Total synthesis of (+)- trans -dihydronarciclasine utilizing asymmetric conjugate addition

Article abstract of DOI:10.1021/ol302757y

A highly efficient short-step construction of the common phenanthridine skeleton of pancratistatin-class alkaloids was accomplished in enantiomerically pure form using chiral ligand-controlled asymmetric conjugate addition. The utility of the intermediate

Full text of DOI:10.1021/ol302757y

ORGANIC
LETTERS
2012
Vol. 14, No. 23
5868–5871
Total Synthesis of (þ)-trans-
Dihydronarciclasine Utilizing Asymmetric
Conjugate Addition
Ken-ichi Yamada,† Yuzo Mogi,†,‡ Magdi A. Mohamed,‡,§ Kiyosei Takasu,† and
Kiyoshi Tomioka*,
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo,
Kyoto 606-8501, Japan, Department of Pharmaceutical Chemistry, Faculty of Pharmacy,
University of Khartoum, El Qasr Avenue, P. O. Box 1996, Khartoum 11111, Sudan, and
Faculty of Pharmaceutical Sciences, Doshisha Women’s College of Liberal Arts, Kodo,
Kyotanabe 610-0395, Japan
tomioka@pharm.kyoto-u.ac.jp
Received October 9, 2012
ABSTRACT
A highly efficient short-step construction of the common phenanthridine skeleton of pancratistatin-class alkaloids was accomplished in
enantiomerically pure form using chiral ligand-controlled asymmetric conjugate addition. The utility of the intermediate was demonstrated by the
total synthesis of (þ)-trans-dihydronarciclasine with mild oxidation from an amine to an amide as a key step.
(þ)-trans-Dihydronarciclasine (1), originally reported
as a hydrogenation product of naturally occurring
narciclasine,1 was isolated from the Chinese medicinal
plant Zephyranthes candida in 1990 by Pettit et al.2 and is
an important member of the Amaryllidaceae alkaloids
(Figure 1). This alkaloid exhibits higher potency against
selected human cancer cell lines than the intensively in-
vestigated (þ)-pancratistatin (2).3 Despite their moderate
molecular size, 1 and 2 are challenging synthetic targets
because of their structural complexity, which includes a
highly oxygenated phenanthridinone core with successive
stereogenic centers on the cyclohexane ring.4 Although
many total syntheses of 2 have been reported, only two
asymmetric syntheses of 1 have been reported5 since the
first total synthesis of racemic trans-dihydronarciclasine
in 2007.6
† Kyoto University.
§ University of Khartoum.
Doshisha Women's College of Liberal Arts.
‡ These two authors have contributed equally to this work.
(1) Mondon, A.; Krohn, K. Chem. Ber. 1975, 108, 445.
(2) Pettit, G. R.; Cragg, G. M.; Singh, S. B.; Duke, J. A.; Doubek,
D. L. J. Nat. Prod. 1990, 53, 176.
Figure 1. Some Amaryllidaceae alkaloids.
(3) Pettit, G. R.; Melody, N. J. Nat. Prod. 2005, 68, 207.
(4) Recent reviews on synthesis of this class of alkaloids: (a) Jin, Z.
Nat. Prod. Rep. 2011, 28, 1126. (b) Kornienko, A.; Evidente, A. Chem.
Rev. 2008, 108, 1982. (c) Manpadi, M.; Kornienko, A. Org. Prep.
Proced. Int. 2008, 40, 107. (d) Chapleur, Y.; Chretien, F.; Ibn Ahmed,
S.; Khaldi, M. Curr. Org. Synth. 2006, 3, 341. (e) Rinner, U.; Hudlicky,
T. Synlett 2005, 365.
(5) (a) Jana, C. K.; Studer, A. Chem.;Eur. J. 2008, 14, 6326. (b)
Hwang, S.; Kim, D.; Kim, S. Chem.;Eur. J. 2012, 18, 9977.
(6) Shin, I.-J.; Choi, E.-S.; Cho, C.-G. Angew. Chem., Int. Ed. 2007,
46, 2303.
ꢀ
r
10.1021/ol302757y
Published on Web 11/12/2012
2012 American Chemical Society

Wepreviouslyreported the asymmetrictotalsynthesisof
another Amaryllidaceae alkaloid, (ꢀ)-lycorine (3), which
has a different carbon skeleton, using an asymmetric
conjugate additionꢀMichael cyclization cascade of linear
R,ω-dialkenoate.7 Herein, we describe the total synthesis
of (þ)-trans-dihydronarciclasine (1) using chiral ligand-
controlled8 asymmetric conjugate addition of cyclic enoate
as a key step.
recovered without the loss of optical purity and was
therefore reusable.
Scheme 2. Construction of Key Intermediate 11 Using Asym-
metric Conjugate Addition of 4 and 5 and Curtius Rearrangement
In our strategy, chiral ligand 6 mediates an asymmetric
conjugate addition reaction9 of aryllithium 4, bearing a
trityloxymethylgroup attheortho position,10 withenoate 5
to give cis-7 enantioselectively (Scheme 1). Epimerization
followed by Curtius rearrangement and subsequent CꢀN
bond formation leads to the construction of phenan-
thridindione 8, a potential common intermediate of
pancratistatin-class alkaloids like 1.
Scheme 1. Synthetic Strategy of 1
Both epimerization at the R-position and hydrolysis of
tert-butyl ester were simultaneously achieved by treatment
with potassium hydroxide, generated in situ from potas-
sium tert-butoxide and water,11 in refluxing dioxane to
afford trans-carboxylic acid 9 as a single diastereomer.
Recrystallization of 9 from hexane/ethyl acetate (1:1)
afforded enantiomerically pure 9 (>99:1 er) in 90% yield.
Introduction of a nitrogen atom using diphenylpho-
sphoryl azide (DPPA)12 efficiently proceeded, forming
the corresponding isocyanate. The isocyanate, however,
had limited reactivity, probably due to steric hindrance,
and only a trace amount of the corresponding tert-butyl
carbamate was formed when heated with tert-butanol. To
enhance the electrophilicity of the isocyanate by in situ-
generated hydrogen chloride,13 the isocyanate resulting
from the Curtius rearrangement was treated with tert-
butanol and chlorotrimethylsilane. Unexpectedly, the
CꢀN bond forming cyclization took place along with the
expected carbamate formation to give 11 in 68% yield in 2
steps. The production of 11 can be explained by a sub-
stitution reaction of the trityloxy group withthe carbamate
nitrogen atom via cationic intermediate 10 under acidic
conditions. Thus, the phenanthridine core of pancratistatin-
class alkaloids was constructed in optically pure form
only in five steps, including the enantiomer enrichment by
recrystallization. To demonstrate the utility of phenan-
thridine 11 as a synthetic intermediate, total synthesis of 1
was further explored.
A toluene solution of enoate 5 was added to a solution of
aryllithium 4, prepared from the corresponding aryl bro-
mide (1.0 equiv) and butyllithium (1.0 equiv) in the pre-
sence of chiral ligand 6 (1.3 equiv) in toluene at ꢀ78 °C.
After 26 h, a 95:5 mixture of cis- and trans-7 was obtained
in 70% combined yield, and 20% of 5 was recovered. The
enantiomeric ratio of cis-7 was 94:6 based on chiral
stationary phase HPLC analysis. The relative and absolute
configurations of cis-7 were confirmed by epimerization to
trans-7 (see Supporting Information) and by conversion
into 1, respectively. With increased amounts of 4 and 6 (2.0
and 2.3 equiv, respectively), 5 was completely consumed,
and the yield of cis-7 was increased to 91% with slightly
higher selectivity (95:5 er, 97:3 dr). Moreover, cis-7 was
produced in high yield and enantioselectivity (92%, 96:4 er)
with comparable diastereoselectivity (96:4 dr) when 3.0
and 3.3 equiv of 4and 6were utilized, respectively (Scheme 2).
It is noteworthy that chiral ligand 6 was quantitatively
First, oxidation of the benzylic methylene group in 11
was investigated to install the lactam moiety. Although
various reaction conditions, such as tert-butylperoxy-
iodane,14 ruthenium trichloride withsodium perchlorate,15
(7) Yamada, K.; Yamashita, M.; Sumiyoshi, T.; Nishimura, K.;
Tomioka, K. Org. Lett. 2009, 11, 1631.
(8) Tomioka, K. Synthesis 1990, 541.
(9) Asano, Y.; Iida, A.; Tomioka, K. Tetrahedron Lett. 1997, 38,
8973.
(11) Gassman, P. G.; Schenk, W. N. J. Org. Chem. 1977, 42, 918.
(12) Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron 1974, 30,
2151.
(13) Benalil, A.; Roby, P.; Carboni, B.; Vaultier, M. Synthesis 1991,
787.
(14) Ochiai, M.; Kajishima, D.; Sueda, T. Tetrahedron Lett. 1999, 40,
5541.
(10) The bulky trityl group of 4 likely prevents chelation of the
oxygen atom to the lithium in the 6-controlled asymmetric conjugate
addition: Yamashita, M.; Yamada, K.; Tomioka, K. J. Am. Chem. Soc.
2004, 126, 1954.
(15) Elango, S.; Yan, T.-H. J. Org. Chem. 2002, 67, 6954.
Org. Lett., Vol. 14, No. 23, 2012
5869

or N-bromosuccinimide with benzoyl peroxide16 were at-
tempted, 11and itsBoc-and/oracetal-deprotectedanalogs
were labile under these oxidation conditions, giving com-
plex mixtures, probably due to the electron rich aromatic
ring. Finally, as shown in Scheme 2, the desired oxidation
was accomplished in a stepwise manner: Treatment of 11
with TFA to hydrolyze the acetal and remove the Boc
group, followed by oxidation of the resulting amine with
iodosobenzene in the presence of a catalytic amount of
tetrabutylammonium iodide (TBAI),17 gave the corre-
sponding imine in 66% yield in 2 steps.18 The desired
lactam 8 was obtained in 83% yield by our mild oxida-
tion of the imine with sodium chlorite.19 Unfortu-
nately, 8 was insoluble in most solvents, which caused
difficulty in further transformations. We therefore
performed this benzylic amine oxidation at a later stage
in the synthesis.
Stereoselective formation of 13 was rationalized by the
reaction pathway shown in Scheme 4. First, the R-position
of ketone 12 was oxidized by iodine(III) species through
the corresponding enolate stereoselectively from the axial
side to give intermediate A. Then, the stereospecific for-
mation of epoxide C via reversively generated hemiacetal B
was followed by ring-opening and the addition of metha-
nol to the resulting intermediate D to produce 13.
Scheme 4. Rationale for the Stereoselective Formation of 13
Thus, the oxygen functionalities were stereoselectively
introduced on the cyclohexane ring as follows (Scheme 3).
Hydrolysis of the acetal moiety of 11 with acetic acid in
aqueous THF at 80 °C gave ketone 12, which was then
stereo- and regioselectively oxidized to dimethyl acetal 13
by iodobenzene diacetate in the presence of sodium hydro-
xide in methanol.20 Other methods for R-oxidation of
ketone utilizing m-CPBA,21 oxaziridine,22 palladium(II),23
The dimethyl acetal moiety of 13 was hydrolyzed with
PPTS in wet acetone, and subsequent protection of the
hydroxy group with a TBS group afforded R-siloxy ketone
14, which was then regioselectively converted into vinyl
triflate 15 in 92% yield by successive treatment with
LHMDS and Comins reagent.26 The triflyloxy group
was removed in 78% yield by catalytic hydrogenolysis
using formic acid as a hydride source,27 and allylic alcohol
17 was obtained in 95% yield after removal of the TBS
group of 16 by TBAF. Stereochemical inversion of the
secondary alcohol 17 was accomplished by modified
Mitsunobu conditions28 to give 4-nitrobenzoate 18 in
87% yield. Dihydroxylation of 18 with osmium tetroxide
and NMO diastereoselectively gave diol 19 in 83% yield
along with its diastereomer in 16% yield, and amine 21
was obtained in 97% yield after acetylation of 19 and
removal of the Boc group of 20.
2-iodoxybenzoic acid,24 or oxodiperoxymolybdenum
3
pyridine HMPA,25 resulted in low yield or a complex
mixture.
3
Scheme 3. Total Synthesis of (þ)-trans-Dihydronarciclasine (1)
The amine was then oxidized to lactam under the afore-
mentioned conditions. Despite the highly functionalized
(16) Ishiguro, T.; Mizuguchi, H; Tomioka, K.; Koga, K. Chem.
Pharm. Bull. 1985, 33, 609.
(17) Huang, W.-J.; Singh, O. V.; Chen, C.-H.; Chiou, S.-Y.; Lee, S.-S.
Helv. Chim. Acta 2002, 85, 1069.
(18) Attempted direct conversion to lactam 8 by a prolonged reaction
with PhIdO and TBAI resulted in a complex mixture.
(19) Mohamed, M. A.; Yamada, K.; Tomioka, K. Tetrahedron Lett.
2009, 50, 3436.
(20) (a) Moriarty, R. M.; Gupta, S. C.; Hu, H.; Berenschot, D. R.;
White, K. B. J. Am. Chem. Soc. 1981, 103, 686. (b) Kamernitzky, A. V.;
Turuta, A. M.; Fadeeva, T. M.; Istomina, Z. I. Synthesis 1985, 326.
(21) Rubottom, G. M.; Vazquez, M. A.; Pelegrina, D. R. Tetrahedron
Lett. 1974, 15, 4319.
(22) (a) Davis, F. A.; Vishwakarma, L. C.; Billmers, J. M.; Finn, J.
J. Org. Chem. 1984, 49, 3241. (b) Davis, F. A.; Sheppard, A. C.
Tetrahedron 1989, 45, 5703.
(23) Ito, Y.; Hirano, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
(24) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc.
2000, 122, 7596.
(25) (a) Vedejs, E. J. Am. Chem. Soc. 1974, 96, 5944. (b) Vedejs, E.;
Engler, D. A.; Telschow, J. E. J. Org. Chem. 1978, 43, 188.
(26) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.
(27) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1984, 25,
4821.
(28) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017.
5870
Org. Lett., Vol. 14, No. 23, 2012

structure of 21, two-step oxidation via imine 22 success-
fully provided 23 in 80% yield. This result clealy demon-
strated the excellent functional group tolerance of our
oxidation method.19
Finally, removal of the methyl and acyl groups afforded
(þ)-trans-dihydronarciclasine (1), whose specific rotation,
1H and 13C NMR, MS, and IR data were consistent with
those previously reported.1,5,6
to the synthesis of other known members of this
class of alkaloids, such as 6- and/or 7-deoxy, and/or
1,10b-dehydro analogs.4 This synthesis highlights
the utility of our protocol for oxidation of an amine
to an amide.
Acknowledgment. We thank JSPS and MEXT, Japan,
for financial support.
In summary, we developed four-step construction
of the common skeleton of the pancratistatin-class
alkaloids using our chiral diether-controlled asym-
metric conjugate addition methodology and achieved
total synthesis of (þ)-trans-dihydronarciclasine. This syn-
thetic strategy is versatile and potentially applicable
Supporting Information Available. Experimental de-
tails, characterization data and NMR spectra of new
compounds, and HPLC traces. This material is available
free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 23, 2012
5871