New modes for the osmium-catalyzed oxidative cyclization

Article abstract of DOI:10.1021/ol100046a

(Figure Presented) The osmium-catalyzed oxidative cyclization of amino alcohol initiators formally derived from 1,4-dienes Is an effective method for the construction of pyrrolidines, utilizing a novel reoxidant (4-nltropyridlne N-oxide = NPNO). The cyclization of enantlopure syn- and anti-amino alcohols gives rise to enantlopure cis- and frans-2,5-disubstituted pyrrolidines, respectively. Moreover, the cyclization of Ws-homoallylic amines bearing an exocyclic chelating group Is shown to be a complementary method for irans-pyrrolidine formation.

Full text of DOI:10.1021/ol100046a

ORGANIC
LETTERS
2010
Vol. 12, No. 5
1060-1063
New Modes for the Osmium-Catalyzed
Oxidative Cyclization
Timothy J. Donohoe,*,† Peter J. Lindsay-Scott,† Jeremy S. Parker,‡ and Cedric
K. A. Callens†,§
Department of Chemistry, UniVersity of Oxford, Chemistry Research Laboratory, Mansfield
Road, Oxford, OX1 3TA, United Kingdom, and AstraZeneca, Process R&D AVlon/
Charnwood, AVlon Works, SeVern Road, Hallen, Bristol, BS10 7ZE, United Kingdom
timothy.donohoe@chem.ox.ac.uk
Received January 8, 2010
ABSTRACT
The osmium-catalyzed oxidative cyclization of amino alcohol initiators formally derived from 1,4-dienes is an effective method for the construction
of pyrrolidines, utilizing a novel reoxidant (4-nitropyridine N-oxide ) NPNO). The cyclization of enantiopure syn- and anti-amino alcohols
gives rise to enantiopure cis- and trans-2,5-disubstituted pyrrolidines, respectively. Moreover, the cyclization of bis-homoallylic amines bearing
an exocyclic chelating group is shown to be a complementary method for trans-pyrrolidine formation.
Various metal-oxo species have been reported to catalyze
the oxidative cyclization of 1,5-dienes to the corresponding
2,5-disubstituted THFs, with varying degrees of success.1
While most metals give cis-THF products exclusively,
ruthenium has been shown to afford trans-THFs as minor
products in certain circumstances.2
In recent years, the osmium-catalyzed oxidative cyclization
of diols and amino alcohols formally derived from 1,5-dienes
has emerged as a powerful method for the construction of
enantiopure THFs 3 and pyrrolidines, respectively (Scheme
1).3 The reaction is stereoselective for the formation of cis-
2,5-disubstituted heterocycles and stereospecific with regards
to syn-addition across the tethered alkene, providing efficient
access to stereodefined THFs and pyrrolidines.
Recent studies from our laboratory have shown that only
Os(VI) is required to perform these cyclization reactions,
while Os(VIII) leads to unwanted dihydroxylation of the
starting material.4 Hence, the optimal reoxidant for this
transformation was shown to be pyridine N-oxide (PNO),
since this was able to oxidize Os(IV) to Os(VI), but not to
Os(VIII) under the reaction conditions.3c In addition, citric
acid was postulated to stabilize Os(VI) with respect to
disproportionation and aid in the hydrolytic release of product
† University of Oxford.
‡ AstraZeneca.
§ Author to whom correspondence regarding the X-ray crystallography
should be addressed.
(1) For a review, see: (a) Piccialli, V. Synthesis 2008, 2585–2607.
Manganese: (b) Klein, E.; Rojahn, W. Tetrahedron 1965, 21, 2353–2358.
(c) Walba, D. M.; Wand, M. D.; Wilkes, M. C. J. Am. Chem. Soc. 1979,
101, 4396–4397. (d) Baldwin, J. E.; Crossley, M. J.; Lehtonen, E.-M. M.
J. Chem. Soc., Chem, Commun. 1979, 918–920. (e) Brown, R. C. D.; Keily,
J. F. Angew. Chem., Int. Ed. 2001, 40, 4496–4498. (f) Brown, R. C. D.;
Bataille, C. J.; Hughes, R. M.; Kenney, A.; Luker, T. J. J. Org. Chem.
2002, 67, 8079–8085. Osmium: (g) de Champdore´, M.; Lasalvia, M.;
Piccialli, V. Tetrahedron Lett. 1998, 39, 9781–9784. (h) Donohoe, T. J.;
Butterworth, S. Angew. Chem., Int. Ed. 2003, 42, 948–951.
(2) (a) Charlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J.
Org. Chem. 1981, 46, 3936–3928. (b) Albarella, L.; Musumeci, D.; Sica,
D. Eur. J. Org. Chem. 2001, 997–1003. (c) Piccialli, V.; Cavallo, N.
Tetrahedron Lett. 2001, 42, 4695–4699. (d) Roth, S.; Go¨hler, S.; Cheng,
H.; Stark, C. B. W. Eur. J. Org. Chem. 2005, 4109–4118.
(3) (a) Donohoe, T. J.; Butterworth, S. Angew. Chem., Int. Ed. 2005,
44, 4766–4768. (b) Donohoe, T. J.; Churchill, G. H.; Wheelhouse (ne´e
Gosby), K. M. P.; Glossop, P. A. Angew. Chem., Int. Ed. 2006, 45, 8025–
8028. (c) Donohoe, T. J.; Wheelhouse (ne´e Gosby), K. M. P.; Lindsay-
Scott, P. J.; Glossop, P. A.; Nash, I. A.; Parker, J. S. Angew. Chem., Int.
Ed. 2008, 47, 2872–2875. (d) Donohoe, T. J.; Winship, P. C. M.; Walter,
D. S. J. Org. Chem. 2009, 74, 6394–6397.
(4) Donohoe, T. J.; Wheelhouse (ne´e Gosby), K. M. P.; Lindsay-Scott,
P. J.; Churchill, G. H.; Connolly, M. J.; Butterworth, S.; Glossop, P. A.
Chem. Asian J. 2009, 4, 1237–1247.
10.1021/ol100046a  2010 American Chemical Society
Published on Web 02/05/2010

to the heterocycle. We postulated that a third system (akin
to the rhenium-mediated oxidative cyclization of bis-
homoallylic alcohols)7 might also be possible, in which
the chelating alcohol function was part of the amine
protecting group, Mode C. If these new modes of oxidative
cyclization could be unlocked with osmium, they might
enable the formation of trans-2,5-disubstituted pyrro-
lidines.
Scheme 1
.
The Osmium-Catalyzed Oxidative Cyclization
Reaction
With this in mind, we examined the oxidative cyclization
of N-Ts amino alcohol 4, since these types of substrate had
proven to be the most reactive toward Os(VI) in the
analogous 1,5-diene series (Scheme 2).8 Treatment of 4 with
Scheme 2. Initial Stoichiometric Studies
molecules from osmium complexes.5 Ongoing research in
our group has also revealed that metal triflates are capable
of promoting the cyclization of bound osmium species 2 at
higher temperatures, where the use of traditional protic acids
gives lower yields of cyclized products and degrades the
starting material.3d Thus, the use of PNO in concert with
citric acid and metal triflates provides a powerful, yet
controlled, system for the oxidative cyclization of suitable
initiators.
In stark contrast, the oxidative cyclization of 1,4-dienes
to THFs has been reported only once in the literature, with
just two examples quoted (both cyclizations proceeded in
30% yield).6 Moreover, the cyclization of diols or amino
alcohols formally derived from 1,4-dienes has yet to be
documented. We were intrigued by the possibility of utilizing
our potent oxidative conditions (that had performed admi-
rably for the cyclization of 1,5-diene derived initiators, Mode
A) in the context of substrates derived from 1,4-dienes, Mode
B (Figure 1). Both modes of cyclization would involve a
stoichiometric Os(VI) and TMEDA at pH 7 furnished osmate
ester 5 in 59% yield, whose structure was proven unambigu-
ously by X-ray crystal structure analysis.9 When complex 5
was exposed to a variety of protic acids and solvents, no
oxidative cyclization occurred. However, stirring with sub-
stoichiometric scandium(III) triflate and citric acid in aqueous
acetonitrile at 60 °C delivered the target pyrrolidine 7 in 79%
yield. The relative stereochemistry of 7 was confirmed by
X-ray crystal structure analysis, providing evidence for the
postulated transition structure 6, since the alcohol and
hydroxymethylene groups in the product were shown to be
on the same face of the pyrrolidine. Interestingly, no
cyclization of 5 was observed when Lewis acids were used
without citric acid.
The reaction was rendered catalytic by utilizing PNO
as reoxidant, and a variety of olefins were shown to be
suitable substrates for oxidative cyclization (Scheme 3).
(5) Dupau, P.; Epple, R.; Thomas, A. A.; Fokin, V. V.; Sharpless, K. B.
AdV. Synth. Catal. 2002, 344, 421–433.
(6) Travis, B.; Borhan, B. Tetrahedron Lett. 2001, 42, 7741–7745.
(7) (a) Tang, S.; Kennedy, R. M. Tetrahedron Lett. 1992, 33, 3729–
3732. (b) Tang, S.; Kennedy, R. M. Tetrahedron Lett. 1992, 33, 5299–
5302.
Figure 1. Possible modes of oxidative cyclization.
(8) For evidence that protected amino alcohols are ligands for osmium,
see: (a) Andersson, M. A.; Epple, R.; Fokin, V. V.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2002, 41, 472–475. (b) Mun˜iz, K.; Almodovar, I.; Streuff,
J.; Nieger, M. AdV. Synth. Catal. 2006, 348, 1831–1835.
(9) X-ray crystal structure analyses were performed on compounds 5,
7, 14, and 20, and on derivatives of compounds 16 and 18 (see the
Supporting Information).
bidentate coordination of the substrate to Os(VI), leading
to the protected amine becoming fused to the heterocycle
and the other coordinating function becoming appended
Org. Lett., Vol. 12, No. 5, 2010
1061

Scheme 3
.
Oxidative Cyclization of N-Ts Amino Alcoholsa
Scheme 4
.
Oxidative Cyclization of Challenging Amino
Alcohols
reaction times for full consumption of the starting materials.
However, under these conditions competing dihydroxylation
was also observed because either (i) the disproportionation
of Os(VI) in acid was vastly accelerated at 90 °C or (ii) PNO
was eventually capable of oxidizing Os(VI) to Os(VIII) at
90 °C. To tackle this problem, these reactions were conducted
with 4-nitropyridine N-oxide (NPNO) as reoxidant, which
gave higher yields of cyclized products, presumably as a
result of its attenuated oxidizing power toward osmium.
Notably, syn-amino alcohol 15 cyclized to cis-pyrrolidine
16 in 67% yield (36 h), while anti-amino alcohol 17 afforded
trans-pyrrolidine 18 in 74% yield (48 h, the first example
of an osmium-catalyzed trans-selective oxidative cyclization
reaction), with no erosion of enantiopurity. Also, the use of
N-Ns protecting groups was tolerated under the reaction
conditions. However, amino alcohol 19 also required the
more forcing conditions (16 h) to cyclize effectively,
probably due to the electron-withdrawing effect of the nitro
group. The structures of compounds 16, 18, and 20 were all
proven by X-ray crystal structure analysis.9 Unfortunately,
the cyclization of diols and transposed amino alcohols
derived from 1,4-dienes failed to give any THF products
when exposed to similar reaction conditions.
a After acetylation (Ac2O, pyridine) of the crude material.
While other Lewis acids required reaction times of up to
48 h to fully consume the starting materials, substoichio-
metric scandium(III) triflate consistently achieved full
conversions for all examples in Scheme 3 in only 16 h.
Notably, amino alcohols 4, 9, and 11 all cyclized
efficiently to pyrrolidines 8, 10, and 12 in high yields as
single diastereomers with catalyst loadings of only 1 mol
%. Moreover, enantiopure amino alcohols 9 and 11
cyclized with no erosion of enantiopurity in the products.10
It was found advantageous to isolate pyrrolidines 8 and
10 as their corresponding diacetates to aid purification.
The structure of 8 was proven by deprotection to diol 7
(see the Supporting Information), while amino alcohols 9
and 11 were assumed to have undergone stereospecific
syn-oxidations with respect to alkene geometry (based on
significant literature precedent for the oxidation of amino
alcohols derived from 1,5-dienes, evidenced by extensive
X-ray crystal structures).3b Allyl silane 13 was also shown
to undergo oxidative cyclization to pyrrolidine 14 in 58%
yield, although this substrate required a catalyst loading
of 5 mol % to achieve full conversion (Scheme 3). The
relative stereochemistry of pyrrolidine 14 was secured by
X-ray crystal structure analysis, clearly highlighting the
stereospecific (syn) nature of the alkene oxidation.9
Next, the reactivity of amino alcohols bearing substitution
R- to nitrogen was investigated (Scheme 4). These substrates
were significantly less reactive toward Os(VI) and required
higher temperatures, increased catalyst loadings, and longer
With an effective protocol established for the formation
of pyrrolidines by cyclization Mode B (see Figure 1 above),
the use of exocyclic-initiator functionalities was examined
next (Mode C). Initial studies revealed that a novel ꢀ-hydroxy
sulfonamide protecting group was ideal for this task (after
cyclization, deprotection could be accomplished by O-
methylation and subsequent reduction, see the Supporting
Information). However, 1,3-initiators have been shown to
be less reactive toward Os(VI) than their 1,2-counterparts,
since the large metal atom has a preference for five-
membered chelates over six, due to more favorable bond
angles.11 Hence, the cyclization of amino alcohols 21 and
(10) Enantiomeric excess measurements were conducted by either (a)
19F NMR spectroscopy on Mosher’s ester derivatives or (b) 1H NMR
spectroscopy with an enantiopure additive, with comparison to racemic
standards in both cases.
(11) Hancock, R. D.; Martell, A. E. Chem. ReV. 1989, 89, 1875–1914.
Org. Lett., Vol. 12, No. 5, 2010
1062

23 also required relatively high catalyst loadings and long
reaction times (48 h) to achieve full conversion of starting
materials, affording pyrrolidines 22 and 24 in high yields
(Scheme 5). It was assumed that these oxidations had
Scheme 6. Formation of trans-Pyrrolidines
Scheme 5. Oxidative Cyclization of Exocyclic Initiators
analogous rhenium-mediated process.7 The trans nature of
28 and 31 was confirmed by gradient NOE enhancements,
while it was assumed that the oxidations had occurred in a
stereospecific (syn) fashion, as before.
In conclusion, two new modes of osmium-catalyzed
oxidative cyclization have been explored for the construction
of pyrrolidines. As a result, trans-2,5-disubstituted hetero-
cycles can be accessed directly from acyclic precursors by
using a novel reoxidant for osmium. This methodology
should find use in the synthesis of natural products.
occurred in a syn-stereospecific manner with respect to alkene
geometry (based on significant literature precedent for the
oxidation of amino alcohols derived from 1,5-dienes).3b
When O-Me compound 25 was exposed to the reaction
conditions, only starting material was recovered, suggesting
that osmium must be coordinated in a bidentate fashion
during cyclization (see transition structure 30, Scheme 6).
Secondary bis-homoallylic amines 27 and 29 also under-
went oxidative cyclization to give trans-pyrrolidines 28 and
31 as single diastereomers (48 h, Scheme 6), albeit in lower
yields due to competing dihydroxylation of these less reactive
substrates. We suggest that the observed stereoselectivity was
a consequence of the bystander methyl group electing to be
trans disposed to the alkene during cyclization (transition
structure 30) to minimize steric congestion, as in the
Acknowledgment. We thank the EPSRC and AstraZeneca
for funding this project and the Oxford Chemical Crystal-
lography Service for the use of their instrumentation.
Supporting Information Available: Experimental pro-
cedures and spectroscopic/X-ray data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL100046A
Org. Lett., Vol. 12, No. 5, 2010
1063