Diastereoselective synthesis of 2,6-trans-disubstituted piperidines via sequential cross-metathesis-cationic cyclisation

Article abstract of DOI:10.1002/adsc.200600482

Ruthenium-catalysed cross-metathesis of protected homoallylamine derivatives with vinyl carbinols furnished allylic alcohols, which underwent stereoconvergent cyclisation to trans-tetrahydropyridines upon treatment with BF₃-OEt₂. The

Full text of DOI:10.1002/adsc.200600482

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DOI: 10.1002/adsc.200600482
Diastereoselective Synthesis of 2,6-trans-Disubstituted Piperidines
via Sequential Cross-Metathesis–Cationic Cyclisation
Stefan Mixa and Siegfried Blecherta,*
a
Technische Universität Berlin, Institut für Chemie, Strasse des 17. Juni 135, 10623 Berlin, Germany
Fax : (+49)-30-3142-3619; e-mail: blechert@chem.tu-berlin.de
Received: September 19, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Ruthenium-catalysed cross-metathesis of
protected homoallylamine derivatives with vinyl
carbinols furnished allylic alcohols, which under-
went stereoconvergent cyclisation to trans-tetrahy-
dropyridines upon treatment with BF3·OEt2. The
new methodology was used for the preparation of
enantiopure piperidine and indolizidine natural
products.
Keywords: cationic cyclisation; cross-metathesis; 6-
endo-trig cyclisation; 3,5-disubstituted indolizidines;
2,6-disubstituted piperidines; ruthenium
Scheme 1. CM cyclisation sequences (PG=protective
group).
Piperidine alkaloids are widespread in nature and ex-
hibit manifold biological activities. 2,6-Disubstituted precursor is needed which facilitates the formation of
piperidines represent an important class within this a carbocation. The piperidine ring is closed by subse-
natural product family, to which belong also a number quent reaction with a moiety containing a nucleophil-
of substituted indolizidines.[1] Since many of these ic nitrogen. An example of this is the intramolecular
compounds possess interesting pharmacological prop- Pd-catalysed amination of allyl alkyl carbonates,
erties, a number of stereoselective synthetic routes to which gives 2-vinylpiperidines.[5] To the best of our
the 2,6-disubstituted piperidine scaffold have been de- knowledge, there is no example yet of a stereoselec-
veloped.[2]
A simple and flexible access to this class of com- ed 1,2,5,6-tetrahydropyridines.
tive cationic 6-endo-trig cyclisation to 2,6-disubstitut-
pounds by the sequential combination of cross-meta-
In order to develop this synthetic method, protect-
thesis (CM) and reductive cyclisation was developed ed allylglycine esters were chosen as starting materi-
in our laboratory. CM of chiral N-carboxybenzyl als. The nature of the N-protecting group was expect-
(Cbz)-protected homoallylamines with vinyl ketones ed to be important for the success of this strategy.
gives d-N-Cbz-amino ketones, which cyclise under hy- Given the utility of the above-mentioned Pd-catalysed
drogenolytic conditions. 2,6-Disubstituted piperidines 6-exo-trig process, CM followed by analogous 6-endo-
are obtained from this process with high cis-selectivi- trig cyclisations of 1-methylallyl carbonates with vari-
ty.[3] The combination of CM and reductive domino ous N-protected glycine esters were investigated ini-
cyclisation was reported to yield 3,5-disubstituted in- tially. However, CM of 1-methylallyl carbonates was
dolizidines, e.g., the alkaloid (+)-monomorine 1.[4] In low yielding, requiring high catalyst loadings, and the
this paper, we present a new sequence of CM and ste- following cyclisations gave low diastereoselectivities.
reocontrolled cyclisation to 2,6-trans-piperidines This approach was therefore problematic. Conversely,
(Scheme 1).
the generation of allylic cations directly from crossed
Cationic cyclisation provides an alternative cyclisa- allylic alcohols was successful. Thus, CM of esters 1
tion mode to reductive procedures. In this method, a with allylic alcohol 2 gave crossed products 3 in high
Adv. Synth. Catal. 2007, 349, 157 – 160
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
157

Stefan Mix and Siegfried Blechert
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yields, using only 1.5–3 mol% of Grubbs 2 catalyst
After suitable reaction conditions and protecting
and two equivalents of the allylic alcohol cross-part- groups were identified, the scope of the reaction se-
ner 2 (Table 1). With 3a–f as substrates, suitable reac- quence of CM and cationic cyclisation was examined.
tion conditions for their cationic cyclisation were in- By varying the substituents R1 in the protected amine
vestigated. The use of 1.25 equivalents of BF3·OEt2 component and R2 in the allylic alcohols we wished to
gave the smoothest reaction within 20 min at 208C in investigate the relationship between substitution pat-
dichloromethane (0.05M) independent of the sub- tern and stereoselectivity (Table 2). Using 4 mol% of
strate involved. Other Lewis acids, such as MeAlCl2 Grubbs 2 catalyst, the CM reactions proceeded as ef-
and SnCl4 gave the same major products, but mediat- ficiently as seen with the model system. Moreover,
ed a less clean reaction. Polyphosphoric acid reacted the cationic cyclisations of the CM products to the pi-
only at elevated temperature to give complex product peridines 16–20 were much more trans-selective, bear-
mixtures.
The BF3·OEt2-mediated cationic 6-endo-trig cyclisa- model system, allthough in slightly lower yields.
tion gave trans-2,6-disubstituted 1,2,5,6-tetrahydropyr- In order to investigate if the cationic cyclisation
ing bulkier substituents than were attached to the
idines with 5:1 selectivity, when starting with the acid- proceeded free of racemisation, tetrahydropyridine
stable carbamates 3a–c. However, the tested sulfon- (+)-20 was synthesised starting with enantiopure ho-
amides 3d,e gave a much lower stereoselectivity. moallylamine derivative (S)-7.[4] Subsequent hydroge-
Using the N-nosyl-protected allylic alcohol 3e a mod- nation and hydrochloride formation gave the natural
erate excess of the cis-product was obtained. Upon
cyclisation, the N-Boc-derivative 3f gave no tetrahy-
dropyridine at all, but [1,3]oxazinan-2-one 5 instead.
Table 2. Variation of substitution pattern.
Table 1. CM-cationic cyclisation with various protective
groups.
Starting
ester
PG
CM (yield)
Cyclisation
(yield)
trans:cis
ratio
Substrates
CM (yield)[a]
Cyclisation trans:cis
(yield)[a]
ratio
1a
Troc
Cbz
Fmoc
Tos
p-Nos
Boc
3a (80%)[a]
3b (74%)[a]
3c (72%)[a]
3d (75%)[b]
3e (78%)[b]
3f (85%)[a]
4a (90%)[a]
4b (80%)[a]
4c (81%)[a]
4d (90%)[b]
4e (90%)[a]
5 (71%)[a]
5:1[c]
5:1[d]
5:1[c]
1:1[c]
1:2.5[c]
1.2:1
1b[6]
1c[7]
1d[8]
1e[9]
1f[10]
1a + 8
1a + 9
6 + 2
11 (78%)
12 (88%)
13 (90%)
14 (82%)
15 (75%)
16 (59%)
17 (66%)
18 (72%)
19 (50%)
20 (58%)
5:1[b]
trans only[b]
trans only[b]
trans only[b]
trans only
6 + 8
(S)-7[c] + 10
[a]
[a]
Isolated yield.
Isolated yields
[b]
[c]
[d]
[b]
Yield determined by 1H NMR.
Assigned by LAH reduction to the corresponding N-
methylpiperidinomethanol, on which NOE could be
seen.
Assigned by conversion to N-benzyl analogue (Ref.[11]).
Assigned by NOE analysis of derived N-methylpiperidi-
nomethanol.
[c]
Prepared according to Ref.[4]
158
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Adv. Synth. Catal. 2007, 349, 157 – 160

Diastereoselective Synthesis of 2,6-trans-Disubstituted Piperidines
product enantiomer (+)-trans-solenopsin A as the hy-
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During the following reductive cyclisation, the en-
drochloride salt 21. Spectroscopic, melting point and docyclic double bond in 25 was hydrogenated and in-
optical rotation measurements of 21 were in agree- dolizidine (À)-26 was formed in 64% yield. More-
ment with literature data.[12]
over, the trans-substituted 5-membered ring in the cy-
Apart from the protecting group dependence of clised product was formed with 2.1:1 diastereoselec-
chemo- and stereoselectivity of this new 6-endo-trig tivity. The stereochemistry was assigned using spectro-
cyclisation, it is noteworthy that the reaction proceeds scopic data from a previous racemic synthesis of all
with apparent stereoconvergence. Whereas the CM four diastereoisomers, which had been conducted to
products 3a–c were formed as E/Z,lk/ul-mixtures of ascertain which of the diastereoisomers is formed by
diastereoisomers in almost equal amounts (confirmed Solenopsis fire ants.[13]
by NMR and GC/MS), their cyclisation gave one
The observed stereoselectivity for the 5-membered
major diastereoisomer in high yield. The only explan- ring closure is usually higher starting with cis-2,6-dis-
ation for this is that both E- and Z-CM products cy- ubstituted piperidines, when the 5-membered ring
clised to the same diastereoisomer, probably after would have cis-substitution.[14] However, given how
forming allyl cations of identic configuration. Mini- difficult the diastereoselective synthesis of enantio-
mised steric interactions between R1 and the adjacent pure indolizidine diastereomers of type 26 still is, the
CH2 group in the preferred ring closure transition synthetic access presented here is simple and effi-
state could explain the observed trans-selectivity, cient.
leading to nucleophilic attack on one face of the allyl
In conclusion, 2,6-disubstituted 1,2,5,6-tetrahydro-
cation. A trans-product would be formed, if R2 was pyridines can be obtained with high trans-selectivity
exo-oriented in the reactive allyl cation configuration. by sequential CM and Lewis acid mediated stereocon-
After establishing the trans-selective synthetic se- vergent cyclisation. The method presented starts with
quence to 2,6-disubstituted piperidines, this method carbamate-protected homoallylamines and vinyl car-
was utilised for the synthesis of the indolizidine natu- binols, and tolerates ester and ketone functionalities.
ral product enantiomer (À)-26 (Scheme 2). The TBS- It is complementary to the cis-selective sequence of
protected g-ketovinyl carbinol 23 was synthesised in 5 CM and reductive cyclisation. Furthermore, the endo-
steps from g-butyrolactone and subsequently reacted cyclic double bond of the cyclisation products may be
with enantiopure Cbz-protected homoallylamine (S)-7 useful for other synthetic transformations.
in a CM reaction. This required elevated temperature
and the use of the more stable Grubbs–Hoveyda cata-
lyst. A separate deprotection of the TBS group was
unnecessary, because CM product 24 (formed as
E,Z,lk,ul-mixture) cyclised smoothly to tetrahydropyr-
idine 25 in excellent yield and with high trans-selectiv-
Experimental Section
Preparation of 6-Hydroxy-2-(2,2,2-trichloroethoxy-
carbonylamino)-hept-4-enyl Acetate (13)
ity.
In a 10-mL, round-bottom, 2-neck flask equipped with
reflux condenser and magnetic stirrer, N-Troc-allylglycinol
Scheme 2. Total synthesis of indolizidine enantiomer (À)-26.
Adv. Synth. Catal. 2007, 349, 157 – 160
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www.asc.wiley-vch.de
159

Stefan Mix and Siegfried Blechert
COMMUNICATIONS
acetate
6
(128 mg, 0.4 mmol), buten-3-ol
2
(58 mg, References
0.8 mmol) and Grubbs 2 catalyst (13.6 mg, 4 mol%) were
dissolved in CH2Cl2 (4 mL) and refluxed for 18 h under an
N2 atmosphere. After removal of solvent and volatile com-
ponents under reduced pressure, the residue was purified by
flash chromatography (SiO2, Hex:MtBE:MeOH, 5:1:0.1).
Product 13 was obtained as mixture of E/Z,lk/ul-diastereo-
isomers as a light brown oil; yield: 130 mg (0.36 mmol,
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90%); H NMR (500 MHz; CDCl3): d=1.18–1.26 (br, 3H),
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4.80 (br, 2H), 5.29–5.50 (br, 1H), 5.50–5.65 (m, 2H);
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(CH3), 34.41 (CH2), 50.34 (CH), 50.36 (CH), 65.20 (CH2),
68.25 (CH), 68.36 (CH), 74.54 (CH2), 95.62 (C), 124.41
(CH), 124.47 (CH), 138.51 (CH), 138.58 (CH), 154.29 (C),
171.03 (C); IR: n=732 (s), 818 (s), 971 (m), 1044 (s), 1100
(s), 1148 (m), 1227 (ss), 1367 (m), 1533 (s), 1717 (ss), 2968
(w), 3333 cmÀ1 (br); EI-MS (708C): m/z=364 (M+), 288
(20), 278 (35), 270 (40), 234 (100%), 218 (98), 86 (35); HR-
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a-cleavage]: 287.9961).
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Conversion to 2,2,2-Trichloroethyl trans-2-Acetoxy-
methyl-6-methyl-3,6-dihydro-2H-pyridine-1-
carboxylate (18)
In a 25-mL, round-bottom flask, cross-metathesis product 13
(105 mg, 0.301 mmol) and BF3·OEt2 (54 mg, 0.38 mmol)
were dissolved in CH2Cl2 (6 mL) and stirred for 30 min at
208C under air. The mixture was then quenched with satu-
rated aqueous NaHCO3 solution (12 mL), stirred vigorously
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phase was washed with brine and dried with Na2SO4. After
concentrating the mixture under reduced pressure, the resi-
due was purified by flash chromatography (SiO2,
Hex:MtBE, 10:1). Product 18 was obtained as a colourless
oil; yield: 72 mg (0.217 mmol, 72%, pure trans-diastereo-
[7] Prepared according to: J. Pernerstorfer, M. Schuster, S.
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[8] Prepared according to: N. J. Turner, G. M. Whitesides,
1
mer); H NMR (500 MHz; CDCl3): d=1.30–1.41 (br, 3H),
2.02 (s, 3H), 2.20–2.30 (br, 1H), 2.36–2.45 (br, 1H), 4.05–
4.14 (br, 2H), 4.18–4.45 (br, 2H), 4.69–4.85 (br, 2H), 5.74–
5.80 (br, 1H), 5.81–5.88 (m, 1H); 13C NMR (125.8 MHz;
CDCl3): d=20.93 (CH3), 22.47 (CH3), 24.80 (CH2), 48.77
(CH), 50.04 (CH), 50.57 (CH), 63.49 (CH2), 63.95 (CH2),
68.66 (CH), 75.19 (CH2), 95.50 (C), 122.31 (CH), 131.14
(CH), 154.69 (C), 170.71 (C); IR: n=715 (m), 1041 (m),
1108 (s), 1130 (m), 1227 (s), 1400 (s), 1712 (s), 1744 (s),
2956 cmÀ1 (w); EI-MS (258C): m/z=345 (M+), 272 (90), 270
(100%), 168 (15), 154 (25), 131 (20); HR-MS: m/z=
343.0150 (calcd. for C12H16O4NCl3 [M+]: 343.0145); anal.
calcd. for C12H16O4NCl3 (%): C 41.82, H 4.68, N 4.06;
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Acknowledgements
The authors thank the Fonds der Chemischen Industrie and
the Schering AG for supporting this work.
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160
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Adv. Synth. Catal. 2007, 349, 157 – 160