Total synthesis of (+)-trans-dihydronarciclasine by a catalytic enantioselective regiodivergent nitroso Diels-Alder reaction

Article abstract of DOI:10.1002/chem.200800903

A method was proposed to demonstrate the total synthesis of (+)-trans-dihydronarciclasine by a catalytic enantioselective regiodivergent nitroso Diels-Alder reaction. The study used enantioselective introso Diels-Alder reaction for the transformation of racemic dienes to the adducts. The study found that ring closure can occur by a Bischler-Napieralski reaction or by lactamization. The Br-Li exchange and transmetalation to copper with Fe-complexed cyclohexadienyl cation and oxidative decomplexation can provide diene in 85% yield. The study observed that the pyridyl group was cleaved by quarternizing the pyridyl moiety with methyl triflate and hydrolysis of the pyridinium salt. The study also observed that the biologically active natural products can be prepared in large amount by using this method.

Full text of DOI:10.1002/chem.200800903

DOI: 10.1002/chem.200800903
Total Synthesis of (+)-trans-Dihydronarciclasine by a Catalytic
Enantio
N
N
Chandan Kumar Jana and Armido Studer*[a]
Isocarbostryls are hydroxylated phenanthridones that
belong to an interesting class of biologically active natural
products of the Amaryllidaceae group.[1] trans-Dihydronarci-
clasine (1), pancratistatin (2), lycoricidine (3), and narcicla-
sine (4) are some members of this family. These compounds
Scheme 1. Retrosynthesis of (+)-trans-dihydronarciclasine 1 (PG=pro-
tecting group).
hydroxylation, O-protection, N-carbamoylation, and pyridyl
group cleavage would lead to compounds 5 in which all the
stereogenic centers are installed. Ring closure can either
occur by a Bischler–Napieralski reaction (R1 =H, R2 =
CO2Me)[6] or by lactamization (R1 =COX, R2 =H). Remov-
al of the protecting groups should finally afford 1.
Bromide 9 was readily prepared on a large scale starting
from o-vanillin (Scheme 2).[8] Br–Li exchange and transme-
talation to copper followed by reaction with a Fe-complexed
cyclohexadienyl cation and subsequent oxidative decom-
plexation provided diene 8a in 85% overall yield.[9] The syn-
theses of dienes 8b–e are described in the Supporting Infor-
mation.
show potent antitumor and antiviral activity.[1] Owing to
their biological activity and their stereochemical complexity,
the isocarbostryls and their derivatives have become inter-
esting and challenging targets for natural product synthe-
sis.[2] trans-Dihydronarciclasine (1) has been shown to have
a far higher activity against selected human cancer cell lines
than the intensively investigated pancratistatin (2).[3] Herein
we report the first total synthesis of enantiomerically pure
(+)-trans-dihydronarciclasine (1).[4–6]
The retrosynthetic analysis is presented in Scheme 1. As a
key step we planned to use our recently developed enantio-
selective nitroso Diels–Alder reaction for the transformation
of racemic dienes 8 to the adducts 7.[7] Reductive N O bond
ꢀ
cleavage should provide 6. Subsequent diastereoselective di-
[a] C. K. Jana, Prof. Dr. A. Studer
NRW Graduate School of Chemistry
Organisch-Chemisches Institut
Westfälische Wilhelms-Universität
Correnstrasse 40, 48149, Münster (Germany)
Fax : (+49)2818336523
E-mail: studer@uni-muenster.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200800903.
Scheme 2. Synthesis of racemic diene 8a.
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Chem. Eur. J. 2008, 14, 6326 – 6328

COMMUNICATION
The enantioselective regiodivergent Diels–Alder reaction
was studied with dienes 8a–e and 2-nitrosopyridine under
the previously reported conditions to afford 7a–e and 10a–
e, respectively (Scheme 3).[7,10] Pleasingly, reaction of diene
Scheme 3. Catalytic regiodivergent nitroso Diels–Alder reaction.
8a afforded the desired regioisomer 7a in 48% yield with
excellent enantioselectivity (>99% ee, Table 1, entry 1). The
relative configuration was assigned by NMR spectroscopy. It
turned out that lower selectivities for the required isomer
Scheme 4. Completion of the total synthesis. a) [Mo(CO)6], NaBH4,
MeOH/H2O; b) K2OsO2(OH)4, NMO, acetone/H2O; c) TBSCl, imida-
zole, DMF, 758C; d) MeMgCl, MeOCOCl, THF; e) MeOTf, CH2Cl2,
08C; f) NaOH, MeOH/H2O, 50 8C; g) TBAF, THF; h) Ac2O, pyridine; i)
Tf2O, DMAP, CH2Cl2; j) BBr3, CH2Cl2; k) NaOMe, MeOH. TBS=tert-
butyldimethylsilyl, Tf=trifluoromethanesulfonyl, TBAF=tetrabutylam-
monium fluoride, DMAP=4-dimethylaminopyridine.
were obtained for dienes 8b–e (R1 ¼
6
H, Table 1, entries 2–
5). Therefore, the synthesis was continued with 7a, and the
lactamization approach for the final ring closure (see
Scheme 1) was abandoned.
Table 1. Enantioselective regiodivergent nitroso Diels–Alder reaction.
In conclusion, we have presented an efficient 17-step syn-
thesis to enantiomerically pure 1 in 5.6% overall yield start-
ing from commercially available o-vanillin. The key step
was a Cu-catalyzed highly stereoselective divergent nitroso
Diels–Alder reaction on racemic diene 8a. The biologically
active natural product is available in larger quantities by
this novel route (up to 50 mg were readily prepared).
Entry
R1
R2
Yield [%][a]
Yield [%][a]
(ee, 7a–e)[b]
(ee, 10a–e)[b]
1
2
3
4
5
H
Me
Me
Me
Me
TBS
48 (>99%, 7a)
53 (86%, 7b)
55 (92%, 7c)
53 (70%, 7d)
54 (73%, 7e)
51 (92%, 10a)
38 (97%, 10b)
45 (95%, 10c)
33 (98%, 10d)
32 (95%, 10e)
CO2Me
CH2OH
CH2OTBS
CONMe2
[a] Yield of isolated product. [b] Determined by HPLC.
Acknowledgements
ꢀ
Reductive N O bond cleavage was achieved by treatment
of 7a with [Mo(CO)6] and NaBH4 in aqueous MeOH to
give 6 (90%; Scheme 4).[11] Diastereoselective dihydroxyla-
tion and persilylation provided 11. Carbamoylation of the
amino group occurred smoothly using the corresponding Mg
amide (97%). The pyridyl group was cleaved by quarterniz-
ing the pyridyl moiety with methyl triflate and consequent
base hydrolysis of the pyridinium salt to give 12 (one pot,
91%).[12] Subsequent desilylation and O-acetylation afforded
triacetate derivative 5 (95%). A Bischler–Napieralski reac-
tion according to a literature procedure[6a] occurred with
good regioselectivity to afford the protected trans-dihydro-
narciclasine 13 (64%).[13] Removal of the protecting groups
finally provided enantiomerically pure (+)-trans-dihydronar-
ciclasine 1 ([a]25D =+4.1 degcm3 gꢀ1 dmꢀ1, c=4.5 mgcmꢀ3,
THF; [a]25D =+4.7 degcm3 gꢀ1 dmꢀ1, c=5.4 mgcmꢀ3,
THF[5]).
We thank Novartis Pharma AG (Young Investigator Award to A.S.) and
the Fonds der Chemischen Industrie for continuous support.
Keywords: biologically active compounds
cycloaddition · natural products · stereoselective synthesis
·
copper
·
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Received: May 12, 2008
Published online: June 18, 2008
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