Synthesis of (2R,4R)- and (2S,4S)-4-hydroxypipecolic acid derivatives and (2S,4S)-(-)-SS20846A

Article abstract of DOI:10.1016/S0040-4039(00)02124-9

Syntheses of protected derivatives of both enantiomers of trans-4-hydroxypipecolic acid (2) and the natural product (-)-SS20846A (3) were accomplished from vinylglycinols. Key transformations involved construction of the piperidine ring via ring-closing metathesis (Grubbs' catalyst) and installation of the 4-hydroxy substituent by Prevost reaction. X-Ray diffraction analyses conclusively established the regio- and stereochemistry of key intermediates.

Full text of DOI:10.1016/S0040-4039(00)02124-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1209–1212
Synthesis of (2R,4R)- and (2S,4S)-4-hydroxypipecolic acid
derivatives and (2S,4S)-(−)-SS20846A
Mark Sabat and Carl R. Johnson*
Department of Chemistry, Wayne State University, Detroit, MI 48202-3489, USA
Received 14 November 2000; accepted 20 November 2000
Abstract—Syntheses of protected derivatives of both enantiomers of trans-4-hydroxypipecolic acid (2) and the natural product
(−)-SS20846A (3) were accomplished from vinylglycinols. Key transformations involved construction of the piperidine ring via
ring-closing metathesis (Grubbs’ catalyst) and installation of the 4-hydroxy substituent by Prevost reaction. X-Ray diffraction
analyses conclusively established the regio- and stereochemistry of key intermediates. © 2001 Elsevier Science Ltd. All rights
reserved.
The enantiopure naturally-occurring 4-hydroxy-2-
pipecolic acids 11a and 21b,c have been isolated from
various green plants.1 These 4-substituted piperidines
constitute important chiral building blocks of biologi-
cally active molecules;2 (2S,4R)-1 was utilized in the
synthesis of palinavir,2a a potent antiviral, and the
synthesis of pipecolic acid derivatives is of considerable
interest.3 (−)-SS20846A (3) is a 2-alkyl-4-hydroxypipe-
ridine natural product, which has been isolated from
Streptomyces sp. S20846. This compound has demon-
strated antibacterial and anticonvulsant properties.
Additionally, ent-3 has shown remarkable DNA bind-
ing properties.4b
(−)-SS20846A4,5 (3), and ent-3, in the protected form,
from protected derivatives of vinylglycinol [(R and S)-
4].6
Treatment of compound (S)-4 with NaH in THF
resulted in high yields of the corresponding oxazolidin-
one,7 which was alkylated with commercially available
This letter discloses syntheses of both enantiomers of
trans-4-hydroxypipecolic acid (2), the natural product
Scheme 1. Reagents and conditions: (a) i. NaH, THF, ii. NaH, 4-bromo-1-butene, LiI, DMF; (b) Grubbs’ catalyst, CH2Cl2; (c) I2,
silver benzoate, benzene; (d) Raney Ni, THF/MeOH; (e) i. KCN, MeOH/H2O (9/1), ii. MOMCl, Hu¨nig’s base, CH2Cl2; (f) i. 3N
NaOH, MeOH/H2O (9/1), reflux 24 h, ii. Boc2O, EtOAc.
* Corresponding author. E-mail: crj@chem.wayne.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02124-9

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M. Sabat, C. R. Johnson / Tetrahedron Letters 42 (2001) 1209–1212
Scheme 2. Reagents and conditions: (g) i. Dess–Martin/THF ii. NaClO2, NaH2PO4; (h) i. Dess–Martin/CH2Cl2 ii.
CH3CHꢀCHꢀPPh3, THF; iii. I2, benzene, hw, 30 min; (i) CH2N2; (j) AcCl/MeOH.
4-bromo-1-butene.8,9 Alternatively, (S)-5 was synthe-
sized directly from (S)-4 using a one-pot two-step pro-
cess.8 Ring-closing metathesis of 5 with Grubbs’
catalyst, bis(tricyclohexylphosphine)benzylidineruthen-
ium(IV) dichloride,10 under standard conditions for 24
h afforded (S)-6 in 88% yield along with a small
amount of recovered 5. Compound (S)-6 when sub-
jected to Prevost reaction conditions afforded 7. Stereo-
chemistry was unequivocally established by X-ray
analysis of 7.11 Dehalogenation of 7 with Pd/C proved
slow even in the presence of triethylamine. However,
Raney nickel afforded 811 successfully in 92% yield.
This compound was subjected to protecting group
exchange in a one-pot procedure with KCN and
MOMCl to afford 9. NaOH hydrolysis of the oxazo-
lidinone ring of 9 followed by Boc2O protection of the
resultant free amine then afforded the key intermediate
10 (Scheme 1).
tives of trans-4-hydroxypipecolic acids. Key transfor-
mations include ring-closing metathesis to construct the
piperidine ring and the Prevost reaction to install the
4-hydroxy regio- and stereoselectively as determined by
X-ray structural analysis of compounds 7 and 8. The
intermediate 10 was additionally used to synthesize the
hydrochloride of the natural product (−)-SS20846A.
Acknowledgements
Support of this work by the National Science Founda-
tion is gratefully acknowledged (CHE-9801679). We
thank Dr. Mary Jane Heeg for the X-ray structure
determinations and Dr. Lew Hryhorczuk for assistance
with mass spectrometry analyses.
The reaction sequence (Scheme 1) was repeated using
R-4 to afford ent-10. Intermediates 10 and ent-10 were
References
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a
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acids 11 and ent-11. The latter was characterized as the
methyl ester 13. The intermediate aldehydes from Dess–
Martin oxidation were also subjected to Wittig olefina-
12
tion with CH3CHꢀCHꢀPPh3 to afford compounds 12
as 20/80 mixtures of E/Z isomers (Scheme 2). Treat-
ment of these mixtures of isomers with I2/benzene/hw13
gave an enriched 85/15 mixture of E/Z isomers.
Attempts at removal of the remaining unwanted Z
isomer by chromatography or through Diels–Alder
14
addition of SO2 were unsuccessful. Full deprotection
of ent-12 was accomplished with acetyl chloride in
MeOH to afford an 85/15 mixture of E/Z isomers of
(2S,4S)-(−)-SS20846A hydrochloride in quantitative
yield possessing spectral properties and optical rotation
in accordance with the literature ([h]D22 −9.8 (c 0.4,
MeOH); lit. for 145b [h]2D2 −10.8 (c 1.1, MeOH)).15
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M. Sabat, C. R. Johnson / Tetrahedron Letters 42 (2001) 1209–1212
1211
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C.; Koch, C.; Maier, A.; Grabley, S.; Thiericke, R. J.
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1998, 39, 5971; (b) Takemoto, Y.; Ueda, S.; Takeuchi, J.;
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1997, 45, 1906.
6. (a) Sabat, M.; Johnson, C. R. Org. Lett. 2000, 8, 1089;
(b) Vinylglycinol was synthesized from 2-butene-1,4-diol
and made enantiopure utilizing a Pseudomonas cepacia
lipase-catalyzed kinetic resolution. Detailed procedures
and other literature sources for this compound are con-
tained in Ref. 6(a).
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1995, 60, 3764; (b) Kimura, M.; Fugami, K.; Tanaka, S.;
Tamaru, Y. Tetrahedron Lett. 1991, 32, 6359; (c) Ohfune,
Y.; Kurokawa, N. Tetrahedron Lett. 1984, 25, 1071; (d)
McKillop, A.; Taylor, R. J. K.; Watson, R. J.; Lewis, N.
Synthesis 1994, 31; (e) Yoo, S.; Lee, S. J. Org. Chem.
1994, 59, 6968; (f) Winkler, J. D.; Stelmach, J. E.; Axten,
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Hashimoto, K.; Shirahama, H. Tetrahedron Lett. 1993,
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T.; Kimura, K.; Ishibuchi, S.; Kunieda, T. Chem. Lett.
1992, 991.
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J. Am. Chem. Soc. 1995, 117, 11839; (b) Chen, X.; Millar,
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13. Naruse, M.; Aoyagi, S.; Kibayashi, C. J. Org. Chem.
1994, 59, 1361.
14. Craig, D.; Fischer, D. A.; Kemal, O.; Marsh, A.; Pless-
ner, T.; Slawin, A. M. Z.; Williams, D. J. Tetrahedron
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15. Selected optical and spectral data: (S)-6 as a clear oil;
[h]2D4 −123.7 (c 1.48, CHCl3); 1H NMR (CDCl3) l 5.91
(ddd, 1H, J=10.5, 10.5, 5.4 Hz), 5.63 (ddd, 1H J=11.7,
10.5, 1.2 Hz), 4.44 (tapp, 1H, J=8.4 Hz), 4.36 (m, 1H),
3.90 (dd, 1H, J=14.1, 7.8 Hz), 3.09–2.99 (m, 2H),
2.42–2.27 (m, 1H), 2.04–1.96 (m, 1H); 13C NMR
(CDCl3) l 158.02, 127.95, 125.89, 68.10, 52.71, 38.30,
23.64. HRMS (EI) calcd for C7H9NO2 139.0633 (M+),
found 139.0632; ent-7 as white crystals; mp 138–140°C;
1
[h]2D1 +50.7 (c 1.1, CDCl3); H NMR (CDCl3) l 8.02 (d,
2H, J=7.2 Hz), 7.62 (t, 1H, J=6.4 Hz), 7.48 (t, 2H,
J=7.2 Hz), 5.61 (dt, 1H, J=3.2, 5.6, Hz), 4.52 (bs, 1H),
4.44 (t, 1H, J=8.8 Hz), 4.19 (dd, 1H, J=9.2, 4.8 Hz),
3.95 (dd, 1H, J=14.0, 6.8 Hz), 3.68 (unresolved ddd, 1H,
J=16.0, 8.0, 4.8 Hz), 3.34 (ddd, 1H, J=30.0, 13.2, 3.2
Hz), 2.78 (m, 1H), 1.96 (dt app, 1H, J=14.4, 3.2 Hz); 13C
NMR (CDCl3) l 165.05, 134.05, 129.88, 129.34, 128.95,
72.14, 69.48, 52.74, 36.47, 31.85, 23.91. HRMS (EI) calcd
for C14H14NO4 260.0922 (M+−I), found 260.0923; 11 as a
1
clear oil; [h]2D3 +22.2 (c 0.2, CDCl3); H NMR (CDCl3) l
8.40–6.80 (bs, 1H), 5.02 & 4.83 (bs overlapping bm, 1H),
4.69 (s, 2H), 4.10 & 3.99 (bd overlapping bd, 1H, J=
12.5, 13.0 Hz), 3.60 (btapp, 1H), 3.37 (s, 3H), 3.07–2.96
(bt overlapping bt, 1H, J=12.0 Hz), 2.52 (bt, 1H, J=
11.0 Hz), 2.16 (s, 1H), 2.09 (bs, 1H), 1.94 (m, 1H), 1.66
(m, 1H), 1.46 & 1.43 (overlapping s, 9H); 13C NMR
(CDCl3) l 174.47b, 156.23, 94.86, 71.29, 55.54, 54.53b,
53.57b, 40.81b, 40.02b, 32.94b, 31.86b, 29.93, 28.52.
HRMS (EI) calcd for C9H15NO6 233.0899 (M+−C4H8),
8. The deprotonation of 4 and alkylation with 4-bromo-1-
butene proved extremely problematic. Typically when
NaH was used as base a 40% yield of 5 or ent-5 was
achieved with a majority of the starting material recov-
ered. The use of n-BuLi as base afforded 5 in only 20%
yield. Attempts to utilize 4-iodo-1-butene or the triflate of
3-hydroxy-1-butene9 proved fruitless. Gratifying
ly, treat-
.

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M. Sabat, C. R. Johnson / Tetrahedron Letters 42 (2001) 1209–1212
found 233.0897; 1H NMR of 14·HCl (CD3OD) l 6.40
cis/trans isomer displays additional peaks at: l 6.80 (dd,
1H, J=10.5, 4.0 Hz), 6.03 (tapp, 1H, J=11.5 Hz), 5.68
(m, 1H), 5.60 (dd, 1H, J=15.5, 7.5 Hz), 4.09 (bt, 1H);
13C NMR of 14·HCl (CD3OD) l 136.44, 133.24, 130.02,
124.09, 61.15, 52.81, 39.02, 35.62, 28.50, 17.10. HRMS
(EI) calcd for C10H17NO 167.1310 (M+), found 167.1309.
(dd, 1H, J=15.5, 10.5 Hz), 6.09 (dd, 1H, J=15.5, 10.5
Hz), (5.89 unresolved dq, 1H, J=15.5, 7 Hz), (5.49 m,
1H), 4.16 (bs, 1H), 4.01 (bt, 1H, J=8.5 Hz), 3.38–3.18
(overlapping m, bd, 2H, J=12.5 Hz), 1.96–1.76 (overlap-
ping bd, bd, d, d 7H, J=14.5, 8.0, 13.5, 11.5 Hz), the
.
.