Stereoselective synthesis of pyrrolidines: Catalytic oxidative cyclizations mediated by osmium

Article abstract of DOI:10.1002/anie.200603240

(Chemical Equation Presented) A new pathway for oxidative cyclization : N-protected α-amino alcohols with distal alkene units cyclize with complete stereoselectivity and stereospecificity to cispyrrolidines, dependent on the substitution pattern of the st

Full text of DOI:10.1002/anie.200603240

Angewandte
Chemie
Synthetic Methods
DOI: 10.1002/anie.200603240
Stereoselective Synthesis of Pyrrolidines:
Catalytic Oxidative Cyclizations Mediated by
Osmium**
Timothy J. Donohoe,* Gwydion H. Churchill,
Katherine M. P. Wheelhouse (nØe Gosby), and
Paul A. Glossop
Since its discovery by Klein and Rojahn in 1965, the oxidative
cyclization of 1,5-dienes to give 2,5-disubstituted tetrahydro-
furans has received a considerable amount of attention with a
number of metal oxo species now capable of accomplishing
this transformation.[1] We have recently developed the use of
catalytic OsO4 under acidic conditions to give cis-tetrahydro-
furans (THFs) in high yields.[2] Attempts to induce asymmet-
ric induction in this reaction with the addition of chiral amine
ligands failed, presumably owing to the low pH of the
reaction. However, we subsequently reported that vicinal
diols derived from1,5-dienes undergo cyclization in a regio-
and stereoselective manner to give cis-THFs under conditions
comparable to diene cyclization (Scheme 1).[3] We have
evidence to suggest that Os complexes to the diol (chelation
is essential) before perfoming an intramolecular, and stereo-
[*] Prof. T. J. Donohoe, Dr. G. H. Churchill, K. M. P. Wheelhouse (nØe
Gosby)
Department of Chemistry
University of Oxford
Chemistry Research Laboratory
Mansfield Road, Oxford OX1 3TA (UK)
Fax: (+44)1865-275-708
E-mail: timothy.donohoe@chem.ox.ac.uk
Homepage:
http://www.chem.ox.ac.uk/researchguide/tjdonohoe.html
P. A. Glossop
Pfizer Global R&D
Pfizer Limited
Ramsgate Road, Sandwich, Kent CT13 9NJ (UK)
[**] We thank the EPSRC and Pfizer for supporting this project. Merck,
AstraZeneca, Pfizer, and Novartis are thanked for unrestricted
funding.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Scheme 1. Stereoselective oxidative cyclization of diols. TMO=Me3NO; TFA=
trifluoroacetic acid.
specific, oxidation of the pendant alkene (A). Furthermore,
there is no loss of stereochemical integrity during the
cyclization, and enantiopure diols give enantiopure THFs;
this methodology was then applied to a formal synthesis of
(+)-cis-solamin.[3]
The results shown above extend the possibility to take this
reaction in a fundamentally new direction and allow the
formation of nitrogen heterocycles via oxidative cyclization of
amino alcohols. Although the oxidative cyclization of 1,5-
dienes has not been modified to form pyrrolidines, we chose
to examine the cyclization of vicinal amino alcohols as our
starting point.[4] Our rationale was that in synthesizing
enantiopure amino alcohols separately, we would be able to
obtain enantiopure pyrrolidines by oxidative cycliza-
tion. If successful, we would uncover a new catalytic
reaction capable of making important heterocycles in a
stereoselective fashion.[5]
Scheme 2. Oxidative cyclization to form pyrrolidines. [a] Reactions
carried out at 408C. Ts=toluene-4-sulfonyl; CSA=camphorsulfonic
acid.
Substrates 3, 5, 7, 9 were readily prepared and
subjected to the oxidation conditions;[6] pleasingly, cis-
pyrrolidines 4, 6, 8, 10 were formed in 80–90% yield
(Scheme 2). The reaction is stereoselective, giving cis-
pyrrolidines in all cases, and stereospecific (see oxida-
tion of 7, 9). Moreover, the syn addition of nitrogen and
oxygen atoms across the distal alkene was proven
rigorously.[7]
The cyclization of the sterically bulky alkene 9 to
give 10 is also notable for its high yield. Catalyst
loadings were successfully reduced to 1 mol% osmium
(4, 8, and 10) and even as low as 0.2 mol% for 3, giving
compound 4 in 68% yield. Furthermore, we have
applied these conditions to the cyclization of enantio-
pure starting materials (7, 9)[6] without loss of enantio-
meric purity during the reaction. Note that trans-
cinnamic acid is added to these oxidations as a sacrificial
alkene[3] and was found to be optimal for these trans-
formations (see below).
The information detailed above reveals that the
range of potentially chelating substrates that can
undergo oxidative cyclization is large. We were
intrigued by the possibility of subjecting other chelating
derivatives to this procedure, to give differently sub-
stituted THFs.
Therefore, enantiopure hydroxy amide 11 was sub-
jected to oxidative conditions and cyclized in high yield
to give the amido THF 12 (Scheme 3).[8] This result
Scheme 3. Alternative chelating functionality for cyclization. Cbz=benzyloxy-
carbonyl; Bn=benzyl.
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demonstrates the generality possible in the initiating func-
tionality. Next, the amino alcohol substrates shown were
subjected to oxidative cyclization to give cis-THFs in good to
excellent yields. The stereospecific syn addition is exemplified
by the stereochemistry of the products 16 and 18.[7] The N-Ts
group was found to be optimal for these cyclizations, although
carbamates do cyclize, albeit in lower yields (see 19).
We investigated the mechanism of cyclization by prepar-
ing the competition substrate 23 (Scheme 4), which bears the
1,2-hydroxysulfonamide functionality and two distal terminal
alkenes. Oxidative cyclization of 23 should forman osmium
chelate (see B),[4] and then cyclization will reveal a preference
for formation of either N- or O-heterocycles. We also wished
Examination of the reaction of 23 revealed interesting
information about the nature of the catalyst involved in
chelation and cyclization (Table 1). In entry 1 it is seen that
stoichiometric OsVI is capable of chelating and then cyclizing
Table 1: Reaction of 23 to give 24.
Entry Conditions
Yield of 24
1
2
3
4
1 equiv K2OsO2(OH)4, CSA, CH2Cl2
1 equiv OsO4, CSA, CH2Cl2
cat. OsO4, CSA, TMO, CH2Cl2
63%
<20%[a]
<5%
cat. OsO4, CSA, trans-cinnamic acid, TMO, CH2Cl2
61%
[a] Products derived from dihydroxylation of 23 were observed.
(OsVI!OsIV).[10] Moreover, entry 2 reveals that OsVIII
preferentially dihydroxylates an alkene rather than
cyclizes a diol onto it.[11] We suspect that the small
amount of 24 formed here comes from dihydroxylation
and subsequent ligand exchange on OsVI and cycliza-
tion. Thus, the role of the sacrificial alkene becomes
clear; it must be dihydroxylated in preference to the
alkene in the substrate. In so doing it prevents
unwanted diol by-products and forms OsVI, which is a
more competent catalyst (compare entries 3 and 4,
Table 1). trans-Cinnamic acid is ideal because the diol
formed from dihydroxylation is polar and easily
separable fromthe cyclized products.
To conclude, we have shown that N-protected 1,2-
amino alcohols are excellent substrates for catalytic
oxidative cyclization. The synthesis of pyrrolidines and
THFs is both stereoselective and stereospecific, high-
yielding, and governed by the position of the heter-
oatoms in the starting material. Enantiopure starting
materials are readily accessible and give enantiopure
products after cyclization.
Scheme 4. Mechanistic probes for pyrrolidine formation.
to examine the role of solvent on any competitive cyclization,
and in this regard it is worth noting that formation of oxygen
and nitrogen heterocycles works best in different solvents
(compare Scheme 2 and Scheme 3).
Received: August 9, 2006
Published online: November 3, 2006
Keywords: catalysis · cyclization · nitrogen heterocycles ·
When 23 was subjected to the OsO4/CSA conditions, the
cis-pyrrolidine 24 was formed in 61% yield. The structure of
24 was proven by X-ray crystallography and none of the
corresponding THF was observed during this reaction. It was
then anticipated that use of the K2OsO2(OH)4/TFA condi-
tions (that is, those which have proved optimal for the
synthesis of THFs; see Scheme 3) would provide the THF
congener of 24. These conditions also returned the pyrrolidine
24, but in a lower yield (46%). The carbamate derivative 26
proved completely inert to OsO4/CSA conditions, but gave a
low yield of the cis-pyrrolidine 27 when subjected to
K2OsO2(OH)4/TFA cyclization. These reactions serve to
underline the overriding preference for cyclization to nitro-
gen-containing heterocycles over those containing oxygen,
and provide further evidence for the enhanced participation
.
osmium · pyrrolidines
[1] Mn: a) E. Klein, W. Rojahn, Tetrahedron 1965, 21, 2353 – 2358;
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ꢀ
ꢀ
of Os N bonds over Os O bonds whenever there is a
choice.[9] The removal of N-protecting groups with Na in
liquid NH3 then established the formation of pyrrolidine 25
fromboth substrates 24 and 27.
[2] Os: a) M. de ChampdorØ, M. Lasalvia, V. Piccialli, Tetrahedron
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[3] D. M. Walba, G. S. Stoudt, Tetrahedron Lett. 1982, 23, 727 – 730;
see also reference [2c].
[4] There is good evidence to suggest that NTs amino alcohols are
ligands for osmium: M. A. Andersson, R. Epple, V. V. Fokin,
K. B. Sharpless, Angew. Chem. 2002, 114, 490 – 493; Angew.
Chem. Int. Ed. 2002, 41, 472 – 475.
[5] For examples of pyrrolidine synthesis using catalysis, see:
a) B. M. Trost, A. B. Pinkerton, D. Kremzow, J. Am. Chem.
Soc. 2000, 122, 12007 – 12008; b) C. V. Galliford, M. A. Beenen,
S. T. Nguyen, K. A. Scheidt, Org. Lett. 2003, 5, 3487 – 3490; c) Q.
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Zhang, Org. Lett. 2006, 8, 2273 – 2276.
[6] The enantiopure amino alcohols reported here were made by a
convenient route that involved: 1) reaction of OTr glycidol with
an allyl Grignard reagent, 2) Mitsunobu inversion with
BocNHTs, and then 3) deprotection. OTr= O-trityl, Boc = tert-
butoxycarbonyl.
[7] The structures of 6, 8, 10, 16, 18, 22, and 24 were proven
unambiguously by X-ray crystallography.
[8] Although the yields are sensitive to the solvent used and the pH,
they are not influenced unduly by the source of osmium.
[9] This preference was first noted by Sharpless and co-workers:
D. W. Patrick, L. K. Truesdale, S. A. Biller, K. B. Sharpless, J.
Org. Chem. 1978, 43, 2628 – 2638.
[10] OsVI is prone to disproportionation under acidic conditions.
Control experiments have shown that this is relatively slow
under the experimental conditions reported here; see: P. Dupau,
R. Epple, A. A. Thomas, V. V. Fokin, K. B. Sharpless, Adv.
Synth. Catal. 2002, 344, 421 – 433.
[11] J. R. Ragazzo, E. J. Behrman, Bioinorg. Chem. 1976, 5, 343 – 352;
while the studies here indicate that OsVI is desirable for
formation of a chelate, we have unpublished results which
show that both OsVI and OsVIII osmate esters can cyclize under
acidic conditions.
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