A new general approach for the stereocontrolled synthesis of functionalised γ- And δ-lactams

Article abstract of DOI:10.1039/c1ob05833a

A new flexible approach for the stereoselective synthesis of substituted 1H-pyrrol-2(5H)-ones and 3,6-dihydro-1H-pyridin-2-ones has been developed. The general strategy employed the stereoselective reduction of a series of α,β-unsaturated ketones under ch

Full text of DOI:10.1039/c1ob05833a

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PAPER
A new general approach for the stereocontrolled synthesis of functionalised
c- and d-lactams†
Mark Daly,a Kathryn Gill,a Mairi Sime,b Graham L. Simpsonc and Andrew Sutherland*a
Received 26th May 2011, Accepted 28th June 2011
DOI: 10.1039/c1ob05833a
A new flexible approach for the stereoselective synthesis of substituted 1H-pyrrol-2(5H)-ones and
3,6-dihydro-1H-pyridin-2-ones has been developed. The general strategy employed the stereoselective
reduction of a series of a,b-unsaturated ketones under chelation control to give the corresponding
allylic alcohols. Overman rearrangement to install the key C–N bond followed by conversion to either
prop-2-enoyl or but-3-enoyl derivatives and a ring closing metathesis reaction gave the target
unsaturated g- and d-lactams. The synthetic utility of these compounds as building blocks was
demonstrated by the preparation of the N-Boc derivative of (-)-coniine.
allylic substitution with the pronucleophile N-Boc-N-(but-2-
Introduction
enoyl)amine followed by ring closing metathesis (RCM).2l Several
efficient methods3 have also been described for the stereoselec-
tive synthesis of 3,6-dihydro-1H-pyridin-2-ones 2 such as the
palladium-catalysed decarboxylative carbonylation of 3-tosyl-5-
vinyloxazolidin-2-ones described by Knight and co-workers.3b
While many methods have been described for the preparation
of either class of heterocycle, only one approach reported by
Spino and co-workers involving the 3,3-sigmatropic rearrange-
ment of azides or cyanates derived from menthyl substituted
allylic alcohols followed by RCM allows the general stereoselective
synthesis of both 1H-pyrrol-2(5H)-ones and 3,6-dihydro-1H-
pyridin-2-ones.2g,2k,3g As part of a programme to identify new
biologically active lactams,3e,4 we were interested in developing
a new approach for the stereoselective synthesis of substituted
1H-pyrrol-2(5H)-ones and 3,6-dihydro-1H-pyridin-2-ones. In this
paper, we now report a general stereoselective synthesis of allylic
secondary alcohols that can be transformed using an Overman
rearrangement and a RCM reaction as the key steps to either 1H-
pyrrol-2(5H)-ones and 3,6-dihydro-1H-pyridin-2-ones. We also
describe the application of this approach for the synthesis of the
Boc-derivative of (-)-coniine 3.
Five and six-ring N-heterocycles are an important class of com-
pounds that are widely used throughout academia and industry.
A significant number of pharmaceuticals and agrochemicals as
well as plastics, additives and modifiers contain a N-heterocyclic
motif. Due to their importance, there have been substantial
efforts in designing and developing highly efficient approaches
for their synthesis.1 In particular, much research has focused
on the stereoselective synthesis of functionalised, unsaturated
g- and d-lactams as key building blocks for the preparation of
medicinally important compounds and natural products.2,3 For
example, 1H-pyrrol-2(5H)-ones 1 have been used in a range of
reactions2 such as conjugate additions, oxidations and pericyclic
processes for the stereoselective synthesis of natural products
including (-)-domoic acid,2a the cytochalasans,2b (+)-pramanicin2e
and the oroidin alkaloids2f as well as for the preparation of
pharmacologically active agents (S)-vigabatrin2j and analogues
of baclofen.2l In a similar fashion, 3,6-dihydro-1H-pyridin-2-ones
such as 2 have been further functionalised for the preparation
of quinolizinones3d and used to prepare the piperidine alkaloids
(+)-a-conhydrine3e and (+)-pumiliotoxin C.3g
A number of elegant approaches have been reported for
the stereoselective preparation of 1H-pyrrol-2(5H)-ones 1.2 For
example, Gallagher and co-workers used the reaction of chiral
cyclic sulfamidates with sulfur-stabilised enolates,2i while the
research group of Helmchen used an asymmetric iridium-catalysed
Results and discussion
aWestCHEM, School of Chemistry, The Joseph Black Building, Univer-
sity of Glasgow, Glasgow, UK, G12 8QQ. E-mail: Andrew.Sutherland@
glasgow.ac.uk; Fax: +44 (0)141 330 4888; Tel: +44 (0)141 330 5936
Our synthesis of 1H-pyrrol-2(5H)-ones and 3,6-dihydro-1H-
pyridin-2-ones is outlined in Scheme 1. It was proposed that
the key substrates, chiral allylic secondary alcohols 6 could be
prepared from commercially available methyl (2S)-2-hydroxy-
3-phenylpropionate (7)5 by conversion to the corresponding
a,b-unsaturated ketone followed by a stereoselective reduction
bGlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, UK,
CM19 5AW
cGlaxoSmithKline, Gunnels Wood Road, Stevenage, UK, SG1 2NY
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra for all new compounds. See DOI: 10.1039/c1ob05833a
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Scheme
1 Proposed route to 1H-pyrrol-2(5H)-ones and 3,6-dihy-
dro-1H-pyridin-2-ones.
(Scheme 1). Overman rearrangement and conversion to the
prop-2-enoyl or but-3-enoyl derivatives 5 would then allow
the use of a RCM reaction to form either 1H-pyrrol-2(5H)-
ones or 3,6-dihydro-1H-pyridin-2-ones. The synthetic route was
designed for the flexible preparation of different analogues
and ring sizes. Thus, various R groups could be incorporated
into the allylic alcohols 6 and by using enoyls of different
length, the late stage synthesis of different ring sizes could be
accomplished.
The first stage of this programme focused on the development
of a general synthesis of allylic secondary alcohols 6. Methyl (2S)-
2-hydroxy-3-phenylpropionate (7) was protected as the MOM-
ether in 89% yield using bromomethyl methyl ether and Hu¨nig’s
base (Scheme 2). Reaction of 8 with the anion of dimethyl
methylphosphonate gave phosphonate ester 9 in 90% yield. Using
standard conditions,6 the Horner–Wadsworth–Emmons reaction
of 9 with a series of aldehydes gave the corresponding E-a,b-
unsaturated ketones 10–12 in 62–92% yield. Stereoselective reduc-
tion of a,b-unsaturated ketones 10–12 was achieved using zinc
borohydride prepared by modification of Gensler’s procedure.7,8
This gave anti-allylic alcohols 14–16 via the 5-membered zinc-
chelate 139,10 in excellent yields and with high diastereoselectivity.
The diastereomers could be separated by column chromatography,
however, it was found easier to do this using the enoyl derivatives
at a later stage of the synthetic route. It should be noted that
initial studies on developing a route to these types of allylic
alcohols was attempted using ethyl (S)-lactate as the starting
material. Reduction of the resulting a,b-unsaturated ketones
with zinc borohydride gave the corresponding allylic alcohols
with low anti : syn selectivity (3 : 1) and thus, the benzyl side
chain of ketones 10–12 derived from 7 is necessary for a highly
stereoselective reduction. With allylic alcohols 14–16 in hand,
these were converted to allylic trichloroacetamides 17–19 using
the Overman rearrangement.11 Reaction of 14–16 with DBU
and trichloroacetonitrile followed by a thermal rearrangement
of the resulting allylic trichloroacetimidates in the presence of
potassium carbonate12 gave compounds 17–19 in 48–84% yields
over the two steps. As expected, the 3,3-sigmatropic rearrangement
proceeded with complete retention of stereochemistry giving the
allyic trichloroacetamides with the same ratio of diastereomers as
observed for allylic alcohols 14–16.13
Scheme 2 Reagents and conditions: i. MOMBr, EtN(iPr)2, CH2Cl2, 40 ◦C,
89%; ii. (MeO)2P(O)Me, nBuLi, THF, -78 ◦C to rt, 90%; iii. RCHO,
K2CO3, MeCN, 75 ◦C; iv. ZnCl2, NaBH4, THF, -78 ◦C; v. Cl3CCN, DBU,
CH2Cl2; vi. D, K2CO3, p-xylene.
Allylic trichloroacetamides 17–19 were then hydrolysed un-
der standard conditions using sodium hydroxide (Scheme 3).
The resulting amines were then either coupled with acryloyl
chloride in the presence of triethylamine to give prop-2-enoyl
derivatives 20–22 or with 3-butenoic acid and EDCI to give
but-3-enoyl derivatives 26–28. At this stage of the synthetic
route, separation of the anti/syn mixture of diastereomers was
readily achieved by column chromatography to give the enoyl
derivatives as single stereoisomers in modest yields over the two
steps.
Following literature precedent for the RCM reaction of sterically
crowded alkenes,2k Grubbs 2nd generation catalyst was used for
the final step. Treatment of prop-2-enoyls 20–22 with 4–5 mol% of
Grubbs 2nd generation catalyst gave 1H-pyrrol-2(5H)-ones 23–
25 in high yields (82–85%). In a similar manner, but-2-enoyls 26–
28 were converted to the corresponding 3,6-dihydro-1H-pyridin-
2-ones 29–31 in 56–89% yields.14 To probe the enantiopurity
of the target compounds, (5R)-5-phenethyl-1H-pyrrol-2(5H)-one
(23) was used as an example and analysed using chiral HPLC.
The enantiopurity was found to be 93% ee.15 The commercially
available methyl (2S)-2-hydroxy-3-phenylpropionate 7 used in
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Scheme 4 Reagents and conditions: i. H2, 10% Pd/C, EtOAc, 100%; ii.
LiAlH4, Et2O, 30 ◦C; iii. Boc2O, Et3N, DMAP, Et2O, 48% over two steps.
pyridin-2-ones has been developed. This involved the use of a
(S)-phenyllactate derivative as a chiral auxiliary that was used in a
chelation controlled stereoselective reduction. The resulting allylic
secondary alcohols were subjected to the key steps of an Overman
rearrangement and a RCM reaction to give the target unsaturated
g- and d-lactams. In this study, we focused on a limited number
of side-chain motifs and the synthesis of specifically 5- and 6-
membered rings. However, we believe this approach can be easily
expanded for the stereoselective preparation of functionalised
unsaturated lactams with a wide range of side-chains and with
various ring sizes. Access to the opposite enantiomers should
also be possible using methyl (2R)-2-hydroxy-3-phenylpropionate
as the starting material, easily prepared in two steps from D-
phenylalanine.5 Work to expand this scope of this process is
currently under way.
Scheme 3 Reagents and conditions: i. 1.0 M NaOH, MeOH, 70 ◦C;
ii. H2C CHCOCl, Et3N, Et2O, -78 ◦C to rt; iii. H2C CHCH2CO2H,
EDCI, DMAP, CH2Cl2, 0 ◦C to rt; iv. Grubbs’ 2nd generation catalyst
(4–5 mol%), CH2Cl2, 40 ◦C.
Experimental
All reagents and starting materials were obtained from commercial
sources and used as received. All dry solvents were purified using
a PureSolv 500 MD solvent purification system. All reactions
were performed under an atmosphere of argon unless otherwise
mentioned. Brine refers to a saturated solution of sodium chloride.
Flash column chromatography was carried out using Fisher matrix
silica 60. Macherey–Nagel aluminium-backed plates pre-coated
with silica gel 60 (UV254) were used for thin layer chromatography
and were visualised by staining with potassium permanganate. 1H
NMR and 13C NMR spectra were recorded on a Bruker DPX
400 spectrometer with chemical shift values in ppm relative to
tetramethylsilane as the standard. Assignment of 1H and 13C
NMR signals are based on two-dimensional COSY and DEPT
experiments, respectively. Infrared spectra were recorded using
Golden Gate apparatus on a JASCO FTIR 410 spectrometer and
mass spectra were obtained using a JEOL JMS-700 spectrometer.
Melting points were determined on a Reichert platform melting
point apparatus. Optical rotations were determined as solutions
irradiating with the sodium D line (l = 589 nm) using an Autopol
V polarimeter. [a]D values are given in units 10-1 deg cm2 g-1. The
chiral HPLC methods were calibrated with their corresponding
racemic mixtures.
this study is known to have an enantiopurity of 98% and
so this approach to optically active 1H-pyrrol-2(5H)-ones and
3,6-dihydro-1H-pyridin-2-ones generates products with excellent
retention of stereochemical integrity.
As highlighted above, 1H-pyrrol-2(5H)-ones and 3,6-dihydro-
1H-pyridin-2-ones are key synthetic intermediates for the prepa-
ration of a wide-range of medicinally important compounds
and natural products.2,3 To demonstrate the utility of this ap-
proach for the stereoselective synthesis of functionalised N-
heterocyclic compounds, (6R)-6-propyl-3,6-dihydro-1H-pyridin-
2-one (31) was used to prepared the N-Boc derivative of (-)-
coniine (Scheme 4). Hydrogenation of 31 with 10% palladium on
carbon gave the saturated piperidin-2-one 32 in quantitative yield.
Reduction of 32 with lithium aluminium hydride gave (-)-coniine.
As the free base of coniine is known to be toxic and volatile,16 the
product was isolated as the Boc-derivative 33, by treatment with
di-tert-butyl dicarbonate under standard conditions. This gave 33
in 48% yield over the two steps.
Methyl (2S)-2-methoxymethoxy-3-phenylpropionate (8)17
Conclusions
In summary, a general stereoselective approach for the flexible
synthesis of either 1H-pyrrol-2(5H)-ones or 3,6-dihydro-1H-
To a solution of methyl (2S)-2-hydroxy-3-phenylpropionate (7)
(4.69 g, 26.0 mmol) stirring at 0 ◦C in dichloromethane (250 mL)
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was added diisopropylethylamine (9.07 mL, 52 mmol) followed
by bromomethyl methyl ether (4.24 mL, 52.0 mmol). The reaction
was heated to 40 C for 18 h then cooled to room temperature.
separated then washed with water (2 ¥ 25 mL), dried (MgSO4),
filtered and concentrated under reduced pressure. Flash column
chromatography (petroleum ether/diethyl ether 1 : 0 to 8 : 2)
afforded (3E,6S)-1,7-diphenyl-6-methoxymethoxyhept-3-en-5-
one (10) (0.10 g, 92%) as a pale yellow oil. nmax/cm-1 (neat) 3028,
2929 (CH), 1693 (CO), 1496, 1454, 1148, 1051; [a]2D3 -36.3 (c 1.1,
CHCl3); dH (400 MHz, CDCl3) 2.55 (2H, q, J 7.4 Hz, 2-H2), 2.78
(2H, t, J 7.4 Hz, 1-H2), 2.85 (1H, dd, J 13.8, 9.1 Hz, 7-HH), 2.95
(1H, dd, J 13.8, 4.2 Hz, 7-HH), 3.03 (3H, s, OCH3), 4.35 (1H,
dd, J 9.1, 4.2 Hz, 6-H), 4.44 (1H, d, J 6.9 Hz, OCHHO), 4.49
(1H, d, J 6.9 Hz, OCHHO), 6.49 (1H, d, J 15.8 Hz, 4-H), 7.01
(1H, dt, J 15.8, 7.4 Hz, 3-H), 7.14–7.32 (10H, m, 2 ¥ Ph); dC (100
MHz, CDCl3) 34.3 (CH2), 34.4 (CH2), 38.9 (CH2), 55.7 (CH3),
81.9 (CH), 96.0 (CH2), 126.2 (CH), 126.3 (CH), 126.7 (CH), 128.4
(2 ¥ CH), 128.4 (2 ¥ CH), 128.5 (2 ¥ CH), 129.5 (2 ¥ CH), 137.2
(C), 140.7 (C), 148.1 (CH), 199.3 (CO); m/z (CI) 325.1806 (MH+.
C21H25O3 requires 325.1804), 294 (100%), 266 (13), 220 (5), 159
(4), 137 (5), 85(9).
◦
The mixture was washed with 1 M hydrochloric acid (100 mL)
and water (100 mL), then dried (MgSO4), filtered, and con-
centrated in vacuo. Flash column chromatography (petroleum
ether/diethyl ether 6 : 4) afforded methyl (2S)-2-methoxymethoxy-
3-phenylpropionate (8) (5.19 g, 89%) as a colourless oil. nmax/cm-1
(neat) 2952 (CH), 1751 (CO), 1438, 1210, 1022, 700; [a]2D3 -56.9
(c 0.9, CHCl3), lit.17 -56.6 (c 1.0, CHCl3); dH (400 MHz, CDCl3)
2.98 (1H, dd, J 13.8, 9.0 Hz, 3-HH), 3.07 (3H, s, OCH3), 3.11 (1H,
dd, J 13.8, 4.0 Hz, 3-HH), 3.73 (3H, s, OCH3), 4.34 (1H, dd, J
9.0, 4.0 Hz, 2-H), 4.51 (1H, d, J 6.8 Hz, OCHHO), 4.64 (1H, d, J
6.8 Hz, OCHHO), 7.21–7.36 (5H, m, Ph); dC (100 MHz, CDCl3)
38.8 (CH2), 51.6 (CH3), 55.3 (CH3), 75.9 (CH), 95.6 (CH2), 126.3
(CH), 127.9 (2 ¥ CH), 129.0 (2 ¥ CH), 136.6 (C), 172.2 (C); m/z
(CI) 225.1124 (MH+. C12H17O4 requires 225.1127), 193 (100%),
162 (12), 133 (39) and 85 (22).
(3S)-1-(Dimethoxyphosphoryl)-2-oxo-3-methoxymethoxy-4-
(4E,7S)-2-Methyl-7-methoxymethoxy-8-phenyloct-4-en-6-one (11)
phenylbutane (9)
The reaction was carried out as described above us-
ing (3S)-1-(dimethoxyphosphoryl)-2-oxo-3-methoxymethoxy-4-
phenylbutane (9) (4.52 g, 14.3 mmol) and 3-methylbutanal
(3.08 mL, 28.6 mmol). Flash column chromatography (petroleum
ether/diethyl ether 95 : 5 to 15 : 85) afforded (4E,7S)-2-methyl-
7-methoxymethoxy-8-phenyloct-4-en-6-one (11) (3.63 g, 92%) as
a pale yellow oil. nmax/cm-1 (neat) 2955 (CH), 1693 (CO), 1625
(C C), 1496, 1455, 1316, 1149, 920; [a]2D1 -37.0 (c 1.0, CHCl3);
dH (400 MHz, CDCl3) 0.92 (6H, d, J 6.8 Hz, 1-H3 and 2-CH3),
1.77 (1H, nonet, J 6.8 Hz, 2-H), 2.11 (2H, td, J 6.8, 1.3 Hz, 3-H2),
2.89 (1H, dd, J 14.0, 9.0 Hz, 8-HH), 3.01 (1H, dd, J 14.0, 4.2 Hz,
8-HH), 3.06 (3H, s, OCH3), 4.40 (1H, dd, J 9.0, 4.2 Hz, 7-H), 4.49
(1H, d, J 6.9 Hz, OCHHO), 4.54 (1H, d, J 6.9 Hz, OCHHO), 6.40
(1H, dt, J 15.6, 1.3 Hz, 5-H), 7.00 (1H, dt, J 15.6, 6.8 Hz, 4-H),
7.20–7.31 (5H, m, Ph); dC (100 MHz, CDCl3) 22.4 (2 ¥ CH3), 27.9
(CH), 39.0 (CH2), 42.0 (CH2), 55.7 (CH3), 81.8 (CH), 96.0 (CH2),
126.6 (CH), 126.7 (CH), 128.4 (2 ¥ CH), 129.5 (2 ¥ CH), 137.2
(C), 148.5 (CH), 199.3 (C); m/z (CI) 277.1802 (MH+. C17H25O3
requires 277.1804), 245 (100%), 217 (13), 215 (10), 157 (4), 111 (6),
85 (7).
To
a solution of dimethyl methylphosphonate (6.39 mL,
60.0 mmol) in tetrahydrofuran (100 mL) stirring at -78 ◦C
was added 1.6 M n-butyllithium in hexane (45 mL, 72.4 mmol)
dropwise and the reaction stirred for
ture was added dropwise to a solution of methyl (2S)-2-
methoxymethoxy-3-phenylpropionate (8) (6.01 g, 26.8 mmol)
in tetrahydrofuran (200 mL) stirring at -78 ◦C. The mix-
ture was allowed to warm to room temperature over
1 h. The mix-
18 h, quenched with
2 M ammonium chloride solution
(50 mL), then concentrated under reduced pressure. The residue
was extracted with ethyl acetate (2 ¥ 100 mL), and the combined
organic layers were dried (MgSO4), filtered and concentrated in
vacuo. Flash column chromatography (100% ethyl acetate) af-
forded (3S)-1-(dimethoxyphosphoryl)-2-oxo-3-methoxymethoxy-
4-phenylbutane (9) (7.62 g, 90%) as a pale yellow oil. nmax/cm-1
(neat) 2955 (CH), 1723 (CO), 1455, 1257, 1031, 810; [a]2D1 -29.6 (c
1.0, CHCl3); dH (400 MHz, CDCl3) 2.92 (1H, dd, J 13.9, 8.6 Hz, 4-
HH), 3.05 (1H, dd, J 13.9, 4.2 Hz, 4-HH), 3.10–3.28 (5H, m, 1-H2
and OMe), 3.77 (3H, s, OCH3), 3.80 (3H, s, OCH3), 4.37 (1H, dd,
J 8.6, 4.2 Hz, 3-H), 4.49 (1H, d, J 6.8 Hz, OCHHO), 4.59 (1H, d,
J 6.8 Hz, OCHHO), 7.21–7.43 (5H, m, Ph); dC (100 MHz, CDCl3)
37.1 (d, JC–P 132 Hz, CH2), 38.0 (CH2), 53.0 (CH3), 53.1 (CH3),
55.9 (CH2), 83.1 (CH), 96.5 (CH2), 126.8 (CH), 128.5 (2 ¥ CH),
129.5 (2 ¥ CH), 136.7 (C), 202.8 (C); m/z (FAB) 317.1158 (MH+.
C14H22O6P requires 317.1154), 285 (93%), 267 (51), 255 (39), 152
(54), 110 (12) and 86 (6).
(4E,7S)-7-Methoxymethoxy-8-phenyloct-4-en-6-one (12)
The reaction was carried out as described above using
(3S)-1-(dimethoxyphosphoryl)-2-oxo-3-methoxymethoxy-4-
phenylbutane (9) (5.28 g, 16.7 mmol) and butanal (3.01 mL,
33.4 mmol). Flash column chromatography (petroleum ether/
diethyl ether 9 : 1 to 8 : 2) afforded (4E,7S)-7-methoxymethoxy-
8-phenyloct-4-en-6-one (12) (2.71 g, 62%) as a yellow oil. nmax/cm-1
(neat) 2959 (CH), 1693 (CO), 1625 (C C), 1455, 1149, 1053, 700;
[a]2D8 -51.7 (c 1.1, CHCl3); dH (400 MHz, CDCl3) 0.93 (3H, t, J 7.4
Hz, 1-H3), 1.49 (2H, sextet, J 7.4 Hz, 2-H2), 2.20 (2H, qd, J 7.4,
1.6 Hz, 3-H2), 2.89 (1H, dd, J 14.0, 9.2 Hz, 8-HH), 3.00 (1H, dd,
J 14.0, 4.4 Hz, 8-HH), 3.06 (3H, s, OCH3), 4.40 (1H, dd, J 9.2,
4.4 Hz, 7-H), 4.48 (1H, d, J 6.8 Hz, OCHHO), 4.54 (1H, d, J 6.8
Hz, OCHHO), 6.40 (1H, d, J 15.7 Hz, 5-H), 7.01 (1H, dt, J 15.7,
7.4 Hz, 4-H), 7.20–7.31 (5H, m, Ph); dC (100 MHz, CDCl3) 13.7
(CH3), 21.3 (CH2), 34.7 (CH2), 39.0 (CH2), 55.7 (CH3), 81.9 (CH),
(3E,6S)-1,7-Diphenyl-6-methoxymethoxyhept-3-en-5-one (10)
To
a
solution of (3S)-1-(dimethoxyphosphoryl)-2-oxo-3-
methoxymethoxy-4-phenylbutane (9) (0.10 g, 0.32 mmol)
in acetonitrile (10 mL) was added anhydrous potassium
carbonate (0.05 g, 0.38 mmol) followed by hydrocinnamaldehyde
(0.09 g, 0.63 mmol) and the reaction was heated to 75 ◦C for 24 h.
The reaction was cooled to room temperature and concentrated
in vacuo. The resulting residue was partitioned between water
(25 mL) and ethyl acetate (25 mL). The organic layer was
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96.0 (CH2), 125.8 (CH), 126.6 (CH), 128.4 (2 ¥ CH), 129.5 (2 ¥
CH), 137.2 (C), 149.4 (CH), 199.4 (C); m/z (CI) 263.1651 (MH+.
C16H23O3 requires 263.1647), 231 (100%), 201 (8), 143 (5), 121 (9),
85 (9).
Hz, 6-H), 4.40 (1H, d, J 6.9 Hz, OCHHO), 4.62 (1H, d, J 6.9 Hz,
OCHHO), 5.58 (1H, ddt, J 15.2, 6.4, 1.2 Hz, 5-H), 5.74 (1H, dt, J
15.2, 7.6 Hz, 4-H), 7.18–7.30 (5H, m, Ph); dC (100 MHz, CDCl3)
22.3 (CH3), 22.4 (CH3), 28.3 (CH), 37.5 (CH2), 41.9 (CH2), 55.7
(CH3), 74.0 (CH), 84.6 (CH), 97.2 (CH2), 126.2 (CH), 128.3 (2 ¥
CH), 128.9 (CH), 129.4 (2 ¥ CH), 133.3 (CH), 138.7 (C); m/z (CI)
261.1854 (MH+-H2O. C17H25O2 requires 261.1855), 262 (23%),
229 (16), 217 (17), 113 (42).
(3E,5R,6S)- and (3E,5S,6S)-1,7-Diphenyl-6-
methoxymethoxyhept-3-en-5-ol (14)
To a solution of anhydrous zinc chloride (1.48 g, 10.8 mmol)
◦
in tetrahydrofuran (200 mL) stirring at 0 C was added sodium
(4E,6R,7S)- and (4E,6S,7S)-7-Methoxymethoxy-
borohydride (0.82 g, 21.5 mmol) and the reaction mixture was
stirred while warming to room temperature over 18 h. Stirring of
the reaction was stopped, the solids allowed to settle, and the
solution was cooled to -78 ◦C. The supernatant solution was
added dropwise via cannula to a solution of (3E,6S)-1,7-diphenyl-
6-methoxymethoxyhept-3-en-5-one (10) (0.87 g, 2.69 mmol) in
tetrahydrofuran (50 mL) at -78 ◦C. The reaction was stirred while
warming to room temperature over 18 h, then cooled to 0 ◦C and
quenched dropwise with water (20 mL). The mixture was parti-
tioned between water (150 mL) and diethyl ether (150 mL). The or-
ganic phase was separated, washed with water (150 mL) then brine
(150 mL), dried (MgSO4), filtered and concentrated under reduced
pressure. Flash column chromatography (petroleum ether/ethyl
acetate 9 : 1 to 7 : 3) afforded (3E,5R,6S)- and (3E,5S,6S)-1,7-
diphenyl-6-methoxymethoxyhept-3-en-5-ol (14) (0.76 g, 87%) in
a 7 : 1 ratio, respectively as a colourless oil. nmax/cm-1 (neat)
3435 (OH), 2927 (CH), 1638 (C C), 1496, 1454, 1036, 699;
NMR spectroscopic data for major diastereomer (3E,5R,6S): dH
(400 MHz, CDCl3) 2.44 (2H, q, J 7.0 Hz, 2-H2), 2.59 (1H, dd,
J 14.1, 5.1 Hz, 7-HH), 2.64–2.75 (3H, m, 1-H2 and 7-HH), 2.99
(1H, d, J 6.8 Hz, OH), 3.23 (3H, s, OCH3), 3.73 (1H, ddd, J 8.1,
5.1, 2.4 Hz, 6-H), 4.07 (1H, td, J 6.8, 2.4 Hz, 5-H), 4.38 (1H, d,
J 6.9 Hz, OCHHO), 4.60 (1H, d, J 6.9 Hz, OCHHO), 5.61 (1H,
ddt, J 15.5, 6.8, 1.3 Hz, 4-H), 5.78 (1H, dt, J 15.5, 7.0 Hz, 3-H),
7.15–7.30 (10H, m, 2 ¥ Ph); dC (100 MHz, CDCl3) 34.2 (CH2),
35.5 (CH2), 37.5 (CH2), 55.7 (CH3), 73.9 (CH), 84.7 (CH), 97.2
(CH2), 125.9 (2 ¥ CH), 126.3 (CH), 128.3 (2 ¥ CH), 128.4 (2 ¥
CH), 128.5 (2 ¥ CH), 129.4 (2 ¥ CH), 133.5 (CH), 138.6 (C), 141.7
(C); m/z (CI) 309.1853 (MH+-H2O. C21H25O2 requires 309.1855),
277 (100%), 265 (24), 247 (18), 175 (6), 131 (16).
8-phenyloct-4-en-6-ol (16)
The reaction was carried out as described above using zinc
chloride (4.63 g, 34.0 mmol), sodium borohydride (2.57 g,
68.0 mmol) and (4E,7S)-7-methoxymethoxy-8-phenyloct-4-en-
6-one (12) (2.23 g, 8.50 mmol). Flash column chromatog-
raphy (petroleum ether/ethyl acetate 85 : 15 to 4 : 1) afforded
(4E,6R,7S)- and (4E,6S,7S)-7-methoxymethoxy-8-phenyloct-4-
en-6-ol (16) (2.25 g, 100%) in a 7 : 1 ratio, respectively as a
colourless oil. nmax(film)/cm-1 3441 (OH), 2924 (CH), 1450, 1149,
1096, 1034, 702; NMR spectroscopic data for major diastereomer
(4E,6R,7S): dH (400 MHz, CDCl3) 0.94 (3H, t, J 7.4 Hz, 1-H3),
1.46 (2H, sextet, J 7.4 Hz, 2-H2), 2.09 (2H, q, J 7.4 Hz, 3-H2),
2.75 (1H, dd, J 14.4, 5.2 Hz, 8-HH), 2.81 (1H, dd, J 14.4, 8.0 Hz,
8-HH), 2.91 (1H, d, J 6.8 Hz, OH), 3.24 (3H, s, OCH3), 3.84 (1H,
ddd, J 8.0, 5.2, 2.6 Hz, 7-H), 4.09 (1H, td, J 6.8, 2.6 Hz, 6-H),
4.56 (1H, d, J 6.8 Hz, OCHHO), 4.61 (1H, d, J 6.8 Hz, OCHHO),
5.58 (1H, dd, J 15.6, 6.8 Hz, 5-H), 5.75 (1H, dt, J 15.6, 7.4 Hz,
4-H), 7.18–7.30 (5H, m, Ph); dC (100 MHz, CDCl3) 13.7 (CH3),
22.4 (CH2), 34.6 (CH2), 37.5 (CH2), 55.7 (CH3), 74.0 (CH), 84.6
(CH), 97.2 (CH2), 126.2 (CH), 128.0 (CH), 128.3 (2 ¥ CH), 129.4
(2 ¥ CH), 134.4 (CH), 138.7 (C); m/z (CI) 247.1699 (MH+-H2O.
C16H23O2 requires 247.1698), 215 (100%), 203 (55), 185 (36), 171
(21), 113 (14), 99 (42).
(3R,4E,6S)- and (3S,4E,6S)-1,7-Diphenyl-3-(2¢,2¢,2¢-trichlo-
methylcarbonylamino)-6-methoxymethoxyhept-4-ene (17)
To a solution of (3E,5R,6S)- and (3E,5S,6S)-1,7-diphenyl-6-
methoxymethoxyhept-3-en-5-ol (14) (1.54 g, 4.7 mmol) and
1,8-diazabicyclo[5.4.0]undec-7-ene (0.71 mL, 4.7 mmol) in
dichloromethane (150 mL) was added trichloroacetonitrile
(0.95 mL, 9.4 mmol) and the reaction stirred for 48 h at room tem-
perature. The mixture was filtered under reduced pressure through
silica gel and washed with diethyl ether (50 mL). Concentration
under reduced pressure gave a yellow oil. The oil was dissolved in p-
xylene (250 mL), and potassium carbonate (0.10 g, 0.7 mmol) was
added to the mixture. The mixture was heated to 140 ◦C for 18 h,
then cooled to room temperature and concentrated in vacuo. Flash
column chromatography (petroleum ether/ethyl acetate 95 : 5 to
7 : 3) gave (3R,4E,6S)- and (3S,4E,6S)-1,7-diphenyl-3-(2¢,2¢,2¢-
trichlomethylcarbonylamino)-6-methoxymethoxyhept-4-ene (17)
(1.85 g, 84% over two steps) in a 7 : 1 ratio, respectively as a
yellow oil. nmax/cm-1 (neat) 3328 (NH), 2928 (CH), 1697 (CO),
1516, 1040, 822; NMR spectroscopic data for major diastereomer
(3R,4E,6S): dH (400 MHz, CDCl3) 1.91 (2H, q, J 7.5 Hz, 2-H2),
2.60 (2H, t, J 7.5 Hz, 1-H2), 2.80 (1H, dd, J 13.6, 6.4 Hz, 7-HH),
2.92 (1H, dd, J 13.6, 6.4 Hz, 7-HH), 3.12 (3H, s, OCH3), 4.27 (1H,
q, J 6.4 Hz, 6-H), 4.39–4.46 (1H, m, 3-H), 4.47 (1H, d, J 6.9 Hz,
(4E,6R,7S)- and (4E,6S,7S)-2-Methyl-7-methoxymethoxy-
8-phenyloct-4-en-6-ol (15)
The reaction was carried out as described above using zinc chloride
(6.50 g, 47.7 mmol), sodium borohydride (3.61 g, 95.5 mmol)
and (4E,7S)-2-methyl-7-methoxymethoxy-8-phenyloct-4-en-6-
one (11) (3.30 g, 11.9 mmol). Flash column chromatography
(petroleum ether/ethyl acetate 95 : 5 to 3 : 1) afforded (4E,6R,7S)-
and
(4E,6S,7S)-2-methyl-7-methoxymethoxy-8-phenyloct-4-
en-6-ol (15) (3.32 g, 100%) in a 10 : 1 ratio, respectively as
a colourless oil. nmax/cm-1 (neat) 3451 (OH), 2955 (CH),
1667 (C C), 1604, 1496, 1454, 1367, 1038, 918; NMR
spectroscopic data for major diastereomer (4E,6R,7S): dH
(400 MHz, CDCl3) 0.92 (3H, d, J 6.8 Hz, 1-H3), 0.93 (3H, d, J 6.8
Hz, 2-CH3), 1.68 (1H, nonet, J 6.8 Hz, 2-H), 1.96–2.03 (2H, m,
3-H2), 2.75 (1H, dd, J 14.0, 5.2 Hz, 8-HH), 2.81 (1H, dd, J 14.0,
8.2 Hz, 8-HH), 2.99 (1H, d, J 6.4 Hz, OH), 3.24 (3H, s, OCH3),
3.84 (1H, ddd, J 8.2, 5.2, 2.4 Hz, 7-H), 4.09 (1H, td, J 6.4, 2.4
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OCHHO), 4.64 (1H, d, J 6.9 Hz, OCHHO), 5.54 (1H, dd, J 15.8,
5.2 Hz, 4-H), 5.61 (1H, dd, J 15.8, 6.4 Hz, 5-H), 6.42 (1H, d, J
8.2 Hz, NH), 7.10–7.32 (10H, m, 2 ¥ Ph); dC (100 MHz, CDCl3)
31.9 (CH2), 36.2 (CH2), 42.2 (CH2), 52.4 (CH), 55.3 (CH3), 76.8
(CH), 92.7 (CCl3), 93.9 (CH2), 126.3 (CH), 126.4 (CH), 128.3 (2 ¥
CH), 128.4 (2 ¥ CH), 128.7 (2 ¥ CH), 129.7 (2 ¥ CH), 131.0 (CH),
132.3 (CH), 137.8 (C), 140.7 (C), 161.0 (CO); m/z (CI) 470.1049
(MH+. C23H2735Cl3NO3 requires 470.1057), 408 (38%), 374 (100),
340 (43).
42.2 (CH2), 52.5 (CH), 55.2 (CH3), 76.9 (CH), 92.8 (C), 93.8
(CH2), 126.3 (CH), 128.2 (2 ¥ CH), 129.7 (2 ¥ CH), 131.5 (CH),
131.8 (CH), 137.8 (C), 161.0 (C); m/z (FAB) 430.0717 (MNa+.
C18H2435Cl3NNaO3 requires 430.0719), 348 (52%), 346 (50), 297
(14), 185 (59), 117 (18).
(3R,4E,6S)-1,7-Diphenyl-3-(prop-2¢-enoylamino)-6-
methoxymethoxyhept-4-ene (20)
To a solution of (3R,4E,6S)- and (3S,4E,6S)-1,7-diphenyl-3-
(2¢,2¢,2¢-trichlomethylcarbonylamino)-6-methoxymethoxyhept-4-
ene (17) (0.67 g, 1.42 mmol) in methanol (100 mL) was added
1 M aqueous sodium hydroxide (50 mL, 50 mmol) and the
solution heated to 70 ◦C for 18 h. The reaction mixture was
cooled, concentrated under reduced pressure and extracted with
dichloromethane (2 ¥ 25 mL) and ethyl acetate (2 ¥ 25 mL). The
combined organic layers were washed with brine (50 mL), dried
(MgSO4), filtered and concentrated in vacuo. The resulting residue
(0.46 g, 1.42 mmol) was dissolved in diethyl ether (15 mL), cooled
to -78 ◦C, and triethylamine (0.26 mL, 1.82 mmol) was added. A
solution of acryloyl chloride (0.12 mL, 1.38 mmol) in diethyl ether
(15 mL) was added dropwise and the reaction mixture was stirred
while returning to room temperature over 18 h. The reaction
mixture was partitioned between water (30 mL) and diethyl ether
(15 mL) and the organic layer was separated, washed with brine
(30 mL), dried (MgSO4), filtered and concentrated in vacuo. Flash
column chromatography (petroleum ether/diethyl ether 1 : 0 to
8 : 2) gave (3R,4E,6S)-1,7-diphenyl-3-(prop-2¢-enoylamino)-6-
methoxymethoxyhept-4-ene (20) (0.26 g, 48%) as a colourless oil.
(4R,5E,7S)- and (4S,5E,7S)-2-Methyl-4-(2¢,2¢,2¢-trichlomethyl-
carbonylamino)-7-methoxymethoxy-8-phenyloct-5-ene (18)
The reaction was carried out as described above using (4E,6R,7S)-
and (4E,6S,7S)-2-methyl-7-methoxymethoxy-8-phenyloct-4-en-
6-ol (15) (2.17 g, 7.79 mmol), 1,8-diazabicyclo[5.4.0]undec-7-
ene (1.17 mL, 7.79 mmol) and trichloroacetonitrile (1.56 mL,
15.6 mmol). Flash column chromatography (petroleum
ether/diethyl ether 1 : 0 to 8 : 2) gave (4R,5E,7S)- and
(4S,5E,7S)-2-methyl-4-(2¢,2¢,2¢-trichlomethylcarbonylamino)-7-
methoxymethoxy-8-phenyloct-5-ene (18) (1.54 g, 52% over two
steps) in a 10 : 1 ratio, respectively as colourless oil. nmax/cm-1
(neat) 3347 (NH), 2956 (CH), 2929, 1693 (CO), 1684 (C C),
1519, 1037, 820; NMR spectroscopic data for major diastereomer
(4R,5E,7S): dH (400 MHz, CDCl3) 0.94 (3H, d, J 7.6 Hz, 1-H3)
0.95 (3H, d, J 7.6 Hz, 2-CH3), 1.37–1.53 (2H, m, 3-H2), 1.60 (1H,
nonet, J 7.6 Hz, 2-H), 2.82 (1H, dd, J 13.6, 6.4 Hz, 8-HH), 2.92
(1H, dd, J 13.6, 7.6 Hz, 8-HH), 3.13 (3H, s, OCH3), 4.24–4.30
(1H, m, 7-H), 4.43–4.49 (2H, m, 4-H and OCHHO), 4.64 (1H,
d, J 6.9 Hz, OCHHO), 5.51 (1H, dd, J 16.0, 6.4 Hz, 5-H), 5.57–
5.66 (1H, m, 6-H), 6.42 (1H, d, J 8.5 Hz, NH), 7.19–7.31 (5H, m,
Ph); dC (100 MHz, CDCl3) 22.4 (CH3), 22.5 (CH3), 24.8 (CH), 42.2
(CH2), 43.8 (CH2), 51.1 (CH3), 55.2 (CH), 76.8 (CH), 92.8 (C), 93.7
(CH2), 126.3 (CH), 128.2 (2 ¥ CH), 129.7 (2 ¥ CH), 131.6 (CH),
131.7 (CH), 137.8 (C), 160.9 (C); m/z (FAB) 444.0886 (MNa+.
C19H2635Cl3NNaO3 requires 444.0876), 360 (100%), 325 (14), 199
(36), 143 (44).
n
max/cm-1 (neat) 3273 (NH), 2941 (CH), 1655 (CO), 1542, 1039,
699; [a]2D7 -20.7 (c 0.8, CHCl3); dH (400 MHz, CDCl3) 1.83 (2H,
q, J 6.9 Hz, 2-H2), 2.57–2.61 (2H, m, 1-H2), 2.79 (1H, dd, J 13.6,
6.1 Hz, 7-HH), 2.90 (1H, dd, J 13.6, 7.5 Hz, 7-HH), 3.09 (3H, s,
OCH3), 4.21–4.26 (1H, m, 6-H), 4.45 (1H, d, J 6.8 Hz, OCHHO),
4.57–4.64 (1H, m, 3-H), 4.63 (1H, d, J 6.8 Hz, OCHHO), 5.34
(1H, d, J 8.6 Hz, NH), 5.53–5.54 (2H, m, 4-H and 5-H), 5.65 (1H,
dd, J 10.2, 1.4 Hz, 3¢-HH), 6.02 (1H, dd, J 17.0, 10.2 Hz, 2¢-H),
6.26 (1H, dd, J 17.0, 1.4 Hz, 3¢-HH), 7.00–7.47 (10H, m, 2 ¥
Ph); dC (100 MHz, CDCl3) 32.1 (CH2), 36.6 (CH2), 42.3 (CH2),
50.3 (CH), 55.2 (CH3), 77.1 (CH), 93.7 (CH2), 126.1 (CH), 126.3
(CH), 126.7 (CH2), 128.2 (2 ¥ CH), 128.4 (2 ¥ CH), 128.5 (2 ¥
CH), 129.7 (2 ¥ CH), 130.8 (CH), 131.1 (CH), 132.9 (CH) 138.1
(C), 141.4 (C), 164.6 (CO); m/z (CI) 380.2227 (MH+. C24H28NO3
requires 380.2226), 318 (100%), 288 (9), 249 (6), 97 (18).
(4R,5E,7S)- and (4S,5E,7S)-4-(2¢,2¢,2¢-Trichlomethylcarbony-
lamino)-7-methoxymethoxy-8-phenyloct-5-ene (19)
The reaction was carried out as described above using (4E,6R,7S)-
and (4E,6S,7S)-7-methoxymethoxy-8-phenyloct-4-en-6-ol (16)
(2.52 g, 9.53 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (1.43 mL,
9.53 mmol) and trichloroacetonitrile (1.91 mL, 19.06 mmol).
Flash column chromatography (petroleum ether/diethyl ether
1 : 0 to 7 : 3) gave (4R,5E,7S)- and (4S,5E,7S)-4-(2¢,2¢,2¢-
trichlomethylcarbonylamino)-7-methoxymethoxy-8-phenyloct-5-
ene (19) (1.94 g, 48% over two steps) in a 7 : 1 ratio, respectively as
colourless oil. nmax/cm-1 (neat) 3325 (NH), 2932 (CH), 1697 (CO),
1512, 1033, 817; NMR spectroscopic data for major diastereomer
(4R,5E,7S): dH (400 MHz, CDCl3) 0.85 (3H, t, J 7.4 Hz, 1-H3),
1.26 (2H, sextet, J 7.4 Hz, 2-H2), 1.47 (2H, q, J 7.4 Hz, 3-H2),
2.72 (1H, dd, J 13.6, 7.0 Hz, 8-HH), 2.84 (1H, dd, J 13.6, 7.0 Hz,
8-HH), 3.05 (3H, s, OCH3), 4.18 (1H, q, J 7.0 Hz, 7-H), 4.29–4.34
(1H, m, 4-H), 4.39 (1H, d, J 6.8 Hz, OCHHO), 4.45 (1H, d, J
6.8 Hz, OCHHO), 5.44 (1H, dd, J 15.6, 6.0 Hz, 5-H), 5.48–5.55
(1H, m, 6-H), 6.33 (1H, br d, J 8.2 Hz, NH), 7.10–7.21 (5H, m,
Ph); dC (100 MHz, CDCl3) 13.7 (CH3), 18.8 (CH2), 36.8 (CH2),
(4R,5E,7S)-2-Methyl-4-(prop-2¢-enoylamino)-7-methoxymethoxy-
8-phenyloct-5-ene (21)
The reaction was carried out as described above using
(4R,5E,7S)- and (4S,5E,7S)-2-methyl-4-(2¢,2¢,2¢-trichlomethyl-
carbonylamino)-7-methoxymethoxy-8-phenyloct-5-ene
(18)
(1.40 g, 3.31 mmol). Flash column chromatography (petroleum
ether/ethyl acetate 8 : 2 to 7 : 3) afforded (4R,5E,7S)-2-methyl-4-
(prop-2¢-enoylamino)-7-methoxymethoxy-8-phenyloct-5-ene (21)
(0.53 g, 48%) as a colourless oil. nmax/cm-1 (neat) 3270 (NH), 2954
(CH), 1654 (CO), 1625 (C C), 1542, 1148, 1040; [a]2D5 +12.7 (c
1.4, CHCl3); dH (400 MHz, CDCl3) 0.89 (3H, d, J 6.8 Hz, 1-H3),
0.91 (3H, d, J 6.8 Hz, 2-CH3), 1.28–1.41 (2H, m, 3-H2), 1.56 (1H,
nonet, J 6.8 Hz, 2-H), 2.78 (1H, dd, J 13.6, 6.4 Hz, 8-HH), 2.88
6766 | Org. Biomol. Chem., 2011, 9, 6761–6770
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(1H, dd, J 13.6, 8.0 Hz, 8-HH), 3.07 (3H, s, OCH3), 4.18–4.23
(1H, m, 7-H), 4.43 (1H, d, J 8.0 Hz, OCHHO), 4.57–4.64 (2H,
m, OCHHO and 4-H), 5.31 (1H, br d, J 8.6 Hz, NH), 5.44 (1H,
dd, J 15.6, 6.0 Hz, 5-H), 5.54 (1H, dd, J 15.6, 7.2 Hz, 6-H), 5.66
(1H, dd, J 10.2, 1.4 Hz, 3¢-HH), 6.06 (1H, dd, J 16.9, 10.2 Hz,
2¢-H), 6.29 (1H, dd, J 16.9, 1.4 Hz, 3¢-HH), 7.19–7.27 (5H, m,
Ph); dC (100 MHz, CDCl3) 22.5 (CH3), 22.6 (CH3), 24.8 (CH),
42.3 (CH2), 44.6 (CH2), 48.7 (CH3), 55.2 (CH), 77.1 (CH), 93.6
(CH2), 126.2 (CH), 126.6 (CH2), 128.1 (2 ¥ CH), 129.8 (2 ¥ CH),
130.5 (CH), 130.9 (CH), 133.6 (CH), 138.1 (C), 164.5 (C); m/z
(CI) 332.2222 (MH+. C20H30NO3 requires 332.2226), 333 (8%),
307 (12), 271 (100), 240 (7).
filtered and concentrated in vacuo. Flash column chromatography
(petroleum ether/ethyl acetate 9 : 1 to 6 : 4) gave (3R,4E,6S)-1,7-
diphenyl-3-(but-3¢-enoylamino)-6-methoxymethoxyhept-4-ene
(26) (0.45 g, 39%) as a colourless oil. nmax/cm-1 (neat) 3287 (NH),
2942 (CH), 1648 (CO), 1546 (C C), 1147, 1040; [a]2D8 -60.8 (c
0.7, CHCl3); dH (400 MHz, CDCl3) 1.72–1.85 (2H, m, 2-H2) 2.56
(2H, t, J 7.8 Hz, 1-H2), 2.79 (1H, dd, J 13.6, 6.0 Hz, 7-HH),
2.90 (1H, dd, J 13.6, 7.6 Hz, 7-HH), 2.95 (2H, dt, J 7.2, 1.1 Hz,
2¢-H2), 3.10 (3H, s, OCH3), 4.21–4.27 (1H, m, 6-H), 4.45 (1H, d,
J 6.8 Hz, OCHHO), 4.48–4.55 (1H, m, 3-H), 4.63 (1H, d, J 6.8
Hz, OCHHO), 5.17–5.25 (2H, m, 4¢-H2), 5.35 (1H, d, J 8.7 Hz,
NH), 5.45–5.54 (2H, m, 4-H and 5-H), 5.86 (1H, ddt, J 17.2, 10.0,
7.2 Hz, 3¢-H), 7.12–7.29 (10H, m, 2 ¥ Ph); dC (100 MHz, CDCl3)
32.1 (CH2), 36.6 (CH2), 41.8 (CH2), 42.3 (CH2), 50.2 (CH), 55.2
(CH3), 77.0 (CH) 93.7 (CH2), 120.1 (CH2), 126.1 (CH), 126.3
(CH), 128.2 (2 ¥ CH), 128.3 (2 ¥ CH), 128.5 (2 ¥ CH), 129.7
(2 ¥ CH), 130.7 (CH), 131.3 (CH), 133.1 (CH), 138.0 (C), 141.4
(C), 169.6 (C); m/z (CI) 394.2376 (MH+. C25H32NO3 requires
394.2382), 374 (35%), 333 (100), 302 (82), 264 (5), 185 (4), 91 (7).
(4R,5E,7S)-4-(Prop-2¢-enoylamino)-7-methoxymethoxy-8-
phenyloct-5-ene (22)
The reaction was carried out as described above using (4R,5E,7S)-
and
(4S,5E,7S)-4-(2¢,2¢,2¢-trichlomethylcarbonylamino)-7-
methoxymethoxy-8-phenyloct-5-ene (19) (0.09 g, 0.23 mmol).
Flash column chromatography (petroleum ether/ethyl acetate
8 : 2 to 6 : 4) gave (4R,5E,7S)-4-(prop-2¢-enoylamino)-7-
methoxymethoxy-8-phenyloct-5-ene (22) (0.03 g, 44%) as a
colourless oil. nmax/cm-1 (neat) 3278 (NH), 2931 (CH), 1656
(CO), 1626 (C C), 1544, 1041, 700; [a]2D5 +3.1 (c 1.0, CHCl3);
dH (400 MHz, CDCl3) 0.92 (3H, t, J 7.3 Hz, 1-H3), 1.24–1.36
(2H, m, 2-H2), 1.45–1.52 (2H, m, 3-H2), 2.80 (1H, dd, J 13.6, 6.0
Hz, 8-HH), 2.91 (1H, dd, J 13.6, 7.6 Hz, 8-HH), 3.10 (3H, s,
OCH3), 4.21–4.26 (1H, m, 7-H), 4.46 (1H, d, J 6.8 Hz, OCHHO),
4.52–4.60 (1H, m, 4-H), 4.65 (1H, d, J 6.8 Hz, OCHHO), 5.31
(1H, d, J 8.9 Hz, NH), 5.46–5.58 (2H, m, 5-H and 6-H), 5.68
(1H, dd, J 10.2, 1.4 Hz, 3¢-HH), 6.08 (1H, dd, J 16.9, 10.2 Hz,
2¢-H), 6.31 (1H, dd, J 16.9, 1.4 Hz, 3¢-HH), 7.18–7.30 (5H, m,
Ph); dC (100 MHz, CDCl3) 13.8 (CH3), 18.9 (CH2), 37.2 (CH2),
42.3 (CH2), 50.2 (CH), 55.2 (CH3), 77.1 (CH), 93.7 (CH2), 126.2
(CH), 126.5 (CH2), 128.1 (2 ¥ CH), 129.7 (2 ¥ CH), 130.6 (CH),
131.0 (CH), 133.3 (CH), 138.1 (C), 168.5 (C); m/z (CI) 318.2067
(MH+. C19H28NO3 requires 318.2069), 292 (45%), 256 (100), 226
(11), 85 (9).
(4R,5E,7S)-2-Methyl-4-(but-3¢-enoylamino)-7-methoxymethoxy-
8-phenyloct-5-ene (27)
The reaction was carried out as described above using
(4R,5E,7S)-
and
(4S,5E,7S)-2-methyl-4-(2¢,2¢,2¢-trichlo-
methylcarbonylamino)-7-methoxymethoxy-8-phenyloct-5- ene
(18) (1.37 g, 2.91 mmol). Flash column chromatography
(petroleum ether/ethyl acetate 9 : 1 to 7 : 3) gave (4R,5E,7S)-2-
methyl-4-(but-3¢-enoylamino)-7-methoxymethoxy-8-phenyloct-5-
ene (27) (0.48 g, 43%) as a colourless oil. nmax/cm-1 (neat) 3277
(NH), 2954 (CH), 1646 (CO), 1635 (C C) 1544, 1040, 916; [a]D23
-15.5 (c 1.1, CHCl3); dH (400 MHz, CDCl3) 0.81 (6H, d, J 6.8
Hz, 1-H3 and 2-CH3), 1.18–1.25 (2H, m, 3-H2), 1.46 (1H, nonet,
J 6.8 Hz, 2-H), 2.71 (1H, dd, J 13.6, 6.0 Hz, 8-HH), 2.81 (1H,
dd, J 13.6, 7.6 Hz, 8-HH), 2.91 (2H, dt, J 7.2, 1.2 Hz, 2¢-H2),
3.00 (3H, s, OCH3), 4.11–4.16 (1H, m, 7-H), 4.35 (1H, d, J 6.8
Hz, OCHHO), 4.40–4.47 (1H, m, 4-H), 4.54 (1H, d, J 6.8 Hz,
OCHHO), 5.11–5.18 (2H, m, 4¢-H2), 5.31 (1H, d, J 8.6 Hz, NH),
5.34–5.44 (2H, m, 5-H and 6-H), 5.82 (1H, ddt, J 17.6, 14.3, 7.2
Hz, 3¢-H), 7.09–7.21 (5H, m, Ph); dC (100 MHz, CDCl3) 18.0
(CH), 22.5 (CH3), 22.6 (CH3), 41.8 (CH2), 42.3 (CH2), 44.3 (CH2),
48.6 (CH), 55.1 (CH3), 77.0 (CH), 93.6 (CH2), 119.9 (CH2), 126.2
(CH), 127.9 (CH), 128.1 (CH), 129.7 (2 ¥ CH), 130.0 (CH), 131.5
(CH), 133.8 (CH), 138.1 (C), 169.4 (C); m/z (CI) 346.2378 (MH+.
C21H32NO3 requires 346.2382), 284 (100%), 254 (5), 107 (9), 81
(24).
(3R,4E,6S)-1,7-Diphenyl-3-(but-3¢-enoylamino)-6-
methoxymethoxyhept-4-ene (26)
To a solution of (3R,4E,6S)- and (3S,4E,6S)-1,7-diphenyl-3-
(2¢,2¢,2¢-trichlomethylcarbonylamino)-6-methoxymethoxyhept-4-
ene (17) (1.37 g, 2.91 mmol) in methanol (100 mL) was added
1 M aqueous sodium hydroxide (50 mL, 50 mmol) and the
solution heated to 70 ◦C for 18 h. The reaction mixture was
cooled, concentrated under reduced pressure and extracted with
dichloromethane (2 ¥ 100 mL) and ethyl acetate (2 ¥ 100 mL). The
combined organic layers were washed with brine (50 mL), dried
(MgSO4), filtered and concentrated in vacuo. The resulting residue
(0.94 g, 2.91 mmol) was dissolved in dichloromethane (50 mL)
and cooled to 0 ◦C, to which was added 3-butenoic acid (0.30 mL,
3.48 mmol), 4-dimethylaminopyridine (0.04 g, 0.30 mmol) and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
(0.67 g, 3.48 mmol). The reaction mixture was stirred while
returning to room temperature over 18 h, then partitioned
between water (50 mL) and ethyl acetate (50 mL). The organic
layer was separated, washed with brine (50 mL), dried (MgSO4),
(4R,5E,7S)-4-(But-3¢-enoylamino)-7-methoxymethoxy-8-
phenyloct-5-ene (28)
The reaction was carried out as described above using (4R,5E,7S)-
and
(4S,5E,7S)-4-(2¢,2¢,2¢-trichlomethylcarbonylamino)-7-
methoxymethoxy-8-phenyloct-5-ene (19) (1.45 g, 3.55 mmol).
Flash column chromatography (petroleum ether/ethyl
acetate 9 : 1 to 7 : 3) gave (4R,5E,7S)-4-(but-3¢-enoylamino)-
7-methoxymethoxy-8-phenyloct-5-ene (28) (0.58 g, 49%) as a
colourless oil. nmax/cm-1 (neat) 3284 (NH), 2931 (CH), 1646
(CO), 1635 (C C), 1544, 1039, 916; [a]2D5 -34.4 (c 1.0, CHCl3);
dH (400 MHz, CDCl3) 0.88 (3H, t, J 7.3 Hz, 1-H3), 1.20–1.30
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(2H, m, 2-H2), 1.39–1.45 (2H, m, 3-H2), 2.78 (1H, dd, J 13.6,
6.0 Hz, 8-HH), 2.89 (1H, dd, J 13.6, 7.6 Hz, 8-HH), 2.99 (2H,
dt, J 7.2, 1.1 Hz, 2¢-H2), 3.09 (3H, s, OCH3), 4.19–4.24 (1H, m,
7-H), 4.43–4.48 (2H, m, OCHHO and 4-H), 4.62 (1H, d, J 6.8
Hz, OCHHO), 5.19–5.27 (2H, m, 4¢-H2), 5.34 (1H, d, J 8.5 Hz,
NH), 5.44–5.47 (2H, m, 5-H and 6-H), 5.91 (1H, ddt, J 17.2,
14.4, 7.2 Hz, 3¢-H), 7.17–7.28 (5H, m, Ph); dC (100 MHz, CDCl3)
13.8 (CH3), 18.9 (CH2), 37.2 (CH2), 41.8 (CH2), 42.3 (CH2), 50.0
(CH), 55.2 (CH3), 77.0 (CH), 93.6 (CH2), 119.9 (CH2), 126.2
(CH), 128.1 (2 ¥ CH), 129.7 (2 ¥ CH), 130.2 (CH), 131.5 (CH),
133.6 (CH), 138.1 (C), 169.5 (C); m/z (FAB) 332.2224 (MH+.
C20H30NO3 requires 332.2226), 270 (100%), 241 (68), 204 (96),
187 (16), 175 (15), 121 (14), 96 (22), 77 (24), 51 (98).
(4.0 mg, 4.25 mmol). Flash column chromatography (100% ethyl
acetate) gave (5R)-propyl-1H-pyrrol-2(5H)-one (25) (0.01 g, 85%)
as a white solid. Mp 98–101 ◦C; nmax/cm-1 (neat) 3150 (NH), 1681
(CO), 1654 (C C), 1379, 1218, 826; [a]2D6 -134.2 (c 0.9, CHCl3);
dH (400 MHz, CDCl3) 0.90 (3H, t, J 7.3 Hz, 3¢-H3), 1.33–1.60
(4H, m, 1¢-H2 and 2¢-H2), 4.13–4.16 (1H, m, 5-H), 6.02 (1H, dt,
J 5.8, 1.6 Hz, 4-H), 7.00 (1H, dt, J 5.8, 1.6 Hz, 3-H), 7.06 (1H, s,
NH); dC (100 MHz, CDCl3) 14.0 (CH3), 19.5 (CH2), 35.3 (CH2),
59.9 (CH), 126.9 (CH), 150.4 (CH), 174.2 (C); m/z (EI) 125.0837
(M+. C7H11NO requires 125.0841), 110 (32%), 82 (100), 69 (39),
55 (29).
(6R)-6-Isobutyl-3,6-dihydro-1H-pyridin-2-one (30)
The reaction was carried out as described above using (4R,5E,7S)-
2-methyl-4-(but-3¢-enoylamino)-7-methoxymethoxy-8-phenyloct-
5-ene (27) (0.16 g, 0.46 mmol) and Grubbs 2nd generation catalyst
(0.02 g, 0.02 mmol). Flash column chromatography (100% ethyl
acetate) gave (6R)-6-isobutyl-3,6-dihydro-1H-pyridin-2-one (30)
(0.06 g, 82%) as a white solid. Mp 69–71 ◦C; nmax/cm-1 (neat)
3206 (NH), 2957 (CH), 1676 (C C), 1655 (CO), 1406, 827; [a]D22
-26.8 (c 0.2, CHCl3); dH (400 MHz, CDCl3) 0.94 (6H, t, J 6.8 Hz,
2¢-CH3 and 3¢-H3), 1.37–1.47 (2H, m, 1¢-H2), 1.74 (1H, nonet, J
6.8 Hz, 2¢-H), 2.91–2.94 (2H, m, 3-H2), 4.04–4.15 (1H, m, 6-H),
5.68–5.77 (2H, m, 4-H and 5-H), 6.03 (1H, br s, NH); dC (100
MHz, CDCl3) 22.2 (CH3), 23.1 (CH3), 24.3 (CH), 31.3 (CH2),
46.6 (CH2), 52.1 (CH), 121.3 (CH), 125.8 (CH), 169.5 (C); m/z
(CI) 154.1231 (MH+. C9H16NO requires 154.1232), 142 (4%), 113
(2), 96 (4), 69 (3).
(5R)-5-Phenethyl-1H-pyrrol-2(5H)-one (23)
A solution of (3R,4E,6S)-1,7-diphenyl-3-(prop-2¢-enoylamino)-
6-methoxymethoxyhept-4-ene (20) (0.19 g, 0.49 mmol) stirring
in dichloromethane (250 mL) was heated to 40 ◦C for 0.25 h.
Grubbs 2nd generation catalyst (0.02 g, 0.02 mmol) was added,
and the mixture stirred at 40 ◦C for 18 h. The reaction was cooled
and the mixture concentrated under vacuum. Flash column chro-
matography (dichloromethane/methanol 99 : 1) afforded (5R)-5-
phenethyl-1H-pyrrol-2(5H)-one (23) (0.08 g, 83%) as a white
solid. 93% ee determined by HPLC analysis using Chiralcel IB
column (5% iPrOH/hexane at 1.00 mL min-1), retention time: tS =
10.9 min, and tR = 13.7 min; Mp 124–126 ◦C (decomposition);
n
max/cm-1 (neat) 3176 (CH), 1676 (CO), 1647 (C C) 1647, 1456,
820; [a]2D3 -93.5 (c 0.5, CHCl3); dH (400 MHz, CDCl3) 1.81–1.92
(1H, m, 1¢-HH), 1.94–2.04 (1H, m, 1¢-HH), 2.68 (2H, t, J 8.0 Hz,
2¢-H2), 4.18–4.26 (1H, m, 5-H), 6.11 (1H, dt, J 5.8, 1.6 Hz, 3-H),
7.05 (1H, dt, J 5.8, 1.6 Hz, 4-H), 7.11–7.24 (5H, m, Ph), 7.75 (1H,
s, NH); dC (100 MHz, CDCl3) 32.4 (CH2), 34.8 (CH2), 59.4 (CH),
126.4 (CH), 127.2 (CH), 128.4 (2 ¥ CH), 128.7 (2 ¥ CH), 140.7 (C),
150.2 (CH), 174.3 (C); m/z (EI) 187.0999 (M+. C12H13NO requires
187.0997), 118 (40%), 87 (100), 85 (100), 47 (100).
(6R)-6-Propyl-3,6-dihydro-1H-pyridin-2-one (31)3h
The reaction was carried out as described above using (4R,5E,7S)-
4-(but-3¢-enoylamino)-7-methoxymethoxy-8-phenyloct-5-ene
(28) (0.30 g, 0.92 mmol) and Grubbs 2nd generation catalyst
(0.04 g, 0.05 mmol). Flash column chromatography (100% ethyl
acetate) gave (6R)-6-propyl-3,6-dihydro-1H-pyridin-2-one (31)
◦
(0.07 g, 56%) as a white solid. Mp 134–136 C (decomposition);
(5R)-5-Isobutyl-1H-pyrrol-2(5H)-one (24)
n
max/cm-1 (neat) 3185 (NH), 2959 (CH), 1679 (C C), 1656 (CO),
The reaction was carried out as described above using (4R,5E,7S)-
2-methyl-4-(prop-2¢-enoylamino)-7-methoxymethoxy-8-phenyl-
oct-5-ene (21) (0.15 g, 0.437 mmol) and Grubbs 2nd generation
catalyst (0.02 g, 0.022 mmol). Flash column chromatography
(100% ethyl acetate) gave (5R)-5-isobutyl-1H-pyrrol-2(5H)-one
(24) (0.05 g, 82%) as a white solid. Mp 76–81 ◦C; nmax/cm-1 3184
(NH), 2925 (CH), 1681 (CO), 1370, 1220, 810; [a]2D4 -203.0 (c 0.7,
CHCl3); dH (400 MHz, CDCl3) 0.98 (3H, d, J 6.6 Hz, 2¢-CH3), 0.99
(3H, d, J 6.6 Hz, 3¢-H3), 1.37–1.50 (2H, m, 1¢-H2), 1.76 (1H, nonet,
J 6.6 Hz, 2¢-H), 4.25–4.29 (1H, m, 5-H), 6.09 (1H, dt, J 5.8, 1.6
Hz, 3-H), 7.08 (1H, dt, J 5.8, 1.6 Hz, 4-H), 7.46 (1H, br s, NH); dC
(100 MHz, CDCl3) 22.3 (CH3), 23.2 (CH3), 26.1 (CH), 42.3 (CH2),
58.5 (CH), 126.7 (CH), 150.9 (CH), 174.4 (C); m/z (CI) 140.1072
(MH+. C8H14NO requires 140.1075), 133 (12%), 113 (16), 97 (20),
81 (66).
1341, 1153, 827; [a]2D6 -122.8 (c 1.0, CHCl3); lit.3h for opposite
enantiomer, [a]2D3 +110.5 (c 0.6, CHCl3); dH (400 MHz, CDCl3)
0.95 (3H, t, J 7.3 Hz, 3¢-H3), 1.34–1.44 (2H, m, 2¢-H2), 1.51–1.61
(2H, m, 1¢-H2), 2.90–2.94 (2H, m, 3-H2), 4.06–4.10 (1H, m, 6-H),
5.66–5.72 (1H, m, 5-H), 5.76 (1H, dtd, J 10.0, 3.2, 1.6 Hz, 4-H),
6.58 (1H, br s, NH); dC (100 MHz, CDCl3) 13.9 (CH3), 17.8 (CH2),
31.2 (CH2), 39.3 (CH2), 53.8 (CH), 121.6 (CH), 125.5 (CH), 169.8
(C); m/z (CI) 140.1078 (MH+. C8H14NO requires 140.1075), 113
(4%), 97 (8), 85 (12), 71 (17).
(6S)-6-Phenethylpiperidin-2-one
A solution of (3R,4E,6S)-1,7-diphenyl-3-(but-3¢-enoylamino)-
6-methoxymethoxyhept-4-ene (26) (0.24 g, 0.60 mmol) in
dichloromethane (250 mL) was heated to 45 ◦C for 0.25 h.
Grubbs 2nd generation catalyst (0.02 g, 0.03 mmol) was added,
and the reaction mixture stirred for 42 h. The mixture was
cooled to room temperature and concentrated under reduced pres-
sure. Flash column chromatography (dichloromethane/methanol
99 : 1) afforded (6R)-6-phenethyl-3,6-dihydro-1H-pyridin-2-one
(29) (0.11 g, 89%) as a white solid. Dihydropyridin-2-one 29 was
(5R)-5-Propyl-1H-pyrrol-2(5H)-one (25)
The reaction was carried out as described above using (4R,5E,7S)-
4-(prop-2¢-enoylamino)-7-methoxymethoxy-8-phenyloct-5-ene
(22) (0.30 g, 0.09 mmol) and Grubbs 2nd generation catalyst
6768 | Org. Biomol. Chem., 2011, 9, 6761–6770
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found to be unstable and so was used without purification. dH (400
MHz, CDCl3) 1.83–1.97 (2H, m, 1¢-H2), 2.68 (2H, td, J 8.0, 1.6
Hz, 2¢-H2), 2.91–2.95 (2H, m, 3-H2), 4.07–4.14 (1H, m, 6-H), 5.69–
5.74 (1H, m, 5-H), 5.80 (1H, dtd, J 10.4, 3.2, 1.6 Hz, 4-H), 6.72
(1H, br s, NH), 7.16–7.33 (5H, m, Ph). To a solution of (6R)-6-
phenethyl-3,6-dihydro-1H-pyridin-2-one (29) (0.11 g, 0.55 mmol)
in ethyl acetate (35 mL) was added 10% palladium on carbon
(0.04 g, 0.04 mmol wrt Pd). The solution was purged with hydrogen
gas for 0.25 h then stirred under an atmosphere of hydrogen at
room temperature for 18 h. The reaction mixture was filtered
ganic layer was dried (MgSO4), filtered and concentrated in vacuo.
Flash column chromatography (petroleum ether/diethyl ether
85 : 15) afforded (6R)-N-(tert-butoxycarbonyl)-6-propylpiperidine
(33) (0.034 g, 48%) as a colourless oil. [a]2D4 -25.6 (c 0.6, CHCl3),
lit.18 [a]2D3 -31.6 (c 0.9, CHCl3); dH (400 MHz, CDCl3) 0.85 (3H,
t, J 7.2 Hz, 3¢-H3), 1.14–1.32 (4H, m, 1¢-H2 and 2¢-H2), 1.38 (9H,
s, OtBu), 1.41–1.63 (6H, m, 3-H2, 4-H2 and 5-H2), 2.67 (1H, td, J
13.6, 2.6 Hz, 6-HH), 3.89 (1H, br d, J 2.6 Hz, 6-HH), 4.14 (1H, br
s, 2-H); dC (100 MHz, CDCl3) 14.1 (CH3), 19.1 (2 ¥ CH2), 19.5 (2 ¥
CH2), 25.7 (CH2), 28.5 (3 ¥ CH3), 31.9 (CH2), 50.1 (CH), 17.9 (C),
155.2 (C); m/z (EI) 227 (M+, 4%), 184 (18), 149 (17), 128 (100).
R
through Celiteꢀ and washed with ethyl acetate (30 mL). The filtrate
was concentrated under reduced pressure to yield a white solid.
Flash column chromatography (dichloromethane/methanol 1 : 0
to 96 : 4) gave (6S)-6-phenethylpiperidin-2-one (0.11 g, 100%) as
a white solid. Mp 84–86 ◦C; nmax/cm-1 (neat) 3214 (NH), 2942
(CH), 1651 (CO), 1603 (C C), 1402, 1343, 1090; [a]2D2 +5.0 (c
1.4, CHCl3); dH (400 MHz, CDCl3) 1.37–1.47 (1H, m, 5-HH),
1.63–1.75 (1H, m, 5-HH), 1.78–1.84 (2H, m, 1¢-H2), 1.86–1.98
(2H, m, 4-H2), 2.30 (1H, ddd, J 16.4, 10.4, 6.0 Hz, 3-HH), 2.35–
2.44 (1H, m, 3-HH), 2.67 (2H, td, J 7.6, 2.8 Hz, 2¢-H2), 3.36–3.42
(1H, m, 6-H), 6.03 (1H, br s, NH), 7.16–7.31 (5H, m, Ph); dC (100
MHz, CDCl3) 19.7 (CH2), 28.4 (CH2), 31.4 (CH2), 31.6 (CH2), 38.6
(CH2), 52.6 (CH2), 126.2 (CH), 128.3 (2 ¥ CH), 128.6 (2 ¥ CH),
140.9 (C), 172.4 (C); m/z (EI) 203.1313 (M+. C13H17NO requires
203.1310), 186 (5%), 125 (27), 112 (66), 98 (100).
Acknowledgements
The authors are grateful to the EPSRC (studentship to M.D.),
GlaxoSmithKline and the University of Glasgow for financial
support.
Notes and references
1 For some recent general reviews see: (a) P. M. Weintraub, J. S. Sabol, J.
M. Kane and D. R. Borcherding, Tetrahedron, 2003, 59, 2953; (b) M. G.
P. Buffat, Tetrahedron, 2004, 60, 1701; (c) A. Deiters and S. F. Martin,
Chem. Rev., 2004, 104, 2199; (d) J. P. A. Harrity and O. Provoost, Org.
Biomol. Chem., 2005, 3, 1349; (e) S. F. Kirsch, Synthesis, 2008, 3183;
(f) S. Kotha, M. Meshram and A. Tiwari, Chem. Soc. Rev., 2009, 38,
2065; (g) E. G. Occhiato, D. Scarpi and C. Prandi, Heterocycles, 2010,
80, 697.
2 For the synthesis of 1H-pyrrol-2(5H)-ones see: (a) Y. Ohfune and M.
Tomita, J. Am. Chem. Soc., 1982, 104, 3511; (b) J. Ackermann, M.
Matthes and C. Tamm, Helv. Chim. Acta, 1990, 73, 122; (c) N. Langlois,
N. Van Bac, N. Dahuron, J.-M. Delcroix, A. Deyine, D. Griffart-
Brunet, A. Chiaroni and C. Riche, Tetrahedron, 1995, 51, 3571; (d) M.
G. B. Drew, R. J. Harrison, J. Mann, A. J. Tench and R. J. Young,
Tetrahedron, 1999, 55, 1163; (e) A. G. M. Barret, J. Head, M. L. Smith,
N. S. Stock, A. J. P. White and D. J. Williams, J. Org. Chem., 1999,
64, 6005; (f) P. J. Dransfield, S. Wang, A. Dilley and D. Romo, Org.
Lett., 2005, 7, 1679; (g) S. Roy and C. Spino, Org. Lett., 2006, 8, 939;
(h) O. Ahmed, P. B. Hitchcock and D. W. Young, Org. Biomol. Chem.,
2006, 4, 1596; (i) J. F. Bower, S. Chakthong, J. Svenda, A. J. Williams,
R. M. Lawrence, P. Szeto and T. Gallagher, Org. Biomol. Chem., 2006,
4, 1868; (j) A. Gheorghem, M. Schulte and O. Reiser, J. Org. Chem.,
2006, 71, 2173; (k) C. Spino, L. Boisvert, J. Douville, S. Roy, S. Lauzon,
J. Minville, D. Gagnon, F. Beaumier and C. Chabot, J. Organomet.
Chem., 2006, 691, 5336; (l) S. Spiess, C. Berthold, R. Weihofen and G.
Helmchen, Org. Biomol. Chem., 2007, 5, 2357; (m) C. Curti, A. Sartori,
L. Battistini, G. Rassu, P. Burreddu, F. Zanardi and G. Casiraghi, J.
Org. Chem., 2008, 73, 5446; (n) G. B. Bajracharya, P. S. Koranne, R. N.
Nadaf, R. Kassem, M. Gabr, K. Takenaka, S. Takizawa and H. Sasai,
Chem. Commun., 2010, 46, 9064.
3 For the synthesis of 3,6-dihydro-1H-pyridin-2-ones see: (a) V. K.
Aggarwal, E. Alonso, G. Fang, M. Ferrara, G. Hynd and M. Porcelloni,
Angew. Chem., Int. Ed., 2001, 40, 1433; (b) J. G. Knight, I. M. Lawson
and C. N. Johnson, Synthesis, 2006, 227; (c) A. Niida, M. Mizumoto,
T. Narumi, E. Inokuchi, S. Oishi, H. Ohno, A. Otaka, K. Kitaura and
N. Fujii, J. Org. Chem., 2006, 71, 4118; (d) G. Calvet, N. Blanchard
and C. Kouklovsky, Org. Lett., 2007, 9, 1485; (e) A. G. Jamieson and
A. Sutherland, Org. Lett., 2007, 9, 1609; (f) J. H. Lee, S. Shin, J. Kang
and S. Lee, J. Org. Chem., 2007, 72, 7443; (g) S. Lauzon, F. Tremblay,
D. Gagnon, C. Godbout, C. Chabot, C. Mercier-Shanks, S. Perreault,
H. DeSe`ve and C. Spino, J. Org. Chem., 2008, 73, 6239; (h) H. Nomura
and C. J. Richards, Org. Lett., 2009, 11, 2892.
(6R)-6-Propylpiperidin-2-one (32)3h
The hydrogenation reaction was carried out as described above
using (6R)-6-propyl-3,6-dihydro-1H-pyridin-2-one (31) (0.07 g,
0.52 mmol). This gave (6R)-6-propylpiperidin-2-one (32) (0.07 g,
100%) as a white solid. Spectroscopic data consistent with
literature.3h Mp 73–76 ◦C; nmax/cm-1 (neat) 2960 (CH), 2360, 1653
(CO), 1410, 1215, 747; [a]2D5 -18.1 (c 1.3, CHCl3); dH (400 MHz,
CDCl3) 0.87 (3H, t, J 7.2 Hz, 3¢-H3), 1.21–1.41 (5H, m, 1¢-HH, 2¢-
H2 and 4-H2), 1.56–1.66 (1H, m, 5-HH), 1.79–1.87 (2H, m, 1¢-HH
and 5-HH), 2.21 (1H, ddd, J 13.6, 8.8, 4.8 Hz, 3-HH), 2.29–2.36
(1H, m, 3-HH), 3.26–3.32 (1H, m, 6-H), 5.76 (1H, br s, NH);
dC (100 MHz, CDCl3) 13.9 (CH3), 18.5 (CH2), 19.8 (CH2), 28.5
(CH2), 31.4 (CH2), 39.1 (CH2), 53.0 (CH), 172.3 (C); m/z (CI)
142.1236 (MH+. C8H16NO requires 142.1232), 113 (26%), 97 (42),
85 (78), 71 (100).
(6R)-N-(tert-Butoxycarbonyl)-6-propylpiperidine (33)18
To a solution of (6R)-6-propylpiperidin-2-one (32) (0.04 g,
0.31 mmol) in diethyl ether (50 mL) was added lithium aluminium
hydride (1.87 mL, 1.87 mmol, 1 M in diethyl ether). The reaction
was heated to 30 ◦C for 18 h. The reaction was quenched with 2 M
potassium hydroxide solution (10 mL) then partitioned between
diethyl ether (20 mL) and water (20 mL). The organic layer was
separated, washed with water (3 ¥ 20 mL), dried (MgSO4), filtered
and concentrated at atmospheric pressure and 40 ◦C. The resulting
residue was dissolved in diethyl ether (20 mL) and di-tert-butyl
dicarbonate (0.27 g, 1.25 mmol), 4-dimethylaminopyridine (0.02 g,
0.13 mmol) and triethylamine (0.18 mL, 1.31 mmol) were added.
The reaction was stirred at room temperature for 18 h, then
washed with 1 M hydrochloric acid (10 mL), saturated sodium
hydrogencarbonate solution (10 mL), and brine (10 mL). The or-
4 (a) F. I. McGonagle, L. Brown, A. Cooke and A. Sutherland, Org.
Biomol. Chem., 2010, 8, 3418; (b) F. I. McGonagle, L. Brown, A. Cooke
and A. Sutherland, Tetrahedron Lett., 2011, 52, 2330.
5 Methyl (2S)-2-hydroxy-3-phenylpropionate (7) can also be easily
prepared in two steps from L-phenylalanine. For example, see: (a) P.
Kock, Y. Nakatani, B. Luu and G. Ourisson, Bull. Soc. Chim. Fr., 1983,
11, 189; (b) W.-R. Li, W. R. Ewing, B. D. Harris and M. M. Joullie´, J.
Am. Chem. Soc., 1990, 112, 7659.
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6 L. S. Fowler, D. Ellis and A. Sutherland, Org. Biomol. Chem., 2009, 7,
4309.
7 W. Gensler, F. Johnson and D. Sloan, J. Am. Chem. Soc., 1960, 82,
6074.
8 P. Crabbe´, G. Garc´ıa and C. Rius, J. Chem. Soc., Perkin Trans. 1, 1973,
810.
9 A similar stereoselective reduction of benzyloxymethyl ether-protected
E-a,b-unsaturated ketones was previously reported: A. Chen, I. Savage,
E. J. Thomas and P. D. Wilson, Tetrahedron Lett., 1993, 34, 6769.
10 Attempted reduction of a,b-unsaturated ketones 10–12 with either
sodium or lithium borohydride gave the corresponding alcohols with
low diastereoselectivity (up to 3 : 1).
11 L. E. Overman and N. E. Carpenter, In: Organic Reactions, L. E.
Overman, Ed., Wiley: Hoboken, NJ, 2005, Vol. 66, 1-107 and references
therein.
13 Retention of stereochemistry during the Overman rearrangement of a
similar class of allylic secondary alcohol has previously been reported
by us: L. J. Drummond and A. Sutherland, Tetrahedron, 2010, 66,
5349. It should be noted that the yields for compounds 18 and 19 are
unoptimised.
14 Due to being partially unstable, (6R)-6-phenethyl-3,6-dihydro-1H-
pyridin-2-one (29) was hydrogenated to the corresponding piperidin-2-
one. This allowed isolation and full characterisation.
15 The enantiomeric excess of compound 23 was determined by chi-
ral HPLC against racemic standards. See experimental for full
details.
16 S. B. Davies and M. A. McKervey, Tetrahedron Lett., 1999, 40,
1229.
17 K. N. Fanning, A. G. Jamieson and A. Sutherland, Org. Biomol. Chem.,
2005, 3, 3749.
18 D. Enders and J. Tiebes, Liebigs Ann. Chem., 1993,
173.
12 T. Nishikawa, M. Asai, N. Ohyabu and M. Isobe, J. Org. Chem., 1998,
63, 188.
6770 | Org. Biomol. Chem., 2011, 9, 6761–6770
This journal is
The Royal Society of Chemistry 2011
©