Synthetic and biosynthetic studies on FR900482 and mitomycin C: An efficient and stereoselective hydroxymethylation of an advanced benzazocane intermediate

Article abstract of DOI:10.1021/ol701960v

We report a simple, efficient, and stereoselective Mukaiyama aldol approach to install the key hydroxymethyl moiety into the benzazocane framework of FR900482. Synthetic investigations revealed that the reaction is highly dependent upon the electronics of the aromatic ring. This approach enabled the economical introduction of a [¹³C] label to study the biosynthesis of these structurally and biogenetically related natural products. Epimerization of the initially formed β-hydroxy ketone may enable access to mitomycin C or FR900482 biosynthetic congeners.

Full text of DOI:10.1021/ol701960v

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5341-5344
Synthetic and Biosynthetic Studies on
FR900482 and Mitomycin C: An
Efficient and Stereoselective
Hydroxymethylation of an Advanced
Benzazocane Intermediate
Hidenori Namiki,† Stephen Chamberland,† Daniel A. Gubler,† and
Robert M. Williams*,†,‡
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado
80523-1872, and UniVersity of Colorado Cancer Center, Aurora, Colorado 80045
rmw@lamar.colostate.edu
Received August 22, 2007
ABSTRACT
We report a simple, efficient, and stereoselective Mukaiyama aldol approach to install the key hydroxymethyl moiety into the benzazocane
framework of FR900482. Synthetic investigations revealed that the reaction is highly dependent upon the electronics of the aromatic ring. This
approach enabled the economical introduction of a [13C] label to study the biosynthesis of these structurally and biogenetically related natural
products. Epimerization of the initially formed
â-hydroxy ketone may enable access to mitomycin C or FR900482 biosynthetic congeners.
FR900482 (2) and congeners FR66979 (3), FK973 (4), and
FK317 (5) have enormous potential as anticancer agents
(Figure 1).1 These new prospective drugs are cytotoxic to
tumors but do not appear to exhibit the deleterious side
effects characteristic of the structurally related drug mito-
mycin C (MMC, 1).2 For example, myelosuppression and
hemolytic uremic syndrome have plagued the broad clinical
utility of MMC since 1974.3 The allure of less toxic and
more active chemotherapeutic agents has spawned numerous
total and formal syntheses of FR900482 and its congeners.4
† Colorado State University.
‡ University of Colorado Cancer Center.
(1) (a) Boger, D. L.; Wolkenberg, S. E. Chem. ReV. 2002, 102, 2477.
(b) Rajski, S. R.; Williams, R. M. Chem. ReV. 1998, 98, 2723.
(2) (a) Nelson, S. M.; Ferguson, L. R.; Denny, W. A. Cell & Chromosome
2004, 3:2. (b) Beckerbauer, L.; Tepe, J.; Eastman, R. A.; Mixter, P. F.;
Williams, R. M.; Reeves, R. Chem. Biol. 2002, 9, 427. (c) Beckerbauer,
L.; Tepe, J.; Cullison, J.; Reeves, R.; Williams, R. M. Chem. Biol. 2000, 7,
805.
Figure 1. Structures of mitomycin C, FR900482, and congeners.
In particular, we recently described a stereoselective, con-
vergent total synthesis of FR900482 (2)5 as well as an
improved synthesis of the benzazocane core of both FR900482
(3) Bradner, W. T. Cancer Treat. ReV. 2001, 27, 35.
10.1021/ol701960v CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/30/2007

and mitomycin C.4 Although our 33-step asymmetric route
is among the most concise syntheses of FR900482 (2) extant,
our interest in exploring the biogenesis of 1 and 2 has
mandated that we improve the unselective hydroxymethy-
lation aldol condensation reaction (dr ≈ 1:1).5
treatment of benzazocane 6 with trimethylsilyl triflate pro-
vided the silyl enol ether which was used without purification
in the hydroxymethylation step. Exposing the enoxysilane
to a catalytic amount of ytterbium(III) triflate and 5 equiv
of formaldehyde over 48 h provided alcohol 7 in 70% yield
as a 84:16 ratio of diastereomers. Scandium(III) triflate was
a superior catalyst and furnished the alcohol 7 in 82% yield
(75% over two steps) as a 91:9 ratio of diastereomers in only
3 h (Scheme 1). The major diastereomer in the aldol reaction
was determined to be the 7S-stereoisomer by X-ray crystal-
lographic analysis of a derivative, diol 8. This derivative was
prepared by stereoselective carbonyl reduction and removal
of the N-nosyl residue of the initial hydroxymethylation
product, alcohol 7.12
Throughout the course of our studies toward the synthesis
of putative biosynthetic intermediates of both FR900482 and
the mitomycins, it became necessary to investigate the
hydroxymethylation of substrates such as 6 (Scheme 1).6
Scheme 1. Hydroxymethylation of Benzazocane 6
Having developed an efficient method for the hydroxym-
ethylation of benzazocane 6, we were interested in exploring
the scope and generality of this protocol with more substrates.
Specifically, we were interested to see the effect, if any,
different protecting groups on the benzazocane nitrogen
might have on the selectivity and general outcome of the
aldol reaction. Consequently, N-alloc benzazocane 10a was
prepared from compound 94 (Scheme 2). Treatment of the
Scheme 2. Hydroxymethylation of Benzazocanes 10a-c
Hydroxymethylation of benzazocane intermediates en route
to FR900482 under basic conditions often resulted in
undesired elimination of the initially formed hydroxymethy-
lation product. In conjunction with their synthetic studies,
Rapoport7 and Danishefsky8 demonstrated that epoxidation
and reductive ring opening of the exo-methylene in their
respective eight- or six-membered ring substrates afforded
the requisite hydroxymethyl compound indirectly. In a recent
full paper describing his total synthesis of FR900482 (2),
Fukuyama reported a one-step, stereoselective, base-catalyzed
hydroxymethylation requiring 115 equiv of aqueous form-
aldehyde.9 Such a large molar excess is impractical in the
context of the preparation of putative biosynthetic intermedi-
ates where an expensive isotopically labeled source of
formaldehyde would be employed.10
With benzazocane 6 in hand, we explored alternate
hydroxymethylation conditions. We were especially intrigued
by the lanthanide triflate-catalyzed Mukaiyama aldol reaction
of enoxysilanes developed by Kobayashi.11 Accordingly,
(4) Ducept, P.; Gubler, D. A.; Williams, R. M. Heterocycles 2006, 67,
597 and references cited therein.
(5) (a) Judd, T. C.; Williams, R. M. J. Org. Chem. 2004, 69, 2825. (b)
Judd, T. C.; Williams, R. M. Angew. Chem., Int. Ed. 2002, 41, 4683.
(6) Prepared in two steps (TASF-mediated desilylation, Dess-Martin
oxidation) from the corresponding silyl ether 12a reported in ref 4.
(7) Paleo, M. R.; Aurrecoechea, N.; Jung, K.-Y.; Rapoport, H. J. Org.
Chem. 2003, 68, 130.
(8) The benzylic, exocyclic olefin in Danishefsky’s synthesis of FR900482
was the product of a Heck cyclization: Schkeryantz, J. M.; Danishefsky,
S. J. J. Am. Chem. Soc. 1995, 117, 4722.
N-alloc benzazocane 10a to identical hydroxymethylation
conditions described earlier to prepare compound 7 provided
the 7S-stereoisomer of alcohol 11 in 71% yield over two
steps with 94:6 dr. We also attempted the same aldol reaction
of 10a with 5 equiv of aqueous 13C-labeled formaldehyde
to furnish labeled alcohol 13C-11 in slightly lower yield (45%
for two steps, 78% brsm, unoptimized). Somewhat surpris-
ingly, treatment of N-pMB benzazocane 10b5 to the same
(9) Suzuki, M.; Kambe, M.; Tokuyama, H.; Fukuyama, T. J. Org. Chem.
2004, 69, 2831.
(10) For example, 13CH2O solution, 20 wt % in H2O, 99% 13C, CAS
No. 3228-27-1, Aldrich Catalog No. 489417, costs US$266.00/gram.
(11) (a) Kobayashi, S.; Hachiya, I. J. Org Chem. 1994, 59, 3590. (b)
Ishikawa, S.; Hamada, T.; Manabe, K.; Kobayashi, S. J. Am. Chem. Soc.
2004, 126, 12236.
(12) X-ray data for compound 8 are included as Supporting Information.
Org. Lett., Vol. 9, No. 26, 2007
5342

conditions did not provide any of the desired alcohol. Even
more startling was that N-Nvoc (Nvoc ) 6-nitroveratryloxy-
carbonyl or 3,4-dimethoxy-6-nitrobenzyloxycarbonyl) ben-
zazocane 10c13 did not undergo hydroxymethylation under
these conditions. Attempted hydroxymethylation of 10b and
10c was apparently unsuccessful since, in each case, the
requisite enoxysilane intermediate could not be formed under
a variety of conditions.
Scheme 4. Electronic Effects on Hydroxymethylation
With these interesting results in hand for benzazocanes
constituted with the FR900482 framework, we were intrigued
whether this methodology could be useful in our studies
toward the asymmetric total synthesis of the mitomycins and
their corresponding biosynthetic precursors. As shown in
Scheme 3, employing identical hydroxymethylation condi-
Scheme 3. Failed Hydroxymethylations of Benzazocane 12
examples shown in Scheme 4, as well as our own, we may
conclude that the more electron-rich the substrate, the more
prone it is toward elimination. Curiously, formation of an
enoxysilane intermediate from an electron-rich arene appears
to be considerably more difficult for application in the
scandium(III) triflate-mediated hydroxymethylation reaction
which we describe.
One powerful and unanticipated consequence of the Lewis
acid catalyzed Mukaiyama aldol approach is that it may be
used for the construction of either the FR900482 or the MMC
scaffold. Because the hydroxymethylation reaction is ste-
reoselective and kinetically controlled, the initially formed
7S-stereoisomer of compound 11 matches the C-9 stereo-
chemistry of MMC (1). On the other hand, equilibration of
compound 11 to the thermodynamically favored 7R-isomer
16 under carefully controlled, base-catalyzed conditions
should allow access to FR900482, potential late-stage
biosynthetic intermediates and their congeners (Scheme 5).
tions as before failed to provide the desired alcohol from
benzazocane 12.14 In tandem with unsuccessful results
observed for FR900482-based benzazocanes 10b and 10c,
our lack of success in forming the enoxysilane intermediate
likely hindered hydroxymethylation of these substrates.
Alternatively, attempts to engender enoxysilane formation
under basic conditions (LHMDS, Me3SiCl) also failed.
Carbamates other than N-alloc (N-Boc and methyl) were
prepared but also failed to undergo hydroxymethylation.
Curiously, attempted hydroxymethylation of 12 using condi-
tions developed by Fukuyama,9 as well as other conditions,
only afforded enone 14 (Scheme 3).
Scheme 5. Attempts to Epimerize Hydroxymethylation Products
From the hydroxymethylation results for both FR900482-
and mitomycin-based benzazocanes, we surmise that the
electronics of the substrate play a crucial role in the success
of this reaction. This observation is not without precedent
for this family of molecules.
Illustrated in Scheme 4 are hydroxymethylation conditions
used by Fukuyama9 and Rapoport7 in their total syntheses
of FR900482, respectively. The major differences among
these substrates that may affect the hydroxymethylation
reaction are the substituents on the arene ring and the
protecting group on the benzazocane nitrogen. From the
(13) Williams, R. M.; Rollins, S. B.; Judd, T. C. Tetrahedron 2000, 56,
521.
(14) Prepared in two steps (TASF-mediated desilylation, Dess-Martin
oxidation) from the corresponding silyl ether 13b reported in ref 4.
Unfortunately, all attempts to epimerize N-nosylsulfonamide
7S-7 gave the undesired enone 15 resulting from elimination.
Org. Lett., Vol. 9, No. 26, 2007
5343

Successful epimerization of compound 11 (7S:7R, 91:9) to
7R-isomer 16 (7S:7R, 12:88), but not N-nosylsulfonamide
7, supports our assertion (vide infra) that electronics play a
significant role in the chemistry of the benzylic position in
these benzazocane architectures.
We attempted to develop a rationale to accommodate why
the 7S-configuration predominates in successful hydroxym-
ethylation reactions of FR900482-derived templates. Because
reactions of medium-ring olefins are known to proceed from
the periphery, the major, kinetic product of the hydroxym-
ethylation reaction results from addition to the lowest energy
conformation of the ring.15,16 The possible low-energy
conformations of the intermediates in these reactions were
determined and analyzed using computational methods
(Figure 2).17 Conformational analysis of the likely intermedi-
ate in these reactions revealed that electrophilic addition of
formaldehyde to the only available face of the electron-rich
olefin in the lowest energy conformer should afford the 7S-
isomer we observed. Furthermore, analysis of successful
hydroxymethylation reactions from our group5,13 and results
reported by Fukuyama9 suggests that electrophilic approach
may proceed via a late transition state.18 In particular, the
development of A1,3-strain19 between the incoming hy-
droxymethyl group and the aryl alkoxy group as the reaction
proceeds may alter the energy barrier for each conformer in
the reaction. This unfavorable steric interaction in the
transition state may explain differences between experimental
selectivities observed and predictions we can make on the
basis of computational analysis.
Figure 2. Comparative experimental and computational analysis
of intermediates in the hydroxymethylation reaction.
putative biosynthetic intermediates of FR900482 and the
mitomycins, as well as the asymmetric total synthesis of the
mitomycins, are currently under investigation in these
laboratories.
In summary, we report an efficient method for the
hydroxymethylation of benzazocanes en route to putative
synthetic and late-stage biosynthetic intermediates of
FR900482 and MMC. Electronics play a major role in this
reaction, as N-Nvoc and N-PMB benzazocanes of FR900482
fail to undergo hydroxymethylation. Efforts to prepare
Acknowledgment. Dedicated to the memory of Professor
Albert I. Meyers. This work was supported by the National
Institutes of Health (CA51875). We also acknowledge a
Graduate Student Fellowship from Eli Lilly (to D.A.G.).
Mass spectra were obtained on instruments supported by the
NIH Shared Instrumentation Grant GM49631.
(15) Still, W. C.; Galynker, I. Tetrahedron 1981, 37, 3981.
(16) This statement is valid if we assume that the energy barrier of
reaction between both conformations of the olefin and the electrophile is
nearly identical, according to Curtin-Hammett/Winstein-Holness kinet-
ics: Seeman, J. I. J. Chem. Educ. 1986, 63, 42.
(17) The lowest energy conformations of the eight-membered ring
possessing a cis-olefin were determined by a Monte Carlo conformational
search. These structures were refined using AM1, then HF/6-31G*. Last,
the energies shown represent single-point HF/6-31G** calculations. Certain
structural simplifications were made to simplify our qualitative computa-
tional experiments. These simplifications reduce computational time but
do not, in our opinion, significantly alter the results. Further details and a
rationale for the computational methods used are included in the Supporting
Information.
Supporting Information Available: Complete experi-
mental procedures, characterization data, and spectral data
for new compounds, details of theoretical experiments, and
crystallographic data in CIF format. This material is available
free of charge via the Internet at http://pubs.acs.org.
(18) Hammond, G. S. J. Am. Chem. Soc. 1955, 77, 334.
(19) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841.
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