Migratory hydroamination: A facile enantioselective synthesis of benzomorphans

Article abstract of DOI:10.1021/ja0360539

We describe a highly efficient, general strategy for the enantioselective synthesis of benzomorphans (45-46% overall yield from commercially available material). The new synthesis demonstrates the effectiveness of an unprecedented diastereoselective cycloisomerization via migratory hydroamination and the power of palladium-catalyzed asymmetric allylic alkylation (AAA) of simple ketone enolates in the context of complex synthesis. The strategy outlined here for the enantioselective synthesis of three contiguous stereogenic centers and the novel cycloisomerization should have many applications in alkaloid synthesis. Copyright

Full text of DOI:10.1021/ja0360539

Published on Web 06/28/2003
Migratory Hydroamination: A Facile Enantioselective Synthesis of
Benzomorphans
Barry M. Trost* and Weiping Tang
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received May 9, 2003; E-mail: bmtrost@stanford.edu
Scheme 1. Retrosynthetic Analysis
Naturally occurring (-)-morphine is extremely important as an
analgesic but suffers from side effects such as addiction.1 Much
effort has been devoted to overcoming this problem by structural
modification.2 As a result, certain nonnatural benzomorphans and
morphinans have succeeded in reducing the addicting effect to a
considerable extent, such as the clinically used pentazocine 4 and
phenazocine 5.3 In addition to their use as analgesics, benzomor-
phans are also useful in the treatment of cocaine addiction (e.g.,
6).4 Not surprisingly, pharmacological activity in these series is
dramatically dependent on absolute configuration. For example, (-)-
pentazocine is 20 times more potent than its enantiomer.5 Despite
the importance of benzomorphans, previous enantioselective syn-
theses of benzomorphans (3-6, Figure 1) utilized either resolution6
or chiral auxiliaries7-9 all through Grewe-type cyclizations2,10 with
one exception.11
chirality inducing metal-ligand complex.19 Gratifyingly, performing
the allylic alkylation of tetralone 1020 and allyl acetate with a
catalyst derived from π-allylpalladium chloride dimer (0.5%) and
(R,R)-ligand 12 (1.0%) in the presence of cesium carbonate21 in
DME gave 11 in good yield and ee as shown in eq 1.
Figure 1. Opium alkaloids and benzomorphans.
We12 recently described a new asymmetric synthesis of opium
alkaloids (1 and 2) involving a novel base-promoted intramolecular
hydroamination13 which requires tungsten light irradiation. This
reaction forges the key piperidine ring of this family of alkaloids,
which previously were cyclized using stoichiometric mercury salts14
or via the chromium tricarbonyl complex15 from free amine. The
benzomorphans served as an ideal target to gain better understanding
of the key cyclization reaction and assess the possibility of
establishing the rather challenging benzylic quaternary carbon
center16 through palladium-catalyzed asymmetric allylic alkylation
(AAA) of a prochiral ketone.17 In formulating a route (Scheme 1),
we envisioned two olefinic intermediates 9 and 8, the former to
set the stereochemistry of the methyl group and the latter to effect
cyclization. Typically, the conversion of 9 to 8 involves multiple
steps requiring stoichiometric reduction and oxidation. Inspired by
a recent report of intermolecular hydroamination of allyl- and
homoallylbenzene,18 the fact that benzomorphan 7 itself is an isomer
of olefin 9 emboldened us to ask a conceptually intriguing question.
Is it possible to cycloisomerize 9 to 7 diastereoselectiVely in one
catalytic step by a migratory hydroamination? In this communica-
tion we explore the cycloisomerization via a catalytic migratory
hydroamination and the power of palladium-catalyzed AAA of a
prochiral ketone for simplifying problems in alkaloid synthesis.
Discrimination of enantiotopic faces of the nucleophile in the
palladium-catalyzed AAA is very challenging as the nucleophile
attacks on the face of the π-allyl system opposite to that of the
Wittig olefination gave almost quantitative yield of exocyclic
olefin 13 (Scheme 2). Although one-pot cleavage (OsO4, NaIO4)
of 13 was not successful, stepwise operations selectively cleaved
the less hindered terminal olefin in the presence of the 1,1-
disubstituted olefin. Reductive amination provided amine 15 in good
yield.
The stage was set for the key speculative step, the migratory
hydroamination. Treatment of amine 15 with a catalytic amount or
even a full equivalent of LDA gave only recovered starting material,
presumably due to the difficulty of the initial isomerization. Thus,
we examined the isomerization under acidic conditions and found
the exocyclic olefin was isomerized to the internal olefin 16 (not
all the way to conjugation!). Despite the need to isomerize 16 to 8
(R ) CH3) first and the difficulty of subsequent addition of a lithium
amide to an electron-rich styrene,12,22 subjecting amine 16 to 20
mol % LDA in THF led to cycloisomerization to form 17 as a
single diastereomer23 in less than 30 min at room temperature. This
result suggests that the failure of cyclization using base alone in
the case of morphine might be due to the more electronically rich
aromatic ring compared to benzomorphans. Increasing the basicity
9
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J. AM. CHEM. SOC. 2003, 125, 8744-8745
10.1021/ja0360539 CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Synthesis of (-)-Metazocinea
Acknowledgment. We thank the National Science Foundation
and the National Institute of Health, General Medical Sciences (GM-
13598), for their generous support of our programs. Mass spectra
were provided by the Mass Spectrometry Facility of the University
of California-San Francisco, supported by the NIH Division of
Research Resources. W.T. thanks Boehringer Ingelheim Pharma-
ceuticals, Inc. for a predoctoral fellowship
Supporting Information Available: Experimental details and
analytical data for all new compounds and data for synthetic benzo-
morphans (PDF). This material is available free for charge via the
Internet at http://pubs.acs.org.
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a Reaction conditions: a) CH2dPPh3, THF; b) 2% OsO4, NMO; c)
NaIO4; d) MeNH2, MgSO4, NaBH4; e) 1.5 equiv TsOH, toluene, reflux; f)
20 mol % BuLi, 20 mol % iPr2NH, THF, rt, 30 min; g) 20 mol % BuLi, 20
mol % iPr2NH, 40 mol % TMEDA, THF, rt, 8 h; h) BBr3, CH2Cl2.
of the medium by addition of 40 mol % TMEDA18 allowed reaction
of 15 and provided 17 more slowly (8 h) but still nearly
quantitatively. We hypothesized that the high diastereoselective
control of C-11 came from intramolecular protonation of the allylic
anion 18 from the alpha face (i.e., cis to the aminoethyl substituent
as depicted in 18′) of an almost flat six-membered ring. This is in
contrast to previous approaches employing Grewe cyclizations
which often gave both epimers.7,24 Finally, demethylation gave (-)-
metazocine (3), whose spectral data is identical to that previously
reported.7,9
To test the scope and selectivity of the migratory hydroamination,
amine 19 was prepared from 14 in a similar way (85% yield) and
treated with the catalyst system as for 15 (eq 2). Amine 20 was
obtained in quantitative yield as a single diastereomer. It is
noteworthy that the olefin of the prenyl substituent was unchanged.
Demethylation with NaSEt provided (-)-pentazocine (4)25 cleanly.
Thus, simply changing the amine in the reductive amination allows
easy variation of the N substituent.
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In conclusion, we have developed a highly efficient general
strategy for the enantioselective synthesis of benzomorphans (46%
and 45% overall yield from commercially available material for
(-)-metazocine and (-)-pentazocine, respectively). It demonstrates
for the first time the efficacy of palladium-catalyzed AAA of simple
ketones in the context of complex synthesis. The unprecedented
diastereoselective migratory hydroamination addresses the control
of C-11 stereogenic center, and should have many applications in
alkaloid synthesis. The strategy outlined here opens the way to
access either enantiomer26 of a variety of C-6, C-11, and N-3
substituted benzomorphan analogues.
(19) Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996, 96, 395.
(20) Prepared in one step (83% yield) from commercially available 7-methoxy-
2-tetralone. Kuehne, M. E. J. Am. Chem. Soc. 1961, 83, 1492.
(21) Sodium carbonate or potassium carbonate gave lower yield and ee.
(22) Tokuda, M.; Fujita, H.; Miyamoto, T.; Suginome, H. Tetrahedron 1993,
49, 2413.
(23) The relative stereochemistry was determined by NOE (see Supporting
Information).
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