Short, enantioselective total syntheses of (-)-8-demethoxyrunanine and (-)-cepharatines A, C, and D

Article abstract of DOI:10.1002/anie.201104487

All together! A unified synthetic strategy has resulted in the first enantioselective total syntheses of the natural products 8-demethoxyrunanine and cepharatines A, C, and D.

Full text of DOI:10.1002/anie.201104487

DOI: 10.1002/anie.201104487
Natural Product Synthesis
Short, Enantioselective Total Syntheses of (À)-8-Demethoxyrunanine
and (À)-Cepharatines A, C, and D**
Kangway V. Chuang, Raul Navarro, and Sarah E. Reisman*
The hasubanan alkaloids are a large collection of natural
products isolated from several medicinal herbs that are used
in traditional Chinese medicine.[1] Members of this family
share a common aza[4.4.3]propellane core, but vary substan-
tially in the oxidation patterns of their peripheral structure.
The least oxidized hasubanans are 8-demethoxyrunanine
(1)[2] and cepharamine (3);[3] runanine (2),[4] aknadinine
(4),[5] and hasubanonine (5)[6] are the result of further
oxidation at the C8-position (Scheme 1). These compounds
are closely related to an isomeric family of natural products,
the cepharatines (7–10), which were isolated in 2011 from S.
cepharantha, the same plant from which cepharamine (3) was
isolated.[7] The structural similarities between the hasubanans
and the cepharatines have led to the hypothesis that both
arise biosynthetically from common precursors. For example,
3, 7, and 8 are proposed to derive from sinoacutine (11),[7,8]
a
compound related, although of the opposite enantiomeric
series, to morphine. Indeed, owing to the topographical
similarities between compounds 1–5 and morphine, there is
speculation that the unnatural enantiomers of the hasubanans
may exhibit analgesic properties.[9]
Scheme 1. Representative members of the hasubanan and cepharatine
alkaloids.
The hasubanan alkaloids have been the subject of
research by a number of synthetic groups over the past
forty years. Although several hasubanans were prepared in
racemic form by total synthesis in the early 1970s,[10,11] the
enantioselective chemical synthesis of this family of com-
pounds has proven far more challenging. The first enantio-
selective total synthesis of a hasubanan alkaloid was the 21-
step synthesis of cepharamine (3) reported by Schultz and
Wang in 1998.[12,13] As part of a program targeting the total
syntheses of several alkaloid natural products, we sought to
develop a unified strategy for the enantioselective prepara-
tion of the hasubanan and cepharatine alkaloids. From the
outset, the objective was to develop a synthetic approach that
could provide access to any member of the hasubanan
alkaloids, starting with the least oxidized members 1 and 3.
Following a plan inspired by nature,[14] we envisioned prepar-
ing the appropriate azapropellane skeleton, and then system-
atically introducing peripheral oxidation as dictated by the
target compound. Ideally, the proposed azapropellane inter-
mediates would also be suited for conversion into the
corresponding cepharatine natural products. Herein, we
report our preliminary results, which establish the viability
of this approach through short and enantioselective total
syntheses of the natural products 8-demethoxyrunanine (1)
and cepharatines A (7), C (8), and D (10).
In accordance with our plan, both the hasubanans and
cepharatines were anticipated to arise from an azapropellane
intermediate of the general structure 12 (Scheme 2). This
azapropellane intermediate was foreseen to derive from
dihydroindolone 13 by an intramolecular Friedel–Crafts-type
alkylation. In a subsequent step, oxidation and rearrangement
of 12 could then give rise to 17, bearing the cepharatine
framework. As an important part of our strategy, it was
anticipated that the arene oxidation patterns of either
runanine and cepharatine D, or cepharamine and cepharatine
A, could be generated from 13 by simply controlling the site
[*] K. V. Chuang, R. Navarro, Prof. S. E. Reisman
The Warren and Katharine Schlinger Laboratory of Chemistry and
Chemical Engineering
Division of Chemistry and Chemical Engineering
California Institute of Technology, Pasadena, CA 91125 (USA)
E-mail: reisman@caltech.edu
Homepage: http://reismangroup.caltech.edu
[**] We thank Dr. Michael Day and Mr. Larry Henling for X-ray
crystallographic structural determination, as well as Prof. Brian
Stoltz, Dr. Scott Virgil, and the Caltech Center for Catalysis and
Chemical Synthesis for access to analytical equipment. Fellowship
support was provided by the Gates Millennium Scholars Program
(R.N.), the NIH (R.N., 1F31GM098025A) and the Amgen Scholars
Program (K.V.C.). HRMS and X-ray crystallographic data were
obtained on instruments purchased through awards to the
California Institute of Technology by the NSF CRIF program (CHE-
0639094, CHE-0541745). Financial support from the California
Institute of Technology and the NSF (CAREER-1057143) is gratefully
acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201104487.
Angew. Chem. Int. Ed. 2011, 50, 9447 –9451
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9447

Communications
Scheme 2. Synthetic plan. TMSE=trimethylsilylethyl.
Scheme 3. Synthesis of enantioenriched dihydroindolones 13a and 26.
dba=dibenzylideneacetone, DMF=N,N’-dimethylformamide,
HMPA=hexamethylphosphoramide, THF=tetrahydrofuran.
of electrophilic aromatic substitution in the Friedel–Crafts
reaction. Literature precedent suggested that the intrinsic
selectivity of the dimethoxy substrate 13a (R1 = H, R2 =
OMe, R3 = H) would favor reaction at the less sterically
encumbered para position, to provide the product with the
runanine oxidation pattern (12a, R1 = H, R2 = OMe, R3 =
H).[15] Alternatively, we anticipated generating the azapro-
pellane bearing the cepharamine oxidation pattern found in
12b (R1 = OTMSE, R2 = H, R3 = Br) by installing an appro-
priate blocking group in the cyclization substrate (e.g. 13b;
R1 = OTMSE, R2 = H, R3 = Br).
To implement the synthetic plan detailed above, the
enantioselective preparation of dihydroindolones 13a and
13b would be required. We recently reported the preparation
of benzoquinone monoketal-derived N-tert-butanesulfini-
mine 14, which undergoes highly diastereoselective 1,2-
addition with a variety of organometallic reagents.[16] Based
on this report, we expected dihydroindolones 13a and 13b to
be accessible from 14 by a short sequence involving Grignard
addition, N methylation, and pyrrolidine formation.
In the forward sense, our synthesis began with N-tert-
butanesulfinimine 14,[16][17] easily prepared on a multigram
scale in two steps from the commercially available 2-bromo-4-
methoxyphenol (Scheme 3). The addition of Grignard
reagent 20a at low temperatures followed by an in situ
N methylation provided sulfinamide 21, which was isolated as
a single diastereomer, in 77% yield. Analysis of the crude
reaction mixture determined that the 1,2-addition proceeded
with 96:4 d.r. Notably, hydrolysis of the dimethyl acetal occurs
during the mildly acidic workup without detectable quantities
of undesired dienone-phenol rearrangement[18] products.
Construction of the required pyrrolidine ring was accom-
plished by a three-step sequence that began with a Pd-
catalyzed cross-coupling between vinyl bromide 21 and
ethoxy vinylstannane 23 to give enol ether 24 in 90% yield
(Scheme 3). After considerable experimentation, it was found
that brief exposure of 24 to 1m HCl in THF at 08C resulted in
cleavage of the sulfinamide and promoted intramolecular
condensation to provide the corresponding indolone.[19]
Chemoselective monoreduction of the indolone was achieved
using sodium borohydride and acetic acid, thus furnishing the
desired dihydroindolone 13a in 96% yield over two steps.
With an eye toward preparing cepharamine (3) or cephara-
tines A (7) and C (8), dihydroindolone 26, bearing a differ-
entially protected arene, was prepared through an analogous
route from 20b (Scheme 3).
With access to dihydroindolones 13a and 26 established,
our efforts turned to implementing the key intramolecular
Friedel–Crafts reactions (Scheme 4). A small screen of Lewis
acids revealed that exposure of dienone 13a to BF3·Et2O
promoted cyclization, however, the yield of recovered 12a
was moderate. Thus, we turned to the use of strong Brønsted
acids, and were pleased to find that use of excess TfOH in
dichloromethane[20] smoothly promoted cyclization exclu-
sively at the C14-position, thus delivering the desired
propellane 12a in 97% yield. It is proposed that the selective
addition to the trisubstituted alkene, in preference to the less-
hindered disubstituted alkene, results from the formation of a
discrete, protonated intermediate that favors the more stable,
tertiary carbocation at the C14-position. Given our desire to
access the cepharamine oxidation pattern, the TMSE-pro-
tected substrate 26 was brominated and exposed to the TfOH
cyclization conditions in situ to furnish azapropellane 30.
Monitoring this reaction revealed that cleavage of the TMSE
group is rapid, and cyclization of the phenol occurs upon
warming the reaction to room temperature.
Having developed an efficient and unified approach to
azapropellanes bearing either the runanine or cepharamine
9448 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 9447 –9451

the epoxide followed by b elimination of the aziridinium to
give enol 15 (see Scheme 2, R1 = H, R2 = OMe). Enol-
facilitated elimination of the amine and intramolecular
aminal formation would provide 28. This rearrangement can
be suppressed by purification of epoxide 27 using Florisil.
Although pleased by our ability to generate the cepharatine
framework from the hasubanan core, we continued to explore
reaction conditions for the formation of 1. After an extensive
survey of reaction conditions,[23] it was discovered that use of
tetrabutylammonium methoxide[24] in THF at 508C for
12 hours provided the natural product 8-demethoxyrunanine
(1) in 68% yield. Using this sequence, 1 is prepared in only
nine steps and in 19% overall yield from the commercially
available phenol 18.
After completion of the synthesis of 8-demethoxyruna-
nine (1), attention turned to improving the yield of hemi-
aminal 28 and elaborating it to cepharatine D (10). After
screening several reaction parameters, it was determined that
epoxidation of 12a followed by prolonged exposure to silica
gel provided direct access to aminal 28 in 76% yield from
propellane 12a (Scheme 5). Desaturation of aminal 28 was
carried out by deprotonation with excess KHMDS at À788C
followed by addition of N-tert-butylbenzenesulfinimidoyl
chloride (29),[25] thus providing cepharatine D (10) in 9
steps and 22% overall yield from 18.
Scheme 4. Preparation of azapropellanes 12a and 30. TfOH=trifluoro-
methanesulfonic acid.
oxidation patterns, we turned to the remaining challenge of
adjusting the oxidation level at the C7-position to that found
in both 1 and 3. To this end, exploratory studies were carried
out using 12a (Scheme 5). We were pleased to find that
exposure of enone 12a to standard nucleophilic epoxidation
conditions[21] (H2O2, LiOH, MeOH) followed by heating to
508C provided 8-demethoxyrunanine (1), albeit in low yield
(10–15%). Presuming that 1 was formed via the epoxide, we
hoped to optimize the yield of the overall process by isolating
this intermediate. Ultimately, it was determined that the
combination of tert-butylhydroperoxide (TBHP) and Tri-
ton B in THF provided clean conversion into epoxide 27.
However, attempts to purify the reaction mixture by chro-
matography on silica gel led to the isolation of epoxide 27
along with hemiaminal 28, a compound bearing the cepha-
ratine framework.[22] One proposed mechanism for the
formation of 28 begins with a nitrogen-assisted opening of
Having converted propellane 12a into the natural prod-
ucts 1 and 10, we sought to carry out a similar reaction
sequence to convert bromopropellane 30 into the correspond-
ing compounds cepharamine (3) and cepharatine A (7)
(Scheme 6). In contrast to the epoxidation of 12a, epoxida-
tion of enone 30 proceeded sluggishly, and despite consid-
erable attempts at optimization, epoxide 31 was isolated in
only 40% yield.
Efforts to drive the epoxidation reaction to completion
were complicated by competitive oxidative rearrangement of
the epoxide product, resulting in formation of a lactone by-
Scheme 5. Enantioselective synthesis of 8-demethoxyrunanine (1) and
cepharatine D (10). KHMDS=potassium hexamethyldisilazide,
TBHP=tert-butylhydroperoxide.
Scheme 6. Enantioselective synthesis of cepharatines A (7) and C (8).
Angew. Chem. Int. Ed. 2011, 50, 9447 –9451
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 9449

Communications
product.[26] Unfortunately, exposure of epoxide 31 to
Bu4NOMe in THF (identical reaction conditions to those
[5] B. K. Moza, B. Bhaduri, D. K. Basu, J. Kunitomo, Y. Okamoto,
E. Yuge, Y. Nagai, Tetrahedron 1970, 26, 427.
[6] M. Tomita, T. Ibuka, Y. Inubushi, Y. Watanabe, M. Matsui,
Tetrahedron Lett. 1964, 5, 2937.
[7] L. He, Y.-H. Zhang, H.-Y. Guan, J.-X. Zhang, Q.-Y. Sun, X.-J.
Hao, J. Nat. Prod. 2011, 74, 181.
[8] N. Kashiwaba, S. Morooka, M. Kimura, M. Ono, J. Toda, H.
Suzuki, T. Sano, J. Nat. Prod. 1996, 59, 476.
utilized to convert 27 into 1) provided only trace amounts of
1
enol ether 32, as detected by H NMR analysis of the crude
reaction mixture. Reasoning that deprotonation of the
phenolic O–H might contribute to the poor reactivity, several
protected variants of 30 were prepared (e.g. methyl-, methox-
ymethyl ether-, allyl-, and benzyl-protected phenols).
Whereas the epoxidation step proceeded with improved
efficiency for these substrates, exposure of the epoxides to a
variety of methoxide sources still provided prohibitively low
quantities of the desired methyl enol ethers (analogous to 32).
These studies illustrate how subtle perturbations in the arene
oxidation patterns can strikingly alter the reactivity of the
azapropellane framework.
Similarly, treatment of enone 30 under the tandem
epoxidation/rearrangement conditions identified for the con-
version of 12a into 28 provided lower yields of the corre-
sponding hemiaminal (33; Scheme 6). However, we were
pleased to find that selective hydrodebromination of the aryl
bromide followed by treatment with PhI(OAc)2 and base
cleanly provided cepharatine A (7) in good yield over two
steps.[27] Finally, cepharatine A could be converted into
cepharatine C (8) by exposure to methanol under mildly
acidic reaction conditions. Using this reaction sequence 7 and
8 could be prepared in 10 and 11 steps, respectively, and each
in 10% overall yield from commercially available starting
materials.
[9] Schultz and Wang first hypothesized about the analgesic
activities of the unnatural enantiomers of the hasubanans; see
Ref. [12].
[10] Completed total syntheses: hasubanonine: a) T. Ibuka, K.
Tanaka, Y. Inubushi, Tetrahedron Lett. 1970, 11, 4811; b) T.
Ibuka, K. Tanaka, Y. Inubushi, Chem. Pharm. Bull. 1974, 22, 782;
metaphanine, c) T. Ibuka, K. Tanaka, Y. Inubushi, Tetrahedron
Lett. 1972, 13, 1393; d) T. Ibuka, K. Tanaka, Y. Inubushi, Chem.
Pharm. Bull. 1974, 22, 907; cepharamine: e) Y. Inubushi, M.
Kitano, T. Ibuka, Chem. Pharm. Bull. 1971, 19, 1820; f) T.
Kametani, H. Nemoto, T. Kobari, K. Shishido, K. Fukumoto,
Chem. Ind. 1972, 13, 538.
[11] Partial or formal syntheses: a) M. Tomita, T. Ibuka, M. Kitano,
Tetrahedron Lett. 1966, 7, 6233; b) T. Ibuka, M. Kitano, Chem.
Pharm. Bull. 1967, 15, 1944; c) M. Tomita, M. Kitano, T. Ibuka,
Tetrahedron Lett. 1968, 9, 3391; d) D. A. Evans, Tetrahedron
Lett. 1969, 10, 1573; e) D. A. Evans, C. A. Bryan, G. M. Wahl, J.
Org. Chem. 1970, 35, 4122; f) S. L. Keely, Jr., A. J. Martinez,
F. C. Tahk, Tetrahedron 1970, 26, 4729; g) D. A. Evans, C. A.
Bryan, C. L. Sims, J. Am. Chem. Soc. 1972, 94, 2891; h) T.
Kametani, T. Kobari, K. Fukumoto, J. Chem. Soc. Chem.
Commun. 1972, 288; i) B. Belleau, H. Wong, I. Monkovic,
Y. G. Perron, J. Chem. Soc. Chem. Commun. 1974, 603; j) T.
Kametani, T. Kobari, K. Shishido, K. Fukumoto, Tetrahedron
In conclusion, a unified synthetic strategy has resulted in
the short, enantioselective total syntheses of 8-demethoxyr-
unanine (1) and cepharatines A (7), C (8), and D (10). Key to
this synthetic strategy was the use of benzoquinone mono-
ketal-derived N-tert-butanesulfinimine 14 to prepare 4-ami-
nocyclohexadienones 21 and 22 with excellent stereocontrol.
Depending on the reaction sequences, either the runanine or
cepharamine arene oxidation patterns could be achieved by
way of a regioselective intramolecular Friedel–Crafts-type
alkylation. Moreover, it was shown that the hasubanan
framework rearranges under mild reaction conditions, thus
providing access to the cepharatine natural products. Ongoing
studies in our laboratory are focused on the development of
oxidation strategies to access cepharamine and the more-
oxidized members of the hasubanans, as well as the applica-
tion of this general approach to the synthesis of the related
acutumine[28] family of alkaloids.
´
1974, 30, 1059; k) I. Monkovic, H. Wong, B. Belleau, I. J.
Pachter, Y. G. Perron, Can. J. Chem. 1975, 53, 2515; l) I.
Monkovic, H. Wong, Can. J. Chem. 1976, 54, 883; m) S. Shiotani,
´
T. Kometani, Tetrahedron Lett. 1976, 17, 767; n) H. Bruderer, D.
Knopp, J. J. Daly, Helv. Chim. Acta 1977, 60, 1935; o) M. A.
Schwartz, R. A. Wallace, Tetrahedron Lett. 1979, 20, 3257; p) D.
Trauner, S. Porth, T. Opatz, J. W. Bats, G. Giester, J. Mulzer,
Synthesis 1998, 653; q) S. B. Jones, L. He, S. L. Castle, Org. Lett.
2006, 8, 3757; r) T. X. Nguyen, Y. Kobayashi, J. Org. Chem. 2008,
73, 5536; s) D. K. Nielsen, L. L. Nielsen, S. B. Jones, L. Toll,
M. C. Asplund, S. L. Castle, J. Org. Chem. 2009, 74, 1187.
[12] A. G. Schultz, A. H. Wang, J. Am. Chem. Soc. 1998, 120, 8259.
[13] As we were preparing this manuscript, a synthetic strategy
similar to ours was reported by Herzon et al., see: S. B. Herzon,
N. A. Calandra, S. M. King, Angew. Chem. 2011, DOI: 10.1002/
ange.201102226; Angew. Chem. Int. Ed. 2011, DOI: 10.1002/
anie.201102226.
[14] For an account on this topic, see: Y. Ishihara, P. S. Baran, Synlett
2010, 1733.
[15] Selected examples: a) W. J. Gensler, A. L. Bluhm, J. Org. Chem.
1956, 21, 336; b) A. Padwa, M. D. Danca, Org. Lett. 2002, 4, 715.
[16] K. V. Chuang, R. Navarro, S. E. Reisman, Chem. Sci. 2011, 2,
1086.
[17] For a seminal report describing the use of N-tert-butanesulfini-
mines, see: J. A. Ellman, D. A. Cogan, J. Am. Chem. Soc. 1999,
121, 268.
[18] A. L. Wilds and C. Djerassi, J. Am. Chem. Soc. 1946, 68, 1715.
[19] Use of prolonged reaction times or weaker acids for sulfinamide
cleavage resulted in diminished yields of 13a because of
competitive decomposition of the indolone intermediate. In
addition, attempts to utilize the des-N-methyl analogue of 21
provided poor yields in the indolone formation step.
[20] W.-D. Z. Li, X.-W. Wang, Org. Lett. 2007, 9, 1211.
Received: June 29, 2011
Published online: August 30, 2011
Keywords: alkaloids · asymmetric synthesis · cepharatines ·
.
hasubanan · total synthesis
[1] M. Matsui in The Alkaloids, Vol. 33 (Ed.: A. Brossi), Academic
Press, New York, 1988, pp. 307 – 347.
[2] X. Wang, H. Jin, Z. Li, G. Qin, Fitoterapia 2007, 78, 593.
[3] M. Tomita, M. Kozuka, Tetrahedron Lett. 1966, 7, 6229.
[4] M. Zhi-Da, L. Ge, X. Guang-Xi, M. Iinuma, T. Tanaka, M.
Mizuno, Phytochemistry 1985, 24, 3084.
9450 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 9447 –9451

[21] P. Antony, R. Sigueiro, T. Huet, Y. Sato, N. Ramalanjaona, L. C.
Rodrigues, A. Mourino, D. Moras, N. Rochel, J. Med. Chem.
2010, 53, 1159.
[22] Castle and co-workers have isolated a similar intermediate
during synthetic studies toward the hasubanans, see Ref. [11s].
[23] All other reaction conditions screened provided hemiaminal 28
as the major product or led to significant decomposition.
[24] V. Di Bussolo, M. Caselli, M. R. Romano, M. Pineschi, P. Crotti,
J. Org. Chem. 2004, 69, 8702.
[25] a) T. Mukaiyama, J. Matsuo, H. Kitagawa, Chem. Lett. 2000,
1250; b) J. Matsuo, Y. Aizawa, Tetrahedron Lett. 2005, 46, 407.
[26] See the Supporting Information.
[27] In this transformation, desaturation presumably occurs by
phenolic oxidation to the ortho-quinone monoketal, followed
by base-mediated elimination of methanol and rearomatization.
[28] M. Tomita, Y. Okamoto, T. Kikuchi, K. Osaki, M. Nishikawa, K.
Kamiya, Y. Sasaki, K. Matoba, K. Goto, Tetrahedron Lett. 1967,
8, 2421.
Angew. Chem. Int. Ed. 2011, 50, 9447 –9451
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
9451