Stereoselective syntheses of piperidinones and their modification by organometallic coupling reactions

Article abstract of DOI:10.1039/b615113b

Dehydropiperidinones stereoselectively obtained from N-arabinosyl imines were iodinated at the enaminone structure. Knochel iodine-magnesium exchange afforded Grignard compounds of these piperidinone derivatives which reacted, either directly or after tra

Full text of DOI:10.1039/b615113b

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Stereoselective syntheses of piperidinones and their modification by
organometallic coupling reactions
Birgit Kranke and Horst Kunz*
Received 17th October 2006, Accepted 13th November 2006
First published as an Advance Article on the web 30th November 2006
DOI: 10.1039/b615113b
Dehydropiperidinones stereoselectively obtained from N-arabinosyl imines were iodinated at the
enaminone structure. Knochel iodine–magnesium exchange afforded Grignard compounds of these
piperidinone derivatives which reacted, either directly or after transmetalation to zinc or copper
intermediates, with alkyl-, aryl- or acylhalides to give correspondingly substituted piperidinones.
Stereoselective conjugate allyl cuprate addition to a thus obtained 5-allyl dehydropiperidinone and
ring-closing metathesis of the product gave a hydroquinolinone containing three stereogenic centers.
Introduction
Numerous natural products feature the piperidine ring as an
essential pharmacophoric motif. Due to various substitution
patterns of piperidine compounds they exhibit a wide variety
of pharmacological properties. Therefore, efficient stereoselective
syntheses of highly functionalized piperidine derivatives are of
major interest to medicinal chemistry.
Recently, we reported the stereoselective synthesis of 2-
substituted N-arabinosyl dehydropiperidinones and their appli-
cation in the construction of chiral 2,3-, 2,5- and 2,6-substituted
piperidinones.1 We here describe the extension of this chemistry
to the preparation of 2,5-disubstituted piperidinones via iodine–
magnesium exchange and its use for the introduction of a range
of functionalities.
Scheme 1 Iodine magnesium exchange.
Results and discussions
The halogen–magnesium exchange2 provides mild conditions for
the synthesis of aryl,3 alkenyl4 and heterocyclic5 magnesium
species bearing sensitive reactive groups.
These organomagnesium derivatives on the one hand react
with various electrophiles, and on the other hand, easily undergo
Scheme 2 Iodination.
metal–metal exchange reactions. During studies on the synthesis
of functionalized piperidines we observed that 2-substituted N-
arabinosyl-5-iodo-5,6-dehydropiperidin-4-ones 1 readily undergo
iodine-magnesium exchange at −30 ◦C within one hour when
treated with isopropyl magnesium bromide in THF. The cor-
responding Knochel–Grignard compounds 2 react with various
electrophiles leading to 2,5-disubstituted piperidine derivatives of
type 3 (Scheme 1).
via an iodine–magnesium exchange, subsequent transmetalation
by treating the Grignard reagents with the THF-soluble copper
salt CuCN·2LiCl,6 and reaction of the formed cuprate with
allylbromide (Scheme 3).
The required halogenated dehydropiperidinones 1a–c are acces-
sible from dehydropiperidinones 4a–c1 by electrophilic iodination
with N-iodosuccinimide exploiting the enamine moiety of 4
(Scheme 2).
Transformation of 5-iododehydropiperidinones 1a and 1b to
5-allyl dehydropiperidinone derivatives 5a and 5b was achieved
Scheme 3 Copper mediated allylation.
Institut fu¨r Organische Chemie, Johannes Gutenberg-Universita¨t Mainz,
Duesbergweg 10-14, 55128, Mainz, Germany. E-mail: hokunz@
uni-mainz.de; Fax: +49 (0)6131 392 4786; Tel: +49 (0)6131 392 2334
Benzoylation of dehydropiperidinone was carried out in a sim-
ilar manner. After iodine–magnesium exchange and subsequent
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transmetalation with CuCN·2LiCl, the intermediate copper com-
pound was treated with benzoyl chloride affording 5-benzoyl
derivative 6 (Scheme 4).
in Scheme 7. Treatment of 5b with an activated allylcuprate
(Yamamoto type cuprate)9 led to N-glycosyl-2,3-diallyl-6-
isopropypiperidinone 10 (Scheme 7).
Scheme 4 Copper mediated benzoylation.
In contrast, formylation was achieved directly without pre-
ceding transmetalation of the formed Grignard reagent.7 Thus,
1b was first treated with iPrMgBr at −30 ◦C for 1 h followed
by addition of N,N-dimethyl formamide leading to 5-formyl
dehydropiperidinone 7 (Scheme 5).
Scheme 7 Cuprate addition and ring closing metathesis.
The relative stereochemistry of the major diastereomer of 10
was determined unequivocally by X-ray analysis. Knowing the
absolute stereochemistry of the arabinosyl fragment, this then
allowed the absolute configuration of the compound 10 to be
deduced (Fig. 1). Interestingly, in this case a 2,6-trans configura-
tion was observed, whereas cuprate addition to 2-substituted N-
arabinosyl dehydropiperidinones, such as 4, preferentially yielded
2,6-cis-configured piperidinones.1 Probably, sterical hindrance by
the 2-isopropyl and the 5-allyl substituents prevents the C1–N-
rotamer shown in formula 5b to convert to the more reactive
rotamer exposing the (Re)-side at C-6 for nucleophilic attack.10 The
latter rotamer, however, is the one by which compounds like 4 react
to preferentially give the 2,6-cis-disubstituted piperidinones.1,11
Scheme 5 Formylation of the organomagnesium species.
Furthermore, Grignard reagents of type 2 also undergo
magnesium–zinc transmetalation leading to organozinc deriva-
tives which are suitable for the application in Negishi cross-
coupling8 reactions.
Thus, conversion of the iododehydropiperidinone 1a into the
corresponding Grignard reagent and transmetalation using ZnBr2
provided organozinc species 8 which was subjected to a palladium
catalyzed coupling reaction with 4-iodobenzoic acid methyl ester
furnishing 2,5-aryl dehydropiperidinone 9 (Scheme 6).
Fig. 1 X-Ray-analysis of piperidinone 10.
The crystal structure of 10 (Fig. 1) shows that the nitrogen
heterocycle adopts a chair conformation with a pyramidally
configured nitrogen due to the exoanomeric effect. The allyl
substituents are in axial positions. The planes of the carbohydrate
and the nitrogen heterocyles are almost perpendicular to each
other, enabling overlap of the nitrogen’s nonbonding orbital and
the r* orbital of the carbohydrate’s C1–O bond.
Scheme 6 Negishi coupling.
The further elaboration of 2,5-disubstituted dehydropiperidi-
nones to provide 2,5,6-trisubstituted piperidinones is illustrated
350 | Org. Biomol. Chem., 2007, 5, 349–354
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ꢀ
ꢀ
In the presence of Grubb’s catalyst 11, diallyl piperidinone 10
underwent ring closing metathesis yielding octahydrochinolinone
12 in quantitative yield (Scheme 7). This methodology offers an
alternative route to the synthesis of trans-hydroquinolines usually
achieved by intramolecular aldol condensation.11
(t, 1H, J2,3a = 6.3 Hz, J2,3b = 6.3 Hz, H-2), 4.37 (d, 1H, J1 ,2
=
9.0 Hz, H-1ꢀ), 3.85 (dd, 1H, J5 a,5 b = 13.3 Hz, J5 a,4 = 2.0 Hz,
ꢀ
ꢀ
ꢀ
ꢀ
H-5ꢀa), 3.49 (d, 1H, J5 b,5 a = 12.9 Hz, H-5ꢀb), 3.05 (dd, 1H, J3a,3b
=
ꢀ
ꢀ
16.4 Hz, J3a,2 = 6.2 Hz, H-3a), 2.83 (dd, 1H, J3b,3a = 16.4 Hz,
J3b,2 = 6.3 Hz, H-3b), 1.23, 1.16, 1.10 (3s, 9H each, C(CH3)3); dC
=
(75.4 MHz, CDCl3) 184.9 (C-4), 177.2, 177.1, 177.0 (pivC O),
154.7 (C-6), 136.8 (ipso-aryl), 134.2 (ipso-aryl), 129.1, 128.0 (aryl),
89.8 (C-1ꢀ), 70.8, 67.7, 66.0 (C-2ꢀ, C-3ꢀ, C-4ꢀ), 66.1 (C-5ꢀ), 57.9
(C-2), 42.1 (C-3), 39.0, 38.9, 38.8 (pivquart), 27.2, 27.1, 27.0 (piv-
CH3). m/z (ESI) 718.2 (M(35Cl)+H), 720.2 (M(37Cl)+H), 740.2
(M(35Cl)+Na), 742.2 (M(37Cl)+Na); HRMS (ESI, m/z) calcd for
C31H42Cl INO8 (M + H) 718.1638, found 718.1634.
Conclusions
In conclusion, enantiomerically pure di- and trisubstituted
piperidine derivatives are accessible from N-glycosyl dehy-
dropiperidinones 4 by regioselective iodination of their enaminone
structure, subsequent Knochel iodine–magnesium exchange and
organometallic C–C-coupling reactions at the enamine structure
of the chiral aliphatic nitrogen heterocycles. Attractive structural
elements such as b-arylethylamine (9) or hydroquinoline deriva-
tives (12) have been synthesized on the basis of this chemistry.
In this reaction N-glycosyl dehydropiperidinones proved versa-
tile precursors of highly substituted nitrogen heterocycles which
are valuable compounds for medicinal chemistry.
(2R)-N-(2ꢀ,3ꢀ,4ꢀ-Tri-O-pivaloyl-a-D-arabinopyranosyl)-5-iodo-2-
isopropyl-5,6-dehydropiperidin-4-one (1b). Iododehydropiperidi-
none 1b was synthesized according to the general procedure using
4b1 (4.0 g, 7.6 mmol) and N-iodosuccinimide (5.4 g, 24 mmol).
Purification was accomplished by flash chromatography to yield
1b (4.31 g, 6.6 mmol, 87%) as colourless amorphous solid. Rf =
0.49 (cyclohexane–ethyl acetate = 2 : 1); [a]2D2 +122.00 (c 1 in
CHCl3); dH (300 MHz, CDCl3) 7.45 (s, 1H, H-6), 5.53 (t, 1H,
Experimental
J2 ,1 = 9.6 Hz, J2 ,3 = 9.6 Hz, H-2ꢀ), 5.26–5.21 (m, 1H, H-4ꢀ),
ꢀ
ꢀ
ꢀ ꢀ
All moisture/air sensitive reactions were carried out under a pos-
itive pressure of argon in oven dried glassware. Dry THF was dis-
tilled from potassium benzophenone ketyl. Dry dichloromethane
was distilled from calcium hydride.
Optical rotation values were measured on a Perkin Elmer 241
polarimeter at k 546 nm and 578 nm and extrapolated to k
589 nm. The values are quoted in 10−1 deg cm2 g−1 and the
concentrations are given in g per 100 ml. Nuclear magnetic
resonance spectra were recorded on a Bruker AC-200, AC-300
or AM-400 NMR spectrometer. ESI mass spectra were recorded
on a Navigator 1 instrument from ThermoQuest or a Finnigan
MAT 95 spectrometer.
5.12 (dd, 1H, J3 ,2 = 9.9 Hz, J3 ,4 = 3.3 Hz, H-3ꢀ), 4.51 (d, 1H,
ꢀ
ꢀ
ꢀ ꢀ
J1 ,2 = 9.2 Hz, H-1ꢀ), 4.03 (dd, 1H, J5 a,5 b = 13.2 Hz, J5 a,4
=
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
2.2 Hz, H-5ꢀa), 3.68 (d, 1H, J5 b,5 a = 13.2 Hz, H-5ꢀb), 3.68–3.60
(m, 1H, H-2), 2.77–2.70 (m, 2H, H-3a, H-3b), 2.34–2.17 (m,
1H, CH(CH3)2), 1.26, 1.12, 1.11 (3s, 9H each, piv-CH3), 0.88
(d, 3H, J = 7.0 Hz, CH3), 0.87 (d, 3H, J = 6.6 Hz, CH3); dC
ꢀ
ꢀ
=
(75.4 MHz, CDCl3) 186.2 (C-4), 177.2, 177.0, 177.0 (pivC O),
154.8 (C-6), 91.6 (C-1ꢀ), 71.1, 67.8, 66.2 (C-2ꢀ, C-3ꢀ, C-4ꢀ), 66.2
(C-5ꢀ), 64.2 (C-5), 58.8 (C-2), 39.0, 39.0, 38.8 (pivquart), 34.7 (C-3),
32.3 (CH(CH3)3), 27.2, 27.1, 27.0 (piv-CH3), 19.6, 17.6 (CH3);
m/z (ESI) 650.3 (M + H), 672.2 (M + Na), 688.2 (M + K);
HRMS (ESI, m/z) calcd for C28H45INO8 (M + H) 650.2185,
found 650.2186.
General procedure for the preparation of 1
To a solution of N-arabinosyl dehydropiperidinone 4 (1 mmol)
in dry THF (20 mL) were added several equivalents (see details
for each compound below) of solid N-iodosuccinimide at −78 ◦C
and stirred until the starting material was completely consumed.
The solution was diluted with diethyl ether (100 mL), washed with
10% aq. Na2S2O3 (3 × 20 mL), and the resulting aqueous layers
were extracted with diethyl ether (3 × 20 mL). The combined
organic phases were washed with brine, dried over MgSO4 and
concentrated in vacuo. The crude product was purified by flash
chromatography.
(2S)-N-(2ꢀ,3ꢀ,4ꢀ-Tri-O-pivaloyl-a-D-arabinopyranosyl)-5-iodo-2-
n-propyl-5,6-dehydropiperidin-4-one (1c). Iododehydropiperidi-
none 1c was synthesized according to the general procedure using
4c1 (524 mg, 1 mmol) and N-iodosuccinimide (900 mg, 4 mmol).
Purification was carried out by flash chromatography (petroleum
ether–ethyl acetate = 8 : 1) to yield 1c (450 mg, 0.7 mmol, 69%) as
a colourless amorphous solid. Rf = 0.57 (petroleum ether–ethyl
acetate = 2 : 1); [a]D26 123.19 (c 1, CHCl3); dH (400 MHz, CDCl3)
7.37 (s, 1H, H-6), 5.50 (t, J2 ,1 = 9.6 Hz, J2 ,3 = 9.6 Hz, H-2ꢀ),
ꢀ
ꢀ
ꢀ ꢀ
5.27–5.23 (m, 1H, H-4ꢀ), 5.12 (dd, 1H, J3 ,2 = 10.0 Hz, J3 ,4
=
ꢀ
ꢀ
ꢀ ꢀ
(2R)-N -(2ꢀ,3ꢀ,4ꢀ -Tri-O-pivaloyl-a-D-arabinopyranosyl)-2-(p-
chlorophenyl)-5-iodo-5,6-dehydropiperidin-4-one (1a). Iododehy-
dropiperidinone 1a was synthesized according to the general pro-
cedure using 4a1 (1.18 g, 2 mmol) and N-iodosuccinimide (1.35 g,
6 mmol). Purification was carried out by flash chromatography
(petroleum ether–ethyl acetate = 6 : 1) to yield 1a (1.33 g, 1.9 mmol,
93%) as a colourless solid. Rf = 0.65 (petroleum ether–ethyl
3.3 Hz, H-3 ), 4.47 (d, 1H, J1 ,2 = 9.0 Hz, H-1ꢀ), 4.03 (dd, 1H,
ꢀ
ꢀ
ꢀ
J5 a,5 b = 13.3 Hz, J5 a,4 = 2.3 Hz, H-5ꢀa), 3.85–3.76 (m, 1H,
ꢀ
ꢀ
ꢀ
ꢀ
H-2), 3.69 (d, 1H, J5 b,5 a = 13.3 Hz, H-5ꢀb), 2.72 (dd, 1H, J3a,3b
=
ꢀ
ꢀ
16.6 Hz, J3a,2 = 5.7 Hz, H-3a), 2.67 (dd, 1H, J3b,3a = 16.64 Hz,
J3b,2 = 2.6 Hz, H-3b), 1.90–1.78 (m, 1H, CH2), 1.67–1.55 (m, 2H,
CH2), 1.40–1.28 (m, 1H, CH2), 1.25 (s, 9H, piv-CH3), 1.11 (s, 18H,
piv-CH3), 0.86 (t, 3H, J = 7.2 Hz, CH3); dC (100.6 MHz, CDCl3)
◦
acetate = 2 : 1); mp: 205 C under decomposition; [a]2D2 +3.77
185.8 (C-4), 177.2, 177.2, 177.0 (pivC O), 154.4 (C-6), 91.7
=
(c 1 in CHCl3). dH (400 MHz, CDCl3) 7.70 (s, 1H, H-6), 7.27 (d,
1H, J = 4.3 Hz, aryl), 7.17 (d, 1H, J = 8.6 Hz, aryl), 5.56 (t,
(C-1ꢀ), 70.8, 67.8, 66.3 (C-2ꢀ, C-3ꢀ, C-4ꢀ), 66.4 (C-5ꢀ), 63.1 (C-5),
53.5 (C-2), 38.9, 38.9, 38.8 (pivquart), 37.9, 32.8 (C-3, CH2), 27.1,
27.1, 27.0 (piv-CH3), 18.8 (CH2), 13.7 (CH3); m/z (ESI) 446.04
(M-2 × pivOH + H), 650.21 (M + H), 672.19 (M + Na), 713.08
1H, J2 ,1 = 9.6 Hz, J2 ,3 = 9.6 Hz, H-2ꢀ), 5.18–5.13 (br s, 1H,
ꢀ
ꢀ
ꢀ ꢀ
H-4ꢀ), 5.05 (dd, 1H, J3 ,2 = 10.0 Hz, J3 ,4 = 3.3 Hz, H-3ꢀ), 4.91
ꢀ
ꢀ
ꢀ ꢀ
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=
J = 7.2 Hz, CH3); dC (75.4 MHz, CDCl3) 191.3 (C O), 177.3,
(M + Na + CH3CN); HRMS (ESI, m/z) calcd for C28H44INO8Na
(M + Na) 672.2004, found 672.1999.
=
=
177.1, 176.9 (PivC O), 148.2 (C-6), 136.7 (–CH2CH CH2),
ꢀ
=
115.5 (–CH2CH CH2), 109.6 (C-5), 91.3 (C-1 ), 71.5, 68.1, 65.8
(2R)-N-(2ꢀ,3ꢀ,4ꢀ-Tri-O-pivaloyl-a-D-arabinopyranosyl)-5-allyl-2-
(C-2ꢀ, C-4ꢀ, C-3ꢀ), 66.0 (C-5ꢀ), 59.2 (C-2), 38.9, 38.9, 38.7 (Pivquart),
(p-chlorophenyl)-5,6-dehydropiperidin-4-one
(5a). Isopropyl-
=
35.7 (C-3), 31.7 (–CH(CH3)2), 30.7 (–CH2CH CH2), 27.1, 27.0
magnesium bromide (4.2 mL, 2.1 mmol, 0.5 M in THF) was
added dropwise to a cold (−40 ◦C) solution of 1a (3.0 g, 4.2 mmol)
in THF (10 mL). The reaction mixture was stirred at −30 ◦C
until complete consumption of the starting material was detected
by TLC (1 h). Subsequently, a solution of CuCN·2LiCl in THF
(1 M, 4.2 mL, 4.2 mmol) was added, and the reaction mixture
was stirred for 30 min at −30 ◦C. After addition of allylbromide
(0.7 mL, 8.4 mmol), the mixture was warmed up to rt, stirred for
5 h and quenched with sat. NH4Cl–NH4OH (20 mL, 9 : 1, v/v).
The mixture was poured into water (50 mL) and extracted with
diethylether (3 × 100 mL). The combined organic layers were
dried over MgSO4 and concentrated in vacuo. The product was
purified by flash chromatography (silica gel, cyclohexane–ethyl
acetate = 6 : 1) yielding 5a (1.9 g, 3.0 mmol, 71%) as a colourless
amorphous solid. Rf = 0.47 (cyclohexane–ethyl acetate = 2 : 1);
[a]2D2 −20.41 (c 1 in CHCl3); dH (400 MHz, CDCl3) 7.30 (d, 2H,
J = 8.6 Hz, aryl), 7.21 (d, 2H, J = 8.6 Hz, aryl), 7.14 (s, 1H, H-6),
=
(PivCH3), 19.6 (CH3), 17.6 (CH3); m/z (ESI) 258.2 (M-3x PivOH
+ H), 360.4 (M-2 × PivOH + H), 385.4 (arabinosyl), 462.4
(M-PivOH + H), 484.4 (M-PivOH + Na), 564.4 (M + H), 586.4
(M + Na), 602.4 (M + K), 627.5 (M + Na + MeCN), 643.6 (M
+ K + MeCN); HRMS (ESI, m/z) calcd for C31H50NO8 (M + H)
564.3531, found 564.3532.
(2R)-N-(2ꢀ,3ꢀ,4ꢀ-Tri-O-pivaloyl-a-D-arabinopyranosyl)-5-benzoyl-
2-isopropyl-5,6-dehydropiperidin-4-one
(6). Isopropylmagne-
sium bromide (0.52 mL, 0.26 mmol, 0.5 M in THF) was added
dropwise to a cold (−40 ◦C) solution of 1b (130 mg, 0.2 mmol) in
THF (2 mL) and stirred at −30 ◦C until the starting material was
completely consumed. Subsequently, a solution of CuCN·2LiCl
in THF (1 M, 0.26 mL, 0.26 mmol) was added, and the mixture
was stirred for 30 min at −30 ◦C. After addition of benzoyl
chloride (0.05 mL, 0.40 mmol) the reaction mixture was allowed
to warm to rt, stirred for 1 h and then quenched by the addition
of sat. NH4Cl solution (1 mL). The mixture was poured into
water (10 mL) and extracted with diethylether (3 × 10 mL).
The combined organic layers were washed with brine, dried over
MgSO4 and concentrated in vacuum. The residue was purified by
flash chromatography (silica gel, cyclohexane–ethyl acetate = 4 :
1) to give 6 (79 mg, 0.13 mmol, 63%) as a light yellow solid. Rf =
0.26 (cyclohexane–ethyl acetate = 2 : 1); [a]2D2 +1.85 (c 1 in CHCl3);
dH (300 MHz, CDCl3) 8.03 (s, 1H, H-6), 7.56–7.28 (m, 5H, aryl),
ꢀ
ꢀ
5.85–5.72 (m, 1H, –CH2–CH CH2), 5.60 (t, 1H, J2 , 1 = 9.6 Hz,
J2 , 3 = 9.6 Hz, H-2ꢀ), 5.14–5.10 (m, 1H, H-4ꢀ), 5.07–5.03 (m
ꢀ
ꢀ
=
=
ꢀ
ꢀ
1H, CH CH2), 5.02–5.00 (m, 1H, CH2), 4.96 (dd, 1H, J3 , 2
=
=
9.8 Hz, J3 , 4 = 3.1 Hz, H-3ꢀ), 4.75 (dd, 1H, J2, 3a = 9.8 Hz, J2, 3b
ꢀ
ꢀ
5.5 Hz, H-2), 4.18 (d, 1H, J1 , 2 = 9.4 Hz, H-1ꢀ), 3.82 (dd, 1H,
ꢀ
ꢀ
J5 a, 5 b = 13.3 Hz, J5 a, 4 = 2.0 Hz, H-5ꢀa), 3.38 (d, 1H, J5 b, 5 a
=
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
=
12.5 Hz, H-5 b), 2.98–2.83 (m, 2H, –CH2–CH CH2), 2.73 (dd,
1H, J3a, 3b = 16.4 Hz, J3a, 2 = 5.5 Hz, H-3a), 2.64 (dd, 1H, J3a, 3b
=
5.57 (t, 1H, J2 ,1 = 9.6 Hz, J2 ,3 = 9.6 Hz, H-2ꢀ), 5.31–5.24 (m,
ꢀ
ꢀ
ꢀ ꢀ
16.4 Hz, J3b, 2 = 9.8 Hz, H-3b), 1.22, 1.14, 1.09 (3s, 9H each,
Piv-CH3); dC (50.3 MHz, CDCl3) 190.4 (C-4), 177.2, 177.1, 176.9
1H, H-4ꢀ), 5.17 (dd, 1H, J3 ,2 = 9.9 Hz, J3 ,4 = 3.3 Hz, H-3ꢀ),
ꢀ
ꢀ
ꢀ ꢀ
(PivC O), 147.8 (C-6), 137.1 (ipso-aryl), 136.1 (CH2CH CH2),
4.76 (d, 1H, J1 ,2 = 8.8 Hz, H-1ꢀ), 4.08 (dd, 1H, J5 a,5 b = 13.2 Hz,
=
=
ꢀ
ꢀ
ꢀ
ꢀ
134.3 (ipso-aryl), 129.1, 128.7 (aryl), 116.2 (CH2CH CH2),
J5 a,4 = 2.2 Hz, H-5ꢀa), 3.83–3.73 (m, 1H, H-2), 3.74 (d, 1H,
=
ꢀ
ꢀ
113.0 (C-5), 88.7 (C-1ꢀ), 71.3, 68.0, 65.5 (C-2ꢀ, C-3ꢀ, C-4ꢀ), 65.9
(C-5ꢀ), 59.7 (C-2), 43.8 (C-3), 39.0, 38.9, 38.8 (Pivquart), 30.7
J5 b,5 a = 13.6 Hz, H-5ꢀb), 2.72 (dd, 1H, J3a,3b = 16.9 Hz, J3a,2
=
ꢀ
ꢀ
8.1 Hz, H-3a), 2.51 (d, 1H, J3b,3a = 16.9 Hz, H-3b), 2.50–2.36
(m, 1H, CH(CH3)2), 1.26, 1.12, 1.10 (3s, 9H each, C(CH3)3),
0.95 (d, 3H, J = 7.0 Hz, CH(CH3)2), 0.92 (d, 3H, J = 7.4 Hz,
=
(CH2CH CH2), 27.2, 27.2, 27.0 (Piv-CH3); HRMS (ESI, m/z)
calcd for C34H46ClNO8 (M+) 632.2985, found 632.2986.
=
CH(CH3)2); dC (75.4 MHz, CDCl3) 191.8 (C-4), 188.2 (Ph–C O),
(2R)-N-(2ꢀ,3ꢀ,4ꢀ-Tri-O-pivaloyl-a-D-arabinopyranosyl)-5-allyl-2-
isopropyl-5,6-dehydropiperidin-4-one (5b). Compound 5b was
prepared according to the above procedure for the synthesis of
5a using 1b (1.04 g, 1.6 mmol), dry THF (10 mL), isopropyl
magnesium bromide (4.2 mL, 2.1 mmol, 0.5 M in THF),
CuCN·2LiCl solution (1.6 mL, 1.6 mmol, 1 M in THF) and
allylbromide (0.3 mL, 3.2 mmol). Purification was achieved by
flash chromatography on silica gel to afford 5b (0.71 g, 1.30 mmol,
79%) as a colourless amorphous solid. Rf = 0.40 (cyclohexane–
ethyl acetate = 2 : 1); [a]2D4 +72.65 (c 1, CHCl3); dH (400 MHz,
=
177.2, 177.1, 176.9 (PivC O), 158.0 (C-6), 139.7 (ipso-aryl),
131.4, 128.8, 127.6 (phenyl), 111.4 (C-5), 93.5 (C-1ꢀ), 70.8, 67.7,
66.0 (C-2ꢀ, C-3ꢀ, C-4ꢀ), 66.5 (C-5ꢀ), 58.9 (C-2), 39.0, 38.8 (Pivquart),
35.8 (C-3), 33.2 (CH(CH3)2), 27.2, 27.1, 27.0 (PivCH3), 19.4, 17.3
(CH3); m/z (ESI) 266.1 (dehydropiperidinone− + H + Na), 307.1
(dehydropiperidinone− + H + Na + MeCN), 385.2 (arabinosyl),
628.3 (M + H), 650.3 (M + Na), 666.2 (M + K), 691.3 (M + Na
+ MeCN).
(2S)-N-(2ꢀ,3ꢀ,4ꢀ-Tri-O-pivaloyl-a-D-arabinopyranosyl)-5-formyl-
2-n-propyl-5,6-dehydropiperidin-4-one (7). Isopropylmagnesium
bromide (0.65 mL, 0.33 mmol, 0.5 M in THF) was added dropwise
to a solution of 1c (162 mg, 0.25 mmol) in dry THF (5 mL)
at −35 ◦C. The solution was stirred at −30 ◦C until complete
consumption of the starting material was detected by TLC (1 h).
After addition of N,N-dimethylformamide (0.04 mL, 0.50 mmol),
the solution was slowly warmed up to rt overnight and the
reaction was quenched by the addition of sat. NH4Cl (5 mL). The
mixture was extracted with diethyl ether (3 × 10 mL), and the
combined organic phases were dried over MgSO4. The solvent
was evaporated in vacuo and the product was purified by flash
=
CDCl3) 6.88 (s, 1H, H-6), 5.80–5.67 (m, 1H, −CH2–CH CH2),
5.60 (t, 1H, J2 , 1 = 9.6 Hz, J2 , 3 = 9.6 Hz, H-2ꢀ), 5.25–5.20
ꢀ
ꢀ
ꢀ
ꢀ
(m, 1H, H-4ꢀ), 5.11 (dd, 1H, J3 , 2 = 9.8 Hz, J3 , 4 = 3.1 Hz,
ꢀ
ꢀ
ꢀ
ꢀ
H-3ꢀ), 5.03–4.92 (m, 2H, CH2), 4.48 (d, 1H, J1 , 2 = 9.4 Hz,
=
ꢀ
ꢀ
H-1ꢀ), 3.98 (dd, 1H, J5 a, 5 b = 13.3 Hz, J5 a, 4 = 2.0 Hz, H-5ꢀa),
ꢀ
ꢀ
ꢀ
ꢀ
3.65 (d, 1H, J5 b, 5 a = 13.3 Hz, H-5ꢀb), 3.54–3.47 (m, 1H, H-2),
ꢀ
ꢀ
=
2.90 (dd, 1H, Jgem = 15.4 Hz, Jvic = 6.4 Hz, –CH2–CH CH2),
=
2.73 (dd, 1H, Jgem = 15.6 Hz, Jvic = 7.0 Hz, −CH2–CH CH2),
2.58 (dd, 1H, J3a, 3b = 16.8 Hz, J3, 2 = 7.4 Hz, H-3a), 2.43 (dd,
1H, J3a, 3b = 16.8 Hz, J3, 2 = 3.5 Hz, H-3), 2.26–2.16 (m, 1H,
–CH–(CH3)2), 1.25, 1.11, 1.09 (3s, 9H each, Piv-CH3), 0.88 (t, 6H,
352 | Org. Biomol. Chem., 2007, 5, 349–354
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chromatography on silica gel (cyclohexane–ethyl acetate = 4 : 1)
to afford 7 (66 mg, 0.12 mmol, 48%) as colourless amorphous
solid. Rf = 0.22 (cyclohexane–ethyl acetate = 2 : 1); [a]2D2 +21.02 (c
1 in CHCl3); dH (300 MHz, CDCl3) 9.80 (s, 1H, CHO), 7.87 (s, 1H,
(2R,5R,6S)-N-(2ꢀ,3ꢀ,4ꢀ -Tri-O-pivaloyl-a-D-arabino-pyranosyl)-
5,6-diallyl-2-isopropylpiperidin-4-one (10). A solution of allyl-
magnesium bromide (2 mL, 2 mmol, 1 M in diethyl ether) was
added to a suspension of copper cyanide (179 mg, 2 mmol) in dry
THF (10 mL) at −40 ◦C and stirred for 30 min. Subsequently, the
mixture was cooled to −78 ◦C and BF3·OEt2 (0.25 mL, 2 mmol)
was added. After 15 min, 5b (225 mg, 0.4 mmol) in dry THF
(10 mL) was added to the cuprate and the mixture was stirred for
3 h at −78 ◦C. The reaction was terminated by the addition of conc.
NH4OH–sat. NH4Cl (1 : 1 v/v, 20 mL). The mixture was allowed
to warm to room temperature, diluted with diethyl ether (50 mL),
and the layers were separated. The organic phase was washed
with conc. NH4OH–sat. NH4Cl (1 : 1, v/v). The aqueous layers
were extracted with diethyl ether. The combined organic phases
were washed with brine, dried over MgSO4 and concentrated in
vacuo. Purification was achieved by flash chromatography on silica
gel to afford 145 mg (0.24 mmol, 60%) of 10 as colourless solid.
H-6), 5.52 (t, 1H, J2 ,1 = 9.4 Hz, J2 ,3 = 9.4 Hz, H-2ꢀ), 5.32–5.26
ꢀ
ꢀ
ꢀ ꢀ
(m, 1H, H-4ꢀ), 5.16 (dd, 1H, J3 ,2 = 9.9 Hz, J3 ,4 = 3.3 Hz, H-3ꢀ),
ꢀ
ꢀ
ꢀ ꢀ
4.66 (d, 1H, J1 ,2 = 8.8 Hz, H-1ꢀ), 4.10 (dd, 1H, J5 a,5 b = 13.2 Hz,
ꢀ
ꢀ
ꢀ
ꢀ
J5 a,4 = 1.8 Hz, H-5ꢀa), 3.94–3.82 (m, 1H, H-2), 3.76 (d, 1H,
ꢀ
ꢀ
J5 b,5 a = 13.2 Hz, H-5ꢀb), 2.67 (dd, 1H, J3a,3b = 16.5 Hz, J3a,2
=
ꢀ
ꢀ
5.9 Hz, H-3a), 2.43 (d, 1H, J3b,3a = 16.5 Hz, H-3b), 1.86–1.58 (m,
2H, CH2), 1.45–1.15 (m, 2H, CH2), 1.26, 1.11, 1.05 (3s, je 9H,
C(CH3)3), 0.87 (t, 3H, J = 7.4 Hz, CH3); dC (75.4 MHz, CDCl3)
=
190.0 (C-4), 186.1 (CHO), 177.2, 177.0, 176.9 (PivC O), 153.8
(C-6), 110.5 (C-5), 93.3 (C-1ꢀ), 70.4, 67.5, 66.0 (C-2ꢀ, C-3ꢀ, C-4ꢀ),
66.7 (C-5ꢀ), 53.8 (C-2), 38.9, 38.9, 38.8 (Pivquart), 38.2 (C-3), 33.5
(CH2), 27.1, 27.1, 27.0 (PivCH3), 18.8 (CH2), 13.6 (CH3); m/z
(ESI) 552.3 (M + H), 574.3 (M + Na), 590.3 (M + K), 1103.6
(2M + H), 1125.6 (2M + Na), 1141.6 (2M + K); HRMS (ESI,
m/z) calcd for C29H46NO9 (M + H) 552.3167, found 552.3165.
◦
Mp: 129 C; Rf = 0.44 (cyclohexane–ethyl acetate = 5 : 1); [a]D22
−10.79 (c 1 in CHCl3); diastereomeric ratio 90 : 10 (determined
by HPLC); HPLC: gradient: 85% CH3CH, 15% H2O → 95%
CH3CN, 5% H2O (20 min); Rt (min) = 21.35 (main diastereomer),
23.52 (second diastereomer); dH (400 MHz, CDCl3) 5.75–5.50 (m,
=
(2R)-N -(2ꢀ,3ꢀ,4ꢀ -Tri-O-pivaloyl-a-D-arabinopyranosyl)-2-(p-
chlorphenyl)-5-p-(methoxycarbonyl)phenyl-5,6-dehydropiperidin-
4-one (9). To a solution of 1a (180 mg, 0.25 mmol) in dry
THF (5 mL) was added dropwise isopropylmagnesium bromide
(0.6 mL, 0.3 mmol, 0.5 M in THF) at −30 ◦C. After complete con-
version of the starting material (2 h), ZnBr2 (0.5 mL, 0.5 mmol, 1 M
in THF) was added and the mixture was warmed up to room tem-
perature. In a second flask, bis(dibenzylidenacetone)palladium
(14.4 mg, 0.025 mmol) and triphenylarsine (31 mg, 0.10 mmol)
in dry THF (2 mL) were stirred for 5 min for the formation
of the active catalyst. 4-Iodobenzoic acid methylester (131 mg,
0.5 mmol) in dry THF (1 mL), and subsequently the solution
ꢀ
ꢀ
ꢀ
ꢀ
2H, 2 × –CH2–CH CH2), 5.68 (t, 1H, J2 , 1 = 9.2 Hz, J2 , 3
=
9.2 Hz, H-2ꢀ), 5.22–5.17 (m, 1H, H-4ꢀ), 5.09 (dd, 1H, J3 , 2 = 9.4 Hz,
ꢀ
ꢀ
ꢀ
=
ꢀ
ꢀ
J3 , 4 = 3.5 Hz, H-3 ), 5.06–4.88 (m, 4H, 2 × CH2), 4.53 (d, 1H,
J1 , 2 = 9.4 Hz, H-1ꢀ), 3.85 (dd, 1H, J5 a, 5 b = 13.1 Hz, J5 a, 4
=
=
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
2.2 Hz, H-5ꢀa), 3.55–3.43 (m 1H, H-2), 3.48 (d, 1H, J5 b, 5 a
ꢀ
ꢀ
12.9 Hz, H-5ꢀb), 3.39–3.30 (m, 1H, H-6), 2.94–2.83 (m, 1H, H-
=
3a), 2.54–2.34 (m, 2H, H-5, 1 × –CH2–CH CH2), 2.27–2.04 (m,
=
5H, H-3b, 3 × –CH2–CH CH2, CH(CH3)2), 1.23, 1.14, 1.12 (3s,
9H each, Piv-CH3), 0.93 (d, 3H, J = 6.7 Hz, CH3), 0.89 (d, 3H,
J = 6.6 Hz); dC (100.6 MHz, CDCl3) 212.5 (C-4), 177.5, 177.3,
◦
=
=
=
prepared from 1a were added stirred at 40 C. The reaction was
176.7 (PivC O), 134.9 (CH2 CHCH2–), 134.6 (CH2 CHCH2–),
ꢀ
=
=
terminated by the addition of sat. NH4Cl (2 mL). The mixture
was diluted with water (10 mL) and extracted with diethyl ether
(3 × 15 mL). The combined organic phases were washed with
brine and dried over MgSO4. The product was purified by flash
chromatography on silica gel (cyclohexane–ethyl acetate = 5 : 1)
to afford 9 (93 mg, 0.13 mmol, 51%) as pale yellow amorphous
solid. Rf = 0.35 (cyclohexane–ethyl acetate = 2 : 1); [a]26 −7.41
(c = 1, CHCl3); dH (300 MHz, CDCl3) 7.97 (d, 2H, J =D8.4 Hz,
C6H4–COOMe), 7.57 (s, 1H, H-6), 7.47 (d, 2H, J = 8.5 Hz, C6H4–
COOMe), 7.31 (d, 2H, J = 8.5 Hz, C6H5–Cl), 7.24 (d, 2H, J =
117.6 (CH2 CHCH2–), 116.3 (CH2 CHCH2-), 87.9 (C-1 ), 73.3,
68.2, 65.3 (C-2ꢀ, C-3ꢀ, C-4ꢀ), 65.0 (C-5ꢀ), 58.0 (C-2), 56.4 (C-6),
=
53.0 (C-5), 38.9, 38.8, 38.8 (Pivquart), 37.0, 36.5 (CH2 CHCH2–
), 36.1 (C-3), 27.2, 27.1, 27.1 (Piv-CH3), 26.6 (–CH(CH3)2), 19.8
(CH3), 14.1 (CH3); m/z (ESI) 300.3 (M-3 × PivOH + H), 402.3
(M-2 × PivOH + H), 504.4 (M-PivOH + H), 526.3 (M-PivOH +
Na), 606.4 (M + H), 628.4 (M + Na), 644.4 (M + K), 669.5 (M +
Na + MeCN); HRMS (ESI, m/z) calcd for C34H56NO8 (M + H)
606.4000, found 606.3999.
Crystal data: C34H55NO8, M = 605.80, space group: P21
8.4 Hz, C6H5–Cl), 5.68 (t, J2 ,1 = 9.6 Hz, J2 ,3 = 9.6 Hz, H-2ꢀ),
(monoklin), lattice parameters: a = 9.576(2)(7) A, b = 20.504(5)
˚
ꢀ
ꢀ
ꢀ ꢀ
5.20–5.14 (m, 1H, H-4ꢀ), 5.04 (dd, 1H, J3 ,2 = 9.9 Hz, J3 ,4 = 3.3 Hz,
A, c = 10.143(2) A, V = 1840.9(8) A , z = 2, F(000) = 660, diffrac-
tometer: CAD4, irridation: Cu Kagraphite monochromator, 6691
reflections measured, 6285 unique (Rint = 0.0243), wR2 = 0.1696
(R1 = 0.0562 for observed reflexes, 0.604 for all reflexes).†
3
˚
˚
˚
ꢀ
ꢀ
ꢀ ꢀ
H-3ꢀ), 4.94–4.85 (m, 1H, H-2), 4.41 (d, 1H, J1 ,2 = 9.2 Hz, H-1ꢀ),
ꢀ
ꢀ
3.59 (s, 3H, OCH3), 3.92–3.83 (m, 1H, J5 a,4 = 2.2 Hz, H-5ꢀa), 3.49
ꢀ
ꢀ
(d, 1H, J5 b,5 a = 13.2 Hz, H-5ꢀb), 2.98 (dd, 1H, J3a,3b = 16.2 Hz,
J3a,2 = 5.9 Hz, H-3a), 2.76 (dd, 1H, J3b,3a = 16.2 Hz, J3b,2 = 7.7 Hz,
H-3b), 1.21, 1.12, 1.11 (3s, 9H each, Piv-CH3); dC (75.4 MHz,
ꢀ
ꢀ
(2R,4aS,8aS)-N-(2ꢀ,3ꢀ,4ꢀ-Tri-O-pivaloyl-a-D-arabinopyranosyl)-
2-isopropyl-trans-6,7-dehydrochinolin-4-one (12).
A
solution
=
CDCl3) 188.4 (C-4), 177.2, 177.1, 177.0 (PivC O), 167.1 (C–
of 10 (48 mg, 0.08 mmol) and Grubb’s catalyst [bis-
(tricyclohexylphosphine)benzylidene ruthenium(IV) dichloride]
(8 mg, 0.01 mmol) in dichloromethane was stirred for 2 h. The sol-
vent was removed in vacuum and the residue was purified by flash
chromatography (silica gel, cyclohexane–ethyl acetate = 20 : 1)
OCH3), 149.3 (C-6), 139.9, 136.9, 134.4 (ipso-aryl), 129.6, 129.2,
128.3 (aryl), 127.8 (ipso-aryl), 127.3 (aryl), 114.1 (C-5), 89.7 (C-
1ꢀ), 71.0 (C-3ꢀ), 67.8 (C-4ꢀ), 66.1 (C-5ꢀ), 65.7 (C-2ꢀ), 58.6, 52.0
(C-2, OCH3), 43.9 (C-3), 38.9, 38.9, 38.8 (Pivquart), 27.2, 27.1,
27.0 (Piv-CH3); m/z (ESI) 726.5 (M(35Cl)+H), 728.5 (M(37Cl)+H),
748.4 (M(35Cl)+Na), 750.4 (M(37Cl)+Na), 789.6 (M(35Cl)+Na +
CH3CN), 791.6 (M(37Cl)+Na + CH3CN); HRMS (ESI, m/z) calcd
for C39H48ClNO10Na (M + Na) 748.2859, found 748.2858.
† CCDC reference numbers 624381. For crystallographic data in CIF
format see DOI: 10.1039/b615113b
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to give 12 (46 mg, 0.08 mmol, quant.) as a colourless amorphous
solid. Rf = 0.25 (cyclohexane–ethyl acetate = 5 : 1); [a]2D4 −8.99 (c
1 in CHCl3); dH (400 MHz, CDCl3) 5.69–5.52 (m, 3H, H-2ꢀ, H-6,
References
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2 First examples: J. Villie´ras, Bull. Soc. Chim. Fr., 1967, 1520; H.
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3 L. Boymond, M. Rottla¨nder, G. Cahiez and P. Knochel, Angew. Chem.,
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E. Negishi, Acc. Chem. Res., 1982, 15, 340.
ꢀ
ꢀ
ꢀ
ꢀ
H-7), 5.24–5.20 (m 1H, H-4), 5.05 (dd, 1H, J3 , 2 = 9.4 Hz, J3 , 4
=
2.7 Hz, H-3ꢀ), 4.38 (m, 1H, H-1ꢀ), 3.90 (dd, 1H, J5 a, 5 b = 13.3 Hz,
ꢀ
ꢀ
H5 a, 4 = 1.6 Hz, H-5ꢀa), 3.56 (d, 1H, J5 b, 5 a = 12.9 Hz, H-5ꢀb),
3.46–3.18 (m, 1H, H-2), 2.80–1.98 (m, 8H, H-3I, H-3II, H-4a,
H-5I, H-5II, H-8I, H-8II, H-8a), 1.72–1.46 (m, 1H, –CH(CH3)2),
1.23, 1.13, 1.11 (3s, 9H each, PivCH3), 0.90 (d, 3H, J = 7.0 Hz,
CH3), 0.83 (d, 3H, J = 6.6 Hz, CH3). dC (75.4 MHz, CDCl3) 210.8
ꢀ
ꢀ
ꢀ
ꢀ
=
(C-4), 177.4, 177.4, 177.0 (PivC O), 125.6, 124.4 (C-6, C-7), 68.5
(C-3ꢀ), 68.4 (C-4ꢀ), 65.3 (C-5ꢀ), 51.3 (C-2), 42.5 (CH2), 38.9, 38.8,
38.7 (Pivquart), 30.7, 29.7 (C-4a, C-8a), 27.3, 27.1, 27.1 (PivCH3),
25.4 (CH2), 20.2 (CH3); m/z (ESI) 194.2 (dehydropiperidinone−
+ H + H), 272.2 (M-3 × PivOH + H), 374.3 (M-2 × PivOH +
H), 476.4 (M-PivOH + H), 498.3 (M-PivOH + Na), 578.5 (M +
H), 600.4 (M + Na), 616.3 (M + K), 641.5 (M + Na + MeCN);
HRMS (ESI, m/z) calcd for C32H51NO8Na (M + Na) 600.3507,
found 600.3500.
9 Y. Yamamoto, Angew. Chem., 1986, 98, 945.
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Kunz, Monatsh. Chem., 2002, 133, 571.
Acknowledgements
This work was supported by Aventis Pharma Deutschland. We
thank Dr D. Schollmeyer, Universita¨t Mainz, for the X-ray
analysis.
354 | Org. Biomol. Chem., 2007, 5, 349–354
This journal is
The Royal Society of Chemistry 2007
©