A Concise Total Synthesis of (+)-FR900482 and (+)-FR66979

Article abstract of DOI:10.1021/jo035828t

The concise, enantioselective total synthesis of the potent antitumor antibiotics (+)-FR900482 and (+)-FR66979 are described. Sharpless asymmetric epoxidation technology has been deployed to construct the optically active aziridine-containing fragment tha

Full text of DOI:10.1021/jo035828t

A Con cise Tota l Syn th esis of (+)-F R900482 a n d (+)-F R66979
Ted C. J udd and Robert M. Williams*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523
rmw@chem.colostate.edu
Received December 16, 2003
The concise, enantioselective total synthesis of the potent antitumor antibiotics (+)-FR900482 and
(+)-FR66979 are described. Sharpless asymmetric epoxidation technology has been deployed to
construct the optically active aziridine-containing fragment that is joined to the aromatic moiety
in a highly convergent manner. Dimethyldioxirane effects the remarkable one-step deprotection/
oxidative cyclization of an eight-membered ring amino-ketone to the unique hydroxylamine
hemiketal ring system that is a distinctive structural motif of FR900482. This reaction has been
exploited in a concise 33-step enantioselective total synthesis of FR900482.
In tr od u ction
become an important and clinically significant antitumor
drug alongside the structurally related and widely used
antitumor drug mitomycin C (MMC, 6).8 Notably, FK317
(4) has been shown not to induce vascular leak syndrome,
a highly detrimental side effect observed in human
clinical trials with the natural products FR900482 (1),
FR66979 (2), and the semisynthetic derivative FK973 (3)
(Figure 1).7
In addition to the significant biological activity ex-
pressed by these natural products, both 1 and 2 have
attracted considerable attention as targets for total
synthesis. The complex functionality in such a compact
structure combined with the unique hydroxylamine
hemiketal moiety has inspired numerous synthetic stud-
ies since their isolation.9 Indeed, previous to the prelimi-
nary communication of our total synthesis,10 three total
syntheses11 and one formal total synthesis12 had since
FR900482 (1) and FR66979 (2) are antitumor antibiot-
ics obtained from the fermentation harvest of Strepto-
myces sandaensis No. 6897 at the Fujisawa Pharmaceu-
tical Co. in Japan.1 Isolated in 1987 and 1989, respectively,
both 1 and 2 have been shown to form DNA interstrand
cross-links at the 5′CpG′3 steps in the minor groove
following reductive activation.2-4 Recent studies from our
laboratory have additionally demonstrated the capacity
of (1) to cross-link the minor groove-binding HMGA1
oncoprotein to DNA in vivo.5 The semisynthetic deriva-
tives FK973 (3),6 and more recently FK317 (4),7 have
shown highly promising antitumor activity in human
clinical trials; FK317 (4) is now in advanced human
clinical trials in J apan and holds significant promise to
(1) (a) Iwami, M.; Kiyoto, S.; Terano, H.; Kohsaka, M.; Aoki, H.;
Imanaka, H. J . Antibiot. 1987, 40, 589. (b) Kiyoto, S.; Shibata, T.;
Yamashita, M.; Komori, T.; Okuhara, M.; Terano, H.; Kohsaka, M.;
Aoki, H.; Imanaka, H. J . Antibiot. 1987, 40, 594. (c) Uchida, I.; Takase,
S.; Kayakiri, H.; Kiyoto, S.; Hashimoto, M.; Tada, T.; Koda, S.;
Morimoto, Y. J . Am. Chem. Soc. 1987, 109, 4108. (d) Shimomura, K.;
Hirai, O.; Mizota, T.; Matsumoto, S.; Mori, J .; Shibayama, F.; Kikuchi,
H. J . Antibiot. 1987, 40, 600. (e) Hirai, O.; Shimomura, K.; Mizota, T.;
Matsumoto, S.; Mori, J .; Kikuchi, H., J . Antibiot. 1987, 40, 607. (f)
Terano, H.; Takase, S.; Hosoda, J .; Kohsaka, M. J . Antibiot. 1989, 42,
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Hopkins, P. B. J . Am. Chem. Soc. 1993, 115, 1199. (e) Huang, H.;
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1995, 2, 575 and references therein.
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R. M. Chem. Biol. 2000, 7, 805. (b) Beckerbauer, L.; Tepe, J . J .;
Eastman, R. A.; Mixter, P.; Williams, R. M.; Reeves, R., Chem. Biol.
2002, 8, 427. For a biochemical model study, see: (c) Rajski, S. R.;
Rollins, S. B.; Williams, R. M. J . Am. Chem. Soc. 1998, 120, 2192.
(6) (a) Shimomura, K.; Manda, T.; Mukumoto, S.; Masuda, K.;
Nakamura, T.; Mizota, T.; Matsumoto, S.; Nishigaki, F.; Oku, T.; Mori,
J .; Shibayama, F. Cancer Res. 1988, 48, 1166. (b) Nakamura, T.;
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K. J apan. J . Pharmacol. 1989, 49, 317. Masuda, K.; Nakamura, T.;
Mizota, T.; Mori, J .; Shimomura, K. Cancer Res. 1988, 48, 5172. (c)
Masuda, K.; Nakamura, T.; Shimomura, K. J . Antibiot. 1988, 41, 1497.
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4683.
10.1021/jo035828t CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/20/2004
J . Org. Chem. 2004, 69, 2825-2830
2825

J udd and Williams
SCHEME 1. Syn th etic P la n for F or m a tion of th e
Eigh t-Mem ber ed Rin g
F IGURE 1. Structures of FR900482 and congeners.
been published. Contemporaneous with our work, two
additional total syntheses of FR900482 and FR6697913
along with an additional formal total synthesis of 114 have
since been disclosed exemplifying the continual synthetic
inspiration derived from this family of natural products.
Resu lts a n d Discu ssion
SCHEME 2. Syn th etic P la n for Con str u ction of
th e Un iqu e Hyd r oxyla m in e Hem ik eta l
Our synthetic interest in both FR900482 and FR66979
originated following the initial isolation of these natural
products and was initiated with a model study describing
the first synthesis of the unusual hydroxylamine hemi-
ketal moiety.9a Following this initial study, efforts from
this laboratory have focused on the synthesis and biologi-
cal evaluation of mitosene progenitors with alternative
triggering mechanisms based on the natural products 1
and 2.15 These studies have provided an efficient syn-
thesis of the optically active aziridine 7 along with the
synthetic strategy for constructing the eight-membered
ring intermediate 10 (Scheme 1). In developing our
approach for the total synthesis of (+)-FR66979 and (+)-
FR900482 we endeavored to exploit these results accord-
ing to the synthetic plan depicted below (Scheme 1).
Optically active aziridine 7 (93.5:6.5 er), derived from
(Z)-1,4-butenediol over 10 steps as previously described,15,16
could be condensed with the known9b,h trisubstituted
nitrobenzene derivative 8 to afford 9. Alcohol 9 in turn
would be elaborated to the eight-membered ring 10
according to our previous synthetic study over six
steps.15c
p-methoxybenzyl (PMB) group to afford 14 (Scheme 2).
This synthetic strategy would unmask the amine in the
desired oxidation state for in situ formation of the hy-
droxylamine hemiketal functionality thus obviating nu-
merous protection-deprotection steps inherent for in-
stalling this functionality.
With the secondary amine 10 in hand, we hoped to
derive the p-methoxybenzyl-protected amine 11. At this
stage we envisioned utilizing a novel strategy for install-
ing the hydroxylamine hemiketal functionality involving
oxidation of 11 to the N-oxide followed by cleavage of the
Following the proposed oxidative transformation, in-
stallment of the urethane followed by removal of the
aziridine carbomethoxy group, reduction of the aryl
carbomethoxy group and cleavage of the phenolic meth-
oxy methyl (MOM) acetal would complete the synthesis.
Notably, this strategy allows for the protecting groups
on both the aziridine and aromatic portion of the molecule
to be maintained throughout the entire synthesis only
to be removed at the very end. With the overall number
of synthetic transformations dedicated to protecting
group manipulations kept to a minimum, along with an
efficient means of installing the hydroxylamine hemiket-
al, we endeavored to complete what promised to be the
shortest total synthesis of both (+)-FR66979 and (+)-
FR900482.
(11) (a) Fukuyama, T.; Xu, L.; Goto, S. J . Am. Chem. Soc. 1992, 114,
383. (b) Schkeryantz, J . M.; Danishefsky, S. J . J . Am. Chem. Soc. 1995,
117, 4722. (c) Katoh, T.; Itoh, E.; Yoshino, T.; Terashima, S. Tetrahe-
dron Lett. 1996, 37, 3471. (d) Yoshino, T.; Nagata, Y.; Itoh, E.;
Hashimoto, M.; Katoh, T.; Terashima, S. Tetrahedron Lett. 1996, 37,
3475. (e) Katoh, T.; Yoshino, T.; Nagata, Y.; Nakatani, S.; Terashima,
S., Tetrahedron Lett. 1996, 37, 3479. (f) Katoh, T.; Itoh, E.; Yoshino,
T.; Terashima, S. Tetrahedron 1997, 53, 10229. (g) Yoshino, T.; Nagata,
Y.; Itoh, E.; Hashimoto, M.; Katoh, T.; Terashima, S. Tetrahedron 1997,
53, 10239. (h) Katoh, T.; Nagata, Y.; Yoshino, T.; Nakatani, S.;
Terashima, S. Tetrahedron 1997, 53, 10253. (i) Katoh, T.; Terashima,
S. J . Synth. Org. Chem., J pn. 1997, 55, 946.
(12) Fellows, I.; Kaelin, D. J r.; Martin, S. J . Am. Chem. Soc. 2000,
122, 10781.
(13) (a) Suzuki, M.; Kambe, M.; Tokuyama, H.; Fukyama, T. Angew.
Chem., Int. Ed. 2002, 41, 4686. (b) Ducray, R.; Ciufolini, M. A. Angew.
Chem., Int. Ed. 2002, 41, 4688.
(14) Paleo, M. R.; Aurrecoechea, N.; J ung, K.-Y.; Rapoport, H. J .
Org. Chem. 2003, 68, 130.
Reaction of 10 with p-methoxybenzyl bromide followed
by deprotection of the O-diethyl isopropylsilyl (DEIPS)
group with tris(dimethylamino)sulfonium diflourotri-
methylsilicate (TASF) in 10:1 DMF/H2O furnished alcohol
(15) (a) Rollins, S. B.; Williams, R. M. Tetrahedron Lett. 1997, 38,
4033. (b) Rollins, S. B.; J udd, T. C.; Williams, R. M. Tetrahedron 2000,
56, 521. (c) J udd, T. C.; Williams, R. M. Org. Lett. 2002, 4, 3711.
(16) Spada, M. R.; Ubukata, M.; Isono, K Heterocycles 1992, 34,
1147.
2826 J . Org. Chem., Vol. 69, No. 8, 2004

Synthesis of (+)-FR900482 and (+)-FR66979
SCHEME 3. Ald ol Con d en sa tion To In sta ll th e C-13 Hyd r oxym eth yl Gr ou p
15 in 68% over two steps (Scheme 3).17 The use of these
mild silyl ether deprotection conditions avoided the
potential formation of the Payne-rearranged epoxide as
a result of the release of the free secondary alcoholate.
Oxidation of 15 with Dess-Martin periodinane afforded
the intermediate ketone (75% yield) as the precursor to
the key aldol reaction.18
proved resistant to standard oxidizing reagents including
m-CPBA and Davis’ reagent22 resulting in only recovered
starting material even following reactions at elevated
temperatures. Furthermore, the more powerful trifluo-
roperacetic acid (TFPAA) led exclusively to the nine-
membered lactone 17 via Baeyer-Villiger rearrangement
and not to the desired N-oxide (Scheme 4). Initial
attempts using dimethyldioxirane (DMDO)23 also failed
to afford any desired product, with no reaction observed
at 0 °C (even after 24 h) while reaction at room temper-
ature furnished p-anisaldehyde along with an unidenti-
fied mixture of products. Use of the alternative oxidizing
reagents VO(acac)2 and Mo(CO)6 in conjunction with tert-
butyl hydrogen peroxide (TBHP) resulted only in the
efficient production of the mitosene species 18 resulting
from the direct oxidative cleavage of the N-PMB group.
Frustrated by the inability to oxidize the tertiary amine,
we examined the use of trifluoromethyl methyl dioxirane,
which has been reported to be one of the most powerful
oxidizing reagents.24 Gratifyingly, reaction of 11 or 16
with an excess of freshly prepared trifluoromethyl methyl
dioxirane at -22 °C furnished the nitrone 19 along with
p-anisaldehyde and p-anisic acid. It appears as though
the dioxiranes are unique among the reagents investi-
gated in having the ability to oxidize the amine along
with concurrent oxidative cleavage of the N-PMB group.
It was anticipated that higher reaction temperatures
(0 °C) might allow for in situ formation of the hydroxy-
lamine hemiketal moiety prior to over-oxidation to the
nitrone. Unfortunately, reaction at 0 °C led only to the
isolation of two inseparable over-oxidized products and
not to the desired hydroxylamine hemiketal.25 Although
disappointing, the initial success with the trifluoromethyl
methyl dioxirane hinted that a similar reaction may
have occurred with the DMDO reactions and that further
over-oxidation may have occurred at the free C-7 hy-
droxymethyl position. Protection of the primary alcohol
The potential susceptibility of the methoxycarbamoyl
and carbomethoxy groups to aqueous base precluded the
use of aqueous formaldehyde solutions and the deploy-
ment of an anhydrous formaldehyde/THF solution was
prepared following a modified version of the procedure
reported by Rodriguez et al.19 Thus reaction of the
intermediate ketone with LDA in dry DMF at -45 °C,
followed by addition of a freshly prepared anhydrous
solution of formaldehyde in THF (ca. ∼1.0 M) gave the
desired aldol adducts11a 11 and 16 in 50% yield as a 1:1
mixture of diastereomers along with 45% recovered
starting material. Competing O-alkylation or possible
retro-aldol reaction during workup may explain the high
recovery of unconverted ketone and extensive investiga-
tion into alternative workup conditions did not result in
an increase in the yield. Furthermore, longer reaction
times (over 2 h) or higher reaction temperatures above
(-45 °C) resulted in only production of the corresponding
exo-methylene elimination product. Moreover, conven-
tional aldol reaction conditions such as using THF or
THF/HMPA mixtures in place of DMF as the reaction
solvent or alternative reactions through the boron eno-
late20 failed to lead to any desired product. Despite the
lack of diastereoselectivity, 16 could readily be converted
to 11 by DBU-mediated epimerization in toluene over 36
h in 70% yield with 30% recovered 16.21
At this stage, we planned to generate the N-oxide of
amine 11 to initiate the key transformation for installing
the hydroxylamine hemiketal. Surprisingly 11 and 16
(17) (a) Scheidt, K A.; Chen, H.; Follows, B. C.; Chemler, S. R.;
Coffey, D. S.; Roush, W. R. J . Org. Chem. 1998, 63, 6436. (b) Kurosu,
M.; Marcin, L. R.; Grinsteiner, T. J .; Kishi, Y J . Am. Chem. Soc. 1998,
120, 6627. (c) Noyori, R.; Nishida, I.; Sakata, J . J . Am. Chem. Soc.
1983, 105, 1598.
(18) (a) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155. (b)
Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277. (c) Meyer,
S. D.; Schreiber, S. L. J . Org. Chem. 1994, 59, 7549.
(19) Rodriguez, L.; Lu, N.; Yang, N.-L. Synlett 1990, 227.
(20) Evans, D. A.; Nelson, J . V.; Vogel, E.; Taber, T. R. J . Am. Chem.
Soc. 1981, 103, 3099.
(21) A similar epimerization was employed by Terashima and co-
workers in their total synthesis of (+)-FR900482 (see ref 11c-i).
(22) (a) Zajac, W. W.; Walters, T. R.; Darcy, M. G. J . Org. Chem.
1988, 53, 5856. (b) Davis, F. A.; Sheppard, A. C. Tetrahedron 1989,
45, 5703.
(23) (a) Murray, R. W.; Singh, M. Organic Syntheses; Wiley: New
York, 1998; Collect. Vol. IX, pp 288. (b) Murray, R. W.; J eyaraman, R.
J . Org. Chem. 1985, 50, 2847. (c) Adam, W.; Chan, Y.-Y.; Cremer, D.;
Gauss, J .; Scheutzow, D.; Schindler, M. J . Org. Chem. 1987, 52, 2800.
(24) (a) Mello, R.; Fiorentino, M.; Fusco, C.; Curci, R. J . Am. Chem.
Soc. 1989, 111, 6749. (b) Mello, R.; Cassidei, L.; Fiorentino, M.; Fusco,
C.; Caterina, F.; Hu¨mmer, W.; J a¨ger, V.; Curci, R. J . Am. Chem. Soc.
1991, 113, 2205. (c) Adam, W.; Asensio, G.; Curci, R.; Gonza´lez-Nu´nez,
M. E.; Mello, R. J . Org. Chem. 1992, 57, 953.
J . Org. Chem, Vol. 69, No. 8, 2004 2827

J udd and Williams
SCHEME 4. Attem p ts To Con str u ct th e Hyd r oxyla m in e Hem ik eta l
SCHEME 5. Con str u ction of th e Hyd r oxyla m in e
Hem ik eta l
found. Standard conditions including reduction with
NaBH4 and NaCNBH3 or hydrogenation with either Pt2O
or Pt/C failed to give any desired products. Likewise,
hydrogenations with several types of iridium complexes
were examined following a successful report of the selec-
tive hydrogenation of a nitrone to a hydroxylamine using
an iridium chloride-BINAP catalyst.27,28 In addition to
elimination of the C-7 silyl ether in several cases, the
tendency for the nitrones to dimerize in solvents other
then methylene chloride complicated this strategy. Hav-
ing failed to find a synthetic means of converting the
nitrone to the desired hydroxylamine hemiketal, efforts
were focused on reevaluating the dimethyldioxirane reac-
tion. Indeed, in a single case, reaction of 20 with DMDO
in the presence of K2CO3 led to the isolation of the desired
hydroxylamine hemiketal. Further investigation of this
inconsistency revealed that varying amounts of water in
the preparation of the DMDO solution accounted for the
observed discrepancy. This factor was confirmed by
performing the DMDO oxidation in a biphasic mixture
of methylene chloride and saturated aqueous sodium
bicarbonate (1:1 v/v) furnishing a 1:1 mixture of nitrone
21 and the desired hydroxylamine hemiketal along with
recovered starting material. Switching to a saturated
aqueous K2CO3 solution afforded the desired hydroxy-
lamine hemiketal 22 as the exclusive product (30-50%
yield) in addition to unreacted 20 (40-50%).29
11 as the O-TBS ether followed by reaction with an excess
of a freshly prepared solution of DMDO (ca 0.1 M)23b led
to clean conversion of 20 to nitrone 21 in 90% yield
(Scheme 5).
Notably, using 3 equiv or less of DMDO led only to the
formation of the nitrone and recovered starting material,
implying that the rate of over-oxidation to the nitrone
exceeded the initial oxidation of 20. Additionally, we
observed that even oxidations with MeReO4 and hydro-
gen peroxide-urea, which is reportedly very similar to
dioxiranes in the oxidation of secondary amines to
nitrones, N-oxide production from tertiary amines, and
oxidative C-H insertions,26 afforded only the mitosene
via direct N-PMB cleavage analogous to that seen with
VO(acac)2/TBHP and Mo(CO)6/TBHP oxidations.
Although the desired hydroxylamine hemiketal could
not be initially accessed directly, the nitrone product did
represent a possible precursor to the desired product
providing a selective reduction of the carbon-nitrogen
double bond over the nitrogen-oxygen bond could be
The exact mechanism for this remarkable transforma-
tion remains unknown at this time but may involve
initial C-H oxidation of the benzylic methylene to the
intermediate carbanolamine 23 (Scheme 6). Previous
reports have demonstrated the ability of dioxiranes to
execute oxidative C-H insertions, including the oxidative
cleavage of benzyl ethers.30 Further oxidation of the
(27) Murahashi, S.-I.; Tsuji, T.; Ito, S. J . Chem. Soc., Chem.
Commun. 2000, 409.
(28) For related Iridium-catalyzed hydrogenations examined, see:
(a) Spindler, F.; Pugin, B.; Blaser, H.-U. Angew. Chem., Int. Ed. Engl.
1990, 29, 558. (b) Morimoto, T.; Achiwa, K. Tetrahedron: Asymmetry
1995, 6, 2661. (c) Morimoto, T.; Kakajima, N.; Achiwa, K. Chem.
Pharm. Bull. 1994, 42, 1951. (d) Chan, Y. N. C.; Meyer, D.; Osborn, J .
A. J . Chem. Soc., Chem. Commun. 1990, 869. (e) Chan, Y. N. C.;
Osborn, J . A. J . Am. Chem. Soc. 1990, 112, 9400.
(29) Saturated Na2CO3 solutions proved ineffective for promoting
the formation of 22 as the Na2CO3 precipitated out of the reaction
media following the addition of the 0.1 M dimethyldioxirane-acetone
solution.
(25) The structure of these products could not be determined by 1H
NMR although curiously, 19F NMR revealed the presence of two
fluorine signals presumably from incorporation of trifluoropropanone.
(26) (a) Murray, R. W.; Iyanar, K; J ianxin, C.; Wearing, J . T.
Tetrahedron Lett. 1995, 36, 6415. (b) Murray, R. W.; Iyanar, K; J ianxin,
C.; Wearing, J . T. Tetrahedron Lett. 1996, 37, 805. (c) Goti, A.; Nannelli,
L. Tetrahedron Lett. 1996, 37, 6025.
2828 J . Org. Chem., Vol. 69, No. 8, 2004

Synthesis of (+)-FR900482 and (+)-FR66979
SCHEME 6. P r op osed Mech a n ism of th e
DMDO-Med ia ted Dep r otection /Cycliza tion
SCHEME 7. Com p letion of th e Syn th esis of
(+)-F R66979 a n d (+)-F R900482
tertiary amine may then be assisted by the adjacent
hydroxyl group to afford the incipient N-oxide 24. This
hypothesis is based on the known ability of vicinal
alcohols to accelerate dioxirane oxidations in 1,2-diol
systems.31 Base-promoted cleavage of the carbanolamine
N-oxide 24 would produce the desired hydroxylamine
hemiketal precluding further oxidation to the nitrone.
The mechanism proposed provides a plausible expla-
nation for the divergence in reactivity between the
dioxiranes versus the other oxidizing reagents employed,
although several other mechanisms are possible and
further studies are warranted. In addition, longer reac-
tion times, alternate solvents, or varying the quantity of
aqueous K2CO3 failed to increase the conversion of the
reaction above 50%. However, the ability to recycle nearly
all of the unreacted starting material (20) provided a
practical platform from which the synthesis could be
advanced. Interestingly, the analogous O-TBS-protected
epi-substrate derived from 16 failed to give the desired
product under the identical conditions furnishing only
the corresponding nitrone product. This may be a con-
sequence of both the C7 hydroxymethyl and aziridine
functionalities being in a cis-configuration and thus
impeding the formation of the hydroxylamine hemiketal
prior to over-oxidation.
With the successful installment of the hydroxylamine
hemiketal bond and completion of the core structure all
that remained was removal of the protecting groups and
incorporation of the urethane. Desilylation followed by
reaction of the resulting primary alcohol with trichloro-
acetyl isocyanate followed by workup with methanol and
silica gel afforded urethane 25 (Scheme 7).32 Removal of
the methoxy methyl ether in the presence of the acid-
sensitive aziridine functionality was accomplished with
trimethylsilyl bromide (TMSBr) at -45 °C over 3 h in
60% yield.33
For the final deprotection, we had initially anticipated
using a diisobutylaluminum hydride-mediated (DIBALH)
reduction of both of the carbomethoxy groups of 26 to
complete the total synthesis of (+)-FR66979. Indeed,
DIBALH-mediated reduction of both of these function-
alities had initially been demonstrated by Danishefsky
et al. on a fully protected intermediate in their total
synthesis of (()-FR900482.11b Likewise, this strategy had
been employed during our earlier synthetic studies on
analogues of FR900482.15a,b Additionally, as a model
study, we successfully converted authentic samples of
both (+)-FR900482 and semi-synthetically derived N-
methyl carbamate protected (+)-FR900482 to (+)-FR66979
through DIBALH-mediated reductions in THF in good
yield. However the additional equivalents of DIBALH
needed to complete the reduction of 26 to FR66979
complicated the recovery of the product from the alumi-
num “ate” salts, resulting in a disappointingly low yield
(0-30%).
In an effort to avoid completing the synthesis on such
a detrimental step, alternative conditions were examined.
Reduction of 26 with an excess of LiBH4 in THF/MeOH
was found to provide the fully reduced natural product
in good yield; however, 2 could only be isolated as the
nitrogen-borane complex. Although such complexes are
historically difficult to cleave, requiring either harsh basic
or acidic conditions incompatible with the intrinsic
stability of 2, a fortuitous report recently described the
mild cleavage of such complexes using catalytic Pd/C.34
Thus, following aqueous workup, the crude product was
stirred in methanol at ambient temperature containing
a catalytic amount of 10% palladium on charcoal, thereby
liberating the product within 2 h and providing fully
synthetic (+)-FR66979 in 78% yield (0.34% overall yield,
32 total steps from commercially available materials). In
addition, we were interested in accessing (+)-FR900482
through oxidation of 2. Terashima’s successful Swern
oxidation of monoacetylated FR66979 provided precedent
for such a transformation and indeed, we were able to
convert FR66979 to FR900482.11c-i,35 Unfortunately, the
low solubility of 2, even using THF/DMSO as the reaction
(30) (a) Murray, R. W.; J eryaraman, M. L. J . Am. Chem. Soc. 1986,
108, 1598. (b) Marples, B. A.; Muxworthy, J . P.; Baggaley, K. H. Synlett
1992, 8, 646. (c) van Heerden, F. R.; Dixon, J . T.; Holzapfel, C. W.
Tetrahedron Lett. 1992, 33, 7399. (d) Csuk, R.; Do¨rr, P. Tetrahedron
Lett. 1994, 35, 9983.
(31) For example: the rate of oxidation of the secondary alcohol of
adamantane-1,2-diol is reported to be three times faster then ada-
mantane-2-ol implying assistance of the proximal hydroxyl group in
the oxidative insertion, see: Curci, R.; D’Accolti, L.; Detomaso, A.;
Fusco, C. Tetrahedron Lett. 1993, 34, 4559.
(34) Couturier, M.; Tucker, J . L.; Andresen, B. M.; Dube´, P.; Negri,
J . T. Org. Lett. 2001, 3, 465.
(32) Koco´vsky, P. Tetrahedron Lett. 1986, 27, 5521.
(33) Hanessian, S.; Delorme, D.; Dufresne, Y. Tetrahedron Lett.
1984, 25, 2515.
(35) (a) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651. (b)
Ireland, R. E.; Norbeck, D. W. J . Org. Chem. 1985, 50, 2198.
J . Org. Chem, Vol. 69, No. 8, 2004 2829

J udd and Williams
media, resulted in only in a 33% conversion. Despite the
moderate yield, the successful oxidation demonstrates the
ability to access both of these natural products through
this synthetic route.
the FR900482-HMGA1-chromosomal cross-link in human
cells. In addition, this chemistry is being deployed to
prepare additional mitosene progenitors for selective
chemical and photochemical triggering as biochemical
probes and as potential antitumor agents with improved
properties. Studies along these lines will be reported in
due course.
Con clu sion
The enantioselective total synthesis of the antitumor
antibiotic (+)-FR66979 (2) has been completed over 32
steps in 0.34% overall yield and (+)-FR900482 has been
accessed from synthetic (+)-FR66979 via one additional
step. The synthesis features a key aldol reaction on a
highly functionalized synthetic precursor for installing
the C-7 hydroxymethyl portion of this antitumor antibi-
otic. In addition, following an extensive investigation into
the oxidation of the key eight-membered ring intermedi-
ates 11 and 20, a novel dimethyldioxirane-mediated reac-
tion, that simultaneously deprotected the N-PMB resi-
due and installed the unique hydroxylamine hemiketal
moiety was discovered.
Ack n ow led gm en t. This work was supported by the
National Institutes of Health (Grant No. CA 51875). 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 Instrumentation Grant No. GM49631.
We are indebted to Fujisawa Pharmaceutical Co. for the
generous gift of natural FR900482. “This paper is
dedicated to Professor Louis S. Hegedus on the occasion
of his 60th birthday.”
Su p p or tin g In for m a tion Ava ila ble: Full experimental
details and characterization. This material is available free
of charge via the Internet at http://pubs.acs.org.
This synthetic route is currently being exploited to
prepare stable- and radioisotopomers of FR66979 and
FR900482 for use in probing the covalent structure of
J O035828T
2830 J . Org. Chem., Vol. 69, No. 8, 2004