Asymmetric total synthesis of (-)-callystatin A employing the SAMP/RAMP hydrazone alkylation methodology

Article abstract of DOI:10.1021/ol0256116

(equation presented) The asymmetric total synthesis of (-)-callystatin A has been achieved. The key steps generating the stereogenic centers rely on the asymmetric α-alkylation of aldehydes or ketones exploiting the SAMP/RAMP hydrazone alkylation methodology, as well as an enzymatic enantioselective reduction of a 3,5-dioxocarboxylate. For the construction of the alkene moieties, highly selective Wittig or Horner-Wadsworth-Emmons reactions were employed.

Full text of DOI:10.1021/ol0256116

ORGANIC
LETTERS
2002
Vol. 4, No. 6
1023-1026
Asymmetric Total Synthesis of
(−)-Callystatin A Employing the
SAMP/RAMP Hydrazone Alkylation
Methodology
Jose L. Vicario, Andreas Job, Michael Wolberg,† Michael Mu1ller,† and
Dieter Enders*
Institut fu¨r Organische Chemie, Rheinisch-Westfa¨lische Technische Hochschule,
Professor Pirlet-Strasse 1, 52074 Aachen, Germany
enders@rwth-aachen.de
Received January 24, 2002
ABSTRACT
The asymmetric total synthesis of (−)-callystatin A has been achieved. The key steps generating the stereogenic centers rely on the asymmetric
r-alkylation of aldehydes or ketones exploiting the SAMP/RAMP hydrazone alkylation methodology, as well as an enzymatic enantioselective
reduction of a 3,5-dioxocarboxylate. For the construction of the alkene moieties, highly selective Wittig or Horner−Wadsworth−Emmons reactions
were employed.
Callystatin A is a polyketide marine natural product isolated
by Kobayashi et al. from the sponge Callyspongia truncata
that shows remarkably high cytotoxic activity (IC50 ) 0.01
ng/mL against KB tumor cells).1 Shortly thereafter, the
Kobayashi group confirmed the absolute configuration of this
product via partial2 and total synthesis3 and also reported
the preparation of several structural analogues, which led to
further insight on structure-activity relationships.4 Subse-
quently, the total synthesis of (-)-callystatin A was reported
by Crimmins and King5 and most recently by the groups of
Smith,6 Kalesse,7 and Marshall.8
The limited quantities of (-)-callystatin A available from
natural sources, together with the possibility of preparing
analogues with improved biological activities, show the
imperative need for total synthesis. In this context, and as
an opportunity to demonstrate the scope and efficiency of
our SAMP/RAMP hydrazone alkylation methodology9 to-
(5) Crimmins, M. T.; King, B. W. J. Am. Chem. Soc. 1998, 120, 9084-
9085.
(6) Smith, A. B., III; Brandt, B. M. Org. Lett. 2001, 3, 1685-1688.
(7) Kalesse, M.; Quitschalle, M.; Khandavalli, C. P.; Saeed, A. Org. Lett.
2001, 3, 3107-3109.
† Present address: Institut fu¨r Biotechnologie 2, Forschungszentrum
Ju¨lich GmbH, 52425 Ju¨lich, Germany.
(1) Kobayashi, M.; Higuchi, K.; Murakami, N.; Tajima, H.; Aoki, S.
Tetrahedron Lett. 1997, 38, 2723-2728.
(2) Murakami, N.; Wang, W.; Aoki, M.; Tsutsui, Y.; Higuchi, K.; Aoki,
S.; Kobayashi, M. Tetrahedron Lett. 1997, 38, 5533-5536.
(3) Murakami, N.; Wang, W.; Aoki, M.; Tsutsui, Y.; Sugimoto, M.;
Kobayashi, M. Tetrahedron Lett. 1998, 39, 2349-2352.
(4) Murakami, N.; Sugimoto, M.; Nakajima, T.; Kawanishi, M.; Tsutsui,
Y.; Kobayashi, M. Bioorg. Med. Chem. 2000, 8, 2651-2661.
(8) Marshall, J. A.; Bourbeau, M. P. J. Org. Chem. 2002, ASAP article.
(9) (a) Enders, D. In Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic Press: Orlando, 1984; Vol. 3, pp 275-339. (b) Enders, D.; Klatt,
M. In Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A.,
Ed.; Wiley: Chichester, 1995; Vol. 1, pp 178-182. (c) Job, A.; Janeck, C.
F.; Bettray, W.; Peters, R.; Enders, D. Tetrahedron 2002, in press.
10.1021/ol0256116 CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/16/2002

Scheme 1
Scheme 2
enantioselectivity, affording the hydroxyketoester 5, which
was easily converted into chlorinated δ-lactone 9 (94% ee
by HPLC) as described in Scheme 2. DIBAL-H reduction
of 9 and subsequent acetalization provided chloroacetal 10,
which upon chloroacetoxy substitution reaction with tet-
rabutylamonium acetate (TBAA) followed by hydrolysis of
the ester moiety afforded hydroxyacetal 11 in good yield.
The key synthetic intermediate 2 was obtained after treatment
of 11 under standard Swern oxidation conditions.
Next we proceeded to the synthesis of the synthetic
intermediate 3, which started with the asymmetric R-alkyl-
ation of aldehyde 12 via its corresponding SAMP hydrazone
13 (Scheme 3). Lithiation of 13 with LDA in THF at 0 °C
followed by alkylation with iodomethane at -100 °C
gether with an enzymatic enantioselective reduction devel-
oped recently,10 we resolved to engage in the task of pursuing
its total synthesis.11
Our retrosynthetic plan is shown in Scheme 1 and includes
disconnections of the C6-C7 and C12-C13 double bonds,
which can be built up by means of a highly E-selective Wittig
olefination12 between allyltributylphosphorus ylide derived
from bromide 3 and aldehyde 2 and between ylide derived
from 4 with the aldehyde obtained by Swern oxidation of
the hydroxyl group present in 3, respectively. Aldehyde 2
should be accessible from ketoester 5, which can be prepared
by enantioselective reduction of a 6-chloro-3,5-dioxohex-
anoate. With respect to bromide 3, it can be obtained by
selective olefination of functionalized aldehyde 6, which is
a suitable compound to be prepared by asymmetric R-alkyl-
ation of the corresponding (S)-1-amino-2-methoxymethyl-
pyrrolidine (SAMP) hydrazone. Finally, stereopentad 4 can
be synthesized by means of a syn-selective aldol reaction
between the enolate derived from 7 and aldehyde 8, both
also suitable to be obtained as single enantiomers by SAMP/
RAMP hydrazone alkylation procedures.
Scheme 3
For the synthesis of aldehyde 2 (Scheme 2) we exploited
the already published enantioselective enzymatic reduction
of 3,5-dioxocarboxylates catalyzed by baker’s yeast.10b
Therefore, reduction of tert-butyl 6-chloro-3,5-dioxohex-
anoate proceeded with virtually full regiocontrol and high
(10) (a) Wolberg, M.; Hummel, W.; Wandrey, C.; Mu¨ller, M. Angew.
Chem., Int. Ed. Engl. 2000, 39, 4306-4308. (b) Wolberg, M.; Hummel,
W.; Mu¨ller, M. Chem. Eur. J. 2001, 7, 4562-4571. (c) Job, A.; Wolberg,
M.; Mu¨ller, M.; Enders, D. Synlett 2001, 1796-1798.
(11) Job, A. Dissertation, RWTH Aachen, 1998-2001.
(12) Tamura, R.; Saegusa, K.; Kakihana, M.; Oda, D. J. Org. Chem.
1988, 53, 2723-2728.
1024
Org. Lett., Vol. 4, No. 6, 2002

Scheme 4
Scheme 5
afforded the R-alkylated hydrazone in >95% de as indicated
by 13C NMR analysis of the crude reaction mixture. Ozo-
nolysis of this alkylated hydrazone cleanly yielded aldehyde
6. For the selective installation of the double bond in the
R,â-unsaturated ester 14, a Horner-Wadsworth-Emmons
procedure was employed using different modified phospho-
nate reagents. Still-Gennari13 coupling with phosphonate
15a yielded the desired product with moderate diastereose-
lectivity (Z/E ratio of 8:1);5 however, it was greatly improved
(34:1) by changing to the modified reagent 15b14 in both
cases with comparable yields. Subsequent DIBAL-H reduc-
tion of the ester moiety followed by bromination with CBr4/
PPh3 in acetonitrile provided the allylic bromide 3. The ee
of the final compound was checked at the allylic alcohol
stage (after DIBAL-H reduction of 14) and was found to be
>98% by GC analysis.
standard ozonolysis procedure. The asymmetric synthesis of
aldehyde 8 was performed in an analogous way by alkylation
of butanal-RAMP hydrazone 16 with iodomethane. Subse-
quent Sn(II)-mediated mismatched aldol reaction16 between
7 and 8 proceeded smoothly to provide hydroxyketone 18
in 87% yield and excellent diastereoselectivity (Scheme 4).
After protection of the hydroxyl moiety as its TBS ether,
removal of the benzyl group by hydrogenolysis, and DIBAL-H
diastereoselective reduction of the obtained â-hydroxyketone,
it was possible to obtain compound 19 as a stereodefined
single isomer after column chromatography. Swern oxidation
of 19 followed by Wittig olefination with Ph3PdC(CH3)CO2-
Et furnished R,â-unsaturated ester 20 in good yield and in a
fully selective way favoring the desired E isomer. Subsequent
DIBAL-H reduction and bromination with CBr4/PPh3 in the
presence of 2,6-lutidine afforded the target stereopentad 4.
In this case, the presence of a base such as 2,6-lutidine in
the bromination reaction was necessary in order to avoid
deprotection of the TBS ether.
For the synthesis of the stereopentad 4 (Scheme 4)15 we
proceeded first with the asymmetric alkylation of 3-pen-
tanone via its (R)-1-amino-2-methoxymethylpyrrolidine
(RAMP) hydrazone derivative 17 with benzyloxymethyl
chloride (BOMCl), yielding ketone 7 (96% ee by GC
analysis) after clean removal of the chiral auxiliary by a
Finally, we proceeded to the assembly of the obtained
synthetic intermediates in order to build up the skeleton of
(-)-callystatin A (Scheme 5). First, the allylic bromide 3
was converted into the tributylphosphonium salt 21, and
subsequently a Wittig reaction was performed by reacting it
with aldehyde 2 in the presence of KOtBu to afford the triene
(13) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405-4408.
(14) Ando, K. J. Org. Chem. 1997, 62, 1934-1939.
(15) Other published syntheses of the C13-C22 fragment of callystatin
A: (a) Marshall, J. A.; Fitzgerald, R. N. J. Org. Chem. 1999, 64, 4477-
4481. (b) Dias, L. C.; Meira, P. R. R. Tetrahedron Lett. 2002, 43, 185-
187.
Org. Lett., Vol. 4, No. 6, 2002
1025

22 in good yield and as a single diastereoisomer. Next,
deprotection of the alcohol moiety with TBAF in THF,
followed by Swern oxidation of the primary alcohol,
furnished cleanly aldehyde 23, which was then coupled with
allylic bromide 4 using again a Wittig reaction. However,
in this case the use of KOtBu as the base that promotes the
formation of the phosphorus ylide did not afford the
olefination product and other bases had to be tested. In this
context, the use of LiCH2S(O)CH3 was found to give the
best results concerning both yield and diastereoselectivity
leading to pentaene 24, as a single E isomer. Afterward, PCC/
HOAc treatment of 24 proceeded with oxidation of the free
alcohol functionality and concomitant hydrolysis/oxidation
of the acetal moiety. The asymmetric synthesis of (-)-
callystatin A was completed with the deprotection of the TBS
ether with HF‚pyridine in THF.
Consequently, this total synthesis can be favorably compared
with other published routes3,5-8 and is efficient enough to
allow the preparation of other modified analogues.
Acknowledgment. This work has been generously sup-
ported by the Deutsche Forschungsgemeinschaft (Sonder-
forschungbereich 380) and the Fonds der Chemischen
Industrie. We thank Degussa AG, BASF AG, Bayer AG,
and Aventis for the donation of chemicals. J.L.V. thanks the
Basque Government (programas de perfeccionamiento y
movilidad de personal investigador de la UPV/EHU) for
financial support.
Supporting Information Available: Spectroscopic and
analytical data for key compounds 6-8, 14, 18, 22, 24, and
(-)-callystatin A and experimental procedures. This material
is available free of charge via the Internet at http://pubs.acs.org.
In summary, a highly efficient asymmetric total synthesis
of (-)-callystatin A has been accomplished. A very important
feature of this synthesis is the creation of the stereogenic
centers in the first stages by using the SAMP/RAMP
hydrazone alkylation protocol together with an enantiose-
lective enzymatic reduction. In this context it should be noted
that this constitutes the first non-ex-chiral pool synthesis of
this cytotoxic polyketide. It is also noteworthy that the
formation of C-C double bonds during the synthesis has
been performed with a very high degree of diastereoselection.
OL0256116
(16) (a) Paterson, I.; Tillyer, R. D. Tetrahedron Lett. 1992, 33, 4233-
4236. (b) Paterson, I.; Norcross, R. D.; Ward, R. A.; Romea, P.; Lister, M.
A. J. Am. Chem. Soc. 1994, 116, 11287-11314. For other Sn(II)-mediated
aldol reactions, see: (c) Mukaiyama, T.; Iwasawa, N.; Stevens, R. W.; Haga,
T. Tetrahedron 1984, 40, 1381-1390. (d) Nagao, Y.; Hagiwara, Y.;
Kumagai, T.; Ochiai, M.; Inoue, T.; Hashimoto, K.; Fujita, E. J. Org. Chem.
1986, 51, 2391-2396. (e) Evans, D. A.; DiMare, M. J. Am. Chem. Soc.
1986, 108, 2476-2478. (f) Evans, D. A.; Weber, A. E. J. Am. Chem. Soc.
1986, 108, 6757-6761. (g) Evans, D. A.; Gage, J. R. J. Org. Chem. 1992,
57, 1961-1963.
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