Synthesis of enantiomerically pure all cis-2,3,6-trisubstituted piperidine: A silicon mediated total synthesis of (+)-carpamic acid

Article abstract of DOI:10.1016/S0040-4039(02)01853-1

A stereoselective total synthesis of (+)-carpamic acid 1 has been achieved from the σ-symmetric 3-[dimethyl(phenyl)silyl]glutaric anhydride 11 featuring its asymmetric desymmetrisation using oxazolidinone 12. The dimethyl(phenyl)silyl group is not only ac

Full text of DOI:10.1016/S0040-4039(02)01853-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7711–7715
Synthesis of enantiomerically pure all cis-2,3,6-trisubstituted
piperidine: a silicon mediated total synthesis of (+)-carpamic acid
Rekha Singh and Sunil K. Ghosh*
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400 085, India
Received 30 May 2002; accepted 30 August 2002
Abstract—A stereoselective total synthesis of (+)-carpamic acid
1 has been achieved from the s-symmetric 3-
[dimethyl(phenyl)silyl]glutaric anhydride 11 featuring its asymmetric desymmetrisation using oxazolidinone 12. The
dimethyl(phenyl)silyl group is not only acting as a masked hydroxy group but also stereodirects ester enolate methylation and
facilitates the Curtius reaction of the b-silyl-amide 23. A highly stereoselective hydrogenation of the imine 10 is the key step in
the construction of the all cis-2,3,6-trisubstituted piperidine. © 2002 Elsevier Science Ltd. All rights reserved.
Hydroxylated piperidine alkaloids1 constitute a large
family of naturally occurring substances, many of
which possess important biological activities.1e,2 The
physiological effects stem from their ability to mimic
carbohydrate substrates in a variety of enzymatic pro-
cesses. Amongst these, the 2,6-disubstituted-3-hydroxy-
piperidine skeleton with a long aliphatic appendage at
the 6-position and all cis stereochemistry is present in
carpamic acid 1, azimic acid 2, spectaline 3,
prosafrinine 4 and cassine 5. The 2,6-trans–2,3-cis stere-
ochemistry is found in julifloridine 6 while that in
prosopinine 7 and prosopine 8 is found to be 2,6-trans–
2,3-trans. The 2,6-cis–2,3-trans stereochemistry is
present in prosophylline 9. A number of approaches for
racemic and asymmetric syntheses of this class of com-
pounds have appeared.3
PhMe2Si functionality.8 The choice of the silicon group
was made as it could provide stereochemical control,9
viability of reactions impossible with a protected OH
group10 and would facilitate reactions11 during the vari-
ous stages of the synthesis.
We propose a potential common intermediate, D1-pipe-
ridine 10 for the syntheses of these molecules. A simple
catalytic hydrogenation of this would provide the 2,6-
cis diastereoisomer while sodium cyanoborohydride
reduction4 would preferably give the 2,6-trans isomer.
The 2,6-cis5 and 2,6-trans6 stereochemistry could also
be anticipated by addition of organometallic reagents
to the CꢀN bond of 10 (when R2=H). There are a
number of ways to make the 2,3-trans diastereoisomer
by inversion7 at the hydroxy group derivable from the
Keywords: substituted piperidine; carpamic acid; silicon mediated;
desymmetrisation; Curtius reaction.
* Corresponding author. Tel.: +91 22 5590265; fax: +91 22 5505151;
e-mail: ghsunil@magnum.barc.ernet.in
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01853-1

7712
R. Singh, S. K. Ghosh / Tetrahedron Letters 43 (2002) 7711–7715
Here we present an enantioselective synthesis of (+)-
carpamic acid as a representative example for a general
synthetic strategy to all 2,6-dialkyl-3-hydroxypiperidi-
nes via the intermediacy of 10. Carpamic acid 1, a
constituent of an alkaloid, carpaine12 is isolated from
Carcica papaya. The plant extract is used in folk
medicine13 and carpaine itself has recently attracted the
interest of medicinal chemists.14 Four racemic synthesis
for carpamic acid have been reported.15–18 The only
asymmetric synthesis of (+)-1 reported, has been from
4-dimethylaminopyridine (DMAP) as an activator in
dichloromethane at room temperature (Scheme 2). The
mixture of 14 and 15 was converted to a mixture of
diazoketones 16 and 17 via their corresponding acid
chlorides. After an easy chromatographic separation,
the major diazoketone 16 was subjected to Wolff
rearrangement25 to give the benzyl ester 18 in 78%
yield. Its hydrogenolysis gave the acid 19 which was
converted to a mixed pivaloic anhydride and subse-
quently reacted with the Grignard reagent derived from
8-benzyloxy-1-bromooctane to furnish ketone 20 in
58% yield (83% based on recovered 19). The ketone was
quantitatively protected as an acetal26 and the oxazo-
lidinone was removed with Ti(OEt)4 in ethanol to give
the ethyl ester 21 in very good yield and 84% recovery
of the oxazolidinone 12.27 As expected, the a-methyla-
tion of 21 took place with high anti selectivity24 (92/8)
to give 22 (74%) which was further converted to the
primary amide 23 in 85% yield. This, on treatment with
Pb(OAc)4/BnOH under modified Curtius reaction con-
ditions,28 afforded the expected Cbz-protected amine 24
in very good yield. The rearrangement was smooth and
was facilitated11 by the presence of the b-silyl group.
The acetal protection was subsequently removed to give
the ketone 25 in 65% overall yield from 20.
D
-glucose.19 Carpamic acid has also been converted
into carpaine.20
Our approach to the synthesis of (+)-1 involved five
phases starting from the known anhydride 11.21 Of
initial importance was the improvement of the
diastereoselectivity for desymmetrisation of the anhy-
dride involving our recently developed methodology22
using oxazolidinone 1223 to set the correct stereochem-
istry at the silicon bearing centre. The resulting mono
acid needed homologation to get the desired ketone.
The next phases of the synthesis addressed the anti
selective silicon directed enolate methylation24 and sili-
con facilitated Curtius reaction11 which set the desired
stereocentres for OH and Me, and also provided the
amino functionality required for the preparation of the
D1-piperidine 10. The fourth stage involved the satura-
tion of the CꢀN to get all cis substituted piperidine.
Functional group transformations on the long alkyl
chain and conversion of PhMe2Si group to OH with
retention of stereochemistry,8 completed the synthesis.
The next important task of the synthesis was Cbz-
deprotection of 25 so as to effect the intramolecular
amine-ketone condensation to give the intermediate
D1-piperidine 10, followed by a highly stereocontrolled
reduction of the imine group. For this, the ketone 25
was subjected to hydrogenolysis which led to removal
of the Cbz- group followed by concomitant intramolec-
ular condensation and subsequent hydrogenation of the
incipient CꢀN to give piperidine 26. The selectivity of
imine hydrogenation appeared to be highly solvent
dependent.† After much experimentation, the best selec-
tivity (>98%) was achieved by employing 5% acetic acid
in toluene giving the desired isomer as its benzyl ether.
This upon removal of the benzyl protection by
hydrogenolysis in acetic acid, gave the hydroxy amine
26‡ which was reacted with benzyl chloroformate to
give 27§ (Scheme 2). The cis relationship between the
We have recently reported22 a desymmetrisation proto-
col for prochiral 3-substituted glutaric anhydrides such
as 11 using anion of oxazolidinone 12.23 The desymme-
trisation selectivity was moderate (13/14=2/1), but the
diastereoisomers were easily separable by fractional
crystallization and/or by chromatography of the
derived esters. The tert-butyl esters of 13 and 14 were
converted to the half ester 15 in a convergent fashion
(Scheme 1) and used in a total synthesis of a pyrrolidine
natural product (+)-preussin.21 During the present
work, the selectivity of desymmetrisation was improved
(13/14=9/2) using oxazolidinone 12 in the presence of
Scheme 1. Reagents and conditions: (a) n-BuLi, THF, 1,3-dimethyl-3,4,5,6-tetrahydropyrimidin-2(1H)-one (DMPU), −78°C; (b)
11.
† In 5% acetic acid in ethanol, the ratio (2,6-cis/2,6-trans) was 82/18 and the 2,6-trans isomer was isolated as its N-ethyl derivative. N-Ethylation
during hydrogenation with Pd/C in ethanol has also been reported; see Ref. 29.
‡ During the preparation of 26, a side product (15%) was also isolated and protected as Cbz-derivative 30. Data for 30: 1H NMR (200 MHz,
CDCl3) l 0.31 (s, 3H), 0.32 (s, 3H), 0.99 (d, J=6.8 Hz, 3H), 1.04–1.80 (m, 14H), 1.80–2.14 (m, 3H), 2.64–2.93 (s, br, 1H), 3.62 (t, J=6.6 Hz,
2H), 4.65 (dq, J=6.7, 3.4 Hz, 1H), 5.02 (d, J=12.3 Hz, 1H), 4.97–5.12 (m, 1H), 5.23 (d, J=12.3 Hz, 1H), 7.15–7.30 (m, 8H), 7.40–7.65 (m, 2H);
13C NMR (50 MHz, CDCl3) l −4.26, −4.16, 14.90, 20.88, 25.64, 27.23, 27.87, 29.10, 29.37, 32.71, 35.27, 49.68, 62.96, 67.14, 111.91, 127.81,
127.98, 128.41, 129.10, 133.74, 136.59, 137.34, 153.75; IR (neat) 3438, 1691, 1661, 1250, 1112 cm−1
.

R. Singh, S. K. Ghosh / Tetrahedron Letters 43 (2002) 7711–7715
7713
Scheme 2. Reagents and conditions: (a) DMAP, CH2Cl2, rt; (b) (COCl)2, DMF, CH2Cl2, rt; (c) CH2N2, Et2O, 0°C; (d)
chromatographic separation; (e) PhCO2Ag, BnOH, Et3N, THF, rt; (f) H2, Pd–C, EtOAc, rt; (g) Piv-Cl, Et3N, THF, 0°C; (h)
BnO-(CH2)8-MgBr, THF, −78°C; (i) (Me3SiOCH2)2, TMSO–Tf, CH2Cl2, −20°C; (j) Ti(OEt)4, EtOH, reflux; (k) Li–TMP, THF,
−78°C; (l) MeI, −78 to 0°C; (m) KOH, MeOH, H2O, reflux; (n) (Im)2CO, CH2Cl2, rt; (o) NH3; (p) Pb(OAc)4, BnOH, DMF,
100°C; (q) TsOH, Me2CO, H2O, reflux; (r) H2 (40–50 psi), Pd–C, AcOH, EtOH or toluene, rt; (s) BnOCOCl, K2CO3, THF, rt;
(t) (COCl)2, DMSO, Et3N, −60°C; (u) KMnO4, t-BuOH, rt; (v) KBr, AcOOH, rt“40°C; (w) H2, Pd–C, AcOH, rt.
substituents at 2,6-positions in 26 was confirmed by 2D
ROESY experiments, while that between 2,3-sub-
stituents (Me and PhMe2Si) from the low J2,3 coupling
constant (3.4 Hz), typical for the axial–equatorial H-2
and H-3 protons. Hydrogen addition to the cyclic imine
10 from the top face has been proposed to be favoured
due to the pseudoaxial positioning of the C-2 methyl
substituent and a pseudoequatorial disposition of the
bulky dimethyl(phenyl)silyl group at C-3 as depicted in
Scheme 2.
§ These compounds existed as a mixture of rotamers. This was verified
by a temperature dependent NMR study of the benzoate derived
from 27 in C6D6/CDCl3 (85/15).

7714
R. Singh, S. K. Ghosh / Tetrahedron Letters 43 (2002) 7711–7715
Having set the three stereocentres at C-2, C-3 and C-6
correctly, all that remained for the synthesis were con-
version of the -CH2OH to carboxylic acid and silyl
function to a hydroxy group. For this, the alcohol 27
was converted to the acid 28§ in two steps involving
Swern’s oxidation to aldehyde followed by KMnO4
oxidation in nearly quantitative yield. Conversion of
the silyl group to hydroxy with retention of configura-
tion was achieved using peracetic acid and potassium
bromide to give the N-Cbz protected carpamic acid 29§
in very good yield (81%). This on hydrogenolysis pro-
vided (+)-carpamic acid (1), mp 228–230°C. Since we
started with the homochiral benzyl ester 18, and the
synthetic sequence is not expected to cause any epimeri-
sation, the enantiomeric purity of (+)-carpamic acid
should be very high (>99%). This was substantiated by
comparison of the specific rotation value ([h]2D1 +5.1, c
1.38, MeOH) of 1 with those reported19 and also from
the spectroscopic data.18
1998, 633–640; (d) Nadin, A. J. Chem. Soc., Perkin.
Trans. 1 1998, 3493–3513; (e) Laschat, S.; Dickner, T.
Synthesis 2000, 1781–1813; (f) Enders, D.; Kirchhoff, J.
H. Synthesis 2000, 2099–2105 and references cited
therein; (g) Sugiura, M.; Hagio, H.; Hirabayashi, R.;
Kobayashi, S. J. Am. Chem. Soc. 2001, 123, 12510–
12517.
4. Toyooka, N.; Yoshida, Y.; Momose, T. Tetrahedron Lett.
1995, 36, 3715–3718.
5. Koulocheri, S. D.; Haroutounian, S. A. Tetrahedron Lett.
1999, 40, 6869–6870.
6. Agami, C.; Couty, F.; Mathieu, H. Tetrahedron Lett.
1998, 39, 3505–3508.
7. Mitsunobu, O. Synthesis 1981, 1.
8. (a) Fleming, I.; Henning, R.; Parker, D. C.; Plaut, H. E.;
Sanderson, P. E. J. J. Chem. Soc., Perkin Trans. 1 1995,
317–337; (b) Jones, G.; Landias, Y. Tetrahedron 1996, 52,
7599–7662.
9. Fleming, I.; Barbero, A.; Walter, D. Chem. Rev. 1997, 97,
2063–2192.
In conclusion, a highly diastereoselective synthesis of
(+)-carpamic acid has been achieved from anhydride
11. The key steps were desymmetrisation of 11 with
oxazolidinone 12, silicon directed highly stereoselective
enolate methylation, silicon facilitated Curtius reaction,
hydrogenation of 10 which took place with very high
selectivity due to the pseudoaxial positioning of the C-2
methyl substituent and a pseudoequatorial disposition
of the bulky PhMe2Si at C-3, and conversion of
PhMe2Si to OH with retention of stereochemistry. As
the half ester 15 could be made in an enantioconvergent
fashion, both the enantiomers of the natural product
could be synthesised by this route.
10. (a) Calaza, M. I.; Paleo, M. R.; Sardina, F. J. J. Am.
Chem. Soc. 2001, 123, 2095–2096; (b) Foubelo, F.;
Gutierrez, A.; Yus, M. Synthesis 1999, 503–514; (c)
Foubelo, F.; Gutierrez, A.; Yus, M. Tetrahedron Lett.
1997, 38, 4837–4840 and references cited therein.
11. Verma, R.; Ghosh, S. K. J. Chem. Soc., Perkin Trans. 1
1998, 2377–2381 and references cited therein.
12. Coke, J. L.; Rice, W. Y. J. Org. Chem. 1965, 30, 3420–
3422 and references cited therein.
13. (a) Watt, J. M.; Breyer-Brandwijk, M. G. The Medicinal
and Poisonous Plants of Southern and Eastern Africa, 2nd
ed.; E. and S. Livingston: London, 1962; (b) Hornick, C.
A.; Sanders, L. I.; Lin, Y. C. Res. Commun. Chem.
Pathol. Pharmacol. 1978, 22, 277; Chem. Abs. 1979, 90,
66761p; (c) Dalziel, J. M. The Useful Plants of West
Tropical Africa; Crown Agents: London, 1937; p. 52.
14. (a) Fahy, J.; Mamatas, S.; Bigg, D.; Kruczynski, A.; Kiss,
R. Fr. Pat. No FR 2704858, 1994, Appl. No FR 1993-
5284; CA 122:133499; (b) Fahy, J.; Mamatas, S.; Bigg,
D.; Kruczynski, A.; Kiss, R. Pat. No. WO 9421648, 1994,
Appl. No WO 94-FR268 19940314; CA 122:10343; (c)
Mulkidzhanyan, K. G.; Sulakvelidze, M. T.; Abuladze,
G. V.; Kutateladze, I. G. Akad. Nauk Gruz. 1992, 144,
441–444; (d) Hornick, C. A.; Sanders, L. I.; Lin, Y. C.
Res. Commun. Chem. Pathol. Pharmacol. 1978, 22, 277–
289.
Acknowledgements
We thank National Facility at TIFR for 500/600 MHz
NMR and NPIL, Mumbai, for providing mass spectra.
References
1. (a) Jones, T. H.; Blum, M. S. In Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New
York, 1983; Vol. 1, Chapter 2, pp. 33–84; (b) Fodor, G.
B.; Colasanti, B. In Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Wiley: New York,
1985; Vol. 3, Chapter 1, pp. 1–90; (c) Strunz, G. M.;
Findlay, J. A. In The Alkaloids; Brossi, A., Ed.; Aca-
demic Press: San Diego, 1986; Vol. 26, pp. 89–183; (d)
Schneider, M. J. In Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Wiley: New York,
1996; Vol. 10, Chapter 3, pp. 155–355; (e) Cook, G. R.;
Beholz, L. G.; Stille, J. R. J. Org. Chem. 1994, 59,
3575–3584.
15. Brown, E.; Bourgouin, A. Tetrahedron 1975, 31, 1047–
1051.
16. Natsume, M.; Ogawa, M. Heterocycles 1980, 14, 169–173
and 615–618.
17. Holmes, A. B.; Swithenbank, C.; Williams, S. F. J. Chem.
Soc., Chem. Commun. 1986, 265–266.
18. Hasseberg, H. A.; Gerlach, H. Liebigs Ann. Chem. 1989,
255–261.
19. Hanessian, S.; Frenette, R. Tetrahedron Lett. 1979, 20,
3391–3394.
20. (a) Narasimhan, N. S. Chem. Ind. (London) 1956, 1526–
1527; (b) Corey, E. J.; Nicolaou, K. C.; Melvin, L. S. J.
Am. Chem. Soc. 1975, 97, 654–655.
21. (a) Verma, R.; Ghosh, S. K. J. Chem. Soc., Perkin Trans.
1 1999, 265–270; (b) Verma, R.; Ghosh, S. K. Chem.
Commun. 1997, 1601–1602.
2. Fodor, G.; Fumeaux, J.-P.; Sankaran, V. Synthesis 1972,
464–472.
3. (a) Brown, E.; Dhal, R.; Casals, P. F. Tetrahedron 1972,
28, 5607–5613; (b) Baliah, V.; Jeyaraman, R.; Chan-
drasekaran, L. Chem. Rev. 1983, 83, 379–423; (c) Bailey,
P. D.; Millwood, P. A.; Smith, P. D. Chem. Commun.

R. Singh, S. K. Ghosh / Tetrahedron Letters 43 (2002) 7711–7715
22. Verma, R.; Mithran, S.; Ghosh, S. K. J. Chem. Soc., 5163.
7715
Perkin Trans. 1 1999, 257–264.
26. Chan, T. H.; Brook, M. A.; Chaly, T. Synthesis 1983,
203–205.
27. Evans, D. A.; Britton, T. C.; Dorow, R. L.; Dellaria, J.
23. Evans, D. A.; Kim, A. S. In Encyclopedia of Reagents for
Organic Synthesis; Paquette, L. A., Ed.; Wiley: New
York, 1995; Vol. 1, pp. 345–356.
F. Tetrahedron 1988, 44, 5525–5540.
24. Crump, R. A. N. C.; Fleming, I.; Hill, J. H. M.; Parker,
D.; Reddy, N. L.; Waterson, D. J. Chem. Soc., Perkin
Trans. 1 1992, 3277–3294.
28. Baumgarten, H. E.; Smith, H. L.; Staklis, A. J. Org.
Chem. 1975, 40, 3554–3561.
29. Aggarwal, V. K.; Roseblade, S. J.; Barrell, J. K.; Alexan-
25. Newman, M. S.; Beal, P. F. J. Chem. Soc. 1950, 72,
der, R. Org. Lett. 2002, 4, 1227–1229.