Leucascandrolide A: A Second Generation Formal Synthesis

Article abstract of DOI:10.1021/ol036071v

(Equation presented) A convergent, second generation formal synthesis of (+)-Leucascandrolide A (1) has been efficiently achieved by providing a flexible, enantiocontrolled strategy toward the bioactive macrolactone component. Advancements for stereocontr

Full text of DOI:10.1021/ol036071v

ORGANIC
LETTERS
2003
Vol. 5, No. 26
5035-5038
Leucascandrolide A: A Second
Generation Formal Synthesis
David R. Williams,* Samarjit Patnaik, and Scott V. Plummer
Department of Chemistry, Indiana UniVersity, 800 East Kirkwood AVenue,
Bloomington, Indiana 47405-7102
williamd@indiana.edu
Received October 23, 2003
ABSTRACT
A convergent, second generation formal synthesis of (+)-Leucascandrolide A (1) has been efficiently achieved by providing a flexible,
enantiocontrolled strategy toward the bioactive macrolactone component. Advancements for stereocontrol in asymmetric allylation methodology
are discussed. Efforts feature novel results for reductions using the Terashima hydride reagent.
Leucascandrolide A (1) was isolated by Pietra and co-
workers from Leucascandra caVeolata, a calcareous sponge
first found in 1989 along the eastern coast of New Caledonia
in the Coral Sea.1 Detailed structural analysis revealed a
pattern of extensive 1,3-oxygenation in an 18-membered
macrolactone that was bridged by ether oxygens forming two
internal pyrans.1 An unusual side chain bearing two Z-olefins,
an oxazole, and a terminal carbamate was attached to the
C5 hydroxyl of the macrolide via an ester linkage. Assays
of leucascandrolide A displayed strong in vitro anticancer
properties with IC50 values of 0.05 and 0.25 µg/mL against
KB tumor and P338 murine leukemia cell lines, respectively.1
Significantly, strong inhibition was also found against
Candida albicans, a pathogenic yeast that infects HIV
patients, presaging the progression to AIDS.1 The macro-
lactone portion of 1 was later shown to be essential for
cytotoxic activity, while the oxazole-containing side chain
contributed to the antifungal properties of the natural product.
This promising bioactivity necessitated further biological
evaluations. However, samples subsequently harvested in
1994 at a location north of the previous sampling area failed
to yield a trace of leucascandrolide A. Pietra has suggested
that 1, as well as leucascandrolide B,2 may have origins in
an opportunistic microbial colonization of extensively dead
portions of the sponge isolated in the earlier sampling. These
facts have prompted numerous efforts toward the synthesis
of 1, which have led to successful pathways for the
preparation of racemic and optically active natural product.3
Herein we report an enantiocontrolled second generation
pathway to the macrolactone of 1 that is readily amenable
to the production of analogues for structure-activity inves-
tigations.
Our previous synthesis of leucascandrolide A (1) demon-
strated the application of reagent-based asymmetric allyla-
(2) D’Ambrosio, M.; Tato`, M.; Pocsfalvi, G.; Debitus, C.; Pietra, F. HelV.
Chim. Acta 1999, 82, 347.
(3) (a) Crimmins, M. T.; Siliphaivanh, P. Org. Lett. 2003, ASAP Article.
(b) Williams, D. R.; Plummer, S. V.; Patnaik, S. Angew. Chem., Int. Ed.
2003, 42, 3934. (c) Paterson, I.; Tudge, M. Angew. Chem., Int. Ed. 2003,
42, 343. Paterson, I.; Tudge, M. Tetrahedron 2003, 59, 6833. (d) Fettes,
A.; Carreira, E. M. Angew. Chem., Int. Ed. 2002, 41, 4098. Fettes, A.;
Carreira, E. M. J. Org. Chem. 2003, ASAP Article. (e) Wang, Y.; Janjic,
J.; Kozmin, S. A. J. Am. Chem. Soc. 2002, 124, 13670. (f) Wipf, P.; Reeves,
J. T. Chem. Commun. 2002, 2066. (g) Kopecky, D. J.; Rychnovsky, S. D.
J. Am. Chem. Soc. 2001, 123, 8420. (h) Hornberger, K. R.; Hamblett, C.
L.; Leighton, J. L. J. Am. Chem. Soc. 2000, 122, 12894.
(1) D’Ambrosio, M.; Guerriero, A.; Debitus, C.; Pietra, F. HelV. Chim.
Acta 1996, 79, 51.
10.1021/ol036071v CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/04/2003

tion4 to provide a highly convergent and stereocontrolled
construction of the natural product.3b During the course of
our studies, Kozmin and co-workers reported a facile
Mitsunobu displacement reaction for convenient attachment
of the intact ester side chain at C5 of racemic 1.3e Thus the
efficient enantiocontrolled preparation of macrolactone 2
could provide for the systematic inclusion of a variety of C5
ester substituents.
Scheme 2a
As summarized in Scheme 1, we envisioned the assembly
Scheme 1
a (a) CH2dC(Br)CH2SiMe3, Mg0, then CuBr‚DMS, THF, -40
°C, then 6, -78 to -20 °C, 75% (>95% dr); (b) LiBH4, MeOH,
Et2O, 0 °C, 81%; (c) DCC‚MeI, THF, 88%; (d) 2-lithiodithiane,
THF, -78 to 0 °C, 96%; (e) NBS, propylene oxide, -78 °C,
CH2Cl2/DMF (3:4), then add Bu3SnLi, CuBr‚DMS to crude allyl
bromide, -78 to -40 °C, 70-80% overall from 9.
formed into primary iodide 8 in 88% yield using dicyclo-
hexylcarbodiimide and methyl iodide.7 A number of standard
procedures for this conversion were not compatible with the
allylic silane. Low-temperature alkylation with 2-lithio-1,3-
dithiane led to 9, and treatment with recrystallized N-
bromosuccinimide at -78 °C in a solution of DMF and
CH2Cl2 gave the intermediate allyl bromide 10. This
transformation is especially notable because NBS is routinely
used to promote the cleavage and hydrolysis of dithioacetals.
Additionally, the decomposition of the reactive allylic
bromide via S-alkylation must be avoided. Thus, the crude
bromide was used directly for displacement with tri-n-
butylstannyl copper8 to provide the C10-C15 component 4.
The transmetalation of stannane 4 (Scheme 3) with
(4R,5R)-2-bromo-4,5-diphenyl-1,3,2-diazoborolidine 119 was
followed by the low-temperature condensation with aldehyde
3 to provide a quantitative yield of the homoallylic alcohol
12 along with small amounts of the corresponding (9S)-
alcohol diastereomer (dr 91:9). The stereochemistry at C9
of 12 was confirmed with NMR analysis of its Mosher
esters;10 however, on a preparative scale, this mixture was
carried forward for two steps.
of macrolide 2 via three readily available components of
modest complexity, which evoked further enthusiasm for
these studies. Moreover, our previous efforts had provided
substantial quantities of the optically pure tetrahydropyran
3 (C1-C9). To that end, we considered the use of stannane
4 in asymmetric allylation methodology for reagent-based
control of stereochemistry at C9 of 2. The subsequent
formation of the C15-C16 carbon bond via a modified
Mukaiyama aldol strategy would utilize the silylenol ether
5. Remaining issues to be addressed involved stereocontrol
in the generation of the 2,6-trans-tetrahydropyran and in the
formation of the equatorial alcohol at C5 of 2.
The application of asymmetric conjugate addition meth-
odology, as reported from these laboratories,5 facilitated a
five-step preparation of the nonracemic allylic stannane 4
(Scheme 2). Diastereoselective 1,4-addition of the organo-
copper species derived from the Grignard reagent of 2-bro-
moallyltrimethylsilane with the (R)-4-phenyl-N-enoyl-1,3-
oxazolidin-2-one 6 gave imide 7 (dr > 20:1), installing the
C12 chirality.6 After reductive cleavage of the chiral auxiliary
with LiBH4, the resultant pure alcohol was directly trans-
A predictive model of our rationalization for this asym-
metric allylation is illustrated in Figure 1. Thus, the allylic
transposition of 4 to the reactive borane 13 is followed by
synclinal complexation of the Lewis acid with respect to the
aldehydic hydrogen in 14. This preorganization is depicted
by the chairlike arrangements 15 and 16. Simple diastereo-
selection, as determined by the (R,R)-auxiliary, is based upon
the unfavorable nonbonded interactions of the sulfonyl
(4) For additional examples: (a) Williams, D. R.; Brooks, D. A.; Meyer,
K. G.; Clark, M. P. Tetrahedron Lett. 1998, 39, 7251. (b) Williams, D. R.;
Brooks, D. A.; Berliner, M. A. J. Am. Chem. Soc. 1999, 121, 4924. (c)
Williams, D. R.; Meyer, K. G. J. Am. Chem. Soc. 2001, 123, 765.
(5) (a) Williams, D. R.; Kissel, W. S.; Li, J. J. Tetrahedron Lett. 1998,
39, 8593. (b) Williams, D. R.; Kissel, W. S.; Li, J. J., Mullins, R. J.
Tetrahedron Lett. 2002, 43, 3723. (c) Nicolas, E.; Russell, K. C.; Hruby,
V. J. J. Org. Chem. 1993, 58, 766.
(7) Scheffold, R.; Saladin, E. Angew. Chem., Int. Ed. Engl. 1972, 11,
229. For a recent application, see: Harmata, M.; Bohnert, G. J. Org. Lett.
2003, 5, 59.
(8) Piers, E.; Chong, J. M.; Gustafson, K.; Andersen, R. J. Can. J. Chem.
1984, 62, 1.
(9) Corey, E. J.; Yu, C.-M.; Kim, S. S. J. Am. Chem. Soc. 1989, 111,
5495.
(10) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512. (b)
Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991,
113, 4092.
(6) The stereochemistry of 7 was assigned by protodesilyation and
comparison with known material (see ref 5a).
5036
Org. Lett., Vol. 5, No. 26, 2003

Scheme 3a
Figure 1. Diasteroselection in allylation reactions.
from the previous allylation, yielding pure 18. Subsequent
oxidative cleavage of the C5 and C11 olefins furnished
diketone 19, which was subjected to the Terashima reduction
via the in situ generation of a LiAlH4 complex of (+)-N-
methylephedrine and N-ethylaniline.16 This unprecedented
utilization of the Terashima reagent effected a highly
selective Felkin-Anh addition to provide the (11R)-alcohol
(dr > 25:1) and also reduced the more accessible C5 ketone
with axial hydride delivery to yield the equatorial hydroxy
group (dr 8:1) in the product diol. Sequential exposure to
aqueous protic acid and then acetic anhydride and pyridine
gave the diacetate 20.
The stage was set for the incorporation of the C16-C22
component via a Mukaiyama aldol process. Thus, Lewis acid
catalysis provided for a diastereofacial condensation of TMS
enol ether 5 with 20 to directly install the E-unsaturated
ketone of 21 (dr > 25:1) in excellent yield (90%). Selective
formation of the trans-tetrahydropyran in 21 was anticipated
by axial nucleophilic addition to the intermediate oxocar-
benium.17 During the course of our investigations, Paterson
and co-workers described similar findings.3c
a (a) (R,R)-11, CH2Cl2, 4, rt, 10 h then -78 °C, 3, 2 h, quant, dr
91:9; (b) PhI(OOCCF3)2, MeOH, 77%; (c) Me3OBF4, proton
sponge, 4 Å MS, CH2Cl2, 97%; (d) OsO4, NMO, acetone, H2O,
then NaIO4, THF/H2O (1:1), 90%; (e) excess LiAlH4/(+)-N-
methylephedrine/N-ethylaniline (1:1:2), Et2O, -78 °C, 96%; (f)
H3PO4, THF/H2O(3:2), then add Ac2O, py., DMAP, CH2Cl2 to
crude lactol, 85%.
substituent and aldehyde in 16.11 Therefore, this C2-sym-
metric (R,R)-controller generally favors re-face addition as
shown in 15. The introduction of steric interactions as a result
of allylic branching in the starting stannane 4 (at C12) provide
additional complexity.12 As illustrated in 16, attempts to
minimize A(1,3) strain in the allyl borane will project methyl
or R1 into the chairlike transition state and serves to
destabilize this situation. On the other hand, the reinforcing
scenario in 15 permits a minimization of A(1,3) interactions13
and directs the C12 methine into the region of the sulfonyl
group of the auxiliary. Our rationale is supported by parallel
experiments using the corresponding (S,S)-borane of 11,
which led to a mismatched condensation favoring the (9S)-
diastereomer of 12 in a modest 2:1 ratio. Stereogenicity in
the aldehyde component 3 (at â-carbon C7) plays a less
significant role in the outcome of these allylations.14
(14) The addition of TMS enol ethers to substrates such as 3 proceed
with a high level of 1,3-anti stereocontrol via open transition states. For a
discussion, see: Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J.
Am. Chem. Soc. 1996, 118, 4322. Similar trends were observed in our C9-
C10 coupling studies, as exemplified by the following reaction:
Upon exchange of the dithiane for the dimethyl acetal
under Stork conditions,15 the C9 secondary alcohol underwent
quantitative methylation. Flash silica gel chromatography at
this point conveniently separated the minor C9 diastereomer
(11) Our molecular modelling indicates nonbonded interactions of the
axially disposed aldehydic H and the sulfonyl oxygens in 16.
(12) Stereogenecity in the starting stannane, which positions a chiral
center at the â-carbon of the C-2 appendage with respect to the allyl
nucleophile (or is more remote), does not affect the diastereofacial selectivity
imposed by the auxiliary. For a full account of this work, see: Williams,
D. R.; Meyer, K. G.; Shamim, K.; Patnaik, S. Can. J. Chem. In press.
(13) The energy requirements for the A(1,3) strain are estimated to be
in the range of 0.4-0.7 kcal/mol for the CH3/H interaction: Hoffmann, R.
W. Chem. ReV. 1989, 89, 1841.
(15) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287.
(16) (a) Terashima, S.; Tanno, N.; Koga, K. J. Chem. Soc., Chem
Commun. 1980, 1026. (b) Terashima, S.; Tanno, N.; Koga, K. Chem Lett.
1980, 981. (c) Tanno, N.; Terashima, S. Chem. Pharm. Bull. 1983, 31, 837.
(17) This stereochemical outcome is anticipated. For recent examples
from these laboratories, see: (a) Williams, D. R.; Mi, L.; Mullins, R. J.;
Stites, R. E. Tetrahedron Lett. 2002, 43, 4841. (b) Williams, D. R.;
Heiderbrecht, R. W., Jr. J. Am. Chem. Soc. 2003, 125, 1843.
Org. Lett., Vol. 5, No. 26, 2003
5037

Following acetylation to 22 and DDQ deprotection, sequen-
tial oxidations under Dess-Martin21 and Pinnick22 conditions
led to the C1 carboxylic acid, which was stirred with sodium
methoxide to produce the seco-acid 23 (98% yield over three
steps). On a preparative scale, flash silica gel chromatography
of the pure seco-acid permitted the convenient separation of
the minor (17S)-diastereomer to give pure 23. Yamaguchi
macrolactonization23 led to the formation of the 18-membered
2 (60%),24 which proved to be identical in all respects with
reported spectroscopic and physical data for this substance
as described by the isolation and characterization studies of
Pietra and co-workers.1,25
Scheme 4a
In summary, a convergent enantiocontrolled pathway to
the macrolide core of leucascandrolide A has been achieved
in 21 steps (7% overall yield) from readily available starting
substances. The reagent-controlled nature of this synthesis
allows the flexibility required for analogue syntheses. Our
asymmetric allylation methodology highlights the role of
vicinal stereochemistry in the stannane component for
reinforcing interactions with the chiral auxiliary. The use of
the Terashima reduction demonstrates a powerful technique
for the stereocontrolled generation of 1,3-polyol derivatives.
a (a) 20, ZnCl2, (1 M in Et2O), CH2Cl2, -78 °C to rt, 90%, dr
>25:1; (b) S-Me-oxazaborolidine, BH3‚THF, THF, -10 °C, 85%,
dr 5:1; (c) Ac2O, pyr, DMAP, CH2Cl2, 95%; (d) DDQ, CH2Cl2,
pH 7 buffer, tBuOH, 96%; (e) Dess-Martin periodinane, NaHCO3,
Acknowledgment. The authors gratefully acknowledge
the National Institute of Health (GM-42897) for the generous
support of our work.
t
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 2, 4, 7-9, 12, and
17-23 on the synthesis pathway are provided. This material
is available free of charge via the Internet at http://pubs.acs.org.
CH2Cl2 then NaClO2, NaH2PO4, 2-methyl-2-butene, aq BuOH, 0
°C; (f) NaOMe MeOH, (98% over 3 steps); (g) 2,4,6-trichloroben-
zoyl chloride, THF, Et3N, slow addition to refluxing solution of
DMAP in PhH, 60%.
OL036071V
Final stages for the synthesis proceeded uneventfully. The
Corey CBS borohydride reduction18 of 21 using (S)-2-methyl-
oxazaborolidine gave a 5:1 mixture of separable C17 alcohols
favoring the (17R)-isomer.19 Unfortunately chirally modified
Terashima16 or Noyori20 reagents commonly deployed for
reduction of aromatic and acetylenic ketones and enones led
to significant (>50%) 1,4-conjugate hydride reduction.
(21) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(22) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981,
37, 2091.
(23) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
(24) Yamaguchi conditions also led to small amounts (5-15%) of the
[3.3.1]-bicyclic lactone i, which can be recycled to the seco-acid 23 via
KOH, aqueous methanol.
(18) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C. P.; Singh, V.
K. J. Am. Chem. Soc. 1989, 109, 7928. (b) Mathre, D. J.; Jones, T. K.;
Xavier, L. C.; Blacklock, T. J.; Reamer, R. A.; Mohan, J. J.; Jones, E. T.
T.; Hoogsteen, K.; Baum, M. W.; Grabowski, E. J. J. J. Org. Chem. 1991,
56, 751.
(19) The stereochemistry of the major (17R)-diastereomer was confirmed
by modified Mosher ester analysis (see ref 10).
(20) Noyori, R.; Tomino, I.; Tanimoto, Y.; Nishizawa, M. J. Am. Chem.
Soc. 1984, 106, 6709; 6717.
(25) In addition, macrolide 2 underwent oxidation to the corresponding
C5 tetrahydropyranone; for direct comparison with a sample independently
prepared from our first generation strategy, see ref 3b.
5038
Org. Lett., Vol. 5, No. 26, 2003