Iodocyclization and prins-type macrocyclization: An efficient formal synthesis of leucascandrolide A

Article abstract of DOI:10.1021/ol200223q

The formal total synthesis of leucascandrolide A has been achieved in 20 steps from a known epoxide with an overall yield of 11.5% following a recently developed strategy for the construction of trans-2,6-disubstituted-3,4- dihydropyrans and a Lewis acid

Full text of DOI:10.1021/ol200223q

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1710–1713
Iodocyclization and Prins-Type
Macrocyclization: An Efficient Formal
Synthesis of Leucascandrolide A
J. S. Yadav,*,†,‡ Manas R. Pattanayak,†,§ Pragna P. Das,† and
Debendra K. Mohapatra*,†
Organic Chemistry Division I, Indian Institute of Chemical Technology, CSIR,
Hyderabad 500 607, India, and King Saud University, P.O. Box 2454, Riyadh 11451,
Saudi Arabia
yadavpub@iict.res.in; mohapatra@iict.res.in
Received January 24, 2011
ABSTRACT
The formal total synthesis of leucascandrolide A has been achieved in 20 steps from a known epoxide with an overall yield of 11.5% following a recently
developed strategy for the construction of trans-2,6-disubstituted-3,4-dihydropyrans and a Lewis acid catalyzed intramolecular Prins-cyclization of an
aldehydic homoallylic alcohol to generate the tetrahydropyran ring with three stereogenic centers and macrocycle concomitantly.
In 1996, Pietra and co-workers identified a new genus of
calcareous sponges Leucascandra caveolata obtained from
the northeastern coast of New Calendonia Coral Sea,
which resulted in the discovery of a highly complex natural
product designated as leucascandrolide A (1) (Figure 1).1
This macrolide exhibits high in vitro cytotoxicity against
human KB and P388 tumor cell lines displaying IC50
values of 0.05 and 0.25 μg/mL, respectively. The natural
product also possesses potent antifungal ability against
Candida albicans, pathogenic yeast that attacks AIDs
patients and other immunocompromised individuals. Ad-
ditionally, following hydrolysis of the C5 ester linkage,
biological testing of the 18-membered macrocyclic core
and the separated side chain demonstrated that the macro-
cyclic domain is solely responsible for the cytotoxicity,
while the oxazole-containing unsaturated side chain ap-
pears to be responsible for the antifungal activity.
The highly oxygenated 18-membered macrolide (1) has
eight stereogenic centers and three alkenes and also fea-
tures two trisubstituted tetrahydropyranrings, one ofthese
having an unusual oxazole-containing side chain axially
appended at C5. A subsequent report indicates that leu-
cascandrolide A is no longer available from its initial
natural source.2 It has been proposed that leucascandro-
lide A and its cometabolite leucascandrolide B are pro-
ducts of opportunistic microbial colonization of the
† Indian Institute of Chemical Technology, CSIR.
‡ King Saud University.
§ University of Hyderabad, Hyderabad 500 046, India.
(1) D’Ambrosio, M.; Guerriero, A.; Debitus, C.; Pietra, F. Helv.
Chim. Acta 1996, 79, 51.
Figure 1. Structure of Leucascandrolide A (1).
r
10.1021/ol200223q
Published on Web 03/09/2011
2011 American Chemical Society

sponge, as evidenced by the large amounts of dead tissue in
the initial harvest of Leucascandra caveolata. Currently,
there is no natural source of leucascandrolide A. Based
on its impressive biological activity, inaccessibility from
natural sources, and structural complexity associated with
ample synthetic challenges, the construction of leucascan-
drolide A has spurred considerable synthetic interest,
resulting in several total and formal syntheses.3-5
hydroxyl under the Mitsunobu protocol. The alcohol
fragment 4 could be obtained through a late stage Prins-
cyclization (Scheme 2). The C11-C15 pyran of 7 could be
prepared following our recently reported protocol. The δ-
hydroxy R,β-unsaturated aldehyde 2 precursor for the
iodocyclization reaction as well as the acid fragment 8
could be obtained starting from a known chiral epoxide 9.
In this article, we present a unique synthetic solution for
the leucascandrolide problem featuring a concise, conver-
gent, and highly stereoselective approach to this complex
natural product. Our interest for 1 arose from studies in
which we demonstrated that the critical trans-2,6-disub-
stituted tetrahydropyran relevant to the C11-C15 frag-
ment would be prepared following a recently developed
iodocyclization of δ-hydroxy R,β-unsaturated aldehyde
with allyltrimethyl silane in the presence of molecular
iodine (Scheme 1).6 The second most important reaction
was to apply a Prins-type macrocyclization which has
recently emerged as a successful strategy in the synthesis
of polyketide derived complex natural products.7
Scheme 2. Retrosynthetic Analysis of Leucascandrolide A (1)
Scheme 1. Iodocyclization Protocol for the Synthesis of 3
Our retrosynthetic analysis for the total synthesis of
leucascandrolide A is illustrated in Scheme 2. Leucascan-
drolide A (1) would be derived from the macrolactone 4 by
attachment of the oxazole containing side chain at the C5
The application of allylation on δ-hydroxy R,β-unsatu-
rated aldehyde 2 with allyltrimethyl silane in the presence
of molecular iodine following our protocol6 facilitated an
eight-step preparation of the trans-2,6-disubstituted dihy-
dropyran 3 as the only product (Scheme 3). The prepara-
tion of 2 commenced with the conversion of the epoxide 98
into a homoallyl alcohol through the copper(I)-catalyzed9
addition of a vinyl Grignard reagent followed by cross-
metathesis with Hoveyda-Grubbs10 catalyst affording the
R,β-unsaturated aldehyde. It was then subjected to
(2) D’Ambrosio, M.; Tato, M.; Pocsfalvi, G.; Debitus, C.; Pietra, F.
Helv. Chim. Acta 1999, 82, 347.
(3) (a) Hornberger, K. R.; Hamblett, C. L.; Leighton, J. L. J. Am.
Chem. Soc. 2000, 122, 12894. (b) Wang, Y.; Janjic, J.; Kozmin, S. A. J.
Am. Chem. Soc. 2002, 124, 13670. (c) Fettes, A.; Carreira, E. M. Angew.
Chem., Int. Ed. 2002, 41, 4098. (d) Fettes, A.; Carriera, E. M. J. Org.
Chem. 2003, 68, 9247. (e) Paterson, I.; Tudge, M. Angew. Chem., Int. Ed.
2003, 42, 343. (f) Paterson, I.; Tudge, M. Tetrahedron 2003, 59, 6833.
(g) Wang, Y.; Jelena, J.; Kozmin, S. A. Pure Appl. Chem. 2005, 77, 1161.
(h) Su, Q.; Panek, J. S. Angew. Chem., Int. Ed. 2005, 44, 1223. (i) Su, Q.;
Dakin, L. A.; Panek, J. S. J. Org. Chem. 2007, 72, 2.
(4) (a) For syntheses of the macrolide core of leucascandrolide A, see:
(a) Kopecky, D. J.; Rychnovsky, S. D. J. Am. Chem. Soc. 2001, 123,
8420. (b) Wipf, P.; Reeves, J. T. Chem. Commun. 2002, 2066.
(c) Williams, D. R.; Plummer, S. V.; Patnaik, S. Angew. Chem., Int.
Ed. 2003, 42, 3934. (d) Williams, D. R.; Patnaik, S.; Plummer, S. V. Org.
Lett. 2003, 5, 5035. (e) Crimmins, M. T.; Siliphaivanh, P. Org. Lett. 2003,
(6) Mohapatra, D. K.; Das, P. P.; Pattanayak, M. R.; Yadav, J. S.
Chem.;Eur. J. 2010, 16, 2072.
(7) Crane, E. A.; Scheidt, K. A. Angew. Chem., Int. Ed. 2010, 49, 8316
and references therein.
ꢀ
5, 4641. (f) Ferrie, L.; Reymond, S.; Capdevielle, P.; Cossy, J. Org. Lett.
(8) (a) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N.
Science 1997, 277, 936. (b) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.;
Tokunaga, M.; Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen,
E. N. J. Am. Chem. Soc. 2002, 124, 1307. (c) Mori, K.; Shikichi, Y.;
Shankar, S.; Yew, J. Y. Tetrahedron 2010, 66, 7161.
2007, 9, 2461. (g) Jung, H. H.; Seiders, J. R.; Florencig, P. E. Angew.
Chem., Int. Ed. 2007, 46, 8464. (h) Ferrie, L.; Boulard, L.; Pradaux, F.;
Bouzbouz, S.; Reymond, S.; Capdevielle, P.; Cossy, J. J. Org. Chem.
2008, 73, 1864. (i) Evans, P. A.; Andrews, W. J. Angew. Chem., Int. Ed.
2008, 47, 5426.
ꢀ
(9) Ahmed, A.; Hoegenauer, E. K.; Enev, V. S.; Hanbauer, M.;
€
(5) For syntheses of fragments and analogues of leucascandrolide A,
see: (a) Crimmins, M. T.; Carroll, C. A.; King, B. W. Org. Lett. 2000, 2,
579. (b) Kozmin, S. A. Org. Lett. 2001, 3, 755. (c) Wipf, P.; Graham,
T. H. J. Org. Chem. 2001, 66, 3242. (d) Dakin, L. A.; Langille, N. F.;
Paneck, J. S. J. Org. Chem. 2002, 67, 6812. (e) Dakin, L. A.; Paneck, J. S.
Org. Lett. 2003, 5, 3995. (f) Ulanovskaya, O. A.; Janjic, J.; Suzuki, M.;
Sabharwal, S. S.; Schumacker, P. T.; Kron, S. J.; Kozmin, S. A. Nat.
Chem. Biol. 2008, 4, 418.
Kaehlig, H.; Ohler, E.; Mulzer, J. J. Org. Chem. 2003, 68, 3026.
(10) (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 2000, 122, 8168. (b) Dinh, M.-T.; Bouzbouz, S.;
Peglion, J. L.; Cossy, J. Tetrahedron 2008, 64, 5703.
ꢀ
ꢀ
(11) (a) Marigo, M.; Franzen, J.; Poulsen, T. B.; Zhuang, W.;
Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 6964. (b) Hayashi, Y.;
Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212.
Org. Lett., Vol. 13, No. 7, 2011
1711

asymmetric epoxidation under Jørgensen’s conditions11a
with H2O2 in the presence of a proline-derived catalyst11b
to furnish an epoxy aldehyde, which on condensation with
Ph3PdCHCO2Et afforded an epoxy ester. The epoxy ester
was treated with trimethyl aluminum (TMA),12 followed
by reduction of an R,β-unsaturated ester with DIBAL-H
and oxidation with TEMPO/BAIB,13 producing δ-hydro-
xy R,β-unsaturated aldehyde 2 which on iodocyclization
in 7with a 12:1 diastereomeric ratio (by HPLC) in 82% yield
as a separable mixture (Scheme 4).
Scheme 4. Synthesis of Fragment 7
afforded 3 in 41% yield over eight steps. The 1H and 13
C
NMR spectra revealed a single isomer which was sup-
ported by HPLC analysis data (de g 99%). The terminal
double bond was oxidatively cleaved following a modified
method14 (NaIO4 and 2,6-lutidine) to obtain aldehyde 15.
Scheme 3. Synthesis of Aldehyde 15
Having the required alcohol fragment 7 in hand, our
next target was to synthesize acid fragment 8. The synthesis
commenced with the copper(I)-catalyzed addition of the
Grignard reagent vinyl magnesium bromide to the epoxide
9 to afford 10 in 85% yield. The resulting homoallylic alcohol
was protected as its TBS-ether using TBSOTf and 2,6-lutidine
in anhydrous CH2Cl2 to obtain 20 in 93% yield. Deprotection
of the p-methoxybenzyl group with DDQ17 in CH2Cl2/H2O
(9:1) yielded the primary hydroxy compound 21 in 94% yield.
The resulting primary hydroxy group was oxidized with
Dess-Martin periodinane18 to afford the corresponding
aldehyde 22 (Scheme 5) which on further oxidation under
Pinnick conditions (NaClO2/NaH2PO4/t-BuOH/H2O/2-
methyl-2-butene) gave acid 8 whose spectral and analytical
data were in good agreement with the reported data.19
With alcohol 7 and acid fragment 8 in hand, our next
task was to couple both of the fragments and verify the
Subsequent oxidation of aldehyde 15 under Pinnick
conditions15 affordeda carboxylic acidwhich on treatment
with diazomethane gave the ester 16 in 78% yield over
three steps. Reduction of the double bond over Pd/C under a
hydrogen atmosphere furnished tetrahydropyran derivative
17 in 93% yield. Nucleophilic addition of the lithiated
derivative of dimethyl methyl phosphonate furnished the
β-keto phosphonate 18 in 92% yield, which on treatment
with 3-methylbutanal in the presence of NaHMDS gave
R,β-unsaturated ketone 19 in 81% yield. Reduction of 19
with the Corey-Bakshi-Shibata (CBS)16 reagent [(S)-2-
methyloxazaborolidine in the presence of borane-dimethyl-
sulfide complex] installed the C17 stereogenic center present
Scheme 5. Synthesis of Acid Fragment 8
(12) Pfaltz, A.; Mattenberger, A. Angew. Chem., Int. Ed. Engl. 1982,
21, 71.
(13) Mico, A. D.; Maragrita, R.; Parlanti, L.; Vescovi, A.; Piancatelli,
G. J. Org. Chem. 1997, 62, 6974.
(14) Ya, W.; Mei, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6, 3217.
(15) (a) Ballakrishna, S. B.; Childers, W. E., Jr; Pinnick, H. W.
Tetrahedron 1981, 37, 2091. (b) Dalcanale, E.; Montanari, F. J. Org.
Chem. 1986, 51, 567.
(16) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C. P.; Singh,
V. K. J. Am. Chem. Soc. 1987, 109, 7925. (b) Corey, E. J.; Bakshi, R. K
Tetrahedron Lett. 1990, 31, 61. (c) Corey, E. J.; Helal, C. J. Angew.
Chem., Int. Ed. 1998, 37, 1986.
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Org. Lett., Vol. 13, No. 7, 2011

Prins-type macrocyclization on an 18-membered macro-
lactone. The coupling of C1-C6 fragment 8 and C7-C23
fragment 7 was initially performed employing dicyclohexyl
carbodiimide (DCC)20 and a catalytic amount of DMAP
in CH2Cl2 to afford ester 23 in 42% yield, whereas EDCI21
and DMAP in CH2Cl2 furnished the ester 23 in 57% yield.
However, a better result was achieved under Yamaguchi
conditions22 to obtain the ester 23 in 93% yield, which
contains all 23 carbons of the target molecule (Scheme 6).
Deprotection of the PMB ether in 23 upon treatment with
DDQ afforded alcohol 24 in 95% yield. The primary
hydroxyl group at C7 was then oxidized to an aldehyde
6 by treatment with Dess-Martin periodinane which
was taken forward for the next reaction without further
purification.
Scheme 6. Synthesis of Macrolide 4
The next important task was to perform the Prins-
macrocyclization. As expected, the construction of 18-
membered macrocycle 4 by intramolecular Prins-cycli-
zation of aldehyde 6 was a significant challenge. After
extensive investigations, we eventually found that treat-
ment of 6 with >30 equiv of TMSOAc and TESOTf in
A 0.01 M solution of AcOH resulted in the Prins adduct
and hydrolysis furnished macrolide 4 in 72% yield over
three steps. The outcome of 4 was derived in an analogy
by a recent report for the synthesis of neopeltolide by
Lee et al.23 This macrocyclization with high diastereos-
electivity (dr > 97:3) and good yield provides an addi-
tional example of the powerful and versatile nature of
the Prins-macrocyclization strategy. Kozmin and co-
workers3b,h have already demonstrated that THE one-
step protocol featuring Mitsunobu esterification could
be utilized to convert alcohol 4 to leucascandrolide A
(1). Thus, the synthesis of macrolide 4 constitutes a
formal synthesis of leucascandrolide A. The spectral
25
(1H, and 13C NMR, IR) and analytical data {[R]D
20
þ54.7 (c 1.18, EtOH); lit.3b [R]D þ58 (c 0.1, EtOH);
lit.3h [R]D þ55 (c 0.05, EtOH)} were in good agreement
23
with the reported values.
In summary, our investigations into the allylation of a δ-
hydroxy R,β-unsaturated aldehyde with an allyltrimethyl
silane in the presence of a catalytic amount of molecular
iodine as a protocol combined with the intramolecular
Prins-macrocyclization has led to a concise formal total
synthesis of leucascandrolide A, which proceeded in only a
20-step longest linear sequence with a 11.5% overall yield
starting from a known epoxide.
(17) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu,
O. Tetrahedron 1986, 42, 3021.
(18) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(19) (a) Bennett, F.; Knight, D. W. Tetrahedron Lett. 1988, 29, 4865.
(b) Maddrell, S. J.; Turner, N. J.; Kerridge, A.; Willetts, A. J.; Crossby, J.
Tetrahedron Lett. 1988, 29, 4865. (b) Maddrell, S. J.; Turner, N. J.;
Kerridge, A.; Willetts, A. J.; Crossby, J. Tetrahedron Lett. 1996, 37,
6001. (c) Kobayashi, Y.; Wang, Y.-G. Tetrahedron Lett. 2002, 43, 4381.
(20) (a) Neises, B.; Steglich, W. Angew Chem., Int. Ed. Engl. 1978, 17,
522. (b) Williams, A.; Ibrahim, I. T. Chem. Rev. 1981, 81, 589.
Acknowledgment. M.R.P. and P.P.D. thank the Council
of Scientific and Industrial Research (CSIR), New Delhi,
India, for financial support in the form of a research fellow-
ship. D.K.M. thanks the Council of Scientific and Industrial
Research (CSIR), New Delhi, India, for a research grant
(INSA Young Scientist Award Scheme).
ꢀ
(c) Mikolajczyk, M.; Kielbasinski, P. Tetrahedron 1981, 37, 233.
(21) (a) Nozaki, S.; Muramatsu, I. Bull. Chem. Soc. Jpn. 1982, 55,
2165. (b) Sheehan, J. C.; Preston, J.; Cruickshank, P. A. J. Am. Chem.
Soc. 1965, 87, 2492.
(22) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(23) Woo, S. K.; Kwon, M. S.; Lee, E. Angew. Chem., Int. Ed. 2008,
47, 3242.
Org. Lett., Vol. 13, No. 7, 2011
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