A Concise and Flexible Total Synthesis of (-)-Diazonamide A

Article abstract of DOI:10.1002/anie.200352577

The remarkable action of an I^III species on a tripeptide containing acyclic tyrosine/ tryptophan is the key step in a total synthesis of (-)-diazonamide A. The completed preparation of this new antimitotic is concise, multiply convergent, and a

Full text of DOI:10.1002/anie.200352577

Angewandte
Chemie
Natural Product Synthesis
A Concise and Flexible Total Synthesis of
(À)-Diazonamide A**
Anthony W. G. Burgett, Qingyi Li, Qi Wei, and
Patrick G. Harran*
Diazonamide A is a potently antimitotic natural product
whose structure was originally assigned as polycycle 1
(Figure 1).[1] We recently synthesized this material—only to
discover that 1 is neither a natural substance nor, in fact,
stable.[2] A reinterpretation of published spectroscopic and X-
ray crystallographic data led to the proposal that diazonami-
de A was actually hydroxy isovaleramide-containing aminal
2.[3] This revision has been recently confirmed through
synthesis.[4] We felt that the differences between 1 and 2,
while seemingly subtle, provided for a very different synthetic
problem. Therefore, minor adaptations of the route used to
prepare 1 were not pursued. Rather, we developed and
[*] Prof. P. G. Harran, A. W. G. Burgett, Q. Li, Q. Wei
Department of Biochemistry
University of Texas
Southwestern Medical Center at Dallas
Dallas, TX 75390-9038 (USA)
Fax: (+1)214-648-6455
E-mail: pharra@biochem.swmed.edu
[**] Funding provided by the NIH (RO1-GM60591), the Howard Hughes
Medical Institute, the Robert A. Welch Foundation, and unrestricted
research awards from AstraZeneca, Eli Lilly, and Pfizer are gratefully
acknowledged. P.H. is a fellow of the Alfred P. Sloan Foundation.
A.B. thanks the medicinal chemistry section of the ACS for a pre-
doctoral fellowship (sponsor: Aventis Pharmaceuticals). We are
indebted to Dr. Nigam Rath (University of Missouri at St. Louis) for
his crystallographic analysis of aminal 15.
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DOI: 10.1002/anie.200352577
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Figure 1. Diazonamide A structure and primary retrosynthesis.
describe here a new sequence—one that generates natural
diazonamide A in a particularly concise manner and along
lines possibly relevant to its biosynthesis.
problem simplifies to central aminal 4. The dihydrobenzofur-
o[2,3b]indole subunit of this molecule is viewed as a remnant
of oxidation. In particular, of a linear peptidyl precursor (e.g.
6) wherein, for example, heterolytic oxidation of the phenol
could initiate an annulation involving phenoxenium ion
capture by the tethered indole and ring closure (as indicated)
within the resultant cyclohexadienone-linked indoleninium
species.[6] With respect to stereoinduction in this scheme,
calculated conformational preferences for 6 (Figure 1[7])
indicate a left handedness to the display of Ca substituents
in its dipeptide segment. To the extent that these computa-
tions and, for that matter ground state conformational
preference, would be predictive[8]—an electron deficient
Lessons learned from earlier work proved valuable.
Peripheral halogenation and acyl substitution can be installed
late on a diazonamide core. In addition, we knew that
potentially complicating issues of atropisomerism[5] during
assembly of this core could be avoided by forming the D/E
biaryl bond intramolecularly in the context of a pre-existing,
correctly configured A/F macrolactam. This implicated seco
halide 3 as a penultimate target—a position from which
photoinduced electron transfer mediated elimination of HBr
could complete the diazonamide ring system.[2] From 3, the
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intermediate generated from the phenol would situate itself
beneath (as shown in Figure 1) the indole unit as they
approached within the bonding distance. Kinetic C10 stereo-
chemistry in 5 would thus reflect whether nucleophilic attack
(by the indole at its 3-position[9]) had occurred from s-cis
rotamer 8 or its trans counterpart 7; the former producing a
desired result. While our ability to predict such a preference
was limited, the construction itself could be evaluated readily.
An oxidation substrate was synthesized beginning with
racemic 7-bromotryptophan methyl ester[10] (Scheme 1).
Treatment of this material with the acid chloride derived
from N-Z-[l]-Val-OH[11] provided an epimeric mixture of
dipeptides 10. Yonemitsu oxidation[12] of the mixture gave one
3-oxazoylindole product whose carbamate then degraded in
HBr/AcOH to give crystalline amine salt 11. Condensation of
11 with l-tyrosine-derived sulfonamide 12[13] subsequently
completed the content of a diazonamide aminal (Scheme 2)—
a fact made strikingly clear by the observation that adding 13
to a cold trifluoroethanol solution of PhI(OAc)2 is sufficient
to generate target lactam 14—presumably through mecha-
nistic events related to those outlined in Figure 1. As
currently performed, aminal 14 is produced alongside its
Scheme 1. Reaction conditions: a) N-Z-[l]-Val-OH, 1-chloro-N,N-2-tri-
methyl-1-propen-1-amine, CH2Cl2 then 9 (0.95 equiv), py (2.0 equiv),
08C (76%). b) DDQ (2.3 equiv), THF, 708C, 2 h (90%). c) 33% HBr in
glacial AcOH, room temperature, 10 min (94%). DDQ=2,3-dichloro-
5,6-dicyano-1,4-benzoquinone, py=pyridine.
C10-(R),C11-(S) diastereoisomer 15 (ꢀ 3:1 favoring 14[14]
)
Scheme 2. Reaction conditions: a) TBTU, (iPr)2NEt, DMF, room temperature (91%). b) PhI(OAc)2 (1.1 equiv), LiOAc (2.0 equiv), 2,2,2-trifluoro-
ethanol, inverse addition, À208C, 10 min. (20–25% 14, 7–8% 15, ~15% 16 (1:1)). TBTU=2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate.
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and comparable amounts of epimeric spirodienones 16.[15]
oxidation/cyclodehydration sequence[2,21] afforded bis(oxa-
zoyl)indole 21 (Scheme 3). Compound 21 was then dissolved
in aqueous CH3CN that contained LiOH and allowed to stand
for 20 minutes. The resultant lithium phenoxide solution was
degassed and photolyzed (Rayonet, 300 nm) to produce
biaryl 24 (single atropdiastereomer) in good yield. This
result is a significant improvement over our earlier D/E
biaryl bond synthesis.[2] As in that photochemistry, we ration-
alize the chemistry in terms of photoinduced electron trans-
fer[22] between the indole chromophore and the adjacent
bromoarene—leading initially to a radical ion pair capable of
mesolytic elimination of bromide. The incipient biradical can
then internally collapse and the resultant indolenone (23)
tautomerize to generate 24. Additional electron density in the
indole subunit benefits the process tremendously, in fact,
more than enough to justify bringing an otherwise superfluous
Notably, C2-epi-13 (derived from d-tyrosine) does not cyclize
similarly nor does 16 convert to 14/15 when resubjected to the
reaction conditions. These data are consistent with the (14 +
15)/16 ratio being a result of kinetic competition between
nucleophilic attack at C8 and C4 of an intervening phenoxe-
nium ion.[16] Populated conformations of 13 evidently permit
macrolactam formation to compete[17] with an ostensibly
favored, more conventional medium-ring spiroannulation
manifold. The latter has been exploited in various contexts
following Kita's seminal demonstrations of the method.[18]
The above five-step synthesis of 14 quickly moved our
effort to its advanced stages. Three functional group manip-
ulations[19] prepared the molecule to serve as an acylating
agent for 7-hydroxytryptamine 19.[20] Condensation of 17 and
19, acetylation of the product, and a two-step benzylic
Scheme 3. Reaction conditions: a) PhSH, Na2CO3, DMF, room temperature. b) Teoc-Cl, CH2Cl2, aqueous K2CO3 (80%—2 steps). c) LiOH, aque-
ous MeOH (99%). d) 19 (1.1 equiv), TBTU, (iPr)2NEt (2 equiv), DMF, (91%). e) Ac2O, py, CH2Cl2/THF (95%). f) DDQ (2.2 equiv), 9:1 THF/H2O
(86%). g) PPh3, (CCl3)2, Et3N, CH2Cl2, 15 min (55%). h) hn (300 nm), 3.0 mm in argon-purged CH3CN/H2O (3:1) that contained LiOH (2 equiv),
room temperature, 3 h (72%). i) 4-nitrophenyltriflate, K2CO3, DMF (87%). j) 20% Pd(OH)2/C, 1 atm H2, EtOAc/MeOH, room temperature (96%).
k) diallyldicarbonate, Et3N, THF, room temperature; add Teoc-Cl, Et3N, room temperature; add [Pd(PPh3)4] (5 mol%), morpholine (5 equiv), 08C,
20 min (78% overall). l) 2,3,4,5,6,6-hexachloro-2,4-cyclohexadien-1-one (2.5 equiv), DMF, room temperature, 24 h (30–50%). m) (Me2N)3SSiMe3F2
(5 equiv), DMF, room temperature (95%). n) (S)-a-hydroxy isovaleric acid (1.1 equiv), (EtO)2P(O)CN, N-methylmorpholine, THF, room tempera-
ture (90%).
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Y. Harigaya, Tetrahedron 2002, 58, 7851 – 7861; b) D. E. Davies,
substituent into the synthesis. After reductive removal of this
spectator phenol (at C19, through its triflate[23]), the molecule
was differentially acylated, carefully chlorinated on its right
periphery with perchloro-2,4-cyclohexadien-1-one,[24] and
treated with tris(dimethylamino)sulfur trimethyldifluorosili-
cate[25] to afford desbromo diazonamide B. Phosphoryl cya-
nide-mediated condensation with commercial (S)-a-hydroxy
isovaleric acid then delivered (À)-diazonamide 2. Synthetic 2
has identical spectroscopic characteristics and co-elutes with a
sample of natural material[26] when a pre-mixture is analyzed
by LC/MS.
The synthesis of (À)-diazonamide A described herein
converges on the target from five segments in a total of
19 operations (longest linear sequence is nine steps). We have
evidence that 2 blocks mitotic cell division by an unprece-
dented mechanism[27] and this preparation will provide
sufficient material and derivatives to explore diazonamide
pharmacology in depth.
T. L. Gilchrist, T. G. Roberts, J. Chem. Soc. Perkin Trans. 1 1983,
1275 – 1280; c) T. F. Jamison, Ph.D. thesis, Harvard University,
1997.
[11] U. Schmidt, M. Kroner, U. Beutler, Synthesis 1988, 475 – 477.
[12] Y. Oikawa, T. Yoshioka, K. Mohri, O. Yonemitsu, Heterocycles
1979, 12, 1457 – 1462.
[13] Prepared from l-tyrosine methyl ester hydrochloride in two
steps: 1) 2-nitrophenylsulfonyl chloride, pH 9.0 phosphate
buffer/CH2Cl2; 2) KOH, aq MeOH (70%—2 steps).
[14] C11 stereochemistry, relative to C10, is governed by geometry.
Only two cis-fused dihydrobenzofuro[2,3b] indole diastereomers
are formed. C10-(R), C11-(S) diastereomer 15 has been charac-
terized by X-ray diffraction (Scheme 2). CCDC-218220 (15)
contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge via www.ccdc.cam.a-
c.uk/conts/retrieving.html (or from the Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge CB21EZ, UK;
fax: (+ 44)1223-336-033; or deposit@ccdc.cam.ac.uk).
[15] Analytical HPLC analyses of crude oxidation mixtures show that
14, 15, and epimers 16 are formed in the ratio 3:1:0.7:0.7.
Spirodienones 16 can be purified by preparative HPLC (C18
CH3CN/H2O gradient) but partially degrade during flash
chromatography on silica gel.
,
Received: August 6, 2003 [Z52577]
Published Online: September 30, 2003
[16] L. Kꢀrti, P. Herczegh, J. Visy, M. Simonyi, S. Antus, A. Pelter, J.
Chem. Soc. Perkin Trans. 1 1999, 379 – 380.
Keywords: antimitotic agents · natural products · oxidation ·
photochemistry · total synthesis
.
[17] We are mindful of another explanation. It is possible that 14 and
15 form as a result of an indolic oxidation. The (14 + 15)/16 ratio
may actually reflect two separate pathways operating rather than
bifurcation through a common intermediate. For example, one
electron oxidation of the indole subunit in 13 would produce a
radical cation (e.g. I). This species could trap the tethered
phenol, relinquish a second electron (to either IIII or III) and the
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[6] Ring closure in 5 could also occur via its phenol tautomer.
[7] Geometry optimization of 6 (R = Ac) was performed by using
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benzyloxy tryptamine (Biosynth AG, Switzerland) over
Pd(OH)2/C (1 equiv ethereal HCl, EtOH, 1 atm H2, > 95%
yield).
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[26] We are grateful to Professor William Fenical (Scripps Oceano-
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[27] G. Wang, A. W. G. Burgett, X. Wang, P. G. Harran, unpublished
results.
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