Formal total synthesis of (+)-zaragozic acid C through an Ireland-Claisen rearrangement

Article abstract of DOI:10.1002/anie.200602507

(Chemical Equation Presented) A simple rearrangement: A formal total synthesis of zaragozic acid C (1) was achieved by the synthesis of intermediate 2. The key step involves an Ireland-Claisen rearrangement of an allylic ester to generate a carbon-carbon bond and two asymmetric centers simultaneously.

Full text of DOI:10.1002/anie.200602507

Communications
Natural Product Synthesis
DOI: 10.1002/anie.200602507
Formal Total Synthesis of (+)-Zaragozic Acid C
through an Ireland–Claisen Rearrangement**
Jens O. Bunte, Anthony N. Cuzzupe, Alica M. Daly, and
Mark A. Rizzacasa*
The zaragozic acids[1] and squalestatins[2] are structurally
related fungal metabolites isolated independently by several
industrial research groups in the early 1990s.[3] These com-
pounds were identified as potent inhibitors[4] of squalene
synthase and showed promise as cholesterol-lowering com-
pounds.[5] In addition, some zaragozic acids inhibit farnesyl
protein transferase and thus show potential as antitumor
agents.[6] The engrossing, highly oxygenated 2,8-dioxabicyclo-
[3.2.1]octane core present in these compounds coupled with
their biological activity sparked great interest within the
synthetic community which, to date, has culminated in five
total syntheses[7] of zaragozic acid C (1),[8] three syntheses of
its congener zaragozic acid A,[9] and one synthesis of the
related 6,7-dideoxysqualestatin H5.[10] Herein, we report a
synthesis of an advanced intermediate which has been
converted into 1.
Our retrosynthetic analysis of 1 is shown in Scheme 1. The
primary target was known intermediate 2, which was con-
verted into zaragozic acid C (1) in four steps.[8a] It was
envisaged that triacetate 2 could be formed by methanoly-
sis[10] of the spirolactone acetal 3 and subsequent acid-
mediated cyclization to secure the 2,8-dioxabicyclo-
[3.2.1]octane core. Functional-group manipulations would
[*] Dr. J. O. Bunte, Dr. A. N. Cuzzupe, A. M. Daly,
Prof. Dr. M. A. Rizzacasa
Schoolof Chemistry
The University of Melbourne
Bio21 Institute, 30 Flemmington Road
Melbourne, Victoria 3010 (Australia)
Fax: (+61)3-9347-8396
E-mail: masr@unimelb.edu.au
Homepage: http://www.chemistry.unimelb.edu.au/staff/masr/
research/MARHomepage.html
[**] Financialsupport for this study was provided by the Austrailan
Research Council: Discovery-Grants Program and the Deutsche
Forschungsgemeinschaft (DFG postdoctoral fellowship to J.O.B.).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
6376
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 6376 –6380

Angewandte
Chemie
Scheme 1. Retrosynthetic analysis of zaragozic acid C (1). Bn=benzyl,
TBS=tert-butyldimethylsilyl, TMS=trimethylsilyl.
then give the triacetate 2. The acetal 3 could be formed by
regioselective addition[11] of the lithium anion derived from
the side-chain iodide 5 to the less-hindered C1 carbonyl
group[12] of the spirobislactone 4. Compound 4 could be
obtained from tertiary alcohol 6, which in turn would be
formed by an Ireland–Claisen rearrangement in the presence
of a b leaving group[13] of the sensitive allylic ester 7 derived
from l-arabinose. This key transformation would form the
Scheme 2. Synthesis of ester 6. DCC=dicyclohexylcarbodiimide,
DiBAL-H=diisobutylaluminum hydride, DMAP=4-dimethylaminopyri-
dine, LDA=lithium diisopropylamide.
raphy. One minor isomer (stereochemistry undetermined)
was obtained pure, whereas the other two were isolated as a
63:37 mixture. The stereochemistry of 6 was determined by its
conversion into the crystalline spirolactone 12 (Scheme 2). A
single-crystal X-ray structure[22] was obtained for 12, which
confirmed the stereochemistry of the major product 6 of the
Ireland–Claisen rearrangement. Interestingly, attempted
rearrangement of the ester synthesized from the para-
methoxybenzyl (PMB)-protected analogue of allyl alcohol
10 and acid 11 failed completely.
The outcome of the [3,3] rearrangement can be explained
by considering the chairlike transition state 13 in which it is
assumed that the geometry of the major ketene acetal formed
is Z[23] (Scheme 2). The C5 stereochemistry results from
rearrangement from the face opposite the b-benzyloxy group,
whereas the C4 stereochemistry arises from the chairlike
transition state as shown.
The conversion of the Claisen product 6 into the
spirobislactone core precursor 4 is outlined in Scheme 3. We
initially investigated the dihydroxylation of the alkene
functionality in 6 as a means of introducing the C3 stereo-
chemistry. Unfortunately, both simple catalytic[24] or asym-
metric[25] dihydroxylation of 6 resulted in preferential for-
mation of the isomer with undesired stereochemistry at C3.
This result led to an alternative method for the introduction of
the C3 stereochemistry. Ozonolysis of the alkene 6 provided
an aldehyde and chelation-controlled addition[9e] of vinyl-
magnesium bromide and gave the desired lactone 14 in a
stereoselective manner (90% d.r.) after acid treatment to
complete lactonization. The stereochemistry for spirolactone
À
C4 C5 bond and the two quaternary asymmetric centers
simultaneously.[14] Furthermore, intermediate 6 contains all
the asymmetric centers required for the core system apart
from that at C3. We have previously utilized the Ireland–
Claisen rearrangement of allyl furanosiduronates in the
presence of a b leaving group for the synthesis of related 2-
alkylcitrate natural products, such as cinatrins B,[15] C1, and
C3,[16] as well as trachyspic acid[17] and a model zaragozic
acid A system devoid of substituents at C4.[18]
The synthesis of the key intermediate 6 is outlined in
Scheme 2. Treatment of ethyl 4-chloroacetoacetate (8) with
the anion derived from benzyl alcohol afforded ether 9.[19]
Exposure of 9 to TBSCl and NEt3[20] in THF at 508C followed
by reduction with DiBAl-H gave the alcohol 10 as a 6:1
mixture of geometric isomers. DCC-mediated coupling of this
alcohol with the l-arabinose derived acid 11[21] afforded the
Ireland–Claisen precursor 7, which could be purified by rapid
chromatography on silica gel. Treatment of a solution of the
ester 7 in THF/hexamethylphosphoramide (HMPA) and the
centrifugate from a 1:1 (v/v) mixture of TMSCl and NEt3 with
LDA at À1008C[13b,c] gave the silyl ketene acetal, which
underwent stereoselective [3,3] rearrangement upon warming
to room temperature. Hydrolysis of the crude TMS ester
followed by methylation and removal of the TBS group
provided ester 6 as the major product along with three other
minor diastereoisomers in 60% yield for the three steps and a
ratio of 3.6:1, respectively. The desired ester 6 was readily
separated from the other minor isomers by flash chromatog-
Angew. Chem. Int. Ed. 2006, 45, 6376 –6380
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
6377

Communications
removal of the chiral auxiliary provided diol 21, which was
converted into the primary monotosylate and treatment of
this with nBuLi resulted in oxetane formation.[8a] Ring
opening of the oxetane with PhLi in the presence of a Lewis
acid gave alcohol 22 in good overall yield. We found that the
synthesis and isolation of the oxetane gave better yields than
the one-pot process reported by Carreira and Du Bois.[8a]
Benzyl group protection proceeded best with NaHMDS as
the base to afford ether 23, and fluoride-induced desilylation
followed by conversion of the primary alcohol into the
iodide[29] gave the side-chain fragment 5 in excellent yield.
The final steps to the zaragozic acid C intermediate 2 are
outlined in Schemes 5 and 6. Treatment of 5 with tBuLi[30] in a
Et2O/hexane solvent mixture at À788C generated the lithium
Scheme 3. Synthesis of spirobislactone 4. imid.=imidazole, MS=molecu-
lar sieves, PCC=pyridinium chlorochromate, PPTS=pyridinium p-toluene-
sulfonate, TFA=trifluoroacetic acid.
14 was assigned based on NOE interactions observed between
H3 and the C4 methylene group in the derived C3 methyl
ester 15.
The hydrolysis of the methyl ketal in 14 proved trouble-
some as most acidic methods caused extensive decomposition
of the substrate. Eventually, we found that acetolysis (Ac2O,
TFA, 08C)[26] cleanly gave the diacetate 16 as a 2:1 mixture of
anomers. Higher temperatures also resulted in acetolysis of
the benzyl groups. The anomeric acetate could now be readily
cleaved with dilute acid and oxidation gave the lactone 17.
Selective acetate methanolysis followed by TMS protection
provided the spirobislactone core precursor 4 in good yield.
With the required spirobislactone 4 in hand, we then
synthesized the iodide 5 required for the C1 side chain as
outlined in Scheme 4. Thus, an Evans aldol reaction[27]
between the boron enolate derived from oxazolidinone 18
and aldehyde 19[28] proceeded in excellent yield and stereo-
selectivity (> 95% de) to afford adduct 20. Reductive
Scheme 5. Synthesis of the 2,8-dioxabicyclo[3.2.1]octane 27. SM=start-
ing material, Bz=benzoyl.
anion, which selectively added to spirolactone 4 at the C1
carbonyl group (2.2:1 ratio of addition products; 72% yield).
Treatment of the C1 addition product with acidic methanol,
however, gave the methyl ketals 3 as a separable mixture and
only
a trace (2% yield) of the desired 2,8-dioxa-
[3.2.1]bicyclooctane. We surmised that the slow step in the
acid-catalyzed process may be opening of the lactone ring and
therefore decided that a decrease in electron density would
assist the methanolysis. Therefore, alkene 3 was oxidatively
cleaved and oxidation[31] followed by methylation afforded
methyl ester 24 along with a by-product 25, as a result of
oxidation of the side-chain O4’ benzyl protecting group.[32] To
our delight, treatment of a mixture of ketals 24 with 0.1m
sulfuric acid in boiling methanol resulted in the formation of
the desired zaragozic acid core system 26 in 44% yield along
with recovered methyl ketals 24 (85% based on recovered
Scheme 4. Synthesis of the side-chain iodide 5. OTf=triflate, pyr. =
pyridine, NaHMDS=sodium hexamethyldisilazane, TBAI=tetrabuty-
lammonium iodide, TBAF=tetrabutylammonium fluoride, TIPS=tri-
isopropylsilyl, p-TsCl=p-toluenesulfonyl chloride.
6378
www.angewandte.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 6376 –6380

Angewandte
Chemie
protection of pentol 28. Studies towards the synthesis of
other members of the zarazozic acid/squalestatin family are
underway.
Received: June 22, 2006
Published online: August 30, 2006
Keywords: Ireland–Claisen rearrangement · lactones ·
.
naturalproducts · totalsynthesis · zaragozic acid
[1] a) K. E. Wilson, R. M. Burk, T. Biftu, R. G. Ball, K. Hoogsteen,
J. Org. Chem. 1992, 57, 7151 – 7158; b) J. D. Bergstrom, M. M.
Kurtz, D. J. Rew, A. M. Amend, J. D. Karkas, R. G. Bosterdor,
V. S. Dansal, C. Dufresne, F. L. V. Middlesworth, O. D. Hensens,
J. M. Liesch, D. L. Zink, K. E. Wilson, J. Onishi, J. A. Millifan, G.
Bills, L. Kaplan, M. Nallin-Omstead, R. G. Jenkins, L. Huang,
M. S. Meinz, L. Quinn, R. W. Burg, Y. L. Kong, S. Mochales, M.
Mojena, I. Martin, F. Pelaez, M. T. Diez, A. W. Alberts, Proc.
Natl. Acad. Sci. USA 1993, 90, 80 – 84.
[2] M. J. Dawson, J. E. Farthing, P. S. Marshall, R. F. Middleton,
M. J. OꢀNeill, A. Shuttleworth, C. Stylli, R. M. Tait, P. M. Taylor,
H. G. Wildman, A. D. Buss, D. Langley, M. V. Hayes, J. Antibiot.
1992, 45, 639 – 647.
Scheme 6. Completion of the formal total synthesis of zaragozic
acid C (1). CSA=10-camphorsulfonic acid, DMP=Dess–Martin peri-
odinane, DMF=N,N-dimethylformamide, MIP=methoxyisopropyl.
[3] Reviews: U. Koert, Angew. Chem. 1995, 107, 849 – 855; Angew.
Chem. Int. Ed. Engl. 1995, 34, 773 – 778; A. Nadin, K. C.
Nicolaou, Angew. Chem. 1996, 108, 1372 – 1766; Angew. Chem.
Int. Ed. Engl. 1996, 35, 1622 – 1656; N. Jotterand, P. Vogel, Curr.
Org. Chem. 2001, 5, 637 – 661; A. Armstrong, T. J. Blench,
Tetrahedron 2002, 58, 9321 – 9349.
[4] A. Baxter, B. J. Fitzgerald, J. L. Hutson, A. D. McCarthy, J. M.
Motteram, B. C. Ross, M. Sapra, M. A. Snowden, N. S. Watson,
R. J. Williams, C. Wright, J. Biol. Chem. 1992, 267, 11705 –
11708.
[5] Review: N. S. Watson, P. A. Procopiou, Prog. Med. Chem. 1996,
33, 331 – 378.
[6] J. B. Gibbs, D. L. Pompliano, S. D. Mosser, E. Rands, R. B.
Lingham, S. B. Singh, E. M. Scolnick, N. E. Kohl, A. Oliff, J.
Biol. Chem. 1993, 268, 7617 – 7620.
[7] Review: S. Nakamura, Chem. Pharm. Bull. 2005, 53, 1 – 10.
[8] a) E. M. Carreira, J. Du Bois, J. Am. Chem. Soc. 1994, 116,
10825 – 10826; E. M. Carreira, J. Du Bois, J. Am. Chem. Soc.
1995, 117, 8106 – 8125; b) D. A. Evans, J. C. Barrow, J. L.
Leighton, A. J. Robichaud, M. Sefkow, J. Am. Chem. Soc.
1994, 116, 12111 – 12112; c) H. Sato, S. Nakamura, N. Watanabe,
S. Hashimoto, Synlett 1997, 451 – 454; S. Nakamura, H. Sato, Y.
Hirata, N. Watanabe, S. Hashimoto, Tetrahedron 2005, 61,
11078 – 11106; d) A. Armstrong, L. H. Jones, P. A. Barsanti,
Tetrahedron Lett. 1998, 39, 3337 – 3340; A. Armstrong, P. A.
Barsanti, L. H. Jones, G. Ahmed, J. Org. Chem. 2000, 65, 7020 –
7032; e) S. Nakamura, Y. Hirata, T. Kurosaki, M. Anada, O.
Kataoka, S. Kitagaki, S. Hashimoto, Angew. Chem. 2003, 115,
5509 – 5513; Angew. Chem. Int. Ed. 2003, 42, 5351 – 5355.
[9] a) K. C. Nicolaou, A. Nadin, J. E. Leresche, E. W. Yue, S.
La Greca, Angew. Chem. 1994, 106, 2312 – 2313; Angew. Chem.
Int. Ed. Engl. 1994, 33, 2190 – 2191; K. C. Nicolaou, E. W. Yue, S.
La Greca, A. Nadin, Z. Yang, J. E. Lereshe, T. Tsuri, Y. Naniwa,
F. De Riccardis, Chem. Eur. J. 1995, 1, 467 – 494; b) D. Stoermer,
S. Caron, C. H. Heathcock, J. Org. Chem. 1996, 61, 9115 – 9125;
S. Caron, D. Stoermer, A. K. Mapp, C. H. Heathcock, J. Org.
Chem. 1996, 61, 9126 – 9134; c) K. Tomooka, M. Kikuchi, K.
Igawa, M. Suzuki, P.-H. Keong, T. Nakai, Angew. Chem. 2000,
112, 4676 – 4679; Angew. Chem. Int. Ed. 2000, 39, 4502 – 4505.
[10] S. F. Martin, S. Naito, J. Org. Chem. 1998, 63, 7592 – 7593; S.
Naito, M. Escobar, P. R. Kym, S. Liras, S. F. Martin, J. Org.
Chem. 2002, 67, 4200 – 4208.
24). Hydrolysis of the methyl esters and formation[33] of the di-
tert-butyl ester gave bicycle 27.
The final major synthetic challenge was the selective
functionalization of the C4 primary alcohol. This quest began
with global debenzylation through hydrogenolysis to give
pentol 28 in high yield.[34] Numerous experiments to selec-
tively protect the C4 primary alcohol failed. In one case, to
form the dimethylacetonide of the 1,2-diol at C4, pentol 28
was exposed to 2,2-dimethoxypropane in DMF in the
presence of catalytic CSA, which resulted in the formation
of an undesired acetonide between the primary alcohol and
the C7 hydroxy group. However, during the course of
monitoring this reaction by TLC, we initially noticed the
selective formation of a spot at a higher Rf value which slowly
disappeared and a spot at a lower Rf value, which corresponds
to the undesired acetonide, was formed. Treatment of 28 with
the same reagents as above, but at 08C for a shorter time,
selectively afforded the compound with a higher Rf value,
which was identified as methoxyisopropyl (MIP) ether 29,
along with recovered starting material 28, which could readily
be recycled. This serendipitous discovery led to the mono-
protection of pentol 28 with a highly acid-labile protecting
group. Acetylation of 29 and treatment with mild acid[35] gave
alcohol 30, which upon two-stage oxidation and ester
formation yielded the target compound 2, the physical data
for which were identical to those reported.[8a,c]
In conclusion, we have completed a synthesis the pre-
cursor of zaragozic acid C (1), in which the C4–C5 bond was
formed in a stereoselective manner with concomitant for-
mation of the quaternary asymmetric centers by an Ireland–
Claisen rearrangement of the sensitive allylic ester 7. Other
highlights of this route include a novel acetolysis of the methyl
ketal 15, selective carbanion addition to the spirobislactone 4,
methanolysis of lactone 24, subsequent formation of the
zaragozic acid bicycle 26, and a selective MIP group
Angew. Chem. Int. Ed. 2006, 45, 6376 –6380
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 6379

Communications
[11] For the selective addition of sulfone carbanions to a spirobislac-
[23] R. E. Ireland, P. Wipf, J. D. Armstrong III, J. Org. Chem. 1991,
56, 650 – 657.
[24] V. VanRheenen, R. C. Kelly, D. Y. Cha, Tetrahedron Lett. 1976,
17, 1973 – 1976.
[25] K. B. Sharpless, W. Amber, Y. L. Bennani, G. A. Crispino, J.
Hartung, K. Jeong, H. Kwong, K. Morikawa, Z. Wang, D. Xu, X.
Zhang, J. Org. Chem. 1992, 57, 2768 – 2771.
[26] F. Nicotra, L. Panza, G. Russo, L. Zucchelli, J. Org. Chem. 1992,
57, 2154 – 2158.
[27] D. A. Evans, J. Bartroli, T. L. Shih, J. Am. Chem. Soc. 1981, 103,
2127 – 2129.
[28] S. Venel, P. Knochel, Tetrahedron Lett. 1994, 35, 5849 – 5892; M.
Delgado, J. D. Martin, J. Org. Chem. 1999, 64, 4798 – 4816.
[29] P. J. Garegg, B. Samuelsson, J. Chem. Soc. Perkin Trans. 1 1980,
2866 – 2869.
tone, see Ref. [10]; for the addition of carbanions to a lactone in
the presence of tert-butyl esters, see Refs. [8b] and [9c].
[12] Numbering based on zaragozic acid C is used throughout.
[13] a) R. E. Ireland, D. W. Norbeck, J. Am. Chem. Soc. 1985, 107,
3279 – 3285; b) L. M. McVinish, M. A. Rizzacasa, Tetrahedron
Lett. 1994, 35, 923 – 926; R. W. Gable, L. M. McVinish, M. A.
Rizzacasa, Aust. J. Chem. 1994, 47, 1537 – 1544; c) R. Di Florio,
M. A. Rizzacasa, J. Org. Chem. 1998, 63, 8595 – 8598; d) B.
Werschkun, J. Thiem, Synthesis 1999, 121 – 137.
[14] Other approaches that formed the C4–C5 bond and two
quaternary asymmetric centers simultaneously: a) aldol reac-
tion: Ref. [8c]; b) acetal [1,2] Wittig rearrangement: Ref. [9c].
[15] A. N. Cuzzupe, R. Di Florio, M. A. Rizzacasa, J. Org. Chem.
2002, 67, 4392 – 4398.
[16] A. N. Cuzzupe, R. Di Florio, J. M. White, M. A. Rizzacasa, Org.
Biomol. Chem. 2003, 1, 3572 – 3577.
[17] S. C. Zammit, M. A. Rizzacasa, J. M. White, Org. Biomol. Chem.
2005, 3, 2073 – 2074.
[18] R. K. Mann, J. G. Parsons, M. A. Rizzacasa, J. Chem. Soc. Perkin
Trans. 1 1998, 1283 – 1293.
[30] W. F. Bailey, E. R. Punzalan, J. Org. Chem. 1990, 55, 5404 – 5406.
[31] B. O. Lindgren, T. Nilsson, Acta Chem. Scand. 1973, 27, 888 –
890.
[32] This selective benzylic oxidation appears to occur during
ozonolysis; we could neither suppress this reaction or increase
the conversion.
[19] T. Meul, R. Miller, L. Tenud, Chimia 1987, 41, 73 – 76.
[20] J.-M. Poirier, L. Hennequin, Tetrahedron 1989, 45, 4191 – 4202.
[21] Synthesized in six steps from l-arabinose in an identical manner
to that reported for the enantiomer: see Ref. [15].
[33] L. J. Mathias, Synthesis 1979, 561 – 576.
[34] The use of acidic methanol was essential for effective global
debenzylation; in the absence of acid, only the O4’ benzyl group
was removed at an acceptable rate.
[22] CCDC-234390 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
[35] CDCl3 untreated with base was used for this transformation; for
an example see Ref. [1a].
6380 www.angewandte.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 6376 –6380