C) and the resulting styrenyl olefin is site-selectively
(>98%) but as an equal mixture of diastereomers.[20] The
primary carbinol of 28 can be oxidized with PCC and then
NaClO2 to afford the corresponding carboxylic acid; subse-
quent treatment with HN(OMe)Me and EDC delivers 31 in
78% overall yield (from 28). Treatment of 31 with MeMgCl,
followed by carbamate reduction and quenching with meth-
anol, constitutes a one-pot conversion to saturated b-amino
ketone 32 in 75% yield. Similar to the formation of [D1]-29,
when the alkylation, reduction, hydroalumination sequence is
terminated by quenching with MeOD, [D1]-32 is obtained in
64% yield.[21]
The studies described herein underline the crucial posi-
tion of high-oxidation-state olefin metathesis catalysts and
point to important future directions in newcatalyst and
method development. Investigations along these lines are in
progress.
Received: December 20, 2006
Revised: March 7, 2007
Published online: May 11, 2007
Keywords: asymmetric catalysis · molybdenum ·
.
olefin metathesis · piperidines · ruthenium
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[3] For a reviewof catalytic ring-opening olefin metathesis reac-
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[4] For catalytic asymmetric ring-closing metathesis processes that
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[5] a) J. J. Van Veldhuizen, J. S. Kingsbury, S. B. Garber, A. H.
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c) A. H. Hoveyda, D. G. Gillingham, J. J. Van Veldhuizen, O.
Kataoka, S. B. Garber, J. S. Kingsbury, J. P. A. Harrity, Org.
Biomol. Chem. 2004, 2, 8 – 23.
Scheme 2. Representative functionalizations of enantiomerically
enriched piperidines obtained through Mo-catalyzed AROM/CM reac-
tions. TBS=tert-butyldimethylsilyl; 9-BBN=9-borabicyclo-
[3.3.1]nonane; LAH=LiAlH4; PCC=pyridinium chlorochromate;
EDC=1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide; HOBt=
1-hydroxybenzotriazole.
[6] For representative asymmetric ring-closing metathesis reactions
promoted by chiral Mo complexes, see: a) J. B. Alexander, D. S.
La, D. R. Cefalo, A. H. Hoveyda, R. R. Schrock, J. Am. Chem.
Soc. 1998, 120, 4041 – 4042; b) D. R. Cefalo, A. F. Keily, M.
Wuchrer, J. Y. Jamieson, R. R. Schrock, A. H. Hoveyda, J. Am.
Chem. Soc. 2001, 123, 3139 – 3140; c) A. F. Kiely, J. A. Jernelius,
R. R. Schrock, A. H. Hoveyda, J. Am. Chem. Soc. 2002, 124,
2868 – 2869; d) J. A. Jernelius, R. R. Schrock, A. H. Hoveyda,
Tetrahedron 2004, 60, 7345 – 7351.
[7] For asymmetric ring-closing metathesis reactions promoted by
Ru-based catalysts, see: a) T. J. Seiders, D. W. Ward, R. H.
Grubbs, Org. Lett. 2001, 3, 3225 – 3228; b) J. J. Van Veldhuizen,
D. G. Gillingham, S. B. Garber, O. Kataoka, A. H. Hoveyda, J.
Am. Chem. Soc. 2003, 125, 12502 – 12508; c) T. W. Funk, J. M.
Berlin, R. H. Grubbs, J. Am. Chem. Soc. 2006, 128, 1840 – 1846.
reduced to afford terminally unsaturated amino ether 27 as a
single diastereomer and in 85% yield of isolated product.
Site-selective hydroboration of enantiomerically enriched 23,
obtained through Mo- or Ru-catalyzed AROM/CM, leads to
the formation of primary alcohol 28. Treatment of 28 with
lithium aluminum hydride at 658C (THF) delivers 29 through
reduction of the carbamate and a rare process: directed
regioselective hydroalumination of the styrenyl alkene.[19]
When the above multistep transformation is quenched with
MeOD, [D1]-29 is obtained in 95% yield and as a single
regioisomer (by 400-MHz NMR analysis; > 98% deuterium
incorporation). When the reaction is quenched with dry O2,
diol 30 is isolated in 55% yield as a single regioisomer
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[8] For Mo-catalyzed AROM/CM reactions, see: a) G. S. Weather-
[15] Formation of 9 is likely due to the reaction of the Mo alkylidene
=
head, J. G. Ford, E. J. Alexanian, R. R. Schrock, A. H. Hoveyda,
J. Am. Chem. Soc. 2000, 122, 1828 – 1829; b) D. S. La, E. S.
Sattely, J. G. Ford, R. R. Schrock, A. H. Hoveyda, J. Am. Chem.
Soc. 2001, 123, 7767 – 7778; for Ru-catalyzed AROM/CM
reactions, see: c) D. G. Gillingham, O. Kataoka, S. B. Garber,
A. H. Hoveyda, J. Am. Chem. Soc. 2004, 126, 12288 – 12290; for
applications to total synthesis, see: d) G. S. Weatherhead, A. G.
Cortez, R. R. Schrock, A. H. Hoveyda, Proc. Natl. Acad. Sci.
USA 2004, 101, 5805 – 5809; e) D. G. Gillingham, A. H. Hov-
eyda, Angew. Chem. 2007, DOI: 0.1002/ange.200700501; Angew.
Chem. Int. Ed. 2007, DOI: 0.1002/anie.200700501, in press; a
recent report provides examples of catalytic AROM/CM of
selected norbornene-derived substrates and styrene with chiral
monodentate Ru–NHC complexes, albeit with little or no E:Z
selectivity (1–1.4:1) and only up to 80% ee for the E product
isomer (4–50% ee for Z isomers): f) J. M. Berlin, S. D. Goldberg,
R. H. Grubbs, Angew. Chem. 2006, 118, 7753 – 7757; Angew.
Chem. Int. Ed. 2006, 45, 7591 – 7595.
generated through AROM/CM (before {LnMo C} is converted
to a terminal olefin) and another molecule of 7 (vs. reaction with
styrene to afford 8).
[16] Molecular models indicate that substrates bearing an exo
heteroatom substituent (substrate corresponding to 20) can
cause the amide group to be situated in a manner that hinders
approach of the bulky Ru carbene from the exo face of the cyclic
olefin.
[17] A. K. Chatterjee, T.-L. Choi, D. P. Sanders, R. H. Grubbs, J. Am.
Chem. Soc. 2003, 125, 11360 – 11370.
[18] For example, see: R. E. Giudici, A. H. Hoveyda, J. Am. Chem.
Soc. 2007, 129, 3824 – 3825.
[19] Preliminary experiments indicate that hydroalumination of 28 is
directed by the hydroxyl (vs. the amine) group. Thus, subjection
of piperidine 23 to the same reaction conditions only results in
carbamate reduction, and the corresponding pyrans bearing the
primary alcohol undergo hydroalumination. For a reviewof
substrate-directed reactions, see: a) A. H. Hoveyda, D. A.
Evans, G. C. Fu, Chem. Rev. 1993, 93, 1307 – 1360; for examples
of hydroxyl-directed hydraoluminations, see: b) H. W. Thomp-
son, E. McPherson, J. Org. Chem. 1977, 42, 3350 – 3352; c) R. B.
Gammill, P. M. Gold, S. A. Mizak, J. Am. Chem. Soc. 1980, 102,
3095 – 3100; d) K. Koch, J. H. Smitrovich, Tetrahedron Lett.
1994, 35, 1137 – 1140; for amine-directed hydroaluminations,
see: e) A. P. Marchand, R. W. Allen, Tetrahedron Lett. 1975, 16,
67 – 70; f) J. Szmsuzkovicz, J. H. Musser, L. G. Lurian, Tetrahe-
dron Lett. 1978, 19, 1411 – 1412; g) W. Granitzer, A. Stutz,
Tetrahedron Lett. 1979, 20, 3145 – 3148.
[20] In addition, primary alcohol 28 is obtained in 45% yield.
Formation of 28 is not due to the presence of adventitious
moisture. When the reaction (O2 quench) is worked up with
MeOD, [D1]-28 is generated as the exclusive by-product. A
portion of the alkylaluminum intermediate might exist in a less
reactive oligomeric form.
[21] As reported previously, b-amino ketones such as 31 are subject
to facile epimerization, presumably through an elimination/
intramolecular conjugate addition process; see: R. W. Bates, K.
Sa-Ei, Tetrahedron 2002, 58, 5957 – 5978.
[9] For a reviewon olefin metathesis methods for synthesis of
heterocycles, see: A. Deiters, S. F. Martin, Chem. Rev. 2004, 104,
2199 – 2238.
[10] For example, see: a) R. W. Bates, K. Sa-Ei, Tetrahedron Lett.
2002, 43, 5957 – 5958; b) F. X. Felpin, J. Lebreton, Tetrahedron
2004, 60, 10127 – 10153.
[11] For applications of catalytic olefin metathesis (non-asymmetric)
to total synthesis of piperidine-containing natural products, see:
a) S. Randl, S. Blechert, J. Org. Chem. 2003, 68, 8879 – 8882; b) P.
Rückert, P. H. Deshmukh, S. Blechert, Tetrahedron Lett. 2006,
47, 7977 – 7981.
[12] S. B. Garber, J. S. Kingsbury, B. L. Gray, A. H. Hoveyda, J. Am.
Chem. Soc. 2000, 122, 8168 – 8179.
ꢁ
[13] Attempts to circumvent N Ru complexation through protona-
tion of the substrateꢀs Lewis basic amine resulted in substrate
ꢁ
decomposition (presumably due to cleavage of the allylic C N
bond).
[14] W. C. P. Tsang, J. A. Jernelius, G. A. Cortez, G. S. Weatherhead,
R. R. Schrock, A. H. Hoveyda, J. Am. Chem. Soc. 2003, 125,
2591 – 2596.
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