Asymmetric synthesis of (+)-pyrido[3,4-b]homotropane

Article abstract of DOI:10.1021/jo8002425

(Chemical Equation Presented) (+)-Pyrido[3,4-b]homotropane (PHT) was efficiently constructed in 12 steps from N,N-diisopropylisonicotinamide. The synthesis features (i) RCM reaction in installing the homotropane skeleton, (ii) Snieckus ortho-lithiation of

Full text of DOI:10.1021/jo8002425

SCHEME 1. Retrosynthetic Analysis of (+)-PHT (1)
Asymmetric Synthesis of
(+)-Pyrido[3,4-b]homotropane
Yingxia Sang,† Jingrui Zhao,†,‡ Xueshun Jia,‡ and
Hongbin Zhai†,§,
*
Laboratory of Modern Synthetic Organic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, Shanghai 200032, China, Department of
Chemistry, Shanghai UniVersity, Shanghai 200436, China,
and The State Key Laboratory of Natural and Biomimetic
Drugs, School of Pharmaceutical Sciences, Peking
UniVersity, 38 College Road, Beijing 100083, China
and pharmacological profiles.1a,3PHT is structurally related to
naturally occurring epibatidine and norferruginine and to a variety
of conformationally restricted nicotine analogs documented in the
literature.1a,3 Moreover, PHT can also be envisioned conceptually
as a hybrid of anatoxin-a and nornicotine.3c So far, two groups1a,3a,b
have communicated the synthesis of PHT. This paper reports a
concise asymmetric synthesis of (+)-PHT starting from com-
mercially available materials.
zhaih@mail.sioc.ac.cn
ReceiVed January 30, 2008
(+)-Pyrido[3,4-b]homotropane (PHT) was efficiently con-
structed in 12 steps from N,N-diisopropylisonicotinamide.
The synthesis features (i) RCM reaction in installing the
homotropane skeleton, (ii) Snieckus ortho-lithiation of N,N-
diisopropylisonicotinamide followed by acylation, (iii) Myer
reduction of bulky tertiary amide to alcohol with LiBH3NH2,
and (iv) utilization of L-glutamic acid to introduce and
establish the requisite stereogenic centers.
The overall retrosynthetic analysis for (+)-PHT (1) is outlined
in Scheme 1. The target molecule should be accessible from
As a family of ligand-gated ion channels widely present in
the human brain, nicotinic acetylcholine receptors (nAChRs)
participate in various biological processes related to numerous
central nervous system (CNS) disorders such as Alzheimer’s
disease, Parkinson’s disease, Tourette’s syndrome, attention-
deficit hyperactivity disorder (ADHD), depression, epilepsy,
schizophrenia, and smoking cessation.1 There have been a
number of studies on the ligands selectively targeting and
activating nAChRs because of their potential therapeutic utility
in the treatment of CNS disorders.2,3 Pyrido[3,4-b]homotropane
(PHT) has emerged as an attractive ligand of this type due to
its unique structural characteristics and impressive biological
(2) For a recent review, see: (a) Wagner, F. F.; Comins, D. L. Tetrahedron
2007, 63, 8065. For our previous work, see: (b) Yang, X.; Luo, S.; Fang, F.;
Liu, P.; Lu, Y.; He, M.; Zhai, H. Tetrahedron 2006, 62, 2240. (c) Luo, S; Fang,
F.; Zhao, M.; Zhai, H. Tetrahedron 2004, 60, 5353. (d) Zhai, H.; Liu, P.; Luo,
S.; Fang, F.; Zhao, M Org. Lett. 2002, 4, 4385. For a part of Rapoport’s work,
see: (e) Lennox, J. R.; Turner, S. C.; Rapoport, H. J. Org. Chem. 2001, 66,
7078. (f) Turner, S. C.; Zhai, H.; Rapoport, H. J. Org. Chem. 2000, 65, 861. (g)
Xu, Y.-z.; Choi, J.; Calaza, M. I.; Turner, S. C.; Rapoport, H. J. Org. Chem.
1999, 64, 4069. For representative work from other labs, see: (h) Ondachi, P. W.;
Comins, D. L. Tetrahedron Lett. 2008, 49, 569. (i) Comins, D. L.; Laura, S.;
King, L. S.; Smith, E. D.; Fe’vrier, F. C. Org. Lett. 2005, 7, 5059. (j) Meijler,
M. M.; Matsushita, M.; Altobell, L. J.; Wirsching, P.; Janda, K. D. J. Am. Chem.
Soc. 2003, 125, 7164. (k) Sarkar, T. K.; Basak, S.; Slanina, Z.; Chow, T. J. J.
Org. Chem. 2003, 68, 4206. (l) Ullrich, T.; Binder, D.; Pyerin, M. Tetrahedron
Lett. 2002, 43, 177. (m) Kanne, D. B.; Abood, L. G. J. Med. Chem. 1988, 31,
506. (n) Glassco, W.; Suchocki, J.; George, C.; Martin, B. R.; May, E. L. J. Med.
Chem. 1993, 36, 3381. (o) Chavdarian, C. G.; Seeman, J. I.; Wooten, J. B. J.
Org. Chem. 1983, 48, 492. (p) Wei, Z. L.; Xiao, Y. X.; Yuan, H. B.; Baydyuk,
M.; Petukhov, P. A.; Musachio, J. L.; Kellar, K. J.; Kozikowski, A. P. J. Med.
Chem. 2005, 48, 1721. (q) Chellappan, S. K.; Xiao, Y.; Kellar, K. J.; Kozikowski,
A. P. 231st National Meeting of the American Chemical Society; Atlanta, GA,
2006; American Chemical Society: Washington, DC, 2006; Abstract MEDI-
159.
† Shanaghai Institute of Organic Chemistry.
‡ Shanghai University.
§ Peking University.
(1) (a) Carroll, F. I.; Hu, X.; Navarro, H. A.; Deschamps, J.; Abdrakhmanova,
G. R.; Damaj, M. I.; Martin, B. R. J. Med. Chem. 2006, 49, 3244. (b) Decker,
M. W.; Meyer, M. D.; Sullivan, J. P. Exp. Opin. InVest. Drugs 2001, 10, 1819.
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Recept. 1999, 395. (g) McDonald, I. A.; Cosford, N.; Vernier, J.-M. Annu. Rep.
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10.1021/jo8002425 CCC: $40.75
Published on Web 03/18/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 3589–3592 3589

SCHEME 2. Synthesis of (+)-PHT (1)
hydrogenation and desulfonylation of sulfonamide 2, obtained
from RCM reaction of diene 3. The conversion of 4 to 3 would
require a series of transformations including imine hydrogena-
tion, secondary amine protection, ester and amide reduction,
oxidation, and Wittig olefination. The generation of 4 would
involve ortho-deprotonation of amide 5 and the subsequent
coupling with lactam 6, followed by Boc deprotection and
intramolecular imine formation.
The current synthesis of (+)-PHT (1) commenced from
N,N-diisopropylisonicotinamide4a,b (5), which was lithiated at
C-3 via a Snieckus directed ortho-metalation (DOM)4c–e with
LDA at -78 °C and then treated with activated lactam 6
(available in three steps from L-glutamic acid5) at -78 °C to
afford ketone 7 in 94% yield (Scheme 2). Ether proved to be a
better solvent than THF for this reaction. Relatively low
substrate concentration (see the Experimental Section), slow
addition rate, and proper control of the temperature proved to
be critical for the success of this reaction. The homo coupling
of the amide (i.e., acylation of 3-lithio intermediate with another
neutral amide) took place to a greater extent if N,N-diethyl-
isonicotinamide was used instead of 5,6 though the diethylamido
group may be better for reduction to the alcohol with
LiBH3NH2.7
Removal of the Boc group in 7 at 0 °C with HCl (generated
in situ from AcCl and MeOH) furnished an ammonium salt,
exposure of which to excess cold saturated aqueous NaHCO3
solution smoothly produced cyclic imine 4 as a viscous oil
(77%). Due to its low stability, 4 was used in the next step as
soon as possible. cis-Pyrrolidine 8 was produced in 83% yield
after hydrogenation of 4 with Pearlman’s catalyst in anhydrous
degassed EtOH under 1 atm of H2 for 36 h. Pd(OH)2 was added
in portions due to its susceptibility to deactivation by the
nitrogen atoms present; otherwise, the reaction ceased before
completion.
Amine 8 was subsequently tosylated (80%) with TsCl in the
presence of Et3N and DMAP. Ether turned out to be a suitable
solvent for this transformation, while only moderate yield was
obtained using dichloromethane or acetonitrile used as the
solvent. Other groups such as Boc, Cbz, and Bn, once considered
for protecting the secondary amine moiety in 8, proved to be
problematic in one way or another. For example, protection with
Boc could be achieved in only 12% yield. Standard Cbz
protection could be achieved using CbzCl but it did not survive
during LiBH3NH27 reduction later. With benzyl-protected amine,
treatment with NaBH4 or LiBH4 failed to reduce the ester group
while DIBAL-H converted the N,N-diisopropylamido to the
corresponding tertiary amine in addition to the reduction of ester
functionality.
Sulfonamide 9 was next converted into diol 11 after a two-
stage reduction sequence comprising (i) ester reduction (NaBH4,
EtOH, 73%) and (ii) Myer amide reduction (BuLi, BH3 ·NH3,
THF, 82%) involving the in situ generated LiBH3NH2, an efficient
reducing species for mild and selective reduction of an amide to a
primary alcohol.7 For the second step, an excess amount of
LiBH3NH2 (8 equiv) was required to ensure a clean and complete
reduction. The crude diol 11 was heated with an aqueous KOH
solution at 50 °C for 3 h in order to destroy the boron complex. It
is noteworthy that reduction of 10 with relatively inexpensive
LiBH3NMe28 produced a diisopropylamine rather than 11.
Swern oxidation9 of both primary hydroxyl groups in 11
afforded a labile dialdehyde (e.g., racemization might occur),
which should be quickly olefinated10 (Ph3PMeBr, KOtBu, THF,
-78 °C, 57% over two steps). During the purification of diene
3 on a silica gel column, the ether component in the eluting
system (petroleum ether/ether, 2:1) was crucial to get rid of the
byproduct, Ph3PdO (which happened to have an Rf value very
close to that of 3) by taking advantage of solubility differences.
In addition, comparable yields of 3 were obtained for the Wittig
reaction when KHMDS or BuLi was used instead of KOtBu.11
(4) (a) Swain, A.; Naegele, S. J. Am. Chem. Soc. 1957, 79, 5250. (b) Shhi,
J.; Hiirsor, I. F.; Perron, Y. G. J. Am. Chem. Soc. 1959, 81, 710. (c) Snieckus,
V. Chem. Res. 1990, 90, 879. (d) Beak, P.; Snieckus, V. Acc. Chem. Res. 1982,
15, 306. (e) Snieckus, V. Heterocycles 1980, 14, 1649.
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Williams, D. J. J. Org. Chem. 1999, 64, 6005. (b) Clive, D. L. J.; Yeh, V. S. C.
Tetrahedron Lett. 1998, 39, 4789.
(8) Fisher, G. B.; Fuller, J. C.; Harrison, J.; Alvarez, S. G.; Burkhardt, E. R.;
Goralski, C. T.; Singaram, B. J. Org. Chem. 1994, 59, 637.
(9) Sudau, A.; Nubbemeyer, U. Angew. Chem., Int. Ed. 1998, 37, 1140.
(10) Kwon, T. W.; Keusenkothen, P. F.; Smith, M. B. J. Org. Chem. 1992,
57, 6169.
(6) (a) Epsztajn, J.; Brzezinski, J. Z.; Czeh, K. Monatsh. Chem. 1993, 124,
549. (b) Epsztajn, J.; Brzezinski, J. Z.; Jozwiak, A. J. Chem. Res., Miniprint.
1986, 1, 6401.
(11) (a) Aggarwal, V. K.; Astle, C. J.; Mark, R.-E. Org. Lett. 2004, 9, 1469.
(b) Kana, S.; Sugino, E.; Shibuya, S.; Hibino, S. J. Org. Chem. 1981, 46, 2979.
(c) Henegar, K. E.; Ashford, S. W.; Baughman, T. A.; Sih, J. C.; Gu, R. L. J.
Org. Chem. 1997, 62, 6588.
(7) Myer, A. G.; Yang, B. H.; Kopecky, D. J. Tetrahedron Lett. 1996, 37,
3623.
3590 J. Org. Chem. Vol. 73, No. 9, 2008

Compound 11. To a suspension of borane-ammonia complex
(predried, 464 mg, 15.0 mmol) in anhydrous THF (25 mL) was
added dropwise BuLi (2.3 M in hexanes, 6.4 mL, 15 mmol) at 0
°C. The resultant solution was stirred at 0 °C for 5 min and at rt
for 5 min and cooled to 0 °C. A solution of 10 (752 mg, 1.64 mmol)
in anhydrous THF (20 mL) was added dropwise to the above
mixture at 0 °C. The mixture was slowly warmed to rt, stirred
overnight, and quenched with saturated aqueous NH4Cl solution.
The organic solvents were evaporated, and solid KOH (3.46 g, 61.7
mmol) was added at 0 °C. The aqueous mixture was heated at 50
°C for 3 h, cooled to rt, and extracted with CHCl3/iPrOH (3:1).
The combined extracts were washed with brine, dried (Na2SO4),
and concentrated. The residue was chromatographed (petroleum
ether/EtOAc, 1:4; EtOAc/MeOH, 200:1) to afford 11 (486 mg, 82%)
as a white solid: [R]24D +88.2 (c 0.37, MeOH); 1H NMR (CDCl3,
300 MHz) δ 1.45–1.63 (m, 1H), 1.67–1.94 (m, 2H), 1.99–2.15 (m,
1H), 2.39 (s, 3H), 3.71–3.92 (m, 3H), 4.69 (d, J ) 14.1 Hz, 1H),
4.76–4.93 (m, 2H), 7.28 (d, J ) 7.8 Hz, 2H), 7.32 (d, J ) 4.8 Hz,
1H), 7.66 (d, J ) 7.5 Hz, 2H), 8.30 (d, J ) 4.8 Hz, 1H), 8.71 (s,
1H) (The OH protons are missing); 13C NMR (CDCl3, 75 MHz) δ
21.5, 27.3, 34.0, 60.2, 61.1, 62.9, 64.7, 121.9, 127.7, 129.9, 133.3,
136.4, 144.2, 146.9, 147.6, 147.8. MS (ESI) 363 (M + H); HRMS
(ESI) calcd for C18H22N2O4S + H 363.1379, found 363.1373.
Compound 3. To a solution of (COCl)2 (0.70 mL, 8.0 mmol)
in CH2Cl2 (20 mL) was added DMSO (1.2 mL, 17 mmol) dropwise
at -78 °C. The mixture was stirred at -78 °C for 15 min, and a
solution of 11 (185 mg, 0.510 mmol) in CH2Cl2 (8 mL) was added
dropwise. Stirring continued for 45 min, and then Et3N (4.6 mL,
33 mmol) was added. The mixture was stirred at -78 °C for 1 h
and then quenched with saturated aqueous NaHCO3 solution,
evaporated to remove CH2Cl2, and extracted with EtOAc. The
combined extracts were dried (NaSO4), filtered, and concentrated
to afford a crude dialdehyde, which was used into the next step
without purification.
With 3 in hand, installment of the desired bicyclo[4.2.1]
system via RCM reaction12 was vigorously explored. The free
base 3 was converted13a into its corresponding HCl salt. RCM
reaction using Grubbs second-generation catalyst12 (12, 19 mol
%) in refluxing toluene/dichloromethane (16:1) furnished pyrido
bicycle 2 as a white solid (64% over two steps from 3). Here,
dichloromethane was included in the reaction medium to
increase the solubility of the HCl salt. Exposure of the diene
free base to catalyst 12 in the presence of Ti(OiPr)4 gave similar
results.13b However, replacement of Ti(OiPr)4 with BEt3 led to
a complex reaction mixture.14 If 3 (free base) was directly
subjected to the metathesis conditions, the product was obtained
in only 20–30% yield, while approximately half of the starting
material remained unreacted. Presumably, basic groups such as
the nitrogen atom of pyridine might coordinate to the ruthenium
and thus deactivate the catalyst.13 Moreover, the RCM reaction
was rather sluggish in refluxing dichloromethane (of relatively
low boiling point) as a single solvent.
Finally, sulfonamide 2 was hydrogenated (H2, Pd/C, MeOH)
and desulfonylated15 (Na, naphthalene, THF, -78 °C) to give
(+)-PHT (1) [[R]28 +35 (c 0.10, CHCl3); lit.1a [R]25 +38.3
D
D
(c 1.34, CHCl3)] in 41% yield (over two steps from 2). The 1H
and 13C NMR spectroscopic data were in accordance with those
disclosed in the literature.1a
In summary, (+)-pyrido[3,4-b]homotropane (PHT) was ef-
ficiently constructed in 12 steps from N,N-diisopropylisonico-
tinamide. Since PHT can be viewed as an annulated nicotine
(or more precisely, nornicotine) derivative, the present work
constitutes a general and rapid synthetic method to a number
of nicotine analogs.
A mixture of KOtBu (290 mg, 2.58 mmol) and Ph3PCH3Br (940
mg, 2.63 mmol) in THF (8 mL) was stirred at -78 °C for 1 h. A
solution of the above crude dialdehyde in THF (8 mL) was added
dropwise via syringe at -78 °C. The mixture was allowed to warm
slowly to rt, stirred overnight, quenched with saturated aqueous
NaHCO3 solution, evaporated to remove THF, and extracted with
EtOAc. The combined organic extracts were dried (NaSO4), filtered,
and concentrated to give a residue, which was chromatographed
(petroleum ether/ether, 2:1) to afford diene 3 (103 mg, 57% for
two steps) as a white solid: [R]25D +23.7 (c 0.40, CHCl3); 1H NMR
(CDCl3, 300 MHz) δ 1.66–1.92 (m, 3H), 2.02–2.17 (m, 1H), 2.40
(s, 3H), 4.38 (q, J ) 6.3 Hz, 1H), 5.13 (dd, J ) 7.5, 5.7 Hz, 1H),
5.22 (d, J ) 15.6 Hz, 1H), 5.33 (d, J ) 17.1 Hz, 1H), 5.54 (d, J )
11.1 Hz, 1H), 5.80 (d, J ) 17.1 Hz, 1H), 5.96–6.12 (m, 1H), 6.94
(dd, J ) 17.1, 11.1 Hz, 1H), 7.22–7.30 (m, 3H), 7.63 (d, J ) 8.1
Hz, 2H), 8.44 (d, J ) 5.4 Hz, 1H), 8.69 (s, 1H); 13C NMR (CDCl3,
75 MHz) δ 21.4, 30.6, 33.7, 59.9, 63.6, 116.5, 119.7, 120.3, 127.6,
129.5, 131.9, 134.3, 135.0, 138.2, 142.5, 143.6, 148.3, 148.7. MS
(ESI) 355 (M + H); HRMS (ESI) calcd for C20H22N2O2S + H
355.1480, found 355.1475.
Experimental Section
The synthesis, purification, and analytical data of the intermedi-
ates 7, 4, 8, and 9 are described in the Supporting Information.
Note that in some cases, extra peaks appeared in the NMR spectra
due to the presence of rotamers.
Compound 10. To a solution of 9 (465 mg, 0.954 mmol) in
EtOH (80 mL) was added NaBH4 (289 mg, 7.64 mmol) in portions
at rt, and the mixture was stirred overnight. Saturated aqueous
NH4Cl solution was added, and the organic solvent was evaporated.
After solid KOH (2.14 g, 38.1 mmol) was added at 0 °C, the
aqueous mixture was heated at 50 °C for 3 h, cooled to rt, and
extracted with CH2Cl2/iPrOH (3:1). The combined extracts were
dried (Na2SO4), filtered, and concentrated. The residue was chro-
matographed (petroleum ether/EtOAc, 3:1 to 2:3) to afford 10 (321
mg, 73%) as a light yellow foam: [R]28D +59 (c 0.79, CHCl3); 1H
NMR (CDCl3, 300 MHz) δ 1.08–1.38 (m, 7H), 1.49–1.73 (m, 6H),
1.78–1.98 (m, 2H), 2.15–2.32 (m, 1H), 2.44 (s, 3H), 3.48–3.73 (m,
2H), 3.75–4.00 (m, 3H), 4.75 (t, J ) 7.4 Hz, 0.2H), 4.91 (t, J )
7.1 Hz, 0.8H), 7.05 (d, J ) 4.8 Hz, 1H), 7.33 (d, J ) 7.8 Hz, 2H),
7.73 (d, J ) 7.5 Hz, 1.6H), 7.84 (d, J ) 8.1 Hz, 0.4H), 8.51 (d, J
Compound 2. To a stirred solution of diene 3 (46 mg, 0.13
mmol) in CH2Cl2 (1 mL) at 0 °C was added dropwise a saturated
solution of HCl (g) in Et2O, and the solvents were evaporated to
give the HCl salt of 3. To a solution of the above HCl salt in
anhydrous degassed CH2Cl2 (5 mL) and toluene (80 mL) was added
12 (11 mg, 0.013 mmol) at rt. The resultant mixture was heated at
reflux under argon. After 10 h, an additional portion of 12 (11 mg,
0.013 mmol) was added, and the mixture was refluxed under argon
for another 10 h (at that point the reaction reached completion as
examined by TLC analysis), cooled to rt, and quenched with
saturated aqueous NaHCO3 solution. The two layers were separated,
and the aqueous layer was extracted with EtOAc. The combined
extracts were dried (Na2SO4), filtered, and concentrated. The residue
was chromatographed (petroleum ether/ether, 2:1) to afford 2 (27
) 4.8 Hz, 1H), 8.89, 9.01 (s, 1H) (The OH proton is missing); 13
C
NMR (CDCl3, 75 MHz) δ 20.2, 20.7, 20.8, 20.8, 21.4, 27.4, 34.8,
46.0, 51.2, 62.1, 63.0, 64.5, 118.7, 127.5, 129.7, 133.7, 136.4, 142.7,
144.1, 147.6, 149.5, 167.5. MS (ESI) 460 (M + H); HRMS (ESI)
calcd for C24H33N3O4S + H 460.2270, found 460.2264.
(12) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(13) (a) Felpin, F.-X.; Girard, S.; Giang, V.-T.; Robins, R. J.; Villie’ras, J.;
Lebreton, J. J. Org. Chem. 2001, 66, 6305. (b) Yang, Q.; Xiao, W. J.; Yu, Z.
Org. Lett. 2005, 7, 871.
(14) Lutz, C.; Graf, C.-D.; Knochel, P. Tetrahedron 1998, 54, 10317.
(15) (a) Heathcock, C. H.; Blumenkopf, T. A.; Smith, K. M. J. Org. Chem.
1989, 54, 1548. (b) Trost, B. M.; Marrs, C. M. J. Am. Chem. Soc. 1993, 115,
6636.
mg, 64% over two steps) as a white solid: [R]28 +32 (c 0.16,
D
J. Org. Chem. Vol. 73, No. 9, 2008 3591

CHCl3); 1H NMR (CDCl3, 300 MHz) δ 1.80–1.93 (m, 1H),
2.06–2.15 (m, 2H), 2.30 (s, 3H), 2.45–2.60 (m, 1H), 4.69–4.78 (m,
1H), 5.10 (dd, J ) 9.5, 4.1 Hz, 1H), 6.00 (d, J ) 11.8 Hz, 1 H),
6.08 (dd, J ) 12.0, 5.1 Hz, 1 H), 6.67 (d, J ) 5.4 Hz, 1H), 6.96 (d,
J ) 8.4 Hz, 2H), 7.32 (d, J ) 8.4 Hz, 2H), 8.30 (d, J ) 4.8 Hz,
1H), 8.36 (s, 1H); 13C NMR (CDCl3, 75 MHz) 8.2 (unidentified
impurity), 21.4, 29.6 (grease), 34.6, 39.7, 58.6, 60.2, 60.5, 125.7,
127.2, 128.3, 128.8, 136.5, 136.7, 140.3, 142.7, 147.4, 149.0. MS
(ESI) 675 (2 M + Na), 327 (M + H); HRMS (ESI) calcd for
C18H18N2O2S + H 327.1167, found 327.1162.
Compound (+)-1. A mixture of 2 (23 mg, 0.070 mmol) and
5% Pd/C (3.0 mg) in degassed MeOH (8 mL) was stirred under
H2 (1 atm) at rt for 5 h. The solid mass was filtered off, and the
filtrate was concentrated to give a crude hydrogenation product as
a pale yellow oil, which was directly used into the next step without
further purification: 1H NMR (CDCl3, 300 MHz) δ 1.72–1.95 (m,
4H), 2.25–2.49 (m, 2H), 2.39 (s, 3H), 2.69 (dt, J ) 15.9, 3.6 Hz,
1H), 2.93 (td, J ) 16.1, 3.6 Hz, 1 H), 4.47–4.58 (m, 1H), 5.04–5.14
(m, 1H), 6.99 (d, J ) 4.5 Hz, 1H), 7.20 (d, J ) 7.8 Hz, 2H), 7.61
(d, J ) 8.1 Hz, 2H), 8.35 (d, J ) 4.8 Hz, 1H). 8.38 (s, 1H).
A solution of sodium naphthalenide in anhydrous THF was
prepared for subsequent use by adding THF (10 mL) to a mixture
of sodium (77 mg, 3.3 mmol) and naphthalene (438 mg, 3.42 mmol)
followed by stirring the resultant mixture at rt for 2 h. To a well-
stirred solution of the above crude hydrogenation product in THF
(10 mL) was added dropwise sodium naphthalenide solution (0.30
mL, 0.10 mmol) at -78 °C. After the mixture was stirred for 1 h,
an additional portion of sodium naphthalenide solution (0.30 mL,
0.10 mmol) was added dropwise and stirring continued for 1 h.
The mixture was quenched with saturated aqueous NaHCO3
solution, stirred for 24 h, and filtered. The solid mass was washed
with ether. The combined filtrates were concentrated under reduced
pressure to give a residue, which was chromatographed (petroleum
ether/EtOAc, 1:1 to 1:2; then EtOAc/MeOH/29% NH3 ·H2O, 10:
1:0.1) to give (+)-1 (5.0 mg, 41% over two steps) as a white solid:
[R]28 +35 (c 0.10, CHCl3); 1H NMR (CDCl3, 300 MHz) δ
D
1.59–1.72 (m, 1H), 1.78–1.95 (m, 3H), 2.06–2.32 (m, 2H), 2.24
(br s, 1H, NH), 2.34–2.50 (m, 1H), 2.70 (dt, J ) 14.5, 3.8 Hz,
1H), 3.09 (td, J ) 14.5, 3.5 Hz, 1H), 3.77–3.86 (m, 1H), 4.36 (dd,
J ) 10.4, 2.1 Hz, 1H), 7.06 (d, J ) 5.1 Hz, 1H), 8.29 (s, 1 H),
8.30 (d, J ) 4.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 29.8,
31.4, 31.7, 33.6, 58.2, 60.5, 125.5, 142.6 (relatively weak), 148.1,
148.5, 149.2; HRMS (ESI) calcd for C11H15N2 + H 175.1235, found
175.1230.
Acknowledgment. Financial support was provided by the
grants from NSFC (90713007; 20772141; 20625204; 20632030),
STCSM (“Post-Venus” Program, 05QMH1416), and MOST_863
(2006AA09Z405; 2006AA09Z446). We are grateful to Professor
Minzhi Deng (SIOC, CAS) for providing the LiBH3NMe2
reagent as a gift and to Professor Fayang Qiu (GIBH, CAS) for
enlightening discussions.
Supporting Information Available: Experimental proce-
dures and analytical data for compounds 7, 4, 8, and 9 and copies
1
of H and 13C NMR spectra for compounds 1-4, and 7–11.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO8002425
3592 J. Org. Chem. Vol. 73, No. 9, 2008