Total synthesis of (+)-neopeltolide by a Prins macrocyclization

Article abstract of DOI:10.1002/anie.200800386

(Chemical Equation Presented) Rings within rings: The total synthesis of (+)-neopeltolide was accomplished by employing an intramolecular Prins macrocyclization of an aldehydic homoallylic alcohol intermediate (see scheme).

Full text of DOI:10.1002/anie.200800386

Communications
DOI: 10.1002/anie.200800386
Natural Products
Total Synthesis of (+)-Neopeltolide by a Prins Macrocyclization**
Sang Kook Woo, Min Sang Kwon, and Eun Lee*
Neopeltolide (1) is a 12-membered macrolide from a Lithistid
sponge of the Neopeltidae family.[1] It is a potent inhibitor of
tumor cell proliferation with IC50 values of 1.2, 5.1, and
0.56 nm against human lung adenocarcinoma (A549), human
ovarian sarcoma (NCI/ADR-RES), and murine leukemia
(P388), respectively, and it is also a potent antifungal agent. A
2,4,6-trisubstituted oxane ring is an integral part of the
macrolactone framework and the substituent at the 4-position
features an oxazole-bearing carboxylate group identical to
that found in leucascandrolide A.[2] A recent total synthesis of
1[3] by Panek and co-workers corrected the stereochemical
assignments at C11 and C13, and a second total synthesis[4] by
Scheidt and co-workers confirmed the revised structure. We
report herein results of our recent efforts on the total
synthesis of 1.
For the expedient construction of 2,4,6-trisubstituted
oxane fragments, a Prins cyclization involving an aldehyde
and a homoallylic alcohol partner appeared to be feasible. In
the retrosynthetic analysis for 1, an intramolecular Prins
cyclization was envisioned; macrolactone A could be pre-
pared from aldehydic homoallylic alcohol B through cyclic
oxocarbenium ion D (Scheme 1). This reaction, if successful,
would lead to the bicyclic macrolactone A in a single step.
This type of cyclization reaction is reported in the literature,[5]
but it has been relatively unexplored for the synthesis of
complex natural products until recently.[6] The homoallylic
alcohol fragment (C) would serve as the precursor for B.
For the synthesis of fragment C, aldehyde 5 was obtained
Scheme 1. Retrosynthetic analysis.
from butanal (3) by a reaction sequence involving an
asymmetric crotyl transfer reaction,[7] protection of the
alcohol group with
a benzyl group, and ozonolysis
(Scheme 2). Titanium(IV) chloride mediated methallylation
proceeded stereoselectively to produce a homoallylic alcohol,
from which ester 7 was obtained by esterification with 2-
diphenylphosphinobenzoic acid (6). The substrate-directed
hydroformylation[8] of 7 preferentially produced desired
aldehyde 8 in a 5:1 ratio. Dimethyl acetal formation,
hydrolysis, and O methylation yielded dimethyl acetal 9.
The aldehyde obtained from 9 was preferentially trans-
formed into desired homoallylic alcohol 10 in a 5.5:1 ratio of
isomers by using the method of Brown for the allylation
(Scheme 3).[9] Intermediate 11 was prepared from 10 by a
sequence involving protecting the alcohol with a tert-butyldi-
methysilyl (TBS) group, cleaving the benzyl group by using
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), and
esterifying with 3,3-diethoxypropanoic acid. Compound 11
was reacted with triethylsilyl trifluoromethanesulfonate
(TESOTf) in acetic acid in the presence of trimethylsilyl
acetate (TMSOAc),[10] and subsequently treated under basic
conditions to yield bicyclic macrolactone 12. Approximately
10% racemization[11] was observed by careful spectroscopic
analysis of 12.
[*] S. K. Woo,M. S. Kwon,Prof. E. Lee
Department of Chemistry
College of Natural Sciences
Seoul National University
Seoul 151-747 (Korea)
Fax: (+82)2-889-1568
E-mail: eunlee@snu.ac.kr
The intramolecular Prins cyclization appeared to be a
viable solution in the synthesis of compounds like 1, and we
were intrigued by the possibility of an alternative Prins
cyclization approach. A second aldehydic homoallylic alcohol
(E) could also produce macrolactone A through cyclic
oxocarbenium intermediate G under the typical Prins con-
ditions (Scheme 4).
[**] This work was supported by a grant from MarineBio21,Ministry of
Maritime Affairs and Fisheries,Korea,and a grant from the Center
for Bioactive Molecular Hybrids (Yonsei University and KOSEF).
BK21 graduate fellowship grants to M.S.K. are gratefully acknowl-
edged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Chemie
Scheme 2. Preparation of fragment C. a) 4,CSA,CH 2Cl2; b) NaH,
BnBr,TBAI,THF/DMF (5:1); c) O 3,CH 2Cl2, À788C; Ph3P; d) CH2C-
(CH3)CH2TMS,TiCl 4,CH 2Cl2, À788C; e) 6,DCC,DMAP,CH 2Cl2;
f) Rh(CO)2(acac),P(OPh) 3,40 bar H 2/CO (1:1),toluene,30 8C;
g) H2SO4,HC(OMe) 3,MeOH; h) KOH,EtOH,reflux; i) NaH,MeI,
THF. CSA=camphorsulfonic acid; TBAI=tetrabutylammonium iodide;
TMS=trimethylsilyl; DCC=1,3-dicyclohexylcarbodiimide; DMAP=4-
dimethylaminopyridine; o-DPPB=o-diphenylphosphinobenzoyl;
acac=acetylacetonate.
Scheme 4. An alternative Prins approach to neopeltolide (1).
Scheme 5. Synthesis of neopeltolide (1). a) TBAF,THF; b) DMP,
CH2Cl2; NaClO2,NaH 2PO4, tBuOH-2-methyl-2-butene-H2O (12:3:2);
c) H2,Pd/C,MeOH; d) 14,DCC,DMAP,CH 2Cl2; e) DDQ,pH 7 buffer,
CH2Cl2; f) TESOTf (20 equiv),TMSOAc (30 equiv),AcOH,RT,30 min;
g) K2CO3,MeOH; h) 2,DIAD,Ph 3P,benzene. TBAF =tetrabutylammo-
nium fluoride; DMP=Dess–Martin periodinane; DIAD=diisopropyl-
azodicarboxylate.
lactone system was constructed efficiently with complete
stereocontrol at the two new stereogenic centers. Finally,
Mitsunobu reaction[4] of 12 with known carboxylic acid 2 (see
Scheme 1 for structure)[14] led to neopeltolide (1).[15]
In the present synthesis, a macrolactone was generated by
a Prins cyclization strategy and it was used successfully in the
total synthesis of neopeltolide (1). Additional applications of
this concept will be reported in due course.
Scheme 3. Intramolecular Prins cyclization. a) HCl,acetone;
b) CH2CHCH2B(dIpc)2,ether, À788C; H2O2,NaOH; c) TBSOTf,26, -
lutidine,CH 2Cl2; d) DDQ,ClCH 2CH2Cl,pH 7 buffer;
e) (EtO)2CHCH2CO2H,DCC,DMAP,CH 2Cl2; f) TESOTf (20 equiv),
TMSOAc (30 equiv),AcOH (0.01 m),RT,30 min; g) K 2CO3,MeOH.
Ipc=isopinocampheyl (superscript d implies that it was prepared from
(+)-a-pinene),DDQ =2,3-dichloro-5,6-dicyano-1,4-benzoquinone,
TBS=tert-butyldimethylsilyl,TESOTf =triethylsilyltrifluoromethanesul-
fonate.
Experimental Section
Carboxylic acid 14 was prepared from known olefin 13[12]
by the removal of a silyl group and an oxidation (Scheme 5).
Benzyl cleavage of 9, esterification of the product secondary
alcohol with 14, and then prolonged exposure to DDQ
produced aldehydic homoallylic alcohol 15 in good yield. This
time, the Prins cyclization of 15 proceeded more efficiently
and hydrolysis of the Prins adduct gave macrolide 12 in
reasonable yield. The efficiency and stereoselectivity[13] of the
Prins reaction was remarkable; the bicyclic oxane/macro-
Macrolide 12: TMSOAc (0.40 mL, 2.73 mmol) was added to a
solution of aldehyde 15 (30 mg, 0.091 mmol) in AcOH (9.0 mL) at
room temperature. TESOTf (0.40 mL, 1.82 mmol) was added drop-
wise to the resulting solution at the same temperature. After 30 min,
the reaction mixture was poured into ether (20 mL) and sat. NaHCO3
(20 mL). The layers were separated, and the aqueous layer was
extracted with ether (20 mL ” 3). The combined organic layers were
dried over MgSO4, filtered, and concentrated. The product from the
crude reaction mixture was dissolved in MeOH (2 mL) and then
K2CO3 (125 mg, 0.91 mmol) was added. The reaction mixture was
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3243

Communications
stirred for 3 h at room temperature and then concentrated. The
[4] D. W. Custar, T. P. Zabawa, K. A. Scheidt, J. Am. Chem. Soc.
2008, 130, 804 – 805.
[5] For examples, see: a) K. H. Schulte-Elte, A. Hauser, G. Ohloff,
Helv. Chim. Acta 1979, 62, 2673 – 2680; b) Y. S. Cho, H. Y. Kim,
J. H. Cha, A. N. Pae, H. Y. Koh, J. H. Choi, M. H. Chang, Org.
Lett. 2002, 4, 2025 – 2028.
[6] In the synthesis of 1 by Scheidt and co-workers (reference [4]),
the intramolecular Prins cyclization of a dioxinone-containing
precursor was catalyzed by Sc(OTf)3 (25% yield).
[7] C.-L. K. Lee, C.-H. A. Lee, K.-T. Tan, T.-P. Loh, Org. Lett. 2004,
6, 1281 – 1283.
residue was dissolved in water (5 mL) and ether (5 mL). The layers
were separated, and the aqueous layer was extracted with ether
(5 mL ” 3). The combined organic layers were dried over MgSO4,
filtered, and concentrated. The residue was separated by flash column
chromatography (hexanes/EtOAc, 3:1) to afford macrolide 12
(20.0 mg, 68%).
Rf = 0.28 (hexanes-EtOAc, 1:1); 1H NMR (500 MHz, CDCl3): d =
5.17–5.13 (m, 1H), 3.83–3.76 (m, 1H), 3.76–3.71 (m, 1H), 3.60–3.56
(m, 1H), 3.31 (s, 3H), 3.20–3.15 (m, 1H), 2.62 and 2.43 (ABX, JAB
=
14.5 Hz, JAX = 4.0 Hz, JBX = 11.0 Hz, 2H), 1.99–1.95 (m, 1H), 1.88–
1.83 (m, 2H), 1.74–1.67 (m, 2H), 1.61–1.56 (m, 1H), 1.54–1.45 (m,
2H), 1.42–1.41 (m, 1H), 1.39–1.29 (m, 3H), 1.26–1.11 (m, 3H), 0.99
(d, J = 6.9 Hz, 3H), 0.94 ppm (t, J = 7.4 Hz, 3H); 13CNMR (125 MHz,
CDCl3): d = 171.1, 78.9, 75.8, 73.5, 72.5, 68.3, 56.5, 44.3, 42.5, 42.5,
42.2, 41.0, 40.2, 37.1, 31.5, 25.8, 19.2, 14.1 ppm; IR (neat): n˜max = 3420,
2953, 2871, 2351, 2318, 1730, 1647, 1383, 1156, 937, 798, 705 cmÀ1; MS
m/z (CI, relative intensity): 329 [M++1, 100], 311 (84), 297 (81), 279
(66), 267 (6), 241 (26), 209 (1), 199 (3), 181 (5), 155 (4), 141 (7), 113
(11), 85 (2); HRMS (CI) calcd. for C18H33O5 [M++1] 329.2328, found
329.2327; [a]D29 = + 22.2 degcm3 gÀ1 dmÀ1 (c = 0.01 gcmÀ3, CHCl3).
[8] a) B. Breit, Chem. Commun. 1997, 591 – 592; b) B. Breit, Eur. J.
Org. Chem. 1998, 1123 – 1134.
[9] P. K. Jadhav, K. S. Bhat, P. T. Perumal, H. C. Brown, J. Org.
Chem. 1986, 51, 432 – 439.
[10] Removal of the TBS group was accompanied by ethoxide
elimination, and we decide to investigate the reactivity of 11
directly. Similar reaction conditions were adopted for free and
silyl-protected homoallylic alcohols in the synthesis of blephar-
ocalyxin D; H. M. Ko, D. G. Lee, M. A. Kim, H. J. Kim, J. Park,
M. S. Lah, E. Lee, Tetrahedron 2007, 63, 5797 – 5805.
[11] The minor product is presumably epimeric at C3, C5, and C7.
For a thorough discussion of the racemization problem in the
Prins cyclization, see: R. Jasti, S. D. Rychnovsky, J. Am. Chem.
Soc. 2006, 128, 13640 – 13648.
Received: January 25, 2008
Published online: March 17, 2008
[12] D.-R. Li, D.-H. Zhang, C. Y. Sun, J.-W. Zhang, L. Yang, J. Chen,
B. Liu, C. Su, W.-S. Zhou, G.-Q. Lin, Chem. Eur. J. 2006, 12,
1185 – 1204.
[13] In the NMR analysis, the presence of the racemization product
was not detected.
Keywords: antitumor agents · cyclization · macrocycles ·
macrolides · oxonium ions
.
[1] A. E. Wright, J. C. Botelho, E. Guzmµn, D. Harmody, P. Linley,
P. J. McCarthy, T. P. Pitts, S. A. Pomponi, J. K. Reed, J. Nat. Prod.
2007, 70, 412 – 416.
[2] M. DꢀAmbrosio, A. Guerriero, C. Debitus, F. Pietra, Helv. Chim.
Acta 1996, 79, 51 – 60.
[3] W. Youngsaye, J. T. Lowe, F. Pohlki, P. Ralifo, J. S. Panek,
Angew. Chem. 2007, 119, 9371 – 9374; Angew. Chem. Int. Ed.
2007, 46, 9211 – 9214.
[14] Carboxylic acid 2 was prepared by using the known sequence
with minor modifications: L. A. Dakin, N. F. Langille, J. S.
Panek, J. Org. Chem. 2002, 67, 6812 – 6815.
[15] [a]2D7 = + 25.8 degcm3 gÀ1 dmÀ1 (c = 0.0065 gcmÀ3, MeOH). The
specific rotation of the natural sample is[1] [a]D24 = +
24.0 degcm3 gÀ1 dmÀ1 (c = 0.0024 gcmÀ3, MeOH).
3244
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