Asymmetric synthesis of the quinolizidine alkaloid (-)-epimyrtine with intramolecular Mannich cyclization and N-sulfinyl δ-amino β-ketoesters

Article abstract of DOI:10.1021/jo030208d

A concise, six-step, enantioselective synthesis of (-)-epimyrtine employing the N-sulfinyl δ-amino β-ketoester chiral building block is described.

Full text of DOI:10.1021/jo030208d

Asym m etr ic Syn th esis of th e Qu in olizid in e Alk a loid
(-)-Ep im yr tin e w ith In tr a m olecu la r Ma n n ich Cycliza tion a n d
N-Su lfin yl δ-Am in o â-Ketoester s
Franklin A. Davis,* Yulian Zhang, and Gopinathan Anilkumar
Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122
fdavis@temple.edu
Received J une 24, 2003
A concise, six-step, enantioselective synthesis of (-)-epimyrtine employing the N-sulfinyl δ-amino
â-ketoester chiral building block is described.
SCHEME 1
N-Sulfinyl δ-amino â-ketoesters 1 are new sulfinimine
(N-sulfinyl imine) derived polyfunctionalized chiral build-
ing blocks that provide efficient access to mono- and
bicyclic alkaloids with a minimum of chemical manipula-
tion and protecting, deprotecting group chemistry (Scheme
1).1 These building blocks have been employed in concise
asymmetric syntheses of mono-,2 di-, and trisubstituted
piperidines;2-4 the quinolizidine alkaloid (-)-lasubine II;
and cis 5-substituted prolines.5.6 The amine salt of 1
undergoes an intramolecular Mannich reaction with al-
dehydes and ketones to produce 2,3,4,6-tetrasubstituted
piperidines 2 and was employed in the enantioselective
synthesis of the dendrobate alkaloid (+)-241D.7 As a test
of this methodology’s ability to rapidly and stereospecifi-
cally assemble densely substituted piperidines as well as
to define the scope and limitations of the intramolecular
Mannich cyclization of 1 we describe here an efficient
asymmetric synthesis of (-)-epimyrtine (3).
enolate of methyl acetate to (R)-(-)-5 to give â-amino
ester (-)-6 in 88% yield and >97% de (Scheme 2). The
sodium enolate was again added to (-)-6 affording (-)-7
in 90% yield. While δ-amino â-ketoesters can often be
prepared in one pot by addition of excess methyl acetate
enolate to the sulfinimine, in this instance yields were
poorer and the selectivity suffered. Next, (-)-7 was
treated with TFA/MeOH and the reaction solution passed
through a short plug of silica gel to remove the sulfinyl
byproducts. The crude trifluoroacetate salt of 8 in MeOH
afforded piperidine 10 on reaction with 1 equiv of
5-benzyloxy pentanal (9)11 in a 3:1 mixture of diastereo-
isomers and in 68% yield for the two steps. Decarboxyl-
ation with LiOH/MeOH or refluxing in HCl gave a single
diastereomeric piperidine 11 in 25% yield. The cis
relationship of the 2,6-substituents is predicted by our
transition state model for the intramolecular Mannich
cyclization in which A1,3 strain favors the cis product.3
This conformation was confirmed by decoupling studies
and NOE experiments that revealed the diaxial orienta-
tion of the C(2) and C(6) protons in 11.
(-)-Epimyrtine (3) and (+)-myrtine (4) are naturally
occurring quinolizidine alkaloids isolated from Vaccinium
myrtillus.8 Although several racemic syntheses of these
compounds have been reported9 there is only a single
asymmetric synthesis of (-)-39 and two asymmetric
syntheses of (+)-4.8b,10 In the synthesis of (-)-3, Gelas-
Mialhe and co-workers employed an intramolecular N-
acyliminium ion cyclization strategy.9
In the method presented here the requisite (RS,R)-
(-)-methyl 3-oxo-5-methyl-5-(p-toluenesulfinylamino)-
hexanoate (7) was prepared by the addition of the sodium
(1) For a review see: Davis, F. A.; Chao, B.; Andemichael, Y. W.;
Mohanty, P. K.; Fang, T.; Burns, D. M.; Rao, A.; Szewczyk, J . M.
Heteroatom Chem. 2002, 13, 486.
(2) Davis, F. A.; Chao, B.; Fang, T.; Szewczyk, J . M. Org. Lett. 2000,
2, 1041.
(3) Davis, F. A.; Chao, B. Org. Lett. 2000, 2, 2623.
(4) Davis, F. A.; Fang, T.; Chao, B.; Burns, D. M. Synthesis 2000,
2106.
(5) Davis, F. A.; Fang, T.; Goswami, R. Org. Lett. 2002, 4, 1599.
(6) Davis, F. A.; Yang, B.; Deng, J . J . Org. Chem. 2003, 68, 5147.
(7) Davis, F. A.; Chao, B.; Rao, A. Org. Lett. 2001, 3, 3169.
(8) (a) Slosse, P.; Hootele, C. Tetrahedron Lett. 1978, 397. (b) Slosse,
P.; Hootele, C. Tetrahedron 1981, 37, 4287.
The difficulty in removing the piperidine 3-carbo-
methoxy group indicated the need for a more efficient
decarboxylation process. The use of tert-butyl esters was
considered a possible alternative because such esters are
(9) For leading references see: Gardette, D.; Gelas-Mialhe, Y.;
Gramain, J .-C.; Perrin, B.; Remuson, R. Tetrahedron: Asymmetry 1998,
9, 1823.
(11) Zhang, R.; Wang, Z.; Wei, F.; Huang, Y. Synth. Commun. 2002,
32, 2187.
(10) Comins, D. L.; LaMunyon, D. H. J . Org. Chem. 1992, 57, 5807.
10.1021/jo030208d CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/18/2003
J . Org. Chem. 2003, 68, 8061-8064
8061

Davis et al.
SCHEME 2
as before, using TsCl and pyridine, resulted in extensive
decomposition.3 Alternatively, treatment of the alcohol
with triphenyl phosphine, CCl4, and triethylamine re-
sulted in (4R,10S)-(-)-epimyrtine (3) in 77% isolated
yield for the two steps. Compound (-)-3 exhibited prop-
erties consistent with those reported for the natural
product.9
In summary, a concise enantioselective synthesis of the
quinolizidine alkaloid (-)-epimyrtine (3) was accom-
plished in six steps with an overall yield of 41% from the
sulfinimine. The decarboxylation step was improved by
employing the tert-butyl ester.
Exp er im en ta l Section
Sulfinimines were prepared as described earlier from (R)-
(-)- and (S)-(+)-p-toluenesulfinamide; acetaldehyde or 5-ben-
zyloxy pentanal (9);11 and Ti(OEt)4.13
(R)-(-)-N-(Acetyliden e)-p-tolu en esu lfin am ide (5). Flash
chromatography (CH2Cl2) afforded 0.13 g (93%) as a yellow
oil; [R]20 -418.2 (c 1.20, CHCl3); IR (neat) 1640, 1095 cm-1
;
D
1H NMR (CDCl3) δ 8.23 (q, 1 H, J ) 5 Hz), 7.55 (d, 2 H, J )
8 Hz), 7.29 (d, 2 H, J ) 8 Hz), 2.38 (s, 3H), 2.19 (d, 3 H, J )
5 Hz); 13C NMR (CDCl3) δ 163.6, 141.7, 129.7, 125.3, 124.4,
22.3, 21.3. Anal. Calcd for C9H11NOS: C, 59.61; H, 6.12; N,
7.73. Found: C, 59.33; H, 6.38; N, 7.60.
(S)-(+)-N-(5-Ben zyloxy-1-p en tylid en e)-p-tolu en esu lfin -
a m id e (12). Flash chromatography (EtOAc/hexane, 2:8) gave
8.3 g (97%) of a yellow oil; [R]20D 235.5 (c 0.94, CHCl3); IR (neat)
generally easily decarboxylated under mild acidic condi-
tions.12 Furthermore, the fact that it was necessary to
redesign our substrate presented the opportunity to
evaluate the effect on the cyclization of transposing
sulfinimine and aldehyde groups. This redesign also
necessitates a change in the absolute configuration of the
sulfinimine.
Treatment of the sulfinimine (S)-(+)-12 with the
sodium enolate of methyl acetate gave the â-amino ester
(SSS)-(+)-13 in excellent yield and >97% de (Scheme 3).
Reaction of the ester with the sodium enolate of tert-butyl
acetate afforded (+)-14 in 90% isolated yield. Removal
of the sulfinyl group with TFA/MeOH, as before, and
reaction of the crude trifluoroacetate amine salt with
acetaldehyde gave tetrasubstituted piperidine (+)-15 in
78% isolated yield for the two steps. Importantly, under
the acidic conditions necessary for the Mannich cycliza-
tion, decarboxylation did not take place. However, re-
fluxing (+)-15 with 10 equiv of TFA in CHCl3 for 2 h gave
an 83% yield of trisubstituted piperidine (-)-16. Notable
is the fact that epimerization of the piperidine stereo-
centers was not detected. The cis structure of the 2,6-
substituents was determined by NOE experiments and
conversion into the natural product (see below).
To complete the synthesis of (-)-epimyrtine (3) all that
was required was deprotection of the benzyl group and
cyclization to form the quinolizidine ring (Scheme 3).
However, initial attempts to remove the benzyl group
with use of Pd/C and H2 at atmospheric pressure were
unsuccessful, but when the pressure was increased to 50
psi (+)-17 was obtained in 80% yield. Interestingly, with
Pd(OH)2, 2 drops of TFA, and atmospheric hydrogen
pressure (+)-17 was isolated in 95% yield. In the absence
of TFA no reaction occurred, which suggests the nitrogen
may be deactivating the catalysts and can be eliminated
if the salt is employed. Next, attempts to effect cyclization
1
3228, 2937, 2862, 1096 cm-1; H NMR (CDCl3) δ 8.05 (t, 1 H,
J ) 4.62 Hz), 7.38 (dd, 2 H, J ) 1.7 Hz, 6.66 Hz), 7.14 (m, 7
H), 4.29 (s, 2 H), 3.28 (t, 2 H, J ) 7.1 Hz), 2.33 (m, 2 H), 2.22
(s, 3H), 1.52 (m, 6 H); 13C NMR (CDCl3) δ 167.4, 14.2, 142.1,
138.9, 130.2, 128.8, 128.0, 127.9, 125.0, 73.3, 70.1, 36.1, 29.5,
22.6, 21.8, 14.6. HRMS calcd for C19H23NO2S (M + Na)
352.1347, found 352.1348. Anal. Calcd for C19H23NO2S: C,
69.27; H, 7.04; N, 4.25. Found: C, 69.43; H, 7.09; N, 4.24.
Typ ica l P r oced u r e for th e P r ep a r a tion of (RS,R)-(-)-
Meth yl N-(p-Tolu en esu lfin yl)-3-a m in o-3-m eth ylp r op a n -
oa te (6). In a 200-mL, oven-dried, one-necked, round-bottomed
flask equipped with a magnetic stirring bar and an argon
balloon were placed ether (40 mL) and NaHMDS (5.81 mL,
5.81 mmol, 1.0 M solution in THF). At this time the reaction
mixture was cooled to -78 °C and methyl acetate (0.46 mL,
5.81 mmol) was added. After the mixture was stirred for 50
min, a solution of sulfinimine (-)-5 (0.8 g, 4.47 mmol) in THF
(6 mL) was added dropwise and stirring was continued for 2
h. The reaction mixture was quenched by addition of sat. NH4-
Cl (50 mL) at -78 °C; the solution was warmed to room
temperature and extracted with EtOAc (2 × 50 mL). The
combined organic phases were washed with brine (25 mL),
dried (Na2SO4), and concentrated to give the crude product,
which was purified by flash chromatography (50% EtOAc/
hexane) to give 1.0 g (88%) as a yellow oil in >97% de; [R]20
D
-128 (c 1.5, CHCl3); IR (neat) 3209, 1739, 1088, 1055, 811
cm-1; 1H NMR (CDCl3) δ 7.57 (d, 2 H, J ) 8 Hz), 7.28 (d, 2 H,
J ) 8 Hz), 4.63 (d, 1 H, J ) 8 Hz), 3.78 (m, 1 H), 3.65 (s, 3H),
2.49 (m, 2 H), 2.40 (s, 3 H), 1.33 (d, 3 H, J ) 6.5 Hz); 13C NMR
(CDCl3) δ 172.4, 142.4, 141.9, 130.2, 126.4, 52.3, 47.8, 42.7,
23.0, 22.0. HRMS calcd for C13H17NO3S (M + Na) 278.0827,
found 278.0824. Anal. Calcd for C12H17NO3S: C, 56.45; H, 6.71;
N, 5.49. Found: C, 56.12; H, 7.01; N, 5.35.
(SS,S)-(+)-Meth yl N-(p-Tolu en esu lfin yl)-3-a m in o-7-ben -
zyloxyh ep ta n oa te (13). Flash chromatography (EtOAc/hex-
ane, 1:9) gave 3.53 g (89%) of a yellow oil; >99% de; [R]20
D
+65.3 (c 0.11, CHCl3); IR (neat) 3206, 2862, 1737, 1437, 1096
(13) (a) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli,
D. L.; Zhang, H. J . Org. Chem. 1999, 64, 1043. (b) Fanelli, D. L.;
Szewczyk, J . M.; Zhang, Y.; Reddy, G. V.; Burns, D. M.; Davis, F. A.
Org. Synth. 1999, 77, 50.
(12) Baty, J . D.; J ones, G.; Moore, C. J . Chem. Soc. C 1967, 2645.
8062 J . Org. Chem., Vol. 68, No. 21, 2003

Synthesis of the Quinolizidine Alkaloid (-)-Epimyrtine
SCHEME 3
cm-1; 1H NMR (CDCl3) δ 7.59 (d, 2 H, J ) 8.3 Hz), 7.36 (m, 7
H), 4.52 (m, 3 H), 3.67 (m, 4 H), 3.51 (t, 2 H, J ) 6.2 Hz), 2.61
(m, 2 H), 2.42 (s, 3 H), 1.65 (m, 6 H); 13C NMR (CDCl3) δ 172.4,
142.7, 141.7, 139.0, 129.9, 128.8, 128.0, 127.9, 125.9, 73.3, 70.4,
Meth yl 2-(4-Ben zyloxybu tyl)-6-m eth yl-4-oxo-piper idin e-
3-ca r boxyla te (10). In a 10-mL, oven-dried, one-necked,
round-bottom flask, equipped with a magnetic stirring bar and
N2 balloon, was placed (-)-7 (0.1 g, 0.337 mmol) in MeOH (2.5
mL). Trifluoroacetic acid (0.16 mL, 2.02 mmol) was added to
the reaction mixture at room temperature and the solution
was stirred for 45 min. The solvent was concentrated and the
residue was passed through a small plug of silica gel and
eluted with 30% EtOAc in hexane (30 mL). The amine salt
was eluted with MeOH (50 mL), the solvent was concentrated,
and the residue was dissolved in CH2Cl2 (1.5 mL). To this
solution was added aldehyde 9 (0.065 g, 0.337 mmol) in CH2-
Cl2 (3.0 mL) and the reaction mixture was stirred at room
temperature for 8 h. At this time the reaction mixture was
quenched with saturated NaHCO3 (1 mL), extracted with
EtOAc (4 × 10 mL), dried (Na2SO4), and concentrated.
Preparative TLC (EtOAc:hexane 1:1) gave 0.077 g (68%) of an
oil as a 3:1 mixture of inseparable diastereomers as determined
53.0, 52.1, 40.8, 36.0, 29.7, 23.2, 21.7. HRMS calcd for C22H29
-
NO2S (M + Na) 426.1712, found 426.1710. Anal. Calcd for
C22H29NO2S: C, 65.48; H, 7.24; N, 3.47. Found: C, 65.00; H,
7.17; N, 3.50.
Typ ica l P r oced u r e for th e P r ep a r a tion of (RS,R)-(-)-
3-Oxo-5-N -(p -t olu e n e su lfin yla m in o)-5-m e t h ylh e xa n o-
a te 7. In a 25-mL, one-necked, round-bottomed flask equipped
with a magnetic stirring bar, rubber septum, and argon balloon
was placed NaHMDS (3.46 mL, 1.0 M solution in THF) in THF
(6 mL). The solution was cooled to -78 °C and anhydrous
methyl acetate (0.28 mL, 3.46 mmol) was added via syringe.
After the mixture was stirred for 1 h at this temperature a
solution of (RS,R)-(-)-6 (0.22 g, 0.87 mmol) in THF (4 mL) was
added and the reaction mixture was quenched after 4 h with
sat. NH4Cl (1 mL). Water (5 mL), was added and the solution
was extracted with EtOAc (2 × 25 mL). The combined organic
phases were dried (Na2SO4) and concentrated. Flash chroma-
1
by integration of the methoxy groups in the H NMR spectra.
(2R,6S)-(+)-2-(4-Ben zyloxybu tyl)-6-m eth ylp ip er id in -4-
on e (11). In a 10-mL, one-necked, round-bottom flask fitted
with a magnetic stirring bar and reflux condenser was placed
ester 10 (0.070 g, 0.21 mmol) in THF (2 mL). Lithium
hydroxide (0.026 g, 0.63 mmol) was added to the solution
followed by H2O (1 mL). The reaction mixture was refluxed
for 12 h and cooled to room temperature, and H2O (2 mL) was
added. The solution was extracted with EtOAc (4 × 5 mL),
and the organic phase was dried (MgSO4) and concentrated.
Preparative TLC (EtOAc:hexane 1:1) gave 0.014 g (25%) of an
tography gave 0.23 g (90%) of a yellow oil; [R]20 -111.0 (c
D
0.84, CHCl3); IR (neat) 3219, 1652, 1558, 1457, 1055 cm-1; 1H
NMR (CDCl3) δ 7.50 (d, 2 H, J ) 8.5 Hz), 7.22 (d, 2 H, J ) 8.5
Hz), 4.65 (d, 1 H, J ) 8 Hz), 3.69 (m, 1 H), 3.66 (s, 3 H), 3.34
(s, 2 H), 2.78 (m, 2H), 2.34 (s, 3 H), 1.29 (d, 3 H, J ) 6.5 Hz);
13C NMR (CDCl3) δ 201.8, 167.8, 142.5, 141.9, 130.1, 126.3,
53.0, 51.0, 50.1, 47.3, 23.0, 21.9. HRMS calcd for C14H19NO4S
(M + Na) 320.0933, found: 320.0937. Anal. Calcd for C14H19
-
NO4S: C, 56.55; H, 6.44; N, 4.71. Found: C, 56.11; H, 6.40;
N, 4.83.
oil; [R]20D 8.3 (c, 0.56, CHCl3); IR (neat) 1706, 1652, 1551 cm-1
;
1H NMR (CDCl3) δ 7.35-7.25 (m, 5 H), 4.49 (s, 2 H), 3.47 (t,
2 H, J ) 6.0 Hz), 3.42 (m, 1 H), 3.31 (m, 1H), 2.52-2.44 (m, 2
H), 2.18-2.11 (m, 2 H), 1.64-1.60 (m, 2 H), 1.42-1.39 (m, 4
H), 1.15 (d, 3 H, J ) 6.5 Hz); 13C NMR (CDCl3) δ 208.7, 137.6,
127.5, 126.8, 126.7, 72.1, 69.7, 51.7, 48.5, 46.8, 46.6, 33.4, 28.6,
21.9, 20.6. HRMS calcd for C17H25NO2 (M + Na) 298.1798,
found 298.1777.
(SS,S)-(+)-ter t-Bu tyl 3-Oxo-5-N-(p-tolu en esu lfin yla m i-
n o)-9-ben zyloxyn on a n oa te (14). The procedure, as de-
scribed above, was applied to the synthesis of (+)-14 except
that the sodium enolate of tert-butyl acetate was added to (+)-
13. Flash chromatography gave 2.0 g (90%) of a yellow oil;
[R]20 46.0 (c 0.5, CHCl3); IR (neat) 3211, 2932, 2861, 1733,
D
1715, 1091 cm-1; 1H NMR (CDCl3) δ 7.55 (d, 2H, J ) 8.2 Hz),
7.33 (m, 7 H), 4.50 (s, 2 H), 4.42 (d, 1 H, J ) 9.3 Hz), 3.68 (m,
1 H), 3.48 (t, 2 H, J ) 6.2 Hz), 3.30 (s, 2 H), 2.87 (t, 2 H, J )
4.7 Hz), 2.40 (s, 3 H), 1.70 (m, 6 H), 1.45 (s, 9 H); 13C NMR
(CDCl3) δ 202.2, 166.1, 142.3, 141.3, 138.6, 129.5, 128.4, 127.6,
127.5, 125.5, 82.2, 72.9, 70.1, 52.4, 51.2, 48.6, 35.4, 29.3, 28.0,
23.0, 21.4. HRMS calcd for C27H37NO5S (M + H) 488.2473,
found 488.2473. Anal. Calcd for C27H37NO5S: C, 66.50; H, 7.65;
N, 2.87. Found: C, 66.51; H, 7.56; N, 2.87.
Typ ica l P r oced u r e for th e P r ep a r a tion of ter t-Bu tyl
(2S,5R,6R)-(+)-2-m et h yl-6-(4-b en zyloxyb u t yl)-4-oxo-p i-
p er id in e-3-ca r boxyla te (15). In
a 200-mL, one-necked,
round-bottomed flask equipped with a magnetic stirring bar,
rubber septum, and argon balloon was placed (+)-14 (1.00 g,
2.05 mmol) in methanol (100 mL). TFA (2 mL) was added
dropwise to the solution and the reaction mixture was stirred
at room temperature for 30 min. The solution was concentrated
and loaded on a short pad of silica and eluted with 30% EtOAc/
J . Org. Chem, Vol. 68, No. 21, 2003 8063

Davis et al.
hexane to remove the side products and then with methanol
to give the amine salt. The methanol solution was concentrated
and CH2Cl2 (60 mL) was added, followed by acetaldehyde (1.13
mL, 20.5 mmol). The reaction mixture was stirred for 1 h at
room temperature and diluted with ethyl acetate (50 mL), and
the solution was treated with K2CO3 (1.00 g) and sat. NaHCO3
(20 mL). The organic phase was separated, dried (Na2SO4),
and concentrated. Flash chromatography (50% EtOAc/hexane)
time the solution was filtered and concentrated. Flash chro-
matography (MeOH/CH2Cl2, 5:95) gave 0.128 g (95%) of a
colorless oil; [R]20 3.57 (c 1.4, MeOH); IR (neat) 3421, 1649
D
cm-1; H NMR (CDCl3) δ 3.61 (t, 2 H, J ) 6.3 Hz), 2.92 (m, 1
1
H), 2.89 (m, 1 H), 2.29 (m, 2 H), 1.99 (m, 2 H), 1.52 (m, 6 H),
1.15 (d, 3 H, J ) 6.2 Hz); 13C NMR (CDCl3) δ 209.6, 62.9, 56.9,
53.8, 52.5, 50.5, 48.4, 37.0, 32.9, 22.9, 22.3. HRMS calcd for
C
C
10H19NO2 (M + H) 186.1480; found 186.1487. Anal. Calcd for
10H19NO2: C, 64.83; H, 10.34; N, 7.56. Found: C, 64.79; H,
gave 0.60 g (78%) of a yellow oil; [R]20 +37.0 (c 1.0, CHCl3);
D
1
IR (neat) 3302, 1733, 1710, 1367, 1150, 1115 cm-1; H NMR
10.25; N, 7.52.
(CDCl3) δ 7.28 (m, 5 H), 4.42 (s, 2 H), 3.40 (t, 2 H, J ) 6.3 Hz),
3.16 (m, 1 H), 2.80 (m, 2 H), 2.38 (dd, 1 H, J ) 2.9 Hz, 13 Hz),
1.95 (m, 1 H), 1.55 (m, 2 H), 1.41 (m, 13H), 1.15 (d, 3 H, J )
6.1 Hz); 13C NMR (CDCl3) δ 202.0, 167.2, 137.4, 127.4, 126.6,
80.6, 71.9, 69.0, 65.2, 55.2, 53.5, 46.8, 35.6, 28.7, 27.0, 21.4,
20.2. HRMS calcd for C22H33NO4 (M + Na) 398.2294, found
398.2296. Anal. Calcd for C22H33NO4: C, 70.37; H, 8.86; N,
3.73. Found: C, 70.03; H, 8.90; N, 3.56.
(4R,10S)-(-)-Ep im yr tin e (3). In a 25-mL, one-necked,
round-bottomed flask fitted with magnetic stirring bar, rubber
septum, and argon balloon were placed (+)-17 (0.036 g, 0.19
mmol) in MeCN (3 mL). A solution of Et3N (0.028 mL, 0.20
mmol) in CCl4 (0.028 mL, 0.29 mmol) was added and the
solution was cooled to 0 °C. At this time triphenylphosphine
(0.047 g, 0.18 mmol) was added and the reaction mixture was
stirred for 45 min, warmed to room temperature, and stirred
for 20 h. To the reaction mixture was added sat. NaHCO3 (5
mL) and the solution was extracted with EtOAc (2 × 15 mL).
The combined organic phases were washed with brine, dried
(Na2SO4), and concentrated. Flash chromatography (MeOH/
(2R,6S)-(-)-2-(4-Ben zyloxybu tyl)-6-m eth yl-4-oxop ip er -
id in e (16). In a 100-mL, one-necked, round-bottomed flask
fitted with magnetic stirring bar, condenser, and argon balloon
was placed (+)-15 (0.40 g, 1.07 mmol) in CHCl3 (50 mL) and
TFA (5 mL). The reaction mixture was refluxed for 2 h and
concentrated. The residue was treated with sat. NaHCO3 (10
mL) and extracted with CHCl3 (2 × 30 mL). The combined
organic phases were dried (Na2SO4), concentrated, and purified
by flash chromatography (MeOH/CH2Cl2, 5:95) to give 0.24 g
CH2Cl2, 2:98) gave 0.025 g (77%) of an oil; [R]20 -17.4 (c 0.7,
D
CHCl3) [lit.9 [R]28 -18 (c 5.4, CHCl3); lit.8b [R]25 -19 (c 0.4,
D
D
CHCl3)]. HRMS calcd for C10H17NO (M + H) 168.1388, found
168.1387. 1H NMR (CDCl3) δ 3.34 (br d, 1 H, J ) 11.0 Hz),
2.50-2.25 (m, 4 H), 2.24-2.12 (m, 1 H), 1.90-1.55 (m, 6 H),
1.50-1.25 (m, 2 H), 1.20 (d, 3 H, J ) 5.7 Hz). Spectral
properties were in agreement with literature values.9
(83%) of a yellow oil; [R]20 -3.6 (c 1.0, C6H6); IR (neat) 3311,
D
2934, 2860, 1715, 1102 cm-1
;
1H NMR (CDCl3) δ 7.25 (m, 5
H), 4.42 (s, 2 H), 3.41 (t, 2 H, J ) 6.3 Hz), 2.89 (m, 1H), 2.88
(m, 1 H), 2.27 (m, 2H), 2.00 (m, 2 H), 1.56 (m, 3 H), 1.42 (m,
4 H), 1.13 (d, 3 H, J ) 6.4 Hz); 13C NMR (CDCl3) δ 210.1, 139.2,
129.1, 128.3, 128.2, 73.6, 70.7, 57.1, 52.8, 50.8, 48.7, 37.5, 30.4,
23.3, 23.1. HRMS calcd for C17H25NO2 (M + Na) 298.1783,
found 298.1787. Anal. Calcd for C17H25NO2: C, 74.14; H, 9.15;
N, 5.09. Found: C, 74.04; H, 9.18; N, 4.71.
(2S,6R)-(+)-2-(4-Hyd r oxybu tyl)-6-m eth yl-4-oxop ip er i-
d in e (17). In a 25-mL, one-necked, round-bottomed flask fitted
with magnetic stirring bar, rubber septum, and hydrogen
balloon was placed (-)-16 (0.20 g, mmol) in THF (5 mL). To
the solution was added Pd(OH)2 (0.02 g, 20% on carbon) and
2 drops of TFA. The reaction mixture was stirred at room
temperature for 3 h under an atmosphere of H2, after which
Ack n ow led gm en t. We thank Dr. Charles Debross-
ie, Director of Temple NMR facilities, for helpful discus-
sion and Dr. Bing Wang (GlaxoSmithKline) for aid in
the NOE studies. This work was supported by a grant
from the National Institute of General Medical Sciences
(GM 51982).
Su p p or tin g In for m a tion Ava ila ble: Spectral data for
compounds where only HRMS is available. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O030208D
8064 J . Org. Chem., Vol. 68, No. 21, 2003