Total synthesis of tulearin C

Article abstract of DOI:10.1002/anie.201106117

With the help of the smaller brother: Although alkyne metathesis will always be the little brother of alkene metathesis, it allows problems to be solved that are currently beyond reach of the more famous sibling. This notion is exemplified by the tulearin macrolides, which could only be selectively forged by ring-closing alkyne metathesis (RCAM)/transreduction using the latest generation of alkyne metathesis catalysts.

Full text of DOI:10.1002/anie.201106117

DOI: 10.1002/anie.201106117
Natural Products
Total Synthesis of Tulearin C**
Konrad Lehr, Ronaldo Mariz, Lucie Leseurre, Barbara Gabor, and Alois Fꢀrstner*
Ring-closing olefin metathesis (RCM) provides efficient
access to carbo- and heterocycles of virtually all ring sizes,
but usually affords mixtures of the corresponding E- and Z-
configured cycloalkenes when applied to medium-sized or
macrocyclic systems.[1,2] Although the product ratios are
difficult to predict, the reversible nature of metathesis
favors the thermodynamically more stable isomer, which is
often the E alkene, in particular when “second generation”
catalysts are used. However, inherently E-selective catalysts
capable of overriding an insufficient or even unfavorable
thermodynamic bias, are currently unknown.[3]
The critical implications of this lack of E-selective meta-
thesis catalysts surface, for example, in an approach to
tulearin A reported in the literature (Scheme 1).[4] The
Scheme 2. Structures of tulearin A and C, and retrosynthetic analysis
required 18-membered core structure 2 was formed from
substrate 1 in an E/Z ratio of only 1.9:1, which could neither
be improved by the use of more active catalysts nor by
changing the peripheral protecting groups.[5]
of 4.
limited supply prevented a detailed biological assessment,
preliminary data showed that the sister compound tulearin A
(5), endowed with a carbamate at the C8-OH group, exhibits
strong and differential antiproliferative effects against human
leukemia cell lines.[9]
Desymmetrization of the cheap dimethyl 3-methylgluta-
rate (9) with the aid of pig liver esterase, followed by
recrystallization of the cinchonidine salt furnished acid 8 in
optically pure form (ꢀ 98% ee, 20 g single largest batch;
Scheme 3).[10] This compound was then converted into lactone
10, which served as a convenient building block for the
northern and the southern sectors of tulearin C (4) alike.
The further elaboration of 10 into the alcohol segment 6
hinged upon a reductive elimination of the derived gem-
dichloro olefin 11.[11] Rather than employing lithium sand in
THF as commonly practiced to generate terminal alkynes
from substrates of this type,[12] we reasoned that the use of
MeLi would allow us to prepare the required nonterminal
alkyne 13 in a single operation.[13] It can be envisaged that the
methyl chloride, generated by an initial metal–halogen
exchange, might C-alkylate the lithium acetylide, derived
from the vinylidene intermediate 12 primarily formed,
provided that premature loss of this low-boiling compound
(b.p. = ꢁ248C) can be avoided. Alternatively and more likely,
MeLi could attack the carbenoid intermediate 12 directly.[14]
Irrespective of the actual mechanism, which is currently under
investigation, the desired nonterminal alkyne 13 was obtained
in up to 90% yield upon exposure of compound 11 to excess
MeLi in Et2O or THF (Scheme 3 and Table 1).
Scheme 1. Stereo-unselective approach to a non-natural isomer of
tulearin A based on RCM.[4] Cy =cyclohexyl, PMB=p-methoxybenzyl,
TBS=tert-butyldimethylsilyl.
Challenged by this outcome, we sought to develop an
alternative solution based on ring-closing alkyne metathesis
(RCAM).[6,7] This transformation greatly benefits from the
recent generation of highly active, exceedingly tolerant, and
user-friendly catalysts.[8] They might allow tulearin C (4) to be
assembled from two fragments, 6 and 7, of similar size and
complexity, both of which can be traced back to (R)-3-methyl
glutarate monoester 8 (Scheme 2). Compound 4 is the least
abundant member of a small family of macrolides isolated
from a Madagascan Fascaplysinopsis sponge.[9] Although the
[*] Dipl.-Chem. K. Lehr, Dr. R. Mariz, Dr. L. Leseurre, B. Gabor,
Prof. A. Fꢀrstner
Max-Planck-Institut fꢀr Kohlenforschung
45470 Mꢀlheim an der Ruhr (Germany)
E-mail: fuerstner@kofo.mpg.de
Although the scope of this new method still needs to be
explored in full detail, the examples compiled in Table 1
suggest that this alkylative elimination provides ready access
to a variety of nonterminal alkynes. As expected, n-alkyl-
lithium reagents other than MeLi can also be employed
(entry 6). All dichloroalkenes derived from lactones with six
[**] Generous financial support by the MPG and the Fonds der
Chemischen Industrie is gratefully acknowledged. We thank the
analytical departments of our Institute for excellent support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201106117.
Angew. Chem. Int. Ed. 2011, 50, 11373 –11377
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11373

Communications
could be cross-coupled with Me2Zn in the presence of
[PdCl2(dppf)] as the catalyst after temporary protection
of the OH group.[19,20] It was imperative though to use
fresh Me2Zn to avoid partial isomerization and/or proto-
deiodination during the Negishi reaction of 19. Under this
condition, the required alcohol segment 6 was obtained in
good yield and excellent purity.
Lactone 10 also served as a convenient starting
material for the preparation of the acid sector of
tulearin C (Scheme 5). Specifically, a Claisen condensa-
tion with EtOAc followed by asymmetric reduction of the
resulting b-ketoester 21 (in equilibrium with the hemi-
ketal form) paved a scalable route to product 22; the best
result (d.r. = 99:1) was obtained with (R)-SYNPHOS (31)
as the ligand in the hydrogenation step.[21] Since all
attempts to C-methylate the trianion derived from 22
were unsatisfactory, the primary hydroxy group was
protected and the resulting TBDPS ether 23 subjected
Table 1: Alkylative elimination of lactone-derived dichoroalkenes.[a]
Entry Dichloroalkene[b] Solvent
t
[h]
Alkyne
Yield
[%]
Scheme 3. a) i) Pig liver esterase, NaOH (1m), MeOH, pH 7 buffer,
1
2
3
THF
THF
Et2O
8
2
48
2[d]
60[c]
80
93
75[c]
90
78%; ii) (ꢁ)-cinchonidine, aq. acetone, then aq. HCl (ꢀ98% ee); b) i)
aq. LiOH; ii) LiBH4, THF; iii) aq. HCl, 92%; c) CCl4, PPh3, THF, reflux,
92%; d) MeLi, Et2O, RT, 90%; e) Dess–Martin periodinane, CH2Cl2;
f) 16, Zn(OTf)2, (ꢁ)-N-methyl ephedrine (20), (iPr)2NEt, toluene, M.S.
(3 ꢁ), 57% (over both steps), d.r.=98:2; g) i) Red-Al, Et2O, M.S. (3 ꢁ),
08C!RT; ii) I2, ꢁ208C, 99%; h) TBSOTf, 2,6-lutidine, CH2Cl2, 94%;
i) Me2Zn, [(dppf)PdCl2]·CH2Cl2 (5 mol%), THF, Et3N, 658C, 90%;
4
5
THF
Et2O
48
6
Et2O
5
4
74[e]
88
ꢂ
j) TBAF, THF, 96%; k) HC CMgBr, [Pd(PPh3)4] (3 mol%), THF, 72%.
dppf=1,1’-bis(diphenylphosphino)ferrocene, M.S.=molecular sieves,
Red-Al=sodium bis(2-methoxyethoxy)aluminium hydride, TBAF=tetra-
n-butylammonium fluoride, TfO=trifluoromethanesulfonyloxy,
THF=tetrahydrofuran.
7
THF
8
9
THF
THF
1
4
88
84
or more ring atoms behaved uniformly well, even though the
reaction times are long when the somewhat higher yielding
diethyl ether is used as the solvent (compare entries 2 and 3,
and 4 and 5). Interestingly however, a striking dependence on
the solvent was observed for substrates derived from five-
membered lactones: in Et2O, the expected alkyne was formed
as the major product (entry 11), whereas the use of THF led
to a trisubstituted allene instead (entry 12). The additional
example shown in entry 13 suggests that this competing
pathway also holds preparative potential. It is assumed that
allene formation occurs if the metal–halogen exchange
leading to the alkyne is outperformed by allylic deprotona-
tion; the necessary orbital overlap may be reached more
easily by conformationally flexible furanoid substrates
(Scheme 4).[15] This and other aspects are subject to ongoing
studies.
10
THF
4
80
11
12
Et2O
THF
72
2
60[f]
58[g]
13
THF
1
84
[a] All reactions were performed using 5 equivalents of MeLi (1.8m in Et2O)
at ambient temperature, unless stated otherwise. [b] Prepared according to
Ref. [11]. [c] Using only 2.1 equivalents of MeLi. [d] The mixture was
warmed from ꢁ788C to ambient temperature over the course of 30 min
and then stirred at RT for 1.5 h. [e] Using nBuLi (1.6m in hexane).
[f] Together with 10% of the corresponding allene. [g] Together with 25% of
the corresponding alkyne.
Oxidation of alcohol 13 to the corresponding aldehyde 14
followed by asymmetric addition of enyne 16 under the aegis
of (ꢁ)-N-methyl-ephedrine (20)[16] gave propargyl alcohol 17
in a diastereomeric ratio of 98:2 (Scheme 3). Treatment of this
product with Red-Al in Et2O[17] followed by an iodine
quench[18] afforded the sensitive dienyl iodide 18, which
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Angew. Chem. Int. Ed. 2011, 50, 11373 –11377

Scheme 4. Possible mechanistic explanation for the dichotomy in the
behavior of dichloroolefin substrates derived from five-membered
lactones.
to a standard Frꢀter–Seebach alkylation.[22] Although the
diastereoselectivity was moderate (d.r. = 85:15), isomerically
pure product could be secured by routine flash chromato-
graphy at the stage of compound 24. Conversion into the
corresponding iodide preceded an advanced Negishi coupling
of the derived organozinc reagent with alkenyl iodide 28.[23]
This coupling partner was best prepared by a zirconocene-
catalyzed hydroalumination/iodination of butynol 26[24] fol-
lowed by alkylation of the rather unstable triflate 27 with
excess propynyllithium. A Sharpless dihydroxylation[25] of the
alkene site in 29 followed by routine protecting group
management led to the required acid 7 in good yield.
Esterification of 6 and 7 set the stage for the crucial ring
closure by RCAM, which proceeded smoothly and with a
remarkable rate when catalyzed by the alkylidyne complex 35
(Scheme 6).[8,26] However, a reaction temperature of 508C
was necessary to override the ring strain of the incipient
cycloalkyne 33. This outcome attests to the excellent perfor-
mance of the latest generation of alkyne metathesis catalysts,
which owe their activity and selectivity to the well-balanced
Lewis acidic character imposed on the high valent Mo center
by the triarylsilanolate ligands.[27] Moreover, these complexes
can be rendered air stable by complexation with phenanthro-
line, which greatly facilitates their handling.[8]
The subsequent conversion of compound 33 into the
corresponding E alkene required some optimization. Despite
our good experiences with BnMe2SiH as a reagent in
ruthenium-catalyzed trans-hydrosilylation reactions,[28–30] ap-
plications to the current target met with limited success. The
addition step was surprisingly inefficient and the protodesi-
lylation troublesome, requiring the use of excess TBAF at
ꢀ 508C, which endangered the integrity of the aldol sub-
structure of this delicate product; attempted desilylations
under acidic conditions caused complex transannular rear-
rangements.[31] Gratifyingly though, the use of (EtO)3SiH
allowed both problems to be solved. The trans addition
catalyzed by [Cp*Ru(MeCN)3]PF6 progressed smoothly,
provided the reaction was performed neat. The resulting
Scheme 5. a) EtOAc, LDA, THF, ꢁ788C, 90%; b) H2 (10 atm), RuCl3 (1
mol%), (R)-SYNPHOS (31; 1 mol%), EtOH, 808C, 89% (d.r.=99:1);
c) TBDPSCl, Et3N, DMAP cat., CH2Cl2, 95%; d) LDA, THF/DMPU,
ꢁ788C!ꢁ408C, then MeI, ꢁ788C!08C, 79% (d.r.=85:15); e)
MOMCl, (iPr)2NEt, CH2Cl2, reflux, 97%; f) TBAF, THF, 83%; g) I2,
PPh3, imidazole, CH2Cl2, 90%; h) i) Zn/Cu, toluene/dimethylacetamide
(19:1), 708C; ii) [Pd(PPh3)4] (5 mol%), 28, 608C, 72%; i) AD-mix-a,
MeSO2NH2, tBuOH, H2O, 08C, 83%; j) HCl, MeOH, 99%; k) TBSOTf,
2,6-lutidine, CH2Cl2, 90%; l) aq. LiOH, MeOH/THF (1:1), 99%;
m) DIBAL-H, Cp2ZrCl2, THF, RT, then I2, ꢁ788C, 80%; n) Tf2O, CH2Cl2,
pyridine, ꢁ208C!RT; o) propynyllithium, THF, ꢁ208C!08C, 76%
(over both steps). Cp=cyclopentadienyl, DIBAL-H=diisobutylalumi-
num hydride, DMAP=4-dimethylaminopyridine, DMPU=1,3-dimethyl-
tetrahydro-2-pyrimidinone, LDA=lithium diisopropylamide, MOM=
methoxymethyl, TBDPS=tert-butyldiphenylsilyl, SYNPHOS=[(5,6),-
(5’,6’)-bis(ethylenedioxy)biphenyl-2,2’-diyl]bis(diphenylphosphine).
regioisomeric alkenylsiloxanes 34 were immediately proto-
desilylated with AgF as a carbophilic fluoride source,[29]
followed by cleavage of the peripheral TBS ethers with
TBAF. Careful inspection by NMR spectroscopy and HPLC
showed that no other isomer integrating to more than 3% was
present in the crude product, from which analytically pure
tulearin C (4) was isolated in up to 60% yield over three
steps.[31b] The spectral data matched well, and the impeccable
purity of the synthetic samples favorably compared to the
authentic natural product (see the Supporting Information).
Although the major application of alkyne metathesis in
the past was the stereoselective preparation of Z-alkenes by a
Lindlar-type semireduction of the cycloalkynes primarily
formed,[7,32] it now becomes increasingly clear that this
method also excels in the E-alkene series.[30] This notion is
showcased by the stereoselective tulearin synthesis outlined
above, which surpasses the approach based on conventional
RCM[4] as long as no inherently E-selective alkene metathesis
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Communications
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Scheme 6. a) EDC·HCl, DMAP, CH2Cl2, 98%; b) 35 (4 mol%), toluene
(2 mm), M.S. (5 ꢁ), 508C, 96%; c) (EtO)3SiH, [Cp*Ru(MeCN)3]PF6 (10
mol%), 08C; d) AgF, THF/MeOH/H2O (10:9:1); e) TBAF, THF, 43–
60% (over three steps). Cp*=pentamethylcyclopentadienyl, EDC=N’-
(3-dimethylaminopropyl)-N-ethylcarbodiimide.
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catalysts are available. Since (cyclo)alkynes also provide
ample opportunity for functionalization by post-metathesis
transformations other than semireductions,[33] the outreach of
this method is significant.
Received: August 29, 2011
Published online: October 11, 2011
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Keywords: alkyne metathesis · alkynes · hydrosilylation ·
natural products · total synthesis
.
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