N-methoxy-N-acylnitrenium ions: application to the formal synthesis of (-)-TAN1251A.

Article abstract of DOI:10.1021/ol015626o

[structure: see text]. A formal synthesis of the muscarinic M(1) receptor antagonist (-)-TAN1251A (7) from L-tyrosine is described. Central to this venture has been the construction of the 1-azaspiro[4.5]decane skeleton present in the natural product by a

Full text of DOI:10.1021/ol015626o

ORGANIC
LETTERS
2001
Vol. 3, No. 7
1053-1056
N-Methoxy-N-acylnitrenium Ions:
Application to the Formal Synthesis of
(−)-TAN1251A
Duncan J. Wardrop* and Arindrajit Basak
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
wardropd@uic.edu
Received January 29, 2001
ABSTRACT
A formal synthesis of the muscarinic M receptor antagonist (−)-TAN1251A (7) from L-tyrosine is described. Central to this venture has been
1
the construction of the 1-azaspiro[4.5]decane skeleton present in the natural product by an N-methoxy-N-acylnitrenium ion-induced
spirocyclization. The dienone generated in this transformation, 10, was converted to (−)-TAN1251A via tricycle 9, an intermediate in Kawahara’s
recent synthesis of racemic 7.
Nitrenium ions 1 remain a focus of attention three decades
after the publication of Gassman’s seminal review article,1
not only because of their suspected role as the reactive
metabolites2 of mutagenic nitro and aminoaromatic com-
pounds but also because of their utility in organic synthesis.1,3
independently by Kikugawa and Glover in 1984, these
powerful electrophiles readily undergo inter- and intra-
molecular substitution reactions with a range of aromatic ring
systems.4 They can be generated by the treatment of
N-alkoxy-N-chloroamides with a variety of Lewis acids,
typically silver4a-d or zinc ions4f or, more conveniently, by
direct oxidation of N-methoxyamides with bis(trifluoroacet-
oxy)iodobenzene.4e,5 As illustrated in Scheme 1, the outcome
Scheme 1. Cyclization of N-Alkoxy-N-acylnitrenium Ions
Among the most easily formed and useful members of
this class are N-alkoxy-N-acylnitrenium ions 2. First reported
(1) Gassman, P. G. Acc. Chem. Res. 1970, 3, 26-33.
(2) (a) Garner, R. C.; Martin, C. N.; Clayson, D. B. In Chemical
Carcinogens, 2nd ed.; Searle, C. E., Ed.; ACS Monograph 182; American
Chemical Society: Washington, DC, 1984; Vol. 1, pp 175-276. (b)
Kennedy, S. A.; Novak, M.; Kolb, B. A. J. Am. Chem. Soc. 1997, 119,
7654-7664. (c) Novak, M.; Xu, L.; Wolf, R. A. J. Am. Chem. Soc. 1998,
120, 1643-1644. (d) McClelland, R. A.; Ahmad, A.; Dicks, A. P.; Licence,
V. E. J. Am. Chem. Soc. 1999, 121, 3303-3310.
(3) (a) Abramovitch, R. A.; Jeyaraman, R. In Azides and Nitrenes:
ReactiVity and Utility; Scriven, E. F. V., Ed.; Academic Press: Orlando,
FL, 1984; pp 297-357. (b) Simonova, T. P.; Nefedov, V. D.; Toropova,
M. A.; Kirillov, N. F. Russ. Chem. ReV. 1992, 61, 584-599. (c) McClelland,
R. A. Tetrahedron 1996, 52, 6823-6858.
10.1021/ol015626o CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/14/2001

of the cyclization of nitrenium ions generated from N-chloro-
N-methoxy-2-phenylacetamides (3) is highly dependent upon
the substitution pattern of the aromatic ring. Unactivated
systems such as 3a cyclize via the Ar2-6 pathway to form
N-methoxybenzolactams 6 while substrates with a 4-methoxy
substituent, such as 3b, undergo spirocyclization (Ar1-5) and
loss of methanol to form dienones 5.4c Glover has proposed
that the ease with which 2 can be generated and the efficiency
with which they undergo N-arylations is due to the fact that
these ions are stabilized by the neighboring oxygen lone pair
and are therefore sufficiently long-lived to undergo cycliza-
tion.4d
Although the pioneering studies of Kikugawa and Glover
established methods for generating N-alkoxy-N-acylnitrenium
ions and explored their reactivity, there have been surpris-
ingly few applications of these intermediates in synthesis.
Notable exceptions, which all involve Ar2-5/6 cyclizations,
include Kikugawa’s total synthesis of eupolauramine,6
preparation of an oxindole model of gelsemine by Fleming,7
and, more recently, Romero’s elegant use of consecutive
nitrenium ion cyclizations in the preparation of the dopamine
D2 receptor agonist PNU-95666E.8 However, to date, as far
as we are aware, there have been no reports of the successful
application of the nitrenium ion-induced Ar1-5 spirocycliza-
tion to the synthesis of a natural product.9 Our interest in
this area was stimulated by the isolation of several alkaloids,
including TAN1251A (7),10 the immunosuppresant FR901483
(8),11 and the cylindricines12 which all contain a 1-azaspiro-
[4.5]decane skeleton that we believed could be readily
accessed using this nitrenium ion chemistry. The successful
realization of this strategy as applied to the synthesis of (-)-
TAN1251A is the subject of this Letter.
industries, which contain the novel 1,4-diazabicyclo[3.2.1]-
octane skeleton.13 TAN1251A is a selective and highly potent
muscarinic M1 receptor antagonist which inhibits the acet-
ylcholine-induced contraction of Guinea-pig ileum with an
ED50 value of 8.0 nM. Since most currently available
muscarinic antagonists are not selective for the numerous
receptor subtypes, there is considerable interest in M1
selective antagonists as they have therapeutic potential for
gastrointestinal and respiratory indications.14 TAN1251A’s
combination of potent biological activity and structural
novelty has attracted the attention of a number of groups:
racemic and asymmetric total syntheses of 7 have recently
been reported by Kawahara15 and Snider.16 Our retrosynthetic
analysis of TAN1251A is illustrated in Scheme 2. We
Scheme 2. Retrosynthetic Analysis of (-)-TAN1251A (7)
envisioned that azaspirocyclization of L-tyrosine derivative
11 using Kikugawa’s4f method would provide dienone 10
which could then serve as a common platform from which
to launch asymmetric syntheses of both 7 and 8. Recognizing
the importance of an amine protecting group capable of
withstanding the oxidative cyclization conditions, we deemed
methyl carbamate to be ideal since it both tolerates bis-
(trifluoroacetoxy)iodobenzene and would serve as a latent
N-methyl group.17 For our initial foray into this area, we
(9) While this work was in progress, Ciufolini and Sorenson indepen-
dently reported complementary methods for preparing spirocyclic pyrroli-
dinones involving the oxidation of phenolic oxazolines, and amines,
respectively. These transformations involve aryl oxidation and subsequent
trapping rather than the formation of N-acylnitrenium ions: (a) Braun, N.
A.; Ousmer, M.; Bray, J. D.; Bouchu, D.; Peters, K.; Peters, E. M.; Ciufolini,
M. A. J. Org. Chem. 2000, 65, 4397-4408. (b) Scheffler, G.; Seike, H.;
Sorenson, E. J. Angew. Chem., Int. Ed. 2000, 39, 4593-4596.
(10) Shirafuji, H.; Tsubotani, S.; Ishimaru, T.; Harada, S. PCT Int. Appl.
1991, WO 91 13,887; Chem. Abstr. 1992, 116, 39780t.
(11) Sakamoto, K.; Tsujii, E.; Abe, F.; Nakanishi, T.; Yamashita, M.;
Shigematsu, N.; Izumi, S.; Okuhara, M. J. Antibiot. 1996, 49, 37-44.
(12) Blackman, A. J.; Li, C.; Hockless, D. C. R.; Skelton, B. W.; White,
A. H. Tetrahedron 1993, 49, 8645-8656.
(13) Although unprecedented in Nature, 1,4-diazabicyclo[3.2.1]octanes
have been the subject of previous synthetic studies: Hirschfield, A.; Taub,
W. Tetrahedron 1972, 28, 1275-1287. Strum, P. A.; Cory, M.; Henry, D.
W.; Ziegler, J. B.; McCall, J. W. J. Med. Chem. 1977, 20, 1333-1337.
(14) Widzowski, D.; Helander, H. F.; Wu, E. S. C. Drug DiscoVery Today
1997, 2, 341-350.
(15) Nagumo, S.; Nishida, A.; Yamazaki, C.; Murashige, K.; Kawahara,
N. Tetrahedron Lett. 1998, 39, 4493-4496.
(16) Snider, B. B.; Lin, H. Org. Lett. 2000, 2, 643-646.
TAN1251A (7) is a member of a family of alkaloids,
recently isolated from Penicillium thomii RA-89 by Takeda
(4) (a) Glover, S. A.; Goosen, A.; McCleland, C. W.; Schoonraad, J. L.
J. Chem. Soc., Perkin Trans. 1 1984, 2255-2260. (b) Kikugawa, Y.;
Kawase, M. J. Am. Chem. Soc. 1984, 106, 5728-5729 (c) Kawase, M.;
Kitamura, T.; Kikugawa, Y. J. Org. Chem. 1989, 54, 3394-3403. (d)
Glover, S. A.; Scott, A. P. Tetrahedron 1989, 45, 1763-1776. (e) Kikugawa,
Y.; Kawase, M. Chem. Lett. 1990, 581-582. (f) Kikugawa, Y.; Shimada,
M.; Matsumoto, K. Heterocycles 1994, 37, 293-301.
(5) For recent reviews of hypervalent iodine(III) reagents, see: (a) Stang,
P. J.; Zhdankin, V. V. Chem. ReV. 1996, 96, 1123-1178. (b) Varvogolis,
A. HyperValent Iodine in Organic Synthesis; Academic Press: San Diego,
1997. (c) Kitamura, T.; Fujiwara, Y. Org. Prep. Proc. Int. 1997, 29, 409-
458.
(6) Kawase, M.; Miyake, Y.; Sakamoto, T.; Shimada, M.; Kikugawa,
Y. Tetrahedron 1989, 45, 1653-1660.
(7) Fleming, I.; Moses, R. C.; Tercel, M.; Ziv, J. J. Chem. Soc., Perkin
Trans. 1 1991, 617-626.
(8) Romero, A. G.; Darlington, W. H.; McMillan, M. W. J. Org. Chem.
1997, 62, 6582-6587.
1054
Org. Lett., Vol. 3, No. 7, 2001

chose to merge our asymmetric route with Kawahara’s15
racemic synthesis at tricycle 9 and accordingly install the
benzyl side chain employing the established protocol.
Our route to 7 commenced from L-tyrosine (12) which
was converted to the corresponding N-methyl carbamate
derivative under Schotten-Baumann conditions18 (Scheme
3). Methylation of the remaining phenol and carboxylic acid
Scheme 4. 1,4-Diazabicyclo[3.2.1]octane Corea
Scheme 3. Nitrenium Ion-Induced Spirocyclizationa
a Reagents and conditions: (a) H2, 10% Pd/C, EtOAc, rt, 6 h;
(b) (CH2OH)2, PPTS, benzene, reflux, 3.5 h; (c) LiAlH4, THF,
reflux, 11 h; (d) BnOCOCl, Et3N, CH2Cl2, 0 °C to rt, 3 h; (e) Zn,
AcOH, 75 °C, 5 h; (f) BrCH2CO2Bn, K2CO3, CH3CN, 40 °C, 15
h; (g) H2, Pd/C, MeOH, rt, 30 min; (h) DPPA, NaHCO3, DMF,
CH2Cl2, 0 °C to rt, 87 h.
a Reagents and conditions: (a) i. MeOCOCl, NaOH, H2O, 5 °C,
1.5 h; ii. NaOH, H2O, 0 °C, 2 h; (b) (MeO)2SO2, K2CO3, acetone,
reflux, 3 h; (c) NaOH, H2O, dioxane, 0 °C, 30 min; (d)
MeONH2‚HCl, DCC, HOBT, NMM, DMF, CH2Cl2, rt, 24 h; (e) i.
PhI(OCOCF3)2, CH2Cl2, MeOH, 0 °C, 10 min; ii. H2O, 0 °C, 5
min.
encouraged to find, however, that reduction of 14 with
LiAlH4 in THF at reflux proceeded smoothly to furnish
N-methoxylamine 15b in 65% yield.22 Capitalizing on this
unexpected result, which conveniently differentiated the two
secondary amines, we proceeded to protect the N-methyl-
amine as the Cbz derivative and then unmask the pyrrolidine
by reductive cleavage of the N-OMe bond with zinc powder
in acetic acid.23 Alkylation of the resulting amine with benzyl
bromoacetate then furnished 16 in 66% yield from 15b. The
Cbz and benzyl protecting group were then simultaneously
removed by hydrogenolysis (1 atm) with Pd/C and the
resulting amino acid submitted directly to DPPA24 coupling
without purification. This cyclization, although slow, pro-
ceeded with reasonable efficiency to provide 9 in 57% yield
from 16.25
Having prepared the 1,4-diazabicyclo[3.2.1]octanone core
of 7 in 13 steps, we now proceeded to install the benzyl
side chain. Accordingly, generation of the enolate of 9 with
LDA in THF and subsequent trapping with p-prenyloxybenz-
aldehyde (17)26 (2 equiv) gave a 1.2:1 mixture of aldol
products in a combined yield of 80%, as reported by
Kawahara (Scheme 5).15 Rather than separate this mixture,
using dimethyl sulfate and K2CO3 in acetone at reflux then
gave 13 in 76% overall yield from 12. This ester was
saponified and the resulting acid then subjected to DCC/
HOBt19 coupling with methoxylamine to furnish N-meth-
oxyamide 11 in 73% yield. Gratifyingly, reaction of 11 with
bis(trifluoroacetoxy)iodobenzene (1.5 equiv) in CH2Cl2 and
MeOH now resulted in the rapid formation of dienone 10
accompanied by varying amounts of the corresponding
dimethyl acetal.20 Although this mixture proved to be
inseparable by flash chromatography, we found that addition
of water to the reaction mixture after cyclization hydrolyzed
the unstable acetal in situ. Using this procedure, 10 could
be obtained without incident in 69% overall yield.
As shown in Scheme 4, hydrogenation (1 atm) of 10 now
proceeded smoothly21 with 10% Pd/C to furnish the saturated
ketone which was then converted to the 1,2-dioxolane
derivative 14 under standard conditions. While our original
plan was to now exhaustively reduce 14 to N-methyldiamine
15a, reaction with borane-dimethyl sulfide complex8 in THF
gave an intractable mixture of several products. We were
(22) For other examples of the reduction of N-methoxyamides to
N-methoxyamines, see: (a) Godjoian, G.; Singaram, B. Tetrahedron Lett.
1997, 38, 1717-1720. (b) Uneme, H.; Mitsudera, H.; Yamada, J.;
Kamikado, T.; Kono, Y.; Manabe, Y.; Numata, M. Biosci., Biotechnol.,
Biochem. 1992, 56, 1293-1299.
(23) Iida, H.; Watanabe, Y.; Kibayashi, C. Tetrahedron Lett. 1986, 27,
5513-5514.
(24) Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc. 1972, 94,
6203-6205.
(25) For a discussion of the peptide coupling of secondary amines, see:
Humphrey, J. M.; Chamberlin, A. R. Chem. ReV. 1997, 97, 2243-2266.
(26) Prepared by the alkylation of p-hydroxybenzaldehyde with 1-bromo-
3-methyl-2-butene: Chari, V. M.; Aurnhammer, G.; Wagner, H. Tetrahedron
Lett. 1970, 11, 3079-3082.
(17) Romero and co-workers have previously reported the successful use
of this protecting group strategy.8
(18) Determann, H.; Zipp, O.; Wieland, T. Liebigs Ann. Chem. 1962,
651, 172-184.
(19) Ko¨nig, W.; Geiger, R. Chem. Ber. 1970, 103, 788-798.
(20) This acetal presumably arises from trapping of the intermediate
oxonium cation by methanol. Use of CH2Cl2 alone led to lower yields of
10.
(21) Interestingly, reductive aromatization, a complication in Ciufolini’s9a
work, was not observed with our spriocyclic system.
Org. Lett., Vol. 3, No. 7, 2001
1055

improved yield of the corresponding enamine which was
finally deprotected by hydrolysis with aqueous HCl in
acetone to provide (-)-TAN1251A. This material was found
to be in close agreement with the reported spectral and
physical data.10,16,27
Scheme 5. Synthesis of (-)-TAN1251Aa
In summary, we have completed a formal synthesis of (-)-
TAN1251A and report the first application of an N-methoxy-
N-acylnitrenium ion-induced spirocyclization to the synthesis
of a natural product. Our progress toward the synthesis of
FR901483 (8) will be reported in due course.
Acknowledgment. We wish to thank the University of
Illinois at Chicago and the National Institutes of Health
(GM59157-01) for financial support and Dr. K. Saito and
Dr. T. Hida, Takeda Chemical Industries, for generously
1
supplying H and 13C NMR spectral data for natural (-)-
TAN1251A.
a Reagents and conditions: (a) i. 9, LDA, THF, 0 °C, 30 min;
ii. 17, -78 °C, 90 min; (b) i. MsCl, Et3N, CH2Cl2, 0 °C, 3 h; ii.
tBuOK, THF, rt, 17 h; (c) AlH3, Et2O, 0 °C, 1 h; (d) 1 M HCl,
acetone, rt, 12 h.
Supporting Information Available: Full experimental
procedures and spectral data for compounds 7, 9-11, and
13-19. This material is available free of charge via the
Internet at http://pubs.acs.org.
we found that reaction with MsCl/Et3N and elimination of
the resulting mixture of mesylates with BuOK gave R,â-
OL015626O
t
unsaturated amide 19 as a single stereoisomer in 75% overall
yield. Reduction of 19 with AlH3 in ether now gave an
(27) Mp 116-118 °C (lit.9 mp 118.5-120°C); [R]D -10.1° (c 0.41,
MeOH) (lit.9 -8.1° (c 0.42, MeOH)).
1056
Org. Lett., Vol. 3, No. 7, 2001