Pd-catalyzed carbonylative lactamization: A novel synthetic approach to FR900482

Article abstract of DOI:10.1021/ol049583y

Matrix presented. An asymmetric synthesis of the benzazocine core of FR900482 has been achieved in 15 steps from 3,5-dinitro-p-toluic acid. Key features of the synthesis include an enantioselective N-methylephedrine-mediated zinc acetylide addition to a h

Full text of DOI:10.1021/ol049583y

ORGANIC
LETTERS
2004
Vol. 6, No. 11
1745-1748
Pd-Catalyzed Carbonylative
Lactamization: A Novel Synthetic
Approach to FR900482
Barry M. Trost* and Michael K. Ameriks†
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
bmtrost@stanford.edu
Received March 5, 2004
ABSTRACT
An asymmetric synthesis of the benzazocine core of FR900482 has been achieved in 15 steps from 3,5-dinitro-p-toluic acid. Key features of
the synthesis include an enantioselective N-methylephedrine-mediated zinc acetylide addition to a highly enolizable arylacetaldehyde and a
novel Pd-catalyzed carbonylative lactamization to form an eight-membered ring.
The anticancer drug mitomycin C (1) has been in widespread
clinical use for over 30 years and remains an important
component of combination cancer therapy and radiotherapy
for solid tumors.1 However, due to its high hematotoxicity,
mitomycin C may soon be replaced by the structurally related
mitomycinoid FK317 (2), which is currently undergoing
advanced clinical trials in Japan.2 FK317 is a semisynthetic
derivative of FR900482 (3), an alkaloid isolated from the
fermentation broth of Streptomyces sandaensis by the
Fujisawa Pharmaceutical Co.3 Analogous to the mitomycins,
the cytotoxicity of both FK317 and FR900482 can be
attributed to covalent cross-linking of duplex DNA in the
minor groove following reductive activation in cells.4 Thus,
due to their potent antitumor activity, intriguing mode of
action, and densely functionalized molecular architecture,
FR900482 and related congeners (i.e., FR66979 4)5 have
attracted considerable attention from the synthetic com-
munity.6
In addition to comprising the core of several natural
products, the benzazocine ring system has been utilized as a
late-stage intermediate in synthetic routes to both the
mitomycins and the Fujisawa mitomycinoids. Varying the
oxidation state of the arylamine in the benzazocine allows
either the pyrrolo[1,2-a]indole framework of the mitomycins
or the bicyclo[3.3.1] hemiketal of the FR900482 alkaloids
to be accessed (Scheme 1).7
Although the direct formation of medium-sized rings from
acyclic precursors is disfavored by entropic and enthalpic
(5) Terano, H.; Takase, S.; Hosoda, J.; Kohsaka, M. J. Antibiot. 1989,42,
145.
(6) For total syntheses of FR900482, see: (a) Fukuyama, T.; Xu, L.;
Goto, S. J. Am. Chem. Soc. 1992, 114, 383. (b) Schkeryantz, J. M.;
Danishefsky, S. J. J. Am. Chem. Soc. 1995, 117, 4722. (c) Kato, T.; Itoh,
E.; Yoshino, T.; Terashima, S. Tetrahedron 1997, 53, 10253. (d) Judd, T.
C.; Williams, R. M. Angew. Chem., Int. Ed. 2002, 41, 4683. (e) Suzuki,
M.; Kambe, M.; Tokuyama, H.; Fukuyama, T. Angew. Chem., Int. Ed. 2002,
41, 4686. For formal syntheses of FR900482, see: (f) Fellows, I. M.; Kaelin,
D. E., Jr.; Martin, S. F. J. Am. Chem. Soc. 2000, 122, 10781. (g) Paleo, M.
R.; Aurrecoechea, N.; Jung, K.-Y.; Rapoport, H. J. Org. Chem. 2003, 68,
130. For a total synthesis of FR66979, see: (h) Ducray, R.; Ciufolini, M.
A.; Angew. Chem., Int. Ed. 2002, 41, 4688.
(7) For reviews of mitomycin syntheses, see: (a) Kasai, M.; Kono, M.
Synlett 1992, 778. (b) Remers, W. A.; Iynegar, B. S. In Recent Progress in
the Chemical Synthesis of Antibiotics; Lukacs, G., Ohno, M., Eds.; Springer-
Verlag: New York, 1990; pp 415-445. For synthetic routes to FR900482
utlizing benzazocines, see ref 6 as well as: (c) Ciufolini, M. A.; Chen, M.;
Lovett, D. P.; Deaton, M. V. Tetrahedron Lett. 1997, 38, 4355. (d) Greshock,
T. J.; Funk, R. L. J. Am. Chem. Soc. 2002, 124, 754. (e) Papaioannou, N.;
Evans, C. A.; Blank, J. T.; Miller, S. J. Org. Lett. 2001, 3, 2879. (f) Yasuda,
N.; Williams, R. M. Tetrahedron Lett. 1989, 30, 3397.
† Present address: Johnson and Johnson Pharmaceutical Research and
Development, 3210 Merryfield Row, San Diego, CA 92121-1126.
(1) Denny, W. A. In Cancer Chemotherapeutic Agents; Foye, W. A.,
Ed.: American Chemical Society: Washington, DC, 1995; pp 491-493.
(2) Becherbauer, L.; Tepe, J. J.; Eastman, R. A.; Mixter, P. F.; Williams,
R. M.; Reeves, R. Chem. Biol. 2002, 9, 427.
(3) Uchida, I.; Shigehiro, T.; Hiroshi, K.; Sumio, K.; Hashimoto, M.;
Tada, T.; Shigetaka, K.; Morimoto, Y. J. Am. Chem. Soc. 1987, 109, 4108.
(4) Williams, R. M.; Ducept, P. Biochemistry 2003, 42, 14696 and
references therein.
10.1021/ol049583y CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/24/2004

et al.,10 propargylic alcohol 9 was isolated in 89% yield and
greater than 99% ee. The enantiopurity of the product was
determined by chiral HPLC comparison with a racemic
standard prepared by adding trimethylsilylethynyl Grignard
to aldehyde 8, and the absolute stereochemistry was tenta-
tively assigned by analogy to similar chiral propargylic
alcohols reported by Carreira and co-workers.
Scheme 1. Benzazocines as Mitomycin/FR900482
Intermediates
Scheme 3. Carreira Asymmetric Alkynylationa
constraints, the presence of sp2-hybridized atoms can facili-
tate the cyclization by minimizing transannular interactions.
Thus, transition-metal-catalyzed carbonylative cyclizations
of vinyl halides represent a promising method for assembling
medium-sized rings because three contiguous sp2-hybridized
atoms are introduced in a single step.8 Herein we disclose
an enantioselective synthesis of the benzazocine core of
FR900482 utilizing a Pd-catalyzed carbonylative cyclization
of an arylhydroxylamine with a tethered vinyl iodide 5 to
form the eight-membered ring 6 (Scheme 2).
a Conditions: (a) N,N-Dimethylformamide dimethylacetal, DMF,
140 °C; then AcOH, THF/H2O. (b) Zn(OTf)2 (1.5 equiv), (+)-N-
methylephedrine (1.6 equiv), Et3N, TMS-acetylene, toluene, rt.
(c) Zn(OTf)2 (0.2 equiv),(+)-N-methylephedrine (0.22 equiv),
TMS-acetylene, toluene, 60 °C.
Although Carreira has developed catalytic conditions for
the asymmetric acetylide addition,11 the higher temperature
required for catalytic turnover promoted a dimerization of
the starting material to afford aldehyde 10. Given the general
tendency for aldehydes without R-branching to undergo some
degree of aldol self-condensation under the basic reaction
conditions, it is surprising that the highly enolizable aryl-
acetaldehyde 8 is a good substrate for the stoichiometric
asymmetric acetylide addition. In fact, it is possible that a
reversible deprotonation of the benzylic hydrogen does occur,
but the two ortho substituents on the aromatic ring provide
enough steric hindrance to inhibit the aldol side-reaction at
room temperature. However, at higher temperatures the aldol
reaction becomes a competing process, leading to undesired
consumption of the starting aldehyde.
The product of the Carreira asymmetric alkynylation 9
could be smoothly transformed to the (Z)-vinyl iodide
substrate 5 for the Pd-catalyzed carbonylative cyclization in
70% yield over five steps (Scheme 4). Following protection
of secondary alcohol 9 as its tert-butyldimethylsilyl ether,
the silylacetylene was converted to (Z)-vinyl iodide 12 by a
two-step procedure involving iododesilylation and diimide
reduction.12 The presence of the bulky tert-butyldimethylsilyl
group prevented overreduction during the diimide reaction,
as a significant amount of alkyl iodide formed when the free
alcohol was used. Subsequent reduction of nitroarene 12 with
samarium diiodide13 at low temperature cleanly afforded a
Scheme 2. Retrosynthesis of FR900482 Benzazocine
In their elegant total synthesis of FR900482, Fukuyama
and co-workers demonstrated that a chiral allylic alcohol
could direct the epoxidation of a proximal olefin in a
functionalized benzazocine.6a In hopes of employing a similar
strategy, we required an asymmetric synthesis of cyclization
precursor 5. To this end, commercially available 3,5-dinitro-
p-toluic acid was converted to aryl ether 7 in four steps as
described by Ziegler and Belema.9 Subsequent condensation
with N,N-dimethylformamidedimethyl acetal afforded a
mixture of E/Z enamines, which were not isolated but
immediately hydrolyzed under acidic conditions to provide
arylacetaldehyde 8 (Scheme 3). Upon addition of this
aldehyde to a toluene solution of the zinc acetylide generated
in situ from Zn(OTf)2, Et3N, (+)-N-methylephedrine, and
trimethylsilylacetylene according to the procedure of Carreira
(8) This strategy has been utilized for the synthesis of azepines and
benzazepines: (a) Farina, V.; Eriksson, M. In Handbook of Organopalla-
dium Chemistry for Organic Synthesis; Negishi, E.-I., de Meijere, A.,
Eds.: Wiley-Interscience: New York, 2002; Vol. 2, p 2351. (b) Crisp, G.
T.; Meyer, A. G. Tetrahedron 1995, 51, 5585. (c) Mori, M.; Chiba, K.;
Ban, Y. J. Org. Chem. 1978, 43, 1684.
(10) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000,
122, 1806.
(11) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687.
(12) Pasto, D. J.; Taylor, R. T. Org. React. 1991, 40, 91.
(13) Kende, A. S.; Mendoza, J. S. Tetrahedron Lett. 1991, 32, 1699.
(9) Ziegler, F. E.; Belema, M. J. Org. Chem. 1997, 62, 1083.
1746
Org. Lett., Vol. 6, No. 11, 2004

Pd(PPh3)4 in THF (0.03M) under an atmosphere of carbon
monoxide, a 36% yield of the desired lactam 14 was
obtained, along with some recovered starting material (49%
brsm; Table 1, entry 1). Formation of the lactam was
confirmed by a new carbonyl stretch at 1700 cm-1 in the IR
spectrum. Furthermore, the allylic methine hydrogen shifted
downfield in the 1H NMR spectrum from 4.58 to 5.56 ppm,
and the observed coupling constant of 11.8 Hz between the
two vinyl protons at 6.25 and 5.66 ppm is diagnostic for a
cis olefin in an eight-membered ring. Additional experimen-
tation revealed that the choice of catalyst and solvent both
dramatically influenced the success of the cyclization. When
Pd(PPh3)2Cl2 was used as the precatalyst, no reaction was
observed in refluxing THF or benzene, and an intractable
mixture of compounds formed in DMF, acetonitrile, and
N-methylpyrrolidinone.
Scheme 4. Synthesis of Cyclization Precursora
a Conditions: (a) TBSCl, imid, CH2Cl2, rt. (b) 10% AgNO3, NIS,
acetone, rt. (c) Dipotassium azodicarboxylate, pyridine, AcOH,
MeOH, rt. (d) SmI2 (4 equiv), THF/MeOH, -78 °C. (e) TBSCl,
imid, CH2Cl2, rt. (f) Zn, NH4Cl, THF/MeOH/H2O, rt. (g) TBDPSCl,
imid, CH2Cl2, rt.
However, when the cyclization was conducted at 65 °C
in N,N-dimethylacetamide, the desired lactam 14 was
produced as the only product in 78% isolated yield (entry
2). Since the incomplete mass balance may be due to
competing oligomerization, more dilute cyclization condi-
tions were explored. However, decreasing the concentration
from 0.03 to 0.01 M lowered the yield of the desired eight-
membered ring from 78 to 41% (entry 3). Switching catalysts
from Pd(PPh3)2Cl2 to Pd(dppf)Cl2 resulted in low conversion
and lactam 14 was isolated in only 20% yield (47% brsm,
entry 4).
sensitive hydroxylamine, which was immediately converted
to the O-tert-butyldimethylsilyl derivative 13 in 91% yield
over two steps. Due to the low solubility of samarium
diiodide in THF, a mild dissolving metal reduction with zinc
dust and aqueous ammonium chloride was employed for
large-scale reductions of the nitro group. As in the samarium
diiodide reduction, the crude hydroxylamine could be directly
silylated under standard conditions to afford the O-tert-
butyldiphenylsilyl derivative 5 in 88% yield over two steps.14
With enantiopure hydroxylamines 5 and 13 in hand, a
thorough investigation of the Pd-catalyzed carbonylative
lactamization was initiated (Table 1).15 Upon refluxing a
dilute solution of hydroxylamine 13, triethylamine, and 5%
To differentiate the silyl protecting groups on the hy-
droxylamine and the allylic alcohol, we also investigated the
Pd-catalyzed carbonylative cyclization of O-tert-butyldi-
phenylsilyl hydroxylamine 5. Under the identical reaction
conditions optimized for the cyclization of the tert-butyldi-
methylsilyl derivative 13, hydroxylamine 5 cleanly produced
the desired lactam 6 in 66% isolated yield (Table 1, entry
5). The product possessed 1H NMR, 13C NMR, and IR data
analogous to that of lactam 14.
It was anticipated that the methyl ester in the lactam
product would present problems during the late-stage aldol
reaction, which introduces the hydroxymethyl side chain in
the benzylic position of FR900482. By activating the benzylic
hydrogen toward deprotonation, the ester increases the
probability of epimerization or dehydration of the aldol
product.6a To avoid these issues and obviate potential
chemoselectivity problems during the reduction of the R,â-
unsaturated lactam, ester 15 was reduced to a primary alcohol
with diisobutylaluminum hydride prior to lactam formation
(Scheme 5). Following desilylation of the acetylene with
basic methanol and protection of the primary alcohol as a
benzyl ether, the hydroxylamine substrate 16 for the Pd-
catalyzed carbonylative lactamization could be assembled
in 69% yield over four steps following the same procedure
described previously. When O-tert-butyldiphenylsilyl hy-
Table 1. Pd-Catalyzed Carbonylative Lactamizationa
CO
%
entry substrate
catalyst
solventb
THF
pressure yieldc
1
2
13
13
Pd(PPh3)4
1 atm
1 atm
36(49)
78
Pd(PPh3)2Cl2 DMA
(0.03 M)
Pd(PPh3)2Cl2 DMA
(0.01 M)
DMA
3
13
1 atm
41
4
5
6
13
5
5
Pd(dppf)Cl2
1 atm
1 atm
4 atm
20(47)
66
35
Pd(PPh3)2Cl2 DMA
Pd(PPh3)2Cl2 DMA
(14) Cowart, M.; Bennett, M. J.; Kerwin, J. F. J. Org. Chem. 1999, 64,
2240.
(15) For examples of Pd-catalyzed carbonylations of hydroxylamines,
see: (a) Szarka, Z.; Skoda-Foldes, R.; Kollar, L.; Berente, Z.; Horvath, J.;
Tuba, Z. Tetrahedron 2000, 56, 5253. (b) Grigg, R.; Major, J. P.; Martin,
F. M.; Whittaker, M. Tetrahedron Lett. 1999, 40, 7709. (c) Herbert, J. M.;
McNeill, A. H. Tetrahedron Lett. 1998, 39, 2421.
a See Supporting Information for experimental details. b All reactions
performed at 65 °C and 0.03 M, except entry 3 (0.01 M). c Number in
parentheses refers to yield based on recovered starting material.
Org. Lett., Vol. 6, No. 11, 2004
1747

in 64% yield. To complete the synthesis of the FR900482
benzazocine core, lactam 17 was reduced with borane-
methyl sulfide complex to provide hydroxylamine 18 in 55%
yield without competing 1,4-reduction or cleavage of the
N-O bond.16
Scheme 5. Synthesis of FR900482 Benzazocinea
In summary, we have reported an asymmetric route to the
benzazocine core of FR900482. The eight-membered ring
was assembled using a palladium-catalyzed carbonylative
lactamization, and this procedure should prove to be useful
for the synthesis of other alkaloids containing azocines and
benzazocines. Current efforts are directed at fully elaborating
the benzazocine core to provide FR900482 and related
mitomycinoids and will be reported in due course.
Acknowledgment. We thank the National Institutes of
Health (NIH) General Medicine Sciences (GM 33049) and
the National Science Foundation for their generous support
of our programs. Mass spectra were provided by the Mass
Spectrometry Regional Center of the University of California-
San Francisco supported by the NIH Division of Research
Resources.
a Conditions: (a) DIBAL-H, THF, -78f0 °C, 99%. (b) K2CO3,
MeOH, 97%. (c) NaH, BnBr, cat Bu4NI, THF, 96%. (d) NIS, 10%
AgNO3, acetone, 94%. (e) Dipotassium azodicarboxylate, pyridine,
AcOH, MeOH, rt, 97%. (f) SmI2 (4 equiv), THF/MeOH, -78 °C,
98%. (g) TBDPSCl, imid, CH2Cl2, 77%. (h) 5% Pd(PPh3)2Cl2, CO
(1 atm), Et3N, DMA (0.03 M), 80 °C, 64%. (i) BH3-SMe2,THF,
0 °C, 55%.
Supporting Information Available: Experimental pro-
cedures for the preparation of new compounds and charac-
terization data. This material is available free of charge via
the Internet at http://pubs.acs.org.
droxylamine 16 was subjected to the same Pd-catalyzed
cyclization conditions optimized for hydroxylamine 5, only
recovered starting material was obtained. Fortunately, simply
increasing the temperature from 65 to 80 °C promoted the
cyclization and afforded the desired eight-membered ring 17
OL049583Y
(16) Brown, H. C.; Choi, Y. M. J. Org. Chem. 1982, 47, 3153.
1748
Org. Lett., Vol. 6, No. 11, 2004