Catalysis-Based Total Synthesis of Latrunculin B

Article abstract of DOI:10.1002/anie.200352413

The highly selective actin-binding latrunculins (e.g. 1) play a prominent role as probe molecules in chemical biology. A highly concise, productive, and inherently flexible approach to 1 illustrates the excellent profile and use of metal-catalyzed C-C bond formations.

Full text of DOI:10.1002/anie.200352413

Communications
Natural Product Synthesis
Catalysis-Based Total Synthesis of
Latrunculin B**
Alois Fürstner,* Dominic De Souza,
Liliana Parra-Rapado, and Jon T. Jensen
Actin is one of the two major components of the cytoskeleton
and not only determines the shape and mechanical properties
of eukaryotic cells but is also responsible for cell motility
processes as fundamental as cytokinesis or exo- and endocy-
tosis. Our present knowledge about the many biological roles
of actin derives to a large extent from a “chemical genetics”
approach based on probe molecules able to dissect this highly
sophisticated and inherently dynamic microfilament struc-
ture.[1] Among them, the latrunculins gained particular
importance because of their striking selectivity and the
surprisingly rapid onset of action.[2] They form 1:1 complexes
with actin monomers that are incapable of polymerizing to
the intact protein filament network.[3] Latrunculin B (1) and
congeners were originally isolated as the ichthyotoxic prin-
ciples of the Red Sea sponge Latrunculia magnifica and were
also found later in taxonomically unrelated organisms from
different marine habitats.[4,5]
Scheme 1. Retrosynthetic analysis of latrunculin B.
Despite the truly remarkable properties of the latruncu-
lins and their widespread use as biochemical tools, the
understanding of the structure–activity relationships (SAR)
of these exquisite actin binders is fairly limited.[6] As a first
step towards a synthesis-driven mapping of the structural
elements essential for biological activity, a concise total
synthesis of latrunculin B (1) was devised which is flexible
enough to allow structural variations at a later stage. This
flexibility was ensured by disconnecting 1 into three simple
building blocks (Scheme 1) that are easy to modify and can be
efficiently assembled through aldol chemistry, esterification,
and formation of the macrocycle by the novel ring-closing
alkyne metathesis (RCAM)/Lindlar reduction manifold.[7]
Therefore, this new approach not only complements the
previous total syntheses of 1 and its homologue latrunculin A
based on macrolactonization,[8,9] but also illustrates the
relevance of novel catalytic transformations recently devel-
oped in this laboratory.
Scheme 2. Synthesis of two building blocks by iron-catalyzed cross-
coupling reactions: a) KHMDS, PhN(Tf)2, THF, ꢀ788C, 61%;
b) [Fe(acac)3] (10 mol%), THF, ꢀ308C, 97%; c) aqueous NaOH,
MeOH, 92%; d) CDI, THF, 71%; e) NaH, PMBBr, THF, 77%; f) aq.
KOH, Et2O, 98%; g) 1-chloro-2,N,N-trimethylprop-1-en-1-ylamine, THF,
ꢀ188C; h) [Fe(acac)3] (1.5 mol%), MeMgBr, THF, ꢀ788C!08C,
80%. HMDS=hexamethyldisilazide, Tf=trifluoromethanesulfonyl,
acac=acetylacetone, CDI=N,N’-carbonyldiimidazole,
PMB=p-methoxybenzyl.
reaction proceeded stereoselectively and very rapidly under
notably mild conditions. To the best of our knowledge, this is
the first case of an iron-catalyzed cross-coupling reaction of
an enol triflate. As such, it adds to the now rapidly growing
number of examples in which cheap and benign iron salts
serve as substitutes for established palladium or nickel
catalysts in a variety of cross-coupling processes in gen-
eral.[10,11]
In full accord with this notion, the synthesis of the
cysteine-derived ketone 9 also takes advantage of iron
catalysis (Scheme 2). Acid chloride 8 was prepared from 6
through standard reactions. Although 9 had previously been
made by an uncatalyzed addition of MeMgBr to 8,[8] we found
the corresponding Fe-catalyzed process to be much more
reliable and convenient; again, the rapid reaction rate is an
additional bonus. The fact that attempted reactions of 8 with
Me2CuLi led to complete decomposition of the starting
material also bears witness to the superiority of the iron-
catalyzed procedure.[12] Although acid chloride 8 is inherently
prone to racemization, one recrystallization of the crude
material sufficed to adjust the ee of ketone 9 to 99%.
The required acid component 5 was easily prepared from
ethyl acetoacetate (2) via triflate 3 (Scheme 2). Reaction of
the latter with the Grignard reagent derived from 1-bromo-3-
pentyne in the presence of [Fe(acac)3] as precatalyst afforded
the desired product 4 in almost quantitative yield; the
[*] Prof. A. Fürstner, Dr. D. De Souza, Dr. L. Parra-Rapado,
Dipl.-Chem. J. T. Jensen
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 by the DFG (Leibniz award to A.F.), the
Swiss National Foundation (fellowship to L.P.-R.), the Fonds der
Chemischen Industrie, the ACS (Cope Scholar Funds), and the
Merck Research Council is gratefully acknowledged.
5358
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200352413
Angew. Chem. Int. Ed. 2003, 42, 5358 –5360

Angewandte
Chemie
The third building block was derived from (+)-citronel-
lene (10; 91 %ee) by selective ozonolysis of the more highly
substituted double bond and acetalization of the resulting
aldehyde.[13] Bromination of 11 provided 12, which was
treated with LiHMDS to give 13 (Scheme 3). Alkyne 13 was
Scheme 3. Synthesis of the third building block: a) O3, CH2Cl2, ꢀ788C, then
Me2S; b) HC(OMe)3, K10 montmorillonite, 75%; c) 4-dimethylaminopyridi-
nium bromide perbromide, DMAP, CH2Cl2, 87%; d) LiHMDS, THF, 90%;
e) BuLi, MeI, THF/DMPU, 95%; f) 1) aqueous HCl, THF; 2) (ꢀ)-Ipc2B(allyl),
ꢀ1008C, Et2O; (iii) TBSCl, imidazole, DMF, 78%; g) O3, MeOH, Sudan red
7B, then Me2S, 94%. DMAP=4-dimethylaminopyridine, DMPU=1,3-
dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, Ipc=isopinocampheyl,
TBS=tert-butyldimethylsilyl, DMF=N,N-dimethylformamide.
Scheme 4. Completion of the total synthesis: a) TiCl4, iPr2NEt, CH2Cl2,
ꢀ788C, 73%; b) aqueous HCl, THF; c) CSA, MeOH, 64% (over two steps);
d) 1) Tf2O, pyridine, CH2Cl2, ꢀ108C; 2) Na salt of 5, 15[crown]-5, THF,
58%; e) [Mo{N(tBu)(3,5-Me2C6H3)}3] (5 mol%), toluene, CH2Cl2, 808C,
70%; f) 1) H2, Lindlar catalyst, CH2Cl2, quant.; 2) CAN, MeCN/H2O, 78%.
CSA=(+)-10-camphorsulfonic acid, CAN=ceric ammonium nitrate.
then methylated by reaction with BuLi and MeI. Deprotec-
tion of the acetal in 14, allylation of the resulting aldehyde
with (ꢀ )-Ipc2B(allyl),[14] and subsequent protection of the
alcohol with a TBS group furnished 15 in diastereomerically
pure form (d.r. > 99.5:0.5). Selective ozonolysis of its alkene
entity afforded the required product 16 for further elabo-
ration.
alkene is another noteworthy aspect of this transformation.
The somewhat strained cycloalkyne 21 (Table 1) thus formed
was subjected to a Lindlar reduction to ensure the stereo-
selective formation of the Z-alkene entity, followed by
Reaction of aldehyde 16 with the titanium enolate[15]
derived from ketone 9 gave aldol 17 as a mixture (2:1) of
diastereomers (Scheme 4). No attempt was made to improve
this result as the stereochemical outcome was conveniently
rectified at the next step by an equilibration process, which is
well-precedented in the latrunculin series.[6a,8] Thus, acid-
catalyzed cleavage of the TBS group in 17 delivered hemi-
acetal 18 (d.r. up to 7:1). Under these conditions, a transient
oxonium ion is formed, which undergoes rapid loss of the
axial OH group at C13; as 1,3-diaxial interactions are avoided
during the re-addition of water to this intermediate, the
formation of product 18 with an equatorially disposed OH
function at that site is highly favored. Glycosylation with
MeOH, conversion of product 19 into the corresponding
triflate, and reaction with the sodium salt of acid 5 furnished
diyne 20, the substrate for the envisaged macrocyclization by
RCAM.
This reaction proceeded exceptionally well in the pres-
ence of [Mo{N(tBu)(3,5-Me2C6H3)}3] precatalyst, which was
activated in situ with CH2Cl2 as recently described by our
group.[16] Neither the dense array of functional groups nor the
branching methyl substituent a to one of the alkyne units
interfere with this catalytic system.[17] The chemoselective
reaction of the triple bonds in the presence of a preexisting
Table 1: Selected data for 21 and 1.
21: [a]2D0 =+61.38 (c=0.75, CH2Cl2); IR (ATR): n=2935, 1695, 1672,
~
1
1512, 1444, 1276, 1248, 1214, 1093, 1031 cmꢀ1; H NMR (400 MHz,
CD2Cl2): d=1.43 (d, 3H, J=6.9 Hz), 1.40–1.57 (m, 2H), 1.86 (d, 3H,
J=1.3 Hz), 1.75–1.90 (m, 4H), 2.08–2.40 (m, 5H), 2.49–2.53 (m, 1H),
3.14 (s, 3H), 3.17–3.32 (m, 4H), 3.79 (s, 3H), 3.83 (dd, 1H, J=3.3 Hz,
9.0 Hz), 4.33 (d, 1H, J=14.4 Hz), 4.91–4.99 (m, 1H), 5.00 (d, 1H,
J=14.4 Hz), 5.19–5.22 (m, 1H), 5.58 (d, 3H, J=1.3 Hz), 6.87 (d, 2H,
J=8.6 Hz), 7.22 ppm (d, 2H, J=8.6 Hz); 13C NMR (100 MHz, CD2Cl2):
d=19.05, 21.86, 24.99, 25.42, 26.33, 29.76, 31.09, 33.37, 33.92, 34.24,
47.36, 47.47, 55.28, 59.23, 65.66, 67.09, 80.96, 86.23, 101.98, 113.93,
118.73, 129.06, 130.00, 156.83, 159.22, 165.74, 172.59 ppm; MS (ESI,
70 eV): m/z (%): 305 (100), 287 (20), 273 (13), 255 (26), 227 (15), 213
(23), 203 (15), 149 (11), 121 (91); HRMS: calcd for C29H37NNaO6S
[M+Na+]: 550.223930, found: 550.22450.
1: [a]2D0 =+1228 (c=0.55, CHCl3); IR (ATR): n=3328, 2952, 1678, 1278,
~
1
1092, 1057 cmꢀ1; H NMR (400 MHz, CDCl3): d=0.95 (d, 3H,
J=6.3 Hz), 1.07–2.39 (m, 11H), 1.90 (d, 3H, J=1.3 Hz), 2.60–2.80 (m,
2H), 3.39 (dd, 1H, J=6.3 Hz, 11.6 Hz), 3.47 (dd, 1H, J=8.8 Hz,
11.6 Hz), 3.81–3.85 (m, 1H), 3.87 (s, 1H, OH), 4.24 (br t, 1H,
J=10.6 Hz), 5.05 (dt, 1H, J=1.5 Hz, 11.2 Hz), 5.25 (dt, 1H, J=3.0 Hz,
11.2 Hz), 5.43–5.46 (m, 1H), 5.68 (d, 1H, J=1.3 Hz), 5.77 ppm (s, 1H,
NH); 13C NMR (100 MHz, CDCl3): d=22.2, 24.0, 26.9, 28.7, 28.8, 30.9,
31.2, 31.4, 35.3, 35.8, 61.3, 62.5, 68.7, 97.8, 117.8, 127.4, 135.8, 154.5,
165.3, 174.7 ppm.
Angew. Chem. Int. Ed. 2003, 42, 5358 –5360
www.angewandte.org
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5359

Communications
[9] a) J. D. White, M. Kawasaki, J. Org. Chem. 1992, 57, 5292 – 5300;
b) J. D. White, M. Kawasaki, J. Am. Chem. Soc. 1990, 112, 4991–
4993.
concurrent cleavage of the N-PMB group and the methyl
glycoside with CAN. Although this final deprotection was
previously described as low-yielding,[8] we were pleased to
find that it provided 1 (Table 1) in satisfactory yield (78%)
simply upon prolongation of the reaction time.
In summary, a concise, productive, and inherently flexible
route to latrunculin B (1) has been outlined based on Fe-
catalyzed cross-coupling reactions[10–12] and alkyne metathe-
sis[16,18] as the key steps. The longest linear sequence
comprises 16 steps, which were performed in 14 operations,
and provides an overall yield of approximately 6%. An
extension of this approach to the synthesis of a focused library
of latrunculin analogues is underway and will be reported in
due course.
[10] a) A. Fürstner, A. Leitner, M. MØndez, H. Krause, J. Am. Chem.
Soc. 2002, 124, 13856 – 13863; b) A. Fürstner, A. Leitner,
Angew. Chem. 2002, 114, 632 – 635; Angew. Chem. Int. Ed.
2002, 41, 609 – 612; c) A. Fürstner, A. Leitner, Angew. Chem.
2003, 115, 320 – 323; Angew. Chem. Int. Ed. 2003, 42, 308 – 311.
[11] For Fe-catalyzed reactions of alkenyl halides, see: a) M. Tamura,
J. K. Kochi, J. Am. Chem. Soc. 1971, 93, 1487 – 1489; b) S. M.
Neumann, J. K. Kochi, J. Org. Chem. 1975, 40, 599 – 606; c) G.
Cahiez, H. Avedissian, Synthesis 1998, 1199 – 1205; d) G. A.
Molander, B. J. Rahn, D. C. Shubert, S. E. Bonde, Tetrahedron
Lett. 1983, 24, 5449 – 5452; e) A. Fürstner, H. Brunner, Tetrahe-
dron Lett. 1996, 37, 7009 – 7012; f) B. Hölzer, R. W. Hoffmann,
Chem. Commun. 2003, 732 – 733.
[12] For iron-catalyzed syntheses of simple ketones, see: a) V.
Fiandanese, G. Marchese, V. Martina, L. Ronzini, Tetrahedron
Lett. 1984, 25, 4805 – 4808; b) C. Cardellicchio, V. Fiandanese, G.
Marchese, L. Ronzini, Tetrahedron Lett. 1987, 28, 2053 – 2056.
[13] A. G. M. Barrett, R. A. E. Carr, S. V. Attwood, G. Richardson,
N. D. A. Walshe, J. Org. Chem. 1986, 51, 4840 – 4856.
Received: July 18, 2003 [Z52413]
Keywords: alkynes · cross-coupling · macrocycles · metathesis ·
.
natural products
[14] U. S. Racherla, Y. Liao, H. C. Brown, J. Org. Chem. 1992, 57,
6614 – 6614.
[15] D. A. Evans, J. S. Clark, R. Metternich, V. J. Novack, G. S.
Sheppard, J. Am. Chem. Soc. 1990, 112, 866 – 868.
[16] a) A. Fürstner, C. Mathes, C. W. Lehmann, J. Am. Chem. Soc.
1999, 121, 9453 – 9454; b) A. Fürstner, C. Mathes, C. W. Leh-
mann, Chem. Eur. J. 2001, 7, 5299 – 5317.
[1] a) J. R. Peterson, T. J. Mitchison, Chem. Biol. 2002, 9, 1275 –
1285; b) K.-S. Yeung, I. Paterson, Angew. Chem. 2002, 114,
4826 – 4847; Angew. Chem. Int. Ed. 2002, 41, 4632 – 4653.
[2] For leading references, see: a) I. Spector, N. R. Shochet, Y.
Kashman, A. Groweiss, Science 1983, 219, 493 – 495; b) I.
Spector, N. R. Shochet, D. Blasberger, Y. Kashman, Cell Motil.
Cytoskeleton 1989, 13, 127 – 144; c) Molecular Motors and the
Cytoskeleton, Part B: K. Ayscough, Methods Enzymol. 1998,
298, 18 – 25; d) K. R. Ayscough, J. Stryker, N. Pokala, M.
Sanders, P. Crews, D. G. Drubin, J. Cell Biol. 1997, 137, 399 – 416.
[3] See i.a.: a) W. M. Morton, K. R. Ayscough, P. J. McLaughlin,
Nat. Cell Biol. 2000, 2, 376 – 378; b) E. G. Yarmola, T. Soma-
sundaram, T. A. Boring, I. Spector, M. R. Bubb, J. Biol. Chem.
2000, 275, 28120 – 28127.
[17] This must be seen in light of the fact that steric hindrance close to
a double bond can be a significant obstacle in conventional
alkene metathesis; the same pertains to sulfur-containing com-
pounds, which are usually highly problematic in alkene meta-
thesis. For a Review, see: A. Fürstner, Angew. Chem. 2000, 112,
3140 – 3172; Angew. Chem. Int. Ed. 2000, 39, 3012 – 3043; see
also: S. J. Connon, S. Blechert, Angew. Chem. 2003, 115, 1944 –
1968; Angew. Chem. Int. Ed. 2003, 42, 1900 – 1923.
[18] For previous applications of RCAM to total synthesis, see
reference [16b] and the following: a) A. Fürstner, K. Grela, C.
Mathes, C. W. Lehmann, J. Am. Chem. Soc. 2000, 122, 11799 –
11805; b) A. Fürstner, K. Radkowski, J. Grabowski, C. Wirtz, R.
Mynott, J. Org. Chem. 2000, 65, 8758 – 8762; c) A. Fürstner, F.
Stelzer, A. Rumbo, H. Krause, Chem. Eur. J. 2002, 8, 1856 – 1871;
d) A. Fürstner, A.-S. Castanet, K. Radkowski, C. W. Lehmann, J.
Org. Chem. 2003, 68, 1521 – 1528.
[4] a) I. Neeman, L. Fishelson, Y. Kashman, Mar. Biol. 1975, 30,
293 – 296; b) Y. Kashman, A. Groweiss, U. Shmueli, Tetrahedron
Lett. 1980, 21, 3629 – 3632; c) A. Groweiss, U. Shmueli, Y.
Kashman, J. Org. Chem. 1983, 48, 3512 – 3516.
[5] a) R. K. Okuda, P. J. Scheuer, Experientia 1985, 41, 1355 – 1356;
b) Y. Kakou, P. Crews, G. J. Bakus, J. Nat. Prod. 1987, 50, 482 –
484; c) C. W. Jefford, G. Bernardinelli, J. Tanaka, T. Higa,
Tetrahedron Lett. 1996, 37, 159 – 162; d) N. K. Gulavita, S. P.
Gunasekera, S. A. Pomponi, J. Nat. Prod. 1992, 55, 506 – 508;
e) J. Tanaka, T. Higa, G. Bernardinelli, C. W. Jefford, Chem. Lett.
1996, 255 – 256; f) D. Mebs, J. Chem. Ecol. 1985, 11, 713 – 716;
g) T. R. Hoye, S.-E. N. Ayyad, B. M. Eklov, N. E. Hashish, W. T.
Shier, K. A. El Sayed, M. T. Hamann, J. Am. Chem. Soc. 2002,
124, 7405 – 7410.
[6] This knowledge is entirely based on derivatizations of the
natural product; see: a) D. Blasberger, S. Carmely, M. Cojocaru,
I. Spector, N. R. Shochet, Y. Kashman, Liebigs Ann. Chem. 1989,
1171 – 1188; b) I. Spector, N. R. Shochet, D. Blasberger, Y.
Kashman, J. Cell Biol. 1986, 103, 1467.
[7] a) A. Fürstner, G. Seidel, Angew. Chem. 1998, 110, 1758 – 1760;
Angew. Chem. Int. Ed. 1998, 37, 1734 – 1736; b) A. Fürstner, O.
Guth, A. Rumbo, G. Seidel, J. Am. Chem. Soc. 1999, 121, 11108 –
11113.
[8] a) A. B. Smith, J. W. Leahy, I. Noda, S. W. Remiszewski, N. J.
Liverton, R. Zibuck, J. Am. Chem. Soc. 1992, 114, 2995 – 3007;
b) A. B. Smith, I. Noda, S. W. Remiszewski, N. J. Liverton, R.
Zibuck, J. Org. Chem. 1990, 55, 3977 – 3979; c) R. Zibuck, N. J.
Liverton, A. B. Smith, J. Am. Chem. Soc. 1986, 108, 2451– 2453.
5360
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 5358 –5360