Enantioselective total synthesis of (+)-stephadiamine through bioinspired aza-benzilic acid type rearrangement

Article abstract of DOI:10.1021/jacs.1c00047

We report the first enantioselective total syntheses of the hasubanan alkaloid (-)-metaphanine and the norhasubanan alkaloid (+)-stephadiamine. Key features of these syntheses include diastereoselective oxidative phenolic coupling reaction and subsequent

Full text of DOI:10.1021/jacs.1c00047

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Enantioselective Total Synthesis of (+)-Stephadiamine through
Bioinspired Aza-Benzilic Acid Type Rearrangement
Minami Odagi,* Taisei Matoba, Keisuke Hosoya, and Kazuo Nagasawa*
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ABSTRACT: We report the first enantioselective total syntheses of the hasubanan alkaloid (−)-metaphanine and the norhasubanan
alkaloid (+)-stephadiamine. Key features of these syntheses include diastereoselective oxidative phenolic coupling reaction and
subsequent regioselective intramolecular aza-Michael reaction, which efficiently construct the hasubanan skeleton with the all-carbon
quaternary stereogenic center at C13. Based on our hypothesis regarding the biosynthetic pathway of (+)-stephadiamine, we found
that (−)-metaphanine is easily converted to (+)-stephadiamine via aza-benzilic acid type rearrangement reaction.
lants of the genus Stephania, which grow naturally in the
Southeast Asia-Pacific region and have been widely used
biosynthetically from (−)-metaphanine (5) through an aza-
benzilic acid type rearrangement reaction via intermediate 7,
which would be generated by condensation of 5 with
ammonia.9 Based on this hypothesis, we considered that this
aza-benzilic acid-type rearrangement might be applied to
synthesize (+)-stephadiamine (6) from its putative biosyn-
thetic precursor, (−)-metaphanine (5). In this report, we
describe enantioselective total syntheses of (−)-metaphanine
(5) and (+)-stephadiamine (6), featuring a diastereoselective
oxidative phenolic coupling reaction and subsequent regiose-
lective intramolecular aza-Michael reaction, as well as the
bioinspired aza-benzilic acid type rearrangement.
P
in traditional Chinese medicines, contain bioactive alkaloids
known as hasubanans.1 More than 40 congeners of these
alkaloids have been identified to date, and they show a wide
range of biological activities, including antiviral, antimicrobial,
and cytotoxic activities.1c Hasubanan alkaloids, exemplified by
compounds 2−5, commonly possess a characteristic tetracyclic
aza[4,4,3]propellane core 1 (Figure 1a).1,2 Owing to the
synthetically challenging structures of these alkaloids as well as
their important biological activities, numerous synthetic studies
have been reported.3−5
In 1984, Ibuka and co-workers isolated a (+)-stephadiamine
(6) from Stephania japonica.6 This norhasubanan alkaloid has
an uncommon structure that differs from those of hasubanan
alkaloids. It contains an aza[4,3,3]propellane scaffold with a
five-membered C-ring, and four stereogenic centers, including
an α-tertiary amine at C14 and an all-carbon quaternary
stereogenic center at C13. The unique caged-type structure of
6 and its absolute configuration were established by X-ray
crystallography analysis of the bromobenzoate derivative. The
biological activity of 6 has not yet been investigated, because
only a limited supply is available from nature. Furthermore,
despite the interesting structure of 6, only one report of its
total synthesis has appeared to date. In 2018, Trauner and co-
workers reported a total synthesis of stephadiamine (6) in
racemic form based upon an elegant cascade reaction of a β-
tetralone derivative for the construction of the characteristic
aza[4,3,3]propellane core, which corresponds to the B,C,D-
rings in 6.7 As a part of their synthesis, they described
enantioselective access to a key intermediate by means of Pd-
catalyzed asymmetric allylation with chiral phosphoric acid.
The biosynthetic pathway of the hasubanan alkaloids has
been explored in part, although it is still not fully established.8
We envisaged that the five-membered C-ring of the
norhasubanan 6 might be formed biosynthetically from the
six-membered hasubanan C-ring, e.g., by reconstruction of the
hemiacetal in 5 to δ-lactone (Figure 1b). That is, we
hypothesized that (+)-stephadiamine (6) would be formed
Our synthetic analysis for the primary target, (−)-meta-
phanine (5), is depicted in Figure 1c. We envisaged that 5
would be obtained by selective oxidation at C8 in enone 8,
which would be synthesized by successive construction of the
B and D rings through a diastereoselective oxidative phenolic
coupling reaction of phenol 10, followed by regioselective
intramolecular aza-Michael reaction of the resulting dienone 9.
In the synthesis of the B ring in 9, the stereochemistry at C13
with the all-carbon quaternary stereogenic center was expected
to be controlled by C10 in 10. According to this synthetic plan,
all of the stereochemistry in the hasubanan skeleton would be
controlled by the stereocenter at C10. We planned to
synthesize phenol 10 by coupling of 11 and 12, which
correspond to the A- and C-rings in 5, respectively.
Our synthesis commenced with the construction of the
stereocenter at C10 in (−)-metaphanine (5) (Scheme 1).
First, the coupling reaction of TMS cyanohydrin 11 and
mesylate 12,10 which correspond to the A- and C-rings,
respectively, was carried out with LiHMDS followed by
Received: January 3, 2021
Published: February 15, 2021
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2699

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azide group in 19 was then reduced to amine under the
Staudinger conditions, and the resulting amine was protected
with a Boc group, followed by deprotection of the MOM
group with a catalytic amount of terabromomethane in 2-
propanol to give phenol 20.17 With the phenol 20 in hand,
oxidative dearomative phenolic coupling reaction was inves-
tigated.18 Thus, phenol 20 was treated with PIDA in
hexafluoro-2-propanol (HFIP) at 0 °C in the presence of
methanol as an additive.19 Under these conditions, the
coupling reaction proceeded to afford the dienone 21 in 34%
yield as a single diastereomer.20 In this reaction, two possible
transition states, TS-1 and TS-2, can be considered regarding
the configuration at C10, and the reaction would preferentially
proceed from the sterically less hindered transition state TS-1
to predominantly form 21 having the desired configuration at
C13.
With the tricyclic hasubanan framework (A,B,C-rings) of 21
in place, construction of the D-ring was investigated by means
of regioselective intramolecular aza-Michael reaction. After
debromination of 21 with sodium formate in the presence of
Pd(PPh3)4, the resulting dienone 9 was subjected to
intramolecular aza-Michael reaction (Table 1). First, we
examined the reaction with Brønsted acids (entries 1, 2). In
the case of trifluoroacetic acid, the sterically less hindered C5
adduct 23 was obtained as the major product (8/23 = 1:4.4
ratio). On the other hand, the adducts at C5 and C14, 23 and
8, were obtained in 68% total yield with an approximately 1:1
ratio upon reaction with hydrochloric acid. Thus, we focused
on basic conditions. In the case of DBU in THF at rt, no
reaction took place, presumably due to the weak basicity, and
the substrate 9 was recovered quantitatively (entry 3). Stronger
bases such as sodium hydride or sodium tert-butoxide gave
mixtures of 8 and 23 in 67% and 60% yields, respectively, with
no selectivity (entries 4, 5). Interestingly, tetracyclic C14
adduct 8 was obtained predominantly (8/23 = 1.9:1 ratio) in
59% yield with potassium tert-butoxide in THF at 0 °C, and
the selectivity was drastically increased to 7.3:1 (8/23) in a
mixed solvent system (THF/HMPA = 9:1) at 0 °C. The
desired 8 was obtained in 51% yield after separation on a silica
gel column (entry 7).
Figure 1. (a) Structures of representative hasubanan alkaloids. (b)
Proposed biosynthetic pathway leading to stephadiamine (6) from 5.
(c) Retrosynthetic analysis of metaphanine (5) and stephadiamine
(6).
treatment with TBAF to give 13 in 78% yield. We next
investigated control of the stereochemistry at C10 of the
ketone in 13 under various asymmetric reduction conditions,
using CBS reduction11 and Noyori’s hydrogenation-transfer
conditions,12,13 but only moderate selectivity was obtained
(see Supporting Information). Thus, we examined various
acylative kinetic resolution (KR) conditions with racemic
alcohol rac-14, obtained by reduction of 13 with sodium
borohydride, using chiral isothiourea catalysts.14 The desired
alcohol (−)-14 was obtained with excellent enantioselectivity
(over 99% ee) by employing a catalytic amount of (2S,3R)-
HyperBTM (15) in the presence of isobutyric anhydride as an
acylating reagent.15,16 Isobutyric ester 16 obtained in this
process was recyclable to the ketone 13 almost quantitatively
by removal of the acyl group under basic conditions, followed
by oxidation of the resulting alcohol.
Then, we shifted our attention to the construction of the all-
carbon quaternary stereogenic center at C13 by means of
oxidative dearomative coupling reaction. The substrate phenol
20 for this conversion was synthesized as follows. Protection of
the alcohol in (−)-14 with silyl ether followed by ozonolysis
and reduction of the allyl group gave alcohol 18. The hydroxyl
group in 18 was converted into azide by mesylation followed
by treatment with sodium azide to give 19 in 72% yield. The
With tetracyclic 8 in hand, we moved on to the syntheses of
(−)-metaphanine (5) and (+)-stephadiamine (6) (Scheme 2).
First, we examined selective oxidation at C8 of enone 8. After
several attempts, we found that the Davis oxaziridine oxidant
rac-24 was effective, affording α-hydroxy ketone 25 in 71%
yield. After oxidation of the hydroxyl group with DMP in 25,
the TIPS ether in the resulting 26 was deprotected with HF·
Et3N to give the hemiacetal 27 in 77% yield from 25. Then, the
double bond in 27 was reduced under hydrogenation
conditions to give 28 in 80% yield. Finally, (−)-metaphanine
(5) was synthesized from 28 by deprotection of the Boc group
with hydrochloric acid followed by reductive methylation of
the resulting amine with formaldehyde and cyanoborohydride
in 45% yield. The structure of the synthetic (−)-metaphanine
(5) was confirmed by X-ray crystallography analysis and
1
comparison of the spectral data of H and 13C NMR with
previously reported values.21,22
As already mentioned, we had hypothesized that stephadi-
amine (6) would be biosynthetically generated from
metaphanine (5). To test this idea, we examined the
transformation of (−)-metaphanine (5) into (+)-stephadi-
amine (6). As we had hoped, aza-benzilic acid type
rearrangement proceeded upon treatment of 5 with ammonia
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Communication
a
Scheme 1. Synthesis of Pivotal Intermediate 8
a
Reagents and conditions: (a) 12 (1.0 equiv), LiHMDS (1.3 equiv), THF, −78 to 0 °C, 45 min; (b) TBAF (1.0 equiv), THF, 0 °C, 5 min (78%, 2
steps); (c) NaBH4 (1.5 equiv), MeOH, 0 °C, 10 min (99%); (d) 15 (10 mol %), (i-PrCO)2O (0.6 equiv), i-Pr2NEt (0.6 equiv), toluene, −60 °C, 8
h ((−)-14, 39%, 99% ee), (16, 51%, 74% ee); (e) NaOH (12 equiv), MeOH, rt, 10 min; (f) DMP (1.5 equiv), CH2Cl2, rt, 1 h (95%, 2 steps); (g)
TIPSCl (2.0 equiv), imidazole (4.0 equiv), DMF, 65 °C, 12 h (95%); (h) O3 (gas), MeOH, −78 °C, 5 min, then NaBH4 (3.0 equiv), 0 °C, 30 min
(76%); (i) MsCl (1.2 equiv), Et3N (1.5 equiv), DMF, 0 °C, 10 min, then NaN3 (2.0 equiv), 65 °C, 6 h (92%); (j) PPh3 (2.0 equiv), H2O (10.0
equiv), THF, 65 °C, 6 h, then Boc2O (2.0 equiv), rt, 1 h; (k) CBr4 (0.2 equiv), i-PrOH, 65 °C, 3 h (74%, 2 steps); (l) PIDA (1.0 equiv), MeOH
(100 equiv), HFIP, 0 °C, 5 min (34%), (m) HCO2Na (1.5 equiv), Pd(PPh3)4 (10 mol %), DMF, 100 °C, 2 h (99% yield); (n) KOt-Bu (5.0
equiv), THF/HMPA, 0 °C, 5 min (51%). LiHMDS = Lithium bis(trimethylsilyl)amide, THF = tetrahydrofuran, TBAF = tetra-n-butylammonium
fluoride, DMP = Dess-Martin periodinane, DMF = N,N-dimethylformamide, MsCl = methanesulfonyl chloride, Boc2O = di-tert-butyl dicarbonate,
PIDA = iodobenzene diacetate, HFIP = 1,1,1,3,3,3-hexafluoro-2-propanol, HMPA = hexamethylphosphoric triamide.
in methanol at room temperature, affording exclusively
(+)-stephadiamine (6) via an imine intermediate 7. Although
purification was difficult because of the instability of 6 on an
ODS or a silica gel column under acidic or basic conditions, as
already reported,6,7 we were able to obtain satisfactory
analytical data, including 1H and 13C NMR spectra, for
identification of the structure of 6 without purification of the
reaction mixture.
In summary, we have achieved the first enantioselective total
syntheses of (−)-metaphanine (5) and (+)-stephadiamine (6).
Based on our hypothesis that (+)-stephadiamine (6) would be
formed biosynthetically from (−)-metaphanine (5), we
investigated this bioinspired aza-benzilic acid-type rearrange-
ment and excitingly found that the reaction proceeds as
expected simply upon treatment with ammonia. The present
syntheses also feature diastereoselective oxidative phenolic
coupling and subsequent regioselective intramolecular aza-
Michael reaction for the construction of the hasubanan
skeleton of (−)-metaphanine (5), and this strategy is expected
to provide access to a variety of hasubanan alkaloids.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c00047.
Experimental Procedures, spectroscopic date for all
compounds, and HPLC analysis (PDF)
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Communication
Table 1. Investigation of Regioselective Aza-Michael
Reaction with Dienone 9
Scheme 2. Completion of the Syntheses of Metaphanine (5)
and Stephadiamine (6)
a
8 and 23
a
b
entry
conditions
yield (%)
ratio (8:23)
c
1
2
3
4
5
6
7
TFA, CH2Cl2, 0 °C to rt.
66
68
1:4.4
1.2:1
c
HCl/1,4-dioxane, CH2Cl2, 0 °C
d
DBU, THF, 0 °C to rt
no reaction
d
NaH, THF, 0 °C
67
60
59
1:1.2
1:1
1.9:1
d
NaOt-Bu, THF, 0 °C
KOt-Bu, THF, 0 °C
KOt-Bu, THF/HMPA (9:1), 0 °C
d
d
e
58 (51)
7.3:1
a
b
Total yield of 8 and 23. Determined from the 1H NMR spectrum of
the crude material, 1.0 equiv. 5.0 equiv. Isolated yield of 8.
c
d
e
AUTHOR INFORMATION
Corresponding Authors
■
Minami Odagi − Department of Biotechnology and Life
Science, Tokyo University of Agriculture and Technology,
Koganei, Tokyo 184-8588, Japan; Email: odagi@
cc.tuat.ac.jp
Kazuo Nagasawa − Department of Biotechnology and Life
Science, Tokyo University of Agriculture and Technology,
Koganei, Tokyo 184-8588, Japan; orcid.org/0000-0002-
0437-948X; Email: knaga@cc.tuat.ac.jp
Authors
Taisei Matoba − Department of Biotechnology and Life
Science, Tokyo University of Agriculture and Technology,
Koganei, Tokyo 184-8588, Japan
Keisuke Hosoya − Department of Biotechnology and Life
Science, Tokyo University of Agriculture and Technology,
Koganei, Tokyo 184-8588, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c00047
a
Reagents and conditions: (a) rac-24 (2.0 equiv), KHMDS (3.0
equiv), THF, −78 °C to rt, 6 h (71%); (b) DMP (3.0 equiv),
NaHCO3 (6.0 equiv), CH2Cl2, rt, 3 h (98%); (c) 3HF·Et3N (50
equiv), MeCN, rt, 6 h (77%); (d) H2 (balloon), Pd/C (10 wt %),
THF, rt, 30 min (80%); (e) HCl (4 M in 1,4-dioxane, 100 equiv),
CH2Cl2, 0 °C to rt, 30 min; (f) HCHO (12.3 M in H2O, 3.0 equiv),
NaBH3CN (1.5 equiv), MeCN, 0 °C, 30 min (45%, 2 steps); (g) NH3
(2 M in MeOH, 200 equiv), rt, 6 h (>90%).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Prof. Dr. Keiichi Noguchi (Tokyo
University of Agriculture and Technology) for his support in
X-ray crystallographic analysis. This research was funded by
Grants-in-Aid for Scientific Research on Innovative Areas
“Middle Molecular Strategy” (18H04387 to K.N.), Grants-in-
Aid for Scientific Research (B) (17H03052 to K.N.), and the
A3-foresight program from the Japan Society for the
Promotion of Science (JSPS). M.O. is grateful for JSPS
KAKENHI Grant Number 20K05488. T.M. thanks the
Support 21 Social Welfare Foundation and pp Scholarship
for financial support. K.H. was supported by Grants-in-Aid for
a JSPS fellowship (19J13325). This work was inspired by the
international and interdisciplinary environment of the JSPS
Asian CORE Program of ACBI (Asian Chemical Biology
Initiative).
REFERENCES
■
(1) (a) Matsui, M. In The Alkaloids: Chemistry and Pharmacology;
Brossi, A., Ed.; Academic Press: New York, 1988; Vol. 33, pp 307−
347. (b) Semwal, D. K.; Badoni, R.; Semwal, R.; Kothiyal, S. K.;
Singh, G. J. P.; Rawat, U. The genus Stephania (Menispermaceae):
Chemical and pharmacological perspectives. J. Ethnopharmacol. 2010,
132, 369−383. (c) King, S. M.; Herzon, S. B. In The Alkaloids:
̈
Chemistry and Biology; Knolker, H.-J., Ed.; Academic Press:
Burlington, MA, 2014; Vol. 73, pp 161−222.
(2) Pihko, A. J.; Koskinen, M. P. Synthesis of propellane-containing
natural product. Tetrahedron 2005, 61, 8769−8807.
(3) For synthetic studies of hasubanan alkaloids, see: (a) Ibuka, T.;
Kitano, M. Studies on the alkaloids of menispermaceous plants.
CCXXXIX. Synthesis of hasubanan derivative from sinomenine.
2702
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J. Am. Chem. Soc. 2021, 143, 2699−2704

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
Chem. Pharm. Bull. 1967, 15, 1944−1947. (b) Tomita, M.; Kitano,
M.; Ibuka, T. Synthesis of ring system related to hasubanan alkaloid.
Tetrahedron Lett. 1968, 9, 3391−3393. (c) Evans, D. A. An approach
to the synthesis of the hasubanan carbocyclic system. Tetrahedron
Lett. 1969, 10, 1573−1576. (d) Evans, D. A.; Bryan, C.; Wahl, G.
Total synthesis of naturally occurring substances. II. The synthesis of
the hasubanan carbocyclic system. J. Org. Chem. 1970, 35, 4122−
4127. (e) Evans, D. A.; Bryan, C. A.; Sims, C. L. Complementarity of
(4 + 2) cycloaddition reactions and [2,3] sigmatropic rearrangements
in synthesis. New synthesis of functionalized hasubanan derivatives. J.
Am. Chem. Soc. 1972, 94, 2891−2892. (f) Kametani, T.; Kobari, T.;
Fukumoto, K. Synthesis of the hasubanan ring system from the
alkaloid reticuline. J. Chem. Soc., Chem. Commun. 1972, 288−289.
(g) Kametani, T.; Kobari, T.; Shishido, K.; Fukumoto, K. Studies on
the syntheses of heterocyclic compoundsDXLVIII. Tetrahedron
1974, 30, 1059−1064. (h) Shiotani, S.; Kometani, T. A novel
synthesis of hasubanan skeleton. Tetrahedron Lett. 1976, 17, 767−770.
(d) Calandra, N. A.; King, S. M.; Herzon, S. B. Development of
enantioselective synthetic routes to the hasubanan and acutumine
alkaloids. J. Org. Chem. 2013, 78, 10031−10057. (e) Tan, S.; Li, F.;
Park, S.; Kim, S. Memory of chirality in bromoalkyne carbocycliza-
tion: Applications in asymmetric total synthesis of hasubanan
alkaloids. Org. Lett. 2019, 21, 292−295. (f) Li, G.; Wang, Q.; Zhu,
J. Unified divergent strategy towards the total synthesis of the three
sub-classes of hasubanan alkaloids. Nat. Commun. 2021, 12, Article
number: 36. DOI: 10.1038/s41467-020-20274-1.
(6) Taga, T.; Akimoto, N.; Ibuka, T. Stephadiamine, a new skeletal
alkaloid from Stephania japonica: The first example of a C-
norhasubanan alkaloid. Chem. Pharm. Bull. 1984, 32, 4223−4225.
(7) Hartrampf, N.; Winter, N.; Pupo, G.; Stoltz, B. M.; Trauner, D.
Total synthesis of the norhasubanan alkaloid stephadiamine. J. Am.
Chem. Soc. 2018, 140, 8675−8680.
(8) (a) Battersby, A. R.; Jones, R. C. F.; Kazlauskas, R.; Poupat, C.;
Thornber, C. W.; Ruchirawat, S.; Staunton, J. The biosynthesis of
hasubanonine and protostephanine. J. Chem. Soc., Chem. Commun.
1974, 773−775. (b) Battersby, A. R.; Jones, R. C. F.; Kazlauskas, R.;
Ottridge, A. P.; Poupat, C.; Staunton, J. Biosynthesis. Part 23.
Degradative studies on the alkaloids hasubanonine and protostepha-
nine from Stephania japonica. J. Chem. Soc., Perkin Trans. 1 1981,
2010−2015. (c) Battersby, A. R.; Jones, R. C. F.; Kazlauskas, R.;
Thornber, C. W.; Ruchirawat, S.; Staunton, J. Biosynthesis. Part 24.
Speculative incorporation experiments with 1-benzylisoquinolines and
a logical approach via C6−C2and C6−C3precursors to the
biosynthesis of hasubanonine and protostephanine. J. Chem. Soc.,
Perkin Trans. 1 1981, 2016−2029. (d) Sugimoto, Y. In Vitro Culture
and the Production of Secondary Metabolites in Stephania. Biotechnol.
Agric. For. 2002, 51, 281−305.
(9) For related reactions, see: (a) Yang, T.-F.; Chen, L.-H.; Kao, L.-
T.; Chuang, C.-H.; Chen, Y.-Y. Condensation-ring expansion reaction
of formyl[2.2.1]bicyclic carbinols with para-substituted phenyl
amines: Application to the preparation of [3.2.1]bicyclic N-aryl-
1,2,3-oxathiazolidine-2-oxide agents. J. Chin. Chem. Soc. 2012, 59,
378−388. (b) Rao, H. S. P.; Vijjapu, S. The Voight reaction on
tertiary α-hydroxy ketones. Tetrahedron 2015, 71, 8391−8406.
(10) For details of the synthesis of 11 and 12, see Supporting
Information.
̈
(i) Bruderer, H.; Knopp, D.; Daly, J. J. Synthese und Rontgenstruktur
von 3-Hydroxy-N-methyl-hasubanan. Helv. Chim. Acta 1977, 60,
1935−1941. (j) Schwartz, M. A.; Wallace, R. A. Synthesis of
morphine alkaloid analogs. Hasubanans and 9,17-secomorphinans.
Tetrahedron Lett. 1979, 20, 3257−3260. (k) Trauner, D.; Porth, S.;
Opatz, T.; Bats, J. W.; Giester, G.; Mylzer, J. New ventures in the
construction of complex heterocycles: Synthesis of morphine and
hasubanan alkaloids. Synthesis 1998, 1998, 653−664. (l) Nguyen, T.
X.; Kobayashi, Y. Synthesis of the common propellane core structure
of the hasubanan alkaloids. J. Org. Chem. 2008, 73, 5536−5541.
(m) Nielsen, D. K.; Nielsen, L. L.; Jones, S. B.; Toll, L.; Asplund, M.
C.; Castle, S. L. Synthesis of isohasubanan alkaloids via
enantioselective ketone allylation and discovery of an unexpected
rearrangement. J. Org. Chem. 2009, 74, 1187−1199.
(4) For total synthesis of hasubanan alkaloids in racemic form, see:
(a) Tomita, M.; Ibuka, T.; Kitano, M. Synthesis of hasubanan from
morphinan. Tetrahedron Lett. 1966, 7, 6233−6236. (b) Ibuka, T.;
Tanaka, K.; Inubushi, Y. The total synthesis of dl-hasubanonine.
Tetrahedron Lett. 1970, 11, 4811−4814. (c) Keely, S. L.; Martinez, A.
J.; Tahk, F. C. The 3-arylpyrrolidine alkaloid synthon. Tetrahedron
1970, 26, 4729−4742. (d) Inubushi, Y.; Kitano, M.; Ibuka, T. Total
synthesis of dl-cepharamine. Chem. Pharm. Bull. 1971, 19, 1820−
1841. (e) Ibuka, T.; Tanaka, K.; Inubushi, Y. Total synthesis of dl-
metaphanine. Tetrahedron Lett. 1972, 13, 1393−1396. (f) Belleau, B.;
(11) For reviews, see: (a) Corey, E. J.; Helal, C. J. Reduction of
carbonyl compounds with chiral oxazaborolidine catalysts: A new
paradigm for enantioselective catalysis and a powerful new synthetic
method. Angew. Chem., Int. Ed. 1998, 37, 1986−2012. (b) Helal, C. J.;
Meyer, M. P. The Corey−Bakshi−Shibata reduction: Mechanistic and
synthetic considerations − Bifunctional Lewis base catalysis with dual
activation. In Lewis Base Catalysis in Organic Synthesis; Vedejs, E.,
Denmark, S. E., Eds.; Wiley: 2016; Chapter 11, p 387.
(12) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R.
Asymmetric transfer hydrogenation of aromatic ketones catalyzed by
chiral ruthenium(II) complexes. J. Am. Chem. Soc. 1995, 117, 7562−
7563.
́
Wong, H.; Monkovic, I.; Perron, Y. G. Total synthesis of 3,14-
dihydroxyisomophinans and 9α-hydroxy-3-methoxyhasubanans. J.
Chem. Soc., Chem. Commun. 1974, 603−604. (g) Ibuka, T.; Tanaka,
K.; Inubushi, Y. Total synthesis of the alkaloid, ( )-hasubanonine.
Chem. Pharm. Bull. 1974, 22, 782−798. (h) Ibuka, T.; Tanaka, K.;
Inubushi, Y. Total synthesis of the alkaloid ( )-metaphanine. Chem.
Pharm. Bull. 1974, 22, 907−921. (i) Achmatowicz, O. J.; Bukowski, P.
Total synthesis of monosaccharides. Synthesis of methyl DL-
pentopyranosides with α-and β-lyxo, β-ribo, α-xylo, and α-arabino
configurations from furfuryl alcohol. Can. J. Chem. 1975, 53, 2524−
́
2529. (j) Monkovic, I.; Wong, H. Synthetic morphinans and
(13) Touge, T.; Hakamata, T.; Nara, H.; Kobayashi, T.; Sayo, N.;
Saito, T.; Kayaki, Y.; Ikariya, T. Oxo-tethered ruthenium(II) complex
as a bifunctional catalyst for asymmetric transfer hydrogenation and
H2 hydrogenation. J. Am. Chem. Soc. 2011, 133, 14960−14963.
(14) Merad, J.; Pons, J.; Chuzel, O.; Bressy, C. Enantioselective
catalysis by chiral isothioureas. Eur. J. Org. Chem. 2016, 2016, 5589−
5610.
(15) Joannesse, C.; Johnston, C. P.; Concellon, C.; Simal, C.; Philp,
D.; Smith, A. D. Isothiourea-catalyzed enantioselective carboxy group
transfer. Angew. Chem., Int. Ed. 2009, 48, 8914−8918.
(16) The absolute configuration of the stereogenic center at C10 in
(−)-14 was determined by X-ray analysis of compound S5. For
details, see Supporting Information.
hasubanans. VI. Total synthesis of 3-hydroxyisomorphinans, 3-
hydroxyhasubanans, and 3,9-dihydroxyhasubanans. Can. J. Chem.
1976, 54, 883−891. (k) Jones, S. B.; He, L.; Castle, S. L. Total
synthesis of ( )-hasubanonine. Org. Lett. 2006, 8, 3757−3760.
(m) Magnus, P.; Seipp, C. Concise synthesis of the hasubanan
alkaloid ( )-cepharatine A using a Suzuki coupling reaction to effect
o,p-phenolic coupling. Org. Lett. 2013, 15, 4870−4871.
(5) For asymmetric total synthesis of hasubanan alkaloids, see:
(a) Schultz, A. G.; Wang, A. First asymmetric synthesis of a
hasubanan alkaloid. Total synthesis of (+)-cepharamine. J. Am. Chem.
Soc. 1998, 120, 8259−8260. (b) Chuang, K. V.; Navarro, R.; Reisman,
S. E. Short, enantioselective total syntheses of (−)-8-demethoxyr-
unanine and (−)-cepharatines A, C, and D. Angew. Chem., Int. Ed.
2011, 50, 9447−9451. (c) Herzon, S. B.; Calandra, N. A.; King, S. M.
Efficient entry to the hasubanan alkaloids: first enantioselective total
syntheses of (−)-hasubanonine, (−)-runanine, (−)-delavayine, and
(+)-periglaucine B. Angew. Chem., Int. Ed. 2011, 50, 8863−8866.
(17) Shih-Yuan Lee, A.; Hu, Y.-J.; Chu, S.-F. A simple and highly
efficient deprotecting method for methoxymethyl and methoxyethox-
ymethyl ethers and methoxyethoxymethyl esters. Tetrahedron 2001,
57, 2121−2126.
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(18) For detailed conditions for oxidative phenolic coupling
reaction, see Supporting Information.
(19) Uyanik, M.; Yasui, T.; Ishihara, K. Hydrogen bonding and
alcohol effects in asymmetric hypervalent iodine catalysis: Enantio-
selective oxidative dearomatization of phenols. Angew. Chem., Int. Ed.
2013, 52, 9215−9218.
(20) Para−para coupling product S1 was obtained as a major side
product. For details, see Supporting Information.
(21) Since detailed 1H and 13C NMR spectral data were not
available from the original publication, we decided to confirm the
structure of 5 by X-ray analysis. For details, see Supporting
Information.
(22) Tomita, T.; Ibuka, T.; Inubuahi, Y.; Takeda, K. Structure of
metaphanine. Tetrahedron Lett. 1964, 5, 3605−3616.
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https://dx.doi.org/10.1021/jacs.1c00047
J. Am. Chem. Soc. 2021, 143, 2699−2704