An efficient enantioselective approach to cyclic β-amino acid derivatives via olefin metathesis reactions

Article abstract of DOI:10.1021/jo060062t

The asymmetric synthesis of polyfunctionalized piperidine- and pyrrolidine-based scaffolds, specifically designed for the preparation of cyclic, conformationally constrained β-amino acids, is realized combining a biocatalytic access to a versatile chiral

Full text of DOI:10.1021/jo060062t

which incorporate the amino group in a heterocyclic ring. For
these reasons, some methods for the synthesis of this type of
cyclic â3-amino acids in optically active form have been
developed, the majority of which based on homologation of
R-amino acids. Arndt-Eistert homologation of (S)-proline has
been used to access homoproline4 and homopipecolic acid.5 An
elegant approach from Enders et al.6 carried out conjugate
addition of lithiated TMS-SAMP to ω-halide-substituted enoates,
leading to the synthesis of cyclic â3-AAs via Michael addition
followed by ring closure. Quite recently, advances in the
enantioselective synthesis of â-AAs have been extensively
reviewed.7
An Efficient Enantioselective Approach to Cyclic
â-Amino Acid Derivatives via Olefin Metathesis
Reactions
Giordano Lesma,* Bruno Danieli, Alessandro Sacchetti, and
Alessandra Silvani*
Dipartimento di Chimica Organica e Industriale e Centro
Interdisciplinare Studi biomolecolari e applicazioni Industriali
(CISI), UniVersita` degli Studi di Milano, Via G. Venezian 21,
20133 Milano, Italy
One possible approach to the synthesis of nitrogen hetero-
cycles involves the olefin metathesis reaction,8 widely used in
the recent past as a result of the development of highly stable
and active ruthenium alkylidenes catalysts.
alessandra.silVani@unimi.it
ReceiVed January 11, 2006
As part of our ongoing project on the asymmetric synthesis
of nitrogen compounds by metathesis reactions,9 here we report
a versatile method for the preparation of a range of function-
alized cyclic â-amino acid derivatives (1-4), based on ring-
closing metathesis (RCM) and cross metathesis (CM) reactions.
The keys to our strategy are the enzymatic asymmetrization of
dimethyl-N-Boc-3-aminoglutarate and the employment of the
resulting chiral monoacid 5 as the centerpiece of different
metathesis-based synthetic routes (Scheme 1).
In line with literature precedents,10 dimethyl-N-Boc-3-ami-
noglutarate was prepared from commercially available dimethyl
2-oxoglutarate and subsequently desymmetrized by means of
enantioselective hydrolysis with pig liver esterase. The chiral
synthon 5 could be obtained in 96% yield on multigram scale,
with >96% ee and 3S configuration11 (Scheme 2).
The asymmetric synthesis of polyfunctionalized piperidine-
and pyrrolidine-based scaffolds, specifically designed for the
preparation of cyclic, conformationally constrained â-amino
acids, is realized combining a biocatalytic access to a
versatile chiral building block with a wide range of trans-
formations based on olefin metathesis.
Preparations of the key dienes 6-8 from monoacid monoester
5 are shown in Scheme 3, pathways A, B, and C, respectively.
The syntheses began with selective reduction of the carboxylic
group of 5 with BH3‚THF to give the alcohol 9 in quantitative
yield. Subsequent oxidation to aldehyde 10 proceeded smoothly
under Swern conditions, followed by standard Wittig reaction
The â-amino acids have aroused considerable attention due
to their important biological properties in drugs and natural
products.1 They are found, for instance, in the anticancer agent
Taxol, macrocyclic peptides, and â-lactams. Furthermore, they
are useful tools in the synthesis of modified peptides and
peptidomimetics.2 Particularly, the incorporation of conforma-
tionally constrained â-amino acids (â-AAs) is a well-established
strategy to increase the stability of peptides to enzymatic
degradation and to reduce the inherent flexibility of the peptide
backbone, improving the ability to adopt stable secondary
structures in solution.3 â-Peptides are relevant in biological
studies to investigate the topology of receptors and also are
prominent candidates in the development of orally active new
drugs. In most cases, constraint in these amino acids is induced
by the presence of a small or midsized ring as a structural
feature. Thanks to their conformational stability, of particular
interest are those C3-monosubtituted â-amino acids (â3-AAs)
(4) Balaspiri, L.; Penke, B.; Papp, G.; Dombi, G.; Kovacs, K. HelV. Chim.
Acta 1975, 58, 969-973.
(5) Morley, C.; Knight, D. W.; Share, A. C. J. Chem. Soc., Perkin Trans.
1 1994, 6, 2903-2907.
(6) (a) Enders, D.; Wahl, H.; Bettray, W. Angew. Chem., Int. Ed. Engl.
1995, 34, 455-457. (b) Enders, D.; Wiedemann, J.; Bettray, W. Synlett
1995, 7, 369-371. (c) Enders, D.; Wiedemann, J. Liebigs Ann. 1998, 8,
699-706.
(7) (a) Juaristi, E.; Quintana, D.; Escalante, J. Aldrichim. Acta 1994, 27,
3. (b) Cole, D. C. Tetrahedron 1994, 50, 9517. (c) Liu, M.; Sibi, M. P.
Tetrahedron 2002, 58, 7991. (d) Gnad, F.; Reiser, O. Chem ReV. 2003,
103, 1603. (e) Ma, J.-A. Angew. Chem., Int. Ed. 2003, 42, 4290. (f) Sewald,
N. Angew. Chem., Int. Ed. 2003, 42, 5794. (g) Seebach, D.; Beck, A. K.;
Bierbaum, D. J. Chem. BiodiVers. 2004, 1, 1111-1239. (h) Juaristi, E.;
Soloshonok, V. In EnantioselectiVe Synthesis of â-Amino Acids; Wiley &
Sons: New York, 2005.
(8) Felpin, F.-X.; Lebreton, J. Eur. J. Org. Chem. 2003, 3693-3712.
(9) (a) Danieli, B.; Lesma, G.; Passarella, D.; Sacchetti, A.; Silvani, A.;
Virdis, A. Org. Lett. 2004, 6, 493-496. (b) Crippa, S.; Danieli, B.; Lesma,
G.; Passarella, D.; Sacchetti, A.; Silvani, A.; Virdis, A. Tetrahedron 2004,
60, 6437-6442. (c) Danieli, B.; Lesma, G.; Passarella, D.; Sacchetti, A.;
Silvani, A. Tetrahedron Lett. 2005, 7121-7123.
* Corresponding author. Tel: 0039 2 50314080. Fax: 0039 2 50314078.
(1) (a) Ballard, C. E.; Yu, H.; Wang, B. Curr. Med. Chem. 2002, 9,
471-498. (b) Steer, D. L.; Lew, R. A.; Perlmutter, P.; Smith, A. I.; Aguilar,
M.-I. Curr. Med. Chem. 2002, 9, 811-822.
(2) (a) Seebach, D.; Abele, S.; Gadermann, K.; Jaun, B. Angew. Chem.,
Int. Ed. 1999, 38, 1595. (b) Abele, S.; Seebach, D. Eur. J. Org. Chem.
2000, 1-15. (b) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173. (c) Porter,
E. A.; Wang, X.; Lee, H.-S.; Weisblum, B.; Gellman, S. A. Nature 2000,
404, 565. (d) Porter, E. A.; Wang, X.; Lee, H.-S.; Weisblum, B.; Gellman,
S. A. Nature 2000, 405, 298.
(10) (a) Ohno, M.; Kobayashi, S.; Iimori, T.; Wang, I.-F.; Izawa, T. J.
Am. Chem. Soc. 1981, 103, 2405-2406. (b) Kunitomo, A.; Kobayashi, S.;
Ohno, M. Chimia 1986, 40, 311-314.
(11) Kan, T.; Fujiwara, A.; Kobayashi, H.; Fukuyama, T. Tetrahedron
2002, 58, 6267-6276.
(3) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. ReV. 2001,
101, 3219-3232.
10.1021/jo060062t CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/14/2006
J. Org. Chem. 2006, 71, 3317-3320
3317

TABLE 1. Ru-Catalyzed RCM Reactions
SCHEME 1. Retrosynthetic Analysis
SCHEME 2a
a All reactions were carried out in CH2Cl2. b Isolated yield after chro-
matography.
SCHEME 4a
a Conditions: (a) (i) AcONH4, 3 Å mol. sieves, AcOH, NaCNBH3,
MeOH, 70%, (ii) Boc2O, Et3N, DMAP, CH2Cl2, 78%; (b) PLE, phosphate
buffer (0.5 M, pH 8), acetone, 96%.
a Conditions: (a) methyl vinyl ketone, 5 mol % C, CH2Cl2, rt, 75%; (b)
3 M HCl/MeOH, then H2, Pd/C, 52%.
SCHEME 3a
date, yielding 12 in overall 60% yield. Alkylation of 12 was
performed as for 11, thus providing diene 8 in 69% yield.
With the â-amino esters properly functionalized 6-8 in hand,
we next examined ring-closing metathesis (RCM) conditions
to achieve the cyclic â-amino esters 1-3, respectively, and the
results are summarized in Table 1. RCM reactions were carried
out using commercially available Grubbs’ ruthenium catalysts,
that is the less expensive first-generation benzylidenebis-
(tricyclohexylphosphine)dichlororuthenium A and the recent
second-generation benzylidene[1,3-bis(2,4,6-trimethylphenyl)-
2-imidazolidinylidene]dichloro(tricyclohexylphosphine)-
ruthenium B, in CH2Cl2 at rt or at reflux. In all cases, ring
closure proceeded smoothly with 5% mol of catalyst and yields
ranging from 45 to 92%. It is worth noting that the diene 6
cyclized equally well in the presence of A or B at rt to give the
six-membered cyclic â-amino ester 1 in high yield. However,
in the case of 7, rt and refluxing conditions with A did not work
as well, while almost quantitative yield of the cyclic product 2
was obtained with B at rt. Finally, diene 8 cyclized readily both
with A at reflux and with B at rt, thus affording the 2,5-
dihydropyrrole derivative 3,12 which was recently described as
an intermediate in the synthesis of some peptidomimetic
inhibitors of CAC1 cysteinyl proteinases.13
a Conditions: (a) 1 M BH3‚THF, THF, -78 °C, 98%; (b) Swern oxid,
93%; (c) (MePh3P)+I-, (Me3Si)2N-K+, THF, 0 °C, 85%; (d) allyl iodide,
(Me3Si)2N-K+, DMF, 0 °C, 75%; (e) (i) TFA, CH2Cl2, (ii) acryloyl chloride,
Et3N, DMAP, CH2Cl2, 79% overall; (f) (i) o-NO2Ph selenocyanate, Bu3P,
THF, 70%, (ii) NaIO4, MeOH/H2O, 0 °C, 86%; (g) allyl iodide,
(Me3Si)2N-K+, DMF, 0 °C, 69%.
with methyltriphenylphosphonium iodide affording 11 in 79%
overall yield. Alkylation of 11 worked efficiently, in the
presence of potassium bis(trimethylsilyl)amide and allyl iodide,
but the desired diene 6 needed to be separated from small
amounts of the competitive CR-alkylation product. We next
prepared diene 7 from 11 via Boc deprotection and acylation
with acryloyl chloride and TEA in CH2Cl2 (79% yield for the
two steps).
We have also briefly investigated the efficiency of a CM
methodology in order to access 2,6-cis-disubstituted piperidines
from N-protected homoallylic amine 11 (Scheme 4). This
approach relies on an highly selective cross-coupling reaction
(12) (a) Cinquin, C.; Bortolussi, M.; Bloch, R. Tetrahedron 1996, 52,
6943-6952. (b) Cinquin, C.; Bortolussi, M.; Bloch, R. Tetrahedron:
Asymmetry 1996, 7, 3327-3332.
(13) Quibell, M.; Benn, A.; Flinn, N.; Monk, T.; Ramjee, M.; Ray, P.;
Wang, Y.; Watts, J. Bioorg. Med. Chem. 2005, 13, 609-625.
From alcohol 9, conversion into the terminal olefin 12 was
achieved by a standard Grieco-Sharpless protocol. Reaction
with o-nitrophenyl selenocyanate afforded the corresponding
o-nitrophenyl selenide which was directly oxidized with perio-
3318 J. Org. Chem., Vol. 71, No. 8, 2006

3.64 (m, br, 2H), 2.65-2.48 (m, 2H), 1.90-1.71 (m, br, 1H), 1.57
(m, 1H), 1.43 (s, 9H); 13C NMR (75 MHz, CDCl3) δC 172.1, 156.6,
79.9, 66.4, 61.4, 58.7, 51.7, 44.1, 39.0, 37.4, 28.3; HRMS m/z calcd
247.1420, found 247.1423. Anal. Calcd for C11H21NO5: C, 53.43;
H, 8.56; N, 5.66; O, 32.35. Found: C, 53.68; H, 8.29; N, 5.81.
of 11 with an R,â-unsatured ketone, followed by N-deprotection
and reductive cyclization.
The CM reaction was carried out first between 11 and methyl
vinyl ketone in CH2Cl2 at rt utilizing catalysts A and B up to
10 mol %. In all cases, both coupling partners were reacted in
a 1:1 ratio, giving exclusively the E-configurated alkene 13 in
moderate yields. The efficiency of the reaction improved
considerably when the more highly active Hoveyda-Grubbs
second-generation (1,3-bis(2,4,6-trimethylphenyl)-2-imidazo-
lidinylidene)dichloro(o-isopropoxyphenylmethylene)ru-
thenium C was employed. This catalyst, which is well suited
to electron-deficient substrates, increased the yield of 13 to 75%,
when the reaction was performed at rt. Alkene 13 was stirred
in a 3 M HCl/MeOH solution for 6 h and then placed under
hydrogen for 12 h, with 10% mol Pd/C. Hydrogenation of the
intermediate iminium ion took place from the least hindered
face, and the 2S,6R-cis-substituted piperidine 4 was formed
exclusively. The cis stereochemistry was unambiguously as-
signed by comparison with NMR literature values for 4 as
chloridrate salt.14
In conclusion, a straightforward strategy involving metathesis
reactions starting from a common chiral intermediate has been
successfully developed. Application of this protocol permits the
asymmetric synthesis of heterocyclic â-amino acids derivatives
1-4, which are suitably protected for solid-phase application.
Additionally, the double bond in 1-3 provides a useful chemical
handle for alternative functionalization chemistries. We are
currently examining further variations of this methodology, as
well as applications to the synthesis of other heterocyclic
systems.
3S-tert-Butoxycarbonylamino-5-oxopentanoic Acid Methyl
Ester 10. To a stirred solution of 2 equiv of oxalyl chloride in 12
mL of anhydrous CH2Cl2 under nitrogen at -78 °C was added 3
equiv of anhydrous DMSO in 4 mL of anhydrous CH2Cl2 dropwise
and the mixture allowed to react for 5 min -78 °C. The alcohol 9
(1 g, 4.0 mmol) in 4 mL of anhydrous CH2Cl2 was added, and the
reaction mixture was stirred for 1 h at -78 °C. On addition of 4
equiv of anhydrous Et3N, the reaction temperature was allowed to
go to rt. The reaction was diluted with 20 mL of CH2Cl2 and then
poured into 50 mL of CH2Cl2/20 mL of 10% aq NH4OH solution.
The aqueous phase was extracted twice with CH2Cl2, and the
combined CH2Cl2 fractions were dried and evaporated. Flash
chromatography of the residue on silica gel (ethyl acetate/hexane
1:1) yielded 911 mg (93%) of 10 as a colorless oil: [R]25D -3.3 (c
1, CHCl3); 1H NMR (300 MHz, CDCl3) δH 9.70 (s, 1H), 5.24 (m,
br, 1H), 4.35 (m, 1H), 3.65 (s, 3H), 2.75 (m, 2H), 2.63 (m, 2H),
1.39 (s, 9H); HRMS m/z calcd 245.1263, found 245.1259. Anal.
Calcd for C11H19NO5: C, 53.87; H, 7.81; N, 5.71; O, 32.61.
Found: C, 53.69; H, 7.99; N, 5.76.
3S-tert-Butoxycarbonylaminohex-5-enoic Acid Methyl Ester
11. To a stirred suspension of [(Me(Ph)3P]+I- (3.4 g, 8.4 mmol) in
dry THF (40 mL) under nitrogen at 0 °C was added dropwise a
solution of potassium bis(trimethylsilyl)amide (0.5 M in toluene,
16.8 mL, 8.4 mmol). The mixture was stirred for 10 min at 0 °C
and then for 20 min at rt. Then the reaction temperature was lowered
to -78 °C, and a solution of 10 (1.5 g, 6.3 mmol) in THF dry (10
mL) was added. The reaction was stirred for 3 h at rt, then a
saturated NH4Cl aqueous solution was added, and the aqueous phase
was extracted with CH2Cl2. The combined organic layers were dried
over Na2SO4, and the solvent was removed under reduced pressure.
Flash chromatography of the residue on silica gel (ethyl acetate/
Experimental Section
hexane 1:4) yielded 1.3 g (85%) of 11 as a colorless oil: [R]25
3S-tert-Butoxycarbonylaminopentanedioic Acid Monomethyl
Ester 5. To a mixture of 3-tert-butoxycarbonylaminopentanedioic
acid dimethyl ester (1 g, 3.6 mmol) in phosphate buffer (0.5 M,
pH 8) (100 mL) and acetone (4 mL) was added pig liver esterase
(PLE, 1200 units). The mixture was stirred at 25 °C for 4 h. The
pH of the mixture was checked periodically, and 0.1 M NaOH was
added by drops, if required, to maintain the pH at 8.0. The resultant
solution was acidified to pH 2.0 by the addition of concd aq HCl
and extracted with CH2Cl2. The combined organic layers were
washed with saturated aq NaCl solution and dried over Na2SO4.
Removal of the solvent under reduced pressure yielded 902 mg
D
-4.7 (c 1, CHCl3); 1H NMR (400 MHz, CDCl3) δH 5.77 (ddt, J )
17.5, 9.6, 7.1 Hz, 1H), 5.11 (m, 2H), 4.97 (m, br, 1H), 2.65 (m, br,
1H), 3.70 (s, 3H), 2.55 (d, J ) 5.6 Hz, 2H), 2.32 (m, 2H), 1.45 (s,
9H); HRMS m/z calcd 243.1471, found 243.1474. Anal. Calcd for
C12H21NO4: C, 59.24; H, 8.70; N, 5.76; O, 26.30. Found: C, 59.36;
H, 8.55; N, 5.90.
3R-tert-Butoxycarbonylaminopent-4-enoic Acid Methyl Ester
12. To a stirred solution of 9 (500 mg, 2.0 mmol) and o-
nitrophenylselenocyanate (685 mg, 3.0 mmol) in THF (15 mL) was
added tributylphosphine (770 µL, 3.0 mmol) under nitrogen at rt.
After 2 h, the solvent was removed under reduced pressure. Flash
chromatography of the residue on silica gel (ethyl acetate/hexane
1:2) yielded 600 mg (70%) of o-nitrophenylselenide derivative. To
a stirred solution of o-nitrophenylselenide derivative (600 mg, 1.4
mmol) in MeOH (20 mL) was added NaIO4 aq solution (0.2 M, 10
mL, 2.0 mmol) dropwise at 0 °C. After 1 h, ether was added and
the mixture washed with saturated NaHCO3 aq solution, water, and
(96%) of pure 5, as a colorless oil: [R]25 -1.50 (c 1, CHCl3)
D
[lit.11 [R]25D -1.36 (c 0.75, CHCl3)]; 1H NMR (300 MHz, CDCl3)
δH 10.98 (s, br, 1H), 5.40 (m, br, 1H), 4.27 (m, br, 1H), 3.66 (s,
3H), 2.65 (m, 4H), 1.40 (s, 9H); 13C NMR (75 MHz, CDCl3) δC
176.1, 171.8, 155.2, 79.9, 51.8, 44.1, 37.9, 28.3; HRMS m/z calcd
261.1212, found 261.1208. Anal. Calcd for C11H19NO6: C, 50.57;
H, 7.33; N, 5.36; O, 36.74. Found: C, 50.69; H, 7.51; N, 5.11.
3S-tert-Butoxycarbonylamino-5-hydroxypentanoic Acid Meth-
yl Ester 9. To a solution of 5 (1.6 g, 6.1 mmol) in dry THF (20
mL) under nitrogen at -78 °C, a solution of borane THF complex
(1M in THF, 9.2 mL, 9.2 mmol) was added dropwise. The mixture
was stirred for 4 h at 0 °C, then a saturated NH4Cl aqueous solution
was added, and the aqueous phase was extracted with CH2Cl2. The
combined organic layers were dried over Na2SO4, and the solvent
was removed under reduced pressure. Flash chromatography of the
brine and dried over Na
2SO4. After removal of the solvent under
reduced pressure, the residue was purified by filtration on silica
25
gel (CH
-23.5 (c 1, CHCl
2Cl2) yielding 276 mg (86%) of 12, as a colorless oil: [R]
D
1
3); H NMR (300 MHz, CDCl3) δH 5.81 (ddd, J
) 16.6, 11.7, 5.9 Hz, 1H), 5.18 (d, J ) 16.6 Hz, 1H), 5.15 (d, br,
1H), 5.10 (d, J ) 11.7 Hz, 1H), 4.48 (m, br, 1H), 3.65 (s, 3H),
2.59 (d, J ) 5.9 Hz, 2H), 1.45 (s, 9H); HRMS m/z calcd 229.1314,
found 229.1318. Anal. Calcd for C
11H19NO4: C, 57.62; H, 8.35;
residue on silica gel (ethyl acetate/hexane 3:1) yielded 1.5 g (98%)
N, 6.11; O, 27.92. Found: C, 57.97; H, 8.29; N, 6.88.
1
of 9 as a colorless oil: [R]25 -23.9 (c 1, CHCl3); H NMR (400
D
3S-(Allyl-tert-butoxycarbonylamino)hex-5-enoic Acid Methyl
Ester 6. To a stirred solution of 11 (650 mg, 2.7 mmol) in dry
DMF (15 mL) under nitrogen at -20 °C was added dropwise a
solution of potassium bis(trimethylsilyl)amide (0.5 M in toluene,
5.9 mL, 2.9 mmol). After 10 min, allyl iodide (498 µL, 5.4 mmol)
MHz, CDCl3) δH 5.38 (m, br, 1H), 4.12 (m, br, 2H), 3.69 (s, 3H),
(14) Munchhof, M. J.; Meyers, A. I. J. Am. Chem. Soc. 1995, 117, 5399-
5400.
J. Org. Chem, Vol. 71, No. 8, 2006 3319

was quickly added and the resulting solution stirred for further 2 h
at 0 °C. It was then poured into a 5% H3PO4 aq solution which
was extracted with CH2Cl2. The combined organic layers were dried
over Na2SO4, and the solvent was removed under reduced pressure.
Flash chromatography of the residue on silica gel (ethyl acetate/
44.7, 40.4 and 39.0, 36.6, 28.8, 28.3; HRMS m/z calcd 255.1471,
found 255.1465. Anal. Calcd for C13H21NO4: C, 61.16; H, 8.29;
N, 5.49; O, 25.06. Found: C, 61.01; H, 8.61; N, 5.44.
2S-(6-Oxo-1,2,3,6-tetrahydropyridin-2-yl)acetic Acid Methyl
Ester 2. To a solution of 7 (400 mg, 2.0 mmol) in CH2Cl2 (35
mL) was added Ru-catalyst B (Grubbs second generation) (5% mol)
under nitrogen, and the solution was stirred for 4 h. The solvent
was then evaporated and the residue purified by flash chromatog-
hexane 1:6) yielded 573 mg (75%) of 6, as a colorless oil: [R]25
D
1
+28.4 (c 1, CHCl3); H NMR (300 MHz, CDCl3, 323 K) δH 5.80
(ddt, J ) 17.1, 9.6, 5.3 Hz, 1H), 5.72 (ddt, J ) 17.6, 9.6, 6.6 Hz,
1H), 5.17-4.98 (m, 4H), 4.16 (m, br, 1H), 3.85-3.67 (m, 2H),
3.62 (s, 3H), 2.69 (dd, J ) 14.9, 7.9 Hz, 2H), 2.52 (dd, J ) 14.9,
6.2 Hz, 2H), 2.43 (m, 1H), 2.34 (m, 1H), 1.44 (s, 9H); HRMS m/z
calcd 283.1784, found 283.1788. Anal. Calcd for C15H25NO4: C,
63.58; H, 8.89; N, 4.94; O, 22.58. Found: C, 63.24; H, 8.79; N,
5.03.
raphy on silica gel (ethyl acetate) yielding 311 mg (92%) of 2, as
1
a colorless oil: [R]25 +21.7 (c 1, CHCl3); H NMR (400 MHz,
D
CDCl3) δH 6.59 (dt, J ) 9.9, 4.1 Hz, 1H), 6.29 (s, 1H), 5.93 (d, br,
J ) 9.9 Hz, 1H), 4.03 (m, 1H), 3.72 (s, 3H), 2.67 (dd, J ) 16.3,
8.7 Hz, 1H), 2.58 (m, 2H), 2.23 (m, 1H); 13C NMR (100 MHz,
CDCl3) δC 171.8, 166.4, 140.2, 125.4, 54.1, 48.1, 40.3, 29.8; HRMS
m/z calcd 169.0739, found 169.0743. Anal. Calcd for C8H11NO3:
C, 56.80; H, 6.55; N, 8.28; O, 28.37. Found: C, 56.55; H, 6.71; N,
8.31.
3S-Acryloylaminohex-5-enoic Acid Methyl Ester 7. A solution
of 11 (394 mg, 1.6 mmol) in CH2Cl2/TFA (2:1) (5 mL) was stirred
at 0 °C for 30 min, poured into a saturated NaHCO3 aq solution,
and extracted with CH2Cl2. The combined organic layers were dried
over Na2SO4, and the solvent was removed under reduced pressure.
To a stirred solution of the crude amine in dry CH2Cl2 (5 mL),
TEA (386 µL, 2.8 mmol), DMAP (20 mg, 0.16 mmol), and acryloyl
chloride (133 µL, 1.6 mmol) were added under nitrogen at 0 °C.
After the mixture was stirred for 12 h at rt, the resulting solution
was diluted with CH2Cl2, washed with aq 1 M HCl, saturated
NaHCO3 aq solution, water, and brine, and dried over Na2SO4. After
removal of the solvent under reduced pressure, the residue was
purified by flash chromatography on silica gel (ethyl acetate/hexane
2:3) yielding 250 mg (79%) of 7, as a colorless oil: [R]25D -7.2 (c
1, CHCl3); 1H NMR (300 MHz, CDCl3) δH 6.32 (d, br, J ) 6.8 Hz
1H), 6.23 (dd, J ) 16.6, 1.9, 1H), 6.06 (dd, J ) 16.6, 9.8, 1H),
5.72 (ddt, J ) 16.6, 9.8, 6.8 Hz, 1H), 5.60 (dd, J ) 9.8, 1.9, 1H),
5.06 (d, br J ) 11.7 Hz, 2H), 4.42-4.29 (m, 1H), 3.65 (s, 3H),
2.56 (d, J ) 4.9 Hz, 2H), 2.43-2.25 (m, 2H); 13C NMR (75 MHz,
CDCl3) δC 172.8, 165.5, 134.5, 131.5, 127.1, 118.9, 52.3, 46.3,
38.9, 37.9; HRMS m/z calcd 197.1052, found 197.1055. Anal. Calcd
for C10H15NO3: C, 60.90; H, 7.67; N, 7.10; O, 24.34. Found: C,
61.01; H, 7.51; N, 7.24.
2R-Methoxycarbonylmethyl-2,5-dihydropyrrole-1- carboxylic
Acid tert-Butyl Ester 3. To a solution of 8 (208 mg, 0.8 mmol) in
CH2Cl2 (15 mL) was added Ru-catalyst B (Grubbs second genera-
tion) (5% mol) under nitrogen, and the solution was stirred for 4
h. The solvent was then evaporated and the residue purified by
flash chromatography on silica gel (ethyl acetate) yielding 172 mg
(89%) of 3, as a colorless oil: [R]25 -203.0 (c 1, CHCl3) [lit.12a
D
[R]25 -189 (c 1, CHCl3)]; H NMR (300 MHz, CDCl3) δH 5.82
1
D
(m, br, 2H), 4.79 (m, br, 1H), 4.14 (m, br, 1H), 4.02 (dd, J ) 15.5,
5.4 Hz, 1H), 3.68 (s, 3H), 3.00 (m, br, 1H), 2.45 (m, br, 1H), 1.47
(s, 9H); 13C NMR (75 MHz, CDCl3) (two distinct conformers) δC
171.5, 153.8, 129.3, 125.7, 79.9 and 79.4, 60.8 and 60.5, 53.4 and
51.3, 51.2, 39.2 and 38.2, 28.1; HRMS m/z calcd 241.1314, found
241.1311. Anal. Calcd for C12H19NO4: C, 59.73; H, 7.94; N, 5.81;
O, 26.52. Found: C, 59.91; H, 8.19; N, 5.77.
3S-tert-Butoxycarbonylamino-7-oxooct-5-enoic Acid Methyl
Ester 13. To a solution of 11 (200 mg, 0.8 mmol) and methyl vinyl
ketone (67 µL, 0.8 mmol) in CH2Cl2 (0.05 M, 16 mL) was added
Ru-catalyst C (Hoveyda-Grubbs second Generation) (5% mol)
under nitrogen, and the solution was stirred for 12 h. The solvent
was then evaporated and the residue purified by flash chromatog-
raphy on silica gel (ethyl acetate/hexane 2:3) yielding 195 mg (75%)
of 13, as a colorless oil: [R]25D +9.2 (c 1, CHCl3); 1H NMR (400
MHz, CDCl3) δH 6.71 (dt, J ) 16.6, 6.8 Hz, 1H), 6.06 (d, J )
16.6 Hz, 1H), 5.10 (d, J ) 7.8 Hz, 1H), 4.08 (m, 1H), 3.66 (s,
3H), 2.53 (t, br, J ) 4.8 Hz, 2H), 2.45 (t, br, J ) 6.8 Hz, 2H), 2.21
(s, 3H), 1.39 (s, 9H); 13C NMR (100 MHz, CDCl3) δC 198.9, 172.3,
155.8, 144.0, 134.4, 80.4, 52.5, 47.4, 39.1, 38.4, 29.0, 27.5; HRMS
m/z calcd 285.1576, found 285.1570. Anal. Calcd for C14H23NO5:
C, 58.93; H, 8.12; N, 4.91; O, 28.04. Found: C, 58.61; H, 8.44; N,
5.08.
3R-(Allyl-tert-butoxycarbonylamino)pent-4-enoic Acid Methyl
Ester 8. To a stirred solution of 12 (200 mg, 0.9 mmol) in DMF
dry (5 mL) under nitrogen at -20 °C was added dropwise a solution
of potassium bis(trimethylsilyl)amide (0.5 M in toluene, 2.0 mL,
1.0 mmol). After 10 min, allyl iodide (166 µL, 1.8 mmol) was
quickly added and the resulting solution stirred for further 2 h at 0
°C. It was then poured into a 5% H3PO4 aq solution, which was
extracted with CH2Cl2. The combined organic layers were dried
over Na2SO4, and the solvent was removed under reduced pressure.
Flash chromatography of the residue on silica gel (ethyl acetate/
hexane 1:6) yielded 167 mg (69%) of 6, as a colorless oil: [R]25
D
1
+42.0 (c 1, CHCl3); H NMR (400 MHz, CDCl3) δH 5.94-5.71
(m, 2H), 5.14 (m, 2H), 5.08 (m, 2H), 4.75 (m, br, 1H), 3.87 (m,
br, 1H), 3.72 (m, 1H), 3.68 (s, 3H), 2.79 (dd, J ) 15.2, 7.6, 1H),
2.69 (dd, J ) 15.2, 7.2 Hz, 1H), 1.48 (s, 9H); 13C NMR (100 MHz,
CDCl3) δC 172.0, 155.6, 137.2, 135.9, 116.7, 80.6, 56.5, 52.1, 49.0,
38.3, 29.0; HRMS m/z calcd 269.1627, found 269.1630. Anal. Calcd
for C14H23NO4: C, 62.43; H, 8.61; N, 5.20; O, 23.76. Found: C,
62.28; H, 8.49; N, 5.31.
(2S,6R)-(6-Methyl-piperidin-2-yl)acetic Acid Methyl Ester 4.
Compound 13 (190 mg, 0.6 mmol) was dissolved in a 3 N HCl
methanolic solution (5 mL) and stirred for 6 h at rt, then Pd/C
10% (20 mg) was added, and the mixture was further stirred under
H2 atmosphere for 12 h. The catalyst was filtered, the solvent was
evaporated to yield 65 mg (52%) of pure 4, as hydrochloride salt:
[R]25D +13.8 (c 1, MeOH) [lit.14 [R]25D +14.5 (c 0.8, MeOH)]; 1H
NMR (300 MHz, MeOH) δH 3.70 (s, 3H), 3.65-3.56 (m, 2H),
3.15-3.11 (m, 1H), 2.92-2.88 (m, 1H), 2.00-1.70 (m, 6H), 1.55
(d, J ) 6.3 Hz, 3H); 13C NMR (75.4 Hz, MeOH) δC 170.5, 54.2,
54.0, 52.3, 37.5, 31.0, 28.3, 22.6, 19.3; HRMS m/z calcd 171.1259,
found 171.1263. Anal. Calcd for C9H17NO2: C, 63.13; H, 10.01;
N, 8.18; O, 18.69. Found: C, 63.55; H, 8.58; N, 18.21.
2S-Methoxycarbonylmethyl-3,6-dihydro-2H-pyridine-1-car-
boxylic Acid tert-Butyl Ester 1. To a solution of 6 (510 mg, 1.8
mmol) in CH2Cl2 (30 mL) was added Ru-catalyst B (Grubbs
secondnd generation) (5% mol) under nitrogen, and the solution
was stirred for 2 h. The solvent was then evaporated and the residue
purified by flash chromatography on silica gel (ethyl acetate/hexane
1:8) yielding 390 mg (85%) of 1, as a colorless oil: [R]25D +28.4
1
(c 1, CHCl3); H NMR (400 MHz, CDCl3) δH 5.70 (m, br, 2H),
Supporting Information Available: 1H and 13C NMR spectra
of compounds 1-3 and 5-13. This material is available free of
charge via the Internet at http://pubs.acs.org.
4.71 (m, br, 1H), 4.21 (d, br, J ) 18.6 Hz, 1H), 3.67 (s, 3H), 3.58
(d, br, J ) 18.6 Hz, 1H), 2.59-2.41 (m, 3H), 1.90 (d, br J ) 17.1
Hz, 1H), 1.48 (s, 9H); 13C NMR (75 MHz, CDCl3) (two distinct
conformers) δC 171.8, 154.6, 123.5, 121.1, 79.8, 51.9, 46.0 and
JO060062T
3320 J. Org. Chem., Vol. 71, No. 8, 2006