Total syntheses of amphidinolide H and G

Article abstract of DOI:10.1002/anie.200704024

(Chemical Equation Presented) Eureka! The first conquest of the exceptionally potent cytotoxic agent amphidinolide H, which exhibits activity in the picomolar range against human epidermoid cancer cells, was long overdue. The successful route critically h

Full text of DOI:10.1002/anie.200704024

Angewandte
Chemie
DOI: 10.1002/anie.200704024
Natural Product Synthesis
Total Syntheses of Amphidinolide H and G**
Alois Fürstner,* Laure C. Bouchez, Jacques-Alexis Funel, Vilnis Liepins, François-Hugues PorØe,
Ryan Gilmour, Florent Beaufils, Daniel Laurich, and Minoru Tamiya
Dinoflagellates of the genus Amphidinium are exceptionally
rich sources of bioactive secondary metabolites.[1] Generally
referred to as “amphidinolides”, the ensemble of complex
macrolides of mixed polyketide origin derived from these
microalgae has evoked considerable interest in the synthetic
and bio-organic chemistry communities.[2,3] The many suc-
cesses notwithstanding, some of the most potent members of
the series such as amphidinolide H (1)[4] and all of its close
relatives (2–4), remain unconquered, despite numerous
attempts.[5,6]
covalent bonds through opening of the epoxide ring.[7] Herein
we report the first total synthesis of this intricate macrolide
which arose only after a careful orchestration of the assembly
process and a scrupulous optimization of the protecting-group
regime.
For the sake of convergence, 1 was dissected into four
building blocks which were to be combined by esterification,
an aldol reaction, metal-catalyzed cross-coupling, and olefin
metathesis (Scheme 1). Although this strategy was a priori
Scheme 1. Retrosynthetic analysis of amphidinolide H (1).
flexible, it was by no means obvious in which order these
crucial steps should be executed. While related aldol pro-
cesses were successful in different model studies toward 1 and
4,[5,6] a late-stage Stille reaction for the formation of the s-cis-
1,3-diene subunit of 4 had previously met with failure.[6a] Since
inter-as well as intramolecular metathesis reactions of vinyl
epoxides are also surprisingly rare,[8] the planning for the final
assembly process had to evolve with time, on the basis of the
knowledge gathering underway.
These uncertainties meant it was imperative to develop
routes to the required building blocks that were not only
productive and scalable, but also modular, such that they
could be adapted to the specific needs of the target. To this
end, conversion of Roche ester 5 into enoate 6[9] followed by
reduction and Sharpless epoxidation[10] afforded 7 in high
yield and optical purity (93% de; Scheme 2). DIBAL-H in
toluene[11] cleanly opened the oxirane ring to give diol 8 by
selective delivery of the hydride to the carbon atom distal to
the alcohol (d.r. > 20:1); it was essential to quench the
reaction with tBuOH at ꢀ608C to avoid cleavage of the
primary TBS ether and hence secure good yields when
working on a large scale. Routine protecting-group intercon-
versions led to the trisilylated derivative 9, the terminal
OTES-group of which underwent a slow but effective Swern
oxidation to give multigram amounts of aldehyde 10.
The exceptional cytotoxicity of 1 against KB human
epidermoid carcinoma cells (IC50 value: 0.52 ngmLꢀ1) rivals
that of many renowned anticancer agents. Interestingly, 1
seems to target the actin cytoskeleton, to which it forms
[*] Prof. A. Fürstner, Dr. L. C. Bouchez, Dr. J.-A. Funel, Dr. V. Liepins,
Dr. F.-H. PorØe, Dr. R. Gilmour, Dr. F. Beaufils, D. Laurich,
Dr. M. Tamiya
Max-Planck-Institut für Kohlenforschung
45470 Mülheim an der Ruhr (Germany)
Fax: (+49)208-306-2994
E-mail: fuerstner@mpi-muelheim.mpg.de
[**] Generous financial support from the MPG, the Fonds der
Chemischen Industrie, the Swiss National Foundation (stipends to
L.C.B. and F.B), the Roche Foundation (stipend to L.C.B.), the
Swedish Research Council (stipend to V.L.), and the JSPS (stipend to
M.T.) is gratefully acknowledged. We thank K. Tücking, S. Schulthoff,
and S. Marcus for technical assistance, Dr. J. Ruiz-Caro for
exploratory studies, and our NMR spectroscopy and chromato-
graphy departments for excellent support. We are also grateful to Dr.
T. Yamamoto, Takasago, for a generous gift of enantiopure
citronellal.
This compound was used in a subsequent boron glycolate
aldol reaction controlled by the reliable Evans auxiliary[12] to
afford 12 with excellent syn selectivity (d.r. > 20:1). This
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Communications
by using the methodology pioneered by Reetz et al.
(Scheme 3).[16] Provided that the catalyst was freshly prepared
from [Rh(cod)2]BF4 and monodentate phosphite 19,[17] opti-
cally active 20 (98% ee) could be secured in batches of 25 g by
Scheme 3. a) [Rh(cod)2]BF4 (0.2 mol%), 19 (0.4 mol%), H2 (1 atm),
1,2-dichloroethane, 95% (98% ee); b) BH3·THF, THF, ꢀ108C!RT;
c) TBSCl, imidazole, DMF, 74% (over 2 steps); d) DIBAL-H, CH2Cl2,
ꢀ788C!ꢀ108C; e) TBDPSCl, imidazole, CH2Cl2, 87% (over 2 steps);
f) PPTS, EtOH, 508C, 75%; g) DMSO, (COCl)2, Et3N, CH2Cl2,
ꢀ788C!RT; h) 23, NaOMe, THF, 84% (over 2 steps); i) (1.) Me3Al,
Cp2ZrCl2, 1,2-dichloroethane; (2.) I2, THF, ꢀ208C, 71–95%; j) TBAF,
THF, 80%; k) DMP, NaHCO3, aq CH2Cl2, 08C!RT, 78%. cod=cy-
cloocta-l,5-diene, Cp=cyclopentadienyl, TBAF=tetra-n-butylammo-
nium fluoride, DMP=Dess–Martin periodinane.
Scheme 2. a) TBSCl, imidazole, DMF; b) DIBAL-H, CH2Cl2, ꢀ788C;
c) DMSO, (COCl)2, Et3N, CH2Cl2, ꢀ788C!RT; d) (iPr)2NEt, LiCl,
(EtO)2P(O)CH2COOEt, MeCN, 69% (over 4 steps); e) DIBAL-H,
CH2Cl2, ꢀ788C, 86%; f) (+)-DET, Ti(OiPr)4 cat., tBuOOH, MS (4 Š),
CH2Cl2, ꢀ208C, 68% (93% de); g) (1.) DIBAL-H, toluene, ꢀ408C;
(2.) tBuOH quench, ꢀ608C!RT, 78%; h) (1.) TBDPSCl, imidazole,
CH2Cl2, 97%; (2.) PPTS, EtOH, 558C; (3.) TESCl, imidazole, CH2Cl2,
85% (over 2 steps); i) DMSO, (COCl)2, (iPr)2NEt, CH2Cl2, ꢀ788C!RT,
82%; j) 11, Bu2BOTf, toluene, ꢀ508C, 82%; k) TBSOTf, 2,6-lutidine,
CH2Cl2, 08C; l) EtSH, nBuLi, THF, 08C, 61% (over 2 steps); m) CuI,
MeLi (2 equiv), Et2O, ꢀ788C!ꢀ108C, 89%; n) PPTS, EtOH, 56%;
o) 16, DCC, DMAP, CH2Cl2, 75%. Bn=benzyl, DCC=1,3-dicyclohex-
ylcarbodiimide, DET=diethyl tartrate, DIBAL-H=diisobutylaluminum
hydride, DMAP=4-dimethylaminopyridine, DMF=N,N-dimethylform-
amide, DMSO=dimethyl sulfoxide, MS=molecular sieves,
PMB=para-methoxybenzyl, PPTS=pyridinium para-toluenesulfonate,
TBDPS=tert-butyldiphenylsilyl, TBS=tert-butyldimethylsilyl, TES=tri-
ethylsilyl, Tf=triflate.
using very low catalyst loadings. Routine oxidation-state and
protecting-group management afforded aldehyde 22, which
was converted into alkyne 24 with the aid of the Ohira–
Bestmann reagent 23.[18] A subsequent zirconium-induced
carboalumination followed by an iodine quench readily
installed the required alkenyl iodide functionality.[6f,19] The
resulting product 25 was converted into the somewhat volatile
aldehyde 26 as a prelude to the coupling with fragment 17
through aldol chemistry.
The only missing building block C was prepared from (S)-
citronellal (27, > 99% ee) as shown in Scheme 4. Conversion
of the carbonyl group into an alkyne followed by chemo-
selective ozonolysis of the trisubstituted olefin afforded
aldehyde 28 which was transformed into its shorter homo-
logue 29 by selective ozonolysis of the corresponding silyl
enol ether; a subsequent Horner–Emmons reaction gave 30 in
respectable yield over the entire sequence, even though some
intermediates were highly volatile and therefore needed to be
handled with care. Reduction of the ester in 30 followed by
Sharpless epoxidation[10] allowed installation of the missing
oxirane to afford 31 with high stereochemical control
(98% de).
Next, we faced the problem of converting the alkyne
terminus of 31 into a suitable donor that was amenable to a
cross-coupling reaction with alkenyl iodides 25 or 26. Even
though the literature indicated that a Stille reaction[20] might
be problematic,[6a] we were confident of accomplishing such a
transformation by recourse to the powerful procedure
transformation has precedence in the studies of Chakraborty
and Suresh, and later Zhang and Carter,[5f,6p] who had
performed related reactions toward the synthesis of amphi-
dinolide H and B1, respectively. Compound 12 was silylated
with TBSOTf and 2,6-lutidine[13] and the resulting product 13
was then converted into thioester 14, which reacted with
Me2CuLi to give the methyl ketone 15 in high yield.[14]
Significantly, this building block exhibits a fully orthogonal
protecting-group pattern, which does not impose any restric-
tions on the final stages of the synthesis. However, the
ultimately successful route to 1 relied on the early installation
of the unsaturated ester, which was readily accomplished by
selective cleavage of the TES moiety with PPTS followed by
esterification of the released alcohol with acid 16[15] to give 17
as a fully functional surrogate of the “south-eastern” part of 1.
The route to building block D commenced with an
asymmetric hydrogenation of the itaconic acid monoester 18
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Angewandte
Chemie
Scheme 4. a) 23, NaOMe, THF; b) O3, CH2Cl2, ꢀ788C, then Me2S;
c) TBSOTf, Et3N, CH2Cl2, ꢀ208C; d) O3, CH2Cl2, ꢀ788C, then Me2S;
e) (EtO)2P(O)CH2COOEt, NaH, THF, 25% (over 5 steps, see text);
f) DIBAL-H, CH2Cl2, ꢀ788C, 69%; g) (+)-DET, Ti(OiPr)4 cat.,
tBuOOH, MS (4 Š), CH2Cl2, ꢀ208C, 72% (98% de); h) TBSCl, imida-
zole, CH2Cl2, 83%; i) Bu3SnSiMe3, [Pd(Ph3P)4] (2 mol%), DMF, sealed
tube, 79–85%; j) TBAF, DMSO, 808C, 91%.
recently developed in our laboratory in response to a similarly
challenging case.[21] To this end, tributylstannane 34 was
prepared in gram quantities by a regioselective, palladium-
catalyzed silylstannation of 32 with commercial
Bu3SnSiMe3,[22] followed by a concomitant cleavage of the
Scheme 5. a) [Pd(Ph3P)4](10 mol%), CuTC, Ph2PO2NBu4, DMF, 82%;
b) DMP, NaHCO3, CH2Cl2, 08C!RT; c) [Ph3PCH3]Br, Na[N(SiMe3)2],
THF, 08C, 65%; c) TBAF, THF, 87%; d) DMP, NaHCO3, aq CH2Cl2,
08C!RT; 75%; e) 17, LDA, THF, ꢀ788C, 52%; f) 38, (10 mol%);
C6H6, 73%. CuTC=copper thiophene-2-carboxylate, Cy=cyclohexyl,
LDA=lithium diisopropylamide, Mes=mesityl=2,4,6-trimethylphenyl.
ꢀ
ꢀ
C Si and O Si bonds in 33 with TBAF in DMSO at 808C.
With all building blocks in hand, the development of a
reliable assembly process became the next goal. First and
foremost, the potentially challenging Stille reaction of 34 and
the sterically compromised iodide 25 was tested, which gave
the desired diene 35 in good yield, provided that it was
performed with a combination of [Pd(PPh3)4], CuTC, and
Ph2PO2NBu4 in DMF (Scheme 5).[21] The reaction proceeded
at ambient temperature under these chloride-free conditions
thus minimizing the risk of thermal decomposition of the
sensitive diene product; other protocols essentially failed to
afford the desired compound.[23] Compound 35 was elabo-
rated into the fully functional “western” part of 1 by oxidation
of its epoxy alcohol using Dess–Martin periodinane[24] and a
Wittig olefination, followed by conversion of the terminal
TBDPS ether into the corresponding aldehyde 36. This
compound was then treated with the lithium enolate derived
from 17 to give aldol 37 in 52% yield (unoptimized). The
observation that 37 was produced as a single isomer is
ascribed to the strong 1,4-anti induction exerted by the
adjacent OPMB substituent.[25]
failure. We assume that an uncontrolled oxidation of the
diene occurs at a competitive rate on treatment with either
DDQ or ceric ammonium nitrate.[29,30] Acidic or reductive
conditions for cleavage of the PMB group were equally
inappropriate.
Cleavage of the PMB group of acyclic diene 37 also failed.
In an attempt to rectify this situation we replaced 17 by a
methyl ketone adorned with silyl only groups that could be
more readily removed (Scheme 6). Based on our previous
work on the total synthesis of amphidinolide Y, however, in
which a similar 1,4-anti-selective aldol reaction had played a
key role,[3b] we were apprehensive that this seemingly minor
modification might have a detrimental impact on the stereo-
chemical outcome. Alkoxy substituents at the a-position of a
methyl ketone donor guide the stereodetermining addition
process by chelation,[25] and a silyloxy moiety is hence unlikely
to provide the same rigorous bias. In fact, the LDA-mediated
reaction of the readily attainable ketone 40[31] with aldehyde
Even though only a few metathesis reactions of vinyl
epoxides had previously been reported,[8,26] exposure of 37 to
catalytic amounts of the Grubbs carbene complex 38[27] in
benzene at ambient temperature resulted in a remarkably
clean cyclization, with formation of the 26-membered cyclo-
alkene 39 in 73% yield as a single isomer; its E configuration
is evident from the large coupling constant of the olefinic
protons (3JH6,H7 = 18 Hz). Although at this stage we were
seemingly only two routine operations away from 1, insur-
mountable problems with the removal of the remaining
protecting groups were encountered. Whereas the cleavage of
the silyl ethers proceeded uneventfully with TASF in THF/
DMF,[28] it was the removal of the PMB group that met with
Scheme 6. a) LDA, THF, ꢀ788C, then 36, 50–60% (d.r. ca. 2:1).
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Communications
36 proceeded with poor selectivity (d.r. ca. 2:1). Since analysis
chloride-free conditions.[21] However, it was necessary to
increase the catalyst loading to ensure complete conversion of
these encumbered partners at ambient temperature. Yet, this
result is auspicious if interpreted in light of the completely
unsuccessful intramolecular Stille coupling at the exact same
site en route to amphidinolide B1 (4) reported in the liter-
ature.[6a]
The epoxy alcohol of 45 was then converted into vinyl
oxirane 46 which underwent a productive RCM reaction to
give 47 as the required E isomer only. The sensitivity of the
material meant, it was again imperative to perform this
macrocyclization at ambient temperature.[33] Finally, TASF[28]
was used to remove all four silyl protecting groups from the
polyol sector of 47 to afford amphidinolide H (1), the
analytical and spectroscopic properties of which were in
good accord with the published data.[4] Since 1 is known to
equilibrate by transesterification with amphidinolide G
(2),[1,4] a synthesis of this ring-expanded congener has also
been achieved. We found that this equilibration was best
performed under slightly acidic conditions (see the
Supporting Information).
of the Mosher ester showed that the major isomer had the
undesired R configuration and separation of the diastereo-
mers was tedious, it became clear that this revised fragment-
coupling strategy was to no avail.
The necessary compromise between the beneficial influ-
ence of the PMB ether on the aldol reaction and the need to
cleave this directing group prior to the installation of the 1,3-
diene moiety enforced a final strategic adjustment. To this
end, the Stille coupling was postponed until after the aldol
step and the elaboration of the proper protecting-group
regimen at the periphery (Scheme 7). Specifically, the lithium
enolate of 17 was treated with the iodine-containing aldehyde
26 to give 42 in good yield and selectivity (d.r. > 10:1).[32]
Masking the newly formed alcohol as the TBS ether allowed
the protecting group at O-21 to be transformed from a PMB
to a TES group. This critical interchange was followed by an
effective cross-coupling reaction of the highly functionalized
substrate 44 with stannane 34 under the previously optimized,
To summarize, we have developed the first total synthesis
of the exceptionally potent cytotoxic macrolide amphidino-
lide H.[34] This venture revealed the sensitivity of some of the
advanced intermediates which could be mastered only after a
scrupulous optimization of the key fragment coupling events
and a careful adjustment of the peripheral protecting-group
pattern. Most notable are the highly selective 1,4-anti-aldol
step for the formation of the stereogenic center at C-18, the
modified Stille coupling under chloride free conditions, and
the application of the Grubbs catalyst in the challenging
macrocyclization of a labile vinyl epoxide. As the underlying
blueprint of this natural product synthesis is convergent, and
hence inherently flexible, we are now in a favorable position
to also prepare other members of the amphidinolide H, G,
and B families. Work along these lines together with efforts to
further streamline the synthesis of the parent compound 1 are
underway and will be reported in due course.
Received: August 31, 2007
Published online: October 30, 2007
Keywords: antitumor agents · cross-coupling · macrolides ·
.
metathesis · natural products
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Scheme 7. a) LDA, THF, ꢀ788C, 70%; b) TBSOTf, 2,6-lutidine, CH2Cl2,
08C, 79–94%; c) DDQ, CH2Cl2/H2O, 08C!RT, 55–62%; d) TESCl,
imidazole, DMAP, DMF, 79%; e) 34, [Pd(Ph3P)4] (0.7 equiv), CuTC,
Ph2PO2NBu4, DMF, 89%; f) DMP, NaHCO3, CH2Cl2, 08C!RT;
g) [Ph3PCH3]Br, Na[N(SiMe3)2], THF, 08C, 65% (over 2 steps); h) 38
(10 mol%), C6H6, 68–72%; i) TASF, aq THF/DMF (10:1), 08C, 55%.
TASF=tris(dimethylamino)sulfonium difluorotrimethylsilicate.
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D. C. Myles, Tetrahedron Lett. 1999, 40, 2275 – 2278; n) H. M.
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[29] For a similar experience with an N-PMB group, see a) A.
Fürstner, L. Turet, Angew. Chem. 2005, 117, 3528 – 3532; Angew.
Angew. Chem. Int. Ed. 2007, 46, 9265 –9270
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 9269
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Communications
Chem. Int. Ed. 2005, 44, 3462 – 3466; b) A. Fürstner, D.
2002, 114, 2203 – 2206; Angew. Chem. Int. Ed. 2002, 41, 2097 –
2101; d) A. Fürstner, T. Dierkes, O. R. Thiel, G. Blanda, Chem.
Eur. J. 2001, 7, 5286 – 5298; e) A. Fürstner, F. Jeanjean, P. Razon,
C. Wirtz, R. Mynott, Chem. Eur. J. 2003, 9, 320 – 326; f) B.
Scheiper, F. Glorius, A. Leitner, A. Fürstner, Proc. Natl. Acad.
Sci. USA 2004, 101, 11960 – 11965; g) A. Fürstner, K. Radkow-
ski, C. Wirtz, R. Goddard, C. W. Lehmann, R. Mynott, J. Am.
Chem. Soc. 2002, 124, 7061 – 7069; h) A. Fürstner, O. R. Thiel, N.
Kindler, B. Bartkowska, J. Org. Chem. 2000, 65, 7990 – 7995;
i) A. Fürstner, T. Müller, J. Am. Chem. Soc. 1999, 121, 7814 –
7821; j) A. Fürstner, K. Langemann, J. Am. Chem. Soc. 1997,
119, 9130 – 9136.
De Souza, L. Turet, M. D. B. Fenster, L. Parra-Rapado, C.
Wirtz, R. Mynott, C. W. Lehmann, Chem. Eur. J. 2007, 13, 115 –
134.
[30] T. W. Greene, P. G. M. Wuts, Protective Groups in Organic
Synthesis, 3rd ed., Wiley, New York, 1999.
[31] Formed from 17 by cleavage of the PMB group with DDQ and
silylation of the resulting alcohol with TESOTf/2,6-lutidine.
[32] The stereochemistry of the newly formed center was confirmed
by analysis of the corresponding Mosher esters.
[33] For another case in which a RCM at ambient temperature was
mandatory, see Ref. [21]. For RCM-based total syntheses from
our research group see the following and references cited
therein: a) A. Fürstner, T. Nagano, J. Am. Chem. Soc. 2007, 129,
1906 – 1907; b) A. Fürstner, C. Müller, Chem. Commun. 2005,
5583 – 5585; c) A. Fürstner, F. Jeanjean, P. Razon, Angew. Chem.
[34] Presented, in part, at the 232nd ACS National Meeting, San
Francisco, Sept. 10 – 14, 2006 (ORGN-652, CODEN: 69IHRD
AN 2006:862792).
9270 www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 9265 –9270
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