Syntheses of optically pure conduramines via the strategy of hetero diels-alder reaction of masked o -benzoquinones with homochiral nitroso dienophiles

Article abstract of DOI:10.1021/ol100840n

Highly stereoselective hetero Diels-Alder reactions of masked o-benzoquinones (MOBs) with homochiral nitroso dienophiles are described along with their application in the syntheses of (+)-ent-conduramine F-1, (+)-conduramine E-1, (-)-conduramine A-1, (+)-

Full text of DOI:10.1021/ol100840n

ORGANIC
LETTERS
2010
Vol. 12, No. 11
2642-2645
Syntheses of Optically Pure
Conduramines via the Strategy of
Hetero Diels-Alder Reaction of Masked
o-Benzoquinones with Homochiral
Nitroso Dienophiles
Ping-Hsun Lu,†,‡ Ching-Shun Yang,† Badugu Devendar,†,‡ and
Chun-Chen Liao*,†,‡
Department of Chemistry, National Tsing Hua UniVersity, Hsinchu 30013, Taiwan, and
Department of Chemistry, Chung Yuan Christian UniVersity, Chungli 32023, Taiwan
ccliao@cycu.edu.tw
Received April 13, 2010
ABSTRACT
Highly stereoselective hetero Diels-Alder reactions of masked o-benzoquinones (MOBs) with homochiral nitroso dienophiles are described
along with their application in the syntheses of (+)-ent-conduramine F-1, (+)-conduramine E-1, (-)-conduramine A-1, (+)-conduramine A-1
tetraacetate, and (-)-ent-conduramine A-1 tetraacetate.
Conduramines are aminocyclohexenetriols formally derived
from conduritols, in which one of the hydroxyl groups is
exchanged with an amino group. They constitute a continuing
and growing class of important compounds with often
interesting biological activities. Indeed, some of the condu-
ramines have significant glycosidase inhibitory effects.1 Some
also serve as important precursors of a wide variety of natural
products, such as (+)-lycoricidine,2 (+)-narciclasine,3 (-)-
lycorine,4 and azasugars5 (Figure 1).
Several research groups6-17 have reported fascinating
syntheses of racemic6-8 and optically pure9-12 conduramines
(2) Hudlicky, T.; Olivo, H. F. J. Am. Chem. Soc. 1992, 114, 9694–
9696.
† National Tsing Hua University.
(3) Elango, S.; Yan, T.-H. J. Org. Chem. 2002, 67, 6954–6959.
(4) (a) Schultz, A. G.; Holoboski, M. A.; Smyth, M. S. J. Am. Chem.
Soc. 1996, 118, 6210–6219. (b) Yamada, K.-I.; Yamashita, M.; Sumiyoshi,
T.; Nishimura, K.; Tomoika, K. Org. Lett. 2009, 11, 1631–1633.
‡ Chung Yuan Christian University.
(1) Paul, B. J.; Willis, J.; Martinot, T. A.; Ghiviriga, I.; Abboud, K. A.;
Hudlicky, T. J. Am. Chem. Soc. 2002, 124, 10416–10426.
10.1021/ol100840n  2010 American Chemical Society
Published on Web 05/07/2010

and their derivatives. Muchowski and co-workers have
developed a synthetic pathway for (()-conduramine A-1
from pyrrole.8 The first asymmetric synthesis of optically
pure (+)-conduramine F-1 was achieved by Paulsen and co-
workers,9 using homochiral polyols. Later, Hudlicky and co-
workers10 synthesized (+)-conduramine A-1 and (+)-
dihydroconduramine A-1 from homochiral cyclohexadienediol
and nitrosyl derivatives. Very recently, Studer and co-workers
reported an enantioselective nitroso Diels-Alder reaction and
its application in the synthesis of (-)-peracetylated condu-
ramine A-1.12b However, the syntheses of chiral condu-
ramines have been limited to methods that use dihydroxy-
diene10 and chiral building blocks, such as L-quebrachitol,9
D-glucose,11 and their derivatives.16,17
variety of functionalized cyclopentenones. We have also
applied this strategy to the synthesis of (()-untenone
efficiently.20 We have carried out the first hetero Diels-Alder
reactions of MOBs with nitroso dienophiles to access highly
functionalized heterocyclic molecules.21 We have published
intriguing results of highly diastereoselective and asymmetric
Diels-Alder reactions of MOBs with homochiral furans,
which lead to highly functionalized tricyclic ring systems
with four stereogenic centers.22 We have also developed
carbohydrate-templated asymmetric Diels-Alder reactions
of MOBs for the synthesis of optically active bicyclo[2.2.2]oct-
5-en-2-ones.23 On the basis of this knowledge, our efforts
turned toward the development of reactions of MOBs with
homochiral nitroso compounds for the syntheses of valuable
optically active intermediates for a wide variety of biologi-
cally important molecules. We herein report a facile and
convenient route for the synthesis of optically pure condu-
ramines starting from MOBs and homochiral nitroso com-
pounds, prepared from (1S)-(+)- and (1R)-(-)-10-camphor-
sulfonic acids.
Since MOBs (as a diene18,19 ) and nitroso dienophiles24
are reactive species, we generated these two species in situ.
MOBs were obtained from 2-methoxyphenols by oxidation
with DAIB in MeOH, and the homochiral nitroso compounds
were created from their hydroxylamine precursors with
Bu4NIO4. Combining the solutions of these two reactive
species, generated in situ at -10 °C, we produced an
optically active nitroso Diels-Alder adduct in a one-pot
operation. The chiral auxiliaries were chosen and prepared
from (1S)-(+)- and (1R)-(-)-10-camphorsulfonic acids.25
Figure 1. Conduramines and various types of interesting natural
products containing conduramine frameworks.
Masked o-benzoquinones (MOBs),18 which are highly
reactive cyclohexa-2,4-dienones, can be generated by the
oxidation of easily accessible 2-methoxyphenols in methanol
with diacetoxyiodobenzene (DAIB) or bis(trifluoroacetoxy-
)iodobenzene (BTIB). In continuation of our ongoing re-
search program on the Diels-Alder reactions using MOBs,19
we have recently disclosed the results of hetero Diels-Alder
reactions of MOBs with singlet oxygen, which afford a
Accordingly, we synthesized the nitroso Diels-Alder
adduct 2, from 2-methoxyphenol 1 and chiral auxiliary A1
at -10 °C. It was obtained as the major product of this
reaction in 86% yield and 89% de. Upon simple recrystal-
lization, 2 was obtained in high de (>99%) (Scheme 1). The
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Org. Lett., Vol. 12, No. 11, 2010
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with high stereoselectivity, and the chiral auxiliary was
removed by LAH to obtain oxazine 4; the camphor-based
residue was oxidized to ketopinic acid which was then
converted to A1 for reuse.25 Reductive cleavage of the
nitrogen-oxygen bond of oxazine 4 in the presence of
Mo(CO)6 gave amino alcohol 5.26
Scheme 1. Syntheses of Allylic Azide 6, Enone 7, and
Precursors of (+)-ent-Conduramine F-1 8 and (+)-Conduramine
E-1 10
Several attempts were made to convert the ketal of 5 to
the ketone without success. Finally, we converted the amine
5 to the azide 6 using TfN3 and CuSO4 (Scheme 1).27
Treatment of allylic azide 6 with TFA at room temperature
gave enone 7 by hydrolysis of the ketal functional group
and [3,3]-sigmatropic rearrangement28 in a one-pot operation.
With enone 7 in hand, Luche reduction gave an inseparable
mixture of alcohols 8 and 9.29 The mixture was treated with
2,2-dimethoxypropane (DMP) to protect the cis-diol 9 and
generate the ketal 10. The compounds 8 and 10 were isolated
in 53% and 33% yields, respectively (Scheme 1).
The alcohol 8 under the Staudinger reaction conditions
provided (+)-ent-conduramine F-1 (11).27 A similar proce-
dure was implemented for the synthesis of compound 12
from the alcohol 10, and subsequent deprotection of the ketal
group in the presence of AcOH produced the (+)-condu-
ramine E-1 13 (Scheme 2).
Scheme 2
.
Total Syntheses of (+)-ent-Conduramine F-1 11 and
(+)-Conduramine E-1 13
After successful delivery of (+)-ent-conduramine F-1 11
and (+)-conduramine E-1 13, our interest was directed to
the synthesis of (-)-conduramine A-1.
To achieve our target synthesis of (-)-conduramine A-1,
we investigated the reaction of the MOB derived from
2-(methoxymethoxy)-phenol 14 with chiral auxiliary A2,
prepared from (1R)-(-)-10-camphorsulfonic acid. This pro-
vide 15a and 15b in 82% yield as an inseparable mixture
which was further treated with DIBALH to reduce the ketone
Figure 2. ORTEP diagram of Diels-Alder adduct 2.
(26) Cicchi, S.; Goti, A.; Brandi, A.; Guarna, A.; De Sarlo, F.
Tetrahedron Lett. 1990, 31, 3351–3354.
absolute configuration of 2 was confirmed by single-crystal
X-ray diffraction (Figure 2 for ORTEP diagram and CCDC
# 751811).
The nitroso Diels-Alder adduct 2 was further treated with
DIBALH to obtain the hydroxyl compound 3 in 79% yield
(27) Nyffeler, P. T.; Liang, C.-H.; Koeller, K. M.; Wong, C.-H. J. Am.
Chem. Soc. 2002, 124, 10773–10778.
(28) Lauzon, S.; Tremblay, F.; Gagnon, D.; Godbout, C.; Chabot, C.;
Shanks, C. M.; Perreault, S.; Deseve, H.; Spino, C. J. Org. Chem. 2008,
73, 6239–6250.
(29) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226–2227.
2644
Org. Lett., Vol. 12, No. 11, 2010

group to give 16a and 16b in 81% yield. The mixture of
16a and 16b was hydrolyzed to hemiketal 17 in the presence
of TFA in 56% yield and 89% de, which was enhanced to
>99% after recrystallization (Scheme 3). The tentative
mechanism for the conversion of 16 to 17 is represented in
Scheme 4.
Scheme 5. Syntheses of (-)-Conduramine A-1 21 and
(+)-Conduramine A-1 Tetraacetate 22
Scheme 3. Synthesis of Key Intermediate 17
We also successfully synthesized (-)-ent-conduramine
A-1 tetraacetate 30, from 2-(methoxymethoxy)phenol 14 and
the homochiral nitroso compound, generated from chiral
auxiliary A1 (prepared from (1S)-(+)-10-camphorsulfonic
acid). All the products (25-29) were well characterized by
spectral data analysis (see Supporting Information).
Scheme 4. Proposed Mechanism for Intermediate 17
In summary, we have developed the first diastereoselective
hetero Diels-Alder reactions of MOBs with homochiral
acylnitroso compounds from (1S)-(+)- and (1R)-(-)-10-
camphorsulfonic acids to furnish bicyclo[2.2.2]octenone
derivatives in high yields and high diastereoselectivities. We
have also successfully applied these derivatives in the
syntheses of (+)-ent-conduramine F-1 11, (+)-conduramine
E-1 13, (-)-conduramine A-1 21, (+)-conduramine A-1
tetraacetate 22, and (-)-ent-conduramine A-1 tetraacetate 30.
The utilization of this methodology for the synthesis of
conduramine-based natural products is in progress.
After several attempts at reduction with various reducing
reagents, such as DIBALH, L-selectride, and NaBH4, the best
results were obtained when hemiketal 17 was treated with
NaBH4 in MeOH. This furnished the desired diol compound
18, which was further treated with DMP to obtain ketal 19.
With the compound 19 in hand, we treated it successively
with LAH and Mo(CO)6 to obtain amino alcohol 20 in 80%
overall yield over two steps. Under acidic conditions,
acetonide 20 was converted into the target (-)-conduramine
A-1 21 in 94% yield after purification by silica gel column
chromatography. To compare the specific rotation with
reported (+)-conduramine A-1 tetraacetate,7 we derivatized
our (-)-conduramine A-1 21 as (+)-conduramine A-1
tetraacetate 22 as depicted in Scheme 5.
Acknowledgment. The financial support from the CYCU
distinctive research area project as grant CYCU-98-CR-CH
and National Science Council (NSC) of Taiwan (grant nos.:
NSC 95-2113-M-007-027-MY3, 98-2119-M-033-001, 98-
2119-M-033-003, 98-2811-M-033-012) is gratefully ac-
knowledged. P.-H. Lu and B.D. thank NSC for postdoctoral
fellowships.
Supporting Information Available: Experimental details,
1H, 13C NMR, DEPT spectra, and HPLC chromatograms for
compounds 2, 17, and 25. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL100840N
Org. Lett., Vol. 12, No. 11, 2010
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