Synthesis of a C4-epi-C1-C6 fragment of FR901464 using a novel bromolactolization

Article abstract of DOI:10.1021/ol049160w

(Chemical Equation Presented) A synthesis of a C4-epi-C1-C6 fragment of the antitumor agent FR901464 is reported. The advanced intermediate prepared in this study contains two of the three correct stereocenters found in the C1-C6 moiety of FR901464. For the preparation of this intermediate, we have developed a highly diastereoselective bromolactolization of a δ-alkenyl ketone.

Full text of DOI:10.1021/ol049160w

ORGANIC
LETTERS
2004
Vol. 6, No. 21
3655-3658
Synthesis of a C4-epi-C1−C6 Fragment
of FR901464 Using a Novel
Bromolactolization
Brian J. Albert and Kazunori Koide*
Department of Chemistry, UniVersity of Pittsburgh, 219 Parkman AVenue,
Pittsburgh, PennsylVania 15260
koide@pitt.edu
Received May 8, 2004 (Revised Manuscript Received August 18, 2004)
ABSTRACT
A synthesis of a C4-epi-C1
contains two of the three correct stereocenters found in the C1
developed a highly diastereoselective bromolactolization of a -alkenyl ketone.
−C6 fragment of the antitumor agent FR901464 is reported. The advanced intermediate prepared in this study
−C6 moiety of FR901464. For the preparation of this intermediate, we have
δ
Discoveries of antitumor agents with novel mechanisms
continue to be important in oncology and medicine.1 In the
quest for an anticancer agent with new modes of actions,
scientists at Fujisawa Pharmaceutical Co. isolated FR901464
(Figure 1) from the culture broth of Pseudomonas sp. No.
for biological studies, it is essential to develop a con-
vergent synthetic strategy for this natural product. In this
paper, we report the preparation of a highly functionalized
C4-epi-C1-C6 fragment of FR901464.4
Chemical syntheses of FR901464 have been accomplished
by two groups. The first total synthesis of FR901464 by the
Jacobsen group5 involves the application of a powerful
enantioselective hetero-Diels-Alder reaction.6 The second
total synthesis by the Kitahara group uses the chiral pool
for starting materials.7 Both groups further functionalized
the B-ring after the union of advanced intermediates, and
installation of the spiroepoxide in the late stages of the
syntheses proved problematic. To prepare various analogues
of FR901464 for biological studies, a convergent synthetic
approach using highly functionalized coupling intermediates
would be desirable.
Figure 1. Structure of FR901464.
2663.2,3 FR901464 increases the transcriptional activity of a
reporter gene driven by the SV40 promoter at 10 nM
concentration.3 This compound also exhibits cytotoxicity
against various human solid tumor cell lines at low nano-
molar concentrations.3 Despite these unique biological activi-
ties of FR901464, the mode of action of FR901464 is
poorly understood. To prepare various FR901464 analogues
(2) (a) Nakajima, H.; Sato, B.; Fujita, T.; Takase, S.; Terano, H.; Okuhara,
M. J. Antibiot. 1996, 49, 1196-1203. (b) Nakajima, H.; Takase, S.; Terano,
H.; Tanaka, H. J. Antibiot. 1997, 50, 96-99.
(3) Nakajima, H.; Hori, Y.; Terano, H.; Okuhara, M.; Manda, T.;
Matsumoto, S.; Shimomura, K. J. Antibiot. 1996, 49, 1204-1211.
(4) The numbering in this paper follows ref 2b.
(5) (a) Thompson, C. F.; Jamison, T. F.; Jacobsen, E. N. J. Am. Chem.
Soc. 2000, 122, 10482-10483. (b) Thompson, C. F.; Jamison, T. F.;
Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 9974-9983.
(6) Dossetter, A. G.; Jamison, T. F.; Jacobsen, E. N. Angew. Chem., Int.
Ed. 1999, 38, 2398-2400.
(7) Horigome, M.; Motoyoshi, H.; Watanabe, H.; Kitahara, T. Tetrahe-
dron Lett. 2001, 42, 8207-8210.
(1) (a) Ferrante, K.; Winograd, B.; Canetta, R. Cancer Chemother.
Pharmacol. 1999, 43, S61-S68. Gibbs, J. B. Science 2000, 287, 1969-
1973. (b) Darnell, J. E., Jr. Nat. ReV. Cancer 2002, 2, 740-749. (c) Pompetti,
F.; Pilla, D.; Giancola, R. BioEssays 2003, 25, 104-107.
10.1021/ol049160w CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/18/2004

install the olefin by the vinylation of epoxyaldehyde 4 and
the ketone by the oxidation of the olefin in 4. We expected
this epoxyaldehyde to be prepared by the coupling of
propargyl alcohol and methallyl bromide promoted by zinc
dust followed by sequential oxidation steps (vide infra).
Scheme 3 illustrates the preparation of alkenyl ketone 3
and its diastereomer 13. The known allyl alcohol 5 was
Scheme 1. Lactol Formations
Scheme 3. Preparation of Alkenyl ketones 13 and 3a
As part of our efforts toward a convergent synthesis of
FR901464, we targeted the highly functionalized C1-C6
fragment of FR901464, 1, which contains a hemiketal
functionality at the C1-position and the spiroepoxide (Scheme
2). Scheme 1 illustrates two concepts of lactol formation. It
Scheme 2. Retrosynthetic Analysis
prepared from propargyl alcohol and methallyl bromide in
the presence of zinc dust in 93% yield according to the
literature.10 The regio- and enantioselective Sharpless epox-
idation of this allyl alcohol afforded the desired epoxy
alcohol 6 in 90% yield and greater than 95% ee.11 Treatment
of this epoxy alcohol with Dess-Martin periodinane afforded
aldehyde 4 in 81% yield.12 With this aldehyde in hand, we
examined various vinylation conditions to produce allylic
alcohols 7 and 8. Addition of vinylmagnesium bromide to
aldehyde 4 in THF resulted in the formation of alcohols 7
and 8 in 23% and 28% yield, respectively, together with the
formation of the primary alcohol 5 in 30% yield. A modified
procedure, in which 2 equiv of ZnCl2 and 4 equiv of
vinylmagnesium bromide were premixed, furnished alcohols
7 and 8 in 15% and 56%, respectively. At this stage, we
separated these diastereomers by standard column chroma-
tography
is well-documented that a six-membered hemiketal can be
formed from the corresponding δ-hydroxyketone as shown
in eq (a) (A f B). In contrast to this widely used approach,
the conceptually different tactic shown in eq (b) has never
been explored. Similar intramolecular cyclization tactics
utilizing aromatic aldehydes/ketones onto alkynes8 and amide
carbonyls onto alkenes9 exist but are conceptually different
from our proposed approach. In the tactic shown in eq (b),
the ketone functionality of δ-alkenyl ketone C is used as a
nucleophile rather than an electrophile: The treatment of C
with N-bromosuccinimide (NBS) provides π-complex D in
situ, which then reacts with the carbonyl oxygen atom, and
subsequent nucleophilic attack of a water molecule furnishes
bromolactol E.
Scheme 2 shows our retrosynthetic analysis of methyl
glycoside 2, a C-4 epimer of 1, based on this alternative
approach. According to eq (b), if the olefin of 3 reacts with
NBS to form the corresponding π-complex, the carbonyl
oxygen atom would react with the complex intramolecularly
to furnish compound 2 in the presence of methanol. To
prepare alkenyl ketone 3 for this cyclization, we planned to
Both alcohols 7 and 8 were protected as the corresponding
triethylsilyl (TES) ethers in quantitative yields upon treatment
with TESCl and imidazole. Subsequently, each of the
resulting silyl ethers 9 and 10 were treated with catalytic
OsO4 and stoichiometric 4-methylmorpholine N-oxide (NMO)
(8) Barluenga, J.; Vazquez-Villa, H.; Ballesteros, A.; Gonzalez, J. M. J.
Am. Chem. Soc. 2003, 125, 9028-9029.
(9) Blot, V.; Reboul, V.; Metzner, P. J. Org. Chem. 2004, 69, 1196-
1201.
(10) Frangin, Y.; Gaudemar, M. J. Organomet. Chem. 1977, 142, 9-22.
(11) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; VCH: Weinheim, 1993; pp 103-158.
(12) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
3656
Org. Lett., Vol. 6, No. 21, 2004

to afford the putative diols 11 and 12 as a mixture of
diastereomers in 58% and 60% total yield, respectively.
Oxidative cleavages of these diols with NaIO4 generated
alkenyl ketones 13 and 3 in quantitative yields. Thus, each
of the key alkenyl ketones 13 and 3 was prepared in seven
steps from commercially available propargyl alcohol and
methallyl bromide.
These results indicate that the NBS-promoted bromolac-
tolization of δ-alkenyl ketone 13 proceeds by the following
manner (Scheme 5). When a bromide ion approaches
Scheme 5. Bromolactolization Pathways That Lead to 14 and
16
Now the stage was set to test the chemistry shown in eq
(b). Gratifyingly, upon treatment of alkenyl ketone 13 with
NBS in THF/H2O, the expected cyclization proceeded to
furnish lactol 14 in 75% yield (Scheme 4). Unambiguous
Scheme 4. Bromolactolizations of 13 and 3a
compound 13, π-complex 17 is formed. This π-complex
either establishes an equilibrium with bromonium ion 1813
or reacts with the carbonyl oxygen atom to form oxocarbe-
nium ion 19. While the formation of bromonium ion 18 is
possible, it has been postulated that related intramolecular
haloetherifications proceed via a transition that resembles a
reactant-like π-complex.14 Therefore, we speculate that the
bromolactolization proceeds via 17, which reacts with the
carbonyl oxygen atom to generate the oxocarbenium ion 19.
This oxocarbenium ion intermediate subsequently reacts with
ROH (R ) H or CH3) to form hemiketal 14 (R ) H) or
ketal 16 (R ) CH3). As the results shown in Scheme 4
indicate, the formation of ether 20 can be ruled out.
structural determination was accomplished after this lactol
was converted to the corresponding methyl glycoside deriva-
tive 16 under standard conditions (cat. PPTS, MeOH) in 40%
yield. Although highly diastereoselective, the NBS-promoted
lactolization generated only the C5-epimer, 14, of the desired
compound 1. Therefore, we turned our attention to alkenyl
ketone 3 to generate the desired configuration at the C5-
position. Under similar conditions as above (NBS, acetone/
H2O), alkenyl ketone 3 was converted to lactol 15 as a sole
diastereomer in 95% yield. Compound 15 contains two of
the three correct stereocenters of the desired fragment 1.
Because compound 15 exists as a mixture of anomers, methyl
glycoside derivative 2 was prepared in 75% yield under the
standard conditions (cat. PPTS, MeOH). The unambiguous
structural characterization of 2 was accomplished by X-ray
crystallographic analysis (Supporting Information).
To account for the high cis-diastereoselectivity of the bro-
molactolization, we further analyzed the possible transition
states (Scheme 6). If a bromide ion approaches compound
Scheme 6. Plausible Transition States for Bromolactolization
(R ) TES)
From the conversions of 13 to 14 and 3 to 15, it was
unclear whether a bromide ion-activated olefin reacted with
the oxygen atom of the ketones (or their hemiketals) or a
water molecule in each transformation, followed by a
spontaneous cyclization. To elucidate the mechanism of the
NBS-promoted cyclizations of 13 and 3, we employed the
cyclizations of these ketones in the mixture of MeOH and
MeCN or THF. Although the isolated yields are moderate,
only 16 and 2 were isolated, and the NMR analysis of the
reaction mixtures did not identify any methyl ethers as a
result of nucleophilic attach of MeOH at the C5-positions.
We also found that these NBS-promoted cyclizations pro-
ceeded smoothly in THF, acetone, and MeCN, but sluggishly
in CH2Cl2.
13 from its R-face, the subsequent cyclization proceeds via
transition state 21 or 22. Transition state 21 appears to be
more favorable than 22 by a stereoelectronic effect: the
π
C5-C6- - -Br bond (- - -: partially formed bond) is electron
deficient, so an electron-withdrawing group destabilizes the
Org. Lett., Vol. 6, No. 21, 2004
3657

transition state. When the C4-O bond is nearly parallel to
the πC5-C6- - -Br bond as shown in 22, the orbital overlap
between the πC5-C6- - -Br bond and σ*C4-O destabilizes
transition state 22.15 In contrast, in transition state 21, the
C4-O bond is nearly orthogonal to the πC5-C6- - -Br bond,
minimizing the destabilization of this transition state by
σ*C4-O. For the same stereoelectronic reason, if a bromide
ion approaches from the â-face of 13, then transition state
23 is more favorable than 24. Thus, transition states 21 and
23 are preferred over 22 and 24 for this stereoelectronic
effect.
In summary, we have developed an NBS-promoted bro-
molactolization of δ-alkenyl ketones to form the correspond-
ing cyclic (hemi)ketals. This method provided the C4-epimer
and the C5-epimer of compound 1, and the reaction condi-
tions are found to be compatible with a TES ether and a
spiroepoxide and highly cis-selective in these cases. This
cyclization method should be applicable to the preparation
of various (hemi)ketals and acetals. To further understand
the origin of the high diastereoselectivity in the transforma-
tions of 13 to 14 and 3 to 15, we are currently investigating
the NBS-promoted cyclizations of related substrates.
Comparison between transition states 21 and 23 reveals
the observed preference for 23: The pseudo-1,3-diaxial
interaction between the epoxide methylene and the C6
methylene destabilizes 21. In contrast, no major steric
encumbrances are present in transition state 23. Therefore,
we postulate that 23 is stereoelectronically and sterically the
most favorable among the four-half-chair transition states
shown in Scheme 6. This preference for 23 accounts for the
formation of 16 from 13.
Acknowledgment. Financial supports were provided by
the American Chemical Society (PRF No. 38542-G1), the
American Cancer Society George Heckman Institutional
Research Grant, and the University of Pittsburgh. We thank
Dr. Fu-Tyan Lin for assistance in NMR experiments, Dr.
Kasi Somayajula for mass spectroscopy, and Dr. Steven Geib
for the X-ray crystallography.
1
Supporting Information Available: H NMR, 13C NMR,
(13) Brown, R. S.; Slebocka-Tilk, H.; Bennet, A. J.; Bellucci, G.;
Bianchini, R.; Ambrosetti, R. J. Am. Chem. Soc. 1990, 112, 6310-6316.
(14) Chamberlin, A. R.; Mulholland, J., R. L.; Kahn, S. D.; Hehre, W.
J. J. Am. Chem. Soc. 1987, 109, 672-677.
(15) Houk, K. N.; Moses, S. R.; Wu, Y.-D.; Rondan, N. G.; Ja¨ger, V.;
Schohe, R.; Fronczek, F. R. J. Am. Chem. Soc. 1984, 106, 3880-3882.
IR, HRMS, and X-ray analysis data for all new compounds
in PDF format. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL049160W
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