Ring closing metathesis mediated synthesis of 4a-aryloxodecahydroisoquinolines, intermediates in the preparation of novel opiates

Article abstract of DOI:10.1021/ol016588b

(matrix presented) The concise syntheses of the 4a-aryldecahydroisoquinolines 1 and 2 through a uniform strategy starting from N-methyl-3-allyl-4-piperidinone are reported in this Letter. Key transformations include a ring closing metathesis reaction to p

Full text of DOI:10.1021/ol016588b

ORGANIC
LETTERS
2001
Vol. 3, No. 22
3483-3486
Ring Closing Metathesis Mediated
Synthesis of
4a-Aryloxodecahydroisoquinolines,
Intermediates in the Preparation of
Novel Opiates
,1
Spiros Liras,* Martin P. Allen,1 and James F. Blake2
Pfizer Global Research and DeVelopment, Groton, Connecticut 06340
spiros_liras@groton.pfizer.com
Received August 15, 2001
ABSTRACT
The concise syntheses of the 4a-aryldecahydroisoquinolines 1 and 2 through a uniform strategy starting from N-methyl-3-allyl-4-piperidinone
are reported in this Letter. Key transformations include a ring closing metathesis reaction to prepare a trans-octahydroisoquinoline common
intermediate and a regiocontrolled hydroboration−oxidation sequence.
The 4a-aryldecahydroisoquinolines 1 and 2 (Scheme 1)-
represent structural fragments of morphine with significant
pharmacological activity. The compounds exhibit potent
affinity for the µ opioid receptor and possess antinociceptive
properties consistent with those of µ receptor agonists.3 The
pharmaceutical importance of these compounds is further
enhanced by their utility as advanced intermediates for the
synthesis of novel selective ligands for the δ opioid receptor.4
Synthetic efforts toward the 4a-aryldecahydroisoquinoline 1
have been previously reported.5 In contrast, the synthesis of
compound 2 has been the subject of fewer reports.6 As part
of a program that aimed at the design and synthesis of novel
δ opioid receptor ligands, we sought to develop concise
syntheses for substrates 1 and 2. In this Letter we report a
uniform approach to the targeted 4a-aryldecahydroisoquino-
lines through common intermediates highlighted by a ring
closing metathesis reaction and a regiochemically controlled
hydroboration-oxidation step.
Scheme 1
(1) CNS medicinal chemistry.
(2) Exploratory Medicinal Sciences, computational chemistry.
(3) For a review of the opioid ligands, see: Casy, A. F.; Parfitt, R. T.
Opioid Analgesics: Chemistry and Receptors; Plenum Press: New York,
1986.
(4) For recent examples, see: (a) Dondio, G.; Ronzoni, S.; Eggleston,
D. S.; Artico, M.; Petrillo, P.; Petrone, G.; Visentin, L.; Farina, C.;
Vecchietti, V.; Clarke, G. D. J. Med. Chem. 1997, 40, 3192. (b) Nagase,
H.; Kawai, K.; Hayakawa, J.; Wakita, H.; Mizusuna, A.; Matsuura, H.;
Tajima, C.; Takezawa, Y.; Endoh, T. Chem. Pharm. Bull. 1998, 46(11),
1695.
10.1021/ol016588b CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/05/2001

Scheme 2
Scheme 3a
For the syntheses of both substrates, we envisioned an
approach as described in Scheme 2. The diallyl piperidine
8, precursor to the ring closing metathesis reaction, would
be accessed following an allylation reaction of the metal-
loenamine generated from compound 5. A ring closing
metathesis of compound 8 would furnish a trans octahy-
droisoquinoline with a quaternary carbon center, which after
a regioselective hydroboration-oxidation sequence would
be converted to the target compounds 1 and 2. The
regiochemical preference of the hydroboration-oxidation
step could be predicted on the basis of molecular orbital
calculations.
The reduction of this plan to practice commenced with
the multigram preparation of 3-allyl-N-methyl-4-piperidinone
3 according to literature procedures.7 Related piperidinones
have been converted to the 3-alkyl-4-aryltetrahydropyridines
similar to 5 via aryl Grignard or aryllithium additions
followed by regioselective dehydration.8 As an alternative
to this strategy, we envisioned the preparation of compound
5 from a precursor vinyl triflate utilizing organopalladium
chemistry (Scheme 3). Thus, the piperidinone 3 was trans-
formed with exclusive regiocontrol to the vinyl triflate 4 in
92% yield with LiHMDS and N-phenyl triflamide9 in THF
at -78 °C. The vinyl triflate was converted to the desired
tetrahydropyridine 5 after Suzuki coupling with the com-
mercially available 3-methoxyphenylboronic acid. The yields
for the Suzuki coupling ranged from 48% to 94%. Optimum
reaction conditions for this step were discovered when the
vinyl triflate and boronic acid were treated with KBr, K3-
PO4, and Pd(PPh3)4 as catalyst in dioxane solvent at 85 °C
to afford compound 5 in 94% yield.10 With tetrahydropyri-
dine 5 available, our attention was turned to the formation
of diallylpiperidine 7. The preparation of diallylpiperidine 7
was achieved via a metalloenamine generation-alkylation
sequence. This sequence was first reported in the context of
a (a) LiHMDS, N-phenyltrifluoromethanesulfonimide, THF -78
°C to rt, 92%; (b) 3-methoxyphenylboronic acid, KBr, K3PO4,
Pd(PPh3)4, 1,4-dioxane, 85 °C, 94%; (c) sec-Buli, allyl bromide,
THF, -45 °C to -78 °C to rt; (d) NaBH4, MeOH, rt, 88% for
steps c and d; (e) ACE-Cl, 1,2-dichloroethane, reflux, then methanol,
reflux; (f) di-tert-butyl dicarbonate, Et3N, dichloromethane, rt, 80%
for steps e and f.
the synthesis of related morphinoid alkaloids.11 In the event,
treatment of compound 5 with sec-BuLi in THF at -45 °C
followed by addition of allyl bromide produced enamine 6
in quantitative yield. The crude enamine was reduced with
NaBH4 in methanol to afford piperidine 7 in 88% yield for
the two steps. The N-methylpiperidine was subsequently con-
verted to the N-Boc equivalent to ultimately produce a com-
pound with an easily removable nitrogen-protecting group,
suitable for analogue formation. Thus, after treatment of 7
with 1-chloroethyl chloroformate in dichloroethane at reflux,
subsequent carbamate methanolysis and treatment of the
crude hydrochloride salt with di-tert-butyl dicarbonate and
triethylamine compound 8 was obtained in 80% overall yield.
With the synthesis of diallylpiperidines 7 and 8 completed,
our attention was turned to the ring closing metathesis trans-
formation (Scheme 4). The diallylpiperidine 8 was converted
to the cyclic olefin 11 after treatment with 0.1 equiv of the
Grubbs catalyst 9 in dichloroethane at 60 °C in 93% yield.
Similarly, the hydrochloride salt of compound 7 was
converted to the corresponding olefin 10 in 88% yield.12
The regioselective functionalization of the olefin in
compound 11 was predicted on the basis of molecular
orbital interactions. Restricted Hartree-Fock calculations
were carried out for the transition states corresponding to
(5) (a) Weller, D.; Gless, R. D.; Rapoport, H. J. Org. Chem. 1977, 42,
1485. (b) Cantrell, B. E.; Paschal, J. W.; Zimmerman, D. M. J. Org. Chem.
1989, 54, 1442. (c) Judd, D. B.; Brown, D. S.; Lloyd, J. E.; McElroy, A.
B.; Scopes, D. I. C.; Birch, P. J.; Hayes, A. G.; Sheehan, M. J. J. Med.
Chem. 1992, 35, 48.
(6) See ref 5c.
(7) Bell, K. H.; Portoghese, P. S. J. Med. Chem. 1973, 16, 203.
(8) (a) Barnett, C. J.; Copley-Merriman, C. R.; Maki, J. J. Org. Chem.
1989, 54, 4795. (b) Werner, J. A.; Cerbone, L. R.; Frank, S. A.; Ward, J.
A.; Labib, P.; Tharp-Taylor, R. W.; Ryan, C. W. J. Org. Chem. 1996, 61,
587.
(9) McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979.
(10) For a review, see: Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95,
2457.
(11) Evans, D. A.; Mitch, C. H.; Thomas, R. C.; Zimmerman, D. M.;
Robey, R. L. J. Am. Chem. Soc. 1980, 102, 5955.
3484
Org. Lett., Vol. 3, No. 22, 2001

Scheme 4a
Figure 1.
both steric and electronic factors in the regioselectivity.16
Experimental results supported the computational chemistry
predictions. Thus, treatment of olefin 11 with a sterically
hindered borane such as 9-BBN in refluxing THF, followed
by oxidation of the organoborane species, yielded in quan-
titative yield a 3:1 ratio of the separable, isomeric alcohols
12 and 13. Conversely, treatment of 11 with the smaller
borane-dimethyl sulfide reagent complex yielded a 3:1 ratio
of alcohols 13 and 12 in a not optimized 52% yield. The
final step for the preparation of isoquinolines 1 and 2 was
the oxidation of the secondary hydroxyl groups. Typically,
Swern oxidation reactions had been employed for this
transformation in good yields. In this instance, oxidation of
alcohols 12 and 13 with TPAP and N-morpholine oxide
afforded ketones 1 and 2 in 88% and 84% yields, respec-
tively.
a (a) Grubbs catalyst 9, 1,2-dichloroethane, 60 °C, 93% for
compound 11, 88% for compound 10; (b) 9-BBN, THF, reflux,
30% aqueous H2O2, EtOH, 6 N NaOH, quantitative yield for 12
and 13 (3:1 ratio); (c) TPAP, NMO, dichloromethane, rt, 88% for
1 and 84% for 2; (d) HCl, EtOAc, rt, 85%.
the hydroboration of 11 with both 9-BBN and borane. The
geometries for this series of molecules were fully optimized
by means of analytical energy gradients13 with the 6-31G-
(d)-basis set14 in the gas phase. The ab initio molecular orbital
calculations were carried out with the Gaussian 94 series of
programs on a Silicon Graphics computer.15 Comparison of
the transition state energies for the reaction of 11 with 9-BBN
shows a preference for product 12 over 13 of 0.616 kcal/
mol, corresponding to a ratio of 2.83:1. The reaction of 11
with borane is predicted to favor the regioisomer, 13, by
0.767 kcal/mol (predicted ratio 1:3.65). Our findings are
consistent with prior ab initio calculations that implicate
The stereochemistry of the major product 12 was con-
firmed from a crystal structure obtained from its hydrochlo-
ride salt 14 (Figure 1). Compound 14 was produced after
removal of the nitrogen-protecting group with HCl in ethyl
acetate at room temperature in 85% yield.
(12) For recent reviews regarding applications of the ring closing
metathesis reaction, see: (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc.
Chem. Res. 1995, 28, 446. (b) Pandit, U. K.; Overkleeft, H. S.; Borer, B.
C.; Bieraugel, H. Eur. J. Org. Chem. 1999, 5, 959. (c) Wright, D. L. Curr.
Org. Chem. 1999, 3, 211. (d) Phillips, A. J.; Abell, A. D. Aldrichimica
Acta 1999, 32, 75. (e) Maier, M. E. Angew. Chem., Int. Ed. 2000, 39,
2073.
In conclusion, the efficient syntheses of the 4a-aryldecahy-
droisoquinolines 1 and 2 through a uniform strategy were
reported in this Letter. The desired compounds exhibit
significant pharmacological activity at opioid receptors and
provide useful intermediates for the synthesis of novel and
selective δ opioid receptor ligands. Key synthetic steps in
this approach include a highly efficient ring closing metath-
esis reaction to form a trans octahydroisoquinoline substrate
and a regioselective hydroboration-oxidation reaction se-
quence.
(13) Schlegel, H. B. J. Comput. Chem. 1982, 3, 214.
(14) Francl, M. M.; Pietro, W. J.; Hehre, W. J.; Binkley, J. S.; Gordon,
M. S.; DeFrees, D. J.; Pople, J. J. Chem. Phys. 1982, 77, 3654.
(15) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Gill, P. M. W.;
Johnson, B. G.; Robb, M. A.; Cheeseman, J. R.; Keith, T.; Petersson, G.
A.; Montgomery, J. A.; Raghavachari, K.; Al-Laham, M. A.; Zakrzewski,
V. G.; Ortiz, J. V.; Foresman, J. B.; Peng, C. Y.; Ayala, P. Y.; Chen, W.;
Wong, M. W.; Andres, J. L.; Replogle, E. S.; Gomperts, R.; Martin, L.;
Fox, D. J.; Binkley, J. S.; DeFrees, D. J.; Baker, J.; Stewart, J. P.; Head-
Gordon, M.; Gonzalez, C.; Pople, J. A. Gaussian 94 ReVision B.3; Gaussian,
Inc.: Pittsburgh, PA, 1995.
(16) Wang, X.; Li, Y.; Wu, Y. D.; Paddon-Row, M. N.; Rondan, N. G.;
Houk, K. N. J. Org. Chem. 1990, 55, 2601.
Org. Lett., Vol. 3, No. 22, 2001
3485

Acknowledgment. The authors thank Dr. Jon Bordner,
small molecule crystallography, Pfizer Global Research and
Development, Groton Laboratories, for the X-ray structure
of compound 14 and Ms. Sharon Mellow for preparation of
the document.
Supporting Information Available: Representative ex-
perimental procedures for the preparation of compounds 4,
5, 7, 8, 11, 12, 13, 1, and 2. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL016588B
3486
Org. Lett., Vol. 3, No. 22, 2001