Communications
application profile of this emerging methodology. Z-Selective
semihydrogenation of the triple bond in 27 with Lindlarꢀs
catalyst in the presence of a large excess of quinoline to
suppress overreduction followed by consecutive cleavage of
the Teoc group and the methyl glycoside in 28 under standard
conditions furnished latrunculin A (1). The spectroscopic and
analytical data for the product were in excellent agreement
with those already reported.[1,5,6]
In summary, a concise and efficient synthesis of the
strongly actin-binding marine natural product latrunculin A
has been achieved. The chosen route features the first
successful implementation of a ring-closing enyne–yne meta-
thesis reaction into a total synthesis and is largely catalysis-
based overall. Furthermore, a practical solution for the
preparation of the key intermediate 3 has been developed
that clearly surpasses prior art. As this building block can also
serve as a convenient platform for the preparation of non-
natural analogues of both 1 and 2, we are now in a favorable
position for a synthesis-driven evaluation of the still largely
unknown structure–activity profile of this important class of
bioactive macrolides. Our investigations along these lines will
be reported shortly.
Scheme 4. Preparation of the acid part: a) (1) NaH, CH2Cl2; (2) Tf2O,
82%; b) Grignard reagent 13, [Fe(acac)3] (15 mol%), ꢀ308C, THF, 67–
83%; c) aq. HCOOH, reflux; d) reagent 16, K2CO3, MeOH, 80% (over
both steps); e) [Cp2Zr(H)Cl], CH2Cl2, then I2, 56%; f) 9-MeO-9-BBN,
ꢂ
NaC CMe, [Pd(PPh3)4] (5 mol%), THF, reflux, 77%; g) KOH, aq. THF,
82%. Tf=trifluoromethanesulfonyl, acac=acetylacetonate, Cp=cyclo-
pentadienyl, BBN=borabicyclo[3.3.1]nonane.
Received: February 1, 2005
Published online: April 21, 2005
Keywords: alkynes · cross-coupling · macrocycles ·
.
metathesis · natural products
Coupling of the fragments now in hand required the
consecutive formation of triflate 21 and substitution with the
sodium salt of acid 20 (see Scheme 5). All attempts to perform
this esterification under Mitsunobu conditions were unre-
warding. We were pleased to note that the resulting product
22 underwent productive enyne–yne metathesis to give the
desired product 23 in the presence of catalytic amounts of
[Mo{N(tBu)(Ar)}3] (26), activated in situ with CH2Cl2 as
previously described.[22,23] This success, however, was
thwarted by our inability to cleave the remaining N-PMB
group from the thiazolidinone ring with either 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ) or cerium ammonium
nitrate (CAN). Although we were apprehensive that this step
might be problematic,[24] it seemed likely that the high ring
strain of the cyclic enyne 23 promotes its degradation by
rendering the single-electron oxidation of this reactive entity
more facile than the cleavage of the PMB group.
To test this hypothesis, cleavage of the N-PMB group
prior to ring closure was attempted. It was gratifying to note
that this change in the order of events paved the way to the
target. Thus, treatment of the acyclic enyne 22 with CAN
afforded product 24 in acceptable yield. Although this
compound could not be cyclized owing to the known
incompatibility of complex 26 with N-unprotected amides,[22]
conversion into the Teoc derivative 25 allowed the crucial
enyne–yne metathesis to proceed with rigorous chemoselec-
tivity at the triple bonds to form the highly strained 16-
membered cyclic product 27 in 70% yield. Not only is this the
smallest ring size ever to be formed by ring-closing enyne–yne
metathesis[11] but the compatibility with the dense and diverse
array of functional groups also attests to the excellent
[1] Isolation: a) I. Neeman, L. Fishelson, Y. Kashman, Mar. Biol.
1975, 30, 293 – 296; b) A. Groweiss, U. Shmueli, Y. Kashman, J.
Org. Chem. 1983, 48, 3512 – 3516; c) Y. Kashman, A. Groweiss,
R. Lidor, D. Blasberger, S. Carmely, Tetrahedron 1985, 41, 1905 –
1914; d) R. K. Okuda, P. J. Scheuer, Experientia 1985, 41, 1355 –
1356; e) Y. Kakou, P. Crews, G. J. Bakus, J. Nat. Prod. 1987, 50,
482 – 484; f) N. K. Gulavita, S. P. Gunasekera, S. A. Pomponi, J.
Nat. Prod. 1992, 55, 506 – 508; g) J. Tanaka, T. Higa, G.
Bernardinelli, C. W. Jefford, Chem. Lett. 1996, 255 – 256; h) D.
Mebs, J. Chem. Ecol. 1985, 11, 713 – 716; i) 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.
[2] I. Spector, N. R. Shochet, Y. Kashman, A. Groweiss, Science
1983, 219, 493 – 495.
[3] Selected reviews: a) K.-S. Yeung, I. Paterson, Angew. Chem.
2002, 114, 4826 – 4847; Angew. Chem. Int. Ed. 2002, 41, 4632 –
4653; b) J. R. Peterson, T. J. Mitchison, Chem. Biol. 2002, 9,
1275 – 1285; c) I. Spector, N. R. Shochet, D. Blasberger, Y.
Kashman, Cell Motil. Cytoskeleton 1989, 13, 127 – 144; d) W. M.
Morton, K. R. Ayscough, P. J. McLaughlin, Nat. Cell Biol. 2000,
2, 376 – 378, and references therein.
[4] a) Y. Gachet, S. Tournier, J. B. A. Millar, J. S. Hyams, Nature
2001, 412, 352 – 355; b) see also: Y. Nakaseko, M. Yanagida,
Nature 2001, 412, 291 – 292.
[5] 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.
[6] 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.
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Angew. Chem. Int. Ed. 2005, 44, 3462 –3466