Synthesis of enantiomerically enriched 2-substituted pyrrolidine analogues of norhygrine. Application of the hetero-diels-alder addition of sulfur dioxide

Article abstract of DOI:10.3987/com-06-s(k)38

The Vogel's reaction cascade (one-pot hetero-Diels-Alder addition of SO₂, ionization of the sultines into zwitterions and their quenching by electron-rich alkenes) has been applied to the preparation of enantiomerically-enriched (1S)-2((2R)-1-b

Full text of DOI:10.3987/com-06-s(k)38

HETEROCYCLES, Vol. 72, 2007
681
HETEROCYCLES, Vol. 72, 2007, pp. 681 - 689. © The Japan Institute of Heterocyclic Chemistry
Received, 4th December, 2006, Accepted, 1st February, 2007, Published online, 6th February, 2007. COM-06-S(K)38
SYNTHESIS OF ENANTIOMERICALLY ENRICHED 2-SUBSTITUTED
PYRROLIDINE ANALOGUES OF NORHYGRINE. APPLICATION OF
THE HETERO-DIELS-ALDER ADDITION OF SULFUR DIOXIDE
Māris Turks‡ and Pierre Vogel*
Laboratory of glycochemistry and asymmetric synthesis (LGSA), ISIC, Swiss
Federal Institute of Technology (EPFL), CH-1015 Lausanne, Switzerland, Fax +41
‡
21 693 93 75; e-mail: pierre.vogel@epfl.ch; Present address: Departement of
Chemistry Standford University, CA 94305, USA
Dedicated to Professor Yoshito Kishi on the occasion of his 70th birthday
Abstract – The Vogel's reaction cascade (one-pot hetero-Diels-Alder addition of
SO2, ionization of the sultines into zwitterions and their quenching by electron-rich
alkenes) has been applied to the preparation of enantiomerically-enriched
(1S)-2((2R)-1-benzoylpyrrolidin-2-yl)pentan-3-one (14). Reaction of SO2 with
(-)-(1E,3Z)-2-methyl-1-((1S)-1-phenylethoxy)penta-1,3-dien-3-ol
benzoate
(5:
derived from (S)-1-phenylethanol (97% ee)) and allyltrimethylsilane in the
presence of a Lewis acid at -78°C provides (-)-(2Z,1'S,4S,5S)-4-methyl-5-
(1'-phenylethoxy)octa-2,7-dien-3-ol benzoate (9). Selective cleavage of the benzyl
ether of 9 and subsequent SN2 displacement with Ph2P(O)N3 provided an azide 11
that was converted into 14.
Pyrrolidines are found in Nature1 and as pharmacophores in drugs.2 The active ingredients of toxic herbs
are often pyrrolidine derivatives.3 Simple derivatives such as hygrine (1) and norhygrine (2) are present in
several plants.4 Recently, enantiomerically pure "trans-lactams" of type 3 have been shown to be potent
human cytomegalovirus (HCMV) protease inhibitors.5 HCMV is one of the nine known human herpes
viruses.6

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HETEROCYCLES, Vol. 72, 2007
R'SO2
R
N
H
N
Me
H
H
Me
N
O
Cl
O
H
O
R'
1 R = Me
2 R = H
3
4
Although several reports7 present synthesis of pyrrolidine derivatives, relatively few are the methods for the
enantioselective preparation of 2-substituted pyrrolidines analogues of 1 – 2.8 A close analogue of the
system described here would be compound 4 (derived from (R)-α-methyl benzylamine).8b We disclosed
here our synthesis of (1S)-2-((2R)-1-benzoylpyrrolidin-2-yl)pentan-3-one (14), a new compound derived
from enantiomerically enriched (97%) (-)-(1E,3Z)-2-methyl-1-((1S)-1-phenylethoxy)penta-1,3-dien-3-ol
benzoate (5), a diene obtained in three steps from inexpensive (1S)-1-phenylethanol (97% ee).9 The method
uses new organic chemistry of sulfur dioxide developed in our laboratory.10
OR*
OR*
OR*
SiMe3
-78°C
SO2/CH2Cl2
+ LA
O
S
O LA
S
(CF3SO2)2NSiMe3
-78°C
BzO
BzO
O
BzO
O
5
R* = (1S)-1-phenylethyl
6
7
OR*
Et3NH+TfO-
MeOH
O
OBz OR*
OBz N3
Ph2PN3, PPh3
1. BH3/THF
2. H2O2/NaHCO3
(40%)
DEAD, 5°C
(82%)
(70%)
SO2SiMe3
BzO
8
9 R = R*
10 R = H
11
CF3COOH,anisole
CH2Cl2, 0-15°C
(75%)
Bz
Dess-Martin
periodinane
CH2Cl2, 25°C
(80%)
OBz N3
OBz N3
O
N
H2/Pd/C
H
OH
MeOH, 25°C
(79%)
O
13
14
12
In the presence of an excess of sulfur dioxide in CH2Cl2 and a catalytic amount of (CF3SO2)2NSiMe3
(Lewis acid promoter) diene (5) equilibrates with the corresponding sultine 6. At -78°C the latter is ionized
into zwitterions 7 that is quenched by allyltrimethylsilane giving sulfinate 8. After SO2 evaporation at
-
-78°C, treatment of the crude reaction mixture with Et3NH+CF3SO3 (made in situ from Et3N,
CF3SO3SiMe3 and MeOH) buffer in anhydrous methanol (-78 to -50°C) led to desulfinylation producing
9.11 Cleavage of the (1S)-phenylethyl ether moiety of 9 was induced by CF3COOH (10 equiv.) in CH2Cl2
containing one equivalent of anisole. This gave 10 in 75% yield, together with 15% of

HETEROCYCLES, Vol. 72, 2007
683
(3S,4S)-4-methyl-5-oxooct-1-en-3-ol benzoate (product of benzoyl group migration). The enantiomeric
excess of alcohol 10 was the same as that of the (1S)-phenylethanol used to prepare diene 5 (97% ee), as
proven by 19F-NMR (CDCl3) of the (S)-MTPA and (R)-MTPA Mosher's ester 10S and 10R. The
1
(3S)-absolute configuration of 10 was suggested by the H-chemical shifts of H2C(2) and H-C(4) of 10S
and 10R12 and confirmed by X-ray radiocrystallography of a derivative of the enantiomer of 10.11
O
O
Ph
Ph
O
O
CF3
OMe
OBz
OBz
OMe
CF3
10S
10R
H MeH H
2.78 2.54 & 2.34 ppm
H MeH H
2.76 2.60 & 2.42 ppm
δH:
δH:
Reaction of alcohol 10 with Ph2P(O)N3 in the presence of diethyl azodicarboxylate and
triphenylphosphine13 provided azide 11 in 82% yield. Hydroboration followed by oxidation of alkene 11
(BH3⋅THF, work-up with 30% aq. H2O2)14 gave alcohol 12 (40%) and unreacted 11 (22%). Dess-Martin
oxidation of 12 furnished aldehyde 13 (80%). Reduction of azide 13 with H2/10% Pd/C in MeOH led to 14,
resulting from the conversion of the azide into a primary amine that cyclized with the aldehyde forming an
intermediate imine that was hydrogenated into a pyrrolidine. Migration of the benzoyl group from the enol
ester to the nitrogen atom of pyrrolidine finally produced 14.
This note demonstrates that the new organic chemistry of sulfur dioxide developed to generate polyketide
and polypropionate fragments11 can be used to prepare enantiomerically enriched pyrrolidine analogue of
hygrine and norhygrine.
EXPERIMENTAL
General, see ref. 9. 1H-NMR assignments were confirmed by 2D-(COSY, NOESY)-1H-NMR spectra.
(-)-(6Z,1'S,4S,5S)-5-Methyl-5-(1'-phenylethoxy)octa-1,6-dien-6-yl benzoate (9). Allyltrimethylsilane (0.2
mL, 1.26 mmol) and 0.5 M (CF3SO2)NH in CH2Cl2 (0.25 mL, 1.26 mmol) were mixed in CH2Cl2 (7 mL)
and stirred at 20°C for 10 min. Then SO2 (ca. 7 mL) dried over a column of P2O5 and Al2O3 was transferred
through the vacuum line to the frozen solution (-196°C). The mixture was allowed to melt and to warm to
-78°C. After 30 min at this temperature a mixture of (-)-(1E,3Z)-2-methyl-1-((1S)-1-phenylethoxy)penta-
1,3-dien-3-ol benzoate (5) [9] (1.45 g, 4.2 mmol) and allyltrimethylsilane (1.34 mL, 8.4 mmol) in anh.
CH2Cl2 (0.7 mL) was added dropwise under vigourous stirring at -78°C. The mixture was stirred at -78°C
for 24 h. Sulfur dioxide and CH2Cl2 were evaporated at -78°C under vacuum for 2 h. Then a premixed
solution of Et3N (0.76 mL, 5.45 mmol), CF3SO3SiMe3 (0.76 mL, 4.2 mmol) in anh. MeOH (2 mL) was

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HETEROCYCLES, Vol. 72, 2007
added at -78°C under vigorous stirring . The temperature was allowed to reach -50°C over 3 h. The reaction
mixture was poured into a ice-cold sat. aq. soln. of NaHCO3 (50 mL) and extracted with CH2Cl2 (30 mL, 3
times). The combined org. extracts were washed successively, with sat. aq. soln. of NaHCO3 (20 mL), brine
(10 mL) and dried (Na2SO4). After solvent evaporation in vacuo the residue was purified by flash
chromatography on silica gel (light petroleum ether/EtOAc 96:4) giving 1.07 g (70%) colorless oil. [α]D25
25
577
25
546
25
435
25
405
= -34, [α]
= -41, [α]
= -36, [α]
= -54, [α]
= -63 (c = 1.04, CHCl3). IR (film) ν: 3065, 2975,
2925, 1730, 1695, 1600, 1450, 1260, 1175, 1090 cm-1. 1H-NMR (400 MHz, CDCl3) δH: 8.08 (d, 2H, 3J =
7.4, Bz), 7.65 (t, 1H, 3J = 7.7, Bz), 7.50 (t, 2H, 3J = 7.7, Bz), 7.23-7.20 (m, 2H, Ph), 7.17-7.14 (m, 3H, Ph),
5.69 (dxdxt, 1H, 3J = 17.3, 3J = 10.2, 3J = 7.0, H-C(2)), 5.33 (q, 1H, 3J = 7.0, H-C(7)), 5.06-4.96 (m, 2H,
H-C(1)), 4.50 (q, 1H, 3J = 6.4, H-C(1')), 3.50 (dxt, 1H, 3J = 7.7, 3J = 4.2, H-C(4)), 2.97 (m, 1H, H-C(5)),
2.28-2.15 (m, 2H, H-C(3)), 1.58 (d, 3H, 3J = 7.0, H-C(8)), 1.44 (d, 3H, 3J = 6.4, H-C(2')), 1.20 (d, 3H, 3J =
13
7.0, Me-C(5)). C-NMR (100.6 MHz, CDCl3) δC: 164.1 (s, CO), 150.2 (s, C(6)), 143.6 (s, Ar), 136.0 (d,
1J(C,H) = 153, Ar), 133.2 (d, 1J(C,H) = 160, Ar), 129.9 (d, 1J(C,H) = 165, Ar), 128.4 (d, 1J(C,H) = 163, Ar),
128.0 (d, 1J(C,H) = 162, Ar), 127 (d, 1J(C,H) = 160, Ar), 126.8 (d, 1J(C,H) = 160, Ar), 116.1 (t, 1J(C,H) =
145, C(1')), 75.7 (d, 1J(C,H) = 143, C(4)), 39.6 (d, 1J(C,H) = 128, C(5)), 34.8 (t, 1J(C,H) = 121, C(3)), 23.9
(q, 1J(C,H) = 129, C(2')), 11.6 (q, 1J(C,H) = 128, 4 Me), 11.0 (q, 1J(C,H) = 128, C(8)). MS-MALDI: Calcd
for C24H28O3Na+ 387.1936 (M+Na+); found: 387.1935. Anal. Calcd for C24H28O3 (364.48): C 79.9, H 7.74.
Found: C 79.12, H 7.72.
(+)-(6Z,4S,5S)-4-Hydroxy-5-methylocta-1,6-dien-6-yl benzoate (10). To a solution of (-)-9 (3.9 g, 10.7
mmol) and anisole (1.22 mL, 10.7 mmol) in CH2Cl2 (65 mL) at 0°C was added CF3COOH (8.1 mL, 0.11
mol). The resulting brownish-pink solution was let to reach +15°C in 2.5 h. Then it was neutralized with
solid NaHCO3, filtered and evaporated in vacuo. The residue was purified by flash chromatography (light
petroleum ether/EtOAc 95:5): 2.09 g (75%) of 10, and 0.42 g (15%) of (3S,4S)-4-methyl-5-oxooct-
1-en-3-ol benzoate. Data of 10. colorless oil. Rf = 0.29 (petroleum ether/EtOAc = 9:1). [α]2D5 = +24,
25
577
25
435
25
405
[α]
= +26, [α]
= +39, [α]
= +39 (c = 0.41, CHCl3). IR (film) ν: 3515, 3070, 2975, 2920, 1735,
1715, 1690, 1600, 1450, 1285, 1260, 1175, 1095, 1070 cm-1. 1H-NMR (400 MHz, CDCl3) δH: 8.14 (d, 3J =
8.4, 4J = 1.3, H-C(Bz)), 7.64 (txt, 3J = 7.0, 4J = 1.3, H-C(Bz)), 7.51 (t, 2H, 3J = 8.3, H-C(Bz)), 5.94 (dxdxdxd,
1H, 3J = 16.6, 3J = 10.2, 3J = 7.7, 3J = 6.4, H-C(2)), 5.39 (q, 1H, 3J = 7.0, H-C(7)), 5.12 (dxq, 1H, 3J = 16.6,
2J = 1.3, 4J = 1.3, Ha-C(1)), 5.09 (dxdxd, 1H, 3J = 10.2, 2J = 1.2, 4J = 1.2, Hb-C(1)), 3.43 (dxtxd, 1H, 3J = 8.3,
3J =3.8, 3J = 2.6, H-C(4)), 3.26 (d, 1H, 3J = 2.6, HO-C(4)), 2.44 (dxq + m, 2H, 3J =8.9, 3J =7.0, H-C(5)),
Ha-C(3)), 2.16 (dxt, 1H, 2J = 14.5, 3J = 7.7, Hb-C(3)), 1.53 (d, 3H, 3J =7.0, H-C(2')), 1.12 (d, 3H, 3J = 7.0,
13
CH3-C(5)). C-NMR (100.6 MHz, CDCl3) δC: 165.5, 149.4, 135.1, 133.8, 130.2, 128.8, 128.7, 117.1,

HETEROCYCLES, Vol. 72, 2007
685
114.6, 71.4, 45.8, 38.0, 14.5, 11.1. MS-MALDI: Calcd for C16H20O3Na+ 283.1310; found: 283.1389. Anal.
Calcd for C16H20O3 (260.33): C 73.82, H 7.74. Found: C 73.76, H 7.80.
(6Z,4S,5S)-5-Methyl-4-(((2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropionyl)oxy)octa-1,6-dien-6-yl
benzoate (10R). To a solution of (+)-10 (26 mg, 0.10 mmol) in pyridine (0.5 mL) at -15°C was added
(S)-1-methoxy-1-trifluoromethyl-1-phenylacetyl chloride (50 mg, 0.20 mmol). The resulting mixture was
allowed to reach 20°C and stirred for 2 h. It was then chilled to -20°C and N,N-dimethylaminoethanol (20
mg, 0.20 mmol) was added. The mixture was allowed to warm to -20°C and stirred for 1 h. It was diluted
with Et2O (30 mL), washed successively with a sat. aq. soln. of CuSO4 (7 mL, 4 times), water (10 mL) 10%
aq. soln. of citric acid (7 mL, 4 times), sat. aq. soln. of NaHCO3 (5 mL, 3 times), dried (Na2SO4) and
evaporated in vacuo. Yield: 44 mg (93%) of 10R. All the NMR measurements were done on the crude
sample. Data of 10R: colorless oil. Rf = 0.44 (petroleum ether/EtOAc 9:1). 1H-NMR (400 MHz, CDCl3) δH:
3
4
3
4
8.09 (dd, 2H, J = 8.0, J = 1.3, H-C(Bz)), 7.64 (tt, 1H, J = 7.0, J = 1.3, H-C(Bz)), 7.58-7.32 (m, 7H,
H-C(Ar)), 5.78 (dxdxdxd, 1H, 3J = 17.3, 3J = 10.0, 3J = 8.0, 3J = 6.2, H-C(2)), 5.30 (dxdxd, 1H, 3J = 8.0, 3J
= 6.8, 3J = 4.3, H-C(4)), 5.24 (q, 1H, 3J = 6.8, H-C(7)), 5.12 (dm, 1H, 3J = 17.3, Ha-C(1)), 5.12 (dm, 1H, 3J
5
3
= 10.0, Hb-C(1)), 3.54 (br. q, 3H, JH,F = 1.2, CH3O-C(2'')), 2.76 (quint, 1H, J = 6.8, H-C(5)), 2.60
(dxdxdxd, 1H, 2J = 14.8, 3J = 5.7, 3J = 3.8, 4J = 1.9, Ha-C(3)), 2.42 (dt, 1H, 2J = 14.8, 3J = 8.0, Hb-C(3)),
1.44 (d, 3H, 3J = 7.4, H-C(8)), 1.01 (d, 3H, 3J = 7.0, CH3-C(5)). 13C-NMR (100.6 MHz, CDCl3) δC: 166.2,
1
164.0, 148.0, 133.4, 133.3, 132.4, 130.1, 129.5, 129.4, 128.6, 128.3, 127.5, 123.4 (q, JC,F = 288, CF3),
118.6, 133.8, 77.2, 55.6, 41.5, 35.1, 13.4, 11.2. 19F-NMR (CDCl3, 376.7 MHz) δF: -71.78 (s, CF3).
MS-MALDI: Calcd for C26H27F3O5Na+ 499.1708; found: 499.1712.
(6Z,4S,5S)-5-Methyl-4-(((2S)-3,3,3-trifluoro-2-methoxy-2-phenylpropionyl)oxy)octa-1,6-dien-6-yl
benzoate (10S). Same procedure as that for 10R, using (R)-1-methoxy-1-trifluoromethyl-1-phenylacetyl
1
chloride. Yield: 94%. Colorless oil, Rf = 0.44 (petroleum ether/EtOAc 9:1). H-NMR (400 MHz, CDCl3)
δH: 8.11 (dd, 2H, 3J = 7.4, 4J = 1.2, H-C(Bz)), 7.64 (tt, 1H, 3J = 7.4, 4J = 1.2, H-C(Bz)), 7.58-7.35 (m, 7H,
H-C(Ar)), 5.78 (dxdxdxd, 1H, 3J = 15.4, 3J = 10.0, 3J = 8.6, 3J = 6.2, H-C(2)), 5.34 (m, 2H, H-C(4), H-C(7)),
3
3
5
5.04 (br. d, 1H, J = 15.4, Ha-C(1)), 5.12 (br. d, 1H, J = 10.0, Hb-C(1)), 3.55 (br. q, 3H, JH,F = 1.2,
3
2
3
3
4
CH3O-C(2'')), 2.79 (quint, 1H, J = 6.8, H-C(5)), 2.54 (dxdxt, 1H, J = 14.8, J = 6.2, J = 2.0, J = 2.0,
Ha-C(3)), 2.34 (dt, 1H, 2J = 14.8, 3J = 7.4, Hb-C(3)), 1.50 (d, 3H, 3J = 6.8, H-C(8)), 1.15 (d, 3H, 3J = 6.8,
13
CH3-C(5)). C-NMR (100.6 MHz, CDCl3) δC: 166.2, 164.0, 148.3, 133.5, 132.6, 132.4, 130.2, 129.6,
1
129.2, 128.6, 128.4, 127.6, 123.5 (q, JC,F = 288, CF3), 118.7, 133.8, 77.1, 55.5, 41.5, 35.2, 14.0, 11.3.
19F-NMR (CDCl3, 376.7 MHz) δF: -71.65 (s, CF3). MS-MALDI: Calcd for C26H27F3O5Na+ 499.1708;
found: 499.1724.

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HETEROCYCLES, Vol. 72, 2007
(+)-(6Z,4R,5R)-4-Azido-5-methylocta-1,6-dien-6-yl benzoate (11). To a chilled (-30°C) solution of (+)-10
(1.34 g, 5.13 mmol) and Ph3P (1.42 g, 5.28 mmol) in THF (45 mL) were sequentially added diethyl
azodicarboxylate (DEAD, 0.84 mL, 5.38 mmol) and Ph2P(O)N3 (1.17 mL, 5.38 mmol). The resulting
mixture was allowed to reach +5°C in 2 h and stirred at this temperature for 2 more hours. Then it was
poured into brine (50 mL) and the aqueous phase was extracted with Et2O (30 mL, 3 times). The combined
organic layers were washed with brine (30 mL) dried (Na2SO4), filtered and evaporated. The resulting oil
was purified by flash chromatography on silica gel (light petroleum ether/EtOAc 95:5) yielding 1.2 g (82%),
25
577
25
546
colorless oil, Rf = 0.72 (light petroleum ether/EtOAc 9:1). [α]2D5 = +1.0, [α]
= +1.5, [α]
= +2.3,
25
435
25
405
[α]
= +7.9, [α]
= +11.0 (c = 0.48, CHCl3). IR (film) ν: 2980, 2920, 2100, 1735, 1695, 1450, 1260,
1
3
3
1090 cm-1. H-NMR (400 MHz, CDCl3) δH: 8.14 (dxd, 2H, J = 7.4, H-C(Bz)), 7.64 (t, 1H, J = 7.4,
H-C(Bz)), 7.51 (t, 2H, 3J = 7.4, H-C(Bz)), 5.83 (dxdxt, 1H, 3J =17.2, 3J = 10.5, 3J = 6.8, H-C(2)), 5.35 (q, 3J
= 6.8, H-C(7)), 5.19 (dxq, 1H, 3J = 16.6, 4J = 1.2, Ha-C(1)), 5.14 (dxq, 1H, 3J = 9.8, 4J = 1.9, Hb-C(1)), 3.53
(dxt, 1H, 3J = 8.6, 3J = 5.5, H-C(4)), 2.57 (qxd, 1H, 3J = 6.8, 3J = 5.5, H-C(5)), 2.45, 2.37 (2m, ABXY, 2J =
14.8, 3J = 8.6, 3J = 6.8, H2C(3)), 1.56 (d, 3H, 3J = 6.8, H-C(8)), 1.20 (d, 3H, 3J = 6.8, CH3-C(5)). 13C-NMR
(100.6 MHz, CDCl3) δC: 164.1, 149.5, 134.2, 133.5, 130.1, 129.4, 128.6, 118.3, 113.3, 64.4, 42.4, 37.0,
13.3, 11.1. MS-CI (NH3) m/z: 304 ([M+19]+, 100), 303 ([M+18]+, 71), 287 ([M+2]+, 77), 286 ([M+1]+, 244
(20), 243 (22), 190 (24), 189 (33), 137 (100) 136 (100), 106 (100), 105 (100). MS-MALDI: Calcd for
C16H19N3O2Na+ 308.1375; found: 308.1343. Anal. Calcd for C16H19N3O2 (285.34): C 67.35, H 6.71, N
14.73. Found: C 67.39, H 6.64, N 14.69.
(6Z,4R,5S)-4-Azido-1-hydroxy-5-methyloct-6-en-6-yl benzoate (12). To a solution of (+)-11 (0.125 g, 0.44
mmol) in THF (2 mL) was added 1 M solution of BH3⋅THF in THF (0.22 mL, 0.22 mmol) at 0°C. The
resulting mixture was stirred at 0°C for 2 h. It was cooled to -78°C and quenched with MeOH (0.14 mL).
Then water (0.7 mL), NaHCO3 (0.24 g) and 30% aq. soln. of H2O2 (0.4 mL) were added successively. The
mixture was stirred at 5°C for 7 h. EtOAc (20 mL) was added, phases were separated, and organic phase
was washed with brine, dried (Na2SO4), filtered and evaporated. The resulting oil was purified by flash
column chromatography on silica gel (light petroleum ether/EtOAc 7:3) yielding 53 mg (40%) of 12 and
unreacted (+)-11 (28 mg, 22%). Data of 12: colorless oil, Rf = 0.37 (light petroleum ether/EtOAc 7:3),
1H-NMR (400 MHz, CDCl3) δH: 8.12 (dd, 2H, 3J = 8.4, H-C(Bz)), 7.62 (t, 1H, 3J = 7.4, H-C(Bz)), 7.50 (t,
2H, 3J = 7.8, H-C(Bz)), 5.34 (q, 1H, 3J = 7.4, H-C(7)), 3.66 (t, 2H, 3J = 5.8, H-C(1)), 3.44 (dxdxd, 1H, 3J =
3
3
3
3
9.0, J = 6.4, J = 3.2, H-C(4)), 2.56 (qxd, 1H, J = 7.0, J = 6.4, H-C(5)), 1.88 (br. s, 1H, HO-C(1)),
3
3
1.84-1.72, 1.66-1.58 (2m, 4H, H-C(2), H-C(3)), 1.55 (d, 3H, J = 7.0, H-C(8)), 1.20 (d, 3H, J = 7.0,

HETEROCYCLES, Vol. 72, 2007
687
CH3-C(5)). 13C-NMR (100.6 MHz, CDCl3) δC: 164.3, 149.5, 133.6, 130.1, 129.3, 128.7, 113.3, 64.9, 62.2,
43.1, 29.7, 29.0, 13.5, 11.1. MS-MALDI: Calcd for C16H21N3O2K+ 342.1220; found: 342.1255.
(6Z,4R,5S)-4-Azido-6-benzoyloxy-5-methyl-6-octenal (13). To a solution of alcohol 12 (38 mg, 0.127
mmol) in CH2Cl2 (1 mL) was added Dess-Martin periodinane (0.135 g, 0.318 mmol) at 0°C. The resulting
mixture was stirred at 25°C for 1 h. It was quenched by addition of sat. aq. soln. of NaHCO3 (2 mL)
followed by Na2S2O3⋅5 H2O (0.5 g). Extractive work-up (CH2Cl2, 3 mL, 3 times), drying (Na2SO4) and
evaporation provided the crude product which was purified by flash column chromatography on silica gel
(light petroleum ether/EtOAc 8:2) giving 29 mg (80%), colorless oil. Rf = 0.74 (CH2Cl2/Et2O 95:5). IR
(film) ν: 2980, 2920, 2110, 1730, 1695, 1600, 1455, 1260, 1090 cm-1. 1H-NMR (400 MHz, CDCl3) δH: 9.18
(s, 1H, H-C(1)), 8.13 (dxd, 2H, 3J = 8,4, 4J = 1.2, H-C(Bz)), 7.64 (txt, 1H, 3J = 7.4, 4J = 1.2, H-C(Bz)), 7.51,
t, 2H, 3J = 7.8, H-C(Bz)), 5.37 (q, 1H, 3J = 6.8, H-C(7)), 3.44 (dxdxd, 1H, 3J = 9.8, 3J = 6.2, 3J = 3.1, H-C(4)),
2
3
3
3
2.71-2.55 (m, 2H, H-C(2)), 2.05 (dxdxdxd, 1H, J = 14.3, J = 8.0, J = 6.8, J = 3.6, Ha-C(3)), 1.80
(dxdxdxd, 1H, 2J = 14.3, 3J = 9.8, 3J = 8.0, 3J = 5.5, Hb-C(3)), 1.55 (d, 3H, 3J = 6.8, H-C(8)), 1.22 (d, 3H, 3J
= 6.8, CH3-C(5)). MS-MALDI: Calcd for C16H19N3O3Na+ 324.1324; found: 324.1387.
(1S)-2-((2R)-1-Benzoylpyrrolidin-2-yl)pentan-3-one (14). To a solution of 13 (25 mg, 0.084 mmol) in
MeOH (1 mL) was added Pd/C (10% Pd on C) (5 mg) and the resulting suspension was stirred under H2
atmosphere (1 bar) for 3 h. Filtration of catalyst and evaporation of solvent provided 17 mg (79%) of pure
1
14, colorless oil. Rf = 0.12 (CH2Cl2/Et2O 95:5). H-NMR (400 MHz, CDCl3) δH: 7.50-7.37 (m, 5H,
H-C(Bz)), 4.40 (dt, 1H, 3J = 8.3, 3J = 5.8, H-C(2')), 3.55 (dq, 1H, 3J = 7.0, 3J = 5.1, H-C(2)), 3.44 (dd, 2H, 3J
= 9.0, 3J = 3.8, H-C(5')), 2.50 (q, 2H, 3J = 7.0, H-C(4)), 2.17-2.01 (m, 2H, H-C(3')), 1.88-1.81, 1.70-1.58
3
3
13
(2m, 2H, H-C(4')), 1.17 (d, 3H, J = 7.0, H-C(1)), 1.05 (t, 3H, J = 7.0, H-C(5)). C-NMR (100.6 MHz,
CDCl3) δC: 214.4, 170.4, 137.0, 130.3, 128.3, 127.4, 60.0, 51.3, 45.8, 36.5, 26.9, 25.2, 13.6, 7.8.
MS-MALDI: Calcd for C16H21N2O2Na+ 282.1470; found: 282.1478.
ACKNOWLEDGEMENTS
This work was supported by the Swiss National Science Foundation and the Secrétariat d'Etat à
l'éducation et à la recherche, SER, Bern (FP6 European project TRIOH). We thank Mr. F. Sepulveda and
Dr. S. R. Dubbaka for technical help.

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HETEROCYCLES, Vol. 72, 2007
REFERENCES
1. V. A. Snieckus, Alkaloids (London), 1974, 4, 50; 1975, 5, 56; A. R. Pinder, Alkaloids (London), 1976,
6, 54; J. D. Hunt and A. McKillop, Rodd's Chem. Carbon Compd. 2nd ed., 1977, 4B, 1; G. Massiot
and C. Delaude, Alkaloids (Academic Press), 1986, 27, 269; A. R. Pinder, Nat. Prod. Rep., 1987, 4,
527; 1989, 6, 67; 1990, 7, 447; 1992, 9, 17; A. O. Plunkett, Nat. Prod. Rep., 1994, 11, 581; D. J.
Robins, Rodd's Chem. Carbon Compd. 2nd ed., 1997, 4B, 1; K. Jenett-Siems, R. Weigl, A. Boehm, P.
Mann, B. Tofern-Reblin, S. C. Ott, A. Ghomian, M. Kaloga, K. Siems, L. Witte, M. Hilker, F.
Mueller, and E. Eich, Phytochemistry, 2005, 66, 1448; D. Tsukamoto, M. Shibano, and G. Kusano,
Natural Medicines (Tokyo, Japan), 2003, 57, 68; H. Takayama, T. Ichikawa, T. Kuwajima, M.
Kitajima, H. Seki, N. Aimi, and M. G. Nonato, J. Am. Chem. Soc., 2000, 122, 8635; M. Tsuda, M.
Sasaki, T. Mugishima, K. Komatsu, T. Sone, M. Tanaka, Y. Mikami, and J. Kobayashi, J. Nat. Prod.,
2005, 68, 273.
2. See e.g.: P. Chand, Expert Opinion on Therapeutic Patents, 2005, 15, 1009; Q. Li and W. Xu, Curr.
Med. Chem. Anti-Cancer Agents, 2005, 5, 53; V. Pande and M. J. Ramos, Curr. Med. Chem., 2003,
10, 1603; G. Stamatiou, G. B. Foscolos, G. Fytas, A. Kolocouris, N. Kolocouris, C. Pannecouque, M.
Witvrouw, E. Padalko, J. Neyts, and E. De Clerq, Bioorg. Med. Chem., 2003, 11, 5485; L. G. Neyens,
W. C. Alpherts, and A. P. Aldenkamp, Prog. Neuro-Psychopharm. Biol. Psychiatry, 1995, 19, 411; S.
Ohki, T. Nagasaka, H. Matsuda, N. Ozawa, and F. Hamaguchi, Chem. Pharm. Bull., 1986, 34, 3606;
N. Uchide and K. Ohyama, J. Antimicrob. Chemother., 2003, 52, 8.
3. R. J. Huxtable, General Pharmacology, 1979, 10, 159; A. E. Johnson, R. J. Molyneux, and G. B.
Merrill, J. Agric. Food Chem., 1985, 33, 50.
4. See e.g.: A. J. Parr, J. Payne, J. Eagles, B. T. Chapman, R. J. Robins, and M. J. C. Rhodes,
Phytochemistry, 1990, 29, 2545; J. F. Stevens, H. Hart, H. Hendriks, and T. M. Malingré,
Phytochemistry, 1992, 31, 3917; J. H. K. Kim, H. Hart, and J. F. Stevens, Phytochemistry, 1996, 41,
1319; A. B. Pomilio, M. D. Gonzáles, and C. C. Eceizabarrena, Phytochemistry, 1996, 41, 1393.
5. W. M. Seganish and B. B. Jarvis, Chemtracts, 2002, 15, 367; A. D. Borthwick, Med. Res. Rev., 2005,
25, 427.
6. D. M. Knipe and P. M. Howley, Fields Virology, Lippincott Williams & Wikins, Philadelphia, 2001,
Vol. 2; R. J. Cohrs and D. H. Gilden, Brain Patol., 2001, 11, 465.
7. W. H. Pearson, Studies in Natural Products Chemistry, 1988, 1, 323; A. Job, C. F. Janeck, W.
Bettray, R. Peters, and D. Enders, Tetrahedron, 2002, 58, 2253; F.-X. Felpin and J. Lebreton, Eur. J.
Org. Chem., 2003, 2693; P. Zhou, B.-C. Chen, and F. A. Davis, Tetrahedron, 2004, 60, 8003; S. G.
Pyne, A. S. Davis, N. J. Gates, J. P. Hartley, K. B. Lindsay, T. Machan, and M. Tang, Synlett, 2004,
2670; S. Husinec and V. Savic, Tetrahedron:Asymmetry, 2005, 16, 2047; C. Najera and J. M.

HETEROCYCLES, Vol. 72, 2007
689
Sansano, Angew. Chem. Int. Ed., 2005, 44, 6272; P.-Q. Huang, Synlett, 2006, 1133.
8. a) See e.g.: S. W. Goldstein, L. E. Overman, and M. H. Rabinowitz, J. Org. Chem., 1992, 57, 1179; I.
Izquierdo, M. T. Plaza, and J. A. Tamayo, Tetrahedron:Asymmetry, 2004, 15, 3635. b) T. G. Back
and K. Nakajima, J. Org. Chem., 2000, 65, 4543.
9. M. Turks, X. Huang, and P. Vogel, Chem. Eur. J., 2005, 11, 465.
10. B. Deguin, J.-M. Roulet, and P. Vogel, Tetrahedron Lett., 1997, 38, 6197; J.-M. Roulet, G. Puhr, and
P. Vogel, Tetrahedron Lett., 1997, 38, 6201; V. Narkevitch, K. Schenk, and P. Vogel, Angew. Chem.
Int. Ed., 2000, 39, 1806; V. Narkevitch, S. Megevand, K. Schenk, and P. Vogel, J. Org. Chem., 2001,
66, 5080; M. Turks, M. C. Murcia, R. Scopelliti, and P. Vogel, Org. Lett., 2004, 6, 3031; L. C.
Bouchez and P. Vogel, Chem. Eur. J., 2005, 11, 4609; L. C. Bouchez, M. Turks, S. R. Dubbaka, F.
Fonquerne, C. Craita, S. LaClef, and P. Vogel, Tetrahedron, 2005, 61, 11473.
11. M. Turks, F. Fonquerne, and P. Vogel, Org. Lett., 2004, 6, 1053.
12. J. A. Dale and H. S. Mosher, J. Am. Chem. Soc., 1973, 95, 512; D. E. Ward and C. K. Rhee,
Tetrahedron Lett., 1991, 32, 7165.
13. J. Cossy, C. Willis, V. Bellosta, and S. Samir BouzBouz, J. Org. Chem., 2002, 67, 1982.
14. A. M. Salunkhe, P. V. Ramachandran, and H. C. Brown, Tetrahedron, 2002, 58, 10059.