Concise enantioselective synthesis of (+)-FR66979 and (+)-FR900482: Dimethyldioxirane-mediated construction of the hydroxylamine hemiketal

Article abstract of DOI:10.1002/anie.200290015

The remarkable one-step deprotection/oxidative cyclization of an eight-membered-ring aminoketone 1 in the presence of dimethyldioxirane gives rise to the unique hydroxylamine hemiketal ring system of FR66979 (2) and FR900482 (3), clinically important anti

Full text of DOI:10.1002/anie.200290015

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OCONH2
OCONH2
OCONH2
Concise Enantioselective Synthesis of
(þ)-FR66979 and (þ)-FR900482:
Dimethyldioxirane-Mediated
Construction of the Hydroxylamine
Hemiketal**
13
10
O
OH
OR1
7
5
7
H2N
Me
OAc
OH
H
OMe
6
1
4
9
H
1
H
NR2
12
OHC
O
O
N
NH
3
NH
H
R
N
N
2
10
11
H
H
O
3: FK973, R1 = R2 = Ac
4: FK317, R1 = Me, R2 = Ac
1: FR900482, R = CHO
2: FR66979, R = CH2OH
5: mitomycin C
Ted C. Judd and Robert M. Williams*
Dedicated to Professor Albert I. Meyers
on the occasion of his 70th birthday.
Scheme 1. Structures of FR900482 (1)and congeners.
The antitumor antibiotic natural products FR900482 (1)
and FR66979 (2)were isolated from Streptomyces sandaensis
No. 6897 by the Fujisawa Pharmaceutical Co. in 1987.[1] Both
compounds have been shown to crosslink DNA preferentially
at 5’CpG’3 steps in the minor groove following reductive
date and features a new method to construct the hydroxyl-
amine hemiketal ring system unique to this family of natural
substances.
Our approach to the construction of 1 and 2 was predicated
on two bold strategies: 1)the labile aziridine would be
installed in the very beginning and carried intact to the end,
and 2)a simultaneous oxidative deprotection of an eight-
membered-ring aminoketone 6 was envisioned to form the
hydroxylamine hemiketal functionality in a single operation
(Scheme 2). Ketone 6 could in turn be obtained from the
eight-membered-ring amine 7, which would ultimately be
derived from the coupling of the optically active aziridine 8
and the trisubstituted nitrobenzene 9.
4]
activation.[2 Additionally, recent studies from our labora-
tory have demonstrated that FR900482 (1)and FK317 ( 4)
crosslink the minor groove-binding HMGA1 oncoprotein to
DNA in vivo, which has very significant implications for the
mode of action of these agents.[5] Both FK973 (3)[6] and FK317
(4),[7] semisynthetic derivatives of FR900482 (1), have shown
highly promising antitumor activity in human clinical trials in
Japan[6] and hold significant promise to replace the structur-
ally related and widely used antitumor drug mitomycin C
(5).[8] Notably, FK317 (4)has been shown not to induce
vascular leak syndrome (VLS), a highly detrimental side
effect observed in human clinical trials with the natural
products FR900482 (1), FR66979 (2), and the semisynthetic
derivative FK973 (3). The mechanistic basis for the anom-
alous difference between 1 and 4 in causing VLS has been
revealed at a biochemical level, but the structural and
chemical basis for these very important phenomena remains
unclear (Scheme 1).[5b]
OR3
OCONH2
R1O
OH
O
OH
H
NR4
H
O
NH
H
R2O2C
R
N
H
N
pMB
1: FR900482, R = CHO
2: FR66979, R = CH2OH
6
In conjunction with these studies, research from our
laboratories has focused on a concise enantioselective total
synthesis of the natural products 1 and 2 that would be
amenable to the preparation of biologically useful analogues.
OR3
H
R1O
R1O
OHC
H
Me
NR4
NR4
+
R2O2C
H
OR3
R2O2C
NO2
N
H
H
To date, there have been three total syntheses of FR900492
[9]
(1)reported;
of these, only one was asymmetric, but
9
8
7
required a 57-step sequence.[9c Additionally, a formal total
synthesis was disclosed recently, applicable to an enantiose-
lective variation.[10] In addition to the above-mentioned
syntheses, several other synthetic approaches have been
reported since the isolation of 1.[11] Herein, we describe a
concise, enantioselective total synthesis of 1 and 2. This
sequence is the shortest total synthesis of 1 and 2 reported to
e]
Scheme 2. Retrosynthesis of FR900482 (1)and FR66979 ( 2). pMB ¼ p-
methoxybenzyl.
Aziridine 14 was prepared according to a recent report
from this laboratory in 21 steps from the commercially
available reagents 10 and 12 (Scheme 3).[12,13]
Reaction of 14 with p-methoxybenzyl bromide, followed by
removal of the DEIPS group with TASF in DMF/H2O[14] and
subsequent oxidation with Dess Martin periodinane[15] af-
forded ketone 15, which corresponds to 6. Treatment of 15
with LDA in dry DMF at À458C followed by the addition of
an anhydrous formaldehyde solution in THF[16] furnished the
aldol adducts 16 and 17 as a ~ 1:1 mixture of diastereomers in
50% yield (45% recovery of unreacted starting material).
Separation of 16 and 17 by preparative thin-layer chromatog-
raphy (PTLC)followed by treatment of the undesired adduct
17 with DBU in toluene afforded a 2.5:1 mixture of epimers
favoring 16, which has the desired configuration at C7.
Treatment of the primary alcohol of 16 with TBSOTf and
[*] Prof. Dr. R. M. Williams, T. C. Judd
Department of Chemistry, Colorado State University
Fort Collins, CO 80523 (USA)
Fax : (þ 1)970-491-3944
E-mail: rmw@chem.colostate.edu
[**] This work was supported by the National Institutes of Health (Grant
CA51875). We are grateful to Boehringer-Ingelheim for fellowship
support to T.C.J. Mass spectra were obtained on instruments
supported by the National Institutes of Health Shared Instrumenta-
tion Grant GM49631. We are grateful to Fujisawa Pharmaceutical Co.,
Japan, for the generous gift of natural FR900482.
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author. Spectroscopic data for
all new compounds is included.
Angew. Chem. Int. Ed. 2002, 41, No. 24
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very clean nature of this reaction allowed the practical
recycling of recovered 18.[18]
The mechanism for the formation of 20 from 18 is
OH
OHC
H
10 steps
NCO2Me
H
presumed to involve initial insertion of the dioxirane
ODEIPS
H
MOMO
OpMB
OH
À
into the C H bond of the N-p-methoxybenzyl meth-
7 steps
ylene residue to form a methanolamine species.[19] The
hydroxy group of the methanolamine is invoked to
direct the DMDO oxidation of the amine to the
corresponding N-oxide species 19.[20] Subsequent col-
lapse of the methanolamine with concomitant loss of
p-anisaldehyde and transannular closure of the incip-
ient hydroxylamine on the ketone furnishes 20.[21]
10: (Z)-1,4- butenediol
11
NCO2Me
MeO2C
H
N
NO2
H
MOMO
Me
4 steps
Me
14
NO2
HO2C
NO2
MeO2C
12: 3,5-dinitro-p-toluic acid
Scheme 3. Synthesis of aziridine precursor 14.[12]
13
Removal of the TBS protecting group followed by
reaction of the primary hydroxy group with trichlor-
oacetyl isocyanate (methanol/silica gel workup)[22]
installed the urethane moiety at C13. TMSBr effected
removal of the methoxymethyl ether (MOM)in the presence
of the acid-sensitive aziridine functionality at À458C over 3 h
to afford 21 in 60% yield.[23]
Final reduction of both carbomethoxy groups with LiBH4/
MeOH in THF[24] followed by Pd-catalyzed cleavage of the
resulting borane amine complex,[25] furnished the natural
product FR66979 (2)in 78% yield. Synthetic 2 was identical
to the natural substance (1H NMR spectra, mobility on TLC,
mass spectra (ESþ), optical rotation, and IR spectra). Finally,
the natural product FR900482 (1)can obtained by Swern
oxidation of 2 in 33% yield.[26,27]
2,6-lutidine gave the silyl ether 18 in essentially quantitative
yield (Scheme 4).
For the construction of 20, a one-step protocol was
employed that both cleaved the N-p-methoxybenzyl residue
and oxidized the amine to the corresponding hydroxylamine,
thus forming the desired hydroxylamine hemiketal. Reaction
of 18 with excess dimethyldioxirane (DMDO)[17] in a 1:1
mixture of CH2Cl2 and saturated aqueous K2CO3 furnished 20
as the only isolated product in 30 50% yield, along with
recovered starting material (40 50%). Attempts to drive this
reaction to completion by varying the stoichiometry of
DMDO, time, temperature, etc., proved unsuccessful. The
OH
O
O
MOMO
MOMO
ODEIPS
H
MOMO
H
H
f
a–c
d
NCO2Me
NCO2Me
H
NCO2Me
MeO2C
MeO2C
H
N
MeO2C
H
N
HN
pMB
16
pMB
OH
15
14
e
O
MOMO
H
H
NCO2Me
MeO2C
N
H
17
pMB
OTBS
OTBS
OTBS
OH
O
O
MOMO
MOMO
MOMO
H
H
g
NCO2Me
NCO2Me
H
H
MeO2C
MeO2C
O
N
N
NCO2Me
H
MeO2C
N
HO
O
pMB
H
19
20
18
OMe
OCONH2
OCONH2
OCONH2
OH
OH
OH
h–j
l
k
OH
H
OH
H
OH
H
O
O
NH
O
NH
NCO2Me
OHC
N
N
MeO2C
N
H
H
H
OH
21
2
1
Scheme 4. Synthesis of 1 and 2. Reagents and conditions: a) p-methoxybenzyl bromide, iPr2NEt, CH2Cl2 (86%); b) TASF, DMF/H 2O, room temperature;
c)Dess Martin oxidation (75%, 2 steps); d)LDA, DMF, À458C; CH2O/THF, À458C, (50%; 16/17 1:1); e) DBU, toluene (70% þ 30% starting material);
f)TBSOTf, 2,6-lutidine, CH 2Cl2, À78!08C (96%); g) DMDO, aqueous K 2CO3/CH2Cl2, 08C!RT (30 50%); h) TBAF, THF, 0 8C (92%); i) Cl 3CCONCO,
CH2Cl2, 08C; then MeOH, silica gel, room temperature (86%); j) TMSBr, CH 2Cl2, À458C (60%); k) LiBH 4/MeOH, THF, room temperature (78%);
l)(COCl) 2, Me2SO, THF, À78!À408C; then Et3N (33%). DEIPS ¼ diethylisopropylsilyl, TASF ¼ tris(dimethylamino)sulfonium difluorotrimethylsilicate,
DMF ¼ N,N-dimethylformamide, LDA ¼ lithium diisopropylamide, DBU ¼ 1,8-diazabicyclo[5.4.0]undec-7-ene, TBSOTf ¼ tert-butyldimethylsilyl
triflate, DMDO ¼ dimethyldioxirane, TBAF ¼ tetrabutylammonium fluoride, TMS ¼ trimethylsilyl.
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Angew. Chem. Int. Ed. 2002, 41, No. 24

COMMUNICATIONS
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The chemistry described herein represents the most concise
total synthesis of either (þ)-FR66979 (2)or ( þ)-FR900482 (1)
reported to date.[28] Future efforts in the preparation and
biological evaluation of synthetic analogues are currently
underway and will be reported in due course.
Received: July 22, 2002 [Z19786]
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a mitosene ([VO(acac)2] or [Mo(CO)6] and tBuOOH; [MeReO3] and
H2O2).
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N
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this time and alternative mechanisms are certainly possible. An
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both functionalities with DIBAL-H on a fully protected intermediate
was employed in a previous total synthesis reported by Danishefsky
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[28] After submission of our manuscript, we recently learned that
Professor Tohru Fukuyama and co-workers (Tokyo University)and
Prof. Marco Ciufolini and co-workers (Universitÿ Claude Bernard
Lyon 1)have independently completed syntheses of FR900482 and
FR66979, respectively. We appreciate receiving preprints of their
manuscripts. See the following communications: M. Suzuki, M.
Kambe, H. Tokuyama, T. Fukuyama, Angew. Chem. 2002, 114, 4880;
Angew. Chem. Int. Ed. 2002, 41, 4686; R. Ducray, M. A. Ciufolini,
Angew. Chem. 2002, 114, 4882; Angew. Chem. Int. Ed. 2002, 41, 4688.
Angew. Chem. Int. Ed. 2002, 41, No. 24
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