An Efficient Access to Enantiomerically Pure Substituted Derivatives of Pipecolic Acid

Full text of DOI:10.1021/jo0000271

J . Org. Chem. 2000, 65, 4435-4439
4435
An Efficien t Access to En a n tiom er ica lly
P u r e Su bstitu ted Der iva tives of P ip ecolic
Acid
Claude Agami, Se´bastien Comesse, and
Catherine Kadouri-Puchot*
Laboratoire de Synthe`se Asyme´trique (UMR CNRS 7611),
Case courrier 47, Universite´ P. et M. Curie, 4 place J ussieu,
75005 Paris, France
kadouri@ccr.jussieu.fr
Received J anuary 10, 2000
F igu r e 1.
Pipecolic acid 1 and its numerous derivatives are
attractive synthetic targets, since these cyclic â-amino
acids are present in many biologically important com-
pounds.1 For example, (2R,4R)-methylpipecolic acid 2 is
a key component for the preparation of a highly selective
thrombin inhibitor,2 and (2S,4S)-hydroxypipecolic acid 3
is a naturally occurring compound isolated from Acacia
species.3,4 The synthesis of trans-configured 6-alkyl sub-
stituted pipecolic acid derivatives is of current interest
since they represent key precursors to antibiotics such
as solenopsin A.5 We now report a general method6 for
the preparation of 6-alkyl and 4,6-disubstituted deriva-
tives of pipecolic acid 4-6. All these compounds present
a trans relation between the 6-substituent and the acid
carboxylic moiety (Figure 1).
Sch em e 1
Sch em e 2a
The general features of these syntheses are illustrated,
in retrosynthetic format, in Scheme 1. It was projected
to construct bicyclic intermediate 8 from a diastereo-
selective intramolecular attack of an allylsilane moiety
onto an iminium ion.7 A diastereoselective addition of an
organometallic compound on oxazolidine 10 would fur-
nish key intermediate 9 possessing the requisite allylsi-
lane moiety.
Resu lts
Syn th esis of (2S,4S,6R)-4-Meth yl-6-eth ylp ip ecolic
Acid 5. Chiral oxazolidine 12 was obtained quantita-
* To whom correspondence should be addressed. Fax: (33) 01 44
27 26 20.
(1) See, for example: (a) Flynn, G. A.; Giroux, E. L.; Dage, R. C. J .
Am. Chem. Soc. 1987, 109, 7914. (b) J ones, J . K.; Mills, S. G.; Reamer,
R. A.; Askin, D.; Desmond, R.; Volante, R. P.; Shinkai, I. J . Am. Chem.
Soc. 1989, 111, 1157. (c) Sehgal, S. N.; Baker, H.; Eng, C. P.; Singh,
K.; Ve´niza, C. J . Antibiot. 1983, 36, 351.
a
Reaction conditions: (a) EtCHO, THF, MgSO4, rt, 98%; (b)
TMSCH2C(dCH2)CH2Li 16, THF, -78 to -20 °C, 73%; (c) CHO-
CHO, THF/H2O, rt, 98%; (d) Me2SO, (COCl)2, NEt3, -60 °C to room
temperature, 91%; (e) H2, PtO2, 70%; (f) H2, Pd(OH)2, 95%.
(2) (a) Kikumoto R.; Tamao Y.; Tezuka T.; Tonomura S.; Hara H.;
Ninomiya K.; Hijikata A.; Okamoto S. Biochemistry 1984, 23, 85. (b)
Okamoto S.; Hijikata A.; Kikumoto R.; Tonomura S.; Hara H.;
Ninomiya K.; Maruyama A.; Sugano M.; Tamao Y. Biochem. Biophys.
Res. Commun. 1981, 101, 440.
tively by reaction of (S)-phenylglycinol 11 with propi-
onaldehyde. This heterocycle was reacted with [2-((tri-
methylsilyl)methyl)prop-2-enyl]lithium 16.8 The reactiv-
ity of simple organolithium compounds onto phenylgly-
cinol-derived oxazolidines is well documented,9 but to the
best of our knowledge, no reaction of the more complex
lithium reagent 16 onto oxazolidines has ever been
described. In the event, oxazolidine 12 reacted with
reagent 16 to afford â-amino alcohols 14 with 73% yield
and a 95/5 diastereomeric ratio. Reaction between glyoxal
and â-amino alcohol 14 gave quantitatively bicyclic
compound 17 (Scheme 2). The creation of the stereocenter
at the ring junction was totally diastereoselective. This
material was an epimeric mixture at the hemiacetal
(3) Clark-Lewis, J . W.; Mortimer, P. I. J . Chem. Soc. 1961, 189.
(4) For recent EPC syntheses of pipecolic acid and some derivatives,
see, for example: (a) Rutjes, F. P. J . T.; Schoemaker, H. E. Tetrahedron
Lett. 1997, 38, 677. (b) Barluenga, J .; Aznar, F.; Valde´s, C.; Ribas, C.
J . Org. Chem. 1998, 63, 3918. (c) Agami, C.; Bihan, D.; Hamon, L.;
Puchot-Kadouri, C. Tetrahedron 1998, 54, 10309. (d) Agami, C.; Bihan,
D.; Hamon, L.; Puchot-Kadouri, C.; Lusinchi, M. Eur. J . Org. Chem.
1998, 2461, 1. (e) Sanchez-Sancho, F.; Herradon, B. Tetrahedron:
Asymmetry 1998, 9, 1951. (f) Rutjes, F. P. J . T.; Veerman, J . J . N.;
Meester, W. J . N.; Hiemstra, H.; Schoemaker, H. E. Eur. J . Org. Chem.
1999, 1127, 7. (g) Di Nardo, C.; Varela, O. J . Org. Chem. 1999, 64,
6119. (h) Cheˆnevert, R.; Morin, M.-P. J . Org. Chem. 1999, 64, 3178.
For a recent review, see: Couty, F. Amino Acids 1999, 16, 297.
(5) J efford, C. W.; Wang, J . B. Tetrahedron Lett. 1993, 34, 2911.
(6) For a preliminary report, see: Agami, C.; Comesse, S.; Kadouri-
Puchot, C.; Lusinchi, M. Synlett 1999, 1094.
(7) Agami, C.; Bihan, D.; Morgentin, R.; Puchot-Kadouri, C. Synlett
1997, 799.
(8) Ryter, K.; Livinghouse, T. J . Org. Chem. 1997, 62, 4842.
(9) Bloch, R. Chem. Rev. 1998, 98, 1413.
10.1021/jo0000271 CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/09/2000

4436 J . Org. Chem., Vol. 65, No. 14, 2000
Notes
Sch em e 3a
Sch em e 4
Sch em e 5
the absolute configuration of the stereogenic centers.
Finally, hydrogenolysis of the compound 26 gave quan-
titatively the enantiopure amino acid 6.
Discu ssion
Asym m etr ic In d u ction d u r in g th e Syn th eses of
â-Am in o Alcoh ols 14 a n d 15. As described above, the
addition of the lithium reagent 16 on the oxazolidines
12 and 13 gave, respectively, â-amino alcohols 14 and
15 with a 95/5 dr. This diastereofacial selectivity can be
rationalized by assuming the formation of the chelated
intermediate 27. This intermediate undergoes an internal
delivery of the nucleophile from the less hindered side
of the chelate, i.e., the Si face of the imine moiety
(Scheme 4). It is well-known9,11a that a primary amine-
derived oxazolidine exists as an equilibrium mixture with
its imine tautomer showing an E geometry.
a
Reaction conditions: (a) PrCHO, THF, MgSO4, rt, 98%; (b)
TMSCH2C(dCH2)CH2Li 16, THF, -78 to -20 °C, 80%; (c) CHO-
CHO, THF/H2O, rt, 98%; (d) OsO4, NaIO4, THF, H2O, rt, 75%; (e)
(CH2SH)2, BF3-Et2O, HCCl3, rt, 95%; (f) Me2SO, (COCl)2, NEt3,
CH2Cl2, -60 °C to room temperature, 77% from 22 and 90% from
21; (g) H2, Raney nickel, 45%; (h) K-Selectride, THF, -78 °C, 54%;
(i) H2, Pd(OH)2, 98% from 24 and 26.
This stereoselective course leads in both cases to an R
configuration at the created stereogenic center. This
result is in agreement with previously reported reactions
between oxazolidines-derived from phenylglycinol and
simple organolithium compounds such as MeLi11 or
PhLi.12
Asym m et r ic In d u ct ion d u r in g t h e Cycliza t ion
Step . The key step of our methodology is based on a
totally stereoselective reaction between the allylsilane
and the iminium ion moieties in intermediate 28 (Scheme
5).
The stereoselective formation of the stereocenter at the
ring junction corresponds to what was already described
on similar iminium ions:7,13 chiral induction by the
phenyl-bearing stereocenter leads the addition of the
olefinic double bond to occur on the less encumbered face,
i.e., the Si face of the cyclic iminium ion. It is worth
noting that during this cyclization leading to compounds
8 the integrity of the stereogenic center bearing the R
substituent was not altered. In connection with the huge
amount of published works in this field,14 this process
center. Swern oxidation of this hemiacetal function was
followed by a diastereoselective hydrogenation of the
ethylenic double bond. Two diastereomers (85/15 dr)
resulted from this reduction. The stereochemistry of the
three created asymmetric centers was determined from
an X-ray analysis of the major compound 19.10 Finally,
hydrogenolysis of lactone 19 afforded the enantiopure
disubstituted derivative of pipecolic acid 5.
Syn th esis of (2S,6R)-6-P r op ylp ip ecolic Acid 4 a n d
(2S,4S,6R)-4-Hyd r oxy-6-p r op ylp ip ecolic Acid 6. Oxa-
zolidine 13 obtained quantitatively from the condensation
between butyraldehyde and (S)-phenylglycinol 11 was
reacted with organolithium reagent 16 with 80% yield
and 95/5 dr to afford amino alcohol 15, which was
transformed into the unsaturated hemiacetal 20. Oxida-
tive cleavage of the ethylenic double bond of compound
20 furnished ketone 21, which reacted with ethane dithiol
to give derivative 22. Swern oxidation of compound 22
provided lactone 23. Removal of the dithiane group by
hydrogen in the presence of Raney nickel followed by a
hydrogenolysis of lactone 24 resulted in the formation of
the diastereomerically pure amino acid 4 (Scheme 3).
In another way, compound 21 was transformed into
lactone 25 by Swern oxidation. A diastereoselective
reduction of the keto group by K-selectride afforded
alcohol 26 as a sole diastereomer. X-ray analysis was
performed on this bicyclic alcohol10 in order to determine
(11) See, for example: (a) Higashiyama, K.; Inoue, H.; Takahashi,
H. Tetrahedron Lett. 1992, 33, 235. (b) Higashiyama, K.; Inoue, H.;
Takahashi, H. Tetrahedron 1994, 50, 1083. (c) Wu, M.-J .; Pridgen, L.
N. J . Org. Chem. 1991, 56, 1340.
(12) See, for example: Delorme, D.; Berthelette, C.; Lavoie, R.;
Roberts, E. Tetrahedron: Asymmetry 1998, 9, 3963.
(13) Agami, C.; Couty, F.; Puchot-Kadouri, C. Synlett 1998, 449.
(14) (a) Hiemstra, H.; Speckamp, W. N. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 2, pp 1047-1082. (b) Overman, L. E.; Ricca, D. J . In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford 1991; Vol. 2, pp 975-1006.
(10) The X-ray analysis were performed by Dr. J . Vaissermann at
the Laboratoire de Chimie des Me´taux de Transition (Universite´ P. et
M. Curie).

Notes
J . Org. Chem., Vol. 65, No. 14, 2000 4437
7.7 Hz, 0.5H), 3.62-3.55 (m, 1.5H), 2.28-2.05 (m, 1H), 1.72-
1.64 (m, 2H), 1.02-0.93 (m, 3H). 13C NMR: 142.5, 140.5, 129.0,
128.7, 128.0, 127.4, 127.3, 127.0, 126.5, 94.1, 93.7, 72.5, 71.5,
62.5, 60.6, 27.6, 27.2, 9.6, 9.5.
Oxa zolid in e (13). 1H NMR: 7.29-7.13 (m, 5H), 4.49-4.38
(m, 1H), 4.30-4.15 (two t, J ) 7.4 and 7.8 Hz, 1H), 4.00 (t, J )
7.6 Hz, 0.5H), 3.80-3.46 (m, 1.5H), 2.28-2.05 (m, 1H), 1.67-
1.55 (m, 2H), 1.48-1.38 (m, 2H), 0.89 (t, J ) 7.2 Hz, 3H). 13C
NMR: 142.7, 140.6, 129.1, 128.8, 128.1, 127.5, 127.4, 127.1,
126.6, 93.2, 92.8, 72.7, 71.7, 62.8, 60.9, 37.0, 36.8, 19.1, 19.0,
14.4.
Gen er a l P r oced u r e for th e Syn th esis of â-Am in o Alco-
h ols. To a solution of organolithium compound 168 (7.5 mmol)
in THF (45 mL), stirred at -78 °C, was added a solution of
freshly prepared oxazolidines (3 mmol) in THF (5 mL). Stirring
was continued for 30 min at -78 °C. The solution was allowed
to reach -20 °C over 45 min. The mixture was hydrolyzed with
a saturated solution of ammonium chloride (25 mL), and the
aqueous layer was extracted with diethyl ether. The combined
organic layers were dried over K2CO3 and evaporated under
reduced pressure to afford a diastereomeric mixture (diastereo-
meric ratios were determined by GC (GC OV17) analysis of crude
material) of â-amino alcohols (95/5 dr) which was chromato-
graphed (AcOEt/PE: 20/80). The minor diastereomer was elimi-
nated during the chromatography step.
F igu r e 2.
can be viewed as a classical ene/iminium reaction since
such a concerted one-step process should not affect this
center. This fact seems to preclude the occurrence of a
two-step process involving an aza-Cope rearrangement
followed by an ene/iminium addition, which has recently
been put forward by Mariano et al.15 in order to explain
their results.
Asym m etr ic In d u ction d u r in g th e Red u ction of
Un sa tu r a ted Bon d s. The attack of hydrogen on lactone
18 as well as the action of K-Selectride on ketone 25
follows the same stereochemical outcome. The major
product resulting from the hydrogenation of the double
bond corresponds to an approach on the Re face of bicyclic
compound 18. The same requirement is involved during
the attack of K-Selectride on ketone 25. Molecular
modelization shows that the more stable conformation
(Figure 2) of compounds 18 and 25 is a cis-bicyclic
structure in which the phenyl and the alkyl substituents
(Et in 18 and Pr in 25) are respectively in an equatorial
and axial geometry. The attack on the Re face can thus
be rationalized on a steric basis.
(1R,2S)-P h en yl-2-(1-eth yl-3-tr im eth ylsila n ylm eth ylbu t-
3-en yla m in o)eth a n ol (14). White solid (yield 73%). Mp: 58 °C.
1
[R]20D: +75 (c 0.9, HCCl3). H NMR: 7.36-7.22 (m, 5H), 4.61-
4.58 (m, 2H), 3.83 (dd, J ) 4.6, 8.3 Hz, 1H), 3.64 (dd, J ) 4.6,
10.6 Hz, 1H), 3.46 (dd, J ) 8.3, 10.6 Hz, 1H), 2.56-2.52 (m, 1H),
2.11 (dd, J ) 6.4, 14.3 Hz, 1H), 1.95 (dd, J ) 6.9 and 13.6 Hz,
1H), 1.80-1.60 (m, 2H), 1.44 (d, J ) 3.2 Hz, 2H), 1.43-1.23 (m,
2H), 0.77 (t, J ) 7.4 Hz, 3H), 0.00 (s, 9H). 13C NMR: 145.6, 142.0,
128.8, 127.8, 127.6, 110.1, 67.0, 62.5, 55.0, 43.8, 28.1, 26.8, 10.3,
-0.9. IR (CHCl3): 2900, 1820, 1750 cm-1. Anal. Calcd for C18H31
-
In conclusion, diastereomerically pure amino acids 4,
5, and 6 were synthesized from (2S)-phenylglycinol in
18%, 43%, and 28% overall yield, respectively, via two
stereoselective key steps: a nucleophilic addition of a
silylated allyllithium reagent on an oxazolidine-derived
imine and an ene-iminium cyclization involving an
allylsilane moiety.
NOSi: C, 70.76; H, 10.23; N, 4.58. Found: C, 70.77; H, 10.25;
N, 4.52.
(1R,2S)-P h en yl-2-(1-pr opyl-3-tr im eth ylsilan ylm eth ylbu t-
3-en yla m in o)eth a n ol (15). White solid (yield: 80%). Mp: 58
°C. [R]20D: +63 (c 0.9, HCCl3). 1H NMR: 7.36-7.21 (m, 5H),
4.60-4.57 (m, 2H), 3.85 (dd, J ) 4.6, 8.3 Hz, 1H), 3.65 (dd, J )
4.6, 10.6 Hz, 1H), 3.47 (dd, J ) 8.3, 10.5 Hz, 1H), 2.62-2.56 (m,
1H), 2.17-2.08 (m, 2H), 2.15 (dd, J ) 6.0, 13.4 Hz, 1H), 1.92
(dd, J ) 6.7, 13.5 Hz, 1H), 1.42 (d, J ) 4.6 Hz, 2H), 1.40-1.10
(m, 4H), 0.75 (t, J ) 6.8 Hz, 3H), 0.00 (s, 9H). 13C NMR: 145.4,
141.8, 128.6, 127.6, 127.4, 109.8, 66.8, 62.2, 53.1, 44.1, 37.6, 26.7,
18.9, 14.2, -1.0. IR (CHCl3): 2900, 1820, 1750 cm-1. Anal. Calcd
for C19H33NOSi: C, 71.41; H, 10.41; N, 4.38. Found: C, 71.45;
H, 10.32; N, 4.28.
Gen er a l P r oced u r e for th e F or m a tion of Hem ia ceta ls.
Glyoxal (40% weight, 1.1 mL) was added to a solution of amino
alcohol 14 or 15 (1.66 mmol) in THF/H2O (v/v: 1/1, 6.6 mL). The
mixture was stirred for 5 h at room temperature, and water (6
mL) was added. Extraction with CH2Cl2 was followed by drying
the organic layers on MgSO4. After evaporation under reduced
pressure, chromatography on silica gel (AcOEt/PE: 20/80) gave
the corresponding hemiacetals (yield: 98%) as a mixture (50/50
for 17 and 70/30 for 20) of diastereomers at C-1.
Exp er im en ta l Section
Gen er a l Meth od s. 1H NMR and 13C NMR spectra (CDCl3
solutions unless otherwise stated) were carried out at 250 and
62.9 MHz. 1H NMR and 13C NMR spectra for lactone 18 were
carried out at 400 and 100 MHz. Column chromatography was
performed on silica gel 230-400 mesh with various mixtures of
ethyl acetate (AcOEt) or diethyl ether (Et2O) and petroleum
ether (PE). Tetrahydrofuran was distilled from benzophenone
ketyl. For X-ray analysis of compounds 19 and 26, data were
collected at room temperature. The program used was CRYS-
TALS. No significant variations were observed in the intensities
of two checked reflections during data collection. The structure
was solved by use of SHELXS86 program, G. M. Sheldrick,
Program for Crystal Structure Solution, University of Go¨ttingen,
1986, and refined by full-matrix least-squares analysis with
anisotropic thermal parameters for all non hydrogen atoms. H
atoms were introduced in calculated positions in the last
refinement.
(4S,6R,9S)-8-Meth ylen e-4-ph en yl-6-eth yloctah ydr opyr ido-
[2,1-c][1,4]oxa zin -1-ol (17). Only the characteristic peaks are
1
given. H NMR: 7.23-7.10 (m, 5H), 4.87 (d, J ) 2.7 Hz, 0.5H),
4.75 (s, 0.5H), 4.65-4.63 (m, 1H), 4.51-4.49 (m, 1H), 4.22 (dd,
J ) 4.1, 11 Hz, 0.5H), 4.06 (dd, J ) 3.8, 10.5 Hz, 0.5H), 3.76 (t,
J ) 11.5 Hz, 0.5H), 3.67 (dd, J ) 3.8, 11.4 Hz, 0.5H), 1.42-0.85
(m, 4H), 0.65 (two t, J ) 6.7 Hz, 3H). 13C NMR: 144.5, 143.8,
139.4, 129.1, 128.9, 128.7, 128.5, 128.4, 128.2, 110.1, 109.8, 96.0,
93.6, 72.3, 65.3, 60.8, 57.6, 57.4, 56.4, 56.2, 55.4, 54.5, 32.8, 32.5,
31.6, 26.3, 23.8, 21.5, 14.6, 11.3. IR (CHCl3): 3324, 2910, 1689,
Gen er a l P r oced u r e for th e P r ep a r a tion of Oxa zolid in es
12 a n d 13. Propionaldehyde or butyraldehyde (5.85 mmol) was
added dropwise to a solution of (2S)-phenylglycinol (800 mg, 5.85
mmol) in THF (12 mL) in the presence of MgSO4. The mixture
was stirred at room temperature for 1 h and filtered over Celite
545. The solution was concentrated under reduced pressure to
afford a mixture of cis and trans oxazolidines in a quantitative
yield. This mixture was engaged in the next step without further
purification.
1635, 1430 cm-1
.
(4S,6R,9a S)-8-Met h ylen e-4-p h en yl-6-p r op yloct a h yd r o-
p yr id o[2,1-c][1,4]oxa zin -1-ol (20). 1H NMR: 7.24-7.12 (m,
5H), 4.86 (d, J ) 2.9 Hz, 0.3H), 4.76 (s, 0.7H), 4.66-4.63 (m,
1H), 4.52-4.47 (m, 1H), 4.20 (dd, J ) 4.0, 11.1 Hz, 0.7H), 4.05
(dd, J ) 3.7, 10.4 Hz, 0.3H), 3.77 (t, J ) 11.7 Hz, 0.7H), 3.66
(dd, J ) 3.7, 11.5 Hz, 0.3H), 1.43-0.80 (m, 4H), 0.64 and 0.63
(two t, J ) 6.7 Hz, 3H). 13C NMR: 144.3, 143.6, 139.3, 139.1,
128.8, 128.6, 128.5, 128.3, 128.1, 127.9, 109.9, 109.6, 95.8, 93.3,
Oxa zolid in e (12). 1H NMR: 7.28-7.17 (m, 5H), 4.47-4.42
(m, 1H), 4.30-4.17 (two t, J ) 7.4 and 7.5 Hz, 1H), 4.00 (t, J )
(15) Wu, X.-D.; Khim, S.-K.; Zhang, X.; Cederstrom, E. M.; Mariano,
P. S. J . Org. Chem. 1998, 63, 841.

4438 J . Org. Chem., Vol. 65, No. 14, 2000
Notes
71.9, 64.9, 57.3, 57.1, 55.1, 54.6, 54.3, 33.1, 32.7, 32.4, 31.3, 29.8,
26.0, 19.6, 19.5, 14.3(CH3). IR (CHCl3): 3324, 2910, 1689, 1635,
hydrogenation was complete into 30 min. The mixture was
filtered through Celite 545 and the residue washed with acetone.
The filtrate was evaporated to dryness, leaving the correspond-
ing crude methylated derivative as a diastereomeric mixture (85/
15 at C-8; 95%) that was recrystallized with pentane to afford
compound 19 as white crystals. Mp: 147 °C. [R]20D: -150 (c 1.2,
1430 cm-1
.
(4S,6R,9a S)-1-Hyd r oxy-4-p h en yl-6-p r op ylh exa h yd r op yr -
id o[2,1-c][1,4]oxa zin -8-on e (21). Osmium tetraoxide (800 µL,
4% solution in H2O, 0.12 mmol) was added to a solution of
hemiacetal 20 (510 mg, 1.78 mmol) in THF/H2O (1/1, v/v, 24 mL)
at room temperature. Stirring was continued for 5 min, and
NaIO4 (1.9 g, 8.9 mmol) was added by fraction over 30 min. After
the end of addition, stirring was maintained for an additional
15 min. The mixture was hydrolyzed with an aqueous solution
of Na2S2O3 (7.5%, 15 mL). The aqueous layer was extracted with
diethyl ether, and the combined organic layers were dried over
MgSO4. After evaporation, the residue was chromatographed
(AcOEt/PE: 30/70) to afford ketone 21 (385 mg, 75%) as a
mixture (60/40) of two diastereomers at C-1. 1H NMR: 7.32-
7.19 (m, 5H), 5.09 (bs, 0.6H), 4.85 (bs, 0.4H), 4.17 (dd, J ) 3.6
and 10.7 Hz, 0.4H), 4.07-3.93 (m, 1H), 3.83 (dd, J ) 3.7 and
11.7 Hz, 1H), 3.65-3.29 (m, 2.6H), 3.07-2.57 (m, 3H), 2.40-
2.28 (m, 0.6H), 2.15-2.08 (m, 0.4H), 1.93-1.84 (m, 1H), 1.40-
1.20 (m, 2H), 1.19-1.08 (m, 2H), 0.76-0.68 (m, 3H). 13C NMR:
210.2, 208.8, 138.6, 129.0, 128.9, 128.6, 128.4, 128.2, 94.9, 92.8,
71.5, 64.7, 57.7, 57.4, 56.6, 56.4, 55.0, 54.6, 41.2, 40.9, 39.7, 34.8,
1
HCCl3). H NMR: 7.45-7.25 (m, 5H), 4.34 (dd, J ) 2.6, 8.3 Hz,
1H), 4.20-4.07 (m, 2H), 3.99 (dd, J ) 2.2, 5.1 Hz, 1H), 2.49-
2.39 (m, 1H), 2.28-2.19 (m, 1H), 1.93-1.77 (m, 1H), 1.75-1.66
(m, 1H), 1.55-1.32 (m, 2H), 1.20-1.05 (m, 1H), 1.00 (d, J ) 6.2
Hz, 3H), 1.00-0.88 (m, 1H), 0.72 (t, J ) 7.4 Hz, 3H). 13C NMR:
172.9, 140.4, 128.7, 127.6, 126.7, 69.7, 62.4, 61.0, 54.4, 39.4, 33.1,
27.1, 25.5, 22.2, 9.3. Anal. Calcd for C17H23NO2: C, 74.79; H,
8.48; N, 5.12. Found: C, 74.67; H, 8.54; N, 5.19.
Cr ysta l d a ta : C17H23NO2, orthorhombic, no centrosymmetric
P21 space group, Z ) 4, Dc ) 1.18 g cm-3, µ(Mo KR) ) 0.72 cm-1
,
a ) 7.650(2) Å, b ) 10.114(1) Å, c ) 19.857(2) Å, â ) 90°, V )
1536.3(5) Å3. The final refinement of 200 parameters using 1032
reflections (with (Fo)2 > 3σ(Fo)2) were used to solve and refine
the structure to R ) 0.0388 and Rw ) 0.0491.
Com p ou n d 22. Ethane dithiol (320 µL, 3.82 mmol) was added
slowly at -10 °C to a solution of hemiacetal 21 (54 mg, 0.19
mmol) and BF3‚Et2O (94 µL, 0.74 mmol) in CHCl3 (1.8 mL) under
inert atmosphere. The mixture was stirred at -10 °C for 2 h
and then allowed to reach rt in 2 h. Addition of a solution of
NaHCO3 (10 mL) was followed by extraction with CH2Cl2. The
organic layers were dried over MgSO4 and evaporated. The
residue was chromatographed (AcOEt/EP: 20/80) to afford
compound 22 (65 mg, 95%) as a mixture of diastereomers in a
34.6, 19.3, 19.2, 14.0. IR (CHCl3): 3370, 2720, 1709, 1470 cm-1
.
Anal. Calcd for C17H23NO3: C, 70.56; H, 8.01; N, 4.84. Found:
C, 70.44; H, 8.17; N, 4.78.
Gen er a l P r oced u r e for Sw er n Oxid a tion . Dimethyl sul-
foxide (0.52 mL, 7.39 mmol) was added dropwise to a solution
of oxalyl chloride (0.27 mL, 3.06 mmol) in dichloromethane (6
mL) at -60 °C. The mixture was stirred for 10 min, and a
solution of hemiacetal 17, 21 or 22 (2.55 mmol) in dichlo-
romethane (5 mL) was introduced. After 30 min at -60 °C,
triethylamine (1.77 mL, 12.7 mmol) was added, and the mixture
was allowed to warm to room temperature in 1 h. Addition of
water (15 mL) and extraction with dichloromethane gave after
evaporation of the combined organic layers a residue that was
chromatographed to afford corresponding lactone.
1
ratio of 70/30. H NMR: 7.27-7.19 (m, 5H), 4.92 (s, 0.3H), 4.84
(bs, 0.7H), 4.15 (dd, J ) 4.1, 11 Hz, 0.7H), 4.12-3.83 (m, 0.3H),
3.95-3.60 (m, 1H), 3.45 (dd, J ) 4.1, 11.7 Hz,1H), 3.32-3.20
(m, 4H), 2.71-2.20 (m, 4H), 1.72-1.66 (m, 2H), 1.34-1.13 (m,
4H), 0.72 (2t, J ) 7.1 Hz, 3H).13C NMR: 138.0, 126.8, 126.3,
91.3, 63.5, 62.9, 55.5, 52.8, 52.1, 38.5, 36.7, 35.5, 34.3, 32.5, 18.6,
12.2. IR (CHCl3): 3324, 2920, 1450 cm-1. HRMS: calcd for
C
19H28NO2S2 (M + H+) m/z ) 366.1561, obsd m/z ) 366.1551.
(4S,6R,9a S)-4-P h en yl-6-p r op ylh exa h yd r op yr id o[2,1-c]-
(4S,6R,9a S)-8-Meth ylen e-4-p h en yl-6-eth ylocta h yd r op yr -
id o[2,1-c][1,4]oxa zin -1-on e (18). Oil (AcOEt/PE: 20/80)
(yield: 91%). [R]D: +81 (c 1.0, HCCl3). 1H NMR (400 MHz):
7.38-7.36 (m, 5H), 4.86 (d, J ) 1.6 Hz, 1H), 4.70 (d, J ) 1.6 Hz,
1H), 4.44 (dd, J ) 4.5, 9.7 Hz, 1H), 4.33-4.24 (m, 2H), 4.02 (dd,
J ) 3.8, 12.0 Hz, 1H), 2.72 (dd, J ) 12.0, 13.9 Hz, 1H), 2.68-
2.61 (m, 1H), 2.43 (dd, J ) 3.8, 14.1 Hz, 1H), 2.29 (dd, J ) 4.3,
13.6 Hz, 1H), 1.70 (d, J ) 13.6 Hz, 1H), 1.55-1.45 (m, 1H), 1.25-
1.13 (m, 1H), 0.81 (t, J ) 7.4 Hz, 3H). 13C NMR (400 MHz):
170.5, 141.3, 136.4, 129.1, 128.8, 128.6, 110.8, 73.8, 56.0, 55.9,
55.7, 33.1, 32.8, 23.5, 10.8. IR (CHCl3): 3320, 2980, 2920, 1750,
1465 cm-1. HRMS: calcd for C17H21NO2 (M + H+) m/z )
272.1651, obsd m/z ) 272.1648.
[1,4]oxa zin -1-on e (24). To a solution of compound 23 (77 mg,
0.212 mmol) in MeOH (2 mL) was added a suspension of Raney
nickel in MeOH (2 mL). The mixture was hydrogenated for 2 h,
filtered on Celite 545, and evaporated under reduced pressure.
The crude residue was chromatographed (Et2O/EP: 25/75) to
afford lactone 24 as a white solid (26 mg, 45%). Mp: 81 °C. [R]20
:
D
1
-26 (c 1, HCCl3). H NMR: 7.39-7.27 (m, 5H), 4.39-4.16 (m,
3H), 4.05 (dd, J ) 3.5, 9.5 Hz, 1H), 2.57-2.54 (m, 1H), 2.18-
1.98 (m, 1H), 1.76-1.62 (m, 5H), 1.30-1.12 (m, 4H), 0.77 (t,
J ) 7.2 Hz, 3H).13C NMR: 172.1, 138.1, 128.7, 128.5, 128.3, 72.8,
57.8, 55.3, 55.0, 34.1, 29.9, 25.3, 19.7, 19.5, 14.1. HRMS: calcd
for C17H24NO2 (M + H+) m/z ) 274.1807, obsd m/z ) 274.1802.
(4S,6R,8S,9a S)-8-Hyd r oxy-4-p h en yl-6-p r op ylh exa h yd r o-
p yr id o[2,1-c][1,4]oxa zin -1-on e (26). A 1 M solution of K-
Selectride in THF (425 µL, 0.42 mmol) was added at -78 °C to
a solution of compound 25 (122 mg, 0.42 mmol) in THF (4.2 mL).
The mixture was stirred at -78 °C for 80 min and then
hydrolyzed by addition of a saturated aqueous solution of
ammonium chloride (5 mL), and the aqueous layer was extracted
with dichloromethane. The combined organic layers were dried
(MgSO4) and evaporated under reduced pressure. The crude
residue was chromatographed on silica gel (AcOEt/EP: 25/75)
to furnish compound 26 as a single diastereomer (67 mg, 54%).
La cton e (23). Oil (AcOEt/PE: 20/80) (yield: 77%). [R]20
:
D
+93 (c 1.7, HCCl3). 1H NMR: 7.34-7.28 (m, 5H), 4.30-4.21 (m,
3H), 4.17 (dd, J ) 3.3, 11.4 Hz, 1H), 3.35-3.28 (m, 2H), 3.26-
3.20 (m, 2H), 2.70-2.66 (m, 1H), 2.52 (dd, J ) 11.4, 13.9 Hz,
1H), 2.17 (dd, J ) 5.6, 14.5 Hz, 1H), 2.13-2.08 (m, 1H), 1.77-
1.65 (m, 2H), 1.36-1.12 (m, 3H), 0.76 (t, J ) 7.1 Hz, 3H). 13C
NMR: 170.6, 136.1, 129.0, 128.8, 128.5, 73.0, 64.5, 55.8, 55.1,
54.0, 40.3, 40.0, 37.3, 36.7, 34.6, 20.1, 14.0. IR (CHCl3): 2990,
1720, 1460, 736 cm-1. HRMS: calcd for C19H26NO2S2 (M + H+)
m/z ) 364.1405, obsd m/z ) 364.1402.
(4S,6R,9a S)-4-P h en yl-6-p r op ylh exa h yd r op yr id o[2,1-c]-
[1,4]oxa zin e-1,8-d ion e (25). Solid (AcOEt/PE: 30/70) (yield:
1
White solid. Mp: 137 °C. [R]20D: -114 (c 0.5, HCCl3). H NMR:
1
90%). Mp: 104 °C. [R]20D: +71 (c 0.5, HCCl3). H NMR: 7.37-
7.35-7.19 (m, 5H), 4.37-4.33 (m, 1H), 4.13-4.00 (m, 4H), 2.49-
2.37 (m, 2H), 1.97-1.83 (m, 2H), 1.70-1.59 (m, 1H), 1.44-1.35
(m, 1H), 1.30-1.08 (m, 4H), 0.57 (t, J ) 7.1 Hz, 3H). 13C NMR:
172.5, 139.4, 128.9, 127.9, 127.0, 70.5, 64.5, 60.4, 59.0, 54.0, 38.7,
36.3, 33.5, 18.2, 14.1. IR (CHCl3): 2817, 1720, 1450 cm-1. Anal.
Calcd for C17H23NO3: C, 70.56; H, 8.01; N, 4.84. Found: C, 70.51;
H, 8.08; N, 4.70.
7.31 (m, 5H), 4.34-4.23 (m, 2H), 4.26 (t, J ) 4.7 Hz,1H), 4.19
(dd, J ) 4.3, 11.7 Hz, 1H), 3.08-3.00 (m, 1H), 2.80 (dd, J ) 11.7,
14.5 Hz, 1H), 2.55 (ddd, J ) 2.0, 4.3, 14.6 Hz, 1H), 2.45 (dd, J )
5.9, 14.1 Hz, 1H), 1.91 (dt, J ) 2.1, 14.1 Hz, 1H), 1.39-1.24 (m,
2H), 1.20-1.08 (m, 2H), 0.74 (t, J ) 6.9 Hz, 3H).13C NMR: 205.4,
168.7, 135.2, 129.3, 128.5, 73.6, 56.3, 56.1, 55.8, 41.6, 40.1, 34.4,
19.1, 13.8. IR (CHCl3): 2990, 2650, 1720, 1450 cm-1. HRMS:
calcd for C17H22NO3 (M + H+) m/z ) 288.1600, obsd m/z )
288.1600.
Cr ysta l d a ta : C17H23NO3, monoclinic, no centrosymmetric C2
space group, Z ) 4, Dc ) 1.21 g cm-3, µ(Mo KR) ) 0.77 cm-1
,
a ) 15.554(17) Å, b ) 6.222(3) Å, c ) 16.784(12) Å, â )102.81-
(7)°, V ) 1536.3(5) Å3. The final refinement of 200 parameters
using 1298 reflections (with (Fo)2 > 3σ(Fo)2) were used to solve
and refine the structure to R ) 0.0596 and Rw ) 0.0694.
Gen er a l P r oced u r e for th e Hyd r ogen olysis of Bicyclic
La cton es. A solution of lactone (0.15 mmol) in absolute ethanol
(4S,6R,8S,9a S)-8-Meth yl-4-p h en yl-6-eth ylocta h yd r op yr -
id o[2,1-c][1,4]oxa zin -1-on e (19). A solution of lactone 18 (100
mg, 0.369 mmol) in benzene/acetone (1/1, 2 mL) was injected
into a hydrogenation flask containing a prehydrogenated sus-
pension of PtO2 (15 mg) in benzene/acetone (1/1, 1 mL). The

Notes
J . Org. Chem., Vol. 65, No. 14, 2000 4439
(1.5 mL) was injected into a hydrogenation flask containing a
prehydrogenated suspension of 20% Pd(OH)2/C (Pearlman cata-
lyst) (0.04 g) in absolute ethanol (1.5 mL). The hydrogenation
was complete in 4-6 h. The mixture was filtered through Celite
545 and the residue washed with ethanol to give after evapora-
tion the corresponding amino acid.
0.92 (t, J ) 7.25 Hz, 3H). 13C NMR (D2O): 171.7, 62.7, 54.9,
51.9, 35.7, 34.0, 32.0, 16.9, 12. HRMS: calcd for C9H18NO3
(M + H+) m/z ) 188.1287, obsd m/z ) 188.1290.
MO Ca lcu la tion s. The geometries of the conformations of
compounds 18 and 25 were optimized by using the Davidson-
Fletcher-Powel algorithm (FLEPO procedure), minimizing the
energy with respect to all internal coordinates.16
(2S,6R)-6-P r op ylp ip er id in eca r boxylic Acid (4). White
solid (yield: 98% from lactone 24). Mp: 240 °C dec. [R]20D: +44
(c 0.8, H2O). 1H NMR (D2O): 3.92 (t, J ) 4.7 Hz, 1H), 3.46-
3.43 (m, 1H), 2.09-2.08 (m, 1H), 1.93-1.58 (m, 5H), 1.48-1.37
(m, 4H), 0.93 (t, J ) 7.2 Hz, 3H). 13C NMR (D2O): 174.1, 56.2,
Ack n ow led gm en t. The authors gratefully acknowl-
edge Dr. M. Lusinchi for her help in obtaining compound
19, Dr. L. Hamon for AM1 calculations and for many
interesting discussions, and Dr. J . Vaissermann for
X-ray analysis of compounds 19 and 26.
53.9, 34.2-27.5-25.3, 19.1-18.2, 13.2. HRMS: calcd for C9H18
-
NO2 (M + H+) m/z ) 172.1338, obsd m/z ) 172.1342.
(2S,4S,6R)-4-Met h yl-6-et h ylp ip er id in eca r b oxylic Acid
(5). White solid (yield: 95% from lactone 19). Mp: 220 °C dec.
[R]20D: +19 (c 0.5, H2O). 1H NMR (D2O): 3.87-3.85 (m, 1H),
3.22-3.16 (m, 1H), 2.16-2.11 (m, 1H), 1.83-1.78 (m, 1H), 1.59-
1.27 (m, 4H), 0.94-0.79 (m, 7H). 13C NMR (D2O): 174.6, 57.9,
Su p p or tin g In for m a tion Ava ila ble: Spectrometric in-
formation (1H NMR) for compounds 4-6, 18, 19, and 22-26
and two ORTEP drawings (X-ray analysis of compounds 19
and 26). This material is available free of charge via the
Internet at http://pubs.acs.org.
56.7, 37.1, 33.6, 27.5, 27.3, 21.9, 9.9. HRMS: calcd for C9H18
-
NO2 (M + H+) m/z ) 172.1338, obsd m/z ) 172.1337.
(2S,4S,6R)-4-Hydr oxy-6-pr opylpiper idin ecar boxylic acid
(6). White solid (yield: 98% from lactone 26). Mp: 220 °C dec.
J O0000271
1
[R]20D: +15 (c 0.6, H2O). H NMR (D2O): 4.09 (dd, J ) 2.5, 5.7
Hz, 1H), 3.82-3.70 (m, 1H), 3.57-3.45 (m, 1H), 2.57-2.49 (m,
1H), 2.22-2.13 (m, 1H), 1.79-1.57 (m, 3H), 1.50-1.33 (m, 3H),
(16) Dewar, M. J . S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J . J . P.
J . Am. Chem. Soc. 1985, 107, 3902.