Synthesis of functional "top-half" partial structures of azinomycin A and B

Article abstract of DOI:10.1021/jo7014888

(Chemical Equation Presented) The design and synthesis of a detailed series of functional "top-half substructures of azinomycin A and B is described.

Full text of DOI:10.1021/jo7014888

Synthesis of Functional “Top-Half” Partial Structures of
Azinomycin A and B
Robert S. Coleman,* Mark T. Tierney, Sarah B. Cortright, and Daniel J. Carper
Department of Chemistry, The Ohio State UniVersity, 100 West 18th AVenue, Columbus, Ohio 43210
coleman@chemistry.ohio-state.edu
ReceiVed July 9, 2007
The design and synthesis of a detailed series of functional “top-half” substructures of azinomycin A and
B is described.
Introduction
Antitumor agents that covalently modify duplex DNA1 form
the armamentarium of cancer chemotherapy.2 Despite significant
advances in intervention in uncontrolled cell growth,3 these
agents are often the first line of therapy for the majority of
cancers. Of critical importance to the clinical use of such agents
is the issue of selectivity and the associated problem of toxicity,
and much effort has been spent on improving the therapeutic
index of chemotherapeutic agents.
The azinomycins (Figure 1) are cytotoxic natural products4
that are structurally and mechanistically unrelated to other
families of antitumor agents.5 These agents possess a novel and
densely functionalized 1-azabicyclo[3.1.0]hexane (aziridino[1,2-
a]pyrrolidine) ring system appended as part of a dehydroamino
acid system to the referent “top-half” backbone. Azinomycin
FIGURE 1. Structures of azinomycin A and B.
(1) Gates, K. S. Covalent Modification of DNA by Natural Products. In
ComprehensiVe Natural Products Chemistry, Vol. 7; Barton, D., Nakanishi,
K., Meth-Cohn, O., Eds.; Pergamon Press: Oxford, 1999; pp 491-552.
(2) (a) Cancer Chemotherapeutic Agents; Foye, W. O., Ed.; American
Chemical Society: Washington, DC, 1995. (b) DNA Adducts: Identification
and Biological Significance; Hemminki, K., Dipple, A., Shuker, D. E. G.,
Kadlubar, F. F., Segerba¨ck, D., Bartsch, H., Eds.; IARC Scientific
Publication No. 125, Oxford University Press: New York, 1994.
(3) (a) Nygren, P.; Larsson, R. J. Intern. Med. 2003, 253, 46. (b) Bernold,
D. M.; Sinicrope, F. A. Clin. Gastroenterol. Hepatol. 2006, 4, 808. (c) van
den Bent, M. J.; Hegi, M. E.; Stupp, R. Eur. J. Cancer 2006, 42, 582. (d)
Molina, J. R.; Adjei, A. A.; Jett, J. R. Chest 2006, 130, 1211.
(4) Ishizeki, S.; Ohtsuka, M.; Irinoda, K.; Kukita, K.; Nagaoka, K.;
Nakashima, T. J. Antibiot. 1987, 40, 60. In vitro cytotoxicity: IC50 ) 0.07
µg/mL 1a and 0.11 µg/mL 1b against L5178Y cells. In vivo antitumor
activity: 193% ILS at 16 µg/kg 1b (3/7 survivors) against P388 leukemia;
161% ILS at 32 µg/kg 1b (5/8 survivors) against Erlich carcinoma. In the
same system, mitomycin C exhibited 204% ILS at 1 mg/kg against P388
leukemia.
B bears an additional carbon (C4)sthe role of which has not
been definedsthat is part of an unprecedented 2-amino-1,3-
dicarbonyl system.
Azinomycins apparently exert their biological effect by the
formation of covalent, interstrand cross-links6 within the major
groove of duplex DNA, presumably via electrophilic epoxide
and aziridine rings. Considerable progress has recently been
made on understanding the in vitro mechanism of action of these
agents, both experimentally with natural compounds and
analogues7,8 and by computer modeling.9 In addition, biosyn-
thetic studies10 and biological evaluation of several series of
analogues have been reported.11,12 In experimental studies on
(5) (a) Nagaoka, K.; Matsumoto, M.; Oono, J.; Yokoi, K.; Ishizeki, S.;
Nakashima, T. J. Antibiot. 1986, 39, 1527. (b) Yokoi, K.; Nagaoka, K.;
Nakashima, T. Chem. Pharm. Bull. 1986, 34, 4554.
(6) Rajski, S. R.; Williams, R. M. Chem. ReV. 1998, 98, 2723.
(7) For a review of synthesis and mode of action of azinomycins:
Hodgkinson, T. J.; Shipman, M. Tetrahedron 2001, 57, 4467.
10.1021/jo7014888 CCC: $37.00 © 2007 American Chemical Society
Published on Web 09/07/2007
7726
J. Org. Chem. 2007, 72, 7726-7735

“Top-Half” Partial Structures of Azinomycin A and B
FIGURE 2. “Top-half” azinomycin partial structures.
azinomycin B,8a we established the sequence preferences for
DNA cross-link formation and demonstrated the lack of
intercalation by the aromatic naphthoate group. Prior work by
Gates and Zang8b demonstrated a weak intercalative binding
by this group, and to date, the role of the naphthoate in
recognition and affinity of DNA binding has not been convinc-
ingly demonstrated. In previous work on azinomycin partial
structures,12 we established that the naphthoate was critical for
effective DNA alkylation and cytotoxicity. Partial structures
bearing the epoxide but lacking the naphthoate were devoid of
activity. The importance of other structural features of the natural
products remain to be demonstrated, among them the role of
the intact backbone system in providing binding affinity for
effective covalent bond formation, and what role, if any, the
C1-C4 dicarbonyl system of azinomycin B plays in biological
activity.
FIGURE 3. Stereoisomeric epoxy amides.
epoxide fragment14 and azabicyclic system15 and culminating
in the total synthesis of azinomycin A in 2001.16 A total
synthesis of azinomycin B has not been reported, although
partial syntheses exist.17 Without a doubt, the greatest synthetic
challenge is the introduction of the reactive azabicyclic system,
particularly with respect to protecting group issues for the C12
hydroxyl group. Because of the modular nature of our synthetic
strategy for construction of the azinomycins,16 ready access to
partial structures and modified versions thereof is available.
Most analogue synthesis has focused on the naphthoic epoxy
amide (left-hand) moiety, often truncating the 1-azabicyclo-
[3.1.0]hexane subunit. Recent work in this area has provided
several left-hand partial structures that exhibit a greater stability
than the natural agents. Replacement of the aziridine with a
nitrogen mustard moiety led to left-hand partial analogues that
could cross-link DNA and intercalate into DNA but had lower
activities than the natural left-hand fragment.18 Omission of the
epoxide along with nitrogen mustard incorporation provided
These structurally complex and unstable agents have attracted
considerable attention from the synthetic organic community,13
starting with early reports on approaches to the naphthoyl
(8) (a) Coleman, R. S.; Perez, R. J.; Burk, C. H.; Navarro, A. J. Am.
Chem. Soc. 2002, 124, 13008. (b) Zang, H.; Gates, K. S. Biochemistry 2000,
39, 14968. (c) Fujiwara, T.; Saito, I.; Sugiyama, H. Tetrahedron Lett. 1999,
40, 315. (d) Armstrong, R. W.; Salvati, M. E.; Nguyen, M. J. Am. Chem.
Soc. 1992, 114, 3144. (e) Lown, J. W.; Majumdar, K. C. Can. J. Biochem.
1977, 55, 630.
(9) (a) Alcaro, S.; Coleman, R. S. J. Org. Chem. 1998, 63, 4620. (b)
Alcaro, S.; Coleman. R. S. J. Med. Chem. 2000, 43, 2783. (c) Alcaro, S.;
Ortuso, F.; Coleman, R. S. J. Med. Chem. 2002, 45, 861. (d) Alcaro, S.;
Ortuso, F.; Coleman, R. S. J. Chem. Inf. Model. 2005, 45, 602.
(10) (a) Liu, C.; Kelly, G. T.; Watanabe, C. M. H. Org. Lett. 2006, 8,
1065. (b) Corre, C.; Landreau, C. A. S.; Shipman, M.; Lowden, P. A. S.
Chem. Commun. 2004, 22, 2600. (c) Corre, C.; Lowden, P. A. S. Chem.
Commun. 2004, 8, 990.
(11) (a) Bryant, H. J.; Dardonville, C. Y.; Hodgkinson, T. J.; Hursthouse,
M. B.; Malik, K. M. A.; Shipman, M. J. Chem. Soc., Perkin Trans. 1 1998,
1249. (b) Hartley, J. A.; Hazrati, A.; Kelland, L. R.; Khanim, R.; Shipman,
M.; Suzenet, F.; Walker, L. F. Angew. Chem., Int. Ed. 2000, 39, 3467.
(12) (a) Coleman, R. S.; Burk, C. H.; Navarro, A.; Brueggemeier, R.
W.; Diaz-Cruz, E. S. Org. Lett. 2002, 4, 3545. (b) LePla, R. C.; Landreau,
C. A. S.; Shipman, M.; Jones, G. D. D. Org. Biomol. Chem. 2005, 3, 1174.
(c) Kelly, G. T.; Liu, C.; Smith, R.; Coleman, R. S.; Watanabe, C. M. H.
Chem. Biol. 2006, 13, 485. (d) Coleman, R. S.; Woodward, R. L.; Hayes,
A. M.; Crane, E. A.; Artese, A.; Ortuso, F.; Alcaro, S. Org. Lett. 2007, 9,
1891.
(13) For a review on the synthesis of DNA cross-linking agents and a
discussion of the historical development of DNA cross-linking agents, see:
Coleman, R. S. Curr. Opin. Drug DiscoVery DeV. 2001, 4, 435.
(14) (a) Uemura, I.; Yamada, K.; Sugiura, K.; Miyagawa, H.; Ueno, T.
Tetrahedron: Asymmetry 2001, 12, 943. (b) Armstrong, R. W.; Tellew, J.
E.; Moran, E. J. Tetrahedron Lett. 1996, 37, 447. (c) Shishido, K.; Omodani,
T.; Shibuya, M. J. Chem. Soc., Perkin Trans. 1 1992, 16, 2053. (d) Bryant,
H. J.; Dardonville, C. Y.; Hodgkinson, T. J.; Shipman, M.; Slawin, A. M.
Z. Synlett 1996, 10, 973. (e) Moran, E. J.; Armstrong, R. W. Tetrahedron
Lett. 1991, 32, 3807. (f) England, P.; Chun, K. H.; Moran, E. J.; Armstrong,
R. W. Tetrahedron Lett. 1990, 31, 2669.
(15) (a) Coleman, R. S.; Kong, J.-S.; Richardson, T. E. J. Am. Chem.
Soc. 1999, 121, 9088. (b) Goujon, J.-Y.; Shipman, M. Tetrahedron Lett.
2002, 43, 9573. (c) Coleman, R. S.; Richardson, T. E.; Carpenter, A. J. J.
Org. Chem. 1998, 63, 5738. (d) Coleman, R. S.; Carpenter, A. J. Tetrahedron
1997, 53, 16313. (e) Coleman, R. S.; Kong, J.-S. J. Am. Chem. Soc. 1998,
120, 3538. (f) Coleman, R. S.; Carpenter, A. J. J. Org. Chem. 1992, 57,
5813. (g) Armstrong, R. W.; Moran, E. J. J. Am. Chem. Soc. 1992, 114,
371. (h) Armstrong, R. W.; Tellew, J. E.; Moran, E. J. J. Org. Chem 1992,
57, 2208. (i) Miyashita, K.; Park, M.; Adachi, S.; Seki, S.; Obika, S.;
Imanishi, T. Bioorg. Med. Chem. Lett. 2002, 12, 1075. (j) Hodgkinson, T.
J.; Kelland, L. R.; Shipman, M.; Vile, J. Tetrahedron 1998, 54, 6029. (k)
Moran, E. J.; Tellew, J. E.; Zhao, Z.; Armstrong, R. W. J. Org. Chem.
1993, 58, 7848.
(16) Coleman, R. S.; Li, J.; Navarro, A. Angew. Chem., Int. Ed. 2001,
40, 1736.
(17) (a) Hashimoto, M.; Sugiura, M.; Terashima, S. Tetrahedron 2003,
59, 3063. (b) Hashimoto, M.; Matsumoto, M.; Terashima, S. Tetrahedron
2003, 59, 3041. (c) Hashimoto, M.; Terashima, S. Heterocycles 1998, 47,
59. (d) Hashimoto, M.; Terashima, S. Tetrahedron Lett. 1994, 35, 9409.
J. Org. Chem, Vol. 72, No. 20, 2007 7727

Coleman et al.
SCHEME 1
SCHEME 2
non-cross-linking compounds that were capable of monoalky-
lation.18 Variations in substitution of the aromatic group for a
series of left-hand primary amides showed significant effects
on the cytotoxic potency of the analogues.19 The amide sub-
stitution pattern for the naphthyl epoxy amide subunit has been
explored by the synthesis of a small series of secondary amides,
resulting in a loss of cytotoxic activity.19 Bis-epoxides, with
variations in linker structure, based on the naphthoyl epoxide
moiety of naturally occurring azinomycins, have been synthe-
sized to examine their merit as DNA cross-linkers.20 Further
“top-half” truncated analogues have included variations of the
azabicyclic system, without the C12/C13 hydroxy groups.21
In this paper, we detail the synthetic efforts at the preparation
of analogues of the “top-half” of azinomycin A and B.
Compounds 2-4 are variations on the azinomycin A backbone.
Compound 2 possesses a glycine methylene at C7 in place of
the dehydroamino acid, whereas 3 bears a simple dehydroalanine
in place of the pyrrolidine ring. Ester 4 is designed to examine
hydrogen-bonding effects on epoxide ring opening. Previous
results with less elaborate systems demonstrated the importance
of the amide linkage at this position.12 The azinomycin B series
5 and 6, each possessing the characteristic azinomycin B C4-
enol, are analogous to 2 and 3 (Figure 2), where the azabicyclic
system has been truncated.
oisomeric epoxy amides (7-10) to examine the effect of
absolute and relative stereochemistry at the C18 and C19
stereogenic centers on DNA alkylation and cytotoxicity. A recent
report described the synthesis of these diastereomeric epoxy
amides for biological studies, using a nonstereoselective epoxide
formation with m-CPBA.22
In a second series of modified azinomycin partial structures
(Figure 3), we have constructed the complete series of stere-
Previous work with 7 demonstrated that this azinomycin
partial structure binds DNA in a mode different from that
observed with the native agent.12 These results indicated that
the azinomycin naphthoate plays an important role in increasing
sequence selective binding affinity and cytotoxic activity. As
compared to the native agent, partial structure 7 altered the
sequence selectivity while retaining a substantial portion of
cytotoxic activity. Therefore, the complete stereoisomeric series
(18) (a) Casely-Hayford, M. A.; Pors, K.; James, C. H.; Patterson, L.
H.; Hartley, J. A.; Searcey, M. Org. Biomol. Chem. 2005, 3, 3585. (b)
Casely-Hayford, M. A.; Pors, K.; Patterson, L. H.; Gerner, C.; Neidle, S.;
Searcey, M. Bioorg. Med. Chem. Lett. 2005, 15, 653.
(19) Hodgkinson, T. J.; Kelland, L. R.; Shipman, M.; Suzenet, F. Bioorg.
Med. Chem. Lett. 2000, 10, 239.
(20) (a) LePla, R. C.; Landreau, C. A. S.; Shipman, M.; Hartley, J. A.;
Jones, G. D. D. Bioorg. Med. Chem. Lett. 2005, 15, 2861. (b) Hartley, J.
A.; Hazrati, A.; Hodgkinson, T. J.; Kelland, L. R.; Khanim, R.; Shipman,
M.; Suzenet, F. Chem. Commun. 2000, 2325.
(21) (a) Landreau, C. A. S.; LePla, R. C.; Shipman, M.; Slawin, A. M.
Z.; Hartley, J. A. Org. Lett. 2004, 6, 3505. (b) Hartley, J. A.; Hazrati, A.;
Kelland, L. R.; Khanim, R.; Shipman, M.; Suzenet, F.; Walker, L. F. Angew.
Chem., Int. Ed. 2000, 39, 3467.
(22) David-Cordonnier, M. H.; Casely-Hayford, M.; Kouach, M.; Briand,
G.; Patterson, L. H.; Bailly, C.; Searcey, M. Chem. Biol. Chem. 2006, 7,
1658.
7728 J. Org. Chem., Vol. 72, No. 20, 2007

“Top-Half” Partial Structures of Azinomycin A and B
SCHEME 3
of 7-10 were synthesized to complete this study of the
naphthoate portion of the azinomycins.
SCHEME 4
Results and Discussion
Preparation of Epoxide-Bearing Partial Structures. Syn-
thesis of the desired epoxy amide compounds 7-1022 (Scheme
1) commenced with enantiomerically pure epoxides (+)-12a
and (-)-12b, obtained via Sharpless epoxidation23 of the
respective enantiomerically enriched allylic alcohol 11.24,25
Esterification of epoxy alcohol 12a with naphthoic acid chloride
1416,26 (CH2Cl2, 25 °C, 12 h) afforded the (2R,3S)-diester 15,
as a single diastereomer, bearing the native azinomycin epoxide
stereochemistry. Hydrogenolysis of the benzyl ester (1 atm H2,
10% Pd/C, THF, 25 °C) followed by activation of the resulting
carboxylic acid 19 with isobutylchloroformate (THF, 0 °C, 30
min) and treatment with aqueous ammonia (0 °C) afforded
epoxy amide 7 in modest yield. Following this same procedure,
amide 10 was obtained from epoxy alcohol 12b. Mitsunobu
esterification of the (2S,3R)- and (2R,3S)-epoxy alcohols 12a
and 12b (THF, 25 °C, 4 h) proceeded smoothly to yield the
(2R,3R)- and (2S,3S)-epoxy diesters 16 and 17, respectively.
Conversion of the epoxy diesters to their respective amides was
accomplished as stated previously and afforded 8 and 9 in
modest yields.
Preparation of Complete “Top-Half” Structural Ana-
logues of Azinomycin A. Structurally related complete “top-
half” azinomycin A compounds were prepared with a conver-
gent, modular approach using naphthoic epoxy acid 19 and
elaborated aminopropanol fragments. (R)-1-Aminopropan-2-ol
was utilized due to its relatively low cost and the subsequent
simplification of 1H and 13C NMR spectra. For convenience of
handling, it was protected with a t-butyldimethylsilyl group, and
the protected amine (20) was used in all synthetic routes.
Synthesis of glycine methylene derivative 2 started with the
EDCI coupling of amine 20 with benzylcarbamate-protected
glycine (2:1 CH2Cl2/THF, 25 °C, 4 h) to afford amide 21
(Scheme 2). Hydrogenolysis of the benzylcarbamate of 21 (1
atm H2, 10% Pd/C, MeOH, 25 °C) afforded the corresponding
amine, which was coupled with naphthoic epoxy acid 19
(Scheme 1) using PyBOP or EDCI (CH2Cl2, 25 °C, 12 h) to
provide 22 in modest yields. Deprotection of the silyl group of
22 with HF‚pyridine (CH3CN, -10 °C, 4 h) provided secondary
alcohol 23, which was subsequently oxidized with IBX (EtOAc,
78 °C, 7 h) to provide partial structure 2.
The azinomycin A partial structure 3 containing a dehy-
droamino acid moiety was prepared with a similar covergent
approach (Scheme 3). (R)-2-Amino-1-(t-butyldimethylsiloxy)-
propane (20) was coupled with benzylcarbamate-protected
L-serine 24 using HBTU (CH2Cl2, 25 °C, 2.5 h) to afford 25.
Hydrogenolysis of the benzylcarbamate of 25 (1 atm H2, 10%
Pd/C, MeOH, 25 °C, 4 h) followed by PyBOP coupling with
naphthoic epoxy acid 19 (CH2Cl2, 0-23 °C, 12 h) provided
26, the complete azinomycin A top piece skeleton. Treatment
with methanesulfonylchloride (CH2Cl2, -40 °C, 3 h) followed
by DBU (CH2Cl2, 22 °C, 1.5 h) then afforded the eliminated
product 27. Deprotection of the silyl group with HF‚pyridine
(CH3CN, 0-25 °C, 45 min) provided alcohol 28, which was
subjected to IBX oxidation (CH3CN, 50 °C, 6 h) to provide
partial structure 3.
(23) (a) Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1. (b) Johnson,
R. A.; Sharpless, K. B. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Ley, S. V., Eds.; Pergamon Press: New York, 1991; Vol. 7, p 389. (c)
Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.;
Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237.
(24) These epoxides were also obtained via the kinetic resolution/
epoxidation of racemic allylic alcohol 11.
(25) (a) Bryant, H. J.; Dardonville, C. Y.; Hodgkinson, T. J.; Shipman,
M.; Slawin, A. M. Z. Synlett 1996, 973. (b) Coleman, R. S.; Sarko, C. R.;
Gittinger, J. P. Tetrahedron Lett. 1997, 38, 5917. (c) Coleman, R. S.;
McKinley, J. D. Tetrahedron Lett. 1998, 39, 3433. (d) Konda, Y.; Machida,
T.; Sasaki, T.; Takeda, K.; Takayanagi, H.; Harigaya, Y. Chem. Pharm.
Bull. 1994, 42, 285.
An ester analogue of the azinomycin A “top-half” partial
structure was also prepared (Scheme 4).12 (R)-2-Amino-1-(t-
butyldimethylsiloxy)propane (20) was coupled with glycolic acid
(26) Shibuya, M. Tetrahedron Lett. 1983, 24, 1175.
J. Org. Chem, Vol. 72, No. 20, 2007 7729

Coleman et al.
SCHEME 5
SCHEME 6
(29) using EDCI (2:1 CH2Cl2/THF, 25 °C, 12 h) to afford amido
alcohol 30. Next, 30 was coupled with naphthoic epoxy acid
19 using EDCI (CH2Cl2, 25 °C, 12 h) to afford 31, the completed
ester structural skeleton. Deprotection of the silyl group of 31
with HF‚pyridine (CH3CN, -5 °C, 45 min) provided alcohol
32, which was followed by Dess-Martin oxidation (CH2Cl2,
25 °C, 1 h) of the secondary alcohol to provide partial structure
4.
Preparation of Complete “Top-Half” Structural Ana-
logues of Azinomycin B. Preparation of the 1,3-dicarbonyl
system of azinomycin B presented considerable synthetic diffi-
culty. Numerous attempts at introducing this moiety such as
late stage oxidation of 1,3-diols resulted in elimination of either
the 1- or the 3-alcohol to afford an olefin. However, introduction
of a protected carbonyl early in the synthesis allowed for late
stage oxidation and introduction of the second carbonyl.
Scheme 5 presents the synthesis of the azinomycin B “top-
half” analogue 5. Benzylcarbamate-protected L-threoninol (33)
was obtained in several steps from L-threonine.27 Silylation of
the primary alcohol with t-butyldiphenylsilyl chloride (imida-
zole, DMF, 25 °C, 24 h) provided 34 and was followed by IBX
oxidation (EtOAc, 78 °C, 14 h) to afford the desired ketone
35. Dimethylacetal 36 was formed by treatment of ketone 35
with trimethylorthoformate (CSA, MeOH, 65 °C, 6 h) to afford
the fully derivatized threonine-based 1,3-dicarbonyl precursor
36. Hydrogenolysis of the benzylcarbamate of 36 (1 atm H2,
10% Pd/C, MeOH, 25 °C, 2 h) followed by EDCI coupling
with benzylcarbamate-protected glycine (CH2Cl2, 25 °C, 12 h)
provided amido acetal 37. Removal of the silyl group with KF‚
H2O/18-crown-6 (CH3CN, 50 °C, 24 h) provided alcohol 38.
Hydrogenolysis of the benzylcarbamate of 38 (1 atm H2, 10%
Pd/C, MeOH, 25 °C, 3 h) and coupling with naphthoic epoxy
acid 19 using EDCI and HOBt (CH2Cl2, 25 °C, 12 h) afforded
39, the fully elaborated top-piece skeleton. Oxidation of the
primary alcohol of 39 with IBX (EtOAc, 78 °C, 6 h) provided
crude aldehyde 40. Treatment with Amberlyst A-15 resin in
aqueous acetone (23 °C, 6.5 h) afforded the desired 1,3-dicar-
bonyl system and azinomycin partial structure 5. The corre-
sponding methyl ether 41 was formed upon treatment of 5 with
trimethylsilyldiazomethane (1:1 toluene/MeOH, 25 °C, 20 min).
In a strategy similar to that used for the azinomycin A partial
structure 4 featuring the dehydroamino acid of the truncated
azabicyclic system, the synthesis of azinomycin B partial
structure 6 employed a late stage elimination of water from a
serine residue (Scheme 6). Hydrogenolysis of dimethylacetal
36 (1 atm H2, 10% Pd/C, MeOH, 25 °C, 3 h) followed by EDCI
coupling with benzylcarbamate-protected L-serine (24) (CH2-
Cl2, 25 °C, 12 h) afforded amido acetal 42. Hydrogenolysis of
the carbamate of 42 (1 atm H2, 10% Pd/C, MeOH, 25 °C, 2 h)
followed by EDCI coupling with naphthoic epoxy acid 19 (CH2-
Cl2, 25 °C, 12 h) afforded diamide 43. The primary alcohol of
43 was transformed into the corresponding methanesulfonate
(CH2Cl2, Et3N, -45-22 °C, 2 h), which underwent base-
promoted elimination upon treatment with DBU (0-22 °C, 1
h) to provide alkene 44. Removal of the t-butyldiphenylsilyl
(27) Jeffery, A. L.; Kim, J.-H.; Wiemer, D. F. Tetrahedron 2000, 56,
5077.
7730 J. Org. Chem., Vol. 72, No. 20, 2007

“Top-Half” Partial Structures of Azinomycin A and B
mg) in CH2Cl2 (20 mL) at -65 °C. The reaction mixture was
allowed to warm to 25 °C and was stirred 12 h. The reaction mixture
was washed with saturated aqueous NaHCO3, water, and saturated
aqueous NaCl, and the organic extract was dried (Na2SO4) and
concentrated. Purification of the residue by flash chromatography
(1.5 cm × 10 cm silica; 20% EtOAc/hexane) afforded the diester
as an oil (55 mg; 77%): 1H NMR (400 MHz, CDCl3) δ 8.60-
8.59 (dd, J ) 7.6, 2.0 Hz, 1H), 7.90 (d, J ) 2.6 Hz, 1H), 7.51 (d,
J ) 2.6 Hz, 1H), 7.40-7.30 (m, 7H), 5.32 (d, J ) 12 Hz, 1H),
5.24 (d, J ) 12 Hz, 1H), 5.22 (s, 1H), 3.94 (s, 3H), 2.97 (d, J )
4.6 Hz, 1H), 2.68 (d, J ) 4.6 Hz, 1H), 2.65, (s, 3H), 1.45 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 167.2, 166.3, 155.9, 135.0, 134.3,
133.1, 128.6, 128.5, 128.3, 128.2, 127.7, 126.8, 125.1, 123.8, 122.0,
108.4, 77.6, 67.5, 55.9, 55.5, 52.1, 20.1, 17.1; HRMS (ESI), m/z
calculated for C25H24O6Na: 443.1471; found: 443.1445.
General Procedure for Preparation of Epoxy Amides 7-10.
The respective epoxy diester was dissolved in THF to a concentra-
tion of 5 mg/mL, and 10% Pd/C (10% w/w loading) was added.
Hydrogen gas was bubbled into the mixture for approximately 3
h. After filtration through Celite, the filtrate was cooled to 0 °C,
and diisopropylethylamine (2.2 equiv) and isobutylchloroformate
(2 equiv) were added. After stirring for 30 min, the mixture was
treated with 30% aqueous NH3, and the reaction mixture was stirred
for an additional 5 min. The mixture was partitioned between EtOAc
and 5% aqueous acetic acid, and the organic extract was washed
with water, saturated aqueous NaHCO3, water, and saturated
aqueous NaCl. Flash chromatography (1.5 cm × 10 cm silica, 80%
EtOAc/hexane) afforded the respective epoxy amides.
(2S,3R)-3,4-Epoxy-2-(3-methoxy-5-methylnapthoyloxy)-3-me-
thylbutanamide (7). Yield (28 mg; 47%): 1H NMR (400 MHz,
CDCl3) δ 8.62 (m, 1H), 7.90 (d, J ) 2.6 Hz, 1H), 7.46 (d, J ) 2.6
Hz, 1H), 7.35 (m, 2H), 6.14 (br s, 1H), 5.67 (br s, 1H), 5.20 (s,
1H), 3.96 (s, 3H), 3.01 (d, J ) 4.6 Hz, 1H), 2.78 (d, J ) 4.6 Hz,
1H), 2.66 (s, 3H), 1.54 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
168.7, 165.5, 155.8, 134.3, 133.2, 128.1, 127.8, 126.9, 125.2, 123.7,
122.1, 108.4, 75.9, 55.8, 55.5, 53.3, 20.1, 17.6; HRMS (ESI), m/z
calculated for C18H19NO5Na: 352.1161; found: 352.1167.
(R)-2-(t-Butyldimethylsilanyloxy)propylamine (20). A solution
of (R)-1-aminopropan-2-ol 20 (0.662 g, 8.81 mmol) and DBU (1.61
g, 10.6 mmol) in CH3CN (10 mL) was cooled to 0 °C. t-
Butyldimethylsilylchloride (1.59 g, 10.6 mmol) was added in one
portion, and the reaction mixture was allowed to warm to 22 °C
and stirred for 12 h. Methanol (0.1 mL) was added, and the solvent
was removed under a stream of N2. The residue was dissolved in
Et2O (25 mL), washed with saturated aqueous NaCl, dried (Na2-
SO4), and concentrated under N2. This afforded amine 20 as an oil
(1.39 g, 83%), which was used without further purification: IR
(film) 3321, 3277, 2944, 1594 cm-1; 1H NMR (400 MHz, CDCl3)
δ 3.75 (m, 1H), 2.61 (m, 2H), 1.26 (br s, 2H), 1.09 (d, J ) 6.1 Hz,
3H), 0.89 (s, 9H), 0.03 (s, 6H). 13C NMR (100 MHz, CDCl3) 70.8,
53.5, 26.9, 20.5, 18.1, -4.6, -4.8; ESI-HRMS, m/z calculated for
C9H23NOSiNa: 212.1447; found: 212.1444.
{[2-(t-Butyldimethylsilanyloxy)propylcarbamoyl]methyl}-
carbamic Acid Benzyl Ester (21). A solution of amine 20 (164
mg, 0.866 mmol), benzylcarbamate-protected glycine (181 mg,
0.866 mmol), and HOBt (117 mg, 0.866 mmol) in 2:1 CH2Cl2/
THF at 25 °C was treated with EDCI (183 mg, 0.953 mmol), and
the reaction mixture was stirred for 4 h. The mixture was poured
onto water (10 mL) and extracted with EtOAc (3 × 100 mL). The
combined organic extracts were washed with 5% aqueous HOAc,
water, saturated aqueous NaHCO3, water, and saturated aqueous
NaCl and were dried (Na2SO4) and concentrated. The residue was
purified by flash chromatography (3 cm × 10 cm silica; 50% EtOAc
in hexanes) to afford the product as a white solid (324 mg; 98%).
IR (film) 3422, 3322, 2956, 1711, 1667 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.36-7.29 (m, 5H), 6.17 (br s, 1H), 5.34 (br s, 1H),
5.12 (s, 3H), 3.92-3.81 (m, 2H), 3.43-3.38 (m, 1H), 3.12-3.06
(m, 1H), 1.11 (d, J ) 6.1 Hz, 3H), 0.88 (s, 9H), 0.06 (s, 6H); 13C
NMR (100 MHz, CDCl3) 164.9, 156.1, 135.7, 127.9, 127.2, 126.7,
group of 44 was accomplished by treatment with KF/18-crown-6
(CH3CN, 5% aqueous HOAc, 50 °C, 2 h). Oxidation of the
resulting alcohol 45 with IBX (DMSO, 50 °C, 6 h) provided
the corresponding aldehyde (46). Immediate treatment with
Amberlyst A-15 resin in aqueous acetone (23 °C, 6.5 h) removed
the dimethylacetal to afford the desired azinomycin B partial
structure 6.
Conclusion
We have described the synthesis of several key partial “top-
half” structures of azinomycin A and B. Currently, DNA
alkylation studies with these partial structures are in progress.
Details of such studies with the stereoisomeric epoxy amides
7-10 have recently been reported, providing insight into the
role of the epoxy amide stereochemistry in DNA alkylation and
cytotoxicity.12d Alkylation studies with “top-half” structures 2-6
will demonstrate the significance of the complete azinomycin
A and B backbone and provide valuable information on the in
vitro mechanism of the azinomycins.
Experimental Section
Benzyl(2R,3S)-3,4-epoxy-2-(3-methoxy-5-methylnaphthoyloxy)-
3-methylbutanoate (16). A solution of naphthoic acid 13 (0.402
g, 1.86 mmol), epoxy alcohol 12a (0.138 g, 0.621 mmol), and
triphenylphosphine (0.408 g, 1.55 mmol) in THF (20 mL) was
cooled to -25 °C. Diethylazodicarboxylate (0.11 mL, 0.68 mmol)
was added dropwise. The reaction mixture was warmed to 25 °C
and stirred for 72 h. After being poured into EtOAc, the mixture
was washed with saturated aqueous NaHCO3, water, and saturated
aqueous NaCl; dried (Na2SO4); and concentrated. Purification of
the residue by flash chromatography (1.5 cm × 10 cm silica; 20%
EtOAc/hexane) afforded the diester as an oil (0.134 g, 52%): 1H
NMR (400 MHz, CDCl3) δ 8.59 (m, 1H), 7.92 (d, J ) 2.6 Hz,
1H), 7.46 (d, J ) 2.6 Hz, 1H), 7.40-7.30 (m, 7H), 5.32 (d, J ) 12
Hz, 1H), 5.25 (d, J ) 12 Hz, 1H), 5.06 (s, 1H), 3.94 (s, 3H), 3.07
(d, J ) 4.5 Hz, 1H), 2.76 (d, J ) 4.5 Hz, 1H), 2.65, (s, 3H), 1.46
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.1, 166.9, 155.8, 135.0,
134.3, 133.1, 128.6, 128.5, 128.3, 128.2, 127.6, 126.8, 125.0, 123.8,
122.0, 108.4, 77.5, 67.5, 55.8, 55.5, 52.1, 20.02, 17.0; HRMS (ESI),
m/z calculated for C25H24O6Na: 443.1471; found: 443.1498.
Benzyl(2S,3R)-3,4-epoxy-2-(3-methoxy-5-methylnaphthoyloxy)-
3-methylbutanoate (17). Triphenylphosphine (0.20 g, 0.76 mmol)
was dissolved in THF (3 mL), and the reaction mixture was cooled
to -20 °C. Diisopropylazodicarboxylate (0.14 mL, 0.69 mmol) was
added dropwise. The reaction mixture was cooled to -78 °C, and
a solution of naphthoic acid 13 (0.20 g, 0.95 mmol) and epoxy
alcohol 12b (0.14 g, 0.63 mmol) in THF (2 mL) was added rapidly
via cannula. The reaction mixture was stirred at 25 °C for 4 h,
when it was diluted with EtOAc and washed with saturated aqueous
NaHCO3, water, and saturated aqueous NaCl. The organic extract
was dried (Na2SO4) and concentrated. Purification of the residue
by flash chromatography (1.5 cm × 10 cm silica, 20% EtOAc/
hexane) afforded the diester as an oil (0.245 g; 92%): 1H NMR
(400 MHz, CDCl3) δ 8.57 (m, 1H), 7.91 (d, J ) 2.6 Hz, 1H), 7.47
(d, J ) 2.6 Hz, 1H), 7.40-7.30 (m, 7H), 5.32 (d, J ) 12 Hz, 1H),
5.24 (d, J ) 12 Hz, 1H), 5.06 (s, 1H), 3.94 (s, 3H), 3.07 (d, J )
4.6 Hz. 1H), 2.76 (d, J ) 4.6 Hz, 1H), 2.66, (s, 3H), 1.46 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 167.2, 166.3, 155.8, 135.0, 134.3,
133.1, 128.6, 128.5, 128.3, 128.2, 127.7, 126.8, 125.1, 123.8, 122.0,
108.4, 77.6, 67.5, 55.9, 55.5, 52.1, 20.1, 17.1: HRMS (ESI), m/z
calculated for C25H24O6Na: 443.1471; found: 443.1477.
Benzyl(2R,3R)-3,4-epoxy-2-(3-methoxy-5-methylnaphthoyloxy)-
3-methylbutanoate (18). Epoxy alcohol 12b (30 mg, 0.14 mmol)
was added to a solution of naphthoic acid chloride 14 (40 mg, 0.17
mmol), diisopropylethylamine (30 µL, 0.17 mmol), and DMAP (2
J. Org. Chem, Vol. 72, No. 20, 2007 7731

Coleman et al.
73.3, 61.2, 47.3, 43.1, 27.5, 20.4, 18.2, -4.4, -4.5; ESI-HRMS,
m/z calculated for C19H32N2O4SiNa: 403.2029; found: 403.2025.
3-Methoxy-5-methylnaphthalene-1-carboxylic Acid ({[2-(t-
Butyldimethylsilanyloxy)propylcarbamoyl]methyl}carbamoyl)-
(2-methyloxiranyl)methyl Ester (22). Hydrogen gas was bubbled
through separate solutions of benzyl ester 15 (181 mg, 0.431 mmol)
and glycine derivative 21 (164 mg, 0.327 mmol) in MeOH (25
mL each), each as a mixture with 10% Pd/C (10% w/w loading),
for 4 h. Both mixtures were filtered through Celite, and the filtrate
was concentrated. The residues were dissolved in CH2Cl2 (25 mL
each), cooled to -20 °C, and combined. The resulting solution was
treated with PyBOP (247 mg, 0.475 mmol) and diisopropylethy-
lamine (61 mg, 0.475 mmol), and the reaction mixture was allowed
to warm to 25 °C and was stirred 12 h. The mixture was poured
onto EtOAc (100 mL) and washed with equal portions of 5%
aqueous HOAc, water, saturated aqueous NaHCO3, water, and
saturated aqueous NaCl. The organic extract was dried (Na2SO4)
and concentrated. Purification of the residue by flash chromatog-
raphy (3 cm × 10 cm silica; 50% EtOAc in hexanes) afforded the
product as a solid (195 mg) that could not be separated from a
minor impurity and was used directly in the next step.
The reaction mixture was poured onto EtOAc (100 mL) and washed
with 5% aqueous HOAc, water, saturated aqueous NaHCO3, water,
and saturated aqueous NaCl. The organic extract was dried (Na2-
SO4) and concentrated, and the residue was purified by flash
chromatography (3 cm × 10 cm silica; 0-3% MeOH/CH2Cl2) to
afford 26 as a solid (97 mg, 55%): 1H NMR (400 MHz, CDCl3)
δ 8.59-8.57 (m, 1H), 7.91 (d, J ) 2.6 Hz, 1H), 7.46 (d, J ) 2.5
Hz, 1H), 7.34-7.32 (m, 2H), 7.28 (d, J ) 7.4 Hz, 1H), 6.81 (t, J
) 5.7 Hz, 1H), 5.22 (s, 1H), 4.50-4.46 (m, 1H), 4.10-4.06 (m,
1H), 3.95 (s, 3H), 3.92-3.88 (m, 1H), 3.72-3.65 (m, 1H), 3.34-
3.27 (m, 2H), 3.14-3.08 (m, 1H), 2.99 (d, J ) 4.6 Hz, 1H), 2.74
(d, J ) 4.6 Hz, 1H), 2.64 (s, 3H), 1.50 (s, 3H), 1.08 (d, J ) 6.2
Hz, 3H), 0.85 (s, 9H), 0.034 (s, 3H), 0.027 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 170.3, 167.4, 165.6, 155.8, 134.3, 133.2, 127.8,
127.7, 126.8, 125.2, 123.6, 122.0, 108.6, 75.9, 67.0, 62.4, 55.8,
55.5, 53.8, 53.1, 46.8, 25.7, 21.2, 20.0, 18.0, 17.6, -4.6, -4.9;
HRMS (ESI), m/z calculated for C30H44N2O8SiNa: 611.2765;
found: 611.2786.
3-Methoxy-5-methylnaphthalene-1-carboxylic Acid {1-[2R-
(t-Butyldimethylsilanyloxy)propylcarbamoyl]vinylcarbamoyl}-
(2-methyloxiranyl)methyl Ester (27). Diisopropylethylamine (12
mg, 96 µmol) and methanesulfonylchloride (6.6 mg, 58 µmol) were
added to a solution of alcohol 26 (29 mg, 48 µmol) in CH2Cl2 (5
mL) at 0 °C and stirred for 3 h. The reaction mixture was warmed
to 23 °C. DBU (15 mg, 0.10 mmol) was added, and the reaction
mixture was stirred for 1.5 h. The mixture was poured onto saturated
aqueous NaHCO3 (3 mL) and extracted with EtOAc (3 × 30 mL).
The combined organic extracts were washed with water and
saturated aqueous NaCl and were dried (Na2SO4) and concentrated.
Purification of the residue by preparative TLC (5% MeOH/CH2-
(2-Methyloxiranyl)-{[(2-oxo-propylcarbamoyl)methyl]-
carbamoyl}methyl Ester (2). IBX (29.8 mg, 0.106 mmol) was
added to a solution of alcohol 23 (31.4 mg, 0.071 mmol) in EtOAc
(4 mL). The resulting heterogeneous solution was stirred at reflux
for 7 h. The cooled solution was then filtered, diluted with EtOAc
(10 mL), washed with Na2S2O3 (2 × 5 mL) and brine (2 × 5 mL),
dried (Na2SO4), and concentrated. Column chromatography (1.5
cm × 10 cm silica, 2% MeOH/CH2Cl2) afforded ketone 2 as a
1
white solid (17.1 mg, 55%). H NMR (400 MHz, CDCl3) δ 8.62
1
Cl2) afforded 27 as a solid (12 mg, 42%); H NMR (400 MHz,
(m, 1H), 7.94 (d, J ) 2.5 Hz, 1H), 7.50 (d, J ) 2.5 Hz, 1H), 7.36
(m, 2H), 6.86 (m, 1H), 6.82 (m, 1H), 5.35 (s, 1H), 4.13 (m, 3H),
3.98 (s, 3H), 3.96 (m, 1H), 3.07 (d, J ) 4.4 Hz, 1H), 2.80 (d, J )
4.4 Hz, 1H), 2.68 (s, 3H), 2.17 (s, 3H), 1.56 (s, 3H); 13C NMR
(100 MHz, CDCl3) 202.5, 168.4, 167.3, 165.8, 156.0, 134.5, 133.4,
127.98, 127.93, 127.1, 125.4, 123.8, 122.3, 108.8, 76.2, 56.2, 55.7,
53.3, 49.8, 42.9, 27.4, 20.3, 18.0; ESI-HRMS, m/z calculated for
C23H26N2O7Na: 465.1638; found: 465.1656.
CDCl3) δ 8.98 (s, 1H), 8.64 (m, 1H), 7.99 (d, J ) 2.5 Hz, 1H),
7.49 (d, J ) 2.5 Hz, 1H), 7.34 (m, 2H), 6.50 (s, 1H), 6.42 (br t,
1H), 5.26 (s, 1H), 5.21 (s, 1H), 3.97 (m, 4H), 3.50 (m, 1H), 3.10
(m, 1H), 3.01 (d, J ) 4.5 Hz, 1H), 2.79 (d, J ) 4.5 Hz, 1H), 2.66
(s, 3H), 1.52 (s, 3H), 1.13 (m, 3H), 0.88 (s, 9H), 0.06 (s, 3H), 0.05
(s, 3H); 13C NMR (400 MHz, CDCl3) δ 165.5, 165.4, 163.2, 155.9,
134.4, 133.9, 133.3, 127.9, 127.7, 127.0, 125.2, 123.8, 121.9, 108.9,
101.4, 76.1, 67.1, 55.9, 55.6, 53.1, 47.1, 25.8, 21.3, 20.1, 17.9, 17.6,
-4.4, -4.8; HRMS (ESI), m/z calculated for C30H42N2O7SiNa:
593.2653; found: 593.2670.
3-Methoxy-5-methylnaphthalene-1-carboxylic Acid (2-Me-
thyloxiranyl)-[1-(2-oxopropylcarbamoyl)vinylcarbamoyl]-
methyl Ester (3). A solution of alcohol 28 (8.0 mg, 17 µmol) in
CH3CN was treated with IBX (15 mg, 53 µmol) and was warmed
at 50 °C for 6 h. Aqueous 10% Na2S2O3 (2 mL) was added, and
the mixture was stirred at 20 °C for 1 h. The resulting mixture was
extracted with EtOAc and washed with saturated aqueous NaHCO3
and saturated aqueous NaCl. The organic extract was dried (Na2-
SO4) and concentrated, and the residue was purified by preparative
TLC (silica, 3% MeOH/CH2Cl2) to afford 3 as a solid (4.3 mg,
57%): 1H NMR (400 MHz, CDCl3) δ 8.85 (br s, 1H), 8.64 (m,
1H) 7.98 (d, J ) 2.7 Hz, 1H), 7.49 (d, J ) 2.7 Hz, 1H), 7.35 (m,
2H), 6.87 (br t, 1H), 6.54 (d, J ) 2.3 Hz, 1H), 5.41 (br m, 1H),
5.25 (s, 1H), 4.22 (d, J ) 4.4 Hz, 2H), 3.97 (s, 3H), 3.01 (d, J )
4.5 Hz, 1H), 2.78 (d, J ) 4.5 Hz, 1H), 2.66 (s, 3H), 2.23 (s, 3H),
1.51 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 202.0, 165.4, 165.4,
163.2, 155.9, 134.4, 133.2, 133.1, 127.9, 127.7, 127.0, 125.2, 123.8,
121.9, 108.8, 103.0, 76.2, 55.8, 55.6, 53.2, 50.1, 27.3, 20.1, 17.6;
HRMS (ESI), m/z calculated for C24H26N2O7Na: 477.1638;
found: 477.1648.
{1-[2S-(t-Butyldimethylsilanyloxy)propylcarbamoyl]-2R-
hydroxyethyl}carbamic Acid Benzyl Ester (25). A solution of
benzylcarbamate-protected L-serine (24) (0.619 g, 2.59 mmol) and
(R)-2-amino-1-(t-butyldimethylsiloxy)propane (20) (0.512 g, 2.70
mmol) in CH2Cl2 (25 mL) was cooled to 0 °C. HBTU (1.08 g,
2.85 mmol) and diisopropylethylamine (0.50 mL, 2.85 mmol) were
added, and the reaction mixture was warmed to 25 °C and stirred
for 2.5 h. The mixture was diluted with EtOAc (150 mL) and
washed successively with water, 10% aqueous HCl, water, saturated
aqueous NaHCO3, and saturated aqueous NaCl. The organic extract
was dried (Na2SO4) and concentrated. Purification of the residue
by flash chromatography (3 cm × 10 cm silica; 0-5% MeOH/
CH2Cl2) afforded the product as a white solid (0.701 g, 66%): 1H
NMR (400 MHz, CDCl3) δ 7.36 (m, 5H), 6.70 (br s, 1H), 5.71 (br
s, 1H), 5.07 (m, 2H), 4.20 (m, 1H), 3.90 (m, 1H), 3.64 (m, 1H),
3.34 (m, 1H), 3.12 (m, 1H), 3.00 (br s, 1H), 2.79 (m, 1H), 1.14 (d,
J ) 6.2 Hz, 3H), 0.89 (s, 9H), 0.08 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 171.1, 155.6, 134.3, 133.2, 127.8, 126.8, 67.1, 62.6, 55.8,
53.7, 53.1, 25.7, 21.2, 18.2, -4.6, -4.9; HRMS (ESI), m/z
calculated for C20H34N2O5SiNa: 433.2129; found: 433.2125.
3-Methoxy-5-methylnaphthalene-1-carboxylic Acid {1-[2S-
(t-Butyldimethylsilanyloxy)propylcarbamoyl]-2R-hydroxyethyl-
carbamoyl}-(2-methyloxiranyl)methyl Ester (26). Hydrogen gas
was bubbled through solutions of benzyl ester 15 (125 mg, 0.298
mmol) and serine derivative 25 (135 mg, 0.327 mmol) in MeOH
(10 mL each), each as a mixture with 10% Pd/C (10% w/w loading),
for 4 h. Both mixtures were filtered through Celite, and the filtrates
were concentrated. The residues were dissolved in CH2Cl2 (5 mL
each) and combined. The resulting solution was cooled to 0 °C
and treated with PyBOP (170 mg, 0.327 mmol) and diisopropyl-
ethylamine (0.057 mL, 0.327 mmol) and stirred for 12 h at 23 °C.
N-[2-(t-Butyldimethylsilanyloxy)propyl]-2-hydroxyaceta-
mide (30). Glycolic acid (0.965 g, 12.7 mmol) was added to a
solution of 20 (2.40 g, 12.7 mmol) in CH2Cl2/THF (2:1, 150 mL)
at 25 °C. Solid EDCI (2.70 g, 13.9 mmol) and HOBt (1.71 g, 12.7
mmol) were added, and the reaction mixture was stirred for 12 h.
The mixture was poured onto EtOAc (400 mL) and extracted with
water, saturated aqueous NaHCO3, water, and saturated aqueous
NaCl. The organic extract was dried (Na2SO4) and concentrated,
7732 J. Org. Chem., Vol. 72, No. 20, 2007

“Top-Half” Partial Structures of Azinomycin A and B
and the residue was purified by flash chromatography (5 cm × 15
cm silica; 10% diethyl ether in hexanes) to afford 30 as an oil (3.02
g, 96%): IR (film) 3400, 3300, 2944, 2856, 1656 cm-1; 1H NMR
(400 MHz, CDCl3) δ 6.60 (br s, 1H), 4.18 (s, 2H), 3.95 (m, 2H),
3.51 (m, 1H), 3.12 (m, 1H), 1.18 (d, 3 H), 0.90 (s, 9H), 0.10 (s,
6H). 13C NMR (100 MHz, CDCl3) δ 172.1, 67.3, 62.0, 46.1, 25.8,
21.3, 18.0, -4.5, -4.9; HRMS (ESI), m/z calculated for C11H25-
NO3SiNa: 270.1501; found: 270.1503.
128.5, 128.1, 128.0, 127.8, 66.8, 63.8, 62.1, 27.2, 26.7, 19.2,; HRMS
(ESI), m/z calculated for C28H33NO4SiNa: 498.2071; found:
498.2077.
[1-(t-Butyldiphenylsilanyloxymethyl)-2,2-dimethoxypropyl]-
carbamic Acid Benzyl Ester (36). A solution of ketone 35 (2.50
g, 5.26 mmol) in MeOH (100 mL) was treated with trimethylortho-
formate (0.840 g, 7.89 mmol) and camphorsulfonic acid (10 mg).
The reaction mixture was warmed at reflux for 6 h. The solvent
was removed, and the residue was dissolved in EtOAc (100 mL)
and water (50 mL). The organic extract was washed with water
and saturated aqueous NaCl, dried (Na2SO4), and concentrated. The
residue was purified by flash chromatography (3 cm × 10 cm silica;
0-5% MeOH/CH2Cl2) to afford 36 (1.70 g, 63%) as a solid: 1H
NMR δ 7.69-7.65 (m, 4H), 7.44-7.31 (m, 11H), 5.18 (d, J )
12.4 Hz, 1H), 5.10 (d, J ) 12.0 Hz, 1H), 5.03 (m, 1H), 4.13-4.05
(m, 1H), 3.87 (dd, J ) 4.0, 10.4 Hz, 1H), 3.78 (dd, J ) 5.6, 10.8
3-Methoxy-5-methylnaphthalene-1-carboxylic Acid {[2-(t-
Butyldimethylsilanyloxy)propylcarbamoyl]methoxycarbonyl}-
(2-methyloxiranyl)methyl Ester (31). Hydrogen gas was bubbled
through a mixture of benzyl ester 19 (30 mg, 71 µmol) and 10%
Pd/C (10% w/w loading) in MeOH (10 mL) for 4 h. The reaction
mixture was filtered through Celite, and the filtrate was concen-
trated. The residue was dissolved in CH2Cl2 (5 mL) and combined
with alcohol 30 (19 mg, 79 µmol). The resulting solution was cooled
to 0 °C and was treated with solid EDCI (15 mg, 79 µmol) and
DMAP (1 mg) and was stirred for 12 h at 25 °C. The mixture was
poured onto EtOAc (100 mL) and washed with equal portions of
5% aqueous HOAc, water, saturated aqueous NaHCO3, water, and
saturated aqueous NaCl. The organic extract was dried (Na2SO4)
and concentrated. The residue was purified by flash chromatography
(3 cm × 10 cm silica; 0-3% MeOH/CH2Cl2) to afford 31 as a
solid (25 mg, 55%): 1H NMR (400 MHz, CDCl3) δ 8.59 (m, 1H),
7.92 (dd, J ) 2.7, 3.3 Hz, 1H), 7.50 (d, J ) 2.5 Hz, 1H), 7.36 (s,
1H), 7.34 (s, 1H), 6.92 (br t, 1H), 5.09 (d, J ) 2.8 Hz, 1H), 4.82
(dd, J ) 3.6, 15.4 Hz, 1H), 4.66 (dd, J ) 10.1, 15.4 Hz, 1H), 3.97
(s, 3H), 3.96-3.91 (m, 1H), 3.37-3.31 (m, 1H), 3.19-3.15 (m,
1H), 3.00 (t, J ) 5.0 Hz, 1H), 2.79 (t, J ) 4.3 Hz, 1H), 2.67 (s,
3H), 1.53 (d, J ) 5.7 Hz, 3H), 1.10 (d, J ) 6.1 Hz, 3H), 0.86 (s,
9H), 0.04 (s, 3H), 0.02 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
166.4, 166.3, 166.2, 155.8, 134.4, 133.4, 127.8, 127.2, 126.9, 125.3,
123.6, 122.6, 108.7, 75.7, 67.1, 63.3, 55.5, 55.3, 52.7, 46.6, 25.8,
21.3, 20.1, 18.0, 17.6, -4.7, -4.9; HRMS (ESI), m/z calculated
for C29H41NO8SiNa: 582.2494; found: 582.2493.
3-Methoxy-5-methylnaphthalene-1-carboxylic Acid (2-Me-
thyloxiranyl)-[(2-oxopropylcarbamoyl)methoxycarbonyl]-
methyl Ester (4). Dess-Martin periodinane (54 mg, 0.13 mmol)
was added in one portion to a solution of 32 (38 mg, 0.085 mmol)
in CH2Cl2 (4 mL) at 25 °C. After 1 h, a saturated aqueous solution
of NaHCO3 (2 mL) was added, and the reaction mixture was stirred
for 10 min. The layers were separated, and the organic phase was
washed with saturated aqueous NaCl, dried (Na2SO4), and con-
centrated. The residue was purified by flash chromatography (1.5
cm × 10 cm silica, 0-3% MeOH in CH2Cl2) to afford 4 (0.032 g,
85%): 1H NMR (400 MHz, CDCl3) δ 8.58 (m, 1H), 7.93 (d, J )
2.6 Hz, 1H), 7.48 (d, J ) 2.5 Hz, 1H), 7.33 (m, 2H), 5.27 (s, 1H),
5.18 (br s, 1H), 4.78 (d, J ) 1.3 Hz, 2H), 4.13 (d, J ) 2.3 Hz, 1H),
4.12 (d, J ) 2.3 Hz, 1H), 3.96 (s, 3H), 3.06 (d, J ) 4.4 Hz, 1H),
3.05 (d, J ) 4.4 Hz, 1H), 2.65 (s, 3H), 2.14 (s, 3H), 1.58 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 202.0, 166.6, 166.2, 166.2, 155.8,
134.4, 133.3, 127.8, 127.3, 126.8, 125.3, 123.5, 122.5, 108.8, 75.8,
63.1, 55.5, 55.4, 52.9, 49.2, 27.1, 20.1, 17.6; HRMS (ESI), m/z
calculated for C23H25NO8Na: 466.1472; found: 466.1459.
Hz, 1H), 3.21 (s, 3H), 3.17 (s, 3H), 1.29 (s, 3H), 1.07 (s, 9H); 13
C
NMR (100 MHz, CDCl3) δ 156.1, 136.6, 135.5, 133.1, 129.6, 128.4,
128.0, 127.9, 127.6, 101.2, 66.7, 63.0, 60.2, 48.5, 48.5, 26.8, 19.1,
18.4; HRMS (ESI), m/z calculated for C30H39NO5SiNa: 544.2490;
found: 544.2521.
{[1-(t-Butyldiphenylsilanyloxymethyl)-2,2-dimethoxypropyl-
carbamoyl]methyl}carbamic Acid Benzyl Ester (37). A mixture
of threonine derivative 36 (300 mg, 0.575 mmol) and 10% Pd/C
(50 mg) in MeOH (10 mL) was treated with H2 (1 atm) for 2 h.
The reaction mixture was filtered through Celite, and the filtrate
was concentrated. The residue was dissolved in CH2Cl2 (20 mL)
and benzylcarbamate-protected glycine (120 mg, 0.632 mmol),
HOBt (89 mg, 0.63 mmol), diisopropylethylamine (0.1 mL), and
EDCI (110 mg, 0.632 mmol) were added at 25 °C. The reaction
mixture was stirred for 12 h and was poured onto water (100 mL)
and extracted with EtOAc (3 × 90 mL). The combined organic
extracts were washed with water and saturated aqueous NaCl, dried
(Na2SO4), and concentrated. The residue was purified by flash
chromatography (3 cm × 10 cm silica; 0-5% MeOH/CH2Cl2) to
afford 37 (260 mg, 82%) as a foam: 1H NMR (400 MHz, CDCl3)
δ 7.65 (m, 4H), 7.45-7.26 (m, 11H), 5.18 (d, J ) 12 Hz, 1H),
5.10 (d, J ) 12 Hz, 1H), 5.02 (br s, 1H), 4.23 (m, 3H), 4.09 (br s,
1H), 3.87 (dd, J ) 3.8, 10.0 Hz, 1H), 3.79 (dd, J ) 5.6, 10.0 Hz,
1H), 3.21 (s, 3 H), 3.17 (s, 3H), 1.29 (s, 3H), 1.06 (s, 9H), 13C
NMR (100 MHz, CDCl3) δ 156.1, 136.6, 135.6, 135.5, 133.2, 133.1,
129.6, 129.6, 128.4, 128.0, 127.9, 127.6, 101.2, 66.7, 63.0, 48.5,
48.5, 26.8, 19.1, 18.4; HRMS (ESI), m/z calculated for C32H42N2O6-
SiNa: 601.2710; found: 601.2716.
3-Methoxy-5-methylnaphthalene-1-carboxylic Acid {[(1-Hy-
droxymethyl-2,2-dimethoxypropylcarbamoyl)methyl]carbamoyl}-
(2-methyloxiranyl)methyl Ester (39). A mixture of benzyl ester
15 (80 mg, 0.19 mmol) and 10% Pd/C (25 mg) in MeOH (10 mL)
was treated with H2 (1 atm) for 3 h. Simutaneously, a mixture of
benzylcarbamate-protected glycine derivative 38 (71 mg, 0.21
mmol) and 10% Pd/C (7 mg) in MeOH (10 mL) was treated with
H2 (1 atm). Both mixtures were filtered through Celite, and the
filtrates were concentrated. The residues were dissolved in CH2-
Cl2 (5 mL each) and combined. HOBt (25 mg, 0.190 mmol) and
EDCI (41 mg, 0.209 mmol) were added at 25 °C. The reaction
mixture was stirred for 12 h and was poured into water (10 mL)
and extracted with EtOAc (3 × 30 mL). The combined organic
extracts were washed with water and saturated aqueous NaCl, dried
(Na2SO4), and concentrated. Purification of the residue by flash
chromatography (1.5 cm × 10 cm silica; 0-5% MeOH/CH2Cl2)
afforded 39 (73 mg, 74%) as a solid: 1H NMR (400 MHz, CDCl3)
δ 8.60 (t, J ) 4.8 Hz, 1H), 7.92 (d, J ) 2.4 Hz, 1H), 7.47 (d, J )
2.4 Hz, 1H), 7.33 (d, J ) 4.8 Hz, 2H), 6.98 (br t, 1H), 6.60 (d, J
) 7.6 Hz, 1H), 5.29 (s, 1H), 4.13 (m, 2H), 3.96 (s, 3H), 3.90 (dd,
J ) 16.8, 5.4 Hz, 1H), 3.70 (m, 2H), 3.45 (br s, 1H), 3.19 (s, 3H),
3.15 (s, 3H), 3.02 (d, J ) 4.4 Hz, 1H), 2.74 (d, J ) 4.4 Hz, 1H),
2.66 (s, 3H), 1.52 (s, 3H), 1.24 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 169.4, 167.6, 165.7, 155.8, 134.4, 133.2, 127.8, 127.1,
126.9, 125.3, 123.7, 122.3, 108.6, 101.6, 76.3, 62.5, 56.0, 55.6,
[1-(t-Butyldiphenylsilanyloxymethyl)-2-oxopropyl]carbamic
Acid Benzyl Ester (35). A solution of alcohol 30 (2.54 g, 5.32
mmol) in EtOAc (100 mL) was treated with IBX (2.24 g, 7.98
mmol), and the reaction mixture was warmed at reflux for 14 h.
The mixture was filtered, and the filtrate was poured onto 10%
aqueous Na2S2O3 (2.5 mL) and stirred at 23 °C for 1 h. The mixture
was extracted with EtOAc (4 × 25 mL), and the combined organic
extracts were washed with saturated aqueous NaHCO3 and saturated
aqueous NaCl and dried (Na2SO4) and concentrated to afford the
crude product as a solid (2.50 g, 99%), which was used without
further purification: 1H NMR (400 MHz, CDCl3) δ 7.61 (m, 4H),
7.45-7.35 (m, 11H), 6.83 (br d, 1H), 5.08 (s, 2H), 4.39 (m, 1H),
4.11 (m, 1H), 3.92 (m, 1H), 2.15 (s, 3H), 1.02 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 204.4, 155.7, 136.3, 135.5, 132.5, 129.9,
J. Org. Chem, Vol. 72, No. 20, 2007 7733

Coleman et al.
55.2, 53.0, 49.0, 48.9, 43.4, 20.1, 17.8, 17.8; HRMS (ESI), m/z
calculated for C26H34N2O9Na: 541.2162; found: 541.2172.
3-Methoxy-5-methylnaphthalene-1-carboxylic Acid {[(1-
Formyl-2,2-dimethoxypropylcarbamoyl)methyl]carbamoyl}(2-
methyloxiranyl)methyl Ester (40). A solution of alcohol 39 (56
mg, 0.11 mmol) in EtOAc (10 mL) was treated with IBX (33 mg,
0.12 mmol), and the reaction mixture was warmed at reflux for 6
h. The reaction mixture was filtered, the filtrate was poured onto
10% aqueous Na2S2O3 (2.5 mL), and the mixture was stirred at 23
°C for 1 h. The mixture was extracted with EtOAc (4 × 25 mL).
The combined organic extracts were washed with saturated aqueous
NaHCO3 and saturated aqueous NaCl and were dried (Na2SO4) and
concentrated to afford the crude product as a solid (54 mg, 96%),
which was used without further purification: 1H NMR (400 MHz,
CDCl3) δ 9.70 (s, 1H), 8.60 (t, J ) 5.0 Hz, 1H), 7.93 (d, J ) 2.8
Hz, 1H), 7.48 (d, J ) 2.8 Hz, 1H), 7.33 (m, 2H), 6.90 (br t, 1H),
6.71 (t, J ) 8.0 Hz, 1H), 5.37 (s, 1H), 4.86, (d, J ) 8.0 Hz, 1H),
4.19 (dd, J ) 16.8, 6.4 Hz, 1H), 3.92 (s, 3H), 3.25 (s, 3H), 3.22 (s,
3H), 3.04 (d, J ) 4.4 Hz, 1H), 2.75 (d, J ) 4.4 Hz, 1H), 2.66 (s,
3H), 1.54 (s, 3H), 1.22 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
190.8, 168.3, 167.3, 165.5, 155.8, 134.4, 133.2, 127.8, 126.9, 125.5,
123.7, 122.2, 108.6, 101.6, 76.1, 61.9, 56.1, 55.6, 55.1, 52.9, 49.2,
49.1, 43.0, 20.1, 19.0, 17.9; HRMS (ESI), m/z calculated for
C26H32N2O9Na: 539.2000; found: 539.2012.
3-Methoxy-5-methylnaphthalene-1-carboxylic Acid {[(1-
Acetyl-2-hydroxyvinylcarbamoyl)methyl]carbamoyl}-(2-methy-
loxiranyl)methyl Ester (5). Aldehyde 40 (54 mg, 0.10 mmol) was
dissolved in 10% aqueous acetone (5 mL) and treated with
Amberlyst A-15 resin (150 mg) for 6.5 h at 23 °C. The reaction
mixture was filtered and concentrated, and the residue was purified
by flash chromatography (1.5 cm × 5 cm silica; 3% MeOH/CH2-
Cl2) to afford 5 as a white solid (43 mg, 88%): 1H NMR (400
MHz, CDCl3) δ 12.24 (d, J ) 12 Hz, 1H), 8.60 (m, 2H), 7.91 (d,
J ) 2.8 Hz, 1H), 7.48 (d, J ) 2.8 Hz, 1H), 7.35 (m, 3H), 6.83 (br
t, 1H), 5.30 (s, 1H), 4.15 (d, J ) 5.6 Hz, 2H), 3.96 (s, 3H), 3.04
(d, J ) 4.4 Hz, 1H), 2.81 (d, J ) 4.4 Hz, 1H), 2.66 (s, 3H), 2.27
(s, 3H), 1.55 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 190.8, 168.3,
167.7, 165.5, 155.8, 150.0, 134.3, 133.3, 127.9, 127.8, 126.8, 125.2,
123.7, 122.1, 116.9, 108.5, 75.8, 56.0, 55.5, 53.2, 42.8, 23.8, 20.1,
17.7; HRMS (ESI), m/z calculated for C24H26N2O8SiNa: 493.1581;
found: 493.1595.
3-Methoxy-5-methylnaphthalene-1-carboxylic Acid {[(1-
Acetyl-2-methoxyvinylcarbamoyl)methyl]carbamoyl}-(2-methy-
loxiranyl)methyl Ester (41). A solution of vinylogous acid 5 (5.0
mg, 0.011 mmol) in toluene/MeOH (1:1, 2 mL) at 25 °C was treated
with trimethylsilyldiazomethane (0.011 mL of a 2.0 M solution in
toluene, 0.021 mmol), and the reaction mixture was stirred for 20
min. The volatiles were removed under a stream of nitrogen, and
the residue was purified by preparative TLC (5% MeOH/CH2Cl2)
to afford the product (5.0 mg, 90%): 1H NMR (400 MHz, CDCl3)
δ 8.61 (m, 1H), 7.93 (d, J ) 2.8 Hz, 1H), 7.35 (d, J ) 2.8 Hz,
1H), 7.32 (d, J ) 7.2 Hz, 2H), 7.18 (s, 1H), 6.82 (br t, 1H), 5.35
(m, 2H), 5.28 (s, 3H), 4.18 (m, 1H), 4.05 (m, 1H), 3.90 (s, 3H),
3.83 (s, 3H), 3.05 (d, J ) 4.4 Hz, 1H), 2.78 (d, J ) 4.4 Hz, 1H),
2.67 (s, 3H), 1.56 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 190.8,
168.2, 167.8, 165.5, 155.8, 150.1, 134.4, 133.3, 127.9, 127.7, 126.8,
125.3, 123.7, 122.1, 116.8, 108.4, 75.8, 60.3, 56.1, 55.6, 53.2, 42.7,
23.8, 20.1, 17.8; HRMS (ESI), m/z calculated for C25H28N2O8Na:
507.1743; found: 507.1748.
{1-[1-(t-Butyldiphenylsilanyloxymethyl)-2,2-dimethoxypropy-
lcarbamoyl]-2-hydroxyethyl}carbamic Acid Benzyl Ester (42).
A solution of threonine derivative 36 (226 mg, 0.453 mmol) in
MeOH (25 mL) was treated with 10% Pd/C (35 mg) and H2 (1
atm) for 3 h. The reaction mixture was filtered through Celite, and
the filtrate was concentrated. The residue was dissolved in CH2Cl2
(25 mL) at 25 °C, and benzylcarbamate-protected serine (24) (114
mg, 0.476 mmol), HOBt (64 mg, 0.45 mmol), and EDCI (91 mg,
0.48 mmol) were added sequentially. The reaction mixture was
stirred for 12 h and then poured onto water (10 mL) and extracted
with EtOAc (3 × 100 mL). The combined organic extracts were
washed with saturated aqueous NaHCO3, water, and saturated aque-
ous NaCl and were dried (Na2SO4) and concentrated to afford crude
42 (225 mg; 82%), which was used directly without purification.
3-Methoxy-5-methylnaphthalene-1-carboxylic Acid {1-[1-(t-
Butyldiphenylsilanyloxymethyl)-2,2-dimethoxypropylcarbamoyl]-
2-hydroxyethylcarbamoyl}-(2-methyloxiranyl)methyl Ester (43).
A mixture of benzyl ester 15 (35 mg. 83 µmol) and 10% Pd/C (10
mg) in MeOH (10 mL) was treated with H2 (1 atm) for 2 h at
25 °C. Simultaneously, a mixture of benzylcarbamate-protected
serine derivative 42 (51 mg, 84 µmol) and 10% Pd/C (5 mg) in
MeOH (10 mL) was treated with H2 (1 atm). Both reaction mixtures
were filtered through Celite, and the filtrates were concentrated.
The residues were dissolved in CH2Cl2 (3.0 mL each) and
combined. HOBt (11 mg, 81 µmol) and EDCI (20 mg, 0.10 mmol)
were added, and the reaction mixture was stirred for 12 h at 25 °C.
The mixture was poured onto water (10 mL) and was extracted
with EtOAc (3 × 30 mL). The combined organic extracts were
washed with water and saturated aqueous NaCl, dried (Na2SO4),
and concentrated. The residue was purified by flash chromatography
(1.5 cm × 5 cm silica; 0-5% MeOH/CH2Cl2) to afford 43 (49
mg, 75%) as a solid: 1H NMR (400 MHz, CDCl3) δ 8.26 (dd, J )
3.2, 7.2 Hz, 1H), 7.91 (d, J ) 2.8 Hz, 1H), 7.63 (m, 5H), 7.47 (d,
J ) 2.8 Hz, 1H), 7.43-7.35 (m, 12H), 6.86 (d, J ) 10.0 Hz, 1H),
5.23 (s, 1H), 4.45 (m, 1H), 4.32 (m, 1H), 3.95 (s, 3H), 3.80 (m,
2H), 3.64 (br s, 1H), 3.13 (m, 1H), 3.07 (s, 3H), 3.04 (s, 3H), 3.00
(d, J ) 4.8 Hz, 1H), 2.76 (d, J ) 4.8 Hz, 1H), 1.51 (m, 3H), 1.22
(s, 3H), 1.02 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.3, 167.4,
165.7, 155.9, 135.7, 134.4, 133.2, 133.1, 129.8, 129.7, 128.3, 128.1,
127.7, 126.9, 125.1, 123.8, 121.9, 108.6, 101.1, 75.9, 55.9, 55.5,
53.8, 53.5, 53.3, 48.8, 48.6, 48.5, 26.8, 20.1, 19.1, 18.4, 17.4; HRMS
(ESI), m/z calculated for C43H54N2O10SiNa: 809.3445; found:
809.3411.
3-Methoxy-5-methylnaphthalene-1-carboxylic Acid {1-[1-(t-
Butyldiphenylsilanyloxymethyl)-2,2-dimethoxypropylcarbamoyl]-
vinylcarbamoyl}(2-methyloxiranyl)methyl Ester (44). A solution
of alcohol 43 (12 mg. 15 µmol) in CH2Cl2 (2 mL) was cooled to
-45 °C. Triethylamine (0.010 mL, 73 µmol) was added followed
by methanesulfonylchloride (2.6 mg, 23 µmol). The reaction
mixture was allowed to warm to 22 °C and stirred for 2 h. After
cooling to 0 °C, DBU (0.010 mL, 66 µmol) was added. The reaction
mixture was warmed to 22 °C and stirred for 1 h. The reaction
mixture was poured onto water and diluted with EtOAc. The organic
extract was washed with 1% aqueous HOAc, water, saturated
aqueous NaHCO3, water, and saturated aqueous NaCl. The organic
extract was dried (Na2SO4) and concentrated, and the residue was
purified by flash chromatography (1 cm × 5 cm silica; 0-25%
EtOAc in CH2Cl2) to afford 44 as an oil (6.0 mg, 52%): 1H NMR
(400 MHz, CDCl3) δ 8.94 (br s, 1H), 8.64 (m, 1H), 7.99 (d, J )
2.6 Hz, 1H), 7.60 (m, 4H), 7.49 (d, J ) 2.5 Hz, 1H), 7.45-7.30
(m, 8H), 6.51 (d, J ) 2.0 Hz, 1H), 6.43 (d, J ) 9.7 Hz, 1H), 5.26
(s, 1H), 5.21 (br t, 1 H), 4.31 (m, 1 H), 3.96 (s, 3H), 3.89 (dd, J )
10.1, 4.0 Hz, 1H), 3.77 (dd, J ) 10.1, 4.0 Hz, 1 H), 3.16 (s, 3H),
3.14 (s, 3H), 3.01 (d, J ) 4.8 Hz, 1H), 2.76 (d, J ) 4.8 Hz, 1H),
2.66 (s, 3H), 1.53 (m, 3H), 1.34 (s, 3H), 1.02 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 165.5, 165.4, 162.7, 155.9, 135.6, 134.4,
133.1, 132.9, 132.8, 129.9, 128.6, 128.1, 127.9, 127.7, 127.0, 125.2,
123.8, 121.8, 108.9, 101.7, 101.2, 76.1, 62.4, 55.9, 55.6, 53.1, 53.0,
48.8, 26.8, 20.1, 19.1, 19.0, 17.6,; HRMS (ESI), m/z calculated for
C43H52N2O9SiNa: 791.3340; found: 791.3320.
3-Methoxy-5-methylnaphthalene-1-carboxylic Acid [1-(1-
Formyl-2,2-dimethoxypropylcarbamoyl)vinylcarbamoyl](2-me-
thyloxiranyl)methyl Ester (46). IBX (4.0 mg, 14 µmol) was added
to a solution of alcohol 45 (6.0 mg, 11 µmol) in DMSO and warmed
at 50 °C for 6 h. A 10% aqueous solution of Na2S2O3 (0.5 mL)
was added, and the mixture was stirred at 20 °C for 1 h. The mixture
was extracted with EtOAc, and the organic extract was washed
with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried
(Na2SO4), and concentrated to afford crude 46 as a white solid (6.0
7734 J. Org. Chem., Vol. 72, No. 20, 2007

“Top-Half” Partial Structures of Azinomycin A and B
mg, 100%), which was used directly without further purification:
1H NMR (400 MHz, CDCl3) δ 9.73 (s, 1H), 8.81 (br s, 1H), 8.62
(m, 1H), 7.97 (d, J ) 2.6 Hz, 1H), 7.48 (d, J ) 2.6 Hz, 1H), 7.33
(m, 2H), 6.62 (br d, J ) 8.0 Hz, 1H), 6.57 (d, J ) 2.0 Hz, 1H),
5.46 (m, 1H), 5.25 (s, 1H), 4.88 (d, J ) 8.0 Hz, 1H), 3.96 (s, 3H),
3.30 (s, 3H), 3.26 (s, 3H), 2.99 (d, J ) 4.4 Hz, 1H), 2.76 (d, J )
4.4 Hz, 1H), 2.66 (s, 3H), 1.52 (s, 3H), 1.26 (s, 3H).
) 4.5 Hz, 1H), 2.79 (d, J ) 4.5 Hz, 1H), 2.67 (s, 3H), 2.32 (s,
3H), 1.53 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 191.0, 165.5,
165.2, 162.2, 155.9, 149.9, 134.4, 133.2, 132.6, 127.8, 127.6, 127.0,
125.3, 123.7, 122.3, 116.7, 108.7, 105.6, 76.1, 55.9, 55.6, 53.3,
23.8, 20.1, 17.6; HRMS (ESI), m/z calculated for C25H26N2O8Na:
505.1587; found: 505.1592.
3-Methoxy-5-methylnaphthalene-1-carboxylic Acid [1-(1-
Acetyl-2-hydroxyvinylcarbamoyl)vinylcarbamoyl]-(2-methylox-
iranyl)methyl Ester (6). Amberlyst A-15 resin (50 mg) was added
to a solution of aldehyde 46 in 10% aqueous acetone (1.5 mL) and
stirred for 6.5 h at 23 °C. The reaction mixture was filtered and
concentrated, and the residue was purified by preparative TLC
(silica; 3% MeOH/CH2Cl2) to afford 6 as a white solid (5.0 mg;
83%): 1H NMR (400 MHz, CDCl3) δ 12.06 (d, J ) 12.4 Hz, 1H),
9.03 (br s, 1H), 8.72 (br s, 1H), 8.62 (m, 1H), 8.01 (d, J ) 2.6 Hz,
1H), 7.50 (d, J ) 2.6 Hz, 1H), 7.39-7.33 (m, 1H), 6.70 (d, J )
2.6 Hz, 1H), 5.60 (m, 1H), 5.28 (m, 3H), 3.98 (s, 3H), 3.02 (d, J
Acknowledgment. This work was supported by a grant from
the National Cancer Institute (NIH R01 CA65875). M.T.T. was
the recipient of an Ohio State University Postdoctoral Fellowship
(2002-2003).
Supporting Information Available: Full experimental proce-
dures and spectral characterization of intermediates and products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO7014888
J. Org. Chem, Vol. 72, No. 20, 2007 7735