Second-generation total synthesis of spirastrellolide F methyl ester: The alkyne route

Article abstract of DOI:10.1002/anie.201103270

Outlandish: The spiroketal embedded in spirastrellolide F methyl ester is a daring site for ring closure, yet it has allowed the power of catalytic alkyne scission and activation to be showcased (see scheme). An improved strategy for the introduction of t

Full text of DOI:10.1002/anie.201103270

DOI: 10.1002/anie.201103270
Natural Product Synthesis
Second-Generation Total Synthesis of Spirastrellolide F Methyl Ester:
The Alkyne Route**
Stefan Benson, Marie-Pierre Collin, Alexander Arlt, Barbara Gabor, Richard Goddard, and
Alois Fꢀrstner*
The spirastrellolides are a small
family of exquisitely potent anti-
mitotic agents of marine origin
which are reported to exert their
function by selective inhibition
of the serine/threonine protein
phosphatase PP2A
(IC50
ca. 1 nm).[1] This activity predes-
tines them as tools for chemical
biology and as possible lead
structures in the quest for novel
therapeutic agents for the treat-
ment of cancer and other meta-
bolic disorders.[2] Although it
took more than four years from
the initial isolation to the full
elucidation of the stereostruc-
ture of these compounds,[1] their
intricate topology and very lim-
ited supply from the natural
source aroused considerable
interest in the synthetic com-
munity even before the mole-
cular architecture had been fully
elucidated.[3–5] These efforts cul-
minated in the first total syn-
thesis
of
spirastrellolide A
methyl ester (2) by Paterson
et al.,[6] followed by the conquest
of the sister compound spira-
strellolide F methyl ester (1) by
our research group shortly there-
after (Scheme 1).[7] Since only
the relative configuration of the
four color-coded stereoclusters
embedded into the framework
of these macrolides but neither
Scheme 1. Structures of spirastrellolide A and F methyl esters, together with our first- and second-
generation retrosynthetic analysis of 1. Bn=benzyl, PMB=para-methoxy-
benzyl.
[*] Dipl.-Chem. S. Benson, Dr. M.-P. Collin, Dipl.-Chem. A. Arlt,
B. Gabor, Dr. R. Goddard, Prof. A. Fꢀrstner
Max-Planck-Institut fꢀr Kohlenforschung
45470 Mꢀlheim an der Ruhr (Germany)
E-mail: fuerstner@kofo.mpg.de
the stereochemical relationships between them nor their
absolute configurations were known at the outset of these
projects, both approaches could not help but envisage frag-
ment coupling reactions at the boundaries of the known
domains. Although quite distinct in their details, both the
synthesis of 2 by Paterson et al. and our own successful route
to 1 relied on a Suzuki cross-coupling, a macrolactonization,
and a stepwise build-up of the side chain containing a fragile
skipped E,Z-configured 1,4-diene motif (Scheme 1). Now
[**] Generous financial support by the MPG and the Fonds der
Chemischen Industrie (Kekulꢁ stipends to S.B. and A.A.) is
gratefully acknowledged. We thank S. Schulthoff for skillful technical
assistance.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103270.
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8739

Communications
that the stereochemistry of these
targets has been established and
confirmed, this major strategic
constraint is no longer valid. We,
therefore, present a conceptually
different approach toward the
macrocyclic edifice of 1 based
on catalytic alkyne activation
reactions. Moreover, an alterna-
tive end game is presented, which
allows the side chain to be
appended to the macrolide core
in a single operation rather than
by the incremental sequence pre-
viously used by the two research
groups.
Scheme 2. a) [CpRu(MeCN)3]PF6 (5 mol%), 10 (10 mol%), MeCN, 608C, then 6, aq acetone, 608C,
88%; b) 11, K2CO3, MeOH, 96%; c) BuLi, MeOTf, THF, ꢀ788C!08C, 93%; d) HF·pyridine, pyridine,
THF, ꢀ108C, 76%; e) Dess–Martin periodinane, CH2Cl2; f) NaClO2, NaH2PO4, tBuOH/H2O (1:1), 2-
methyl-2-butene, 92% (over both steps). TBS=tert-butyldimethylsilyl, Cp=cyclopentadienyl, Tf=tri-
fluoromethanesulfonyl.
The strategic design element
of this new approach is the late-
stage unveiling of the spirocyclic
BC ring system of 1 upon activation of a dihydroxy-alkyne
precursor with a carbophilic Lewis acid catalyst such as AuI or
PtII (Scheme 1).[8,9] Of the two possible modes that can
a priori be envisaged, it was decided not to follow the route
triflate 21. This transformation was best achieved by addition
of lithiated methyl phenyl sulfone[16] and subsequent cleavage
of the PhSO2 group in 18 under free-radical conditions; the
resulting ketone 19 then gave triflate 21 on deprotonation
with LiHMDS and quenching of the generated enolate with
triflimide 20 as the preferred electrophile.[17]
The assembly of these fragments to the required RCAM
precursor benefitted from the intelligence gathered in our
first-generation total synthesis of spirastrellolide F.[4,7] Specif-
ꢀ
via the C17 C18 cycloalkyne 3, since this particular com-
pound, upon activation of the triple bond, might be prone to
elimination of MeOH with formation of a conjugated enyne;
no such escape route exists for the regioisomer 4, with the
ꢀ
acetylene moiety at the C16 C17 position. This key inter-
mediate for its part could derive from precursor 5 by what is
arguably the most advanced application of ring-closing alkyne
metathesis (RCAM)[10] reported to date and a particularly
stringent test for the functional-group tolerance of the
available catalysts.[11] Access to 5 can be secured from
building blocks, for which scalable preparations have already
been worked out during our previous total synthesis cam-
paign.
To this end, the known terminal alkyne 6[7a] was homo-
logated by first subjecting it to a ruthenium-catalyzed anti-
Markovnikov hydration according to the method developed
by Hintermann and co-workers (Scheme 2).[12] This procedure
furnished the desired aldehyde 7 in 88% yield. This product
was treated with the Ohira–Bestmann reagent 11[13] and the
resulting terminal alkyne end-capped with a methyl group.
Selective desilylation of the primary alcohol in 8 with
buffered HF·pyridine, followed by stepwise oxidation, readily
furnished the required carboxylic acid segment 9.
Access to the C17–C24 sector was similarly straightfor-
ward starting from compound 12, which had previously been
prepared on a multigram scale (Scheme 3).[7] Replacement of
the silyl group by a methyl substituent followed by oxidative
cleavage of the alkene terminus in 13 gave aldehyde 14, which
was subjected to a Mukaiyama aldol reaction with the TMS-
ketene acetal 15.[14] Under the aegis of MgBr2·OEt2, this
transformation provided product 16 with a diastereomeric
ratio of > 10:1 in a highly reproducible 70% yield.[7,15] Its
elaboration to the isopropylidene acetal 17, which later plays
an essential role as a conformational control element for
setting the stereocenter at C24,[7b] was uneventful, as was the
conversion of the methyl ester group into the required enol
Scheme 3. a) K2CO3, MeOH, 89%; b) BuLi, THF, ꢀ788C!08C, then
MeOTf, ꢀ788C, 80%; c) OsO4 cat., (DHQ)2PYR, K3[Fe(CN)6], K2CO3,
tBuOH, H2O, 08C!RT, 77% (brsm); d) Pb(OAc)4, CH2Cl2, 88%;
e) MgBr2·OEt2, toluene, ꢀ788C!RT, 70% (d.r. ꢁ10:1); f) TBAF, THF,
08C!RT, 88%; g) 2,2-dimethoxypropane, camphorsulfonic acid cat.,
CH2Cl2, 08C !RT, 87%; h) PhSO2Me, BuLi, THF, then 17, ꢀ788C!
08C; i) azoisobutyronitrile, Bu3SnH, toluene, reflux, 79% (over two
steps); j) 20, LiHMDS, THF, ꢀ788C!RT, 57%. LiHMDS=lithium
hexamethyldisilazide, (DHQ)2PYR=hydroquinine-(2,5-diphenyl-4,6-pyr-
imidindiyl) diether, TBAF=tetrabutylammonium fluoride.
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endanger any of the acid-labile
motifs in 25.[20] Most notable is its
compatibility with the secondary
chloride substituent and the frag-
ile bis(spiroacetal) that forms the
northern hemisphere; likewise,
the strictly chemoselective meta-
thetic activation of the alkynes in
the presence of the alkene moiety
is noteworthy.
With cycloalkyne 26 in hand,
the stage was set for the spirocyc-
lization meant to forge the BC
ring system. To this end, the two
PMB ethers in 26 were cleaved
with DDQ and the resulting diol
27 treated with catalytic amounts
of AuCl or AuCl·SMe2 in CH2Cl2.
Although this simple carbophilic
Lewis acid had already been used
successfully in some advanced spi-
rocyclization reactions,[8,22–24] we
were disappointed to find that it
furnished exclusively the wrong
Scheme 4. a) 9-H-9-BBN dimer, THF; b) aq
NaOH (1m), [PdCl2(dppf)] (20 mol%), Ph3As
(20 mol%), 21, THF, 76%; c) 1. 9, 2,4,6-trichloro-
benzoyl chloride, Et3N, toluene, 08C; 2. 24,
DMAP, toluene, 08C!RT, 85%; d) 28 (8 mol%),
5 ꢂ M.S., toluene, 87%; e) DDQ, CH2Cl2, 08C!
RT, 91%. 9-BBN=9-borabicyclo[3.3.1]nonane,
dppf=1,1’-bis(diphenylphosphino)ferrocene,
DMAP=4-dimethylamino-pyridine; M.S.=molec-
ular sieves.
ically, the well accessible “northern” hemi-
sphere 22[4] was hydroborated with 9-H-9-
BBN dimer and the resulting borane 23
subjected to an alkyl-Suzuki cross-coupling
reaction with alkenyl triflate 21
(Scheme 4).[18] The resulting alcohol 24
was esterified with acid 9 under Yamaguchi
conditions[19] to give diyne 25 in readiness
for ring closure. Gratifyingly, this elaborate
substrate cyclized smoothly to cycloalkyne
26 when exposed to catalytic amounts of
the molybdenum alkylidyne complex 28,
which is arguably the most efficient and, at
the same time, most functional group
tolerant alkyne metathesis catalyst cur-
rently available.[20,21] Product 26 was
formed in a spot-to-spot reaction and
isolated in 87% yield. The excellent appli-
cation profile of 28 is ascribed to its
triphenylsilanolate ligands. These impart
a well-balanced level of Lewis acidity on
the MoVI center, which is high enough to
ensure an outstanding catalytic perfor-
mance, yet sufficiently tempered not to
Scheme 5. a) AuCl·SMe2 (10 mol%), CH2Cl2, then MeOH, PPTS cat., 36%, see text for
details; b) 32 (10 mol%), CH2Cl2, 4 ꢂ M.S., 62% (endo/exo=ca. 5:1); c) PPTS cat., toluene,
808C, 81%. PPTS=pyridinium p-toluenesulfonate.
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Communications
regioisomer in our case. Indeed, only the highly labile five-
membered enol ether was formed by a 5-exo-dig cyclization of
the C13-OH group onto the alkyne unit (Scheme 5). This
compound had to be transformed to the corresponding
furanoid methyl glycoside 29 (d.r. = 2.3:1) to avoid decom-
position upon work up. No trace of the regioisomeric enol
ether 30 formed by 6-endo cyclization or the desired
spiroacetal could be detected in the crude mixture.[25]
Gratifyingly though, a screening of catalysts showed that
this inherent bias of the substrate could be overridden with
more advanced gold catalysts bearing bulky ancillary ligands.
The best results were obtained with complex 32,[26] which
furnished the six-membered enol ether derivative 30 as the
major product. Although the exo/endo ratio was somewhat
variable in different runs,[27] this result paved the way to
spiroketal 31 upon treatment of 30 with catalytic amounts of
PPTS in toluene at 808C. Under these forcing conditions, the
hindered OH group at C21 was found to attack the enol ether
bond of 30, with the formation of the correct doubly anomeric
BC ring system in 81% yield. An X-ray structure analysis of
product 31 confirmed its constitution as well as the correct
configuration of all the 19 chiral centers set at this stage
(Figure 1).
Figure 1. Structure of 31 in the solid state.[28]
Since 31 intercepts our initial total synthesis of 1,[7b] its
elaboration into spirastrellolide F could follow the previously
disclosed route based on a fully
afforded fully protected spirastrellolide F 34 as a single
isomer in 76% yield. The deprotection of this material to
diastereoselective reduction of
the exocyclic double bond at
C24. This transformation is
directed by the adjacent isopro-
pylidene acetal as the conforma-
tional control element, which
ensures that hydrogen can be
delivered only from the open
Re face (see Figure 1).[7] Routine
management of the protecting
groups and oxidation state then
allowed the primary benzyl ether
in the resulting product 33a to be
cleaved and the released alcohol
to be oxidized to aldehyde 33b as
the starting point for the intro-
duction of the side chain. This
end game, however, had previ-
ously been accomplished in a
stepwise manner.[7] Therefore,
we chose to revisit this final
phase in an attempt to improve
on the convergence of the total
synthesis (Scheme 6). Accord-
ingly, d-(+)-malic acid (35) was
transformed into phosphonium
Scheme 6. a) 2,2-dimethoxypropane, PPTS cat., 84%; b) BH3·THF, THF, 08C!RT; c) Ph3PBr2, imid-
azole, CH2Cl2, 08C!RT, 68% (over two steps); d) PPh3, MeCN, microwave, 1508C; e) KHMDS, THF/
CH2Cl2 (2:1), ꢀ788C, then 37, ꢀ788C!08C; f) TBAF, NH4F, THF, 08C!RT, 56% (over three steps);
g) 1-phenyltetrazole-5-thiol, PPh3, DIAD, THF, 08C!RT; h) NaOMe cat., MeOH/CH2Cl2 (1:4), 08C!RT,
86% (over both steps); i) (NH4)6Mo7O24·4H2O, aq H2O2, EtOH, 58C, 65%; j) TESCl, imidazole, CH2Cl2,
08C!RT, 90%; k) see Ref. [7]; l) Pd(OH)2 cat., H2 (1 atm), EtOAc; m) Dess–Martin periodinane,
CH2Cl2, NaHCO3, 08C!RT, 67% (over two steps); n) 40, KHMDS, THF, ꢀ788C!ꢀ608C, then 33b,
ꢀ658C, 76%; o) PPTS cat., MeOH/Et2O/H2O (7:2:1), 508C, 55%. KHMDS=potassium hexamethyldi-
salt 36 and the derived ylide
treated with the known aldehyde
37[4] to give Z-alkene 38, which
was swiftly converted into sulfone
40. A Julia–Kocienski olefina-
tion[29] between this product and
the macrocyclic aldehyde 33b silazide, DIAD=diisopropylazodicarboxylate, TES=triethylsilyl.
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5515; c) A. Fꢀrstner, B. Fasching, G. W. O’Neil, M. D. B. Fenster,
C. Godbout, J. Ceccon, Chem. Commun. 2007, 3045 – 3047.
[5] I. Paterson, S. M. Dalby, Nat. Prod. Rep. 2009, 26, 865 – 873.
[6] a) I. Paterson, E. A. Anderson, S. M. Dalby, J. H. Lim, J.
Genovino, P. Maltas, C. Moessner, Angew. Chem. 2008, 120,
3058 – 3062; Angew. Chem. Int. Ed. 2008, 47, 3016 – 3020; b) I.
Paterson, E. A. Anderson, S. M. Dalby, J. H. Lim, J. Genovino, P.
Maltas, C. Moessner, Angew. Chem. 2008, 120, 3063 – 3067;
Angew. Chem. Int. Ed. 2008, 47, 3021 – 3025; c) I. Paterson, S. M.
Dalby, P. Maltas, Isr. J. Chem. 2011, 51, 406 – 419.
[7] a) G. W. O’Neil, J. Ceccon, S. Benson, M.-P. Collin, B. Fasching,
A. Fꢀrstner, Angew. Chem. 2009, 121, 10124 – 10129; Angew.
Chem. Int. Ed. 2009, 48, 9940 – 9945; b) S. Benson, M.-P. Collin,
G. W. O’Neil, J. Ceccon, B. Fasching, M. D. B. Fenster, C.
Godbout, K. Radkowski, R. Goddard, A. Fꢀrstner, Angew.
Chem. 2009, 121, 10130 – 10134; Angew. Chem. Int. Ed. 2009, 48,
9946 – 9950.
the targeted marine natural product as its methyl ester was
performed with PPTS in a mixed solvent system, as previously
described.[7]
In summary, a concise second-generation total synthesis of
the complex antimitotic macrolide spirastrellolide F methyl
ester (1) has been achieved. It features the power of
contemporary metal-catalyzed alkyne chemistry in the meta-
thetic closure of the macrocyclic scaffold and the subsequent
formation of the southern acetal domain by carbophilic
activation of the p bond. Together with an improved strategy
for the introduction of the labile side chain, this conceptually
new route to 1 opens the door for further investigations into
this demanding family of target molecules. At the same time,
this case study helps to widen the scope of ring-closing alkyne
metathesis beyond the formation of stereodefined cyclo-
alkenes by semireduction of the products primarily formed,
which previously constituted the major application of this
powerful transformation.[30,31]
[8] a) K. Utimoto, Pure Appl. Chem. 1983, 55, 1845 – 1852; b) B. Liu,
J. K. De Brabander, Org. Lett. 2006, 8, 4907 – 4910; c) A.
Aponick, C.-Y. Li, J. A. Palmes, Org. Lett. 2009, 11, 121 – 124;
d) review: B. Alcaide, P. Almendros, J. M. Alonso, Org. Biomol.
Chem. 2011, 9, 4405 – 4416.
Received: May 12, 2011
[9] a) A. Fꢀrstner, P. W. Davies, Angew. Chem. 2007, 119, 3478 –
3519; Angew. Chem. Int. Ed. 2007, 46, 3410 – 3449; b) D. J.
Gorin, F. D. Toste, Nature 2007, 446, 395 – 403; c) E. Jimꢁnez-
NfflÇez, A. M. Echavarren, Chem. Rev. 2008, 108, 3326 – 3350;
d) A. S. K. Hashmi, Chem. Rev. 2007, 107, 3180 – 3211.
[10] a) A. Fꢀrstner, G. Seidel, Angew. Chem. 1998, 110, 1758 – 1760;
Angew. Chem. Int. Ed. 1998, 37, 1734 – 1736; b) A. Fꢀrstner, O.
Guth, A. Rumbo, G. Seidel, J. Am. Chem. Soc. 1999, 121, 11108 –
11113; c) A. Fꢀrstner, C. Mathes, C. W. Lehmann, Chem. Eur. J.
2001, 7, 5299 – 5317.
[11] a) A. Fꢀrstner, P. W. Davies, Chem. Commun. 2005, 2307 – 2320;
b) W. Zhang, J. S. Moore, Adv. Synth. Catal. 2007, 349, 93 – 120;
c) R. R. Schrock, C. Czekelius, Adv. Synth. Catal. 2007, 349, 55 –
77; d) X. Wu, M. Tamm, Beilstein J. Org. Chem. 2011, 7, 82 – 93.
[12] a) A. Labonne, T. Kribber, L. Hintermann, Org. Lett. 2006, 8,
5853 – 5856; b) L. Hintermann, T. T. Dang, A. Labonne, T.
Kribber, L. Xiao, P. Naumov, Chem. Eur. J. 2009, 15, 7167 – 7179;
c) F. Boeck, T. Kribber, L. Xiao, L. Hintermann, J. Am. Chem.
Soc. 2011, 133, 8138 – 8141; d) L. Hintermann in C-X Bond
Formation, Vol. 31 (Ed.: A. Vigalok), Springer, Berlin, Top.
Organomet. Chem. 2010, pp. 123 – 155.
Published online: July 26, 2011
Keywords: alkyne metathesis · gold · molybdenum ·
.
natural products · total synthesis
[1] a) D. E. Williams, M. Roberge, R. Van Soest, R. J. Andersen, J.
Am. Chem. Soc. 2003, 125, 5296 – 5297; b) D. E. Williams, M.
Lapawa, X. Feng, T. Tarling, M. Roberge, R. J. Andersen, Org.
Lett. 2004, 6, 2607 – 2610; c) D. E. Williams, R. A. Keyzers, K.
Warabi, K. Desjardine, J. L. Riffell, M. Roberge, R. J. Andersen,
J. Org. Chem. 2007, 72, 9842 – 9845; d) K. Warabi, D. E.
Williams, B. O. Patrick, M. Roberge, R. J. Andersen, J. Am.
Chem. Soc. 2007, 129, 508 – 509.
[2] For reviews on phosphatase inhibitors, see a) A. McCluskey,
A. T. R. Sim, J. A. Sakoff, J. Med. Chem. 2002, 45, 1151 – 1175;
b) R. E. Honkanen, T. Golden, Curr. Med. Chem. 2002, 9, 2055 –
2075; c) L. Bialy, H. Waldmann, Angew. Chem. 2005, 117, 3880 –
3906; Angew. Chem. Int. Ed. 2005, 44, 3814 – 3839.
[3] a) I. Paterson, E. A. Anderson, S. M. Dalby, O. Loiseleur, Org.
Lett. 2005, 7, 4121 – 4224; b) I. Paterson, E. A. Anderson, S. M.
Dalby, O. Loiseleur, Org. Lett. 2005, 7, 4125 – 4128; c) J. Liu,
R. P. Hsung, Org. Lett. 2005, 7, 2273 – 2276; d) Y. Pan, J. K.
De Brabander, Synlett 2006, 853 – 856; e) I. Paterson, E. A.
Anderson, S. M. Dalby, J. H. Lim, P. Maltas, C. Moessner, Chem.
Commun. 2006, 4186 – 4188; f) C. Wang, C. J. Forsyth, Org. Lett.
2006, 8, 2997 – 3000; g) J. Liu, J. H. Yang, C. Ko, R. P. Hsung,
Tetrahedron Lett. 2006, 47, 6121 – 6123; h) I. Paterson, E. A.
Anderson, S. M. Dalby, J. Genovino, J. H. Lim, C. Moessner,
Chem. Commun. 2007, 1852 – 1854; i) A. B. Smith, D.-S. Kim,
Org. Lett. 2007, 9, 3311 – 3314; j) C. Wang, C. J. Forsyth, Hetero-
cycles 2007, 72, 621 – 632; k) K. A. Keaton, A. J. Phillips, Org.
Lett. 2008, 10, 1083 – 1086; l) S. Chandrasekhar, C. Rambabu,
A. S. Reddy, Org. Lett. 2008, 10, 4355 – 4357; m) J.-H. Yang, J.
Liu, R. P. Hsung, Org. Lett. 2008, 10, 2525 – 2528; n) J. L.-Y.
Chen, M. A. Brimble, Chem. Commun. 2010, 46, 3967 – 3969;
o) A. B. Smith, H. Smits, D. S. Kim, Tetrahedron 2010, 66, 6597 –
6605; p) G. Sabitha, A. S. Rao, J. S. Yadav, Synthesis 2010, 505 –
509.
[13] a) S. Ohira, Synth. Commun. 1989, 19, 561 – 564; b) S. Mꢀller, B.
Liepold, G. J. Roth, H. J. Bestmann, Synlett 1996, 521 – 522.
[14] K. Hattori, H. Yamamoto, J. Org. Chem. 1993, 58, 5301 – 5303.
[15] M. S. M. Timmer, A. Abidekian, P. H. Seeberger, Angew. Chem.
2005, 117, 7777 – 7780; Angew. Chem. Int. Ed. 2005, 44, 7605 –
7607.
[16] Y.-G. Suh, B.-A. Koo, E.-N. Kim, N.-S. Choi, Tetrahedron Lett.
1995, 36, 2089 – 2092.
[17] Triflimide 20 was preferred over PhN(Tf)2 or Comins reagent
because the by-products formed were more readily separable
from the enol triflate. Moreover, this reagent can be sublimed,
thus ensuring dryness and hence high yields in the reaction with
the enolate, cf. Ref. [7].
[18] a) N. Miyaura, T. Ishiyama, H. Sasaki, M. Ishikawa, M. Satoh, A.
Suzuki, J. Am. Chem. Soc. 1989, 111, 314 – 321; b) review: S. R.
Chemler, D. Trauner, S. J. Danishefsky, Angew. Chem. 2001, 113,
4676 – 4701; Angew. Chem. Int. Ed. 2001, 40, 4544 – 4568.
[19] Review: A. Parenty, X. Moreau, J.-M. Campagne, Chem. Rev.
2006, 106, 911 – 939.
[20] J. Heppekausen, R. Stade, R. Goddard, A. Fꢀrstner, J. Am.
Chem. Soc. 2010, 132, 11045 – 11057.
[21] a) V. Hickmann, M. Alcarazo, A. Fꢀrstner, J. Am. Chem. Soc.
2010, 132, 11042 – 11044; b) K. Micoine, A. Fꢀrstner, J. Am.
Chem. Soc. 2010, 132, 14064 – 14066.
[4] a) A. Fꢀrstner, M. D. B. Fenster, B. Fasching, C. Godbout, K.
Radkowski, Angew. Chem. 2006, 118, 5632 – 5636; Angew.
Chem. Int. Ed. 2006, 45, 5506 – 5510; b) A. Fꢀrstner, M. D. B.
Fenster, B. Fasching, C. Godbout, K. Radkowski, Angew. Chem.
2006, 118, 5636 – 5641; Angew. Chem. Int. Ed. 2006, 45, 5510 –
Angew. Chem. Int. Ed. 2011, 50, 8739 –8744
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[22] a) Y. Li, F. Zhou, C. J. Forsyth, Angew. Chem. 2007, 119, 283 –
[30] For further applications of RCAM to the formation of products
other than stereodefined olefins, see a) A. Fꢀrstner, A.-S.
Castanet, K. Radkowski, C. W. Lehmann, J. Org. Chem. 2003,
68, 1521 – 1528; b) A. Fꢀrstner, O. Larionov, S. Flꢀgge, Angew.
Chem. 2007, 119, 5641 – 5644; Angew. Chem. Int. Ed. 2007, 46,
5545 – 5548; c) A. Fꢀrstner, S. Flꢀgge, O. Larionov, Y. Takahashi,
T. Kubota, J. Kobayashi, Chem. Eur. J. 2009, 15, 4011 – 4029.
[31] For representative total syntheses relying on an RCAM/semi-
reduction, see Ref. [21] and the following: a) V. V. Vintonyak,
M. E. Maier, Angew. Chem. 2007, 119, 5301 – 5303; Angew.
Chem. Int. Ed. 2007, 46, 5209 – 5211; b) B. J. Smith, G. A.
Sulikowski, Angew. Chem. 2010, 122, 1643 – 1646; Angew.
Chem. Int. Ed. 2010, 49, 1599 – 1602; c) M. G. Nilson, R. L.
Funk, Org. Lett. 2010, 12, 4912 – 4915; d) A. Fꢀrstner, M. Bindl,
L. Jean, Angew. Chem. 2007, 119, 9435 – 9438; Angew. Chem. Int.
Ed. 2007, 46, 9275 – 9278; e) A. Fꢀrstner, D. 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; f) A. Fꢀrstner, L.
Turet, Angew. Chem. 2005, 117, 3528 – 3532; Angew. Chem. Int.
Ed. 2005, 44, 3462 – 3466; g) A. Fꢀrstner, K. Radkowski, J.
Grabowski, C. Wirtz, R. Mynott, J. Org. Chem. 2000, 65, 8758 –
8762; h) A. Fꢀrstner, K. Grela, C. Mathes, C. W. Lehmann, J.
Am. Chem. Soc. 2000, 122, 11799 – 11805.
286; Angew. Chem. Int. Ed. 2007, 46, 279 – 282; b) B. M. Trost,
B. M. O’Boyle, J. Am. Chem. Soc. 2008, 130, 16190 – 16192;
c) B. M. Trost, B. M. O’Boyle, D. Hund, J. Am. Chem. Soc. 2009,
131, 15061 – 15074; d) C. Fang, Y. Pang, C. J. Forsyth, Org. Lett.
2010, 12, 4528 – 4531.
[23] For a leading study on the formation of enol ethers in the context
of natural product synthesis from hydroxy-alkynes by means of
gold catalysis, see a) B. M. Trost, G. Dong, Nature 2008, 456,
485 – 488; b) B. M. Trost, G. Dong, J. Am. Chem. Soc. 2010, 132,
16403 – 16416.
[24] A. Fꢀrstner, Chem. Soc. Rev. 2009, 38, 3208 – 3221.
[25] Other catalysts such as AuCl3 or PtCl4 decomposed the starting
material.
[26] C. Nieto-Oberhuber, S. López, A. M. Echavarren, J. Am. Chem.
Soc. 2005, 127, 6178 – 6179.
[27] This is ascribed to the instability of the furanoid product; its
decomposition may alter the observed ratio.
[28] Anisotropic displacement parameters are drawn at the 50%
probability level. CCDC 824552 contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
´
[29] P. R. Blakemore, W. J. Cole, P. J. Kocienski, A. Morley, Synlett
1998, 26 – 28.
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