Development of a flexible strategy towards FR900482 and the mitomycins

Article abstract of DOI:10.1002/chem.201003489

FR900482 and the mitomycins are two intriguing classes of alkaloid natural products that have analogous biological mechanisms and obvious structural similarity. Both classes possess potent anticancer activity, a feature that has led to their investigation

Full text of DOI:10.1002/chem.201003489

DOI: 10.1002/chem.201003489
Development of a Flexible Strategy towards FR900482 and the Mitomycins
Barry M. Trost,*[a] Brendan M. OꢀBoyle,[b] Wildeliz Torres,[c] and Michael K. Ameriks[d]
Abstract: FR900482 and the mitomy-
cins are two intriguing classes of alka-
loid natural products that have analo-
gous biological mechanisms and obvi-
ous structural similarity. Both classes
possess potent anticancer activity, a
feature that has led to their investiga-
tion and implementation for the clini-
cal treatment of human cancer. Given
the structural similarity between these
tion. Realization of this strategy with
respect to FR900482 was accomplished
through the synthesis of 7-epi-
FR900482, which displayed equal po-
tency relative to the natural product
against two human cancer cell lines.
With the challenging goal of a synthesis
of either mitomycin or FR900482 in
mind, several methodologies were ex-
plored. While not all of these methods
ultimately proved useful for our syn-
thetic goal, a number of them led to in-
triguing findings that provide a more
complete understanding of several
methodologies. In particular, amination
via p-allyl palladium complexes for the
synthesis
of
tetrahydroquinolines,
eight-membered heterocycle formation
via carbonylative lactamization, and
À
amination through late-stage C H in-
natural products, we envisioned
a
sertion via rhodium catalysis all fea-
tured prominently in our synthetic
studies.
common synthetic strategy by which
both classes could be targeted through
assembling the mitomycin skeleton
prior to further oxidative functionaliza-
Keywords: alkaloids · asymmetric
catalysis · aziridine · natural prod-
ucts · mitomycin
Introduction
FR900482 and the mitomycins (Figure 1) are an important
class of bioactive natural products that have been extensive-
ly investigated due to their intriguing molecular architecture
and potential anticancer properties.[1] Indeed, numerous syn-
thetic approaches have been reported that are based upon
several unique strategies.[2,3] While laudable, these methods
are hampered by length and multiple exchanges of protect-
ing groups limiting their overall synthetic efficiency.
We hoped to improve on previous efforts by reducing the
number of sythetic steps to the desired target. It was also
envisioned that a common intermediate could potentially
access either the mitomycin or the FR900482 ring system
Figure 1. FR900482 and mitomycin family of compounds.
[a] Prof. B. M. Trost
Department of Chemistry, Stanford University
Stanford, CA 94305-5080 (USA)
Fax : (+1)650-725-0002
with maximal flexibility for the variation of the aromatic
core. Thus potentially either natural product or analogues of
both classes could be prepared through a common synthetic
strategy. Because no asymmetric route to the mitomycin
family has yet been reported, the ability to access either
enantiomer of the mitomycin system would represent a sig-
nificant milestone in synthetic methods toward this family of
natural products. Herein we disclose our venture toward
that goal.
E-mail: bmtrost@stanford.edu
[b] Dr. B. M. OꢀBoyle
Merck Research Laboratories: BMB 3-128
33 Avenue Louis Pasteur, Boston, MA 02115 (USA)
[c] Dr. W. Torres
Department of Chemistry, University of Puerto Rico
Rꢁo Piedras Campus, PO Box 23346, San Juan, PR 00931-3346 (USA)
[d] Dr. M. K. Ameriks
Johnson & Johnson Pharmaceutical Research & Development
L.L.C., 3210 Merryfield Row, San Diego, CA 92121 (USA)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003489.
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FULL PAPER
Results and Discussion
Pd-catalyzed amination: Our initial retrosynthesis of 1 envi-
sioned that the [3.3.1]-bicyclic core of FR900482 would be
assembled via transannular hemiketalization of the eight-
membered hydroxylamine derivative 8 (Scheme 1). The key
transformation involved an 8-endo cyclization of palladium
p-allyl complex 11 to generate the benzazocine 10. This in-
termediate could in turn be derived from allene 12 or the
corresponding allylic carbonate 13.
To examine whether this cyclization would be possible,
anilines 20a–e were prepared. Hydropalladation of the ter-
minal allene was anticipated to precede 8-endo cyclization
onto the palladium p-allyl complex. Under a variety of con-
ditions (Table 1) formation of the desired benzazocine core
was not observed and instead the tetrahydroquinoline ring
system was formed (21a–e) with good to excellent diaste-
reoselectivity in some cases. Both the yield and the diaste-
reoselectivity of the cyclization varied with the electronic
and steric environment of the arylamine nucleophile and
allene electrophile.
Further experimentation focused on synthesis of the cor-
responding allylic carbonates (22a and 22b). It was antici-
pated that some of the entropic barrier to 8-endo cyclization
could be overcome by generation of the anti p-allyl com-
plex, which must be the initial intermediate resulting from
ionization of 22a or 22b (Table 2). Furthermore, the 8-endo
product must arise from attack on the anti p-allyl, as the syn
intermediate would lead to a trans olefin within the newly
formed ring. Again good yields and excellent diastereoselec-
tivities could be obtained, but only for the undesired tetra-
hydroquinolines 23a and 23b. Thus, it appears that Pd-cata-
lyzed cyclizations to form benzazocins cannot be achieved
when the formation of a tetrahydroquinoline is a competing
process.
While both of these amination methods were ultimately
not productive for continuing on with the synthesis, it is im-
portant to note that the 1,2,3,4-tetrahydroquinolines 24 are
a class of medicinally important compounds in their own
right. Among these L-689560[6] (25) and virantmycin (26)[7]
are two examples of highly substituted tetrahydroquinolines
that might be amenable to synthesis through this method
(Figure 2).
Scheme 1. Original retrosynthetic analysis of FR-900482.
While this retrosynthetic analysis is unconventional, prec-
edent existed for cyclization to yield an eight-membered car-
bocycle in preference to a possible six-membered isomer
through a palladium p-allyl alkylation.[4] For example, both
allylic carbonates and allenes were known to favor the for-
mation of the larger eight- or nine-membered rings, with
little or none of the smaller six- or seven-membered ring
systems [Eq. (1–3)]. Although an aniline would be the nu-
cleophile in our case we were hopeful that regioselective
formation of the benzazocine would be possible considering
that the benzazocine core has minimal transannular intera-
tions, which typically disfavor medium-sized ring forma-
tion.[5] This should allow for nucleophilic attack at the steri-
cally more accesssible terminal position of the p-allyl
unit.
Carbonylative lactamization: Our initial retrosynthetic anal-
ysis was modified in favor of a carbonylative lactamization
approach (Scheme 2). While carbonylative lactamization
had not been reported for the formation of eight-membered
heterocycles, this method appeared well suited for formation
of the benzazocine core of FR-900482. Preparation of 27 ap-
peared feasible with minimal difficulty and cyclization
seemed likely particularly because the olefin and aromatic
ring would preclude the transannular interactions and de-
crease the entropic barrier that causes eight-membered rings
to be notoriously difficult to prepare. Synthesis of the requi-
site lactamization precursor 27 (with incorparation of a
handle required for asymmetric synthesis) was accomplished
through a Carreira alkynylation of aldehyde 29 with tri-
AHCTUNGTREGmNNNU ethylsilyl acetylene to yield alkyne 31 (Scheme 3) in good
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B. M. Trost et al.
Table 1. Selected optimization studies for Pd–p-allyl alkylation of 20.
yield and excellent enantio-
AHCTUNGTRENGNsUN electivity. The success of this
reaction with the highly epimer-
izable substrate is noteworthy
and multiple other alkynylation
methods were unsuccessful.
While other protocols for this
reaction (including Carreriaꢀs
catalytic conditions) were at-
tempted, none gave the desired
product in acceptable yield.
Thus, the synthesis of three lac-
tamization precursors (27a,
27b, and 27c) was accom-
plished through incorporation
of iodine, cis-reduction of the
alkyne with diimide, and Sm or
Zn reduction of the nitro group
to the hydroxylamine oxidation
state. It should be noted that
samarium(II) iodide functioned
with excellent chemoselectivity
even in the presence of the
vinyl iodide.
Entry
Substrate
Pd Source[a]
[Pd2dba3]·CHCl3
[Pd2dba3]·CHCl3
[Pd2dba3]·CHCl3
Solvent
T [8C]
Yield [%][b]
d.r.[c]
1
20a
20a
20a
20a
20a
20b
G
THF
THF
dioxane
dioxane
dioxane
THF
90
90
100
100
100
80
sm
sm
sm
94
94
27
10
21a
–
–
–
2[d]
3[d]
4
E
A
[{Pd
[{Pd
U
92:8
76:24
62:38
5[d]
6
A
7
20c
[Pd
N
dioxane
100
>95:5
+ 37% 20a
88
trace pdt
8
9
20d
20e
[Pd
[Pd
U
dioxane
dioxane
100
100
85:15
–
[a] 5% of Pd source. [b] Isolated yield [c] Diastereomeric ratios were determined by NMR analysis of the
crude reaction mixture. [d] 4% TBAT was used as an additive.
Table 2. Selected optimization studies for Pd–p-allyl alkylation of 22.
Entry Substrate Pd Source[a]
Solvent Ligand
Yield [%][c]
1
2
3
4
5
6
7
8
22a
22a
22a
22a
22a
22b
22b
22b
22b
22b
22b
22b
N
PPh3
dppp
23
51
P
P
–
ACHTUNGTRENNUNG
G
ACHTUNGTRENNUNG
23
P
P
P
P
P
ACHTUNGTRENNUNG
Scheme 2. Modified retrosynthetic analysis of FR-900482.
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
9
ACHTUNGTRENNUNG
[b]
10
11
12
N
THF
ACHTUNGTRENNUNG
With cyclization substrates 27a–c in hand, a thorough in-
vestigation of the palladium-catalyzed cabonylative lactami-
zation was performed (Table 3). Upon refluxing a dilute so-
lution of vinyl iodide 27a, triethylamine, triphenylphos-
phine, and 5% tetrakis(triphenylphosphine)palladium(0) in
THF (0.03m) under an atmosphere of carbon monoxide, a
36% yield of the desired eight-membered ring 28a was ob-
tained, along with some recovered starting material (49%
brsm, entry 1). Changing the base (entry 2) failed to increase
the yield, while changing the palladium catalyst and reaction
concentration significantly improved the yield (entries 3 and
4). These optimized reaction conditions proved applicable
to modification of the substrate as well. Modification of the
protecting group on the hydroxylamine to TBDPS was toler-
ated, as was employing benzyl ether 27c (entries 5 and 6).
E
DMSO dppf
DMSO
85
82
U
–
[a] 10% of Pd source unless stated otherwise. [b] 20% of Pd source.
[c] All yields are isolated yields after silica gel chromatography.
Figure 2. Pharmaceutically important tetrahydroquinolines.
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Synthesis of FR900482 and Mitomycins
FULL PAPER
37 of the molecule. Several al-
ternative reactions might ac-
complish this, but a Nozaki–
Hiyama–Kishi or reductive ynal
coupling seemed the most
likely methods of success.
As shown in Scheme 5, the
aromatic fragment 43 was pre-
pared in three steps from
known aldehyde 41.[8] A Sono-
gashira coupling[9] of 41 and
TMS acetylene was followed by
protection of the aldehyde as
an acetal. An iron metal reduc-
tion of the nitro group gave ani-
line 43 in a 34% overall yield
from 41.
Synthesis of the aziridine
fragment began from the
known DYKAT of butadiene
monoepoxide (44) and phthali-
mide (45) outlined in Equa-
tion (4).[10] This reaction yields
Scheme 3. Synthesis of vinyl iodides 27a, 27b, and 27c. a) cat AgNO3, NIS, acetone, 87%; b) DIBAL-H, THF;
c) K2CO3, MeOH; d) NaH, BnBr, Bu4NI, THF; e) 35, pyr., AcOH, MeOH; f) SmI2 (4 equiv), THF, MeOH;
g) Zn (2.2 equiv), THF, MeOH, H2O; h) TBDPSCl or TBSCl, imidazole, CH2Cl2.
At this stage multiple attempts to install the aziridine
functionality on 28 failed. The lactams 28a–c could be selec-
tively reduced (BH3·SMe2, THF, 08C, 55%), however, aziri-
dination of either the unsaturated lactam or cis-
olefin failed under various nitrene or epoxide based
approaches.
the protected amino-alcohol 47 in nearly quantitative yield
and excellent enantioselectivity.
In order to circumvent these difficulties, an alter-
native approach was devised in which the aziridine
moiety would be introduced earlier in the synthesis.
Aziridine and aromatic fragment approaches: The
revised approach relied on an early and convergent
union of an aziridine (39) and aromatic fragment
(40) (Scheme 4) and a late stage intraACTHNUTRGNEmNUG olecular
À
C C bond formation to complete the eight-membered core
After conversion of the phthalimide to a Boc carbamate
(48), the introduction of the second stereocenter was accom-
plished in diastereoselective fashion through a syn-directed
epoxidation[11] yielding 49 (Scheme 6). Furthermore, heating
the reaction mixture results in selective decomposition of
the minor anti epoxide through formation of an oxazolidi-
none. While the two epoxide diastereomers were chromato-
graphically separable, it proved helpful to heat the reaction
for a longer duration on larger scale to simplify the purifica-
tion process.
Table 3. Selected optimization studies for Pd-catalyzed carbonylative lac-
tamization.
It was anticipated at this stage that the desired aziridine
(39) could be prepared via an aza-Payne rearrangement[12]
of 50 if an appropriate base and oxaphilic electrophile is
used. Unfortunately, attempts to accomplish this transforma-
tion under a variety of conditions proved fruitless and only
the oxazolidinone was obtained. One alternative to epoxide
opening would be a suitably activated diol, provided reason-
able diastereoselectivity could be achieved. Fortunately,
under the conditions of Sharpless, good diastereoselectivity
and excellent yield were obtained for the formation of diol
52 from 51 (Table 4).
Entry Substrate Pd Source
Solvent Ligand Base
Yield
[%][a]
1
2
3
4
5
6
27a
27a
27a
27a
27b
27c
[Pd
[Pd
A
N
THF
THF
PPh3
PPh3
Et3N
iPr2NEt 36
36
N
Et3N
Et3N
Et3N
Et3N
41
78
66
64
N
CHTUNGTRENNUNG
R
CHTUNGTRENNUNG
A
CHTUNGTRENNUNG
[a] Isolated yield. [b] 0.01m [c] 0.03m.
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7893

B. M. Trost et al.
lation was sufficiently clean
that the immediate product was
never purified beyond sepa-
AHCTUNGERTGrNNUN atory funnel workup to
remove reagents employed in
the dihydroxylation. Instead,
cleavage of the phthalimide
protecting group and in situ
protection of the polar amino-
diol as a tert-butyl carbamate
was accomplished under the
conditions
described
in
Scheme 6 to prepare 53.
Chemoselective protection of
the primary alcohol with a tert-
butyldiphenylsilyl group and in
situ mesylation, followed by
warming the crude mesylate in
dimethylformamide and cesium
carbonate resulted in the for-
mation of aziridine 54. Aziri-
dines 55 and 56 were prepared
Scheme 4. Revised retrosynthesis of FR900482; Nozaki–Hiyama–Kishi coupling strategy.
Scheme 5. Synthesis of aromatic subunit 45.
Scheme 6. Synthesis of amino-epoxide 50.
Table 4. Stereoselective dihydroxylation of 51.
Scheme 7. Completion of the aziridine fragment.
Entry Catalyst and Ligand
Yield
[%]
d.r.[a]
via desilylation of the TBDPS ether 56 and Dess–Martin oxi-
dation. This entire synthetic sequence requires eight steps
from butadiene monoepoxide and gives 56 in 27% overall
yield.
Alternatively, diol 53 could be bis-mesylated and analo-
gous conditions resulted in selective three-membered ring
formation providing mesylate 57. Compound 57 could also
be prepared by mesylation of 55 (MsCl, Et3N, CH2Cl2,
90%).
1
2
OsO4 (1 mol%), NMO, THF
K2OsO2(OH)4 (1 mol%), (DHQ)2PHAL
(2 mol%)
K2OsO2(OH)4 (1 mol%), (DHQ)2PYR
(2 mol%)
K2OsO2(OH)4 (1 mol%), (DHQ)2AQN
(2 mol%)
98
71
1.25:1
5:1
3
4
5
98
90
85
8.5:1
5:1
K2OsO2(OH)4 (1 mol%), (DHQD)2PHAL
(2 mol%)
1:1.5
[a] Diastereomeric ratio determined by NMR.
While attempts at coupling the fragments 43 and 57 via
nucleophilic addition failed, reductive amination of 43 and
56 proved to be a reliable method for accomplishing this
transformation (Scheme 8). This reaction was limited to the
With this result in hand, the desired aziridine fragment
was quickly completed (Scheme 7). The Sharpless dihydroxy-
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Synthesis of FR900482 and Mitomycins
FULL PAPER
function with the triflate that
had been already installed on
the aromatic ring 41, it seemed
more logical to approach the
difficult Heck reaction with the
most activated precursor possi-
ble. To accomplish this, the tri-
flate was exchanged for an
iodine atom via nucleophilc ar-
omatic substitution yielding aryl
iodide 65. Furthermore, be-
cause the Songashira reaction
(in the previous approach;
Scheme 5) had proven quite
sensitive to the electronic
Scheme 8. Synthesis of reductive cyclization precursor 61.
nature of the aromatic ring, it
aniline oxidation state and failed for the corresponding hy-
droxylamine. Because aldehyde 56 was quickly reduced
even in the presence of triacetoxyborohydride, it was essen-
tial to drive the dehydration prior to addition of the reduc-
ing agent. As a result incorporation of the desired hydroxyl-
amine oxidation state directly was complicated. Similar con-
ditions to yield a coupling product through the intermediacy
of a nitrone were not successful.
The desired eight-membered benzazocine core (60 or 61)
was anticipated to arise through a reductive cyclization
under the conditions of Montgomery[13] and Jamison,[14] or
via prior elaboration of the alkyne (58 or 59) to facilitate an
intramolecular Nozaki–Hiyama–Kishi coupling reaction
(Scheme 8). However, none of the approaches proved fruit-
ful for the continuation of the synthesis and the synthetic
approach needed to be modified prior to continuing for-
ward.
seemed prudent to employ an
electron withdrawing group as a surrogate for the C12 alde-
hyde. As such, the aldehyde was oxidized in a single step to
methyl ester 66 by employing N-iodosuccinimide as an oxi-
dizing reagent under basic conditions.[16] Finally an iron
mediated reduction[17] proved to be chemoselective for the
conversion of the nitro group to the amine in the presence
of the iodide yielding 67 in only six linear steps from 5-nitro-
vanillin. Furthermore, this route proved to be extremely
scaleable and chromatography was only required in the final
step to remove the excess iron from the product. In total,
20–25 grams of 67 were prepared in the duration of this
study.
Modification of the aziridine fragment might appear to be
much more challenging. However, during the course of the
first generation studies above, Trost and Aponick reported a
DYKAT reaction employing divinylcarbonate (68) and
phthalimide to produce amino-alcohol 69 as a single diaste-
reomer in very high enantioselectivity.[18] To employ this re-
action in our synthesis, the subsequent dihydroxylation was
required to be chemo and diastereoselective. It has been
demonstrated that allylic groups play a pronounced role in
the rate of dihydroxylation under Sharpless conditions,[19]
thus it was anticipated that the required selectivity might be
accomplished with the proper choice of protecting group.
To test this possibility, the
À
We envisioned that a more established C C bond-forming
reaction, such as the Heck coupling,[15] would provide the
sought after benzazocine core 41. However, in order to
prove this hypothesis the parent aromatic and aziridine frag-
ments of the convergent approach in Scheme 4 would have
to be modified accordingly (Scheme 9).
The preparation of a suitable aromatic fragment was rela-
tively trivial. Although the Heck reaction could potentially
tert-butylsilyl ether 70 was pre-
pared in three steps from hexa-
1,5-diene-3,4-diol
from TCI-America as a stereo-
random mixture, see
(available
Scheme 10). The DYKAT reac-
tion was initially performed
under the conditions reported
by Trost and Aponick[18] to give
the amino-alcohol 69 in 72%
yield and 99% ee as a single
diastereomer. It was subse-
quently determined that the
catalyst loading could be low-
ered to 0.5 mol% of [Pd-
Scheme 9. Revised retrosynthesis of FR900482; Heck coupling strategy.
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B. M. Trost et al.
nor TBS protection would be required. While not useful for
the present purpose, 76 may prove to be a versatile synthetic
intermediate at some later date and is prepared in only two
steps from commercial sources.
With aziridine 74 and aniline 67 in hand reductive amina-
tion proved successful and provided 77 in good yield
[Eq. (6)]. Our efforts then turned to the investigation of the
À
crucial C6 C7 bond formation that was planned to proceed
via Heck coupling.
Scheme 10. Synthesis of a modified aziridine fragment.
ACHTUNGTRENNUNG(allyl)Cl]2 and 1.5 mol% of the (R,R)-Trost naphthyl ligand
without a decrease in yield. Lowering the catalyst loading
further resulted in substantially lowered yield due to incom-
plete conversion, even when the concentration of the reac-
tion medium was increased to maintain the same catalyst
concentration. After silyl protection, 70 was submitted to
the Sharpless dihydroxylation under conditions identical to
those optimized on the first generation system. The reaction
was remarkably selective for the desired product. While
there was another isomer present in the reaction mix
G
While conditions analogous to those reported by Dani-
(~10%), it could not be determined by NMR analysis
whether this side-product was a diastereomer, or a product
of dihydroxylation of the opposite olefin. Aziridine 74 was
accessed in five additional steps via the same sequence that
was used for the first generation aziridine synthesis (29%
overall yield from 68 in six linear steps).
It should be noted that nucleophiles other than phthali-
mide were successful in the DYKAT reaction. Trost[20] re-
cently reported that utilization of N,N-benzoyl-tert-butylcar-
bamate (75) results in nucleophilic addition of the imide to
the p-allyl palladium species, followed by migration of the
benzoyl group. With divinyl carbonate this reaction is suc-
cessful [Eq. (5)] and results in the direct formation of
amino-alcohol 76 in 52% yield (based on the imide or 40%
yield based on divinylcarbon-
shefsky (PdACTHGNUTERNNU[G PPh3]4, CH3CN, Et3N, reflux) gave almost no
conversion, the conditions of Overman[21] gave complete
conversion to a single identifiable product (78) which was
isolated in 87% yield [Eq. (7)]. However, this product was
clearly not the desired exo-cyclic olefin that would be ex-
pected from a Heck reaction. Olefin peaks in the d = 5–
6 ppm region were not observed; however, mass spectro-
scopic analysis of the product revealed the anticipated mo-
lecular weight ([M]+ =580.2974 amu). After in depth NMR
experiments (COSY, HMBC, HSQC and ROESY) the
structure of this new product was determined to be the
structure indicated below. Remarkably, transannular amina-
tion outcompetes the expected b-hydride elimination in this
case, giving rise to 78.[22]
ate). This reaction was not opti-
mized further. Side-products
were obtained indicating that
subsequent ionization of the al-
lylic benzoyl group is somewhat
competitive with the initial ioni-
zation.
Unfortunately,
the
Sharpless dihydroxylation de-
scribed above was completely ineffective when 76 is em-
ployed as a substrate and several diol products were ob-
tained as an inseparable mixture. This strategy would have
saved two steps as neither removal of the phthalimide group
This reaction, while intriguing, presented a substantial ob-
stacle to the synthesis of FR900482. Several changes were
made to Heck precursor 77 in an attempt to favor formation
of the expected Heck product (37, see Scheme 11). Removal
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Synthesis of FR900482 and Mitomycins
FULL PAPER
through inversion (86, Tf2O,
pyridine, CH2Cl2) or double in-
version
([Ir
G
87,
DABCO) and the desired Heck
reaction proceeded in excellent
yield for both substrates
(Scheme 13).
Hydroboration of 82a with 9-
BBN (Scheme 14) led to a 4:2:1
mixture of 90a, 90b along with
the ring-opened aziridine (89).
À
Ideally for the C H insertion
the hydroxymethyl and C8 hy-
drogen should be cis, thus 90b
appeared to be ideally substi-
tuted to access the mitomycin
Scheme 11. Synthesis of a modified aromatic fragment.
of the TBS group (nBu4NF, THF, quant.) followed by the
same Heck reaction conditions led to the formation of two
products (presumably diastereomers) neither of which con-
tained olefin signals that would be indicative of an exocyclic
double bond. In contrast, protection of the aniline with a tri-
fluoroacetate or acetate gave a product which was unreac-
tive under the same Heck reaction conditions, even after
prolonged reflux (dioxane 1018C). Microwave irradiation of
the same reaction mixture resulted in eventual cleavage of
the trifluoroacetate (presumably via nucleophilic action of
the carbonate base) and immediate formation of the same
tetracycle (78) as described above. At this point, the assem-
bly of the eight-membered benzazocine core was aban-
doned.
It was then anticipated that incorporation of a pyrrolidine
ring system prior to the Heck reaction would allow us to
reach the desired [3.3.1]bicyclononane ring system present
in FR900482. In addition, this strategy would allow us to
target either the mitomycin ring system or the FR900482
system through modification of the aromatic ring fragment
(Scheme 12).
Scheme 12. C8 oxidation strategy.
For this strategy to be feasible, modification to the correct
oxidation state at C8 was essential. One method to accom-
À
plish this goal is to perform a C H insertion reaction direct-
ed by the neighboring C7 hydroxymethyl group in 83 or 84.
ring system. Alternatively, hydroboration of 82b led to ex-
clusive formation of the trans stereochemistry between the
C7 hydroxymethyl and C8 hydrogen substituents (91).
In order to continue forward, the carbamate 92 and sulfa-
mate ester 94 were prepared (Scheme 15). Although the
trans-substituted diastereomers (92 and 94) appeared to be a
À
To set up the C H insertion, hydroboration of 82 in a dia-
stereoselective manner was crucial. The high number of het-
eroatoms in such a compact structure makes this novel ap-
proach very challenging since there are several activated
carbons that could hypothetically react; 1) the two positions
adjacent to the aniline nitrogen (C8 and C11); 2) the benzyl-
ic position (C7); 3) the aziridine carbons (C9 and C10); and
4) the benzylic carbons contiguous to the oxygen atom in
the OBn group (C13). It was anticipated that a sulfamate
ester, such as 83 might favor insertion at the desired C8 po-
sition over C7 as has been demonstrated by the studies of
Du Bois.[23] However, 84 was also explored since the carba-
mate is present in the natural product and its implementa-
tion would lead to a streamlined synthetic approach. Either
pyrrolidine diastereomer (81a and 81b) was prepared
À
less compelling C H insertion starting material, it was inves-
tigated first since the higher diastereoselectivity in the prior
hydroboration allowed access to pure material without tedi-
ous separation of diastereomers. Exposure of 92 to the con-
ditions of Du Bois, yielded the five-membered spirocyclic
product 93. The sulfamate ester 94 also favored the same re-
gioselectivity rather than the desired C8 insertion product.
À
Diastereomers 96 and 99 were also attempted in the C H
insertion reaction (Scheme 16). The 1:1 mixture of primary
carbamates 96 led to formation of a 1:1 mixture of the unde-
À
sired five-membered C H insertion product 97 (b diastereo-
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B. M. Trost et al.
The 1:1 diastereomeric mix-
ture of sulfonamides 99 also led
to a 1:1 mixture of products.
The a diastereomer favored in-
sertion at C11 to form the ten-
membered ring 101 (10% NOE
between -CH2OR and H9). The
b diastereomer formed the very
unexpected zwiterionic product
100 by attack of the aniline ni-
trogen (10% NOE between
H7–H9 and 6% NOE between
-CH2OR and H8). This intrigu-
ing compound proved stable
since its NMR was identical
after weeks at room tempera-
ture on the bench.
Scheme 13. Successful Heck reaction.
The isolation of these large
rings was very surprising. Nev-
ertheless, it has been reported
by Selkti that structural parameters such as conformational
factors play a strong influence and could favor the intramo-
lecular formation of a seven-membered ring in piperidine
substrates.[24]
Due to these difficulties, a Polonovski/deoxygenation se-
quence more reminiscent of Ziegler[25] and Dmitrienkoꢀs[26]
original work was examined. To this end, dihydroxylation of
either 82a or 82b and protection of the resulting diol was
anticipated to yield material that would serve in the desired
C8 oxidation. Again, 82a was modestly selective for dihy-
droxylation from the a face leading to 102a as the major
stereoisomer (Scheme 17), which could be readily separated
from the minor epimer after protection of the diol as a
cyclic carbonate. Olefin 82b led exclusively to a single dia-
stereomer, which was also protected as a cyclic carbonate
(102b).
Scheme 14. Hydroboration of 82a and 82b.
It must be noted that the stereochemistry arising at C8
for the formation of 102a was inaccurately assigned in our
original communication.[27] The stereochemistry at C7, which
was assigned by comparison to C8 was also reversed. This
misassignment resulted from the rather large NOE enhance-
ment that was observed in 102a and epi-102a between C8
and C9. It was only after synthesis of the C8 epimer 102b
and further NOE studies that the correct assignment of ste-
reochemistry was realized (Figure 3). This finding reversed
stereochemistry in several intermediates which had been
previously reported, but did not affect the end result as
these centers were ultimately irrelevant to the final outcome
of the synthesis.
Carbonates 102a, epi-102a and 102b were all subjected to
the Polonovski conditions optimized by Ziegler (m-CPBA,
CH2Cl2 then Ac2O, THF).[28] Compound 102b successfully
yielded the C8 acetate 103. In contrast to Zieglerꢀs observa-
tion that hydrolysis of the acetate occured readily, hydrolysis
of 103 did not occur upon exposure to aqueous sodium bi-
carbonate. Hydrolysis under more forcing conditions
(Cs2CO3, MeOH) led to hydrolysis of the carbonate and iso-
À
Scheme 15. Investigation of the C H insertion reaction.
À
mer) and ten-membered C H insertion product 98 (a dia-
stereomer).
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Synthesis of FR900482 and Mitomycins
FULL PAPER
dation led to a mixture of 107
and 108. Surprisingly, the com-
position of this mixture was de-
pendent on the quality and pu-
rification of 106. Exposure of
106 to slightly acidic conditions
(SiO2 chromatography) led to
intractable mixtures of diaste-
reomers 107 and 108. However,
purification of 106 by reversed
phase HPLC (NH4OH buffer
0.1%/ACN) led to pure quanti-
ties of 107. The most likely ex-
planation for these observations
is that the aminal is formed ki-
netically as a single diastereo-
À
Scheme 16. Further investigation of the C H insertion reaction.
mer, but exposure to acid re-
sults in epimerization of the C8
stereochemistry. Equilibration of these diastereomers after
oxidative ring expansion was not observed under acidic or
basic conditions. Thus, it is proposed that the oxidative ring
expansion is stereospecific and different aminal diastereo-
mers result in opposite diastereomers after the oxidative
ring expansion.
Completion of the synthesis rested upon deoxygenation of
107. After a variety of failed attempts to selectively cleave
the cyclic carbonate, it was observed that hydrogenolysis of
the benzyl ether followed by treatment with sodium borohy-
dride in methanol resulted in not only hydrolysis of the
cyclic carbonate, but also led to incorporation of a methoxy
group at C7 [Eq. (8)].
Scheme 17. Dihydroxylation of 82a and 82b.
lation of the corresponding triol. Hydrolysis with methoxide
and methanol led to spontaneous rearrangement to the in-
ternal cyclic carbonate 104. None of these products partici-
pated successfully in the desired oxidative ring expansion re-
action.[29] It was anticipated that a benzylic epoxide might
prove amenable to deoxygenation following the oxidative
expansion reaction. Thus, 105 was prepared, but its extreme
instability to acid disqualified it as a potential precursor to
the desired bicylic system (Scheme 18).
As an alternative, the Polonovski/oxidation sequence was
attempted on epi-102a and 102a. While the minor diastereo-
mer failed to give any desired product, 102a led to the an-
ticipated aminal product (106) in moderate yield over two
steps (Scheme 19). Exposure of this product to a second oxi-
The remarkable transformation outlined in Equation (8)
was attributed to facile formation of an ortho-quinone me-
thide intermediate (see Scheme 20), which rendered C7
electrophilic in nature and resulted in the capture of metha-
nol through solvolysis. It was immediately recognized that
this reaction might provide
access to the desired deoxygen-
ated product if conditions could
be found to favor a net reduc-
tive termination of the reaction
rather than a redox neutral so-
volysis. Investigation focused
on adjustment of the reaction
medium, which might slow or
render reversible the undesired
Figure 3. Reassignment of C8 stereochemistry.
solvolysis. While iPrOH gave
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7899

B. M. Trost et al.
primary carbamate via treat-
ment with trichloroacetyl isocy-
anate followed by in situ hy-
drolysis of the trichloroacetyl
group. Exchange of the methyl
ester for an ethyl thioester
(111) was followed by Fukuya-
ma reduction with palladium on
carbon to yield the correspond-
ing aldehyde.[31] The tert-butyl
carbamate was removed via hy-
drolysis with saturated aqueous
potassium carbonate in metha-
nol, liberating the free aziri-
dine. The product is isolated as
a 3:2 mixture of separable hem-
iketal isomers, however, com-
parison to an authentic sample
(NMR, TLC) shows that nei-
ther isomer matches the natural
product, clearly demonstrating
our product to be epimeric at
C7.
Scheme 18. Polonovski and oxidation/ring expansion of 102.
The likely mechanism which
led to the epimeric C7 stereo-
chemistry
is
outlined
in
Scheme 20. Previous experi-
mentation by Danishefsky had
Scheme 19. Successful polonovski/oxidative ring expansion.
Scheme 21. Completion of the synthesis of epi-FR900482.
generated an ortho-quinone methide intermediate in the ab-
sence of a reducing reagent.[32] In our case deoxygenation of
107 most likely begins with exchange of the phenol for a
phenoxyboronate complex such as 113. Subsequent intramo-
lecular reduction causes chemoselective cleavage of the
cyclic carbonate to be possible in the presence of the tert-
butyl carbamate protecting group. However, the resulting
tetraol (114) is disposed for elimination of its tertiary ben-
zylic alcohol to generate ortho-quinone methide 115. This
reactive intermediate is proposed to decompose through a
hydride shift yielding aldehyde 116, which is reduced from
the less hindered face. Alternatively, the ortho-quinone me-
Scheme 20. Mechanism of the deoxygenation.
only very limited solublity of sodium borohydride, ethanol
affected the same reaction yielding 110 as the sole identifia-
ble product (see Scheme 21).
With 110 in hand, but no evidence to confirm the stereo-
chemistry at C7, further effort focused on completion of the
synthetic route.[30] The primary alcohol was converted to a
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Synthesis of FR900482 and Mitomycins
FULL PAPER
Table 5. Comparative biological testing of FR900482 and epi-
thide could be directly reduced by sodium borohydride
which would presumably lead to the opposite configuration
at C7. The observation that the hydroxymethyl group is
formed on the convex face of the molecule seems more con-
sistent with very fast decomposition of the ortho-quinone
methide through a hydride shift and then a slower reduction
of an aldehyde, which is thermodynamically favored to be
on the less hindered face of the molecule.
FR900482.[a]
IC50 [mm]
SKBr3
MCF-7
FR900482
7-epi FR900482
0.980
1.000
1.020
1.100
[a] Comparison of FR900482 and epi-FR900482 was performed side by
side at Kosan Biosciences. Activity within the range of experimental
error was observed.
A substantial amount of effort failed to introduce the C7-
hydroxymethyl substituent in the configuration required for
the natural product. While it was disappointing not to have
the natural product in hand after so much effort, we were
excited by the possibility that the C7 epimer of FR900482
might have comparable activity based on the established
biological mechanism of this natural product.
Conclusion
This work highlights several novel and challenging ap-
proaches toward FR900482 and mitomycin congeners. Each
strategy allowed us to gain a better knowledge in terms of
the scope and limitations of the synthetic methodology em-
ployed and in terms of the reactivity of the intermediate
species involved. For example, we were able to synthesize a
challenging eight-membered benzazacine heterocycle,
through a carbonylative lactamization. Palladium-catalyzed
p-allyl alkylation instead afforded highly substituted tetrahy-
droquinolines which are important pharmacophores. Large
N-heterocyclic rings were also produced under Rh-catalyzed
It is known[33] that reduction of the hydroxylamine to the
aniline oxidation state is the triggering event that precedes
formation of the reactive mitosene intermediate capable of
cross-linking DNA (Scheme 22). For FR900482 and epi-
FR900482 the triggering event should be the same, generat-
ing intermediates 117 and 119, respectively. It is unknown
what mechanism the reductive activation proceeds by and it
À
seemed quite possible that the initial N O bond reduction
À
might be sensitive to the stereochemistry at C7. Further-
more, dehydration to mitosene intermediate 118 is not in-
stantaneous. Studies on the mitomycins have demonstrated
the lifetime of an aminal intermediate such as 117 or 119 is
strongly dependent on the substitution of the aromatic
ring.[34] Thus it also seems likely that the lifetime of such an
intermediate could be strongly dependent on the stereo-
chemistry at C7. However, if these two steps are compara-
ble, the stereochemistry at C7 would not be expected to
have any influence on the biological activity since the even-
tual mitosene intermediate 118 is identical.
C H insertion conditions, highlighting the importance of
proximity effects in these reactions. Our synthetic efforts ul-
timately led to 7-epi-FR900482 in 23 linear steps (29 total)
and 1.4% overall yield which represents a route that is the
shortest yet disclosed for the preparation of close FR900482
analogs. It also demonstrates that the stereochemistry at C7
is irrelevant to the biological activity of FR900482.
Prior to this study, it was not possible to predict based on
what was known about the biological mechanism that a C7
epimer should be equally active compared to the natural
product. The question comes down to what is the mecha-
nism by which the compound is activated since the C7 ste-
reocenter is obliterated. The fact that this stereocenter is ir-
relevant to activity suggests the activation mode may be
non-enzymatic. Because 7-epi-FR900482 has analogous in
vitro activity compared to the natural product, its synthesis
is functionally equivalent to that of the natural product
whose syntheses all are signifi-
In fact, when FR900482 and epi-FR900482 were tested
side by side comparable cyctotoxicity was collected from
each within the experimental margin of error (Table 5).
cantly longer. Furthermore, it is
also possible that this epimer
could have an improved biolog-
ical profile compared to the
natural product, particularly be-
cause it may not have all the
deleterious side-effects that
have caused FK973 to be with-
drawn from clinical trials. This
is especially true because the
convergent synthetic route pre-
sented above allows for signifi-
cant variation of functional
groups on epi-FR900482 that
would not be possible by semi-
Scheme 22. Biological mechanism of action for epi-FR900482 and FR900482.
synthesis.
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B. M. Trost et al.
According to the known procedure of Trost,[18] a dry 250 mL flask was
charged with sodium carbonate (0.1060 g, 1.0 mmol), phthalimide
(2.2364 g, 15.2 mmol), (R,R)-naphthyl ligand (0.2373 g, 0.30 mmol) and
[(h3-C3H5)PdCl]2 (0.0366 g, 0.10 mmol). The reaction vessel was evacuat-
ed and backfilled with nitrogen several times and then degassed methyl-
ene chloride (120 mL) was injected. A separate flask was charged with
divinylcarbonate 68, which was dissolved in degassed methylene chloride
(40 mL). After 15 min the divinylcarbonate solution (20 mmol, 2.800 g)
was transferred via canula into the reaction flask. The reaction was
stirred at room temperature for 96 h, after which time the solvent was re-
moved under reduced pressure and the remaining crude material was pu-
rified by flash chromatography on silica gel (gradient, 10 to 30% EtOAc/
PE) to afford the product 69 as a white solid (3.503 g, 72%). The enan-
tiomeric excess was determined via evolution on a Chiracell AS column
with 5% iPrOH/heptane at a flow rate of 1 mLminÀ1. Monitoring at
230 nm showed the (S,S) enantiomer with a retention of 19.8 min and the
(R,R) enantiomer which eluted at 28.3 min. This method showed the
enantiomeric excess to be greater than 99%. Rf =0.35 (hexane/EtOAc
4:1); [a]2D3ꢀ =À86.4 (c=1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3): d =
7.87–7.81 (m, 2H), 7.76–7.71 (m, 2H), 6.22 (ddd, J=6.9, 10.4, 17.3 Hz,
1H), 5.83 (ddd, J=4.7, 10.5, 15.3 Hz, 1H), 5.43–5.15 (m, 4H), 4.89 (t, J=
6.6 Hz, 1H), 4.72–4.65 (m, 1H), 3.52 ppm (d, J=8.7 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d = 168.8, 137.3, 134.2, 132.1, 131.6, 123.5, 118.8,
116.8, 72.7, 58.6 ppm; IR (thin film): n˜ = 3463, 1707, 1387 cmÀ1; HRMS
(EI+): m/z: calcd for C11H6NO3: 243.0895, found 243.0892 [M]+.
Thus, the synthesis of 7-epi-FR900482 demonstrates that a
substantially shorter route to such structural types is possi-
ble and that an unnatural analogue can have equal activity
relative to the natural product. We have learned much
about the synthesis of such structures and about the biologi-
cal mechanism that makes these structures valuable. Thus,
the main objective of creating a more efficient synthesis of
highly active FR analogues for further structure–activity
studies in order to find a potent analog devoid of undesired
side-effects has indeed been accomplished.
Experimental Section
General methods: Reactions were carried out in flame- or oven-dried
glassware (overnight, 1208C) equipped with a Teflon-coated magnetic
stirring bar under a positive stream of argon or nitrogen. All reagents
and solvents obtained from commercial sources were used without fur-
ther purification. Anhydrous toluene, benzene, diethyl ether, hexane, di-
chloromethane, dimethylformamide and tetrahyrofuran (THF) were ob-
tained from a Solv-Tek solvent purification system by passing through a
column of activated alumina. Acetone was distilled from calcium sulfate.
Methanol was distilled from magnesium methoxide. Reactions were
monitored by thin layer chromatography (TLC) using 0.25 mm pre-
coated Silica Gel 60 F254 glass plates (EMD Chemicals Inc.). Normal
and flash column chromatography were performed with 32–63 mm stan-
dard grade silica gel (Sorben Technologies). Nuclear magnetic resonance
(NMR) spectra were recorded on a Varian UI-600 (1H at 600 MHz, 13C
at 150 MHz), UI-500 (1H at 500 MHz, 13C at 125 MHz) or Mercury 400
(1H at 400 MHz, 13C at 100 MHz) magnetic resonance spectrometers. In-
frared spectra were obtained neat on NaCl plates using a Nicolet IR 100
FT-IR Spectrometer (Thermo Scientific) and reported in wavenumbers
(cmÀ1). High-resolution FAB mass spectrometry (HRMS) data were
measured on a Micromass Q-Tof API US mass spectrometer (Waters
Corporation, Milford MA) in positive electrospray ionization mode (+
ESI). Melting points were determined on a Thomas-Hoover melting
point apparatus in open capillaries and are uncorrected. Optical rotation
data was obtained with a Jasco DIP-360 digital polarimeter at the sodium
D line (589 nm) in the solvent and concentration indicated.
Heck Reaction: Synthesis of exocyclic olefin 82a
Aryl iodide 81a (45.8 mg, 0.080 mmol), palladium acetate (1.9 mg,
7.9 mmol), triphenylphosphine (8.9 mg, 31.6 mmol) and silver carbonate
(43.8 mg, 0.16 mmol) were transferred to a round bottomed flask. The
flask was evacuated and refilled with nitrogen three times. Dioxane
(1.6 mL, freshly distilled over sodium) was injected and the reaction was
heated to 808C in an oil bath. After 1 hour the reaction was complete
and allowed to cool. The heterogenous suspension was filtered though
celite to remove palladium black and the filter cake was washed with
ethyl acetate. The filtrate was concentrated under reducted pressure.
Flash chromatography (20% EtOAc/hexane) gave compound 82a as a
yellow foam (33.0 mg, 93%). Rf =0.30 (hexane/EtOAc 4:1); [a]2D3ꢀ =+23
(c=0.90, CDCl3); IR (thin film): 2948, 1716 (sharp), 1566; 1H NMR
(500 MHz, CDCl3): d = 7.48–7.33 (m, 5H), 7.18 (d, J=0.9 Hz, 1H), 7.00
(d, J=1.0 Hz, 1H), 6.04 (d, J=3.2 Hz, 1H), 5.38 (d, J=2.5 Hz, 1H), 5.18
(s, 2H), 4.68 (t, J=2.7 Hz, 1H), 3.90 (s, 3H), 3.69 (d, J=11.8 Hz, 1H),
3.38 (dd, J=4.3, 12.1 Hz, 1H), 3.34 (t, J=4.4 Hz, 1H), 3.25 (dd, J=0.4,
4.9 Hz, 1H), 1.49 ppm (s, 9H); 13C NMR (125 MHz, CDCl3): d = 167.1,
160.6, 159.4, 155.8, 144.0, 136.5, 132.8, 128.9, 128.4, 127.9, 121.5, 110.0,
108.1, 105.8, 82.2, 71.6, 70.6, 55.9, 52.6, 49.2, 45.6, 28.2 ppm; HRMS (EI+
): m/z: calcd for C26H28N2O5: 448.1998, found 448.1998 [M]+.
General procedure for carbonylative lactamization: Synthesis of lactam
28a
A solution of vinyl iodide 27a (296 mg, 0.423 mmol) in DMA (4.1 mL)
was added at once to a solution of dichlorobis(triphenylphosphine)palla-
dium(II) (14.8 mg, 0.021 mmol), and triethylamine (90.0 mg, 0.124 mL,
0.889 mmol) in DMA (10.0 mL). Carbon monoxide was bubbled through
the resulting red solution for 30 min. The reaction mixture was heated to
658C and stirred at that temperature for 5.5 h. After cooling to room
temperature, water was added and the reaction mixture was extracted
with EtOAc (ꢃ3). The combined organic extracts were washed with
brine, dried (MgSO4), filtered, and concentrated under reduced pressure
to give 28a as a brown oil. Purification by column chromatography (SiO2,
30% Et2O/pet ether to 50% Et2O/pet ether) afforded the lactam as a
white solid (198 mg, 78%). M.p. 53–558C; Rf =0.37 (50% Et2O/pet
ether); [a]2D2 =À13.88 (c=5.28, CH2Cl2); 1H NMR (300 MHz, CDCl3): d
= 7.81 (s, 1H), 7.56 (d, J=1.2 Hz, 1H), 7.33 (m, 5H), 6.25 (dd, J=8.3,
11.7 Hz, 1H), 5.66 (d, J=11.7 Hz, 1H), 5.55 (m, 1H), 5.09 (s, 2H), 3.89
(s, 3H), 2.88 (m, 2H), 1.01 (s, 9H), 0.77 (s, 9H), 0.15 (d, J=1.7 Hz, 6H),
Acknowledgements
We gratefully acknowledge D. Barrett and Astellas Pharmaceuticals for
providing an authentic sample of FR900482 and Dr. Yong Li and Hugu
Menzella for biological testing of FR900482 and its epimer. We also ac-
knowledge S. Lynch for his invaluable help in the acquisition of 2D
NMR data. We thank the Stanford Graduate Fellowship Program and
NIH (GM 33049) for their financial support of our program and Johnson
Matthey for their supply of precious metal salts.
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À0.15 (s, 3H), À0.26 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d
=
169.3, 167.4, 156.3, 154.1, 151.4, 137.1, 129.4, 128.4, 127.8, 127.4, 117.4,
116.5, 108.1, 105.5, 70.1, 69.9, 52.1, 31.1, 30.3, 26.1, 25.7, 18.1, 17.9, À5.24,
À5.30, À5.60 ppm; IR (CDCl3): n˜ = 1724, 1700, 1586, 1434, 1325, 1252,
1234 cmÀ1
597.2943.
; HRMS: m/z: calcd for C32H47NO6Si2: 597.2942; found:
DYKAT reaction of divinyl carbonate 68: Synthesis of alcohol 69
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Synthesis of FR900482 and Mitomycins
FULL PAPER
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Received: December 2, 2010
Revised: January 31, 2011
Published online: May 26, 2011
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