A convenient method for synthesis is of optically active 2,3- methanopipecolic acid

Article abstract of DOI:10.1016/S0040-4039(00)00675-4

2,3-Didehydro-1,2-bis(methoxycarbonyl)-6-methoxypiperidine (4), prepared from L-lysine by using electrochemical oxidation, was cyclopropanated with high diastereoselectivity (96.6% de), and the cyclopropanated product was transformed to optically active 2,3-methanopipecolic acid (1). In this transformation, the 6-methoxy group of 4 was found to be an effective chiral auxiliary. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00675-4

Tetrahedron Letters 41 (2000) 4619±4622
A convenient method for synthesis of optically active
2,3-methanopipecolic acid
Yoshihiro Matsumura,* Mayumi Inoue, Yasuharu Nakamura, Idi Ludwig Talib,
Toshihide Maki and Osamu Onomura
Faculty of Pharmaceutical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
Received 16 March 2000; revised 20 April 2000; accepted 21 April 2000
Abstract
2,3-Didehydro-1,2-bis(methoxycarbonyl)-6-methoxypiperidine (4), prepared from l-lysine by using electro-
chemical oxidation, was cyclopropanated with high diastereoselectivity (96.6% de), and the cyclopropanated
product was transformed to optically active 2,3-methanopipecolic acid (1). In this transformation, the
6-methoxy group of 4 was found to be an e€ective chiral auxiliary. # 2000 Elsevier Science Ltd. All rights
reserved.
Keywords: amino acids and derivatives; electrochemical reactions; cyclopropanation; asymmetric synthesis.
Optically active 2,3-methanoamino acids have become very important as enzyme inhibitors and
mechanistic probes because of their interesting properties due to the restricted conformation.1
One such compound of recent interest is optically active 2,3-methanopipecolic acid (1) since
l-pipecolic acid is found as a constituent in pharmaceutically important compounds such as the
immunosuppressive agents FK-5062 and rapamycin.3 However, there has been reported only one
method for the synthesis of 1,4 while a variety of synthetic methods have been developed for
optically active or inactive acyclic and ®ve-membered 2,3-methanoamino acids.5 We describe
herein a new convenient method for the synthesis of optically active 1 starting from l-lysine.
Scheme 1 shows our strategy which consists of the following ®ve steps: (1) transformation of
Na,No-bisprotected l-lysine ester 2 to 6-methoxypipecolate 3; (2) didehydrogenation of 3 at the
2,3-position; (3) diastereoselective cyclopropanation of 2,3-didehydrogenated pipecolate 4
a€ording 2,3-methano-6-methoxypipecolate 5; (4) reductive removal of 6-methoxy group of 5 for
the conversion to 2,3-methanopipecolate 6, and (5) deprotection of 6 to a€ord optically active
1. A satisfactory result by means of this scheme would depend on both the chirality of 4 at the
6-position and the diastereoselectivity in the cyclopropanation of 4.
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00675-4

4620
Scheme 1.
The transformation of 2 to 3 in step 1 was easily achieved according to our reported method;
namely, an electrochemical oxidation of 2 in methanol followed by an acid-catalyzed cyclization
without the isolation of the oxidation product 7 (Eq. (1)).6 The presence of diastereomers of 3 was
not clari®ed at this stage since 3 showed one spot in the chromatography and ambiguous NMR
spectra possibly due to the existence of rotamers.7 On the other hand, the fact that no optical loss
of the chirality at the 2-position occurred in step 1 was ascertained by converting 3 to optically
pure methyl 1-methoxycarbonylpipecolate.8,9
ꢀ1†
Then, in step 2, 3 was phenylthiolated at the 2-position by the treatment with potassium bis(tri-
methylsilyl)amide (KHMDS) and diphenyldisul®de, successively, and the resulting product, 2-
phenylthiolated 8, was oxidized with m-CPBA to give 2,3-didehydropipecolate 4 in good yield
(Eq. (2)). The optical purity of 4 was determined to be 88% ee by CSP (chiral stationary phase)-
HPLC analysis.10 On the basis of this result, the ratio of diastereomers of 3 was found to be
94:6.
ꢀ2†
The reactions with respect to steps 3±5 are shown in Eq. (3). The treatment of 4 with dimethyl-
sulfoxonium methylide in DMSO gave 2,3-methano-6-methoxypipecolate 5 in good yield (step 3).
The subsequent reductive elimination of the 6-methoxy group of 5 was nicely done by adding
NaBH4 in portions to a solution of 5 in formic acid at ambient temperature to a€ord 2,3-methano-
pipecolate 6 (step 4). The optical purity of 6 could be determined to be 85% ee by CSP-GC.11

4621
Thus, the cyclopropanation of 4 was found to proceed with 96.6% de since 4 with 88% ee was
used. Finally, 6 was hydrolyzed into (2S,3R)-1 by treatment with trimethylsilyl iodide in CHCl3
(step 5). The absolute stereocon®guration of (2S,3R)-1 was determined as the assigned structure
by comparison of the optical rotation with the reported data.12
ꢀ3†
As described above, the cyclopropanation of 4 proceeded with excellent diastereoselectivity
(96.6% de). The high diastereoselectivity might be explained in terms of the steric or electrostatic
repulsion between sulfoxonium ylide and the 6-methoxy group of 4 (Fig. 1).13 That is, sulfoxonium
yilde may approach 4 from the side opposite to the 6-methoxy group which occupies the quasi-
axial orientation of the chair form of 4 owing to the allylic 1,3-strain in 4.
Figure 1. Mechanism for diastereoselective cyclopropanation of 4
In summary, we have presented a new route to the facile synthesis of optically active 2,3-
methanopipecolic acid 1 starting from easily available l-lysine, and also demonstrated that the
6-methoxy group of the key intermediate 4 is an e€ective chiral auxiliary for the synthesis of optically
active 1.
Acknowledgements
One of the authors (Y.M.) thanks the Ministry of Education, Science and Culture, Japan for a
Scienti®c Research Grant (B) (No.09450335).

4622
References
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Breckernridge, R. J.; Suckling, C. J. Tetrahedron 1986, 42, 5665±5677. (d) Ner, S. K.; Suckling, C. J.; Bell, A. R.;
Wrigglesworth, R. J. Chem. Soc., Chem. Commun. 1987, 480±482. (e) Ahmad, S.; Phillips, R. S.; Stammer, C. H.
J. Med. Chem. 1992, 35, 1410±1417.
2. Siekierka, J. J.; Hung, S. H. Y.; Poe, M.; Lin, C. S.; Sigal, N. H. Nature 1989, 341, 755±757.
3. Harding, M. W.; Galat, A.; Uehling, D. E.; Schreiber, S. L. Nature 1989, 341, 758±760.
4. A ®rst synthesis of optically active (2S,3R)-methanopipecolic acid via (S)-1,2,5-pentanetriol from l-glutamic acid,
see: Hercouet, A.; Bessieres, B.; Le Corre, M.; Toupet, L. Tetrahedron Lett. 1996, 37, 4529±4532.
5. For examples, see: (a) Stammer, C. H. Tetrahedron 1990, 46, 2231±2254. (b) Alami, A.; Calmes, M.; Daunis, J.;
Jacquier, R. Bull. Soc. Chim. Fr. 1993, 130, 5±24. (c) Burgess, K.; Ho, K.-K.; Moye-Sherman, D. Synlett 1994,
575±583. (d) Burgess, K.; Ke, C.-Y. J. Org. Chem. 1996, 61, 8627±8631. (e) Jimenez, J. M.; Ortuno, R. M.
Tetrahedron: Asymmetry 1996, 7, 3203±3208.
6. (a) Shono, T.; Matsumura, Y.; Inoue, K. J. Chem. Soc., Chem. Commun. 1983, 1169±1171. (b) Shono, T.;
Matsumura, Y.; Tsubata, K.; Uchida, K. J. Org. Chem. 1986, 51, 2590±2592.
7. 1H NMR spectrum of 3: (200 MHz, CDCl3) ꢀ 1.40±1.70 (m, 3H), 1.80±2.00 (m, 2H), 2.25±2.40 (m, 1H), 3.23±3.38
(m, 3H), 3.70±3.80 (m, 6H), 4.67±4.75 and 4.88±4.95 (2m, 1H), 5.26 and 5.44 (2br s, 1H).
8. The conversion of 3 to optically pure methyl 1-methoxycarbonylpipecolate (>99.9% ee) was achieved by treating
with NaBH4 in acetic acid (80% yield). Daicel Chiralcel OD (4.6 mmf, 25 cm) [n-hexane:ethanol=15:1 (v/v), 1.0
mL/min, detection at 210 nm, 5.5 min for (S)-isomer, 10 min for (R)-isomer].
9. The absolute con®guration at the 6-position of 3 could not be determined but the main isomer was estimated to
possess a cis-structure as described in the literature; Irie, K.; Aoe, K.; Tanaka, T.; Saito, S. J. Chem. Soc., Chem.
Commun. 1985, 633±635.
10. Daicel Chiralcel OD (4.6 mmf, 25 cm) [n-hexane:ethanol=9:1 (v/v), 1.0 mL/min, detection at 210 nm, 5.5 min for
20
D
1
(S)-4, 7 min for (R)-4]. (S)-4 (88% ee): ‰ꢁŠ +29.3 (c 0.9, MeOH); H NMR (200 MHz, CDCl3) ꢀ 1.70±1.90 (m,
1H), 1.94±2.44 (m, 3H), 3.42 (s, 3H), 3.74 (s, 3H), 3.78 (s, 3H), 5.50 (t, J=2.5 Hz, 1H), 6.15 (t, J=3.8 Hz, 1H).
Anal. calcd for C10H15NO5: C, 52.40; H, 6.60; N, 6.11. Found: C, 52.78; H, 6.59; N, 5.92.
11. Astec Criraldex G-TA (0.25 mmf, 30 m) [130ꢁC, 38 min for (2S,3R)-6, 39 min for (2R,3S)-6]. (2S,3R)-6 (85% ee):
25
D
1
‰ꢁŠ ^25.6 (c 0.9, MeOH); H NMR (200 MHz, CDCl3) ꢀ 0.80±0.91 (m, 1H), 1.32±1.42 (m, 1H), 1.57±2.04 (m,
5H), 2.65±2.90 (m, 1H), 3.69 (s, 3H), 3.71 and 3.73 (2s, 3H), 3.70±3.94 (m, 1H). Anal. calcd for C10H15NO5: C,
56.33; H, 7.09; N, 6.57. Found: C, 56.12; H, 6.99; N, 6.42.
21
D
27
D
12. ‰ꢁŠ ^45.6 (c 0.3, MeOH) [lit.4 ‰ꢁŠ ^57.5 (c 1, MeOH)].
13. Methylation of 2,3-didehydro-1,2-bis(methoxycarbonyl)-6-(TBS-ethyl)piperidine, an analogue of 4, proceeded
with excellent diastereoselectivity, see: Momose, T.; Toyooka, N. J. Org. Chem. 1994, 59, 943±945.