Enantioconvergent synthesis of (+)-aphanorphine via asymmetric pd-catalyzed alkene carboamination

Article abstract of DOI:10.1021/ol2009895

A concise asymmetric synthesis of (+)-aphanorphine has been achieved via a new enantioconvergent strategy. A racemic γ-aminoalkene derivative is transformed into a 1:1 mixture of enantiomerically enriched diastereomers using an asymmetric Pd-catalyzed car

Full text of DOI:10.1021/ol2009895

ORGANIC
LETTERS
2011
Vol. 13, No. 11
2932–2935
Enantioconvergent Synthesis of
(þ)-Aphanorphine via Asymmetric
Pd-Catalyzed Alkene Carboamination
Duy N. Mai, Brandon R. Rosen, and John P. Wolfe*
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann
Arbor, Michigan 48109-1055, United States
jpwolfe@umich.edu
Received April 14, 2011
ABSTRACT
A concise asymmetric synthesis of (þ)-aphanorphine has been achieved via a new enantioconvergent strategy. A racemic γ-aminoalkene
derivative is transformed into a 1:1 mixture of enantiomerically enriched diastereomers using an asymmetric Pd-catalyzed carboamination. This
mixture is then converted to an enantiomerically enriched protected aphanorphine derivative by a FriedelꢀCrafts reaction, which generates a
quaternary all-carbon stereocenter. The natural product is obtained in three additional steps.
The tricyclic alkaloid aphanorphine was isolated from
the blue-green alga Aphanizomenon flos-aquae in 1988 by
Shimizu and Clardy.1 Although to date no biological activity
of aphanorphine has been reported, aphanorphine shares
common structural features with other bioactive (analgesic)
benzomorphan alkaloids, such as morphine, pentazocine,
and eptazocine (Figure 1). As such, aphanorphine has been
the target of numerous synthetic efforts over the past 23
years.2ꢀ4
(1) Gulavita, N.; Hori, A.; Shimizu, Y.; Laszlo, P.; Clardy, J.
Tetrahedron Lett. 1988, 29, 4381–4384.
(2) For recent syntheses of (ꢀ)-aphanorphine, see: (a) Medjahdi, M.;
ꢀ
ꢀ
Gonzalez-Gomez, J. C.; Foubelo, F.; Yus, M. Eur. Org. Chem. 2011,
2230–2234. (b) Donets, P. A.; Goeman, J. L.; Van der Eycken, J.;
Robeyns, K.; Van Meervelt, L.; Van der Eycken, E. V. Eur. J. Org.
Chem. 2009, 793–796. (c) Yang, X.; Cheng, B.; Li, Z.; Zhai, H. Synlett
2008, 2821–2822. (d) Yang, X.; Zhai, H.; Li, Z. Org. Lett. 2008, 10, 2457–
2460. (e) Grainger, R. S.; Welsh, E. J. Angew. Chem., Int. Ed. 2007, 46,
5377–5380. (f) Li, M.; Zhou, P.; Roth, H. F. Synthesis 2007, 55–60. (g)
Bower, J. F.; Szeto, P.; Gallagher, T. Org. Biomol. Chem. 2007, 5,
143–150.
Figure 1. Benzomorphan alkaloids.
(3) For syntheses of (ꢀ)-aphanorphine prior to 2007, see: (a) Takano,
S.; Inomata, K.; Sato, T.; Takahashi, M.; Ogasawara, K. J. Chem. Soc.,
Chem. Commun. 1990, 290–292. (b) Bower, J. F.; Szeto, P.; Gallagher, T.
Chem. Commun. 2005, 5793–5795 and references cited therein..
(4) For syntheses of (þ)-aphanorphine, see ref 2a and: (a) Ma, Z.;
Zhai, H. Synlett 2007, 161–163. (b) Ma, Z.; Hu, H.; Xiong, W.; Zhai, H.
Tetrahedron 2007, 63, 7523–7531. (c) Katoh, M.; Inoue, H.; Honda, T.
Heterocycles 2007, 72, 497–516. (d) Katoh, M.; Inoue, H.; Suzuki, A.;
Honda, T. Synlett 2005, 2820–2822. (e) Meyers, A. I.; Schmidt, W.;
Santiago, B. Heterocycles 1995, 40, 525–529. (f) Takano, S.; Inomata,
K.; Sato, T.; Ogasawara, K. J. Chem. Soc., Chem. Commun. 1989,
1591–1592.
Most approaches to the synthesis of enantiopure apha-
norphine either employ chiral-pool starting materials or
(5) (a) Fadel, A.; Arzel, P. Tetrahedron: Asymmetry 1995, 6, 893–900.
(b) Kita, Y.; Futamura, J.; Ohba, Y.; Sawama, Y.; Ganesh, J. K.;
Fujioka, H. J. Org. Chem. 2003, 68, 5917–5924. (c) Taylor, S. K.;
Ivanovic, M.; Simons, L. J.; Davis, M. M. Tetrahedron: Asymmetry
2003, 14, 743–747.
r
10.1021/ol2009895
Published on Web 05/10/2011
2011 American Chemical Society

use stoichiometric amounts of a chiral reagent or auxiliary
to set the absolute stereochemistry of the natural product.
In contrast, asymmetric catalysis has only occasionally
been used to control the absolute configuration in apha-
norphine syntheses.2b,2g,3b,5 In these instances, the stereo-
center was generated via reduction or desymmetrization of
a prochiral starting material.
to that used in three prior aphanorphine syntheses.4b,10 As
shown in Scheme 1, the catalyst-controlled asymmetric
Pd-catalyzed carboamination reaction of racemic sub-
strate 5 could be used to set the C2 stereocenter of
pyrrolidines 6a,b, thereby providing a mixture of enantio-
merically enriched diastereomers. This mixture of diaster-
eomers would then be converted to one product (8) in a
FriedelꢀCrafts alkylation reaction, which would proceed
via intermediate carbocation 7, and would generate the all-
carbon quaternary stereocenter in an enantioconvergent
CꢀC bond-forming step.11 A two-step sequence of reduc-
tion and demethylation could then be employed to trans-
form 8 to aphanorphine.
Scheme 1. Asymmetric Carboamination/FriedelꢀCrafts Alky-
lation Strategy
The enantioconvergent strategy outlined above has
several attractive features: (a) the substrate required for
the asymmetric carboamination reaction could be pre-
pared in a concise, straightforward manner; (b) analogues
of the natural product could potentially be generated
through use of different aryl halides in the carboamination
step; (c) either enantiomer of the natural product should be
accessible, as the absolute stereochemistry in the carboa-
mination reaction would be controlled by the ligand; and
(d) this general strategy could potentially be adapted to
provide access to a broad array of fused- or bridged
bicyclic alkaloids that contain a benzylic all-carbon qua-
ternary stereocenter.
To test the feasibility of this strategy, we elected to
pursue a synthesis of the non-natural (þ)-enantiomer of
aphanorphine; only a few prior studies have targeted (þ)-
aphanorphine,4 and the ligand needed to generate this
compound, (R)-Siphos-PE,12 is commercially available.13
In order to obtain 8 in high ee it would be necessary to
generate a 1:1 mixture of diastereomers in the asymmetric
carboamination of (()-5, as any degree of substrate con-
trol in the reaction of (()-5 would lead to erosion of
enantiomeric purity in the final product. However, prior
studies have illustrated that diastereoselectivities are gen-
erally low in Pd-catalyzed carboamination reactions of
substrates bearing a single homoallylic substituent,14 and
the similarity in size of the homoallylic groups in (()-5
(methyl vs OTMS) suggested that there would be little
We sought to explore an alternative, catalytic enantio-
convergent route to the construction of aphanorphine,
which could also potentially provide access to other inter-
esting bicyclic alkaloids.6 Enantioconvergent transforma-
tions or strategies have significant potential synthetic
utility, as they effect the conversion of both enantiomers
of a racemic starting material to a single enantiomerically
enriched product.7,8 We envisioned that a simple racemic
starting material could be converted to enantiomerically
enriched aphanorphine through use of two key transfor-
mations: an enantioselective Pd-catalyzed carboamination
reaction that was recently developed in our laboratory9
and an intramolecular FriedelꢀCrafts ring closure similar
(6) One prior synthesis of (ꢀ)-aphanorphine employed an enantio-
convergent strategy in which a racemic intermediate was transformed to
an enantiopure intermediate via lipase-catalyzed resolution followed by
a subsequent Wharton rearrangement. This synthesis afforded the
natural product in 23 steps (longest linear sequence) from commercially
available materials. See: Shimizu, M.; Kamikubo, T.; Ogasawara, K.
Heterocycles 1997, 46, 21–26.
(11) For examples of enantioconvergent processes that generate
CꢀC bonds, see: (a) Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz,
B. M. Angew. Chem., Int. Ed. 2005, 44, 6924–6927. (b) Trost, B. M.;
Crawley, M. L. Chem. Rev. 2003, 103, 2921–2943.
(12) (R)-Siphos-PE = (11aR)-(þ)-10,11,12,13-tetrahydrodiindeno-
[7,1-de:10,70-fg][1,3,2]dioxaphosphocin-5-bis[(R)-1-phenylethyl]amine:
(7) For recent reviews on enantioconvergent synthesis, see: (a) Turner,
N. J. In Asymmetric Organic Synthesis with Enzymes; Gotor, V., Alfonso, I.,
Garcia-Urdiales, E., Eds.; Wiley-VCH: Weinheim, 2008; pp 115ꢀ132. (b)
Mohr, J. T.; Ebner, D. C.; Stoltz, B. M. Org. Biomol. Chem. 2007, 5,
€
3571–3576. (c) Huerta, F. F.; Minidis, A. B. E.; Backvall, J.-E. Chem. Soc.
Rev. 2001, 30, 321–331. (d) Strauss, U. T.; Felfer, U.; Faber, K. Tetra-
hedron: Asymmetry 1999, 10, 107–117.
(8) For selected recent examples of enantioconvergent strategies in
natural product syntheses, see: (a) Bender, C. F.; Yoshimoto, F. K.;
Paradise, C. L.; De Brabander, J. K. J. Am. Chem. Soc. 2009, 131,
11350–11352. (b) Petrova, K. V.; Mohr, J. T.; Stoltz, B. M. Org. Lett.
2009, 11, 293–295. (c) Ueberbacher, B. J.; Osprian, I.; Mayer, S. F.;
Faber, K. Eur. J. Org. Chem. 2005, 1266–1270. (d) Fehr, C.; Galindo, J.;
Etter, O. Eur. J. Org. Chem. 2004, 1953–1957. (e) Yoshida, N.;
Ogasawara, K. Org. Lett. 2000, 2, 1461–1463. (f) Ducray, P.; Rousseau,
B.; Mioskowski, C. J. Org. Chem. 1999, 64, 3800–3801.
(13) The compound sold as (S)-Siphos-PE is not the enantiomer of
(R)-Siphos-PE, but is instead a diastereomer with the opposite config-
uration of the spirocyclic bis-phenoxide moiety but the same configura-
tion of the bis(phenethyl)amide group.
(14) (a) Ney, J. E.; Wolfe, J. P. Angew. Chem., Int. Ed. 2004, 43,
3605–3608. (b) Bertrand, M. B.; Wolfe, J. P. Tetrahedron 2005, 61,
6447–6459. (c) Jepsen, T. H.; Larsen, M.; Nielsen, M. B. Tetrahedron
2010, 66, 6133–6137.
(9) Mai, D. N.; Wolfe, J. P. J. Am. Chem. Soc. 2010, 132, 12157–12159.
(10) (a) Zhai, H.; Luo, S.; Ye, C.; Ma, Y. J. Org. Chem. 2003, 68,
8268–8271. (b) Hu, H.; Zhai, H. Synlett 2003, 2129–2130.
Org. Lett., Vol. 13, No. 11, 2011
2933

substrate bias toward either diastereomer. Thus, we
anticipated that this approach should afford 8 with a
good degree of asymmetric induction. The precursor
(()-5 for the key asymmetric alkene carboamination
reaction was prepared in three steps from commer-
cially available N-Boc-1-amino-2-propanol 9 (Scheme
2). Oxidation of 9 to ketone 10 followed by addition of
allylmagnesium bromide afforded racemic tertiary al-
cohol 11 in good yield. Protection of the tertiary
alcohol with TMS-imidazole proceeded smoothly to
afford aminoalkene (()-5.
With a concise route to enantiomerically enriched diastereo-
mers 6a,b in hand, we sought to complete the synthesis of
(þ)-aphanorphine. We envisioned that a FriedelꢀCrafts
alkylation of 6a,b should provide 8, which could be
transformed to the target in two steps (reduction and
demethylation). Unfortunately, the FriedelꢀCrafts alky-
lation proved to be problematic (eq 1). A variety of
conditions were surveyed for reactions of 6a,b and desily-
lated analogues 14a,b, but all provided low yields of the
desired product 8. Competing cleavage of the N-Boc group
was frequently observed, along with formation of numer-
ous side products.
Scheme 2. Synthesis of Carboamination Substrate
Although the conversion of 6a,b to 8 was not successful,
the N-tosylated derivative 13 has previously served as an
intermediate in Zhai’s syntheses of aphanorphine.2b,c,4b,10
Thus, after some modification of literature procedures,16 13
was transformed to 15 in 64% yield via cleavage of the N-
tosyl group with Red-Al followed by N-methylation under
EschweilerꢀClarke conditions (Scheme 4). Although BBr3-
mediated demethylation of 15 has been a key feature of prior
syntheses,2ꢀ4 this step proved to be quite challenging.18
The coupling reaction between 5 and 4-bromoanisole was
examined using our previously reported conditions for en-
antioselective alkene carboamination reactions (Scheme 3).
After slight optimization of reaction conditions,15,16 the
transformation afforded a 1:1 mixture of diastereomers 6a
and 6b in 75% yield. We initially sought to separate the
diastereomers and assay each individually to determine
enantiomeric purity. Unfortunately, separation of the iso-
mers was not possible. In addition, routes to prepare racemic
samples of each diastereomer appeared to be cumbersome.
As such, we elected to transform the mixture of isomers 6a,b
to known compound 13,2b,c,4b,10 which we could then assay
for enantiomeric purity. To this end, treatment of 6a,b with
TFA led to cleavage of both the N-Boc and O-TMS groups,
and tosylation of the resulting pyrrolidine derivative pro-
vided 12a,b in 83% yield (1:1 dr) over two steps. The
enantioconvergent intramolecular FriedelꢀCrafts alkyla-
tion of the mixture of diastereomers 12a,b provided 13 in
63% yield,4b,10 and analysis by chiral HPLC indicated the
molecule had been formed with 81% ee.17
Scheme 4. Completion of the Synthesis
However, after some experimentation, we found that the
conditions reported by Funk provided satisfactory results.19
With careful control of reaction temperature, and gradual
warming from ꢀ30 to 0 °C in 10 °C increments over the
course of 2 h, we were able to effect the conversion of 15 to
16 in 63% yield.
Scheme 3. Pd-Catalyzed Carboamination of 5 and Conversion
to 13
(15) In our prior studies, optimal results were achieved with substrate
concentrations of 0.2 M. However, best results were obtained in reac-
tions of 5 using 0.33 M concentrations of substrate.
(16) See the Supporting Information for complete experimental
details.
(17) The enantioselectivity of this transformation is consistent with
our prior results on Pd-catalyzed enantioselective alkene carboamina-
tion reactions that generate pyrrolidine products. See ref 9.
(18) Many of the previously described approaches to aphanorphine
are formal syntheses that terminate prior to the challenging demethyla-
tion step.
(19) Fuchs, J. R.; Funk, R. L. Org. Lett. 2001, 3, 3923–3925.
2934
Org. Lett., Vol. 13, No. 11, 2011

In conclusion, we have developed a concise synthesis of
(þ)-aphanorphine 16 that affords the target molecule in 10
steps and 13% overall yield from commercially available
starting materials. Importantly, this synthesis demonstrates
the viability of a new, enantioconvergent strategy for the
construction of benzomorphan-type alkaloids. The four-
step sequence in which 5is transformed to 13 not only effects
construction of two CꢀC bonds, one CꢀN bond, and two
rings but also converts a racemic substrate to an enantio-
merically enriched product. A quaternary all-carbon stereo-
center is generated during the enantioconvergent CꢀC
bond-forming step, and the product is formed with a
synthetically useful level of stereocontrol. Further studies
on the expansion of this strategy and its extension to other
targets of interest are currently underway.
Acknowledgment. We acknowledge the NIH-NIGMS
for financial support of this work (GM-071650). Addi-
tional funding was provided by GlaxoSmithKline,
Amgen, and Eli Lilly. We thank Professors R. L. Funk
(Department of Chemistry, The Pennsylvania State
University) and J. R. Fuchs (Department of Medicinal
Chemistry, The Ohio State University) for helpful
discussions.
Supporting Information Available. Experimental pro-
cedures, characterization data for all new compounds,
descriptions of stereochemical assignments, and copies of
1H and 13C NMR spectra for all new compounds reported
in the text. This material is available free of charge via the
Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 11, 2011
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