Synthetic studies on altemicidin: Stereocontrolled construction of the core framework

Article abstract of DOI:10.1021/ol701940f

(Chemical Equation Presented) The stereoselective synthesis of the key intermediate for altemicidin has been accomplished. The synthesis commenced with a bicyclo[3.3.0] framework, which was readily obtained via an intramolecular C-H insertion reaction. A Curtius rearrangement was employed as a key step to stereoselectively construct the β-hydroxyl α-disubstituted-α- amino acid structure. Synthesis of vinylogous urea was achieved using hydrolysis of nitrile intermediate.

Full text of DOI:10.1021/ol701940f

ORGANIC
LETTERS
2008
Vol. 10, No. 2
169-171
Synthetic Studies on Altemicidin:
Stereocontrolled Construction of the
Core Framework
Toshiyuki Kan,*,† Yuichiro Kawamoto,‡ Tomohiro Asakawa,† Takumi Furuta,† and
Tohru Fukuyama*,‡
School of Pharmaceutical Sciences, UniVersity of Shizuoka and COE Program in the
21st century, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan, and Graduate School
of Pharmaceutical Sciences, UniVersity of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan
kant@u-shizuoka-ken.ac.jp; fukuyama@mol.f.u-tokyo.ac.jp
Received August 9, 2007
ABSTRACT
The stereoselective synthesis of the key intermediate for altemicidin has been accomplished. The synthesis commenced with a bicyclo[3.3.0]
framework, which was readily obtained via an intramolecular C H insertion reaction. A Curtius rearrangement was employed as a key step to
-amino acid structure. Synthesis of vinylogous urea was achieved using hydrolysis
−
stereoselectively construct the
of nitrile intermediate.
â-hydroxyl r-disubstituted-r
Altemicidin (1), a six-azainden monoterpene alkaloid isolated
from the Actinomycete strain by Takeuchi et al. in 1989,1
has exhibited potent acaricidal activity, as well as the
inhibition of tumor cell growth. Furthermore, acylated
analogues of 1 have recently been shown to be strong
inhibitors of isoleucyl, leucyl, and valyl tRNA synthetase.2
Although this remarkable biological activity, coupled with
its highly complex structure, has made 1 an attractive target
for total synthesis, only Kende has reported the total synthesis
of 1 in 1995.3 The unique â-hydroxyl R-disubstituted-R-
amino acid structure4 and its potent bioactivities have
prompted us to investigate its total synthesis. Herein, we
report a stereocontrolled synthesis of key intermediate 19
for the total synthesis of 1.
The heart of our synthetic plan is illustrated in Scheme 1.
Scheme 1. Structure and Synthetic Strategy of 1
† University of Shizuoka and COE Program in the 21st century.
‡ University of Tokyo.
(1) (a) Takahashi, A.; Kurasawa, S.; Ikeda, D.; Okami, Y.; Takeuchi, T.
J. Antibiot. 1989, 42, 1556. (b) Takahashi, A.; Ikeda, D.; Nakamura, H.;
Naganawa, H.; Kurasawa, S.; Okami, Y.; Takeuchi, T.; Iitaka, Y. J. Antibiot.
1989, 42, 1562.
(2) (a) Banwell, M. G.; Crasto, C. F.; Easton, C. J.; Forrest, A. K.; Karoli,
T.; March, D. R.; Mensah, L.; Nairn, M. R.; O’Hanlon, P. J.; Oldham, M.
D.; Yue, W. Bioorg. Med. Chem. Lett. 2000, 10, 2263. (b) Houge-Frydrych,
C. S. V.; Gilpin, M. L.; Skett, P. W.; Tyler, J. W. J. Antibiot 2000, 53,
364.
The highly polar sulfonamide and vinylogous urea would
be introduced in a later stage of the synthesis. Because a
(3) Kende, A. S.; Liu, K.; Jos Brands, K. M. J. Am. Chem. Soc. 1995,
117, 10597.
(4) Ohfune, Y.; Shinada, T. Eur. J. Org. Chem. 2005, 5127.
10.1021/ol701940f CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/15/2007

9
Curtius rearrangement5 could incorporate nitrogen onto the
quaternary carbon of 2, azabicyclo[4.3.0]skeleton 2 would
serve as a key intermediate. The cyclic enamide would be
constructed from cyclopentene 3 by cleaving the double bond
and subsequently introducing nitrogen and recyclization. The
quaternary carbon and the secondary alcohol would be
stereoselectively installed by employing â-ketoester 4.
Recently, we developed an efficient synthesis of optically
active bicyclo[3.3.0] framework 4 using an intramolecular
C-H insertion reaction.6 Thus, the present synthetic study
has an advantage that is readily applicable to enantioselective
synthesis.
Synthesis of bicyclo[3.3.0] framework 6 was accomplished
via a rhodium carbenoid-mediated C-H insertion reaction
of diazoester 5.7 Although optically active 6 was readily
available, the racemic form was employed in this preliminary
study (Scheme 2). Upon treatment of â-ketoester 6 with
sequent stereoselective reduction of 7 with NaBH(OAc)3
gave 8. Because alkylation occurred from the convex face
of 6 and reduction proceeded via chelating with the primary
hydroxyl group of 7, the stereoselective construction of 8
was efficiently accomplished. After protecting the primary
alcohol as TBDPS and the secondary alcohol with MOM
ether, the conversion to cyclic enamide from 9 was examined.
Because directly installing the nitrogen group is difficult
after oxidative cleavage of the double bond of 9, an
intermolecular delivery of nitrogen was employed. Depro-
tection of the allyl group of 9, conversion to the acid chloride,
and treatment with ammonia gave amide 10. After dihy-
droxylation of 10, treating with Pb(OAc)4 generated dialde-
hydes where the amide nitrogen selectively attacked the
closer aldehyde to provide hemiaminal 11. After conversion
to the dimethyl acetal and methyl hemiaminal, selective
reduction of hemiaminal was achieved by treatment with
NaBH3CN to give lactam 12. The opening the γ lactam of
12 was achieved by combining the activation by Ns imide10,11
and using the neighboring effect of the primary alcohol for
the lactam intermediate. Treatment of 12 with LHMDS and
NsCl proceeded smoothly to provide 13. After removal of
the TBDPS group with TBAF and subjection to aqueous
KOH, lactam cleavage occurred smoothly to give 14.
Presumably this reaction proceeds through the â-lactone
intermediate. Conversion of 14 into cyclic enamide 15 was
performed by treatment with CSA and quinoline.
Scheme 2. Synthesis of the Enamide 15
With requisite enamide 15 in hand, we then focused our
attention on introducing a nitrogen atom onto the quaternary
carbon and a C1 unit onto the enamide, as shown in Scheme
3. Upon treatment of 15 with DPPA12 and Et3N, the
rearrangement proceeded easily to give 16. The oxazolidi-
none ring of 16 was formed by trapping in situ generated
isocyanate by the primary alcohol. After formylation of
enamide by modified Vilsmeier reaction,13 the amide group
was protected as a Boc imide. Subsequent N-methylation
was carried out by the deprotection of the Ns group and
treatment with LHMDS and MeI. Conversion from the
aldehyde to the nitrile group was performed by treatment
with hydroxylamine and subsequent addition of acetic
anhydride to the oxime intermediate to provide 18.14 After
hydrolysis of the oxazolidinone ring under basic conditions,
oxidation to the corresponding aldehyde was achieved by
Dess-Martin oxidation.15 Conversion from the nitrile group
to the desired amide was performed by treatment with a
(9) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560.
(10) For a review on Ns chemistry: (a) Kan, T.; Fukuyama, T. J. Synth.
Org. Chem., Jpn. 2001, 59, 779. (b) Kan, T.; Fukuyama, T. Chem. Commun.
2004, 1204.
(11) (a) Fukuyama, T.; Jow, C.-K.; Hidai, Y.; Kan, T. Tetrahedron Lett.
1995, 36, 6373. (b) Fukuyama, T.; Cheung, M.; Jow, C.-K.; Hidai, Y.; Kan,
T. Tetrahedron Lett. 1997, 38, 5831. (c) Fukuyama, T.; Cheung, M.; Kan,
T. Synlett 1999, 1301. (d) Kurosawa, W.; Kan, T.; Fukuyama, T. Org. Synth.
2002, 79, 186.
(12) (a) Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc. 1972,
94, 6203. (b) For a recent review on DPPA: Shioiri, T. Farumashia 2006,
42, 411.
(13) For a review on Vilsmeier reaction: (a) Jones, G.; Stanforth, S. P.
Org. React. 1997, 49, 1. (b) Jones, G.; Stanforth, S. P. Org. React. 2000,
56, 355.
formalin in the presence of a catalytic amount of KHCO3,
hydroxymethylation proceeded smoothly to afford 7.8 Sub-
(5) (a) Curtius, T. Ber. Dtsch. Chem. Ges. 1890, 23, 3023. (b) Review
on Curtius rearrangement: Smith, P. A. S. Org. React. 1946, 3, 337.
(6) For a review on C-H insertion reactions: (a) Doyle, M. P.;
Mckervey, M. A.; Ye, T. Modern Catalytic Methods for Organic Synthesis
with Diazo Compounds: From Cyclopropanes to Ylides; Wiley: New York,
1998. (b) Davies, H. M. L.; Beckwith, R. E. J. Chem. ReV. 2003, 103, 2861.
(7) Kan, T.; Inoue, T.; Kawamoto, Y.; Yonehara, M.; Fukuyama, T.
Synlett 2006, 10, 1583.
(8) Tsuji, J.; Nisar, M.; Shimizu, I. J. Org. Chem. 1985, 50, 3416.
(14) Newman, M. S.; Closson, R. D. J. Am. Chem. Soc. 1944, 66, 1553.
170
Org. Lett., Vol. 10, No. 2, 2008

have already been reported by Kende in a similar compound,
we have now focused our attention on the synthesis of
optically active 1 beginning with chiral 6, which has already
been reported by our group.
Scheme 3. Synthesis of the Key Intermediate 19
Thus, we accomplished the stereoselective synthesis of key
intermediate 19, which contains four sequential stereocenters
and vinylogous urea, for the total synthesis of 1. The
synthesis employed a bicyclo[3.3.0] framework, which was
readily obtained by a desymmetric C-H insertion reaction.
We are currently investigating the synthesis of (-)-altemi-
cidin (1).
Acknowledgment. This work was financially supported
by the SUNBOR Foundation, Uehara Memorial Foundation,
and a Grant-in-Aid for Scientific Research on Priority Areas
17025011 from The Ministry of Education, Culture, Sports,
Science and Technology (MEXT) of Japan.
Supporting Information Available: Detailed experi-
mental procedures and spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL701940F
(15) (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(b) Boeckman, R. K., Jr.; Mullins, J. J. Org. Synth. 1988, 77, 141. (c)
Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537.
(16) Ghaffar, T.; Parkins, A. W. J. Mol. Catal. A: Chem. 2000, 160,
249.
catalytic amount of Perkins reagent16 in the presence of water
to give the desired 19. Because deprotection of the Boc group
and MOM ether and subsequent incorporation of sulfonamide
Org. Lett., Vol. 10, No. 2, 2008
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