Total synthesis of (±)-hasubanonine

Article abstract of DOI:10.1021/ol0613564

Total synthesis of the alkaloid (±)-hasubanonine is described. A key feature of the route is generation of a phenanthrene intermediate via a Suzuki coupling-Wittig olefination-ring-closing metathesis sequence. Conversion of the phenanthrene into the targe

Full text of DOI:10.1021/ol0613564

ORGANIC
LETTERS
2006
Vol. 8, No. 17
3757-3760
Total Synthesis of (±)-Hasubanonine
Spencer B. Jones, Liwen He, and Steven L. Castle*
Department of Chemistry and Biochemistry, Brigham Young UniVersity,
ProVo, Utah 84602
scastle@chem.byu.edu
Received June 2, 2006
ABSTRACT
Total synthesis of the alkaloid (
±
)-hasubanonine is described. A key feature of the route is generation of a phenanthrene intermediate via a
ring-closing metathesis sequence. Conversion of the phenanthrene into the target molecule required six
Suzuki coupling Wittig olefination
−
−
steps including dearomatization by means of oxidative phenolic coupling, anionic oxy-Cope rearrangement, and a final acid-promoted cyclization.
Production of an undesired rearranged product in the last step could be suppressed by moderating the acid strength.
Hasubanonine (1, Figure 1), a member of the hasubanan
family of alkaloids,1 was isolated from the vine Stephania
japonica.2 Although it bears some structural resemblance to
the morphine alkaloids, neither 1 nor any other hasubanan
alkaloid examined to date possesses analgesic activity.1a
Schultz noted that the relative orientation of the aromatic
ring and the nitrogen atom is reversed in the two classes of
alkaloids and posited that the unnatural enantiomers of
hasubanan alkaloids may function as painkillers. Accord-
ingly, Schultz performed a synthesis of unnatural (+)-cephara-
mine,3 which is the only asymmetric synthesis to date of a
hasubanan alkaloid.4,5 However, to the best of our knowledge,
no studies of the analgesic properties of this or any other
unnatural hasubanan alkaloid enantiomer have been reported.
As a prelude to an asymmetric synthesis, we report a concise
total synthesis of (()-1 utilizing a strategy that is also well-
suited for the construction of other hasubanan alkaloids.
Figure 1. Hasubanonine (1) and morphine (2).
Our retrosynthetic analysis of 1 is presented in Scheme 1.
At the outset of our planning, we recognized that the route
we developed to the propellane-type6 tricyclic core of the
alkaloid acutumine7 would be applicable to the construction
of 1. Thus, we anticipated that dihydrophenanthrene 3 could
be transformed into 1 via a five-step sequence that includes
an oxidative phenolic coupling, an anionic oxy-Cope rear-
rangement, and a Michael-type cyclization. The immediate
precursor to 3, phenanthrene 4, was disconnected into aryl
iodide 5 and arylboronic ester 6. This simplification takes
advantage of a phenanthrene synthesis reported by Iuliano
(1) (a) Matsui, M. In The Alkaloids; Brossi, A., Ed.; Academic Press:
New York, 1988; Vol. 33, pp 307-347. (b) Inubushi, Y.; Ibuka, T. In The
Alkaloids; Manske, R. H. F., Ed.; Academic Press: New York, 1977; Vol.
16, pp 393-430. (c) Bentley, K. W. In The Alkaloids; Manske, R. H. F.,
Ed.; Academic Press: New York, 1971; Vol. 13, pp 131-143.
(2) (a) Tomita, M.; Ibuka, T.; Inubushi, Y.; Watanabe, Y.; Matsui, M.
Chem. Pharm. Bull. 1965, 13, 538. (b) Tomita, M.; Ibuka, T.; Inubushi,
Y.; Watanabe, Y.; Matsui, M. Tetrahedron Lett. 1964, 2937. (c) Kondo,
H.; Satomi, M.; Odera, T. Annu. Rep. ITSUU Lab. 1951, 2, 35.
(3) Schultz, A. G.; Wang, A. J. Am. Chem. Soc. 1998, 120, 8259.
(4) Total synthesis of (()-hasubanonine: (a) Ibuka, T.; Tanaka, K.;
Inubushi, Y. Chem. Pharm. Bull. 1974, 22, 782. (b) Ibuka, T.; Tanaka, K.;
Inubushi, Y. Tetrahedron Lett. 1970, 4811.
10.1021/ol0613564 CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/15/2006

from the nitro compound. Regioselective iodination of 3,4-
dimethoxybenzaldehyde (9) according to the directed ortho
metalation11 protocol of Comins12 produced 10, which was
subjected to a Suzuki coupling with bis(pinacolato)diboron13
to provide arylboronic ester 6.
Scheme 1. Retrosynthetic Analysis of 1
Suzuki coupling14 of 5 and 6 constructed a hindered
trisubstituted biaryl axis, delivering dialdehyde 11 in 79%
yield (Scheme 3). Conversion of both aldehydes into terminal
alkenes was accomplished via Wittig olefination, and ring-
closing metathesis of the resultant diene 12 with the Grubbs
second-generation ruthenium catalyst15 provided phenan-
threne 4 in 92% yield from 11. Cleavage of the benzyl ether
and reduction of the phenanthrene were both accomplished
by catalytic hydrogenation, affording phenolic dihydro-
phenanthrene 3 in excellent yield (95%).
At this point, we commenced the transformation of 3 into
1 by means of our previously developed sequence. Accord-
ingly, treatment of 3 with PhI(OAc)2 in the presence of
MeOH16 resulted in a facile oxidative phenolic coupling that
produced masked o-benzoquinone17 13. 1,2-Addition of
allylmagnesium chloride to 13 provided tertiary alcohol 14,
which was transformed into ketone 15 via an anionic oxy-
Cope rearrangement.18 Ozonolysis of 15 was regioselective,
delivering the aldehyde derived from oxidative cleavage of
the terminal olefin. Reductive amination of the crude
aldehyde afforded a secondary amine, which cyclized to form
hemiaminal 16 as evidenced by NMR spectroscopy. Notably,
this ozonolysis-reductive amination sequence was more
facile relative to our earlier work on the acutumine core, in
which oxidation of the tetrasubstituted alkene by O3 was
competitive with the desired process. We believe that the
less-hindered nature of the terminal olefin of 15 compared
to the corresponding olefin in the acutumine substrate is
responsible for the improved regioselectivity.7
that consists of a Suzuki coupling followed by Wittig
olefination and ring-closing metathesis.8 We reasoned that
both 5 and 6 should be available in straightforward fashion
from known or commercially available aromatic compounds.
The syntheses of 5 and 6 are shown in Scheme 2. Nitration
Scheme 2. Syntheses of 5 and 6
To our surprise, subjection of 16 to our previously
developed conditions (TMSOTf, 4 Å MS, CH2Cl2, -10 °C)
for cyclization of an amine onto an R,â-unsaturated ketal19
did not afford 1. Rather, an unstable constitutional isomer
of 1 was obtained, as evidenced by HRMS. We have
tentatively assigned the structure of this product as hemi-
aminal 17 on the basis of H NMR of a partially purified
sample.20 We presume that this compound arises from a
pinacol-like rearrangement of the oxocarbenium ion derived
of 4-benzyloxy-2,3-dimethoxybenzaldehyde (7, available in
two steps from commercially available 2,3-dimethoxyphe-
nol)9 afforded 8.10 A sequence of nitro reduction, diazoti-
zation, and iodination delivered aryl iodide 5 in 41% yield
1
(5) Other synthetic work in the hasubanan alkaloid area: (a) Trauner,
D.; Porth, S.; Opatz, T.; Bats, J. W.; Giester, G.; Mulzer, J. Synthesis 1998,
653. (b) Schwartz, M. A.; Wallace, R. A. Tetrahedron Lett. 1979, 3257.
(c) Shiotani, S.; Kometani, T. Tetrahedron Lett. 1976, 767. (d) Monkovic´,
I.; Wong, H. Can. J. Chem. 1976, 54, 883. (e) Monkovic´, I.; Wong, H.;
Belleau, B.; Pachter, I. J.; Perron, Y. G. Can. J. Chem. 1975, 53, 2515. (f)
Kametani, T.; Kobari, T.; Shishido, K.; Fukumoto, K. Tetrahedron 1974,
30, 1059. (g) Kametani, T.; Nemoto, H.; Kobari, T.; Shishido, K.; Fukumoto,
K. Chem. Ind. (London) 1972, 538. (h) Ibuka, T.; Tanaka, K.; Inubushi, Y.
Chem. Pharm. Bull. 1974, 22, 907. (i) Inubushi, Y.; Kitano, M.; Ibuka, T.
Chem. Pharm. Bull. 1971, 19, 1820. (j) Evans, D. A.; Bryan, C. A.; Sims,
C. L. J. Am. Chem. Soc. 1972, 94, 2891. (k) Evans, D. A.; Bryan, C. A.;
Wahl, G. M. J. Org. Chem. 1970, 35, 4122. (l) Keely, S. L., Jr.; Martinez,
A. J.; Tahk, F. C. Tetrahedron 1970, 26, 4729.
(10) The unusual regioselectivity of this nitration is precedented, as
nitration of 2,3,4-trimethoxybenzaldehyde affords 2,3,4-trimethoxy-6-
nitrobenzaldehyde exclusively; see: (a) Lin, A. J.; Pardini, R. S.; Lillis, B.
J.; Sartorelli, A. C. J. Med. Chem. 1974, 17, 668. (b) Cherkaoui, M. Z.;
Scherowsky, G. New. J. Chem. 1997, 21, 1203.
(11) Snieckus, V. Chem. ReV. 1990, 90, 879.
(12) Comins, D. L.; Brown, J. D. J. Org. Chem. 1989, 54, 3730.
(13) Zhu, L.; Duquette, J.; Zhang, M. J. Org. Chem. 2003, 68, 3729.
(14) Lin, S.; Yang, Z.-Q.; Kwok, B. H. B.; Koldobskiy, M.; Crews, C.
M.; Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 6347.
(15) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(6) For a review on the synthesis of propellane-containing natural
products, see: Pihko, A. J.; Koskinen, A. M. P. Tetrahedron 2005, 61,
8769.
(7) Reeder, M. D.; Srikanth, G. S. C.; Jones, S. B.; Castle, S. L. Org.
Lett. 2005, 7, 1089.
(16) Yen, C.-F.; Peddinti, R. K.; Liao, C.-C. Org. Lett. 2000, 2, 2909.
(17) For a review on the chemistry of masked o-benzoquinones, see:
Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem. ReV. 2004, 104, 1383.
(18) (a) Paquette, L. A. Tetrahedron 1997, 53, 13971. (b) Evans, D. A.;
Golob, A. M. J. Am. Chem. Soc. 1975, 97, 4765.
(8) Iuliano, A.; Piccioli, P.; Fabbri, D. Org. Lett. 2004, 6, 3711.
(9) Kurosawa, K.; Ollis, W. D.; Sutherland, I. O.; Gottlieb, O. R.; De
Oliveira, A. B. Phytochemistry 1978, 17, 1389.
(19) These conditions (reported in ref 7) are based on the work of
Matsumoto: Yasui, Y.; Koga, Y.; Suzuki, K.; Matsumoto, T. Synlett 2004,
615.
3758
Org. Lett., Vol. 8, No. 17, 2006

Scheme 3. Coupling of 5 and 6 and Attempted Conversion into 1
from interaction of 16 with TMSOTf or TfOH.21 The
A mechanistic explanation for the production of 17 and 1
from 16 is depicted in Scheme 5. Treatment of 16 with a
formation of 17 was quite rapid (e10 min) and could also
be accomplished by treatment of 16 with BCl3 or HCl.
Unfortunately, attempts to convert 17 into 1 were fruitless.
After considerable experimentation, we discovered that tri-
fluoroacetic acid facilitated the clean transformation of 16
into 1.22 Optimized conditions entailed warming a solution
of 16 in CH2Cl2 at 35 °C in the presence of 3 equiv of TFA
and 10 wt equiv of 4 Å MS for 22 h (Scheme 4). Reactions
Scheme 5. Rationale for the Formation of 17 and 1 from 16
Scheme 4. Successful Conversion of 16 into 1
conducted at room temperature were sluggish, proceeding
to <50% completion after 24 h. We attribute the modest rate
of reaction to the fact that the amino ketone tautomer of 16
required for cyclization is present in very low concentra-
tion.23 In contrast, the substrate analogous to 16 in our syn-
thesis of the acutumine core did not form a hemiaminal; thus,
it cyclized rapidly without interference from the rearrange-
ment.7
strong Lewis or Brønsted acid presumably results in the
formation of an oxocarbenium ion which rapidly undergoes
a pinacol-like rearrangement, affording hemiaminal 17.
However, it is likely that the oxocarbenium ion is not
generated when 16 is exposed to the slightly weaker acid
(20) Compound 17 is completely unstable to SiO2, neutral alumina, basic
alumina, and Florisil. It can be partially purified by rapid chromatography
on SiO2 that has been pretreated with Et3N or NaOH, but attempts to obtain
a pure sample were thwarted by decomposition.
(21) We believe that reactions employing TMSOTf are actually mediated
by TfOH, as they do not proceed in the presence of Et3N.
Org. Lett., Vol. 8, No. 17, 2006
3759

TFA. Rather, cyclization of the amino ketone tautomer of
16 to provide 1 may proceed via an SN2′-type pathway in
which a ketal methoxy group is activated by hydrogen
bonding to the carboxylic acid. We do not believe that 17
lies on the pathway to 1, as treatment of 17 with TFA did
not provide 1, and 17 was not detected in the formation of
1 under the conditions shown in Scheme 4.24 Finally, it is
noteworthy that the acid-sensitive methyl enol ether moiety
of 16 was stable under most of the conditions examined
provided that a sufficient quantity of 4 Å MS was present.
In conclusion, we have synthesized (()-hasubanonine via
an efficient route that features convergent construction of a
phenanthrene intermediate followed by a sequence that in-
cludes oxidative dearomatization, anionic oxy-Cope rearrange-
ment, and acid-promoted cyclization. The final transforma-
tion was plagued by an undesired rearrangement which was
ultimately avoided by attenuating the acid strength. The net
result of the aforementioned reactions is to annulate a pyrroli-
dine onto a phenolic aromatic ring, and the method is robust
enough to create hindered propellane-type systems. This
synthesis could be used to prepare other hasubanan alkaloids
by simply modifying the structure of the aryl iodide or the
arylboronic ester used in the Suzuki coupling. Additionally,
development of an enantioselective total synthesis of un-
natural (+)-1 merely requires the performance of an asym-
metric allylation25 on ketone 13. Studies along these lines
are currently in progress and will be reported in due course.
Acknowledgment. We thank Brigham Young University
(Annual Fund Student Mentorships and Undergraduate
Research Awards to S.B.J., startup funding to S.L.C.) and
the National Institutes of Health (GM70483) for support of
this work. We also thank Daniel K. Nielsen for assistance
in the preparation of starting materials.
(22) The only published NMR spectroscopic data for 1 that we are aware
of consist of partially assigned 1H spectra acquired on 60 MHz instruments
(see ref 2 and Singh, R. S.; Kumar, P.; Bhakuni, D. S. J. Nat. Prod. 1981,
44, 664). Accordingly, we obtained high-field 1H, 13C, COSY, and HETCOR
spectra of our product, all of which are consistent with structure 1.
1
(23) This tautomer was not observed in H or 13C NMR spectra of 16.
(24) Interestingly, pure 1 is completely consumed when treated with 10
equiv of TFA to afford a complex mixture from which 17 can be identified
on the basis of TLC and HRMS. This may occur via protonation of the
tertiary amine followed by methoxy-assisted ring opening to afford an oxo-
carbenium ion (i.e., the amino ketone tautomer of the species portrayed in
Scheme 5). The preference of the oxocarbenium ion to give 17 instead of
1 upon cyclization is a kinetic rather than a thermodynamic phenomenon,
as 1 is 2.71 kcal/mol more stable than 17 according to semiempirical PM3
calculations. Moreover, 1 is significantly more stable to standard purification
techniques as documented above. We believe that the facile decomposition
of 17 (possibly triggered by enol ether hydrolysis) is responsible for our in-
ability to convert it into the more stable 1. Further experiments are necessary
to clarify the intriguing relationship between these two compounds.
Supporting Information Available: Experimental pro-
cedures, characterization data, and NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0613564
(25) Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103, 2763.
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Org. Lett., Vol. 8, No. 17, 2006