Total synthesis of diazonamide A

Article abstract of DOI:10.1002/1521-3773(20020916)41:18<3495::AID-ANIE3495>3.0.CO;2-7

Ever since its discovery in 1991, diazonamide A (1) has been eyed by synthetic chemists as a potential target because of its puzzling molecular architecture and potent biological activity. The race to synthesize this intriguing natural product was further

Full text of DOI:10.1002/1521-3773(20020916)41:18<3495::AID-ANIE3495>3.0.CO;2-7

COMMUNICATIONS
402; Angew. Chem. Int. Ed. 1998, 37, 388; R. Noyori, Asymmetric
Catalysis in Organic Synthesis, Wiley, New York, 1994; K. Fuji, Chem.
Rev. 1993, 93, 2037.
Total Synthesis of Diazonamide A**
K. C. Nicolaou,* Marco Bella, David Y.-K. Chen,
Xianhai Huang, Taotao Ling, and Scott A. Snyder
[2] For reviews of the palladium-catalyzed asymmetric allylic alkylation,
see B. M. Trost, D. L. Van Vranken, Chem. Rev. 1996, 96, 395; A.
Heumann, M. Reglier, Tetrahedron 1995, 51, 975; T. Hayashi in
Catalytic Asymmetric Synthesis (Ed.: I. Ojima), VCH, New York,
1993; M. Sawamura, Y. Ito, Chem. Rev. 1992, 92, 857; J. C. Fiaud, In
Metal-Promoted Selectivity in Organic Synthesis (Eds.: M. Graziani,
A. J. Hubert, A. F. Noels), Kluwer Academic, Dordrecht, 1991; G.
Consiglio, R. M. Waymouth, Chem. Rev. 1989, 89, 257.
In 1991, Fenical and co-workers reported structure 1 for
diazonamide A, a marine natural product which had been
isolated from the colonial ascidian diazona angulata.[1]
A
Me
Me
[3] a) B. M. Trost, G. M. Schroeder, J. Am. Chem. Soc. 1999, 121, 6759;
b) B. M. Trost, R. Radinov, E. M. Grenzer, J. Am. Chem. Soc. 1997,
119, 7879.
[4] S.-L. You, X.-L. Hou, L.-X. Dai, X.-Z. Zhu, Org. Lett. 2001, 3, 149, and
references therein; T. Hayashi, K. Kanehira, T. Hagihara, M. Kumada,
J. Org. Chem. 1988, 53, 113.
Me
Me
H
H
N
N
H2N
N
N
B
Cl
A
O
O
O
Cl
O
E
[5] K. Ishihara, S. Nakamura, M. Kaneeda, H. Yamamoto, J. Am. Chem.
Soc. 1996, 118, 12854 12855.
[6] T. Ohwada, K. Okabe, T. Ohta, K. Shudo, Tetrahedron 1990, 46, 7539
7555.
[7] W. Vaccaro, C. Amore, J. Berger, R. Burrier, J. Clader, H. Davis, M.
Domalski, T. Fevig, B. Salisbury, R. Sher, J. Med. Chem. 1996, 39,
1704 1719.
[8] Du Pont de Nemours and Co., FR 2283681 1976; DE 2539907 1976.
[9] W. Nerinckx, M. Vandewalle, Tetrahedron: Asymmetry 1990, 1, 265.
[10] B. B. Snider, B. M. Cole, J. Org. Chem. 1995, 60, 5376.
[11] A. P. Degnan, A. I. Meyers, J. Org. Chem. 2000, 65, 3503, and
references therein.
[12] C.-H. Lin, S. R. Haadsman-Svensson, A. Lahti, R. B. McCall, M. F.
Piercey, K. D. Schreur, P. F. Von Voigtlander, M. W. Smith, C. G.
Chidester, J. Med. Chem. 1993, 36, 1053; M. Takeda, M. Konda, Y.
Honma, H. Inoue, S. Saito, H. Kugita, S. Nurimoto, G. Hayashi, J.
Med. Chem. 1975, 18, 697.
G
C
F
NH
O
D
HO
OH
1: original structure of diazonamide A
Me
Me
N
Me
HO
Me
H
1
H
N
37
N
N
29
Cl
A
O
30
10
O
O
B
Cl
26
O
24
E
G
C
NH
F
18
16
H
O
N
D
H
2: revised structure of diazonamide A
[13] The compatibilityof ketone enolates with palladium has also been
demonstrated in the palladium-catalyzed arylation of ketone enolates.
This method also provides an alternative catalytic asymmetric route to
quaternarycenters bearing an aryl group, see T. Hamada, A. Chieffi, J.
Arhman, S. L. Buchwald, J. Am. Chem. Soc. 2002, 124, 1261; J. M. Fox,
X. Huang, A. Chieffi, S. L. Buchwald, J. Am. Chem. Soc. 2000, 122,
1360; M. Kawatsura, J. F. Hartwig, J. Am. Chem. Soc. 1999, 121, 1473;
J. Ahman, J. P. Wolfe, M. V. Troutman, M. Palucki, S. L. Buchwald, J.
Am. Chem. Soc 1998, 120, 1918; M. Palucki, S. L. Buchwald, J. Am.
Chem. Soc. 1997, 119, 11108.
[14] K. Shishido, K. Goto, S. Miyoshi, Y. Takaishi, M. Shibuya, J. Org.
Chem. 1994, 59, 406; C. K.-F. Chiu, S. V. Govindan, P. L. Fuchs, J. Org.
Chem. 1994, 59, 311; W. Nerinckx, M. Vandewalle, Tetrahedron:
Asymmetry 1990, 1, 265; R. H. Burnell, J.-M. DuFour, Can. J. Chem.
1987, 65, 21; T. Volpe, G. Revial, M. Pfau, J. d©Angelo, Tetrahedron
Lett. 1987, 28, 2367, and references therein.
[15] C. Chassaing, A. Haudrechy, Y. Langlois, Tetrahedron Lett. 2000, 41,
785; A. Haudrechy, C. Chassaing, C. Riche, Y. Langlois, Tetrahedron
2000, 56, 3181; S. Kaneko, T. Yoshino, T. Katoh, S. Terashima,
Tetrahedron 1998, 54, 5471; X.-C. He, B. Wang, D. Bai, Tetrahedron
Lett. 1998, 39, 411; A. P. Kozikowski, Y. Xia, E. R. Reddy, W.
Tuckmantel, I. Hanin, X. C. Tang, J. Org. Chem. 1991, 56, 4636; T.
Hayashi, K. Kaneshira, T. Hagihara, M. Kumada, J. Org. Chem. 1988,
53, 113; see also D. L. Bai, X. C. Tang, X. C. He, Curr. Med. Chem.
2000, 7, 355. For analogues, see P. Camps, E. GÛmez, D. MuÊoz-
Torrero, M. ArnÛ, Tetrahedron: Asymmetry 2001, 12, 2909.
decade later, Harran and his group synthesized the proposed
structure 1 onlyto prove that it was in error, and advanced
structure 2 for diazonamide A instead.[2] In the intervening
time, numerous efforts directed at the total synthesis of 1 had
been reported;[3 13] no research activities related to the newly
proposed structure 2 have yet been disclosed. The appeal of
diazonamide A (2) stems both from its biological activity
(cytotoxicity against several tumor cell lines with IC50 values
< 15 ngmLꢀ1) and its highlystrained and unprecedented
[*] Prof. Dr. K. C. Nicolaou, Dr. M. Bella, Dr. D. Y.-K. Chen,
Dr. X. Huang, Dr. T. Ling, S. A. Snyder
Department of Chemistryand The Skaggs Institute for Chemical
Biology
The Scripps Research Institute
10550 North TorreyPines Road, La Jolla, CA 92037 (USA)
Fax : (þ 1)858-784-2469
E-mail: kcn@scripps.edu
and
Department of Chemistryand Biochemistry
Universityof California, San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
[**] We thank Dr. D. H. Huang and Dr. G. Siuzdak for NMR spectroscopic
and mass spectrometric assistance, respectively. We also wish to
acknowledge Mr. William R. Webb for his expertise in obtaining low-
resolution mass spectral data. We thank Dr. Paraskevi Giannakakou
and Aurora O©Brate of the Winship Cancer Institute, Emory
UniversitySchool of Medicine, for the biological assays. Financial
support for this work was provided byThe Skaggs Institute for
Chemical Biology, American BioScience, the National Institutes of
Health (USA), predoctoral fellowships from the National Science
Foundation and Pfizer (S.A.S.), and postdoctoral fellowships from The
Skaggs Institute for Research (M.B., X.H., and T.L.).
Angew. Chem. Int. Ed. 2002, 41, No. 18
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0044-8249/02/4118-3495 $ 20.00+.50/0
3495

COMMUNICATIONS
structure. Because of its scarcityfrom natural sources and its
potential as a lead for the development of new chemo-
therapeutic agents, 2 presents a unique opportunityfor
chemical synthesis. In this communication, we report a total
synthesis of diazonamide A (2) which required the develop-
ment of new synthetic technologies and strategies and which
provides a solution to this formidable molecular puzzle.
The revised structure of diazonamide A (2) represented a
greater synthetic challenge than the one posed by the
originallyproposed structure ( 1) in that it contains an
additional ring (ring H) and a nitrogen atom instead of the
oxygen substituent in ring F which leads to a structurally
unique aminal moiety. In addition to the rigidity associated
with this EFGH tetracyclic system, its quaternary center
(C10) preeminentlystood as the central cornerstone of any
synthetic strategy. The two 12-membered rings of the
structure were also expected to pose considerable recalci-
trance to formation owing to their severelyconstrained
environments. In all, structure 2, with its ten exquisitely
arrayed rings and unique elements of stereochemistry,
amounted to a rare challenge to modern synthetic chemistry.
Scheme 1 presents the blueprint of our strategytowards this
target molecule in retrosynthetic format. Thus, excision of the
polycyclic framework and chlorination; f) fusion of the aminal
bicyclic network; and g) attachment of the isovaleric acid side
chain (the operations to be executed in that order). The
proposed late introduction of the side chain would allow for
expedient construction of analogues, including the synthesis
of the natural product©s epimer at C37 for purposes of
structural and biological comparison.
While all of the defined building blocks (3 7) were readily
generated from commerciallyavailable starting materials
according to literature procedures, the construction of the
quaternarycenter (C10) with its peripheral structural motifs
required considerable process development. To this end, the
model studydepicted in Scheme 2 was designed and executed.
Thus, 7-bromoisatin (8)[14] was treated with excess PhMgBr to
afford tertiaryalcohol 9 in 96% yield. Upon mixing com-
pound 9 with tyrosine derivative 10 in the presence of TfOH,
and following acetylation of the resultant primary amine (as
TfOH cleaved the Cbz group), phenolic lactam 11 emerged in
84% yield as a mixture of diastereomers (ca. 1:1).[15] Exposure
of 11 to excess BH3¥SMe2 resulted in the formation of the
bicyclic aminal system 14 (40% overall yield, unoptimized)
containing some of diazonamide A©s most challenging struc-
tural features, presumablyvia intermediates 12 and 13 as
suggested in Scheme 2.
Prompted bythis encouraging set of preliminaryresults, we
then proceeded to applythe developed chemistryto the target
molecule 2 as shown in Scheme 3. Having failed to success-
fullyutilize the known oxazole ester derivative 15[16] in the
intended coupling reaction, we resorted to its reduction
macrolactamization
side-chain extension
and oxazole formation
Me
O
Me
N
Me
HO
Me
H
H
chlorination
N
N
N
Cl
O
O
Cl
O
peptide coupling
NH
NHCbz
CO2Me
N
H
O
O
a) PhMgBr
+
O
2
aminal formation
macrocyclic closure
N
HO
H
Br
N
Br
H
O
O
8
9
OH 10
NH2
Me
HO
Me
OH
b) TfOH; Ac2O
•TFA
N
H
H
N
H
O
OMe
OMe
N
Me
Me
3
4
CO2Me
Me
Me
O
O
O
O
c) BH3•SMe2
BocHN
10
O
CbzHN
O
N
H
Br
N
Br
O
N
H
O
OH
HO
HO
N
Br
12
MOM
11
OBn
OH
5
6
7
Scheme 1. General retrosynthetic analysis of diazonamide A (2). Cbz ¼
benzyloxycarbonyl, Boc ¼ tert-butoxycarbonyl, MOM ¼ methoxymethyl,
TFA ¼ trifluoroacetic acid.
H
N
H
N
OMe
OMe
O
Me
Me
A
O
O
O
E
G
F
H
O
side chain and the chlorine atoms, and rupture of the
macrolactam, aminal, oxazole, and bis-aryl ring systems as
shown, led to fragments 3 7. In the synthetic direction, the
challenge was thus reduced to the following milestone events:
a) construction of the required building blocks; b) assembly
of the quaternarycenter with its substituents; c) formation of
the 12-membered macrolactam ring system; d) introduction
of the indole oxazole domain; e) closure of the 12-membered
N
N
Br
Br
H
HO
13
14
Scheme 2. Model studies exploring the generation of the C10 quaternary
center: a) PhMgBr (3.0 equiv), THF, 08C, 96%; b) 10 (1.1 equiv), TfOH
(10 equiv), CH2Cl2, 08C, 20 min; then Ac2O (10 equiv), CH2Cl2, 258C,
5 min, 84%; c) BH3¥SMe2 (3.0 equiv), THF, 258C, 4 h, 40%. TfOH ¼ tri-
fluoromethanesulfonic acid. Note: compounds 11 14 are mixtures of C10
epimers (ca. 1:1).
3496
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0044-8249/02/4118-3496 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 18

COMMUNICATIONS
(LiBH4) and selective protection (60% overall yield)[17] to
afford benzyl ether 6 as an alternative substrate for this
process. Reaction of 6 with 2.0 equiv of nBuLi in THF at
ꢀ788C resulted in the formation of dianion 16 which was
treated with 1.1 equiv of isatin derivative 7[18] at ꢀ788C to
afford, upon standard workup, tertiaryalcohol 17 in 73%
yield. The crucial step of establishing the quaternary center
assemblywith its structural entourage was then accomplished
byrefluxing 17 with tyrosine derivative 5 (4.0 equiv) in 1,2-
dichloroethane in the presence of pTsOH to furnish com-
pound 18, which had lost both the MOM and the Boc
protective groups, in 33% yield. It is important to note that
the triflic acid conditions utilized successfullyin the model
study(Scheme 2) failed in this instance; onlydecomposition
products were obtained, which most likelyarose from the
oxazole moiety. Reprotection of the primary amine in18 with
(Boc)2O led to two C10 epimers whose chromatographic
properties allowed their convenient separation to yield pure
19 and its epimer (not shown). Since the configuration of the
quaternarycenter in these intermediates could not be
determined at this stage, both epimers were separatelycarried
forward to the corresponding macrolactams (22 and its C10
epimer) whose spectroscopic data were suggestive of their
structures (see below). The following step involved protection
of the phenolic hydroxy group and the oxoindole amide
nitrogen atom, an objective which was accomplished by
exposing 19 to excess MOMCl and K2CO3 to afford com-
pound 20 (94% yield). This precursor (20) was then trans-
formed to the coveted macrolactam 21 byfirst liberating the
carboxylic acid (LiOH) and the amino groups (TFA), in that
order, and then cyclizing the resultant amino acid through the
action of HATU and collidine in DMF/CH2Cl2 in 36% overall
yield. This challenging formation of the 12-membered ring
required high-dilution conditions to minimize formation of
dimers and higher oligomers. It should also be noted that
MOM protection of the precursor considerablyimproved the
yield of this ring closure as compared to that obtained with
unprotected material (i.e., 19). Furthermore, of the two C10
epimers, onlyone cyclized smoothlywhereas the other led to
preferential dimerization even under extremelyhigh dilution
conditions. The next step in the sequence required removal of
the benzyl group in the presence of the Cbz and the aryl
bromine moieties, a challenging task that was accomplished
bythe use of BCl 3 in CH2Cl2 at ꢀ788C followed bytreatment
with NaOH. In this reaction, the two MOM groups in 21 were
concomitantlycleaved to yield compound 22 in 61% overall
Me
Me
Me
Me
Me
BocN
BocHN
O
BocHN
Me
c) nBuLi
a) LiBH4
O
N
N
O
N
b) NaHMDS,
BnBr
OBn
CO2Me
OBn
16
15
6
O
O
N
MOM
Br
7
CO2Me
Me
Me
CbzHN
Me
N
Me
N
H2N
BocHN
MeO2C
CbzHN
OBn
Br
OBn
Br
O
O
5
OH
10
d) pTsOH,
ClCH2CH2Cl
HO
N
N
H
MOM
HO
O
O
18
17
e) (Boc)2O
(separation of C10 epimers)
Me
O
Me
O
Me
N
Me
BocHN
MeO2C
BocHN
MeO2C
N
OBn
Br
OBn
Br
CbzHN
f) MOMCl
CbzHN
N
N
H
MOM
MOMO
HO
O
O
19
20
g) LiOH
h) TFA
i) HATU,
collidine
Me
Me
Me
Me
N
H
H
N
N
CbzHN
CbzHN
N
OBn
Br
OH
j) BCl3;
NaOH
O
O
O
O
O
N
N
H
Br
MOM
O
MOMO
HO
21
22
Scheme 3. Synthesis of advanced macrolactam 22: a) LiBH4 (2.0m in THF,
3.0 equiv), EtOH (10 equiv), Et2O/THF (2:1), 0!258C, 3 h, 83 %;
b) NaHMDS (1.0m in THF, 2.0 equiv), THF, ꢀ788C, 10 min, then TBAI
(0.1 equiv), BnBr (10 equiv), ꢀ78!258C, 24 h, 72%; c) nBuLi (2.0 equiv),
THF, ꢀ788C, 20 min, then 7 (1.1 equiv), 10 min, 73%; d) 5 (4.0 equiv),
pTsOH (4.0 equiv), ClCH2CH2Cl, 838C, 15 min, 33%; e) (Boc)2O
(1.1 equiv), aq. NaHCO3/dioxane (1:2), 258C, 2 h, 65%; f) MOMCl
(30 equiv), K2CO3 (40 equiv), acetone, 0!258C, 2 h, 94%; g) LiOH
(20 equiv), MeOH/THF/H2O (2:10:1), reflux, 10 min, 98%; h) TFA,
10 min, 98%; i) HATU (2.2 equiv), collidine (6.6 equiv), DMF/CH2Cl2
(1:2, 3.0 î 10ꢀ4 m), 258C, 12 h, 36%; j) BCl3 (1.0m in hexanes, 20 equiv),
CH2Cl2, ꢀ788C, 2 h; then THF, sat. aq. NaHCO3, 10% aq. NaOH, 258C,
30 min, 61%. NaHMDS ¼ sodium salt of 1,1,1,3,3,3-hexamethyldisilazane,
TBAI ¼ tetra-n-butylammonium iodide, pTsOH ¼ p-toluenesulfonic acid,
HATU ¼ 2-(1H-9-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hex-
afluorophosphate.
1
yield.[19] At this stage, the H NMR spectroscopic data of the
more accessible macrolactam epimer (see Table 1) were
reminiscent of those of diazonamide A (2). Therefore, we
assumed the structure of this epimer to be that of 22 (that is to
say, the one corresponding to the targeted natural product).
Having chosen epimer 22 as the most likelycandidate to
yield diazonamide A (2), its further elaboration proceeded as
shown in Scheme 4. Thus, selective protection of the phenolic
hydroxy group of 22 (Boc2O), followed bysequential oxida-
tion first with IBX and then with NaClO2 , furnished the
expected carboxylic acid whose coupling with indole ammo-
nium salt 4 in the presence of EDC and HOBt led to 23 (41%
overall yield from 22). This keto amide was then converted to
the corresponding oxazole system through a Gabriel Rob-
inson cyclodehydration effected by a unique set of conditions
(POCl3/pyridine)[20] which set the stage for the critical
Angew. Chem. Int. Ed. 2002, 41, No. 18
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0044-8249/02/4118-3497 $ 20.00+.50/0
3497

COMMUNICATIONS
Table 1. Selected data for compounds 22 and 26.
residues were installed at their proper positions byelectro-
philic aromatic substitution (NCS, 53% yield). Second, the
resulting product was exposed to TFA to effect removal of the
Boc group and furnish phenolic intermediate 25 (98% yield).
Chemoselective reduction of the five-membered ring lactam
of 25 with DIBAL-H initiated ring closure with participation
of the adjacent phenolic hydroxy group to afford the desired
cyclic aminal 26 in 55% overall yield. Finally, hydrogenolysis
of the Cbz group with H2 and Pearlman×s catalyst followed by
installation of the remaining peptide side chain with isovaleric
acid ((S)-3) in the presence of EDC/HOBt furnished structure
2 in 82% overall yield. The 1H NMR signals of synthetic 2 in
[D4]MeOH matched those reported for natural diazonami-
de A precisely, while those of the C37 epimer obtained by
employing (R)-3 in the final step were slightly, but diagnos-
tically, different.[22] Based on this data, we confirm structure 2
for diazonamide A.
22: Rf ¼ 0.41 (silica gel, ethyl acetate); IR (film): n˜max ¼ 3392, 1715, 1649,
1614, 1508, 1455, 1390, 1261, 1220, 1126, 1090, 1020, 750, 597 cmꢀ1; 1H NMR
(600 MHz, CD3CN): d ¼ 8.66 (s, 1H), 7.47 (d, J ¼ 7.9 Hz, 1H), 7.37 (m, 4H),
7.34 (m, 1H), 7.27 (brd, 1H), 7.22 (s, 1H), 7.07 (d, J ¼ 7.4 Hz, 1H), 7.02 (d,
J ¼ 7.4 Hz, 1H), 6.90 (t, J ¼ 7.9 Hz, 1H), 6.70 (d, J ¼ 7.9 Hz, 1H), 6.23 (s,
1H), 6.04 (brd, 1H), 5.07 (AB, J ¼ 12.3 Hz, n˜AB ¼ 21.9 Hz, 2H), 4.45 (t, J ¼
7.4 Hz, 1H), 4.11 (t, J ¼ 9.2 Hz, 1H), 3.63 (qd, J ¼ 9.2, 5.7 Hz, 2H), 3.06 (t,
J ¼ 12.7 Hz, 1H), 2.77 (brs, 1H), 2.62 (d, J ¼ 12.7 Hz, 1H), 2.04 (m, 1H),
1.01 (d, J ¼ 7.4 Hz, 3H), 0.91 ppm (d, J ¼ 7.4 Hz, 3H); 13C NMR (150 MHz,
CD3CN): d ¼ 175.5, 173.4, 164.6, 155.9, 153.0, 144.7, 142.4, 139.0, 138.0,
133.6, 133.0, 130.6, 130.0, 129.3, 128.8, 128.7, 128.6, 127.7, 125.4, 124.2, 116.2,
102.9, 67.0, 57.6, 57.0, 55.8, 38.4, 30.7, 19.6, 19.3 ppm; HR-MS (matrix-
assisted laser desorption/ionization, MALDI) for C33H31BrN4O7Naþ
[MþNaþ]: calcd: 697.1268, found: 697.1266
cyclization event required to form
the second 12-membered ring of
diazonamide A. Most gratifyingly,
radical cyclization of this precursor
with Ph3SnH/AIBN induced the
desired ring closure to 24, albeit
in low yield (ca. 10%). The effi-
ciencyof this ring closure was
improved to 30% byresorting to
a Witkop-type reaction[21a] based
on
a a
literature procedure,[2a]
process that was proven effective
in previous instances of macrocycle
construction.[21b,c] Significantly, and
in contrast to the Ph3SnH-induced
reaction (in which the majorityof
the substrate was reductivelyde-
brominated), the bulk of the re-
maining material from this process
remained unchanged which al-
lowed for productive recycling of
recovered starting material. As
such, this observation lends further
support that this particular macro-
cyclization
through a mechanism based on
intramolecular photo-induced
reaction
proceeds
electron transfer from the D-ring
indole chromophore to the adja-
cent benzenoid E-ring,[2a] rather
than some exclusivelyradical-
based event in which case the
halogen in the starting material
would most likelybe expelled.
With the establishment of both
macrocyclic scaffolds of diazona-
mide A through the successful gen-
eration of 24, completion of the
synthesis required only a few fin-
ishing touches (see Scheme 4).
First, the two, still missing, chlorine
Scheme 4. Final stages and completion of the total synthesis of diazonamide A (2): a) (Boc)2O (30 equiv),
sat. aq. NaHCO3/dioxane (1:2), 258C, 24 h, 91% based on recovered starting material; b) IBX (3.0 equiv),
DMSO, 258C, 2 h; c) NaClO2 (5.0 equiv), NaH2PO4 (5.0 equiv), resorcinol (5.0 equiv), DMSO/H2O (10:1),
0!258C, 2 h, 69% over two steps; d) 4 (3.0 equiv), EDC (5.0 equiv), HOBt (5.0 equiv), NaHCO3 (15 equiv),
DMF, 258C, 12 h, 65%; e) POCl3/pyridine (1:4), 258C, 2 h, 52%; f) hn (200 nm), epichlorohydrin (3.0 equiv),
LiOAc (2.0 equiv), MeCN/H2O (3:1), 258C, 15 min, 30%–or Ph3SnH (2.0 equiv), AIBN (0.1 equiv), C6H6,
808C, 3 h, 10%; g) NCS (4.0 equiv), CCl4/THF (1:1), 608C, 2 h, 53%; h) TFA, 258C, 10 min, 98%; i) DIBAL-
H (1.0m in toluene, 100 equiv, added portionwise), THF, ꢀ78!258C, 3 h, 56%; j) H2 (2.0 atm), Pd(OH)2/C
(20 wt%, catalytic), EtOH, 25 8C, 2 h; k) (S)-3 (5.0 equiv), EDC (5.0 equiv), HOBt (5.0 equiv), NaHCO3
(15 equiv), DMF, 258C, 12 h, 82% over two steps. IBX ¼ 1-hydroxy-1,2-benziodoxol-3(1H)-one, py ¼ pyri-
dine, AIBN ¼ 2,2’-azobisisobutyronitrile, NCS ¼ N-chlorosuccinimide, DIBAL-H ¼ diisobutylaluminum
hydride.
3498
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0044-8249/02/4118-3498 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 18

COMMUNICATIONS
[13] For highlights of previous synthetic studies towards the diazonamides,
see: a) V. Wittmann, Nachr. Chem. 2002, 50, 477 482; b) T. Ritter,
E. M. Carreira, Angew. Chem. 2002, 114, 2601 2606; Angew. Chem.
Int. Ed. 2002, 41, 2489 2495.
[14] 7-Bromoisatin (8) was prepared from 2-bromoaniline bya procedure
similar to that reported for the synthesis of 7-iodoisatin: V. Lisowski,
M. Robba, S. Rault, J. Org. Chem. 2000, 65, 4193 4194.
[15] This general approach was inspired bythe work of Olah et al.: D. A.
Klumpp, K. Y. Yeung, G. K. S. Prakash, G. A. Olah, J. Org. Chem.
1998, 63, 4481 4484, and references therein. One should note,
however, that the present strategyto access such quaternarycenters
is novel in that no previous report had indicated that two different
aromatic residues could be so incorporated onto an isatin derivative as
required for diazonamide A.
[16] Oxazole 15 was prepared from Boc-protected l-valine and racemic
serine methyl ester following the procedure reported by: S. V.
Downing, E. Aguilar, A. I. Meyers, J. Org. Chem. 1999, 64, 826 831.
[17] The use of NaHDMS was crucial in obtaining the desired benzylated
product (16) in high yield. Other bases such as NaH or LiHMDS/
HMPA led to significant amounts of bis-benzylated material by
enabling engagement of the Boc-protected amine.
[18] MOM-protected 7-bromoisatin (7) was prepared from 7-bromoisatin
(8) bytreatment with LiHDMS and MOMCl. This protection was
required to allow the use of stoichiometric amounts of the more
precious oxazole species in the coupling reaction.
[19] In the conversion of 20 to 21, partial cleavage of the phenolic MOM
group was observed. The resulting material, however, was also
serviceable for the subsequent steps leading to 22.
[20] To the best of our knowledge, this particular reagent combination to
generate an oxazole has not been reported previously, though simple
dehydration with neat POCl3 is known: R. L. Dow, J. Org. Chem. 1990,
55, 386 388. In our hands, this protocol provides a powerful method
for oxazole construction in instances where more conventional
dehydration procedures fail.
[21] a) O. Yonemitsu, P. Cerutti, B. Witkop, J. Am. Chem. Soc. 1966, 88,
3941 3945; b) H. G. Theuns, H. B. M. Lenting, C. A. Salemink, H.
Tanaka, M. S. Shibata, K. Ito, R. J. J. Lousberg, Heterocycles 1984, 22,
2007 2011; c) M. Mascal, C. J. Moody, J. Chem. Soc. Chem. Commun.
1988, 589 590.
In conclusion, a path has now been chartered for the total
synthesis of the long-sought diazonamide A which confirmed
its structure as 2, and through which this valuable, but scarce,
natural substance is now rendered available for biological
investigations.[23] Further synthetic work is expected to
facilitate chemical biologystudies and establish a clear
structure activityprofile for this highlyunusual molecular
architecture.
Received: August 9, 2002 [Z19936]
[1] N. Lindquist, W. Fenical, G. D. Van Duyne, J. Clardy, J. Am. Chem.
Soc. 1991, 113, 2303 2304.
[2] a) J. Li, S. Jeong, L. Esser, P. G. Harran, Angew. Chem. 2001, 113,
4901 4906; Angew. Chem. Int. Ed. 2001, 40, 4765 4770; b) J. Li,
A. W. G. Burgett, L. Esser, C. Amezcua, P. G. Harran, Angew. Chem.
2001, 113, 4906 4909; Angew. Chem. Int. Ed. 2001, 40, 4770 4773.
[3] a) K. C. Nicolaou, S. A. Snyder, K. B. Simonsen, A. E. Koumbis,
Angew. Chem. 2000, 112, 3615 3620; Angew. Chem. Int. Ed. 2000, 39,
3473 3478; b) K. C. Nicolaou, X. Huang, N. Giuseppone,
P. Bheema Rao, M. Bella, M. V. Reddy, S. A. Snyder, Angew. Chem.
2001, 113, 4841 4845; Angew. Chem. Int. Ed. 2001, 40, 4705 4709.
[4] a) J. Li, X. Chen, A. W. G. Burgett, P. G. Harran, Angew. Chem. 2001,
113, 2754 2757; Angew. Chem. Int. Ed. 2001, 40, 2682 2685; b) X.
Chen, L. Esser, P. G. Harran, Angew. Chem. 2000, 112, 967 970;
Angew. Chem. Int. Ed. 2000, 39, 937 940; c) S. Jeong, X. Chen, P. G.
Harran, J. Org. Chem. 1998, 63, 8640 8641.
[5] a) E. Vedejs, M. A. Zajac, Org. Lett. 2001, 3, 2451 2454; b) E. Vedejs,
J. Wang, Org. Lett. 2000, 2, 1031 1032; c) E. Vedejs, D. A. Barba, Org.
Lett. 2000, 2, 1033 1035.
[6] a) P. Wipf, J.-L. Methot, Org. Lett. 2001, 3, 1261 1264; b) P. Wipf, F.
Yokokawa, Tetrahedron Lett. 1998, 39, 2223 2226.
[7] a) J. D. Kreisberg, P. Magnus, E. G. McIver, Tetrahedron Lett. 2001, 42,
627 629; b) P. Magnus, E. G. McIver, Tetrahedron Lett. 2000, 41, 831
834; c) F. Chan, P. Magnus, E. G. McIver, Tetrahedron Lett. 2000, 41,
835 838; d) P. Magnus, J. D. Kreisberg, Tetrahedron Lett. 1999, 40,
451 454.
[8] D. E. Fuerst, B. M. Stoltz, J. L. Wood, Org. Lett. 2000, 2, 3521 3523.
[9] a) S. Schley, A. Radspieler, G. Christoph, J. Liebscher, Eur. J. Org.
Chem. 2002, 369 374; b) A. Radspieler, J. Liebscher, Synthesis 2001,
745 750.
[10] a) F. Lach, C. J. Moody, Tetrahedron Lett. 2000, 41, 6893 6896;
b) M. C. Bagley, S. L. Hind, C. J. Moody, Tetrahedron Lett. 2000, 41,
6897 6900; c) M. C. Bagley, C. J. Moody, A. G. Pepper, Tetrahedron
Lett. 2000, 41, 6901 6904; d) C. J. Moody, K. J. Doyle, M. C. Elliott,
T. J. Mowlem, J. Chem. Soc. Perkin Trans. 1 1997, 2413 2419; e) C. J.
Moody, K. J. Doyle, M. C. Elliott, T. J. Mowlem, Pure Appl. Chem.
1994, 66, 2107 2110.
[11] a) H. C. Hang, E. Drotleff, G. I. Elliott, T. A. Ritsema, J. P. Konopel-
ski, Synthesis 1999, 398 400; b) J. P. Konopelski, J. M. Hottenroth,
H. M. Oltra, E. A. Veliz, Z. C. Yang, Synlett 1996, 609 611.
[12] A. Boto, M. Ling, G. Meek, G. Pattenden, Tetrahedron Lett. 1998, 39,
8167 8170.
[22] Especiallyrevealing was the C37 proton signal (400 MHz,
[D4]MeOH) which, in the case of 2, coincided preciselywith the
reported value for the natural product (d ¼ 3.88 ppm), whereas in the
case of its C37 epimer the signal for this proton appeared at d ¼
3.92 ppm. We should note that we were unable to obtain a sample of
natural diazonamide A for direct comparison.
[23] Synthetic diazonamide A (2) exhibited potent cytotoxic activity at
single digit nm concentrations against various human cancer cell lines
of distinct origin, including ovarian carcinoma 1A9, lung carcinoma
A549, prostate carcinoma PC-3, breast carcinoma MCS-7, and the
taxol-resistant 1A9/PTX10 cell line. Its C37 epimer, although less
active, also exhibited significant activityagainst the same cell lines. We
thank Dr. Paraskevi Giannakakou and Aurora O©Brate of the Winship
Cancer Institute, EmoryUniversitySchool of Medicine, for these
biological assays.
Angew. Chem. Int. Ed. 2002, 41, No. 18
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0044-8249/02/4118-3499 $ 20.00+.50/0
3499