Reactivity-based one-pot synthesis of a Lewis Y carbohydrate hapten: A colon-rectal cancer antigen determinant

Article abstract of DOI:10.1002/1521-3773(20021104)41:21<4098::AID-ANIE4098>3.0.CO;2-P

The stereospecific synthesis of a tumor-related carbohydrate antigenic hapten, Lewis Y, from three basic building units 1 - 3 has been achieved by a reactivity-based one-pot strategy. RRV = relative reactivity value.

Full text of DOI:10.1002/1521-3773(20021104)41:21<4098::AID-ANIE4098>3.0.CO;2-P

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extraction of ZnII but not CdII. The highest selectivity with
single ligands (Table 1) are 7.6-fold (6) and 3.1-fold (8).
Interestingly both 6 and 8 are ketone-derived ligands with 2-
aryl substituents, suggesting that this combination of sub-
stituents enhances extraction of ZnII.
These studies demonstrate that dynamic combinatorial
chemistry is a useful tool for the discovery of newmetal ion
complexes. Synergistic interactions of ligands are useful for
building in selectivity for metal ions by using simple ligand
substituent effects. This method has potential for practical
applications given that the ligands are inexpensive and readily
synthesized. However, there remains much to learn about the
construction of an effective library of metal ion complexes.
Future work will focus on exploring strategic positions for
substitutents on different types of ligands and on increasing
the complexity of the library by using metal complexes that
bind three ligands.
[9] J. Rydberg, T. Sekine in Principles and Practices of Solvent Extraction
(Eds.: J. M. Rydberg, C. Musikas, G. R. Choppin), Marcel Dekker,
NewYork, 1992, pp. 101 156.
[10] G. R. L. Cousins, S.-A. Poulsen, J. K. M. Sanders, Chem. Commun.
1999, 1575 1576.
[11] G. R. L. Cousins, R. L. E. Furlan, Y.-F. Ng, J. E. Redman, J. K. M.
Sanders, Angew. Chem. 2001, 113, 437 442; Angew. Chem. Int. Ed.
2001, 40, 423 428.
[12] R. L. E. Furlan, G. R. L. Cousins, J. K. M. Sanders, Chem. Commun.
2000, 1761 1762.
[13] T. Bunyapaiboonsri, O. Ramstrom, S. Lohmann, J.-M. Lehn, L. Peng,
M. Goeldner, ChemBioChem 2001, 2, 438 444.
[14] M. L. Dietz, A. H. Bond, B. P. Hay, R. Chiarizia, V. J. Huber, A. W.
Herlinger, Chem. Commun. 1999, 1177 1178.
[15] Y. Sasaki, G. R. Choppin, J. Radioanal. Nucl. Chem. 1997, 222, 271
274.
[16] D. A. J. Voss, L. A. Buttrey-Thomas, T. S. Janik, M. R. Churchill, J. R.
Morrow, Inorg. Chim. Acta 2001, 317, 149 156.
Experimental Section
Extraction solutions were stirred in foil-wrapped vials with teflon-lined
crimp caps for 2 h and were analyzed for ZnII or CdII by use of dithizone
indicator.[8] Standard deviations in measurements are 10% or less.
Total Synthesis of Leucascandrolide A**
Alec Fettes and Erick M. Carreira*
Acylhydrazone ligands were prepared by heating a solution of either 2-
pyridinecarboxaldehyde (PCA) or 2-acetylpyridine in ethanol, a stoichio-
metric amount of the corresponding acylhydrazide, and a fewdrops of
hydrochloric acid. Concentration of the solution and cooling followed by
recrystallization from ethanol or ethanol/hexane yielded the ligand. In a
typical preparation, benzoic hydrazide (0.272 g, 2.00 mmol) was added to a
solution of PCA (0.190 mL, 2.00 mmol) in ethanol (20 mL) and a fewdrops
of hydrochloric acid was added. The solution was gently heated and stirred
for 0.25 h. Upon cooling, a white precipitate (1) formed, which was washed
with ethanol, recrystallized, and dried in vacuo. 1H NMR (400 MHz,
[D6]DMSO, 248C, TMS): d ¼ 12.0 (s, 1H; NH), 8.60 (d, 3J(H,H) ¼ 4 Hz,1H;
H10), 8.46 (s, 1H; H6), 7.92 (m, 4H; H7, H8, H1, H5), 7.60 (t, 3J(H,H) ¼
4.2 Hz, 1H; H9), 7.53 (t, 3J(H,H) ¼ 4.7 Hz, 2H; H2, H4), 7.40 ppm (t,
3J(H,H) ¼ 5.6 Hz, 1H; H3) (see Supporting Information for ligand-
numbering scheme); ESI-MS: m/z (%): 226(52) [PCA-BAHþHþ],
248(100) [PCA-BAHþNaþ].
Leucascandrolide A (1), a polyoxygenated marine macro-
lide of a newgenus, was isolated in 1996 by Pietra and co-
Me
11
9
7
O
O
OMeO
O
O
17
1
N
H
N
O
O
MeO
Me
O
1
Me
[Zn(1À)2] was prepared by dissolving Zn(NO3)2 (0.788 g, 2.65 mmol) in hot
ethanol (100 mL), followed by the addition of PCA (5.30 mmol), and
benzoic hydrazide (0.721 g, 5.30 mol). Triethylamine (5.30 mmol) was
added and the solution was heated to boiling for 0.25 h. Upon cooling, a
bright yellowprecipitate was recovered and recrystallized from ethanol.
1H NMR (400 MHz, [D1]chloroform, 258C, TMS): d ¼ 8.50 (s, 1H; H6),
8.21 (d, 3J(H,H) ¼ 7.6 Hz, 2H; H1, H5), 8.06 (d, 3J(H,H) ¼ 4.8 Hz, 1H;
H10), 7.72 (t, 3J(H,H) ¼ 7.6 Hz,1H; H8), 7.38 (m, 4H; H9, H2, H4, H7),
7.14 ppm (t, 3J(H,H) ¼ 5.2 Hz, 1H; H3); ESI MS: m/z (%): 513(100),
514(32), 515(63), 516(29), 517(44), [Zn(PCA-BAH)2þHþ].
workers from the calcareous sponge Leucascandra caveolata
along the east coasts of NewCaledonia. [1] Despite subsequent
intensive efforts, later expeditions failed to provide additional
leucascandrolide A.[2] Leucascandrolide A (1) displays strong
cytotoxic activity in vitro on human KB and P388 cancer cell
lines (IC50 ¼ 50 and 250 ngmLÀ1, respectively) as well as
powerful antifungal activity. An elegant total synthesis has
been recently reported by Leighton and co-workers,[3] and a
formal synthesis has been documented by Rychnovsky and
co-workers[4] along with synthetic studies of the core by
Crimmins et al.[5] and Kozmin[6] and a synthesis of the oxazole
side chain by Wipf et al.[7] The lack of availability of
Received: May 29, 2002 [Z19404]
[*] Prof. Dr. E. M. Carreira, A. Fettes
Laboratorium f¸r Organische Chemie
ETH Hˆnggerberg, HCI H-335
8093 Z¸rich (Switzerland)
[1] J.-M. Lehn, Chem. Eur. J. 1999, 5, 2455 2463.
[2] P. A. Brady, J. K. M. Sanders, J. Chem. Soc. Perkin Trans. 1 1997, 3237
3253.
[3] O. Storm, J. L¸ning, Chem. Eur. J. 2002, 8, 793 798.
[4] V. Goral, M. I. Nelen, A. V. Eliseev, J.-M. Lehn, Proc. Natl. Acad. Sci.
USA 2001, 98, 1347 1352.
Fax : (þ 41)1-632-1328
E-mail: carreira@org.chem.ethz.ch
[**] We thank the ETH, SNF, Aventis, Eli Lilly, Merck, and Hoffmann-
LaRoche for their generous support of our research program. We are
grateful to Prof. Armido Studer (Marburg) for kindly supplying the
silylated cyclohexadiene he has developed for tin-free radical
reactions.
[5] I. Huc, M. J. Krische, D. P. Funeriu, J.-M. Lehn, Eur. J. Inorg. Chem.
1999, 1415 1420.
[6] B. Klekota, M. H. Hammond, B. L. Miller, Tetrahedron Lett. 1997, 38,
8639 8642.
[7] C. M. Karan, B. L. Miller, J. Am. Chem. Soc. 2001, 123, 7455 7456.
[8] D. M. Epstein, S. Choudhary, M. R. Churchill, K. Keil, A. V. Eliseev,
J. R. Morrow, Inorg. Chem. 2001, 40, 1591 1596.
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
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Leucascandrolide A (1) from natural sources, its powerful
biological activity as well as its unusual structure compelled us
to embark on a program aimed at its total synthesis. Herein,
we describe a concise, stereocontrolled, enantioselective total
synthesis of the natural product which is realized through the
application of modern enantio- and diastereoselective meth-
ods for asymmetric synthesis.
Me Me
Me Me
O
a)
OH
O
O
O
O
+
Me
Me
H
42 %
91 % ee
Me
O
OTMS
7
8
b) 78 %
OR OR
O
OH
O
O
c–e)
92 %
H
Me
OBu
In our retrosynthetic strategy, we envisioned macrolacto-
nization and late-stage introduction of the C17 side chain
(Scheme 1). Additionally, the 2,6-trans-substituted tetrahy-
dropyran would require a trans-selective intramolecular
oxidative cyclization of a 6-hydroxy alkene. Cyclization retron
2 would be derived from methyl ketone 3 and aldehyde 4 by
stereoselective aldol addition. The key building block 4 could
be conveniently assembled by employing (R)-isopropylidene
glyceraldehyde (5) and acetylene 6 by using a method we have
described recently.[8]
10 (R = TES)
f, g) 80 %
OH OH
9
OR
O
h)
O
Me
OEt
63 %
Me
O
OEt
11
12 (R = H)
13 (R = TBS)
i) 96 %
OTBS
O
O
j)
The synthesis of methyl ketone 14 commences with the
enantioselective addition of trimethylsilyl dienolate 7 to
crotonaldehyde catalyzed by our (R)-Tol-BINAP copper(i)
fluoride complex (2 mol%) to give aldol adduct 8 in 42%
Me
7 O
OEt
86 %
14
Scheme 2. a) (R)-Tol-BINAP
(2.1 mol%),
Cu(OTf)2
(2.0 mol%),
Bu4NPh3SiF2 (4.0 mol%), THF, À788C, then 7 and crotonaldehyde, 4 h,
then TFA, 42%; b) nBuOH, reflux, 1 h, 78%; c) NaBH4, Et3B, MeOH,
THF, À788C, 5 h; d) TESCl, imid., DMAP, DMF, RT, 12 h; e) DIBAL-H,
toluene, À788C, 30 min, 92% (3 steps) (d.r. > 95:5); f) DBU, LiCl,
(EtO)2P(O)CH2CO2Et, CH3CN, RT, 2 h; g) TBAF, THF, RT, 2 h, 80%
(2 steps); h) tBuOK (10 mol%), THF, 08C, 63% (d.r. 10:1); i) TBSCl,
imid., DMAP, DMF, RT, 96%; j) PdCl2 (20 mol%), CuCl, O2, DMF/H2O
7:1, RT, 86%. DBU ¼ 1,8-diazabicyclo[5.4.0]undec-7-ene, DIBAL-H ¼ di-
isobutylaluminium hydride, DMAP ¼ 4-N,N-dimethylamino pyridine,
imid. ¼ imidazole, TBAF ¼ tetrabutylammonium fluoride, TBS ¼ tert-bu-
tyldimethylsilyl, TES ¼ triethylsilyl, TFA ¼ trifluoroacetic acid, TMS ¼ tri-
methylsilyl, (R)-Tol-BINAP ¼ (R)-2,2’-Bis(di-p-tolyl-phosphino)-[1,1’]-bi-
naphthyl.
yield and 91% ee (by HPLC) (Scheme 2).[9] The C O
¼
addition reactions of crotonaldehyde are typically executed
only with some difficulty, because of its susceptibility towards
polymerization; thus, formation of product 8 in high levels of
enantioselectivity is noteworthy. When adduct 8 was heated at
reflux in n-butanol, keto ester 9 was isolated (78%), which,
following syn reduction,[10] protection of the corresponding
diol, and semireduction of the butyl ester with DIBAL-H in
toluene, furnished aldehyde 10 (92% over 3 steps). Horner-
Wadsworth-Emmons olefination under the conditions devel-
oped by Roush and Masamune[11] followed by deprotection of
the silyl ethers afforded 11 (80% over 2 steps). This diol ester
was observed to undergo cyclization readily upon treatment
with catalytic amounts of tBuOK to give the thermodynami-
cally favored 2,6-syn-disubstituted tetrahydropyran 12 in 63%
yield.[12] The free secondary alcohol was then protected to
furnish silyl ether 13 (96%). Further elaboration of this
intermediate to methyl ketone 14 necessitated the execution
of a regioselective Wacker oxidation, which would need to
proceed without jeopardizing the stereocenter at C7.[13] We
were pleased to discover that 13 participated in a high-
yielding, highly regioselective Wacker oxidation reaction that
gave access to the desired methyl ketone 14 in 86% yield. It is
worth noting that this advanced intermediate possesses one of
the tetrahydropyran rings found in the natural product with
attendant stereocenters and, importantly, is accessed in nine
steps and 30% overall yield from 8.
The next key intermediate, aldehyde 19, was conveniently
prepared starting from known alcohol 15 (Scheme 3).[14]
Oxidation of 15 to the corresponding aldehyde (TEMPO/
bleach) was followed by conversion to terminal alkyne 6 in
87% yield according to the Bestmann Roth protocol.[15] The
addition of 6 to (R)-isopropylidene glyceraldehyde (5)[16] was
effected employing the method we have recently developed
for the in situ generation of Zn-alkynilides under mild
conditions. In the context of this project we aimed to establish
Scheme 1. Retrosynthetic Analysis. TIPS ¼ triisopropylsilyl.
Angew. Chem. Int. Ed. 2002, 41, No. 21
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Me
Me
Me
Me
c)
a, b)
OTBS
OTBS
OR2
HO
87 %
OH
O
O
OH OH
OR1
O
75 %
OTIPS
15 OTIPS
6
d.r. 94:6
a)
b)
OBz O
19 + 14
80 %
97 % 17
Me
Me
O
O
Me
OEt
O
Me
Me
O
O
Me
O
d,e)
Me
O
Me
Me
O
Me
O
90 %
20
OTIPS
16
OBz
OH
OR
21 (R1 = Bz, R2 = Et)
22 (R1 = H, R2 = Me)
c) 92 %
17 (R = TIPS)
18 (R = H)
f) 96 %
Me
Me
d)
65 %
Me
O
g)
O
H
87 %
Me
O
Me
OBz
11
9
7
OTBS
OTBS
OR2
O
19
OR
O
O
O
OH
OH
O
Scheme 3. a) TEMPO, bleach, KBr, CH2Cl2, pH 8.6 buffer, RT, 15 min;
b) (MeO)2P(O)CN2CO2CH3, K2CO3, MeOH, 16 h, RT, 87% (2 steps);
c) Zn(OTf)2, (À)-N-methylephedrine, Et3N, toluene, then 5, RT, 48 h, 75%
(d.r. 94:6); d) LiAlH4, THF, RT, 5 h; e) BzCl, Et3N, DMAP, CH2Cl2, RT,
15 h, 90% (2 steps); f) TBAF, THF, 08C!RT, 24 h, 96%; g) TPAP, NMO,
CH2Cl2, RT, 30 min, 87%. Bz ¼ benzoyl, NMO ¼ N-methyl morpholine N-
oxide, TEMPO ¼ 2,2,6,6-tetramethylpiperidine-1-oxyl, TPAP ¼ tetrapro-
pylammonium perruthenate.
g)
R1
O
O
O
O
O
Me
Me
O
Me
Me
26 (R = H)
27 (R = Me)
23 (R1 = SeTIPP, R2 = Me)
24 (R1 = H, R2 = Me)
25 (R1 = H, R2 = H)
h) 49 %
(3 steps)
e) 80 %
f)
whether the reaction could be executed in a reagent-
controlled manner with a chiral aldehyde possessing a stereo-
genic center at Ca.[17] In this respect, we were delighted to find
that 6, upon treatment with Zn(OTf)2, (À)-N-methylephe-
drine, and Et3N in toluene, cleanly adds to 5 to give
propargylic alcohol 16 in 75% yield and 94:6 diastereoselec-
tivity. Adduct 16 was converted to allylic benzoate (E)-17 by
reduction with lithium aluminum hydride followed by ben-
zoylation (90% over two steps). Desilylation of 17 with TBAF
gave 18 (96%) and subsequent Ley oxidation[18] led to
aldehyde 19 (87%) in seven steps and 49% overall yield
from 15.
Scheme 4. a) Bu2BOTf, EtiPr2N, Et2O, À788C, then 19, 5 h, 80% (d.r. >
95:5); b) TABH, AcOH, CH3CN, À408C, 70 h, 97% (d.r. > 95:5);
c) K2CO3, MeOH, RT, 40 h, 92%; d) TIPPSeBr, 2,6-di-tert-butyl-4-meth-
ylpyridine, CH2Cl2, À788C, 74% (d.r. 88:12); e) 2,4-dimethoxy-3-methyl-3-
tert-butyldimethylsilylcyclohexa-1,4-diene, AIBN, n-hexane, reflux, 1 h,
80%; f) TMSOK, Et2O, RT, 24 h; g) 2,4,6-trichlorobenzoylchloride, Et3N,
DMAP, DMF, RT; h) Me3OBF4, proton sponge, 4 ä M.S., CH2Cl2, RT,
49% (3 steps). AIBN ¼ 2,2’-azoisobutyronitrile, M.S. ¼ molecular sieves,
proton sponge ¼ N,N,N’,N’-tetramethyl-1,8-diaminonaphthalene, TABH ¼
tetramethylammonium triacetoxy borohydride, TIPP ¼ 2,4,6-triisopropyl-
phenyl.
With the two key fragments in hand, we next turned to the
critical, convergent coupling step. We were pleased to observe
that 14 and 19 participated in an aldol addition reaction
with Bu2BOTf/H¸nig©s base to give b-hydroxy ketone 20
in excellent yield (80%) as a single diastereomer (by 1H
NMR) possessing the requisite 1,5-anti configuration
(Scheme 4).[19] Unfortunately, 20 failed to undergo reduction
under Tishchenko conditions.[20] Alternatively, anti diol 21 was
propylphenylselenyl bromide is unprecedented. Reductive
deselenylation of 23 to 24 (80%) was achieved under tin-free
conditions with the silylated 1,4-cyclohexadiene reagent
recently developed by Studer and Amrein.[25] Following ester
hydrolysis with TMSOK, seco acid 25 was obtained. Our
objective at this point in the synthesis was to differentiate the
two secondary hydroxy groups at C9 and C17 through a
regioselective macrolactonization reaction.[26] To our surprise,
however, lactonization of the seco acid under the standard
Yamaguchi conditions with various solvents (benzene, tolu-
ene, xylene, THF) failed to give any product. Instead a
complex mixture of oligomers was obtained.
In earlier feasibility studies in our laboratory, we had
observed that macrolactonization proceeded smoothly under
Yamaguchi conditions from the precursor incorporating a C9
methyl ether.[27] We hypothesized that the structure possessing
a hydrogen-bonded network involving the C9 hydroxy group
preorganizes the C7 C11 backbone in an arrangement that
places the C9 oxygen atom between the tetrahydropyrans thus
precluding cyclization.[28] Consequently, we speculated that
conducting the lactonization in a polar solvent able to disrupt
hydrogen bonds would help the system adopt the necessary
conformation for cyclization. Indeed, the use of DMF as
[21]
obtained from 20 by using Me4NBH(OAc)3 (97%, d.r. >
1
95:5 by H NMR). Cleavage of the C17 benzoate (K2CO3,
MeOH) gave access to key intermediate 22 (92%).
The second tetrahydropyran ring was installed by an
electrophile-mediated cyclization of the C11 hydroxy group
[22]
¼
onto the C C double bond.
A number of electrophiles,
including I2, IBr,[23] and Hg(OAc)2 were screened, albeit all
gave disappointing levels of diastereoselectivity (1:1). We
subsequently decided to investigate selenium electrophiles,
and promising results with phenylselenyl chloride (d.r. 3:1,
anti:syn) prompted us to examine bulkier, substituted phenyl-
selenyl halides.[24] In this respect, 2,4,6-triisopropylphenylse-
lenyl bromide was the reagent of choice: Indeed 22 underwent
clean cyclization in CH2Cl2 to the desired 2,6-trans-substituted
tetrahydropyran 23 (74%, d.r. 88:12 by 1H NMR). To the best
of our knowledge, the stereoselective formation of 2,6-
substituted trans tetrahydropyrans mediated by 2,4,6-triiso-
solvent cleanly leads to macrocycle 26, which, after O-
[29]
methylation of the C9 alcohol with Me3OBF4
in the
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COMMUNICATIONS
[8] a) D. E. Frantz, R. F‰ssler, E. M. Carreira, J. Am. Chem. Soc. 2000,
122, 1806 1807; b) E. El-Sayed, N. K. Anand, E. M. Carreira, Org.
Lett. 2001, 3, 3017 3020; c) N. K. Anand, E. M. Carreira, J. Am.
Chem. Soc. 2001, 123, 9687 9688; d) D. Boyall, F. LÛpez, H. Sasaki, D.
Frantz, E. M. Carreira, Org. Lett. 2000, 2, 4233 4236.
[9] a) J. Kr¸ger, E. M. Carreira, J. Am. Chem. Soc. 1998, 120, 837 838;
b) B. L. Pagenkopf, J. Kr¸ger, A. Stojanovic, E. M. Carreira, Angew.
Chem. 1998, 110, 3312 3314; Angew. Chem. Int. Ed. 1998, 37, 3124
3126; ; c) R. A. Singer, E. M. Carreira, J. Am. Chem. Soc. 1995, 117,
12360 12361.
presence of proton sponge, furnished 27 (49% over 3 steps
from 24).
Hydrolysis of the acetonide present in 27 gave diol 28
(80%) without cleavage of the silyl ether; subsequent
oxidative cleavage of the glycol furnished the corresponding
aldehyde, setting the stage for the introduction of the C17 side
chain (Scheme 5). Towards this aim, we used the Kocienski
modification of the Julia Lythgoe olefination[30] with sulfone
[10] K.- M. Chen, K. G. Gunderson, G. E. Hardtmann, K. Prasad, O.
Repic, M. J. Shapiro, Chem. Lett. 1987, 1923 1926.
[11] M. A. Blanchette, W. Choy, J. T. Davis, A. P. Essenfeld, S. Masamune,
W. R. Roush, T. Sakai, Tetrahedron Lett. 1984, 25, 2183 2186.
[12] D. A. Evans, J. A. Gauchet-Prunet, J. Org. Chem. 1993, 58, 2446
2453.
Me
Me
OR
OTBS
O
OMeO
O
O
OMeO
O
a)
b, c)
27
[13] a) E. Keinan, K. K. Seth, R. Lamed, J. Am. Chem. Soc. 1986, 108,
3474 3480; b) J. Tsuji, Synthesis 1984, 369 384.
80 %
73 %
O
O
[14] J. W. Bode, E. M. Carreira, J. Am. Chem. Soc. 2001, 123, 3611 3612.
[15] S. M¸ller, B. Liepold, G. J. Roth, H. J. Bestmann, Synlett 1996, 521
522.
[16] (R)-isopropylidene glyceraldehyde was prepared from d-mannitol:
C. R. Schmid, J. D. Bryant, M. Dowlatzedah, J. L. Phillips, D. E.
Prather, R. D. Schantz, N. L. Sear, C. S. Vianco, J. Org. Chem. 1991,
56, 4056 4058.
HO
Me
OH
28
Me
d) 96 %
30 (R = TBS)
31 (R = H)
Ph
N
N
N
N
Me
as in ref. [3]
Leucascandrolide A (1)
Me
S
[17] Additions to 5 are known to be fairly nonselective: S. H. Kang, W. J.
Kim, Tetrahedron Lett. 1989, 30, 5915 5918.
O O
29
[18] W. P. Griffith, S. V. Ley, G. P. Whitcombe, A. D. White, J. Chem. Soc.
Chem. Commun. 1987, 1625 1627.
[19] a) I. Paterson, K. R. Gibson, R. M. Oballa, Tetrahedron Lett. 1996, 37,
8585 8588; b) I. Paterson, R. M. Oballa, R. D. Norcross, Tetrahedron
Lett. 1996, 37, 8581 8584; c) D. A. Evans, P. J. Coleman, B. CÙtÿ, J.
Org. Chem. 1997, 62, 788 789.
Scheme 5. a) AcOH/THF/H2O 2:1:1, 458C, 5 h, 80%; b) Pb(OAc)4,
EtOAc, 08C, 15 min; c) 29, KHMDS, DME, À788C!08C, 73% (2 steps)
(E:Z > 95:5); d) TBAF, THF, 08C!RT, 7 h, 96%. DME ¼ 1,2-dimethoxy
ethane, KHMDS ¼ potassium hexamethyldisilazide.
[20] D. A. Evans, A. H. Hoveyda, J. Am. Chem. Soc. 1990, 112, 6447 6449.
[21] D. A. Evans, K. T. Chapman, E. M. Carreira, J. Am. Chem. Soc. 1988,
120, 3560 3578.
[22] For a review, see: a) M. Frederickson, R. Grigg,Org. Prep. Proced. Int.
1997, 29, 35 62; b) M. Frederickson, R. Grigg, Org. Prep. Proced. Int.
1997, 29, 63 115.
[23] J. J.-W. Duan, A. B. Smith III, J. Org. Chem. 1993, 58, 3703 3711.
[24] B. H. Lipshutz, T. Gross, J. Org. Chem. 1995, 60, 3572 3573.
[25] A. Studer, S. Amrein, Angew. Chem. 2000, 39, 3196 3198; Angew.
Chem. Int. Ed. 2000, 39, 3080 3082.
[26] L. Mandolini, J. Am. Chem. Soc. 1978, 100, 550 554.
[27] The groups of Leighton and Rychnovsky have reported similar
macrolactonizations with C9 methyl ether derivatives.
[28] Molecular mechanics calculations for the macrolide portion of
Leucascandrolide A reveal that the C9 oxygen atom resides periph-
erally: see ref. [1].
29[31] to provide olefin (E)-30 as a single isomer (by 1H NMR)
(73% over 2 steps). Deprotection of the secondary silyl ether
furnished macrolide 31, which was identical in all respects
(1H NMR, 13C NMR, IR, HRMS, [a]D) with the intermediate
reported previously.[1,3,4] With a formal synthesis of 1 in hand,
we proceeded to complete the total synthesis following the
Leighton strategy to give fully synthetic leucascandrolide A.[3]
In summary, we have reported an expedient, stereocon-
trolled total synthesis of leucascandrolide A (23 steps longest
linear sequence, 2% overall yield). The salient methodolog-
ical features of the approach include: 1) the use of a reagent-
controlled zinc alkynilide addition to isopropylidene glycer-
aldehyde; 2) catalytic, enantioselective dienolate aldol addi-
tion to crotonaldehyde; 3) the use of a selenium-mediated
cylization reaction for the formation of a trans-substituted
tetrahydropyran. Moreover, interesting observations concern-
ing hydrogen-bonding effects and conformational flexibility
were made in the context of the macrocyclization reaction
that may be applicable to other systems.
[29] R. E. Ireland, L. Liu, T. D. Roper, J. L. Gleason, Tetrahedron 1997, 53,
13257 13284.
[30] a) P. R. Blakemore, W. J. Cole, P. J. Kocienski, A. Morley, Synlett 1998,
26 28; b) J. B. Baudin, G. Hareau, S. A. Julia, O. Ruel, Tetrahedron
Lett. 1991, 32, 1175 1178.
[31] Sulfone 29 was prepared by Mitsunobu reaction followed by oxidation
with oxone.
Received: July 9, 2002 [Z19696]
[1] M. D©Ambrosio, A. Guerriero, C. Debitus, F. Pietra, Helv. Chim. Acta
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[2] a) M. D©Ambrosio, M. Tato, G. Pocsfalvi, C. Debitus, F. Pietra, Helv.
Chim. Acta 1999, 82, 347 353; b) M. D©Ambrosio, M. Tato, G.
Pocsfalvi, C. Debitus, F. Pietra, Helv. Chim. Acta 1999, 82, 1135.
[3] K. R. Hornberger, C. L. Hamblett, J. L. Leighton, J. Am. Chem. Soc.
2000, 122, 12894 12895.
[4] D. J. Kopecky, S. D. Rychnovsky, J. Am. Chem. Soc. 2001, 123, 8420
8421.
[5] M. T. Crimmins, C. A. Carroll, B. W. King, Org. Lett. 2000, 2, 597 599.
[6] S. A. Kozmin, Org. Lett. 2001, 3, 755 758.
[7] P. Wipf, T. H. Graham, J. Org. Chem. 2001, 66, 3242 3245.
Angew. Chem. Int. Ed. 2002, 41, No. 21
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