Leucascandrolide A: Synthesis and Related Studies

Article abstract of DOI:10.1021/jo034964v

The total synthesis of the biologically active marine natural product leucascandrolide A is reported. A convergent strategy is employed, allowing for the rapid assembly of the macrolide moiety. Key steps of our approach include the diastereoselective addi

Full text of DOI:10.1021/jo034964v

Leu ca sca n d r olid e A: Syn th esis a n d Rela ted Stu d ies
Alec Fettes and Erick M. Carreira*
Laboratorium fu¨r Organische Chemie, ETH Ho¨nggerberg, Wolfgang Pauli Strasse 10,
CH-8093 Zu¨rich, Switzerland
carreira@org.chem.ethz.ch
Received J uly 4, 2003
The total synthesis of the biologically active marine natural product leucascandrolide A is reported.
A convergent strategy is employed, allowing for the rapid assembly of the macrolide moiety. Key
steps of our approach include the diastereoselective addition of a zinc alkynilide to (R)-isopropylidene
glyceraldehyde, the enantioselective copper(I) fluoride catalyzed aldol addition of a TMS-dienolate
to crotonaldehyde, and the formation of a 2,6-trans-substituted tetrahydropyran by selenium-
mediated intramolecular cyclization. Moreover, dramatic solvent effects observed in the macro-
lactonization reaction suggest that hydrogen-bonding effects play a critical role. An improved route
to a key intermediate of our synthesis is documented.
In tr od u ction
Over the past few decades, marine organisms have
emerged as a rich source of natural products displaying
potent biological activity. A myriad of diverse structures
with, in some cases, fascinating physiological properties,
have been isolated.1 One important class of these natural
products are represented by macrolides2 such as the
spongistatins3 and bryostatins.4
In 1996, Pietra and co-workers reported the charac-
terization of leucascandrolide A (1),5 a powerfully bioac-
tive marine macrolide isolated from a calcareous sponge
of a new genus, Leucascandra caveolata Borojevic and
Klautau, collected in 1989 along the east coast of New
Caledonia (Figure 1). Leucascandrolide B (2), isolated
from the same sponge, displays few structural similarities
and significantly reduced bioactivity relative to 1.6
Although leucascandrolide A was isolated in significant
amounts (70 mg of 1 from 240 g of sponge, 0.03%), later
expeditions, aimed at isolating additional quantities of
1, only harvested samples of the sponge that failed to
provide the natural product. The origin of this poly-
acetate-derived natural product still remains a puzzle,
but it is most likely microbial. The fact that samples of
Leucascandra caveolata collected in 1994 did not contain
any trace of 1 or 2 suggests that the earlier sample was
colonized by microorganisms that were the source of
these macrolides.
F IGURE 1. Structures of Leucascandrolide A (1) and B (2).
Leucascandrolide A is the first powerfully bioactive
metabolite isolated from a calcareous sponge. The raw
extracts from the sponge collected in 1989 are strongly
antimicrobial and cytotoxic. The purified compound
displays strong cytotoxic activity in vitro on human KB
throat epithelial cancer cell lines (IC50 0.05 µg/mL) and
P388 murine leukemia cell lines (IC50 0.25 µg/mL). Its
antifungal properties are demonstrated by growth inhibi-
tion of Candida albicans, a pathogenic yeast that op-
portunistically attacks AIDS patients. Structure-activity
relationship studies indicate that the C5 side chain has
no major impact on the cytostatic properties. However,
this structural element proved to be essential for the
antifungal properties.
The gross structure and relative configuration of leu-
cascandrolide A were assigned on the basis of HR-EI-
MS, 13C NMR, and DEPT experiments, as well as
elaborate two-dimensional NMR studies. The absolute
configuration could be determined by Mosher-ester analy-
sis.7
* Phone: (+41) 1 6322830. Fax: (+41) 1 6321328.
(1) Reviews on marine natural products have appeared: Chem. Rev.
1993, 93, 1673-1944.
(2) Norcross, R. D.; Paterson, I. Chem. Rev. 1995, 95, 2041-2114.
(3) For a review on spongistatins, see: Pietruszka, J . Angew. Chem.,
Int. Ed. 1998, 37, 2629-2636.
(4) Pettit, G. R.; Leet, J . E.; Herald, C. L.; Kamano, Y.; Boettner, F.
E.; Baczynskyj, L.; Nieman, R. A. J . Org. Chem. 1987, 52, 2854-2860
and references therein.
As can be seen from Chart 1, leucascandrolide A
displays several distinctive architectural features: the
structure is characterized by a repeating 1,3-dioxygen-
(5) D’Ambrosio, M.; Guerriero, A.; Debitus, C.; Pietra, F. Helv. Chim.
Acta 1996, 79, 51-60.
(6) (a) D’Ambrosio, M.; Tato`, M.; Pocsfalvi, G.; Debitus, C.; Pietra,
F. Helv. Chim. Acta 1999, 82, 347-353. (b) D’Ambrosio, M.; Tato`, M.;
Pocsfalvi, G.; Debitus, C.; Pietra, F. Helv. Chim. Acta 1999, 82, 1135.
(7) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543-2549.
10.1021/jo034964v CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/31/2003
9274
J . Org. Chem. 2003, 68, 9274-9283

Leucascandrolide A: Synthesis and Related Studies
F IGURE 2. Retrosynthetic approach.
ation pattern, a peculiar side chain bearing a 2,4-
disubstituted oxazole, and an 18-membered macrolactone
that encompasses two trisubstituted tetrahydropyrans,
one of which is 2,6-trans-disubstituted.
A, as well as a full account of our studies and obser-
vations, leading to its convergent and expedient syn-
thesis.17
Because the biological origin of leucascandrolide A is
currently unknown, total synthesis is its only reliable
source. Accordingly, considerable efforts toward its syn-
thesis have been made by several groups, including our
own, culminating in the first total synthesis reported by
Leighton, confirming the relative and absolute stereo-
chemical configuration originally proposed by Pietra.8
Elegant syntheses by Rychnovsky,9 Wipf,10 Kozmin,11 and
Paterson12 have also been documented. Additionally,
interesting studies by Crimmins,13 Hoffmann,14
O’Doherty,15 and Panek16 underline the importance and
appeal of this natural product.
Syn th esis P la n
Our retrosynthetic planning, outlined in Figure 2, was
chosen on the basis of convergence and synthetic flexi-
bility. Initial scission of the C5 side chain provides the
leucascandrolide A macrolide 3, containing the entirety
of stereogenic centers found in the natural product. The
proposed late-stage introduction of the C17 side chain
would allow for expedient access to leucascandrolide A
analogues and avoid problems associated with chemo-
selectivity in the route. Macrocyclization was intended
to proceed by lactonization of ω-hydroxy acid 4. Retro-
synthetic unraveling of the 2,6-trans-disubstituted tetra-
hydropyran gave a 6-hydroxy olefin, a transformation
that was planned, in the synthetic direction, to proceed
by electrophile-mediated cyclization. The cyclization
precursor would be formed by a convergent, diastereo-
selective boron-aldol addition reaction to form the C10-
C11 bond in 5. This approach delimits the synthetic
challenge to the preparation of two key intermediates of
comparable size and stereochemical complexity: alde-
hyde 6 and methyl ketone 7. Our synthesis of 6 is based
on the diastereoselective addition of alkyne 8 to (R)-isopro-
pylidene glyceraldehyde (9) mediated by (-)-N-methyl
ephedrine and zinc triflate using a protocol recently
developed in our group for the mild and asymmetric
addition of alkynes to aldehydes. Methyl ketone 7 derives
from TMS-dienolate 10 by enantioselective aldol addition
to crotonaldehyde (11).
The lack of availability of leucascandrolide A from
natural sources and its potent biological profile, as well
as recent methodological developments in our group,
compelled us to initiate a program aiming at the syn-
thesis of this architecturally unique macrolide. We now
report an improved total synthesis of leucascandrolide
(8) Hornberger, K. R.; Hamblett, C. L.; Leighton, J . L. J . Am. Chem.
Soc. 2000, 122, 12894-12895.
(9) Kopecky, D. J .; Rychnovsky, S. D. J . Am. Chem. Soc. 2001, 123,
8420-8421.
(10) (a) Wipf, P.; Reeves, J . T. Chem. Commun. 2002, 2066-2067.
(b) Wipf, P.; Graham, T. H. J . Org. Chem. 2001, 66, 3242-3245.
(11) (a) Kozmin, S. A. Org. Lett. 2001, 3, 755-758. (b) Wang, Y.;
J anjic, J .; Kozmin, S. A. J . Am. Chem. Soc. 2002, 124, 13670-13671.
(12) Paterson, I.; Tudge, M. Angew. Chem., Int. Ed. 2003, 42, 343-
347.
(13) Crimmins, M. T.; Carroll, C. A.; King, B. W. Org. Lett. 2000, 2,
597-599.
(14) Vakalopoulos, A.; Hoffmann, H. M. R. Org. Lett. 2001, 3, 177-
180.
(15) Hunter, T. J .; O’Doherty, G. A. Org. Lett. 2001, 3, 1049-1052.
(16) Dakin, L. A.; Langille, N. F.; Panek, J . S. J . Org. Chem. 2002,
67, 6812-6815.
(17) This work has been communicated in preliminary form: Fettes,
A.; Carreira, E. M. Angew. Chem., Int. Ed. 2002, 41, 4098-4101.
J . Org. Chem, Vol. 68, No. 24, 2003 9275

Fettes and Carreira
Resu lts a n d Discu ssion
unexplored the use of chiral aldehydes as substrates
leading to the formation of diastereomeric propargylic
alcohols.24
The synthesis of leucascandrolide A commenced with
the preparation of known alcohol 16 from (1R,2R)-(-)-
pseudoephedrine propionamide 12 by a high-yielding,
four-step reaction sequence reported by Bode and Car-
reira in the course of their total syntheses of epothilone
natural products18 (Scheme 1). Asymmetric alkylation of
the lithium enolate of 12 with allyl iodide, using the
protocol reported by Myers,19 gave amide 13 (dr > 95:5
SCHEME 3
1
by H NMR). Subsequent BH3‚NH3-mediated reduction
led to alcohol 14, which was protected as a triisopropyl-
silyl ether under standard conditions. Hydroboration of
the monosubstituted double bond in 15 with 9-BBN gave
the desired compound 16 in 75% yield over four steps.
The synthetic route called for the use of (R)-isopro-
pylidene glyceraldehyde (9) and optically active alkyne
8. Although the remote stereogenic center in the alkyne
was not expected to bias the diastereofacial differentia-
tion in the aldehyde, the situation was far less clear as
it concerned the chiral aldehyde. Of additional impor-
tance was the question of whether isopropylidene glyc-
eraldehyde would be compatible with the reaction con-
ditions; the use of this capricious aldehyde would
constitute a notable and useful extension of the method.
The zinc alkynilide of 8, prepared in situ by reaction
of 8 with Zn(OTf)2 (1.1 equiv), (-)-N-methyl ephedrine
(1.1 equiv), and Et3N (1.2 equiv), cleanly added to
aldehyde 925 to give propargylic alcohol 18 in 75% yield
and 94:6 diastereoselectivity as assayed by 1H NMR,
favoring the 1,2-syn configuration (Scheme 4).26 In the
course of finding optimal conditions, we noted that the
use of high-purity isopropylidene glyceraldehyde 9 proved
to be crucial to the formation of addition product 18 in
high yield and diastereoselectivity. When (+)-N-methyl
ephedrine was used, under otherwise identical conditions,
the product possessing a 1,2-anti relationship was ob-
SCHEME 1a
a
Reaction conditions: (a) LDA, LiCl, allyl iodide, THF, -78 °C
f 0 °C, 2 h (dr > 95:5); (b) LDA, NH3‚BH3, THF, rt, 2 h; (c) TIPSCl,
imidazole, DMAP, rt, 1 h; (d) 9-BBN, THF, rt, 6 h, 75% over four
steps.
Oxidation of the primary alcohol in 16 to the corre-
sponding aldehyde was conveniently achieved with the
biphasic NaClO/TEMPO/KBr system20 (Scheme 2). Con-
version to the terminal alkyne 8 could be carried out by
various methods. Addition of lithiated trimethylsilyl
diazomethane21 was found to give the best yields (90%
over two steps). On a large scale, however, the use of the
Ohira reagent22 (17) using the protocol reported by
Bestmann23 was the method of choice and gave alkyne 8
in 87% yield over two steps.
(20) (a) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J . Org. Chem.
1987, 52, 2559-2562. (b) For a review on the use of stable nitroxyl
radicals for the oxidation of alcohols, see: De Nooy, A. E. J .; Besemer,
A. C.; Van Bekkum, H. Synthesis 1996, 1153-1174.
(21) Miwa, K.; Aoyama, T.; Shioiri, T. Synlett 1994, 107-108.
(22) Ohira, S. Synth. Commun. 1989, 19, 561-564.
(23) (a) Mu¨ller, S.; Liepold, B.; Roth, G. J .; Bestmann, H. J . Synlett
1996, 521-522. For other methods of conversion of aldehydes to
terminal alkynes, see: (b) Corey, E. J .; Fuchs, P. L. Tetrahedron Lett.
1972, 36, 3769-3772. (c) Wang, Z.; Campagna, S.; Yang, K. H.; Xu, G.
Y.; Pierce, M. E.; Fortunak, J . M.; Confalone, P. N. J . Org. Chem. 2000,
65, 1889-1891.
(24) Addition of a chiral aldehyde possessing a remote stereocenter
to 3-methyl-butyn-3-ol was reported by Carreira and Bode in the
recently published epothilone A synthesis. See ref 18b for details.
SCHEME 2a
a
Reaction conditions: (a) aq NaClO, TEMPO (2.0 mol %), KBr
(10 mol %), CH2Cl2, pH 8.6 carbonate buffer, 0 °C, 15 min; (b)
(MeO)2P(O)CN2CO2CH3, K2CO3, MeOH, 16 h, rt, 87% (over two
steps).
The total synthesis of leucascandrolide A provided the
opportunity to investigate whether zinc acetylide addi-
tions (Scheme 3) could be carried out with highly func-
tionalized aldehydes on preparatively useful scales.
Additionally, our previous studies in this area had left
(25) (R)-Isopropylidene glyceraldehyde (9) was prepared in two steps
from D-mannitol and distilled immediately prior to use: Schmid, C.
R.; Bryant, J . D.; Dowlatzedah, M.; Phillips, J . L.; Prather, D. E.;
Schantz, R. D.; Sear, N. L.; Vianco, C. S. J . Org. Chem. 1991, 56, 4056-
4058.
(26) (a) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J . Am. Chem.
Soc. 2000, 122, 1806-1807. (b) Sasaki, H.; Boyall, D.; Carreira, E. M.
Helv. Chim. Acta 2001, 84, 964-971. (c) El-Sayed, E.; Anand, N. K.;
Carreira, E. M. Org. Lett. 2001, 3, 3017-3020. (d) Anand, N. K.;
Carreira, E. M. J . Am. Chem. Soc. 2001, 123, 9687-9688. (e) Boyall,
D.; Lo´pez, F.; Sasaki, H.; Frantz, D.; Carreira, E. M. Org. Lett. 2000,
2, 4233-4236. For related processes, see: (f) Frantz, D. E.; Fa¨ssler,
R.; Carreira, E. M. J . Am. Chem. Soc. 1999, 121, 11245-11246.
(18) (a) Bode, J . W.; Carreira, E. M. J . Am. Chem. Soc. 2001, 123,
3611-3612. (b) Bode, J . W.; Carreira, E. M. J . Org. Chem. 2001, 66,
6410-6424.
(19) (a) Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J . L. J . Am.
Chem. Soc. 1994, 116, 9361-9362. (b) Myers, A. G.; Gleason, J . L.;
Yoon, T. Y. J . Am. Chem. Soc. 1995, 117, 8488-8489.
9276 J . Org. Chem., Vol. 68, No. 24, 2003

Leucascandrolide A: Synthesis and Related Studies
SCHEME 4 a
SCHEME 6 a
a
Reaction conditions: (a) LiAlH4, THF, rt, 5 h; (b) BzCl, Et3N,
a
Reaction conditions: (a) 8, Zn(OTf)2, (-)-N-methyl ephedrine,
DMAP, CH2Cl2, rt, 15 h, 90% (over two steps); (c) nBu4NF, THF,
0 °C f rt, 24 h, 96%; (d) 4 Å MS, NMO, CH2Cl2, then TPAP, rt,
30 min, 87%.
Et3N, toluene, then 9, rt, 48 h, 75% (dr ) 94:6); (b) 4 Å MS, NMO,
CH2Cl2, then TPAP, rt, 30 min, 75%; (c) 20, iPrOH, rt.
SCHEME 5
tection of the silyl ether34 with nBu4NF (96%) and
subsequent Ley oxidation29 (TPAP, NMO, 4 Å MS,
CH2Cl2) of the resulting alcohol 22 furnished aldehyde
23 in 87% yield. Under these mild oxidation conditions,
no epimerization R to the aldehyde took place. The
synthesis outlined proceeds in seven steps and 49%
overall yield from 16.
In the synthesis of the second key intermediate, we
were interested in investigating whether the catalytic,
enantioselective addition of dienolate 10 to aldehydes
using the (R)-Tol-BINAP copper(I) fluoride complex was
amenable to the preparation of aldol adduct 24 on a
multigram scale.35 This would require the use of cro-
tonaldehyde as an electrophile, an aldehyde that has been
shown to be prone to polymerization under similar
reaction conditions. The catalyst is conveniently prepared
in situ from (R)-Tol-BINAP, copper(II) triflate, and
tained as the sole diastereomer, indicating that reagent
control is dominant in this addition.27 The lack of dia-
stereoselectivity observed with the corresponding lithium
alkynilide underscores the significance of these results.28
The sense of stereochemical induction was confirmed by
oxidation of 18 to ketone 19 (TPAP, NMO, 4 Å MS,
CH2Cl2, 75%)29 and subsequent asymmetric transfer
hydrogenation to 18 using Noyori’s catalyst30 20.
The stereochemical outcome of the addition process can
be rationalized by the mechanistic pathway represented
in Scheme 5.31 The model is analogous to that proposed
by Noyori for diethyl zinc additions to aldehydes;32 two
metal centers operate synergistically in a highly or-
ganized transition state wherein both electrophilic and
nucleophilic components are activated.
36
nBu4NPh3SiF2 (Scheme 7).
This reaction can be conducted on a multigram scale
utilizing as little as 2 mol % catalyst.37 Dioxenone 24 was
obtained with a high degree of enantioselectivity (91%
ee as determined by HPLC) and 44% yield. Conversion
of aldol adduct 24 to keto ester 26 was achieved by
thermal retro-Diels-Alder reaction leading to acetone
extrusion and subsequent trapping of intermediate ketene
25 with solvent 1-butanol (78%) (Scheme 8).38
(33) Pronounced inverse correlation between the Lewis basicity of
the solvent and the extent of cis reduction was observed: (E)-olefins
are obtained in THF and E/Z mixtures in Et2O. For a possible rationale,
see: (a) Grant, B.; Djerassi, C. J . Org. Chem. 1974, 39, 968-970. (b)
Blunt, J . W.; Hartshorn, M. P.; Munro, M. H. G.; Soong, L. T.;
Thompson, R. S.; Vaughan, J . J . Chem. Soc., Chem. Commun. 1980,
820-821.
(34) For an excellent review on the silyl ether deprotection, see:
Nelson, T. D.; Crouch, R. D. Synthesis 1996, 1031-1069.
(35) (a) Kru¨ger, J .; Carreira, E. M. J . Am. Chem. Soc. 1998, 120,
837-838. (b) Pagenkopf, B. L.; Kru¨ger, J .; Stojanovic, A.; Carreira, E.
M. Angew. Chem., Int. Ed. 1998, 37, 3124-3126. (c) Kru¨ger, J .;
Carreira, E. M. Tetrahedron Lett. 1998, 39, 7013-7016. (d) Singer, R.
A.; Carreira, E. M. J . Am. Chem. Soc. 1995, 117, 12360-1236. (e) Kim,
Y.; Singer, R. A.; Carreira, E. M. Angew. Chem., Int. Ed. 1998, 37,
1261-1263.
Reduction of propargylic alcohol 18 to the correspond-
33
ing (E)-allylic alcohol using LiAlH4 followed by benzo-
ylation under standard conditions (BzCl, Et3N, CH2Cl2)
gave 21 in 90% yield over two steps (Scheme 6). Depro-
(27) A similar result was obtained with (2S)-2-(tert-butyldimethyl-
silyloxy)-propanal: El-Sayed, E.; Anand, N. K.; Carreira, E. M. Org.
Lett. 2001, 3, 3017-3020.
(28) Additions of lithium acetylides to this aldehyde are known to
be fairly nonselective: Kang, S. H.; Kim, W. J . Tetrahedron Lett. 1989,
30, 5915-5918.
(36) Use of nBu4NPh3SiF2 as anhydrous fluoride source has been
reported and extensively used by DeShong. nBu4NPh3SiF2 is conve-
niently prepared in two steps from triphenylsilanol, aqueous hydro-
fluoric acid, and nBu4NF: (a) Pilcher, A. S.; Ammon, H. L.; DeShong,
P. J . Am. Chem. Soc. 1995, 117, 5166-5167. (b) Handy, C. J .; Lam, Y.
F.; DeShong, P. J . Org. Chem. 2000, 65, 3542-3543.
(29) Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639-666.
(30) Hashiguchi, S.; Fujii, A.; Haack, K. J .; Matsumura, K.; Ikariya,
T.; Noyori, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 288-290.
(31) Evans, D. A. Science 1988, 240, 420-426.
(32) Yamakawa, M.; Noyori, R. J . Am. Chem. Soc. 1995, 117, 6327-
6335.
(37) Reaction was run on as much as 140 mmol of TMS-dienolate
10 without deterioration of the optical purity.
J . Org. Chem, Vol. 68, No. 24, 2003 9277

Fettes and Carreira
SCHEME 7 a
0 °C gave access to the desired 2,6-cis-disubstituted
tetrahydropyran 29 in 63% yield and 10:1 diastereo-
selectivity.41 The diastereomers could be easily separated
by flash chromatography, and the undesired isomer 30
could be isomerized to 29 by resubmission to identical
reaction conditions, showing that cyclization takes place
under thermodynamic control. Protection of the second-
ary hydroxy group as a tert-butyldimethylsilyl ether
(TBSCl, imidazole, DMAP, DMF) gave 31 (96%).
In a subsequent investigation en route to leucascan-
drolide A, we realized that the reaction sequence from
26 to 31 was rendered awkward by protective-group
manipulations and needed further refinement and short-
ening. In the improved route, syn reduction of keto ester
26 was followed by acidic workup (PPTS, benzene).
Protection of the secondary alcohol (TBSCl, imidazole,
DMAP, rt, DMF) afforded lactone 32 in 77% yield
(Scheme 9). Reduction of lactone 32 to the corresponding
lactol 33 (DIBAL-H, toluene, -78 °C) and subsequent
Horner-Wadsworth-Emmons reaction (triethylphospho-
noacetate, NaH, THF, -78 °C) furnished a diastereomeric
mixture of tetrahydropyrans 31 and 34 in 76% overall
yield.42 We were quite confident that we would be able
to ensure diastereoselectivities similar to those previously
obtained, given the fact that equilibration is possible
under basic conditions (vide supra) and that A-values for
hydroxy groups and the corresponding silyl ethers are
nearly identical.43 Upon treatment with catalytic amounts
of tBuOK (10 mol %), the mixture cleanly equilibrated
to the thermodynamically more stable isomer 31 (dr )
9:1). Not only is this modified reaction sequence two steps
a
Reaction conditions: (a) (R)-Tol-BINAP (2.1 mol %), Cu(OTf)2
(2.0 mol %), nBu4NPh3SiF2 (4.0 mol %), THF, -78 °C, then 10
and 11, 4 h, then TFA, 44%.
SCHEME 8 a
SCHEME 9 a
a
Reaction conditions: (a) nBuOH, reflux, 1 h, 78%; (b) Et3B,
MeOH, THF, -78 °C, then 26 followed by NaBH4, 5 h; (c) TESCl,
imidazole, DMAP, DMF, rt, 12 h; (d) DIBAL-H, toluene, -78 °C,
30 min, 92% (over three steps) (dr > 95:5); (e) DBU, LiCl,
(EtO)2P(O)CH2CO2Et, CH3CN, 27, rt, 2 h; (f) nBu4NF, THF, rt, 2
h, 80% (over two steps); (g) tBuOK (10 mol %), THF, 0 °C, 63%
(dr ) 10:1); (h) TBSCl, imidazole, DMAP, DMF, rt, 20 h, 96%;
In our earlier published approach,17 conversion of keto
ester 26 to the corresponding syn diol by stereoselective
reduction using the method of Prasad (NaBH4, Et3B,
MeOH, THF, -78 °C)39 was followed by protection of the
diol as bis-O-triethylsilyl ethers (TESCl, imidazole, DMAP,
DMF) and semireduction of the butyl ester to aldehyde
27 with DIBAL-H in toluene (92% over three steps). Sub-
sequent olefination with triethylphosphonoacetate under
Roush-Masamune conditions40 (DBU, LiCl, CH3CN) and
deprotection of the silyl ethers with nBu4NF in THF led
to diol 28 (80% over two steps). Treatment of diol 28 with
catalytic amounts of tBuOK (10 mol %) in THF at
a
Reaction conditions: (a) Et3B, MeOH, THF, -78 °C, then 26
followed by NaBH4, 5 h; then PPTS, PhH, reflux, 90 min; (b)
TBSCl, imidazole, DMAP, DMF, rt, 2 h, 77% (over two steps); (c)
DIBAL-H, toluene, -78 °C, 1 h; (d) (EtO)2P(O)CH2CO2Et, NaH,
THF, -78 °C f rt, 72% (over two steps); (e) tBuOK (10 mol %),
THF, 0 °C, 4 h, 90% (dr ) 9:1).
(40) (a) Blanchette, M. A.; Choy, W.; Davis, J . T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,
2183-2186. (b) Eschenmoser first recognized that a tertiary amine and
a lithium salt may be used instead of strong alkoxide or amide bases
for the generation of enolates: Roth, M.; Dubs, P.; Gotschi, E.;
Eschenmoser, A. Helv. Chim. Acta 1971, 54, 710-734.
(41) Eliel, E. L.; Hargrave, K. D.; Pietrusiewicz, K. M.; Manoharan,
M. J . Am. Chem. Soc. 1982, 104, 3635-3643. (b) Evans, D. A.; Gauchet-
Prunet, J . A. J . Org. Chem. 1993, 58, 2446-2453.
(38) Clemens, R. J .; Hyatt, J . A. J . Org. Chem. 1985, 50, 2431-
2435.
(39) (a) Chen, K. M.; Gunderson, K. G.; Hardtmann, G. E.; Prasad,
K.; Repic, O.; Shapiro, M. J . Chem. Lett. 1987, 1923-1926. (b) Chen,
K. M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro, M. J .
Tetrahedron Lett. 1987, 28, 155-158.
(42) Lactol 33 was formed as a mixture of diastereomers.
(43) Schneider, H. J .; Hoppen, V. J . Org. Chem. 1978, 43, 3866-
3873.
9278 J . Org. Chem., Vol. 68, No. 24, 2003

Leucascandrolide A: Synthesis and Related Studies
SCHEME 11 a
shorter than the initially reported route, but the overall
yield from 26 to 31 is also improved (50% vs 44%).
Transformation of 31 to the desired methyl ketone 35
was intended to be carried out by Wacker oxidation
(Scheme 10). Despite the great synthetic utility of this
process, this reaction has found only limited application
in the synthesis of complex molecules because of regio-
selectivity issues.44 Indeed, oxidation of 1,2-disubstituted
olefins generally leads to a mixture of isomeric ketones.
However, good regioselectivity is often achieved in the
oxidation of allylic or homoallylic ethers and esters,45
although in the reported cases yields tend to be rather
low (35-44%).46 This enhanced regiocontrol has been
speculated to be attributable to a nonsymmetrical bond-
ing of palladium to the olefin as a consequence of
coordination to the allylic or homoallylic oxygen.46,47
When olefin 31 was treated with PdCl2 (0.2 equiv), CuCl
(1.2 equiv), and oxygen in a DMF/H2O 7:1 mixture,
methyl ketone 35 was obtained in good yield (86%) and
complete regioselectivity. Although the reasons for this
unusual result remain unclear, the Wacker process
constitutes a good alternative to a two-step hydrobora-
tion/oxidation pathway. Thus, methyl ketone 35 was
obtained in seven steps and 39% overall yield from known
aldol adduct 24.
a
Reaction conditions: (a) 35, Bu2BOTf, EtiPr2N, Et2O, -78 °C,
then 23, 5 h, 80% (dr > 95:5); (b) 35, (-)-DIPCl, Et3N, Et2O, -78
°C, then 23, 24 h, 81% (dr > 95:5); (c) TABH, AcOH, CH3CN, -40
°C, 70 h, 97% (dr > 95:5)
induction from the ketone and from the chiral boron
reagent was expected to operate synergistically, stereo-
induction from the aldehyde was expected to work in the
opposite direction by Felkin-Anh51 control. In both cases,
the anti Felkin-Anh â-hydroxy ketone 36 was obtained
in good yields (80% with Bu2BOTf, 81% with (-)-DIPCl)
as a single diastereomer, displaying the requisite 1,5-
anti configuration found in the natural product.
SCHEME 10 a
Evans-Tishchenko reduction52 of the C9 ketone in 36
would have been ideal, since the resulting 1,3-anti diol
monoester 38 could have allowed for selective methyl-
ation of the C9 alcohol and thus full differentiation of
all hydroxy groups (Scheme 12). Earlier studies in our
laboratories had shown the feasibility of such an ap-
proach: model compound 39, the C18 epimer of ent-36,
was reliably reduced to 40 using acetaldehyde and
catalytic amounts of SmI2 (10-30 mol %) in excellent
yields (>90%).53 Ketone 36 proved to be resistant to these
reaction conditions, and the desired product 38 was not
formed. Instead, starting hydroxy ketone 36 was isolated,
along with variable amounts of retro-aldol products.
Recently, Scott has reported the use of Sc(OTf)3 as a
catalyst for stereoselective Tishchenko reduction of â-hy-
droxy ketones.54 This protocol, when applied to 36, did
not lead to any improvement. Thwarted by the Tish-
chenko reduction, which was not without consequences
for the subsequent steps, our synthetic planning needed
some adjustment. As an alternative, reduction using
tetramethylammonium triacetoxyborohydride cleanly af-
forded diol 37 in 97% yield and complete diastereoselec-
a
Reaction conditions: (a) PdCl2 (20 mol %), CuCl (1.2 equiv),
air, DMF/H2O 7:1, rt, 48 h, 86%.
With multigram quantities of both key fragments 23
and 35 in hand, we next investigated their coupling by
boron-mediated aldol addition (Scheme 11).48 To this end,
we examined the use of (-)-DIPCl (triple asymmetric
induction) reported by Paterson49 and Bu2BOTf (double
asymmetric induction) reported by Evans.50 π-Facial
selectivity of the diastereotopic carbonyl was imparted
by the chiral aldehyde, the chiral ketone, and, in the case
of (-)-DIPCl, the chiral boron reagent. Whereas the
(44) No regioselectivity problems are generally encountered in the
oxidation of terminal, monosubstituted olefins. Indeed, in this case,
exclusive formation of the corresponding methyl ketones is generally
observed. For an exception, see: Pellissier, H.; Michellys, P. Y.; Santelli,
M. Tetrahedron 1997, 53, 7577-7586.
(45) (a) Tsuji, J .; Nagashima, H.; Hori, K. Tetrahedron Lett. 1982,
23, 2679-2682. (b) Lai, J . Y.; Shi, X. X.; Dai, L. X. J . Org. Chem. 1992,
57, 3485-3487.
(46) Wacker oxidation of
a closely related tetrahydropyranyl-
substituted olefin gave only one regioisomer, albeit in moderate yields
of 35-44%. For details, see: Keinan, E.; Seth, K. K.; Lamed, R. J .
Am. Chem. Soc. 1986, 108, 3474-3480.
1
tivity (>95:5 by H NMR) (Scheme 11).55 The presence
(47) Pellissier, H.; Michellys, P. Y.; Santelli, M. Tetrahedron 1997,
53, 10733-10742.
(48) For an excellent review of asymmetric aldol reactions using
boron enolates, see: Cowden, C. J .; Paterson, I. Org. React. 1997, 51,
1-200.
(51) Anh, N. T.; Eisenstein, O. Tetrahedron Lett. 1976, 155-158.
(52) (a) Evans, D. A.; Hoveyda, A. H. J . Am. Chem. Soc. 1990, 112,
6447-6449. (b) Tishchenko, V. J . Russ. Phys. Chem. Soc. 1906, 38,
355.
(53) THF (0.1 M) solutions of SmI2 were freshly prepared from Sm
and diiodoethane by standard procedures: (a) Girard, P.; Namy, J .
L.; Kagan, H. B. J . Am. Chem. Soc. 1980, 102, 2693-2698. (b) Evans,
D. A.; Hoveyda, A. H. J . Am. Chem. Soc. 1990, 112, 6447-6449.
(54) Gillespie, K. M.; Munslow, I. J .; Scott, P. Tetrahedron Lett. 1999,
40, 9371-9374.
(49) (a) Paterson, I.; Oballa, R. M.; Norcross, R. D. Tetrahedron Lett.
1996, 37, 8581-8584. (b) Paterson, I.; Gibson, K. R.; Oballa, R. M.
Tetrahedron Lett. 1996, 37, 8585-8588. (c) Paterson, I.; Collett, L. A.
Tetrahedron Lett. 2001, 42, 1187-1191.
(50) (a) Evans, D. A.; Coleman, P. J .; Coˆte´, B. J . Org. Chem. 1997,
62, 788-789. (b) The observation of double asymmetric induction using
Cy2BCl in related systems was first reported by Paterson: see ref 49
for details.
J . Org. Chem, Vol. 68, No. 24, 2003 9279

Fettes and Carreira
SCHEME 12 a
SCHEME 13 a
a
Reaction conditions: (a) MeCHO, SmI2 (10-30 mol %), THF,
-78 °C, >85%.
of two secondary hydroxy groups left us with the problem
of their differentiation, which we postponed to a later
stage.
Deprotection of the allylic benzoate in 37 using K2CO3
in methanol with concomitant transesterification of the
C1 ethyl ester afforded triol 41 in 92% yield (Scheme 11)
and set the stage for one of the key steps of the
leucascandrolide A synthesis: formation of the second
tetrahydropyran ring by intramolecular electrophile-
mediated cyclization onto a 6-hydroxy olefin (Scheme
13).56 Although the related formation of tetrahydrofurans
is well precedented, only a few examples leading to
tetrahydropyrans have been reported. This ring closure
was expected to lead selectively to the 2,6-trans-disub-
stituted tetrahydropyran by preferential formation of
intermediate onium ion 42 as compared to 43 on the basis
of previous studies by Chamberlin and Hehre.57
Iodine-based electrophiles (I2 or IBr), however, showed
little stereochemical preference, and a 1:1 diastereomeric
mixture of easily separable 44 and 45 was obtained with
I2 and IBr.58 Given that nucleophilic opening of the onium
ion intermediates is a stereospecific process, the dia-
stereochemical relationship between C16 and C17 (1,2-
syn in 44 vs 1,2-anti in 45) is correlated to the relative
configuration of the newly installed stereocenter at C15.
Upon treatment with K2CO3 in methanol, iodides 44 and
a
Reaction conditions: (a) K2CO3, MeOH, rt, 40 h, 92%; (b) IBr,
2,6-di-tert-butyl-4-methylpyridine, toluene, -78 °C, 2 h, 50% (dr
) 1:1).
45 were converted to the corresponding epoxides 46 and
47, respectively. Unambiguous stereochemical assign-
ments of the relative configuration at C16 were made
1
possible by comparison of the H coupling constants of
the vicinal epoxide protons (Scheme 14). Iodide 44 was
shown to possess the requisite 2,6-trans-disubstituted
tetrahydropyran ring, given the coupling constant of
3J H-H ) 4.36 Hz for 46, characteristic for cis-epoxide.
Epoxide 47 displays a coupling constant of 3J H-H ) 2.16
Hz, typical for trans-epoxide.
The use of selenium electrophiles led to a breakthrough
in our efforts to optimize the diastereoselectivity. Phenyl-
selenyl chloride gave a promising 75:25 selectivity of 48/
49 (Scheme 15). Encouraged by this result, we turned
our attention to bulkier, substituted arylselenyl reagents.
In this respect, 2,4,6-triisopropylphenylselenyl bromide
(TIPPSeBr) has been reported by Lipshutz to give
improved selectivities in electrophile-mediated cycliza-
tions of homoallylic alcohols to tetrahydrofurans59 as
compared to phenylselenyl chloride.60 The use of this
reagent gave the best results when applied to our system,
(55) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J . Am. Chem.
Soc. 1988, 110, 3560-3578.
(56) For reviews on electrophile-mediated cyclizations onto carbon-
carbon multiple bonds, see: (a) Frederickson, M.; Grigg, R. Org. Prep.
Proced. Int. 1997, 29, 33-62. (b) Frederickson, M.; Grigg, R. Org. Prep.
Proced. Int. 1997, 29, 63-115.
(57) (a) Chamberlin, A. R.; Mulholland, R. L. Tetrahedron 1984, 40,
2297-2302. (b) Chamberlin, A. R.; Mulholland, R. L.; Kahn, S. D.;
Hehre, W. J . J . Am. Chem. Soc. 1987, 109, 672-677.
(58) Compared to I2, IBr was shown to give enhanced diastereose-
lectivities at low temperatures in electrophilic cyclizations of homoal-
lylic carbonates: (a) Duan, J . J .-W.; Smith, A. B., III. J . Org. Chem.
1993, 58, 3703-3711. (b) Duan, J . J .-W.; Sprengeler, P. A.; Smith, A.
B., III. Tetrahedron Lett. 1992, 33, 6439-6442.
(59) Cyclizations of this type have been referred to as hybrid 6-endo-
tet/5-exo-tet by Warren: McIntyre, S.; Warren, S. Tetrahedron Lett.
1990, 31, 3457-3460.
(60) Lipshutz, B. H.; Gross, T. J . Org. Chem. 1995, 60, 3572-3573.
9280 J . Org. Chem., Vol. 68, No. 24, 2003

Leucascandrolide A: Synthesis and Related Studies
SCHEME 14 a
CHART 1. P u ta tive Ar r a n gem en ts for th e
Cycliza tion
In the earlier studies with IBr, we had observed that
reductive deiodination of iodide 44 to 52 could be
achieved in excellent yields (97%) using tributyltin hy-
dride/AIBN in refluxing benzene (Scheme 16). How-
ever, purification and toxicity concerns associated with
organotin reagents prompted us to investigate modern,
alternative methods.63 The silylated cyclohexadiene 53
recently reported by Studer could be used for tin-free
radical reduction, providing 52 in an operationally much
simpler way that did not require the use of deoxygenated
solvents.64 Mechanistically, the reduction is suggested to
proceed via a cyclohexadienyl radical, which undergoes
aromatization with concomitant generation of a tert-
butyldimethylsilyl radical able to propagate the chain
reaction. Thus, upon treatment with 53 and AIBN in
refluxing hexane, iodide 44 afforded 52 in 85% yield,
whereas selenide 50 was converted to 52 in 80% yield.
In preparation for the subsequent macrocyclization
reaction, hydrolysis of 52 using TMSOK (Scheme 18)
afforded seco acid 56, which was used without further
purification. It is worth noting that initial attempts using
LiOH or NaOH proved to be low-yielding.
a
Reaction conditions: (a) K2CO3, MeOH, rt, 15 h, 57%; (b)
K2CO3, MeOH, rt, 15 h, 69%.
SCHEME 15 a
The failure of the Tishchenko reduction at an earlier
point in the synthesis (vide supra) still left unresolved a
hydroxy group differentiation problem (at C9 and C17).
At this point, we planned to examine whether selective
macrolactonization would lead to differentiation. Al-
though formation of the eight-membered lactone 59 is
conceivable,65 we expected the thermodynamic bias to be
considerably in favor of the larger macrocycle 57.66 In an
earlier model study, macrolactonization of 54,67 the C18
epimer of ent-56, was achieved in 80% yield employing
the Yamaguchi protocol68 (formation of the mixed anhy-
dride by treatment with 2,4,6-C13(C6H2)COCl/Et3N, fol-
lowed by DMAP-promoted cyclization) (Scheme 17).69
a
Reaction conditions: (a) 2,6-di-tert-butyl-4-methylpyridine,
CH2Cl2, -78 °C, followed by slow addition (over 1 h) of PhSeCl, 1
h, 78% (dr ) 75:25 48/49); (b) 2,6-di-tert-butyl-4-methylpyridine,
CH2Cl2, -78 °C, followed by slow addition (1 h) of 41, 4 h, 74%
(dr ) 88:12 50/51).
leading to selenide 50 in 74% yield and a diastereomeric
ratio of 88:12. Typical reaction procedures involve treat-
ment of a solution of triol 41 and 2,6-di-tert-butyl-4-
methylpyridine (5.0 equiv) in CH2Cl2 at -78 °C with a
solution of the selenyl halide (4.0 equiv).61
(62) (a) Houk, K. N.; Moses, S. R.; Wu, Y. D.; Rondan, N. G.; J a¨ger,
V.; Schohe, R.; Fronczek, F. R. J . Am. Chem. Soc. 1984, 106, 3880-
3882. (b) Stork, G.; Kahn, M. Tetrahedron Lett. 1983, 24, 3951-3954.
(63) For a review on tin-hydride substitutes in reductive radical
chain reactions, see: Studer, A.; Amrein, S. Synthesis 2002, 835-849.
(64) Studer, A.; Amrein, S. Angew. Chem., Int. Ed. 2000, 39, 3080-
3082.
(65) Harrison, J . R.; Holmes, A. B.; Collins, I. Synlett 1999, 972-
974.
(66) For a general discussion on the energetics of lactonization,
see: Mandolini, L. J . Am. Chem. Soc. 1978, 100, 550-554.
(67) Seco acid 54 was prepared from 40 by O-methylation of the C9
hydroxy group, followed by a reaction pathway similar to that described
for the conversion of diol 37 to seco acid 56.
To the best of our knowledge, the stereoselective
formation of 2,6-trans-disubstituted tetrahydropyrans by
intramolecular cyclization mediated by bulky selenium
electrophiles is unprecedented. As a working model that
accounts for the observed stereochemical outcome in the
cyclization reaction, we propose that B represents the
favored intermediate (Chart 1). The arrangement in B
places the hydroxyl group in the outside position,62 where
it avoids destabilizing nonbonding interactions with the
bulky aryl group.
(68) Inanaga, J .; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. J pn. 1979, 52, 1989-1993.
(69) Leighton and Rychnovsky have reported similar Yamaguchi
macrolactonization reactions with substrates incorporating a C9 methyl
ether, giving macrocycles in good yields. See ref 8 and 9.
(61) (a) The relative configuration of 50 could be assigned only after
reductive removal of the phenylselenyl moiety by comparison with 52
obtained from iodide 44. (b) In the absence of 2,6-di-tert-butyl-4-
methylpyridine, deprotection of the C5 silyl ether was observed.
J . Org. Chem, Vol. 68, No. 24, 2003 9281

Fettes and Carreira
SCHEME 16 a
a
Reaction conditions: (a) nBu3SnH, AIBN, PhH, reflux, 1 h, 97%; (b) 53, AIBN, hexane, reflux, 2 h, 85%; (c) 53, AIBN, hexane, reflux,
2 h, 80%.
SCHEME 17 a
F IGURE 3. Postulated hydrogen-bonded array.
a
Reaction conditions: (a) 2,4,6-trichlorobenzoyl chloride, Et3N,
meric products despite slow addition (up to 24 h) and high
dilution (10-3 M).
THF, rt, 1 h; then addition to DMAP in THF, 80%.
SCHEME 18 a
The difference in reactivity between acids 54 and 56
could be ascribed to various factors. Indeed, subtle
stereochemical modifications have been shown to criti-
cally influence macrocyclization reactions and impact
their success or failure.70 We hypothesized that the
difference in reactivity was attributable to the presence
of a network of hydrogen bonds in 56 that is absent in
54. This network leads to an arrangement that may lock
the molecule in a conformation that is unfavorable for
ring closure. Molecular-mechanics calculation reveals
that in the preferred conformation of the macrocyclic
structure, the C9 methyl ether resides peripherally, a
disposition that is not compatible with the postulated
hydrogen-bonded array, where the C9 hydroxy group
supposedly resides between the tetrahydropyran rings
(Figure 3).5
This hypothesis could be tested. As such, we attempted
the cyclization reaction in a polar solvent able to disrupt
hydrogen bonds. Indeed, the use of DMF led to the
formation of the desired macrocycle 57 upon addition of
the intermediate mixed anhydride to a solution of DMAP.
The protocol used involves addition of the mixed anhy-
dride (2.4 × 10-3 M in THF/DMF) to a solution of DMAP
(10 equiv; 1.5 × 10-2 M in DMF) over 3 h (Scheme 18).71
a
Reaction conditions: (a) TMSOK, Et2O, rt, 24 h; (b) 2,4,6-
trichlorobenzoyl chloride, Et3N, rt, 1 h, then dilution with DMF
and slow addition (3 h) to DMAP in DMF, rt, 2 h; (c) Me3OBF4,
Proton Sponge, 4 Å MS, rt, 30 min, 49% (over three steps).
(70) Woodward, R. B.; Logusch, E.; Nambiar, K. P.; Sakan, K.; Ward,
D. E.; Auyeung, B. W.; Balaram, P.; Browne, L. J .; Card, P. J .; Chen,
C. H.; Chenevert, R. B.; Fliri, A.; Frobel, K.; Gais, H. J .; Garratt, D.
G.; Hayakawa, K.; Heggie, W.; Hesson, D. P.; Hoppe, D.; Hoppe, I.;
Hyatt, J . A.; Ikeda, D.; J acobi, P. A.; Kim, K. S.; Kobuke, Y.; Kojima,
K.; Krowicki, K.; Lee, V. J .; Leutert, T.; Malchenko, S.; Martens, J .;
Matthews, R. S.; Ong, B. S.; Press, J . B.; Babu, T. V. R.; Rousseau, G.;
Sauter, H. M.; Suzuki, M.; Tatsuta, K.; Tolbert, L. M.; Truesdale, E.
A.; Uchida, I.; Ueda, Y.; Uyehara, T.; Vasella, A. T.; Vladuchick, W.
C.; Wade, P. A.; Williams, R. M.; Wong, H. N. C. J . Am. Chem. Soc.
1981, 103, 3213-3215.
By contrast, 56 proved to be recalcitrant to cyclization
when submitted to otherwise identical conditions, and
no trace of 57 could be isolated. Various solvents typically
used in this type of reaction were screened (benzene,
toluene, xylene, THF). However, these studies were
frustrated by the unexpected inertness of 56 toward
cyclization, leading to the exclusive formation of oligo-
(71) We were worried that the increased polarity of the solvent may
lead to epimerization at C3 by retro-Michael/Michael reaction. How-
ever, no scrambling of this stereogenic center was observed as judged
by 1H NMR.
9282 J . Org. Chem., Vol. 68, No. 24, 2003

Leucascandrolide A: Synthesis and Related Studies
SCHEME 19 a
in the absence of R-branching or conjugation, involved
treatment of sulfone 61 with KHMDS in DME as a
solvent, followed by addition of the aldehyde and warm-
ing to ambient temperature. The desired disubstituted
olefin 62 was formed as the sole geometric isomer in 73%
yield over two steps. No trace of the (Z)-isomer could be
1
detected by H NMR analysis.
Completion of the formal synthesis required, as the
final step, the cleavage of the C5 tert-butyldimethylsilyl
ether. Deprotection of 62 with excess nBu4NF in THF
proceeded smoothly and provided the leucascandrolide
A macrolide 3 in 98% yield. This synthetic material
proved to be identical in all respects (1H NMR, 13C NMR,
[R]D, IR, HRMS) to the material obtained by degradation
from the natural product5 and to the material previously
synthesized by Leighton8 and Rychnovsky.9 With 3 in
hand, we completed the total synthesis of leucascan-
drolide A, which could be achieved by the two-step
sequence involving esterification and Still-Gennari modi-
fication of the Wittig olefination as previously reported
by Leighton, giving fully synthetic leucascandrolide A.5,8
Con clu sion
The structure of leucascandrolide A, its biological
profile, and its lack of availability conspire to make this
natural product an important target for chemical syn-
thesis. We have described a synthesis route that ef-
fectively provides access to the macrolide core in 19 steps
and, following attachment of the C5 side chain, to the
natural product in an additional two steps. The salient
features of the route include: the use of a selenium-
mediated cyclization affording a 2,6-trans-substituted
tetrahydropyran and the application of modern methods
for asymmetric C-C bond formation such as alkynyl-zinc
addition to (R)-isopropylidene glyceraldehyde and an
enantioselective dienolate aldol addition reaction to cro-
tonaldehyde. The full account of the work described
herein provides a detailed discussion of the investigations
conducted in the course of implementing these new
methods; additionally, we document unexpected observa-
tions pertaining to an unwieldy reduction of a hydroxyl
ketone intermediate and the influence of putative hy-
drogen-bonding effects on macrolactonization. Moreover,
we delineate a synthesis of the key C1-C10 methyl
ketone intermediate that is considerably improved over
the approach we initially reported. Given the intense
research activity on this marine natural product, the
investigations we have detailed should find relevance in
ongoing research of its chemistry and biology.
a
Reaction conditions: (a) AcOH/THF/H2O 2:1:1, 45 °C, 5 h, 80%;
(b) Pb(OAc)4, EtOAc, 0 °C, 15 min; (c) 61, KHMDS, DME, -78 °C
f -55 °C, 2 h; 73% (over two steps); (d) nBu4NF, THF, 0 °C f rt,
7 h, 98%; (e) PPh3, DEAD, THF, rt, 16 h, 86%; (f) Oxone, MeOH,
H2O, rt f 50 °C, 21 h, 90%.
No trace of the eight-membered macrocycle 59 could be
detected by H NMR.
O-Methylation of the C9 alcohol was conveniently
achieved with Me3OBF4 in combination with proton
sponge and 4 Å molecular sieves to give 58 in 49% yield
from methyl ester 52.72
Unmasking of the C18, C19 diol was achieved in 80%
yield by careful hydrolysis of the isopropylidene ketal in
58 under mild acidic conditions by heating to 45 °C in
AcOH/THF/H2O 2:1:1,73 leaving the C5-OTBS group
undisturbed (Scheme 19). Subsequent cleavage (Pb(OAc)4,
EtOAc, 0 °C) of the resulting 1,2-diol 60 resulted in the
formation of an aldehyde, which was used without
further purification and taken immediately to the next
step. The C17 side chain was introduced using the one-
pot Kocien´ski74 modification of the J ulia-Lythgoe olefi-
nation75 with sulfone 61.76 This approach, particularly
alluring since the reaction leads to high (E)-selectivities
1
Ack n ow led gm en t. ETH, SNF, Aventis, Eli Lilly,
Merck, and F. Hoffmann-LaRoche are acknowledged for
their generous support of our research program. We are
grateful to Prof. Armido Studer (Marburg University)
for a generous gift of cyclohexadiene 49. Dr. J effrey W.
Bode is gratefully acknowledged for numerous fruitful
discussions and suggestions.
(72) (a) Ireland, R. E.; Liu, L. B.; Roper, T. D.; Gleason, J . L.
Tetrahedron 1997, 53, 13257-13284. (b) Evans, D. A.; Ratz, A. M.;
Huff, B. E.; Sheppard, G. S. Tetrahedron Lett. 1994, 35, 7171-7172.
(73) Nicolaou, K. C.; Daines, R. A.; Uenishi, J .; Li, W. S.; Papahatjis,
D. P.; Chakraborty, T. K. J . Am. Chem. Soc. 1988, 110, 4672-4685.
(74) (a) Blakemore, P. R.; Cole, W. J .; Kocien´ski, P. J .; Morley, A.
Synlett 1998, 26-28. (b) Kocien´ski, P. J .; Bell, A.; Blakemore, P. R.
Synlett 2000, 365-366.
(75) (a) Baudin, J . B.; Hareau, G.; J ulia, S. A.; Ruel, O. Tetrahedron
Lett. 1991, 32, 1175-1178. (b) J ulia, M.; Paris, J . M. Tetrahedron Lett.
1973, 14, 4833-4836. (c) Kocien´ski, P. J .; Lythgoe, B.; Ruston, S. J .
Chem. Soc., Perkin Trans. 1 1978, 829-834.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectral data for all relevant compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(76) Sulfone 61 was prepared from 3-methyl-1-butanol and com-
mercially available 1-phenyl-5-mercaptotetrazole using the Mitsunobu
protocol (86%) followed by oxidation of the resulting sulfide to the
corresponding sulfone 61 with oxone in 90% yield.
J O034964V
J . Org. Chem, Vol. 68, No. 24, 2003 9283