Chemistry of lactam-derived vinyl phosphates: Stereoselective synthesis of (+)-fagomine

Article abstract of DOI:10.1055/s-0028-1088202

The synthesis of (+)-fagomine, based on the Pd-catalyzed methoxycarbonylation reaction of a lactam-derived vinyl phosphate and the stereoselective hydroboration-oxidation of the enamine double bond, is presented. The target product is obtained in 23% over

Full text of DOI:10.1055/s-0028-1088202

LETTER
913
Chemistry of Lactam-Derived Vinyl Phosphates: Stereoselective Synthesis of
(+)-Fagomine
S
ynthesis of (+)
a
-Fagomineura Bartali,a Dina Scarpi,a Antonio Guarna,a Cristina Prandi,b Ernesto G. Occhiato*a
a
Dipartimento di Chimica Organica ‘U. Schiff’, Università di Firenze, Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy
Fax +39(055)4573531; E-mail: ernesto.occhiato@unifi.it
b
Dipartimento di Chimica Generale e Chimica Organica, Università di Torino, Via P. Giuria 7, 10125 Torino, Italy
Received 17 December 2008
OR1
N
OR1
N
OH
Abstract: The synthesis of (+)-fagomine, based on the Pd-cata-
lyzed methoxycarbonylation reaction of a lactam-derived vinyl
phosphate and the stereoselective hydroboration–oxidation of the
enamine double bond, is presented. The target product is obtained
in 23% overall yield in eight steps from a known lactam.
OH
OR2
OH
CO2Me
N
H
R3
R3
1
2
OR1
3
OR1
Key words: palladium, carbonylation, stereoselective hydrobor-
ations, piperidine alkaloids, (+)-fagomine
OR1
or
N
R3
4
OTf
N
R3
6
O
N
R3
5
OP(O)(OPh)2
The palladium-catalyzed alkoxycarbonylation of lactam-
derived vinyl triflates1 and phosphates2 has been effec-
tively applied in the past to the synthesis of several natural
compounds.3 We have recently included such a reaction in
a synthetic sequence to efficiently obtain enantiopure
(2S,4R)-4-hydroxypipecolic acid from commercially
available ethyl (3S)-4-chloro-3-hydroxybutanoate.4 The
success of this approach, coupled with our general interest
in the application of lactam-derived vinyl triflates and
phosphates in the synthesis of heterocyclic compounds,5
led us to investigate an analogous synthetic route for the
preparation of enantiopure (+)-fagomine (1). (+)-Fago-
mine (1, Scheme 1), a 1,2-dideoxy-azasugar isolated from
Castanospermum australe (Leguminosae)6 and the seeds
of Japanese buckwheat Fagopyrum esculentum (Poly-
gonaceae)7 exhibits strong antihyperglycemic effect in
streptozocin-induced diabetic mice and in potentiation of
the glucose-induced insulin secretion.8 Due to its biologi-
cal importance, and because in general polyhydroxylated
piperidine alkaloids are important glycosidase inhibitors,9
a number of stereoselective syntheses of naturally occur-
ring (+)-fagomine have been reported,10 whereas, not un-
surprisingly, the synthesis of its enantiomer has been
realized only twice so far.10a,f The synthesis of (+)-fago-
mine (1) we describe here can be easily extended to the
preparation of its unnatural enantiomer as both the enantio-
mers of chiral precursor ethyl 4-chloro-3-hydroxybutyrate
(Scheme 2) are commercially available.
Scheme 1
OPMB
N
1. KHMDS, THF
–78 °C
OH
Cl
ref. 4
CO2Et
2. (PhO)2P(O)Cl
THF, –78 °C
O
(S)-7
CO2Me
8
Pd(OAc)2, Ph3P, CO
MeOH, Et3N, DMF
50 °C
DDQ
CH2Cl2–H2O
(18:1)
OPMB
OPMB
N
CO2Me
N
OP(O)(OPh)2
CO2Me
CO2Me
9 (85%)
10 (95%)
OH
OTBS
N
TBSCl
imidazole, DMF
40 °C
DIBAL-H, Et2O
–78 °C
N
CO2Me
CO2Me
CO2Me
11 (81%)
CO2Me
12 (91%)
OTBS
OTBS
SEMCl
DIPEA, CH2Cl2
1. BH3⋅THF, –78 to 0 °C
2. Me3NO, THF, 65 °C
OSEM
OH
N
N
CO2Me
14 (76%)
CO2Me
13 (73%)
In analogy to the synthesis of (2S,4R)-4-hydroxypipecolic
acid,4 we based the synthesis of (+)-fagomine on the pos-
sible stereocontrol exerted by the bulky 4-silyloxy substit-
uent in the addition of borane to the enamine double bond
of 2 (Scheme 1). Compound 2 should be easily prepared
OH
OTBS
2 N HCl
reflux
OH
OH
OH
OSEM
.
HCl
N
H
N
CO2Me
1 (100%)
SYNLETT 2009, No. 6, pp 0913–0916
x
x.
x
x.
2
0
0
9
15 (70%)
Scheme 2
Advanced online publication: 16.03.2009
DOI: 10.1055/s-0028-1088202; Art ID: D41608ST
© Georg Thieme Verlag Stuttgart · New York

914
L. Bartali et al.
LETTER
from key intermediate 3, which in turn can be obtained by all yield in eight steps from known lactam 8) as its hydro-
Pd-catalyzed methoxycarbonylation of the corresponding chloride salt possessing analytical and spectroscopic
lactam-derived vinyl triflate 4. One drawback of our syn- data21 in accordance to those reported.10f
thesis of 4-hydroxypipecolic acid was the difficulty in ob-
taining high and reproducible yields in the two-step
sequence of triflate formation (from 6) and carbonylation,
due to the instability of vinyl triflate 4. This triflate could
not be purified by chromatography without observing
variable degradation or p-methoxybenzyl alcohol elimi-
nation, and therefore was used as a crude reaction mixture
in the subsequent carbonylation reaction, affecting the
yield of this step. For the synthesis of (+)-fagomine we
therefore opted for the transformation of 6 into vinyl
phosphate 5. Lactam-derived vinyl phosphates are in fact
reported to be generally much more stable than the corre-
sponding triflates and this proved true in our case.11 More-
over, diphenylchlorophosphate is much cheaper than the
triflimides generally employed for trapping the enolates.
SEMO
OTBS
OTBS
6
oxidation
4
MeO2C
N
N
H
2
3
MeO2C
SEMO
OH
BH2
H
Scheme 3
Given the consistency in obtaining excellent yields of key
intermediate 10 by the two-step sequence from 8 involv-
ing phosphate generation and Pd-catalyzed carbonylation,
we are currently investigating the application of the pro-
cedure to the synthesis of the various diastereomers of
fagomine and other polyhydroxylated piperidine alka-
loids. Moreover, since chiral ethyl (R)-4-chloro-3-hy-
droxybutyrate (96% ee) is commercially available, the
application of the methodology to the synthesis of (–)-fago-
mine is an obvious extension.
Chiral precursor (S)-7 (96% ee) was transformed into
enantiopure N-protected lactam 8 according to the report-
ed methodology.4 Phosphate 9 was prepared by treatment
of 8 with a slight excess of KHMDS (0.5 M in toluene) in
THF at –78 °C, followed by addition of diphenylchloro-
phosphate.12 After an appropriate workup, phosphate 9
proved stable for days as a crude reaction mixture, and it
could be purified by chromatography on silica gel (85%).
We found that if the phosphate was immediately used af-
ter chromatography, the yields of the subsequent carbon-
ylative step were much higher and reproducible (from 86–
95% in various experiments).12
Acknowledgment
We thank Prof. Naoki Toyooka for providing a procedure for the re-
duction with DIBAL-H; Ministero dell’Università e della Ricerca
(MIUR) and Università di Firenze for financial support, and Cassa
di Risparmio di Firenze for granting a 400 MHz NMR spectrometer.
Maurizio Passaponti and Brunella Innocenti are acknowledged for
their technical support.
Deprotection of 9, necessary to introduce a bulky group at
position 4,13 was carried out by using DDQ in dichlo-
romethane and water,4 significantly increasing the report-
ed yield by a modification of the workup procedure.14 Use
of CAN for the removal of the protecting group resulted
in lower yield due to the acidity generated by this oxidant,
whereas an attempt of directly converting PMB (p-meth-
oxybenzyl) ether 10 into tert-butyldimethylsilyl (TBS)
ether 12, according to the procedure by Oryiama, failed.15
After protection of the 4-OH group as TBS ether, reduc-
tion of the methyl ester with DIBAL-H16 provided alcohol
13 in 73% yield,17 and subsequent protection of the OH
group as the SEM ether gave 14 (76%) under standard
conditions.18 With compound 14 in hand, the stage was set
for the hydroboration–oxidation step, which was carried
out as described by Hiemstra and Speckamp for an analo-
gous substrate.3f We were delighted to observe that both
steps proceeded smoothly and that the bulky 4-silyloxy
References and Notes
(1) Foti, C. J.; Comins, D. L. J. Org. Chem. 1995, 60, 2656.
(2) Nicolaou, K. C.; Shi, G.-Q.; Namoto, K.; Bernal, F. Chem.
Commun. 1998, 1757.
(3) (a) Toyooka, N.; Nemoto, H.; Kawasaki, M.;
Martin Garraffo, H.; Spande, T. F.; Daly, J. W. Tetrahedron
2005, 61, 1187. (b) Occhiato, E. G.; Prandi, C.; Ferrali, A.;
Guarna, A. J. Org. Chem. 2005, 70, 4542. (c) Toyooka, N.;
Fukutome, A.; Nemoto, H.; Daly, J. W.; Spande, T. F.;
Garraffo, H. M.; Kaneko, T. Org. Lett. 2002, 4, 1715.
(d) Bamford, S. J.; Luker, T.; Speckamp, W. N.; Hiemstra,
H. Org. Lett. 2000, 2, 1157. (e) Toyooka, N.; Okumura, M.;
Takahata, H. J. Org. Chem. 1999, 64, 2182. (f) Luker, T.;
Hiemstra, H.; Speckamp, W. N. J. Org. Chem. 1997, 62,
3592. (g) Toyooka, N.; Okumura, M.; Takahata, H.;
Nemoto, H. Tetrahedron 1999, 55, 10673. (h) Luker, T.;
Hiemstra, H.; Speckamp, W. N. J. Org. Chem. 1997, 62,
8131.
(4) Occhiato, E. G.; Scarpi, D.; Guarna, A. Eur. J. Org. Chem.
2008, 524.
group, which in 14 is axially oriented to remove the A(1,2)
-
(5) Most recent papers: (a) Cavalli, A.; Pacetti, A.; Recanatini,
M.; Prandi, C.; Scarpi, D.; Occhiato, E. G. Chem. Eur. J.
2008, 14, 9292. (b) Deagostino, A.; Larini, P.; Occhiato,
E. G.; Pizzuto, L.; Prandi, C.; Venturello, P. J. Org. Chem.
2008, 73, 1941. (c) Bartali, L.; Guarna, A.; Larini, P.;
Occhiato, E. G. Eur. J. Org. Chem. 2007, 2152. (d) Bartali,
L.; Larini, P.; Guarna, A.; Occhiato, E. G. Synthesis 2007,
1733. (e) Larini, P.; Guarna, A.; Occhiato, E. G. Org. Lett.
2006, 8, 781.
strain with 3-H (Scheme 3), effectively directed the hy-
droboration to the opposite face, providing, after oxida-
tion, compound 15 as a single diastereoisomer.19,20
Interestingly, the stereoselectivity in the addition of bo-
rane to 14 was higher than that observed in the hydroge-
nation of 12 for the synthesis of 4-hydroxypipecolic acid,
but the latter was carried out at 50 °C.4 Finally, exhaustive
deprotection of 15 provided (+)-fagomine (1) (23% over-
(6) Molyneux, R. J.; Benson, M.; Wong, R. Y.; Tropea, J. H.;
Elbein, A. D. J. Nat. Prod. 1988, 51, 1198.
Synlett 2009, No. 6, 913–916 © Thieme Stuttgart · New York

LETTER
Synthesis of (+)-Fagomine
915
(7) Koyama, M.; Sakamura, S. Agric. Biol. Chem. 1974, 38,
1111.
bath) for 2 h under static CO pressure. The solution was
diluted with H2O (46 mL) and extracted with Et2O (4 × 46
mL), washed with brine (30 mL), and dried over Na2SO4.
After filtration and evaporation of the solvent, the oily
residue was chromatographed (EtOAc–n-hexane, 1:2, Rf =
0.27) to give 10 (633 mg, 95%) as a thick pale yellow oil.
Spectroscopic and analytical data as reported.4
(8) (a) Nojima, H.; Kimura, I.; Chen, F.-J.; Sugiura, Y.; Haruno,
M.; Kato, A.; Asano, N. J. Nat. Prod. 1998, 61, 397.
(b) Taniguchi, S.; Asano, N.; Tomino, F.; Miwa, I. Horm.
Metab. Res. 1998, 30, 679. (c) Kato, A.; Asano, N.; Kizu,
H.; Matsui, K.; Watson, A. A.; Nash, R. J. J. Nat. Prod.
1997, 60, 312.
(13) We have already shown that generation of the enolate from
a 4-silyloxy-substituted lactam causes both elimination of
silanol (TBSOH) and migration of the silyl group to the
enolate O atom. Thus, the phosphate has to be prepared from
the lactam with a PMB-protected 4-OH group, see ref. 4.
(14) When the reaction is complete, before proceeding with the
extractions, the pale brown solid was filtered under vacuum
through a layer of Celite washing with CH2Cl2.
(9) Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.;
Nash, R. Phytochemistry 2001, 56, 265.
(10) (a) Kumari, N.; Reddy, B. G.; Vankar, Y. D. Eur. J. Org.
Chem. 2009, 160. (b) Yokoyama, H.; Ejiri, H.; Miyazawa,
M.; Yamaguchi, S.; Hirai, Y. Tetrahedron: Asymmetry
2007, 18, 852. (c) Castillo, J. A.; Calveras, J.; Casas, J.;
Mitjans, M.; Vinardell, M. P.; Parella, T.; Inoue, T.;
Sprenger, G. A.; Joglar, J.; Clapés, P. Org. Lett. 2006, 8,
6070. (d) Takahata, H.; Banba, Y.; Ouchi, H.; Nemoto, H.;
Kato, A.; Adachi, I. J. Org. Chem. 2003, 68, 3603.
(e) Takahata, H.; Banba, Y.; Cheimi, A.; Hideo, N.; Kato,
A.; Adachi, I. Tetrahedron: Asymmetry 2001, 12, 817.
(f) Désiré, J.; Dransfield, P. J.; Gore, P. M.; Shipman, M.
Synlett 2001, 1329. (g) Effenberger, F.; Null, V. Liebigs
Ann. Chem. 1992, 1211. (h) Pederson, R. L.; Wang, C.-H.
Heterocycles 1989, 28, 477. (i) von der Osten, C. H.;
Sinskey, A. J.; Barbas, C. F.; Pederson, R. L.; Wang, Y.-F.;
Wang, C.-H. J. Am. Chem. Soc. 1989, 111, 3924. (j) Fleet,
G. W. J.; Fellows, L. E.; Smith, P. W. Tetrahedron 1987, 43,
979. (k) Fleet, G. W. J.; Smith, P. W. Tetrahedron Lett.
1985, 26, 1469.
(15) Oriyama, T.; Yatabe, K.; Kawada, Y.; Koga, G. Synlett
1995, 45.
(16) Momose, T.; Toyooka, N. J. Org. Chem. 1994, 59, 943.
(17) Typical Procedure
To a solution of 12 (266 mg, 0.81 mmol) in anhyd Et2O (23
mL), cooled at –78 °C, was added dropwise a solution of
DIBAL-H (1.78 mL of a 1 M solution in n-hexane, 1.78
mmol) under stirring and nitrogen atmosphere. After 1 h, the
reaction mixture was heated to 0 °C and left under stirring
for 30 min. Then sat. aq NH4Cl (3.5 mL) was added, and the
mixture was diluted with 11 mL of CH2Cl2. Then it was
filtered through a Celite layer, the phases were separated,
and the aqueous one was extracted with CH2Cl2 (3 × 20 mL).
The combined organic extracts were dried over Na2SO4,
filtered, and concentrated. Chromatography (SiO2, eluant
EtOAc–n-hexane 1:3, Rf = 0.25) afforded 13 (177 mg,) in
73% yield as a colorless oil; [a]D20 +149.3 (c 0.35, CHCl3).
1H NMR (400 MHz, CDCl3): d = 5.15 (d, J = 4.1 Hz, 1 H),
4.31–4.26 (m, 1 H), 4.19–4.13 (m, 1 H + 1 H), 3.82 (ddd,
J = 12.9, 5.0, 3.8 Hz, 1 H), 3.76 (s, 3 H), 3.40 (ddd, J = 12.9,
9.4, 4.7 Hz, 1 H), 1.81–1.77 (m, 2 H), 0.88 (s, 9 H), 0.08 (s,
3 H), 0.07 (s, 3 H). 13C NMR (100 MHz, CDCl3): d = 154.7
(s), 139.4 (s), 115.9 (d), 65.0 (t), 62.1 (d), 53.2 (q), 40.8 (t),
32.3 (t), 25.9 (q, 3 C), 18.1 (s), –4.4 (q), –4.6 (q). MS: m/z =
301 (0.5) [M+], 244 (100). Anal. Calcd for C14H27NO4Si: C,
55.78; H, 9.03; N, 4.65. Found: C, 55.44; H, 8.94; N, 4.39.
(18) Compound 14.
(11) For a review see: (a) Occhiato, E. G. Mini-Rev. Org. Chem.
2004, 1, 149. Recent progresses in the use of heterocyclic-
derived vinyl phoshpates: (b) Claveau, E.; Gillaizeau, I.;
Blu, J.; Bruel, A.; Coudert, G. J. Org. Chem. 2007, 72, 4832;
and references therein. (c) Lo Galbo, F.; Occhiato, E. G.;
Guarna, A.; Faggi, C. J. Org. Chem. 2003, 68, 6360.
(12) Typical Procedure
To a solution of KHMDS (5.85 mL of a 0.5 M solution in
toluene, 2.93 mmol) in THF (15.5 mL), cooled at –78 °C and
under nitrogen atmosphere, was added a solution of 8 (687
mg, 2.34 mmol) in THF (6 mL) and the resulting mixture
was stirred for 1.5 h. Afterward a solution of (PhO)2P(O)Cl
(605 mL, 2.93 mmol) in THF (5 mL) was added, stirring was
continued for 1 h at –78 °C before allowing the temperature
to rise to 0 °C. Then, a 10% NaOH aq soln (47 mL) was
added, the mixture was extracted with Et2O (3 × 40 mL),
washed with 10% NaOH (30 mL), and dried over anhyd
K2CO3 for 30 min. After filtration and evaporation of the
solvent (without heating and leaving a small volume of
solvent), the crude phosphate was chromatographed
(EtOAc–n-hexane, 1:2, +1% Et3N, Rf = 0.26) on a short layer
of SiO2 (3.5 cm of SiO2 in a column with internal diameter
of 3 cm) to give 9 (1.044 g, 85%) as a pale yellow oil.
1H NMR (200 MHz, CDCl3): d = 7.40–7.16 (m, 12 H), 6.86
(d, J = 8.8 Hz, 2 H), 5.25 (t, J = 2.9 Hz, 1 H), 4.43 (s, 2 H),
4.07–3.96 (m, 1 H), 3.79 (s, 3 H), 3.84–3.72 (m, 1 H), 3.55
(s, 3 H), 3.35 (td, J = 12.8, 2.6 Hz, 1 H), 2.09–1.92 (m, 1 H),
1.87–1.68 (m, 1 H). 13C NMR (50 MHz, CDCl3): d = 159.0
(s), 154.1 (s), 150.4 (s, 2 C), 141.1 (s), 129.7 (d, 4 C), 129.5
(s), 129.1 (d, 2 C), 125.5 (d, 2 C), 120.0 (d, 4 C), 113.8 (d, 2
C), 98.8 (d), 69.7 (d), 68.5 (t), 55.3 (q), 53.3 (q), 42.8 (t),
29.7 (t). MS: m/z = 525 (1) [M+], 121 (100).
Chromatography (SiO2): eluant: EtOAc–n-hexane (1:12
then 1:6), Rf = 0.46; [a]D22 +126.1 (c 0.49, CHCl3). 1H NMR
(400 MHz, CDCl3): d = 5.24 (d, J = 3.5 Hz, 1 H), 4.67 (s, 2
H), 4.50 (d, J = 13.1 Hz, 1 H, part of an AB system), 4.39 (d,
J = 13.1 Hz, 1 H, part of an AB system), 4.19 (m, 1 H), 3.89
(ddd, J = 12.9, 5.5, 3.7 Hz, 1 H), 3.72 (s, 3 H), 3.66–3.60 (m,
2 H), 3.39 (ddd, J = 12.9, 9.2, 4.3 Hz, 1 H), 1.83–1.78 (m, 2
H), 0.96–0.92 (m, 2 H), 0.88 (s, 9 H), 0.08 (s, 3 H), 0.07 (s,
3 H), 0.02 (s, 9 H). 13C NMR (100 MHz, CDCl3): d = 154.2
(s), 137.0 (s), 115.0 (d), 93.9 (t), 68.0 (t), 65.3 (t), 62.7 (d),
52.8 (q), 41.5 (t), 33.2 (t), 25.9 (q, 3 C), 18.1 (s),18.0 (t), –
1.4 (q, 3 C), –4.4 (q), –4.6 (q). MS: m/z = 431 (1) [M+], 228
(37), 73 (100). Anal. Calcd for C20H41NO5Si2: C, 55.64; H,
9.57; N, 3.24. Found: C, 55.31; H, 9.62; N, 3.02.
(19) Typical Procedure
To a solution of 14 (77 mg, 0.18 mmol) in anhyd THF (8.4
mL), under nitrogen atmosphere and cooled at –78 °C, was
added a solution of BH3·THF (612 mL of a 1.0 M solution in
THF, 0.612 mmol). After 5 min, the flask was submerged in
an ice bath and left at 0 °C for 22 h. Then, under vigorous
stirring, Me3NO (trimethylamine N-oxide, 162 mg, 2.16
mmol) was added and, after mounting a condenser, the
reaction was heated at 65 °C (external bath) for 2 h. After
cooling, EtOAc (16 mL) was added, the organic layer was
washed with brine (2 × 8 mL) and dried over anhyd Na2SO4.
Phosphate 9 (1.044 g, 1.99 mmol) was immediately
dissolved in DMF (6 mL), Ph3P (123 mg, 0.47 mmol) and
Pd(OAc)2 (53 mg, 0.24 mmol) were added, and the solution
was stirred 10 min under a CO atmosphere (balloon). Then
Et3N (649 mL, 4.68 mmol) and MeOH (3.8 mL, 93.6 mmol)
were added and stirring was continued at 50 °C (external
Synlett 2009, No. 6, 913–916 © Thieme Stuttgart · New York

916
L. Bartali et al.
LETTER
Chromatography (EtOAc–n-hexane, 1:3, Rf = 0.22) afforded
15 (56 mg, 70%) as a colorless oil; [a]D22 –1.4 (c 0.175,
CHCl3). 1H NMR (400 MHz, CDCl3): d = 4.65 (d, J = 6.6
Hz, 1 H, part of an AB system), 4.61 (d, J = 6.6 Hz, 1 H, part
of an AB system), 4.41 (br m, 1 H), 3.99 (dd, J = 10.7, 8.8
Hz, 1 H), 3.90 (br d, J = 13.3 Hz, 1 H), 3.89–3.86 (m, 1 H),
3.69 (s, 3 H), 3.70–3.67 (m, 1 H), 3.66–3.49 (m, 1 H + 2 H),
3.20 (td, J = 13.3, 2.5 Hz, 1 H), 2.01 (m, 1 H), 1.42 (br dd,
J = 13.7, 2.3 Hz, 1 H), 0.95–0.90 (m, 2 H), 0.89 (s, 9 H), 0.06
(s, 3 H), 0.05 (s, 3 H), 0.00 (s, 9 H). 13C NMR (100 MHz,
CDCl3): d = 157.3 (s), 94.4 (t), 68.7 (d), 68.4 (d), 65.0 (t),
64.5 (d), 57.3 (t), 52.7 (q), 34.3 (t), 27.9 (t), 25.7 (q, 3 C),
18.1 (s), 17.9 (t), –1.5 (q, 3 C), –5.0 (q), –5.1 (q). MS: m/z =
449 (0.1) [M+], 244 (85), 156 (53), 73 (100). Anal. Calcd for
C20H43NO6Si2: C, 53.41; H, 9.64; N, 3.11. Found: C, 53.05;
H, 9.32; N, 2.88.
6-H and one of the protons (CH2OSEM) on the side chain at
C-2. In N-protected piperidines analogues to 15, the C-2
substituent is forced towards an axial orientation to relieve
the A(1,3) strain with the N-protection. See: (a) Comins, D.
L.; Joseph, S. P. In Advances in Nitrogen Heterocycles, Vol.
2; Moody, C. J., Ed.; JAI Press: Greenwich CT, 1996, 251–
294. (b) Ha, J. D.; Kang, C. H.; Belmore, K. A.; Cha, J. K.
J. Org. Chem. 1998, 63, 3810; and ref. 3f.
(21) Typical Procedure
A suspension of 15 (55 mg, 0.12 mmol) in 2 N HCl (aq) was
refluxed for 18 h. After cooling at r.t., it was washed with
Et2O (5 × 10 mL), concentrated, and triturated with CHCl3
to give 1·HCl (22 mg, 100%) as pale yellow solid after 12 h
under vacuum; [a]D23 +12.3 (c 0.38, H2O); lit.10f [a]D20 +12.9
(c 0.93, H2O). 1H NMR (400 MHz, D2O): d = 3.97 (dd,
J = 12.5, 3.1 Hz, 1 H, part of an ABX system), 3.91 (dd,
J = 12.5, 5.1 Hz, 1 H, part of an ABX system), 3.75 (ddd,
J = 14.0, 10.1, 4.7 Hz, 1 H), 3.56 (pseudo t, J = 10.1 Hz, 1
H), 3.48 (br d, J = 12.1 Hz, 1 H), 3.19–3.10 (m, 1 H + 1 H),
2.27–2.22 (m, 1 H), 1.81–1.74 (m, 1 H). 13C NMR (100
MHz, D2O): d = 70.9 (d), 70.1 (d), 60.9 (d), 58.2 (t), 42.4 (t),
29.1 (t).
(20) The relative stereochemistry of 15 was assigned by NOESY-
1D studies which also, together with the coupling constant
values, showed that all substituents are axially oriented.
There is no large trans-diaxial coupling constant between 2-
H and 3-H, 3-H and 4-H, and between 4-H and either of the
protons on C-5, as all of them are in equatorial position.
Consistently, a strong NOE effect was found between axial
Synlett 2009, No. 6, 913–916 © Thieme Stuttgart · New York