An enantioselective total synthesis of (+)-aigialospirol

Article abstract of DOI:10.1021/ol702195w

(Chemical Equation Presented) A concise and enantioselective total synthesis of (+)-aigialospirol is described here, featuring the first complex natural product synthesis that employs a cyclic ketal-tethered ring-closing metathesis strategy and an unexpected stereoselective epimerization of a benzylic hydroxyl group. The 15-step synthetic sequence illustrates the proof-of-concept that such an approach can be competitive with the classical spiroketal formation in the natural product synthesis.

Full text of DOI:10.1021/ol702195w

ORGANIC
LETTERS
2007
Vol. 9, No. 23
4857-4859
An Enantioselective Total Synthesis of
)-Aigialospirol
(+
Ruth Figueroa, Richard P. Hsung,* and Christle C. Guevarra
DiVision of Pharmaceutical Sciences and Department of Chemistry, Rennebohm Hall,
777 Highland AVenue, UniVersity of Wisconsin, Madison, Wisconsin 53705-2222
rhsung@wisc.edu
Received September 6, 2007
ABSTRACT
A concise and enantioselective total synthesis of (+)-aigialospirol is described here, featuring the first complex natural product synthesis that
employs a cyclic ketal-tethered ring-closing metathesis strategy and an unexpected stereoselective epimerization of a benzylic hydroxyl group.
The 15-step synthetic sequence illustrates the proof-of-concept that such an approach can be competitive with the classical spiroketal formation
in the natural product synthesis.
Recently, Isaka1 reported the isolation of (+)-aigialospirol
(1), which was obtained after an extended fermentation of
the marine fungus Aigialus parVus BCC 5311 that was found
in the mangrove Ascomycete. Although useful biological
activities of 1 remain unknown, natural products of marine
fungi origins in general represent medicinally significant
structural scaffolds.2 More significantly, 1 is thought to be
biosynthetically related to the known resorcylic macrolactone
hypothemycin (3),3-6 which was also found from the same
fungus, and 3 possesses potent antimalarial7 and anticancer8
properties. Specifically, (+)-aigialospirol 1 is postulated to
be from hypothemycin (3) through macrolactone 2 via (a)
translactonization and (b) spiroketal formation. The macro-
lactone 2 was derived from a hydrative opening of the
epoxide in 3 with inversion of stereochemistry at C1′
(Scheme 1). Transformations in a reverse direction from 1
to 3 are not known.
Scheme 1. Aigialospirol and Hypothemycin
(1) Vongvilai, P.; Isaka, M.; Kittakoop, P. Prasert Srikitikulchai, P.;
Kongsaeree, P.; Thebtaranonth, Y. J. Nat. Prod. 2004, 67, 457.
(2) Faulkner, D. J. Nat. Prod. Rep. 2001, 18, 1.
(3) (a) Nair, M. S. R.; Carey, S. T. Tetrahedron Lett. 1980, 21, 2011.
(b) Nair, M. S. R.; Carey, S. T.; James, J. C. Tetrahedron 1981, 37, 2445.
(4) Revised structure of hypothemycin: Agatsuma, T.; Takahashi, A.;
Kabuto, C.; Nozoe, S. Chem. Pharm. Bull. 1993, 41, 373.
(5) For a leading review on syntheses of hypothemycin and related
resorcylic macrolides, see: Winssinger, N.; Barluenga, S. Chem. Commun.
2007, 22.
Our recent interest9 in developing cyclic ketal-tethered
methods for constructing spiroketals10,11 led us to (+)-
aigialospirol (1). We recognized that 1 represents a unique
opportunity to demonstrate the expediency of a cyclic ketal-
tethered ring-closing metathesis (RCM)12 as a strategy in the
total synthesis of spiroketal-containing natural products and
10.1021/ol702195w CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/20/2007

that it can challenge the classical approach using keto diols
(see 4) in the spiroketal synthesis. We report here the first
total synthesis of (+)-aigialospirol featuring a cyclic ketal-
tethered RCM in constructing the spiroketal core and a facile
epimerization of the benzylic hydroxyl group.
Our synthesis commenced with (S)-glycidol as the chiron
source for the C2′ stereocenter and prepared the known
dihydro-R-pyrone 613,14 in 62% yield over four steps (Scheme
2). Dihydroxylation15 of 6 followed by acetonide formation
noteworthy that the overall sequence leading to the key RCM
precursor 11 is short.
With cyclic ketal 11 in hand, the ring-closing metathesis
proceeded smoothly to give spiroketal 12 in 86% yield
employing 12.5 mol % of Grubb’s first generation catalyst
(Scheme 3).12 However, at this stage, NOE experiments using
Scheme 3. Cyclic Ketal-Tethered RCM and C6′
Epimerization
Scheme 2. Synthesis of Key Cyclic Ketal
12 confirmed our earlier fear when examining NOEs of 11,13
which only hinted that the stereochemistry at the C6′
spiroketal center could be wrong. The assignment of 12
implies that the alcohol 10 had added to the oxocarbenium
ion A (see Scheme 2) in an equatorial manner anti to the
C5′ oxygen. Fortuitously, when we removed the acetonide
group under acidic conditions, we found that the spiroketal
center had completely epimerized to the desired C6′ stereo-
center as evident by both NOE and X-ray structure of diol
13.
gave δ-lactone 7, and addition of vinyl Grignard to 7 gave
an equilibrating mixture of lactol 8 and vinyl ketone 9 in
88% yield overall. After being exposed to 1.00 equiv of
Tf2NH at -78 °C for 1 h,16,17 the key formation of cyclic
ketal 11 was accomplished in 76% yield from the lactol-
ketone mixture and the chiral homoallylic alcohol 10.13 While
the C6′ stereochemistry was confirmed at a later stage, cyclic
ketal 11 was isolated as a single diastereomer. It is
B3LYP/6-31G* calculations revealed that the acetonide-
protected spiroketal 12 is actually 0.68 kcal mol-1 more
stable than its corresponding C6′ epimer, whereas ∆E is 2.13
kcal mol-1 in favor of 13 over its C6′ epimer. Such an
enhanced stability is likely a result of hydrogen bonding
between C4′-OH and spiroketal oxygen, which was seen in
the X-ray structure and the minimized molecular model of
13.
(6) For a total synthesis of hypothemycin, see: (a) Selle`s, P.; Lett, R.
Tetrahedron Lett. 2002, 43, 4621 and 4627. For syntheses of other related
resorcylic macrolides, see: (b) Yang, Z. Q.; Geng, X.; Solit, D.; Pratilas,
C. A.; Rosen, N.; Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 7881.
(c) Barluenga, S.; Dakas, P. Y.; Ferandin, Y.; Meijer, L.; Winssinger, N.
Angew. Chem., Int. Ed. 2006, 45, 3951. (d) Lu, J.; Ma, J.; Xie, X.; Chen,
B.; She, X.; Pan, X. Tetrahedron: Asymmetry 2006, 17, 1066. (e) Grosche,
P.; Akyel, K.; Marzinzik, A. Synthesis 2005, 2015. (f) Garbaccio, R. M.;
Stachel, S. J.; Baeschlin, D. K.; Danishefsky, S. J. J. Am. Chem. Soc. 2001,
123, 10903. (g) Lampilas, M.; Lett, R. Tetrahedron Lett. 1992, 33, 773
and 777.
(7) Isaka, M.; Suyarnsestakorn, C.; Tanticharoen, M.; Kongsaeree, P.;
Thebtaranonth, Y. J. Org. Chem. 2002, 67, 1561-1566.
(12) (a) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18. (b)
Hoveyda, A. H.; Schrock, R. R. Chem.sEur. J. 2001, 7, 945. (c) Schrock,
R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 4592. (d) Walters,
M. A. In Progress in Heterocyclic Chemistry; Gribble, G. W., Joule, J.,
Eds. Pergamon: New York, 2003; Vol. 15, p 1. (e) Nakamura, I.;
Yamamoto, Y. Chem. ReV. 2004, 104, 2127. (f) Deiters, A.; Martin, S. F.
Chem. ReV. 2004, 104, 2199. (g) McReynolds, M. D.; Dougherty, J. M.;
Hanson, P. R. Chem. ReV. 2004, 104, 2239. (h) Wallace, D. J. Angew.
Chem., Int. Ed. 2005, 44, 1912.
(8) (a) Tanaka, H.; Nishida, K.; Sugita, K.; Yoshioka, T. Jpn. J. Cancer
Res. 1999, 90, 1139. (b) Schirmer, A.; Kennedy, J.; Murli, S.; Reid, R.;
Santi, D. V. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 4234.
(9) (a) Ghosh, S. K.; Hsung, R. P.; Wang, J. Tetrahedron Lett. 2004,
45, 5505. (b) Liu, J.; Hsung, R. P. Org. Lett. 2005, 7, 2273.
(10) For reviews, see: (a) Aho, J. E.; Pihko, P. M.; Rissa, T. K. Chem.
ReV. 2005, 105, 4406. (b) Mead, K. T.; Brewer, B. N. Curr. Org. Chem.
2003, 7, 227. (c) Brimble, M. A.; Fares, F. A. Tetrahedron 1999, 55, 7661.
(d) Fletcher, M. T.; Kitching, W. Chem. ReV. 1995, 95, 789. (e) Perron, F.;
Albizati, K. F. Chem. ReV. 1989, 89, 1617.
(11) For related work, see: (a) Keller, V. A.; Martinellie, J. R.; Strieter,
E. R.; Burke, S. D. Org. Lett. 2002, 4, 467. (b) Kinderman, S. S.; Doodeman,
R.; van Beijma, J. W.; Russcher, J. C.; Tjen, K. C. M. F.; Kooistra, T. M.;
Mohaselzadeh, H.; van Maarseveen, J. H.; Hiemstra, H.; Schoemaker, H.
E.; Rutjes, F. P. J. T. AdV. Synth. Catal. 2002, 344, 736. (c) Leeuwenburgh,
M. A.; Appeldoorn, C. C. M.; van Hooft, P. A. V.; Overkleeft, H. A.; van
der Marel, G. A.; van Boom, J. H. Eur. J. Org. Chem. 2000, 837. (d) Scholl,
M.; Grubbs, R. H. Tetrahedron Lett. 1999, 40, 1425. (e) Bassindale, M. J.;
Hamley, P.; Leitner, A.; Harrity, J. P. A. Tetrahedron Lett. 1999, 40, 3247.
(13) See Supporting Information.
(14) Hansen, T. V. Tetrahedron: Asymmetry 2002, 13, 547.
(15) Khalaf, J. K.; Datta, A. J. Org. Chem. 2005, 70, 6937.
(16) For leading references on using HNTf2, see: (a) Sakakura, A.;
Suzuki, K.; Nakano, K.; Ishihara, K. Org. Lett. 2006, 8, 2229. (b) Sun, J.;
Kozmin, S. A. J. Am. Chem. Soc. 2005, 127, 13512. For the acidity of
HNTf2, see: (c) Thomazeau, C.; Olivier-Bourbigou, H.; Magna, L.; Luts,
S.; Gilbert, B. J. Am. Chem. Soc. 2003, 125, 5264 and references cited
therein.
(17) (a) Ko, C.; Hsung, R. P. Org. Biomol. Chem. 2007, 7, 431. (b)
Ghosh, S. K.; Ko, C.; Liu, J.; Wang, J.; Hsung, R. P. Tetrahedron 2006,
62, 10485.
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Org. Lett., Vol. 9, No. 23, 2007

To complete our total synthesis, we elected to utilize
spiroketal 12 instead of 13 and pursue the epimerization of
C6′ spiroketal center at the very end. As shown in Scheme
4, desilylation and oxidation of 12 gave aldehyde 14.
to 16 in C6D6 at rt when being frozen in C6D6 at -10 °C or
under a prolonged exposure to silica gel. Given that there is
no apparent energetic difference between 16 and 17 from
our preliminary calculations, one possible pathway is shown
in Scheme 5.
Scheme 4. Total Synthesis of (+)-Aigialospirol (1)
Scheme 5. A Possible Mode for the C1′ Epimerization
This pathway features a C1′ scrambling that is intra-
molecular in nature and involves the hemi-orthoaminal
intermediate 19 that would allow for “swapping (or a
turnstile-like mechanism)” of the original C7 amido carbonyl
oxygen atom with the C1′ hydroxy oxygen atom (red). It is
likely that the formation of 19 is more readily from 17 with
a â-C1′-OH. This model is consistent with the observation
that C1′ epimerization occurs under basic, acidic, or neutral
conditions. It is noteworthy that this epimerization involves
the same C1′ stereocenter that is critical in the biosynthetic
relation between hypothemycin and aigialospirol. We are
currently probing the origin of this intriguing epimerization.
We have described here an enantioselective total synthesis
of (+)-aigialospirol featuring a cyclic ketal-tethered ring-
closing metathesis strategy and an unexpected stereoselective
epimerization of a benzylic hydroxy group. This 15-step
synthetic sequence from (S)-glycidol firmly demonstrates that
cyclic ketal-tethered RCM can be competitive with the
classical spiroketal synthesis.
Subsequent addition of the aryl lithium intermediate, gener-
ated via a Snieckus’ directed ortho-metalation18 of amide
15,6a afforded a readily separable mixture of alcohols 16 and
17 with an isomeric ratio 1:1.4. Given that we were uncertain
which was the desired C1′ epimer, we pursued the lactone
formation employing both alcohols 16 and 17. Intriguingly,
we found that both 16 and 17 led to the same lactone 18
(with loss of the TBS group). Lactone 18 was taken to (+)-
aigialospirol after removal of the acetonide group con-
comitant with C6′ epimerization. Our synthetic sample
completely matches the reported spectroscopic data for (+)-
aigialospirol.1
While this concludes the total synthesis effort, we were
intrigued by the lactonization/epimerization. A careful
examination revealed that alcohol 16 gave lactone 18, while
alcohol 17 readily epimerized to 16 under the same lacton-
ization conditions, which is basic. In fact, pure 17 epimerizes
Acknowledgment. Authors thank PRF-AC (42106) for
support, and Dr. Victor Young and Ben Kucera (University
of Minnesota) for X-ray analysis. C.C.G. thanks UW for an
NIH-CBI Training Grant. We thank Professor Dr. Masahiko
Isaka (National Center for Genetic Engineering and Bio-
technology (BIOTEC), Pathumthani, Thailand) for kindly
providing the original spectra data of (+)-aigialospirol.
Supporting Information Available: Experimental de-
tails, characterization data, X-ray structural analysis, and
NMR spectral for all new compounds are available. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(18) (a) Snieckus, V. Heterocycles 1980, 14, 1649. (b) Beak, P.; Snieckus,
V. Acc. Chem. Res. 1982, 15, 306. (c) Snieckus, V. Chem. ReV. 1990, 90,
879. (d) Anctil, E. J.-G.; Snieckus, V. J. Organomet. Chem. 2002, 653,
150.
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