Nonracemic betti base as a new chiral auxiliary: Application to total syntheses of enantiopure (2S,6R)-dihydropinidine and (2S,6R)-isosolenopsins

Article abstract of DOI:10.1021/jo0480444

(Chemical Equation Presented) Total syntheses of enantiopure alkaloidal natural products (2S,6R)-dihydropinidine (as hydrochloride) and (2S,6R)-isosolenopsins (as hydrochlorides) were achieved in four steps and in 80-82% total yields by using a synthetic strategy of the formation-cleavage of 1,3-oxazinane. (S)-Betti base was proved to be an excellent chiral auxiliary and a novel Pd/C catalyzed N-debenzylation straightforward to amine hydrochloride was developed in the presence of CH₂Cl₂.

Full text of DOI:10.1021/jo0480444

SCHEME 1
Nonracemic Betti Base as a New Chiral
Auxiliary: Application to Total Syntheses
of Enantiopure (2S,6R)-Dihydropinidine
and (2S,6R)-Isosolenopsins
Xinyan Wang, Yanmei Dong, Jianwei Sun, Xuenong Xu,
Rui Li, and Yuefei Hu*
Department of Chemistry, Tsinghua University,
Beijing 100084, P. R. China
phenylglycinol [(R)-1] and 1,5-pentandial in the presence
of a nucleophilic moiety, followed by alkylations at two
newly created chiral carbons (C5 and C9) separately.
However, a major drawback to this otherwise efficient
synthetic approach has been dissatisfactory diastereose-
lectivity in both key steps.2b,4,5
yfh@mail.tsinghua.edu.cn
Received November 3, 2004
Since a result6 obtained from four structurally similar
amino-hydroxy auxiliaries revealed that their stereose-
lectivities can be improved significantly by increasing
steric hindrance at the carbon atom connected by the
hydroxyl group, it is believed that the drawbacks that
occurred in the formation-cleavage of oxazolidine arose
more from the structural nature of 2-phenylglycinol (1)
than from the synthetic strategy. Therefore, there is a
great need to find a better alternative chiral auxiliary to
enhance the stereoselectivity of this synthetic strategy.
Herein, we introduce nonracemic Betti base (3) as a new
chiral auxiliary and a novel N-debenzylation straight-
forward to amine hydrochloride for the stereoselective
syntheses of 2,6-dialkylpiperidines. As typical application
examples (Chart 1), the total syntheses of enantiopure
alkaloidal natural products (2S,6R)-dihydropinidine (7a,
as hydrochloride) and (2S,6R)-isosolenopsins (7b-e, as
hydrochlorides) were achieved under extremely mild
conditions in high total yields (80-82%).
Total syntheses of enantiopure alkaloidal natural products
(2S,6R)-dihydropinidine (as hydrochloride) and (2S,6R)-
isosolenopsins (as hydrochlorides) were achieved in four
steps and in 80-82% total yields by using a synthetic
strategy of the formation-cleavage of 1,3-oxazinane. (S)-Betti
base was proved to be an excellent chiral auxiliary and a
novel Pd/C catalyzed N-debenzylation straightforward to
amine hydrochloride was developed in the presence of
CH2Cl2.
Betti base [3, 1-(aminophenylmethyl)-2-naphthol] struc-
turally is a 1,3-amino-hydroxy compound and its hydroxy
group links to bulky naphthalene (Scheme 2). Its non-
racemic derivatives have been employed as chiral ligands
in metal ion catalyzed asymmetric reactions for a long
Since chiral 2,6-dialkylpiperidines exhibit notable bio-
logical activities1 and have a representative structure
that occurs in a number of biologically important complex
alkaloidal natural products,2 their synthesis has at-
tracted considerable attention and served as a good
vehicle for the testing of synthetic methodology.2-5 Promi-
nent among these synthetic methods are those that use
5-substituted hexahydro-3-phenyl-5H-oxazolo[3,2-a]pyr-
idine (2) as a precursor, which was derived from chiral
auxiliary 2-phenylglycinol (1).2b,4,5 They owe their success
mainly to a well-established synthetic strategy involved
in the formation-cleavage of oxazolidine. As illustrated
in Scheme 1, the strategy includes two key steps: con-
struction of precursor 2 by a condensation of R-(-)-2-
(3) For selected reports, see: (a) Munchhof, M. J.; Meyers, A. I. J.
Am. Chem. Soc., 1995, 117, 5399-5400. (b) Chenevert, R.; Dickman,
M. J. Org. Chem. 1996, 61, 3332-3341. (c) Reding, M. T.; Buchwald,
S. L. J. Org. Chem. 1998, 63, 6344-6347. (d) Ciblat, S.; Besse, P.;
Papastergiou, V.; Veschambre, H.; Canet, J.-L.; Troin, Y. Tetrahedron:
Asymmetry 2000, 11, 2221-2229. (e) Wilkinson, T. J.; Stehle, N. W.;
Beak, P. Org. Lett. 2000, 2, 155-158. (f) Kumareswaran, R.; Hassner,
A. Tetrahedron: Asymmetry 2001, 12, 2269-2276. (g) Itoh, T.; Yamaza-
ki, N.; Kibayashi, C. Org. Lett. 2002, 4, 2469-2472. (h) Amat, M.; Llor,
N.; Hidalgo, J.; Escolano, C.; Bosch, J. J. Org. Chem. 2003, 68, 1919-
1928. (i) Shu, C.; Liebeskind, L. S. J. Am. Chem. Soc. 2003, 125, 2878-
2879. (j) Singh, O. V.; Han, H. Org. Lett. 2004, 6, 3067-3070. (k)
Yamauchi, S.; Mori, S.; Hirai, Y.; Kinoshita, Y. Biosci. Biotechnol.
Biochem. 2004, 68, 676-684. (l) Kranke, B.; Hebrault, D.; Schultz-
Kukula, M.; Kunz, H. Synlett 2004, 671-674.
* Address correspondence to this author. Phone: +86-10-62795380.
Fax: +86-10-62771149.
(1) For selected reports, see: (a) Blum, M. S.; Walker, J. R.;
Callahan, P. S.; Novak, A. F. Science 1958, 128, 306-307. (b) Yi, G.
B.; McClendon, D.; Desaiah, D.; Goddard, J.; Lister, A.; Moffitt, J.;
Vander Meer, R. K.; deShazo, R.; Lee, K. S.; Rockhold, R. W. Int. J.
Toxicol. 2003, 22, 81-86.
(2) For selected reviews, see: (a) Bailey, P. D.; Millwood, P. A.;
Smith, P. D. Chem. Commun. 1998, 633-640. (b) Husson, H.-P.; Royer,
J. Chem. Soc. Rev. 1999, 28, 383-394. (c) Laschat, S.; Dickner, T.
Synthesis 2000, 1781-1813. (d) Groaning. M. D.; Meyers, A. I.
Tetrahedron 2000, 56, 9843-9873. (e) Michael, J. P. Nat. Prod. Rep.
2001, 18, 520-542.
(4) (a) Guerrier, L.; Rorer, J.; Grierson, D. S.; Husson, H.-P. J. Am.
Chem. Soc. 1983, 105, 7754-7755. (b) Grierson, D. S.; Royer, J.;
Guerrier, L.; Husson, H.-P. J. Org. Chem. 1986, 51, 4475-4477. (c)
Royer, J.; Husson, H.-P. J. Org. Chem. 1985, 50, 670-673. (d)
Poerwono, H.; Higashiyama, K.; Yamauchi, T.; Kubo, H.; Ohmiya, S.;
Takahashi, H. Tetrahedron 1998, 54, 13955-13970. (e) Agami, C.;
Couty, F.; Mathieu, H. Tetrahedron Lett. 1998, 39, 3505-3508.
(5) Kartritzky, A. R.; Qiu, G.; Yang, B.; Steel, P. J. J. Org. Chem.
1998, 63, 6699-6703.
(6) Yamazaki, N.; Ito, T.; Kibayashi, C. Tetrahedron Lett. 1999, 40,
739-742.
10.1021/jo0480444 CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/28/2005
J. Org. Chem. 2005, 70, 1897-1900
1897

CHART 1
CHART 2
SCHEME 2a
Restricted rotation of 2,6-dialkylpiperidine moiety in 6a
and 0 °C within 20 min. Comparing with the formation
of 2a,b derived from nonracemic 2-phenylglycinol (1),2b,4,5
the highly diastereoselective and convenient formation
of 4 could possibly benefit from the bulky size of naph-
thalene and high reactivity of the hydroxy group in the
naphthol moiety of Betti base (3). Then key precursor 5
was obtained as a single diastereomeric product in 96%
yield simply by stirring the mixture of 4 and MeMgCl in
THF at 0 °C for 2 h. We surprisingly observed that no
alkylation occurred at C7a when 5 was treated with
n-PrMgBr in THF, even at refluxing temperature over-
night. However, when the same reaction proceeded in
diethyl ether at -10 °C for 10 min, desired product 6a
was obtained in 96% yield. The control experiments
revealed that the alkylations at C11 in 4 and C7a in 5
with Grignard reagents, in fact, are well solvent-
controlled regioselective alkylations. Thus, no dimethyl-
ation could occur in the reaction of 4 with MeMgCl in
THF at a wide range of temperatures.
a Reagents and conditions: (a) OHC(CH2)3CHO, BtH, CH2Cl2,
0 °C, pH 8-9, 20 min, 92%; (b) MeMgCl, THF, 0 °C, 2 h, 96%; (c)
RMgBr, Et2O, -10 °C, 10 min; (d) 10% Pd/C, H2, MeOH-CH2Cl2,
rt, 48 h, 90-93% for two steps.
time.7,8 Surprisingly, it has never been employed as a
chiral auxiliary in asymmetric synthesis. In our recent
work,8d,e diastereopure (7aR,11R,13S)-11-(1H-benzotri-
azol-1-yl)-7a,8,10,11-tetrahydro-13-phenyl-9H,13H-naphtho-
[1,2-e]pyrido[2,1-b][1,3]oxazine (4) was prepared in high
yield from (S)-Betti base [(S)-3], by which diastereopure
alkylations at C7a and C11 in isolated cases were
achieved. These results strongly suggest that a highly
stereoselective synthesis of 2,6-dialkylpiperdine could be
achieved by using nonracemic Betti base (3) as a chiral
auxiliary with a similar synthetic strategy of the forma-
tion-cleavage of 1,3-oxazinane.
Our four-step route for the total syntheses of enan-
tiopure alkaloidal natural products 7a-e (as hydrochlo-
rides) is shown in Scheme 2. In an improved procedure,
the salt of (S)-Betti base [(S)-3] with L-(+)-tartaric acid
[it is a precursor of (S)-3 in the optical resolution]
condensed with pentane-1,5-dial and benzotriazole to give
a diastereopure product 4 in 92% yield under pH 8-9
Following the procedure for the preparation of 6a,
6b-e were produced smoothly by alkylation of 5 with
the corresponding Grignard reagents (RMgBr, R )
-C9H19, -C11H23, -C13H27, -C15H31), respectively. How-
ever, the structural assignments of 6a-e suffered seri-
ously from their ambiguous 1H NMR and 13C NMR
spectra. These results arose from the unusual coalescence
phenomenon that occurred at room temperature led by
restricted rotation of the 2,6-dialkylpiperidine moiety,
because a six-membered intramolecular hydrogen bond
between the nitrogen atom and the hydroxy group formed
in each molecule. For example, the hydrogen bond in 6a
(Chart 2) was so strong that its -OH signal appeared at
1
δ 12.00 ppm in H NMR spectrum and several signals
continued to be very broad weak peaks up to 60 °C in 1H
NMR and 13C NMR measurements in CDCl3. Fortu-
nately, the conversions of 5 into 6a-e were almost
quantitative yields and can be clearly monitored by IR
and TLC. In practice, crude 6a-e were used in the next
step without further purification and characterization.
In published literature, a number of methods have
been developed for N-debenzylation of benzylamines. The
most prominent among them was Pd/C-catalyzed hydro-
genolysis featured for its convenience, high yield, and
clean product.9 By a routine procedure, 6a was N-
debenzylated smoothly over Pd/C catalyst in MeOH at
room temperature and atmospheric pressure for 18 h.
After purification by column chromatography, desired
(2S,6R)-dihydropinidine (7a) was obtained in 25% yield.
However, 7a‚HCl as white crystals was obtained in 79%
yield by treatment of the crude product with Et2O
(7) (a) Cardelliccnio, C.; Ciccarella, G.; Naso, F.; Schingaro, E.;
Scordari, F. Tetrahedron: Asymmetry 1998, 9, 3667-3675. (b) Cardel-
licchio, C.; Ciccarella, G.; Naso, F.; Perna. F.; Tortorella, P. Tetrahedron
1999, 55, 14685-14692. (c) Bernardinelli, G.; Fernandez, D.; Gosmini,
R.; Meier, P.; Ripa, A.; Schupfer, P.; Treptow, B.; Kundig, E. P.
Chirality 2000, 12, 529-539. (d) Palmieri, G. Tetrahedron: Asymmetry
2000, 11, 3361-3373. (e) Liu, D.-X.; Zhang, L.-C.; Wang, Q.; Da, C.-
S.; Xin, Z.-Q.; Wang, R.; Choi, M. C. K.; Chan, A. S. C. Org. Lett. 2001,
3, 2733-2735. (f) Cimarelli, C.; Mazzanti, A.; Palmieri, G.; Volpini, E.
J. Org. Chem. 2001, 66, 4759-4765. (g) Wang, Y.; Li, X.; Ding K.
Tetrahedron: Asymmetry 2002, 13, 1291-1297. (h) Ji, J.; Qiu, L.; Yip,
C. W.; Chan, A. S. C. J. Org. Chem. 2003, 68, 1589-1590.
(8) (a) Lu, J.; Xu, X.; Wang, C.; He, J.; Hu, Y.; Hu, H. Tetrahedron
Lett. 2002, 43, 8367-8369. (b) Lu, J.; Xu, X.; Wang, S.; Wang, C.; Hu,
Y.; Hu, H. J. Chem. Soc., Perkin Trans. 1 2002, 2900-2903. (c) Dong,
Y.; Sun, J.; Wang, X.; Xu, X.; Cao L.; Hu, Y. Tetrahedron: Asymmetry
2004, 15, 1667-1672. (d) Xu, X.; Lu, J.; Li, R.; Ge, Z.; Dong, Y.; Hu, Y.
Synlett 2004, 122-124. (e) Xu, X.; Lu, J.; Dong, Y.; Li, R.; Ge, Z.; Hu,
Y. Tetrahedron: Asymmetry 2004, 15, 475-479.
(9) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999. (b) Hartung,
W. H.; Simonoff, R. Org. React. 1953, 7, 263-326.
1898 J. Org. Chem., Vol. 70, No. 5, 2005

TABLE 1. N-Debenzylation by Pd/C-Catalyzed Hydrogenolysis in CH2Cl2-MeOH
saturated with dry HCl after the hydrogenolysis of 6a.
These results clearly revealed that the dissatisfactory
yields of 7a resulted from the currently inefficient workup
procedure because 7a has relatively high volatility.
Ideally, straightforward conversion of benzylamine into
the corresponding amine hydrochloride during its hydro-
genolysis could prevent the loss of volatile amine, but no
such procedure has been reported in the literature up to
date.
Luckily for us, when CH2Cl2 was used as a cosolvent
with the purpose to increase the solubility of 6a in its
N-debenzylation, 7a‚HCl was obtained unexpectedly in
97% yield simply by filtrating out the catalyst and
evaporating off the solvent after hydrogenolysis of 6a.
The controlled experiments confirmed that the hydro-
chloride in 7a‚HCl comes from hydrodechlorination of
CH2Cl2 during the hydrogenolysis. The published litera-
ture has also reported that CH2Cl2 can be hydrodechlo-
rinated by Pd-based catalysts to release hydrochloride,
chloromethane, and methane in variable ratios.10
To determine the scope of the reaction, different
benzylamines were tested. As shown in Table 1, all
substrates (6b-j) were N-debenzylated straightforward
to the corresponding amine hydrochlorides in excellent
yields. 6b-e gave (2S,6R)-isosolenopsin hydrochlorides
(7b-e‚HCl) smoothly in 94-96% yields. Another highly
volatile alkaloidal natural product (R)-2-pipecoline11 was
also obtained as its hydrochloride (7f‚HCl) in 98% yield.
The method was so efficient that gaseous dimethylamine
was captured as dimethylamine hydrochloride (7g‚HCl)
in almost quantitative yield. However, the secondary
benzylamines, such as N-ethylbenzylamine, N-(tert-bu-
tyl)benzylamine, and N-benzylethanolamine, failed to
give the desired products. The advantage of this method
is 2-fold. First, the traditional two-step operation, the
N-debenzylation by Pd/C-catalyzed hydrogenolysis and
the conversion of amine into its hydrochloride, is com-
bined into a single easy performance. Second, volatile
amine, even gaseous amine, can be obtained in high yield
in its N-debenzylation. This method may make the widely
used N-debenzylation by Pd/C-catalyzed hydrogenolysis
more efficient in modern organic synthesis.
Since the stereochemistry of alkylations at C7a and
C11 in 4 has been found in our previous works8 and the
absolute configurations of dihydropinidines and iso-
solenopsins have been well established in the literature,2b,12
therefore, the stereochemistry of 7a-e was easily rec-
ognized as cis-2S,6R from their NMR spectra and optical
rotation values. We hypothesize that the regioselective
alkylation on C11 in 4 may go through an SN2 mecha-
nism. Thus the Bt-group was replaced with complete
inversion of configuration. However, a planar iminium
salt2b,5 must serve as an intermediate in alkylation on
C7a in 5, by which a new C-C bond was formed with
retention of configuration.
(11) (a) Munchhof, M. J.; Meyers, A. I. J. Org. Chem. 1995, 60,
7084-7085. (b) Burke, A. J.; Davies, S. G.; Christopher Garner, A.;
McCarthy, T. D.; Roberts, P. M.; Smith, A. D.; Rodriguez-Solla, H.;
Vickers, R. J. Org. Biomol. Chem. 2004, 2, 1387-1394.
(12) Leclercq, S.; Thirionet, I.; Broeders, F.; Daloze, D.; Vander Meer,
R.; Braekman, J. C. Tetrahedron 1994, 50, 8465-8478.
(10) (a) Malinowski, A.; Lomot, D.; Karpinski, Z. Appl. Catal. B 1998,
19, L79-L86. (b) Prati, L.; Rossi, M. Appl. Catal. B 1999, 23, 135-
142.
J. Org. Chem, Vol. 70, No. 5, 2005 1899

C, 83.60; H, 8.37; N, 3.75. Found: C, 83.78; H, 8.17; N, 3.70. By
In summary, total syntheses of enantiopure alkaloidal
natural products (2S,6R)-dihydropinidine (7a, as hydro-
chloride) and (2S,6R)-isosolenopsins (7b-e, as hydro-
chlorides) were achieved with the shortest steps and
unprecedented high total yields by using a strategy of
the formation-cleavage of 1,3-oxazinane. (S)-Betti base
[(S)-3] was proved to be an excellent chiral auxiliary and
its naphthol moiety played an important role in diste-
reoselectivity and reactivity. Thus, (S)-3 condensed with
pentane-1,5-dial and benzotriazole to diastereopurely
yield 4 in 92% yield. By using THF as solvent, a solvent-
controlled monoalkylation of 4 was achieved to give
diastereopure 5 in 96% yield. Then 5 was alkylated with
the corresponding Grignard reagent followed by a novel
N-debenzylation straightforward to amine hydrochloride
by Pd/C-catalyzed hydrogenolysis in the presence of
CH2Cl2 to yield target products 7a-e in 90-93% yields
(two steps), respectively.
the exact same procedure, compounds 6b-e were prepared by
using other Grignard reagents (RMgBr, R ) -C9H19, -C11H23
,
-C13H27, -C15H31, respectively), which were used to the next
step without further purification.
A Typical Procedure for the Preparation of (2S,6R)-2-
Methyl-6-propylpiperidine Hydrochloride [7a‚HCl, (2S,6R)-
Dihydropinidine Hydrochloride]. A mixture of compound 6a
(560 mg, 1.5 mmol), 10% Pd-C catalyst (160 mg, 0.15 mmol) in
MeOH (20 mL), and CH2Cl2 (10 mL) under H2 was stirred at
room temperature and atmospheric pressure until the absorption
of hydrogen ceased. After the catalyst was filtered out, the
filtrate was evaporated and Et2O (20 mL) was added. The
desired product 7a‚HCl as white crystals was collected by
filtration. Mp 240-242 °C (MeOH); [R]25 -13.2 (c 0.2, EtOH)
D
[lit.3e mp 242-243 °C, [R]25 -13.3 (c 1.0, EtOH)]. IR: ν 2955,
D
1
2935, 1459, 1380 cm-1. H NMR: δ 9.41 (br s, 1H), 9.07 (br s,
1H), 3.15-2.98 (m, 1H), 2.98-2.81 (m, 1H), 2.18-1.43 (m, 10H),
1.43-1.10 (m, 3H), 0.90 (t, J1 ) 7.2 Hz, 3H). 13C NMR: δ 58.4,
54.5, 35.1, 30.7, 27.4, 22.8, 19.4, 18.8, 13.7. Anal. Calcd for
C9H19N‚HCl: C, 60.83; H, 11.34; N, 7.88. Found: C, 60.87; H,
11.43; N, 7.76.
(2S,6R)-2-Methyl-6-nonylpiperidine Hydrochloride [7b‚
HCl, (2S,6R)-Isosolenopsin Hydrochloride]. Mp 176-177
°C; [R]25D -12.5 (c 0.2, CHCl3) [lit.3d as an enantiomeric isomer,
mp 174-175 °C, [R]25D +11.1 (c 0.92, CHCl3)]. IR: ν 2924, 2853,
Experimental Section
(7aR,11R,13S)-11-(1H-Benzotriazol-1-yl)-7a,8,10,11-tet-
rahydro-13-phenyl-9H,13H-naphtho[1,2-e]pyrido[2,1-b][1,3]-
oxazine (4). To a stirred solution of (S)-3 (as a salt of L-(+)-
tartaric acid, 11.97 g, 30 mmol) and benzotriazole (4.29 g, 36
mmol) in CH2Cl2 (120 mL) was added dropwise pentane-1,5-dial
(25% aqueous solution, 14.40 g, 36 mmol) at 0 °C under nitrogen.
Then K2CO3 powder was added to adjust the pH to 8-9. Twenty
minutes later (monitored by TLC), an aqueous solution of NaOH
(1.0 M, 60 mL) was added and stirring was continued for another
15 min. Then resultant mixture was filtered through a pad of
Celite. The filtrate was washed with H2O and brine and dried
over anhydrous Mg2SO4. After the removal of the solvent, the
residue was purified by recrystallization to give the desired
product 4 (11.92 g, 92%) as a colorless crystal, mp 180-182 °C
1465, 1380 cm-1 1H NMR: δ 9.45 (br s, 1H), 9.07 (br s, 1H),
.
3.13-2.98 (m, 1H), 2.98-2.80 (m, 1H), 2.20-1.50 (m, 10H),
1.50-1.10 (m, 15H), 0.86 (t, J1 ) 6.6 Hz, 3H). 13C NMR: δ 58.6,
54.5, 33.2, 31.8, 30.7, 29.6, 29.5, 29.3, 29.2, 27.4, 25.7, 22.9, 22.6,
19.4, 14.0. Anal. Calcd for C15H31N‚HCl: C, 68.80; H, 12.32; N,
5.35. Found: C, 68.96; H, 12.46; N, 5.42.
(2S,6R)-2-Methyl-6-decanylpiperidine Hydrochloride [7c‚
HCl, (2S,6R)-Isosolenopsin A Hydrochloride]. Mp 147-148
°C; [R]25D -9.9 (c 0.2, CHCl3) [lit.12 [R]20D -10.3 (c 1.3, CHCl3)].
1
IR: ν 2921, 2852, 1383 cm-1. H NMR: δ 9.43 (br s, 1H), 9.06
(br s, 1H), 3.13-2.96 (m, 1H), 2.96-2.80 (m, 1H), 2.20-1.48 (m,
10H), 1.48-1.10 (m, 19H), 0.86 (t, J1 ) 6.5 Hz, 3H). 13C NMR:
δ 58.6, 54.5, 33.2, 31.8, 30.7, 29.6 (3C), 29.5, 29.3, 29.2, 27.4,
25.6, 22.8, 22.6, 19.4, 14.1. Anal. Calcd for C17H35N‚HCl: C,
70.43; H, 12.52; N, 4.83. Found: C, 70.44; H, 12.46; N, 4.80.
(2S,6R)-2-Methyl-6-tridecanylpiperidine Hydrochloride
[7d‚HCl, (2S,6R)-Isosolenopsin B Hydrochloride]. Mp 140-
(CH2Cl2/CH3OH), [R]25 +164.8 (c 0.2, CHCl3) [lit.8e mp 196-
D
197 °C (EtOH), [R]25 +152.6 (c 1.6, CHCl3)].
D
(7aR,11S,13S)-7a,8,10,11-Tetrahydro-11-methyl-13-phen-
yl-9H,13H-naphtho[1,2-e]pyrido[2,1-b][1,3]oxazine (5). To
a cold solution (ice-water bath) of 4 (12.96 g, 30 mmol) in dry
THF (200 mL) was added MeMgCl (3.0 M in THF, 24 mL, 72
mmol) dropwise under nitrogen. After the reaction was stirred
at 0 °C for 2.0 h (monitored by TLC), a saturated aqueous
solution of NH4Cl (50 mL) was added to quench the reaction.
Then the resultant mixture was extracted with CH2Cl2. The
combined organic layers were washed with H2O and brine and
dried over anhydrous Mg2SO4. After the removal of the solvent,
the residue was purified by chromatography (silica gel, EtOAc:
PE ) 1:15) to give the desired product 5 (9.48 g, 96%) as a
142 °C; [R]25 -9.4 (c 0.2, CHCl3) [lit.3d as an enantiomeric
D
isomer, mp 145-146 °C, [R]25D +8.5 (c 1.0, CHCl3)]. IR: ν 2919,
1
2851, 1591, 1465, 1385 cm-1. H NMR: δ 9.43 (br s, 1H), 9.07
(br s, 1H), 3.13-2.97 (m, 1H), 2.97-2.80 (m, 1H), 2.20-1.49 (m,
10H), 1.49-1.10 (m, 23H), 0.86 (t, J1 ) 6.6 Hz, 3H). 13C NMR:
δ 58.6, 54.5, 33.2, 31.9, 30.7, 29.6, 29.5, 29.3, 29.2, 27.4, 25.7,
22.9, 22.6, 19.4, 14.0. Calcd for C19H39N.HCl: C, 71.77; H, 12.68;
N, 4.40. Found: C, 71.60; H, 12.48; N, 4.41.
(2S,6R)-2-Methyl-6-pentadecanylpiperidine Hydrochlo-
ride [7e‚HCl, (2S,6R)-Isosolenopsin C Hydrochloride]. Mp
137-139 °C; [R]25D -8.0 (c 0.2, CHCl3) [lit.3d as an enantiomeric
isomer, mp 140-141 °C, [R]25D +8.2 (c 1.0, CHCl3)]. IR: ν 2919,
2850, 1591, 1465, 1441, 1385 cm-1. 1H NMR: δ 9.41 (br s, 1H),
9.05 (br s, 1H), 3.12-2.98 (m, 1H), 2.98-2.80 (m, 1H), 2.20-
1.45 (m, 10H), 1.45-1.10 (m, 27H), 0.86 (t, J1 ) 6.3 Hz, 3H).
13C NMR: δ 58.5, 54.4, 33.2, 31.8, 30.6, 29.6 (7C), 29.5, 29.3,
29.2, 27.4, 25.6, 22.8, 22.6, 19.4, 14.0. Calcd for C21H43N‚HCl:
C, 72.89; H, 12.82; N, 4.05. Found: C, 72.83; H, 12.66; N, 4.08.
Products 7f-j‚HCl were prepared by the exact same proce-
dure and have identical physical data as reported in published
literature.
colorless crystal, mp 120-122 °C. [R]25 +161.6 (c 0.2, CHCl3).
D
IR: ν 2935, 1624, 1515, 1465 cm-1. H NMR: δ 7.06-7.72 (m,
1
11H), 5.19 (s, 1H), 4.95-4.96 (m, 1H), 3.51-3.53 (m, 1H), 1.44-
2.01 (m, 6H), 0.95-0.97 (m, 3H). 13C NMR: δ 154.2, 143.8, 131.5,
129.0 (2C), 128.8, 128.6, 128.5, 128.0 (2C), 126.9, 126.2, 123.1,
122.8, 119.0, 114.2, 81.6, 60.5, 54.4, 32.1, 29.6, 18.4, 14.1. MS
m/z (%): 329 (M+, 0.82), 313 (26), 232 (46), 231 (100), 202 (16).
Anal. Calcd for C23H23NO: C, 83.85; H, 7.04; N, 4.25. Found:
C, 83.89; H, 7.11; N, 4.31.
A Typical Procedure for the Preparation of 1-[(S)-
[(2S,6R)-2-Methyl-6-propylpiperidyl]phenylmethyl]-2-naph-
thalenol (6a). To a stirred solution of n-PrMgBr made from Mg
(365 mg, 15 mmol) and 1-bromopropane (1.84 g, 15 mmol) in
anhydrous Et2O (40 mL) was added dropwise a solution of 5 (494
mg, 1.5 mmol) in Et2O (15 mL) at -10 °C. Then a saturated
aqueous solution of NH4Cl (10 mL) was added to quench the
reaction and the separated organic layer was washed with H2O
and brine and dried over anhydrous Mg2SO4. Removal of the
solvent gave the crude product 6a (538 mg, 96%) as a yellowish
Acknowledgment. We are grateful to the National
Natural Science Foundation of China for financial
support.
Supporting Information Available: 1H NMR and 13C
NMR spectra of compounds 4, 5, and 7a-j‚HCl. This material
is available free of charge via the Internet at http://pubs.acs.org.
foamy solid, mp 102-103 °C; [R]25 +134.8 (c 0.2, CHCl3). IR:
D
ν 3447, 2961, 1525, 1447, 1231 cm-1; MS m/z (%): 372 (M+ - H,
0.28), 233 (24), 232 (85), 231 (100). Anal. Calcd for C26H31NO:
JO0480444
1900 J. Org. Chem., Vol. 70, No. 5, 2005