Synthesis of (-)-homogalanthamine from naltrexone

Article abstract of DOI:10.1021/jo1022487

Acetylcholinesterase inhibitor (-)-homogalanthamine 3 was synthesized from μ opioid antagonist naltrexone (2) in 16% total yield. The synthesis features Grob fragmentation as a key reaction, which was especially accelerated in the presence of 15-crown-5.

Full text of DOI:10.1021/jo1022487

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pubs.acs.org/joc
Synthesis of (-)-Homogalanthamine from Naltrexone
Naoshi Yamamoto,† Hideaki Fujii, Satomi Imaide, Shigeto Hirayama, Toru Nemoto, Junji Inokoshi,
Hiroshi Tomoda, and Hiroshi Nagase*
School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
S Supporting Information
b
ABSTRACT: Acetylcholinesterase inhibitor (-)-homogalantha-
mine 3 was synthesized from μ opioid antagonist naltrexone (2) in
16% total yield. The synthesis features Grob fragmentation as a
key reaction, which was especially accelerated in the presence of
15-crown-5.
(-)-Galanthamine (1),1 an alkaloid isolated from the Caucasian
snowdrop, Galanthus woronowii, and also from another species of
the Amaryllidaceae family, Lycoris radiate, is a prescription drug
for the treatment of Alzheimer’s disease in Europe and the
United States.2 It has a unique dual mechanism on the choliner-
gic system, not only inhibiting acetylcholinesterase (AChE)
activity but also allosterically modulating the nicotinic acetylcho-
line receptor.3 Moreover, it exhibits less toxicity than tacrine,
rivastigmine, and donepezil.4 Therefore, many reports have
described the syntheses of galanthamine5 and its derivatives,5a
including a C-ring,6 D-ring,7 quaternary ammonium, and bis-
interacted derivatives,8 to evaluate their inhibitory effects on
AChE. However, to the best of our knowledge, no report has
previously described the synthesis of (-)-homogalanthamine 3.
Figure 1. Commonalities in the structures of (-)-galanthamine (1),
In the course of our opioid research, commonalities in the
naltrexone (2), and (-)-homogalanthamine 3.
structures of (-)-galanthamine (1), (-)-homogalanthamine 3,
and μ opioid antagonist naltrexone (2) (Figure 1) prompted us
Scheme 1. Retrosynthetic Analysis of (-)-Homogalantha-
mine 3
to attempt the synthesis of (-)-homogalanthamine 3 from
naltrexone (2). We were also interested in whether a transforma-
tion from 2 to 3 would impact the pharmacological effects of 3 on
either AChE or the opioid receptor. Herein, we report the
practical synthesis of (-)-homogalanthamine 3 from naltrexone
(2) and some preliminary results of the inhibitory effect of 3
on AChE.
Our retrosynthetic analysis is outlined in Scheme 1. We
reasoned that (-)-homogalanthamine 3 could be synthesized
from ketone 4 by the following sequential reactions; dehydro-
genation, transposition of the oxygen functionality, and reduc-
tion of the carbamate. The key intermediate 4 could be
constructed by Grob fragmentation of N-chloroamine 5 due to
its favorable geometry; the C9-C14 bond being broken is in an
antiperiplanar relationship to the leaving group (N-Cl bond).9
In turn, compound 5 could be obtained from naltrexone (2) by
the reductive removal of the 6-ketone group in 2, removal of the
N-substituent, and N-chlorination.
ketone to a methylene. Our attempts included Wolff-Kishner11
or Clemmensen reduction and desulfurization of the dithioacetal
First, naltrexone (2) was converted to naltrexone methyl ether
(6)10 (Scheme 2). Next, we attempted the reductive removal of
the 6-ketone group in 6 by general methods for converting a
Received: November 11, 2010
Published: March 07, 2011
r
2011 American Chemical Society
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|

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NOTE
Scheme 2. Removal of the 6-Ketone Group in Naltrexone
Methyl ether (6)
Scheme 4. Grob Fragmentation of N-Chloroamine 5
Scheme 5. Synthesis of (-)-Homogalanthamine 3 from the
Key Intermediate 4
Scheme 3. Synthesis of N-Chloroamine 5
of 6 with Raney Ni, but all procedures led to a cleavage of the 4,5-
ether bond. Next, we attempted to synthesize 10 by E2 elimina-
tion of mesylate 8 and subsequent hydrogenation of the resulting
olefin. Stereoselective reduction of 6 with NaBH(OAc)3 in acetic
acid12 and subsequent mesylation of 6-alcohol 7 afforded mesy-
late 8 (Scheme 2). Unfortunately, treatment of 8 with t-BuOK
gave bicyclic compound 9 by intramolecular SN2 reaction.13 The
successful conversion of the resulting 9 to the objective com-
pound 10 was achieved by LiBHEt3 reduction,14 but the yield
was less than 57% (Scheme 2). To suppress the intramolecular
SN2 reaction13 and to accelerate the rate of the objective
elimination reaction, the mesylate group in 8 was substituted
with iodide (Scheme 3). The resulting iodide was subjected to E2
elimination reaction with DBU to give olefin 11 along with its
isomer 12. The mixture of olefins 11 and 12 was hydrogenated
with Wilkinson’s catalyst (5 mol %) in benzene to afford
the objective compound 10 quantitatively. Compound 10 was
converted to the secondary amine 13 by a previously reported
method;15 this was followed by N-chlorination with NCS9a,16
in CHCl3 at -30 °C to give N-chloroamine 5 in 83% yield.
With N-chloroamine 5 in hand, Grob fragmentation of 5 was
investigated (Scheme 4). Fortunately, the reaction of 5 with NaH
in the presence of 15-crown-5 proceeded smoothly.17 The C9-
C14 bond was cleaved, followed by a LiBH4 reduction to afford a
mixture of hemiaminal 14 and amine 15. This mixture was then
treated with ClCO2Me. This opened the five-membered hemi-
aminal ring in 14 and simultaneously protected the nitrogen to
give the carbamate 4. In parallel, treatment of 15 with ClCO2Me
formed a carbonate that was hydrolyzed to give alcohol 16. Then,
16 was oxidized by PCC to provide 4. Thus, the key intermediate
4 was prepared from 5 in 4 steps with a 70% yield.
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Finally, the key intermediate 4 was converted into (-)-
homogalanthamine 3 (Scheme 5). Theintermediate 4 was treated
with LDA and PhSSPh, followed by m-CPBA, and then refluxed
in toluene to afford 1718 in 82% total yield. The desired R-allylic
alcohol 18a was synthesized by Luche reduction19 at -78 °C,
followed by separation of the β-isomer by column chromatogra-
phy and recrystallization in 76% yield. The allylic rearrangement
of the oxygen functionality in 18a was achieved by acetylation of
the allylic alcohol and the PdCl2(MeCN)2-catalyzed [3,3] sigma-
tropic rearrangement in refluxing EtOAc to give 19 in two steps
(97% yield).20 Simultaneous reduction of both the carbamate and
acetate groups in 19 with LiAlH4 at 50 °C afforded the desired
(-)-homogalanthamine 3 in 92% yield. Demethylation of 3 was
carried out with thiolate anion,21 prepared in situ from an
orderless dodecanethiol12f,22,23 with t-BuOK, to provide crystal-
line compound 20. The structure of 20 was determined by X-ray
analysis (see the Supporting Information).
washed with brine, dried over NaSO4, and evaporated under reduced
pressure to afford a yellow solid (a mixture of 4 and 16). To a solution of
the solid in CH2Cl2 (200 mL) were added NaOAc (92 g, 1.12 mol) and
PCC (24 g, 112 mmol). After being stirred for 3 h at rt, the reaction
mixture was filtered through Celite, and the filtrate was concentrated
under reduced pressure. The obtained residue was purified by silica gel
column chromatography (EtOAc/n-hexane, 3:2) and recrystallized from
a CHCl3-n-hexane solution to afford ketone 4 (4.5 g, 70%) as a
colorless prismatic crystal. Ketone 4 was a mixture of rotamers. 4: mp
126-128 °C; IR (KBr) 2950, 1703, 1623, 1507, 1478, 1437, 1404, 1274,
1239, 1203, 1170, 1123, 1041, 1002, 755 cm-1; 1H NMR (400 MHz,
CDCl3) δ 1.54-1.78 (m, 2H), 1.88-2.05 (m, 1H), 2.06-2.64 (m, 7H),
3.16-3.32 (m, 1H), 3.37-3.54 (m, 1.8H), 3.45 (s, 1.2H), 3.60 (s,
1.8H), 3.61-3.80 (m, 1.2H), 3.88 (s, 1.2H), 3.89 (s, 1.8H), 4.69-4.77
(m, 1H), 6.60 (d, J = 8.4 Hz, 0.4H), 6.66 (d, J = 8.4 Hz, 0.6H), 6.76 (d, J =
8.4 Hz, 0.4H), 6.79 (d, J = 8.4 Hz, 0.6H); 13C NMR (100 MHz, CDCl3)
δ 18.1, 18.2, 29.0, 29.5, 30.8, 36.1, 37.1, 38.2, 38.4, 43.8, 44.4, 48.8, 49.3,
52.2, 52.4, 55.9, 56.0, 60.5, 60.6, 93.2, 93.6, 112.5, 112.8, 121.8, 122.1,
127.9, 128.2, 128.9, 129.0, 142.7, 142.8, 149.6, 149.9, 156.4, 157.0, 213.0,
213.2; HRMS (ESI) [M þ Na]þ calcd for C19H23NO5Na 368.1474,
found 368.1462.
The inhibitory activity of the obtained 3 (IC50 = 3.0 μM) toward
AChE was about 1/5 as potent as that of (-)-galanthamine (1)
(IC50 = 0.6 μM). Phenolic compound 2024 derived from 3 showed
no binding affinity for the opioid receptors in the competitive
binding assay, indicating that the cleavage of the C9-C14 bond in
naltrexone (2) abolished its affinity for opioid receptors.
’ ASSOCIATED CONTENT
In conclusion, we succeeded in the synthesis of (-)-homo-
galanthamine 3 in 16% total yield from the μ opioid antagonist,
naltrexone (2). The key reaction was a Grob fragmentation to
obtain the important intermediate 4. This synthesis is advanta-
geous, because naltrexone (2) is readily available, our synthetic
route for the (-)-homogalanthamine 3 is practical, and the total
yield was very high. Thus, we can easily obtain the intermediates
of (-)-homogalanthamine 3 and their derivatives. We are cur-
rently examining the application of this synthetic route to the
synthesis of compounds that are more active and less toxic than
(-)-galanthamine (1).
S
Supporting Information. Experimental procedures, full
b
characterization of compounds, and 1H NMR spectra and X-ray
crystallographic file of compound 20 (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: nagaseh@pharm.kitasato-u.ac.jp.
Present Addresses
†Faculty of Pharmaceutical Sciences, Hoshi University, 2-4-41
Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
’ EXPERIMENTAL SECTION
Grob Fragmentation of N-Chloroamine 5 and the Subse-
quent Reductions (Synthesis of Ketone 4). To a suspension of
NaH (dry, 1.4 g, 56 mmol) in THF (30 mL) was added 15-crown-5
(3.7 mL, 18.7 mmol) and the mixture stirred at rt for 15 min under an
argon atmosphere. A solution of N-chloroamine 5 (6.0 g, 18.7 mmol) in
THF (120 mL) was gradually added to the suspension. After the
disappearance of 5 was observed by TLC analysis, LiBH4 (46 mL, 2.0
M in THF, 92 mmol) was added to the reaction mixture. After being
stirred for 11 h, the mixture was treated with i-PrOH (100 mL), followed
by 6 M HCl (100 mL) at 0 °C, and stirred at rt for additional 2 h. The
reaction mixture was treated with 12 M aqueous NaOH to adjust to pH
9-10 and then concentrated under reduced pressure and extracted with
i-PrOH/CHCl3 (1:3) (200 mL, 100 mL, 50 mL). The combined organic
layer was washed with brine, dried over Na2SO4, and evaporated under
reduced pressure. The obtained residue was filtered through a short silica
gel column (NH4OH/MeOH/CHCl3, 1:9:100) and concentrated
under reduced pressure to afford a pale yellow oil (a mixture of 14
and 15). To a solution of the oil in CH2Cl2 (120 mL) were added Et3N
(7.8 mL, 56 mmol) and methyl chloroformate (2.2 mL, 28 mmol) at
0 °C under an argon atmosphere. After being stirred at rt for 1 h, the
mixture was concentrated under reduced pressure. To a solution of the
residue in pyridine (100 mL) was added 4 M aqueous NaOH (50 mL),
and the mixture was stirred at rt for 14 h under an argon atmosphere.
The mixture was treated with saturated aqueous NH4Cl to adjust to pH
9-10 and then concentrated under reduced pressure and extracted with
CHCl3 (100 mL, 50 mL, 25 mL). The combined organic layer was
’ ACKNOWLEDGMENT
We acknowledge the Institute of Instrumental Analysis of
Kitasato University, School of Pharmacy, for its facilities. We also
acknowledge the Uehara Memorial Foundation for financial
support.
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