Diastereoselective One-Pot Synthesis of 7- and 8-Substituted 5-Phenylmorphans

Article abstract of DOI:10.1021/ol2021862

Novel 7- and 8-alkyl and aryl substituted 5-phenylmorphans were synthesized from substituted allyl halides and N-benzyl-4-aryl-1,2,3,6-tetrahydropyridine by a highly efficient and diastereoselective reaction series, "one-pot" alkylation and ene-imine cycl

Full text of DOI:10.1021/ol2021862

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5322–5325
Diastereoselective One-Pot Synthesis of
7- and 8-Substituted 5-Phenylmorphans
Hwan Jung Lim,†,‡ Jeffrey R. Deschamps,§ Arthur E. Jacobson,† and Kenner C. Rice*,†
Drug Design and Synthesis Section, CBRB, 5625 Fishers Lane, Room 4N03,
National Institute on Drug Abuse and the National Institute on Alcohol Abuse and
Alcoholism, National Institutes of Health, DHHS, Rockville, Maryland 20852,
United States, and Center for Biomolecular Science and Engineering,
Naval Research Laboratory, Washington, D.C. 20375, United States
kr21f@nih.gov
Received August 11, 2011
ABSTRACT
Novel 7- and 8-alkyl and aryl substituted 5-phenylmorphans were synthesized from substituted allyl halides and N-benzyl-4-aryl-1,2,3,6-
tetrahydropyridine by a highly efficient and diastereoselective reaction series, “one-pot” alkylation and ene-imine cyclization followed by sodium
borohydride reduction. Mild cyclization conditions gave the desired substituted 5-phenylmorphans in good yield as a single diastereomer.
The molecular structure of the 5-phenylmorphans (1,
Figure 1) was conceptualized1 as a structurally simplified
fragment of morphine or heroin (Figure 1), and some
N-substituted 5-phenylmorphans were found to have mor-
phine-like activity.2 Recently Hiebel et al.3 synthesized a
C9βꢀOH N-phenethyl-5-phenylmorphan (the 1R,5R,9S-
enantiomer of 2, Figure 1) that had extremely high affinity
for the μ-opioid receptor and was far more potent than
morphine in vivo; its epimer (1R,5R,9R) had 230-fold less
affinity. This is a remarkable effect of the stereochemistry
at a single OH group. In order to determine what
pharmacological profile would be conferred by substi-
tuents at the C-7 or C-8 positions we needed to find a
synthetic path to these less accessible compounds. Only
7-amino4 and 6,7- and 7,8-fused indole derivatives5
synthesized from 7-keto-5-phenylmorphan, and C3 and
C7-alkyl or alkenyl 5-phenylmorphans have been re-
ported thus far, the latter by Zimmerman6 who used a
phosphoric acid/formic acid mixture and did not assign
the stereochemistry of his products.
Although synthetic strategies have been developed for
5-phenylmorphans,1,2,7,8 we hoped to find a concise synth-
esis of the desired target molecules. We thought that a
7-keto derivative might be used as an intermediate,
but found that the 7-keto group had unexpectedly low
reactivity toward CꢀC bond forming reactions such as
Wittig olefination.9 Among available strategies, a 3-step
Probes for Narcotic Receptor Mediated Phenomena. 45.
† Drug Design and Synthesis Section, CBRB, NIDA-NIAA
§ Naval Research Laboratory
(5) Bertha, C. M.; Flippen-Anderson, J. L.; Rothman, R. B.; Porreca,
F.; Davis, P.; Xu, H.; Becketts, K.; Cha, X.-Y.; Rice, K. C. J. Med.
Chem. 1995, 38, 1523.
‡ Present address: LG Chem Research Park, 104-1 Munji-dong, Yuseong-gu,
Daejeon, 305-380 South Korea.
(6) Zimmerman, D. M. U.S. Patent 4,278,797; Eli Lilly and Com-
pany: U.S., 1981; p 1.
(7) Rogers, M. E.; May, E. L. J. Med. Chem. 1974, 17, 1328.
(8) Bonjoch, J.; Casamitjana, J.; Bosch, J. Tetrahedron 1988, 44,
1735.
(1) May, E. L.; Murphy, J. G. J. Org. Chem. 1954, 19, 618.
(2) May, E. L.; Murphy, J. G. J. Org. Chem. 1955, 20, 1197.
(3) Hiebel, A. C.; Lee, Y. S.; Bilsky, E. J.; Giuvelis, D.; Deschamps,
J. R.; Parrish, D. A.; Aceto, M. D.; May, E. L.; Harris, E. M.; Coop, A.;
Dersch, C. M.; Partilla, J. S.; Rothman, R. B.; Jacobson, A. E.; Rice,
K. C. J. Med. Chem. 2007, 50, 3765.
(9) Lim, H. J., unpublished results.
(10) Evans, D. A.; Mitch, C. H.; Thomas, R. C.; Zimmerman, D. M.;
Robbey, R. L. J. Am. Chem. Soc. 1980, 102, 5955.
(11) Burke, T. R., Jr.; Jacobson, A. E.; Rice, K. C.; Weissman, B. A.;
Huang, H. C.; Silverton, J. V. J. Med. Chem. 1986, 29, 748.
(4) Thomas, J. B.; Atkinson, R. N.; Namdev, N.; Rothman, R. B.;
Gigstad, K. M.; Fix, S. E.; Mascarella, S. W.; Burgess, J. P.; Vinson,
N. A.; Xu, H.; Dersch, C. M.; Cantrell, B. E.; Zimmerman, D. M.;
Carroll, F. I. J. Med. Chem. 2002, 45, 3524.
10.1021/ol2021862 This article not subject to U.S. Copyright. Published 2011 by the American Chemical Society
Published on Web 09/12/2011

Table 1. Alternative Cyclization Conditions
cyclization
conditions
temp (°C),
time (in days) yield (%)a
Figure 1. 5-Phenylmorphan fragment (-1 of morphine or her-
oin, and potent analogue (-2.
entries
1
2
3
4
5
HCO2H/H3PO4 (1:1)
rt, 7
48
56
41
38
44
p-TsOH (2 equiv), toluene
p-TsOH (0.2 equiv), CH2Cl2
TfOH (0.2 equiv), CH2Cl2
30% TFA in CH2Cl2
reflux, 2b
rt, 3
synthesis using allyl bromide reported by Evans et al.
brought our attention to the possibility of applying that
methodology in a novel way to prepare 6-, 7-, and 8-sub-
stituted 5-phenylmorphans.10,11 However, after the origi-
nal report,10 the reaction scope and mechanism were not
studied. We decided to investigate the methodology of
Evans et al., to see whether it could be applied to the
synthesis of the C-7 or C-8 substituted 5-phenylmorphans.
In the original report10 the N-methyl tetrahydropiper-
idine 3i was alkylated using allyl bromide 5a to generate an
all-carbon quaternary center (6a, Scheme 1). A mixture of
rt, 3
rt, 3
a Isolated yields of 8b (3 steps overall). b Prolonged reaction time did
not increase the yield.
toluene cyclized the ene-enamine 6b giving a single diaste-
reomer in higher yields within a shorter time than the case
with the mixed acid conditions (entry 2, Table 1). In
contrast to the acidic conditions of Evans et al., the crude
cyclized enamine 7b under our modified conditions could
be directly reduced with sodium borohydride to give the
desired amine 8b.8 Thus, the use of p-TsOH eliminated
the necessity of removing the acid before the reduction.
Not only did the use of a stoichiometric amount of the
reagent at elevated temperature work for the reaction, but
a catalytic amount of p-TsOH at room temperature also
gave the desired product with only a small reduction in
yield (entry 3, Table 1). Other, stronger, acids also gave the
desired product at room temperature, albeit with lower
yields (entries 4ꢀ5, Table 1).
Scheme 1. Substituted 5-Phenylmorphans via Series of Alkyla-
tion, Cyclization, and (NaBH4) Reduction Reactions
Using our optimized conditions, other substituted allyl
bromides and chlorides were tested (5cꢀh, Scheme 1). The
unsubstituted phenyl moiety 5b and the bromo- and
chloro-compounds 5c,d all underwent the desired reaction
in good yields (entries 1ꢀ3, Table 2). The simple methyl
substituted 5e also worked well, providing the desired
7-methyl 5-phenylmorphan 8e (entry 4, Table 2).
All of these R2-(β)-substituted allyl bromides gave only
single diastereomers 8bꢀe. Reaction with the R1-(γ)-methyl
substituted (E)-1-bromobut-2-ene, 5f, provided 8-methyl
substituted 5-phenylmorphan 8f as a single diastereomer
in good yield (entry 5, Table 2). Moreover, cyclohexyl-
fused 5-phenylmorphan 8g was synthesized as a single
compound (entry 6, Table 2).
However, the R3-(R)-methyl substituted compound (5h)
gave 8h as an inseparable diasteromeric mixture of the
C6-methyl isomers (entry 7, Table 2) with 20% of the
diastereomerically pure C8-methyl isomer8f arising from γ-
alkylation. When the R1-(γ)-disubstituted compound (1-
bromo-3-methylbut-2-ene) 5i was used, a 5-membered
cyclization product 8i formed. Under the original condi-
tions of Evans et al., a mixture of cyclization adducts were
obtained from 5i. Interestingly, the reaction of 2,5-dimethoxy
substituted compound 3iii with 3-bromo-2-methylprop-1-ene
neat acids (1:1 HCO2H and H3PO4) was used for the
cyclization of the crude alkylated product 6a (where
R1 = R2 = R3 = H). The cyclized enamine 7a (R1 =
R2 = R3 = H) of Evans et al. was then isolated from a
strong acid and reduced. Although the cyclization worked
well, the reaction was slow (66 h at rt), there were problems
isolating the cyclized product from the highly acidic media,
and no substituted allyl bromides were tested.
For our functionalized allylic substrates we explored
more practical and efficient cyclization conditions and
examined milder acids in organic solvents. To test the
scope of the reaction, β-phenyl-substituted allyl bromide
5b was used. The original conditions were initially applied,
and the desired product 8b was obtained in moderate yield
(entry 1, Table 1). We then screened organic acids for the
cyclization. p-Toluenesulfonic acid (p-TsOH) in refluxing
Org. Lett., Vol. 13, No. 19, 2011
5323

into their phenolic relatives 9b,f,g using known
procedures.13 Crystalline HBr salts of 9b,f,g were obtained
for X-ray crystallographic structure analyses to determine
the relative stereochemistry of substituents at C-7 and C-8
with regard to the piperidine ring (Figure 2). For clarity, if
a substituent is on the same side of the cyclohexane ring as
the piperidine ring, it is called cis; otherwise it is trans.
X-ray analyses showed that substituents at C-7 were trans-
oriented and those at C-8 were cis. Substituents such as
a methyl group did not show selectivity at C-6. These
selectivities provided information that enabled us to postu-
late a possible mechanism for this highly selective cyclization.
Table 2. Synthesis of 5-Phenylmorphans 8bꢀj Using Substi-
tuted Allyl Halides 5bꢀi
Figure 2. Ortep plots of 9b,f,g (one enantiomer was drawn for 9f).
a Diastereomeric mixture. b 20% of 8f was also obtained. c When the
original reaction conditions (HCO2H/H3PO4, 1:1) were used, the desired
product was not obtained. d Not isolated - NMR and MS indicated
product. e Yield of the cyclized enamine 7i. f Yield of 8j after reduction of 7j.
In the report by Evans et al.,10 it was briefly noted that
this cyclization might occur by ene-imine cyclization fol-
lowed by a hydride shift. Although this appeared to
reasonablyexplainthe formationof theobtainedproducts,
there was neither evidence for this hypothesis nor explana-
tion for why this reaction was highly diastereoselective for
β-and γ-substituted allylic groups with ene-enamine sub-
strates, which are not R-substituted.
(5e) gave enamine 7j (entry 9, Table 2), structurally similar
to an intermediate in the synthesis of a para-a oxide-
bridged phenylmorphan.12 The enamine was further re-
duced to obtain the amine 8j (entry 9, Table 2).
We hypothesized that the exceptional diastereoselectiv-
ities were due to the following: (1) Alkylation on the Re-
faceof the olefin that occurred relatively fast because of the
more favored Zimmerman-Traxler chairlike TS.10 It
would have to be the most rapid alkylation to obtain, as
was found, a single stereoisomer at the C-8-position, as in
Allyl bromides such as cinnamyl bromide 5k, bromocy-
clohex-2-ene 5l, and O-TBDPS protected substrate 5m did
not undergo the cyclization. Moreover, N-carbethoxy
protected substrate 3iv, instead of N-Bn, did not undergo
the desired cyclization reaction. In order to examine the
relative stereochemistry of the substituents in the cyclized
products, representative products 8b,f,g were converted
(13) Cheng, K.; Kim, I. J.; Lee, M. J.; Adah, S. A.; Raymond, T. J.;
Bilsky, E. J.; Aceto, M. D.; May, E. L.; Harris, L. S.; Coop, A.; Dersch,
C. M.; Rothman, R. B.; Jacobson, A. E.; Rice, K. C. Org. Biomol. Chem.
2007, 5, 1177.
(12) Yamada, K.; Flippen-Anderson, J. L.; Jacobson, A. E.; Rice,
K. C. Synthesis-Stuttgart 2002, 2359.
5324
Org. Lett., Vol. 13, No. 19, 2011

8fꢀg. (2) The hydride shift after cyclization must only occur
intramolecularly to obtain the stereochemistry found at the
7-position, i.e., the trans products 8bꢀe,g. If the hydride
came from an intermolecular source, the opposite stereo-
chemistry would have been found; moreover, the intramo-
lecular hydride shift is the most likely way to generate an
imine after the cyclization. (3) If the chiral center at C-6 was
generated via a nonselective alkylation, it would give the
diastereomeric mixture 8h (Scheme 2).
that gave trans selectivity at C-7 and cis selectivity at C-8.
Further evidence to support our hypothesis can come from
the use of more diversely substituted allyl bromides, and
these will be tested in future work. Also, pharmacological
data for structureꢀactivity relationship (SAR) studies
will be carried out and reported in subsequent publica-
tions using compounds 8 and 9 with N-substituents
other than N-benzyl or N-methyl.
Acknowledgment. The work of the Drug Design and
Synthesis Section was supported by the NIH Intramural
Research Programs of the National Institute on Drug
Abuse (NIDA) and the National Institute of Alcohol Abuse
and Alcoholism (NIAAA). The X-ray crystallographic
work was supported by NIDA through an Interagency
Agreement #Y1-DA1101 with the Naval Research Labora-
tory. We thank Dr. K. Gawrisch and Dr. W. Teague
(NIAAA), for NMR data, N. Whittaker and Dr. H. Yeh
(Laboratory of Analytical Chemistry, NIDDK), for MS and
1H NMR data, and Dr. Jason A. Deck (Division of Food
Contact Notifications, Office of Food AdditiveSafety, Center
for Food Safety and Applied Nutrition, FDA) and Dr.
Malliga Iyer (NIDA) for discussions and suggestions.
Scheme 2. Possible Mechanism of the Highly Stereoselective
Cyclization
Supporting Information Available. Atomic coordinates
for 9b, 9f, and 9g have been deposited with the Cambridge
Crystallographic Data Centre (deposition numbers
837805, 837804, and 837806, respectively). Copies of the
data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax:
þ44(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk.
Detailed experimental procedures, spectroscopic data,
and X-ray crystallographic data are also provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, our improved series of reactions, alkylation,
cyclization, and then reduction, were successfully applied to
the synthesis of new 7- and 8-substituted 5-phenylmorphans
in good yields as single diastereomers. The stereochemistry
of the products was confirmed by X-ray crystallographic
analyses. A possible mechanism, based on the analyses, that
explains the obtained data suggests 6-membered Re-face
CꢀC bond formation and an intramolecular hydride shift
as key aspects of the highly diastereoselective cyclization
Org. Lett., Vol. 13, No. 19, 2011
5325