Total synthesis of zaragozic acid A (squalestatin S1). Degradation to a relay compound and reassembly of the natural product

Article abstract of DOI:10.1021/jo961533m

Zaragozic acid A (squalestatin S1) (1) was converted into the simpler derivative 2, which was reconverted into the natural product, thus establishing 2 as a viable relay compound for total synthesis of 1. The degradation consisted of formation of the tri-tert-butyl ester (3), from which the two side chains were sequentially removed to obtain 8. Aldehyde 8 was converted into dimethyl acetal 2 in standard fashion. The C6 acyl side chain 14 was prepared from (S)-2-methylbutanol ('active amyl alcohol'), and the desired 4S configuration was obtained by use of Evans asymmetric enolate methylation. The C1 alkyl side chain was prepared as stannane 23a from (R)-2-methyl-3-phenylpropanol (21). For conversion of 2 back into zaragozic acid A, the dimethyl acetal was first converted into the cyclic acetal 17, thus protecting the C7 hydroxyl group. The remaining hydroxyl group was then acylated with acid 14 to obtain 18, which was transformed into aldehyde 20. The C1 alkyl chain was elaborated by the addition of a chiral α-alkoxyorganocerium reagent, obtained from 23a, to aldehyde 20. The resulting mixture of diastereomeric secondary alcohols was converted into zaragozic acid A (1) in six steps.

Full text of DOI:10.1021/jo961533m

J . Org. Chem. 1996, 61, 9115-9125
9115
Tota l Syn th esis of Za r a gozic Acid A (Squ a lesta tin S1).
Degr a d a tion to a Rela y Com p ou n d a n d Rea ssem bly of th e Na tu r a l
P r od u ct
Doris Stoermer, Ste´phane Caron, and Clayton H. Heathcock*
Department of Chemistry, University of California, Berkeley, California 94720
Received August 7, 1996X
Zaragozic acid A (squalestatin S1) (1) was converted into the simpler derivative 2, which was
reconverted into the natural product, thus establishing 2 as a viable relay compound for total
synthesis of 1. The degradation (Scheme 1) consisted of formation of the tri-tert-butyl ester (3),
from which the two side chains were sequentially removed to obtain 8. Aldehyde 8 was converted
into dimethyl acetal 2 in standard fashion. The C6 acyl side chain 14 was prepared from (S)-2-
methylbutanol (“active amyl alcohol”), and the desired 4S configuration was obtained by use of
Evans asymmetric enolate methylation (Scheme 2). The C1 alkyl side chain was prepared as
stannane 23a from (R)-2-methyl-3-phenylpropanol (21) as shown in Scheme 5. For conversion of
2 back into zaragozic acid A, the dimethyl acetal was first converted into the cyclic acetal 17, thus
protecting the C7 hydroxyl group. The remaining hydroxyl group was then acylated with acid 14
to obtain 18, which was transformed into aldehyde 20 (Scheme 4). The C1 alkyl chain was
elaborated by the addition of a chiral R-alkoxyorganocerium reagent, obtained from 23a , to aldehyde
20. The resulting mixture of diastereomeric secondary alcohols was converted into zaragozic acid
A (1) in six steps (Scheme 6).
In 1992 the isolation of several potent (picomolar)
inhibitors of squalene synthase was reported indepen-
dently by chemists at Glaxo1 and Merck.2 These com-
pounds were named “squalestatins” by the Glaxo group
and “zaragozic acids” by the Merck group. Additional
squalestatins3 and zaragozic acids4 were subsequently
reported.5 The archetypal representative of this group
of natural products is zaragozic acid A (squalestatin S1),
1. As inhibitors of squalene synthase, the zaragozic acids
interfere with cholesterol biosynthesis downstream from
the step inhibited by mevinolin and its analogs. They
are of potential significance because inhibition of HMG
CoA reductase early in the biosynthetic pathway inter-
feres with the production of important biomolecules
X Abstract published in Advance ACS Abstracts, December 1, 1996.
(1) (a) Dawson, M. J .; Farthing, J . E.; Marshall, P. S.; Middleton,
R. F.; O’Neill, M. J .; Shuttleworth, A.; Stylli, C.; Tait, R. M.; Taylor,
P. M.; Wildman, H. G.; Buss, A. D.; Langley, D.; Hayes, M. V. J .
Antibiot. 1992, 45, 639. (b) Sidebottom, P. J .; Highcock, R. M.; Lane,
S. J .; Procopiou, P. A.; Watson, N. S. J . Antibiot. 1992, 45, 648. (c)
Baxter, A.; Fitzgerald, B. J .; Hutson, J . L.; McCarthy, A. D.; Motteram,
J . M.; Ross, B. C.; Sapra, M.; Snowden, M. A.; Watson, N. S.; Williams,
R. J .; Wright, C. J . Biol. Chem. 1992, 267, 11705.
(2) (a) Bergstrom, J . D.; Kurtz, M. M.; Rew, D. J .; Amend, A. M.;
Karkas, J . D.; Bostedor, R. G.; Bansal, V. S.; Dufresne, C.; Van-
Middlesworth, F. L.; Hensens, O. D.; Liesch, J . M.; Zink, D. L.; Wilson,
K. E.; Onishi, J .; Milligan, J . A.; Bills, G.; Kaplan, L.; Nallin Omstead,
M.; J enkins, R. G.; Huang, L.; Meinz, M. S.; Quinn, L.; Burg, R. W.;
Kong, Y. L.; Mochales, S.; Mojena, M.; Martin, I.; Pelaez, F.; Diez, M.
T.; Alberts, A. W. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 80. (b)
Hensens, O. D.; Dufresne, C.; Liesch, J . M.; Zink, D. L.; Reamer, R.
A.; VanMiddlesworth, F. Tetrahedron Lett. 1993, 34, 399. (c) Dufresne,
C.; Wilson, K. E.; Zink, D.; Smith, J .; Bergstrom, J . D.; Kurtz, M.; Rew,
D.; Nallin, M.; J enkins, R.; Bartizal, K.; Trainor, C.; Bills, G.; Meinz,
M.; Huang, L.; Onishi, J .; Milligan, J .; Mojena, M.; Pelaez, F.
Tetrahedron 1992, 48, 10221. (d) Wilson, K. E.; Burk, R. M.; Biftu, T.;
Ball, R. G.; Hoogsteen, K. J . Org. Chem. 1992, 57, 7151.
(ubiquinones, dolichols, isopentenylnucleosides) in addi-
tion to cholesterol. Through intervention at the step in
which the triterpene skeleton is created, possible side
effects that accompany hypercholesterolemic therapy
might be avoided. In this article, we report the inter-
conversion of zaragozic acid A (squalestatin S1, 1)6 with
2. In the accompanying article, we report the de novo
synthesis of 2, thus completing a total synthesis of 1.7
(6) For other zaragozic acid total syntheses, see: (a) Carreria, E.
M.; Du Bois, J . J . Am. Chem. Soc. 1994, 116, 10825. (b) Carreira, E.
M.; Du Bois, J . J . Am. Chem. Soc. 1995, 117, 8106. (c) Nicolaou, K. C.;
Yue, E. W.; Yoshimitsu, N.; De Riccardis, F.; Nadin, A.; Leresche, J .
E.; La Greca, S.; Yang, Z. Angew. Chem., Int. Ed. Engl. 1994, 33, 2184.
(d) Nicolaou, K. C.; Nadin, A.; Leresche, J . E.; La Greca, S.; Tsuri, T.;
Yue, E. W.; Yang, Z. Angew. Chem., Int. Ed. Engl. 1994, 33, 2187. (e)
Nicolaou, K. C.; Nadin, A.; Leresche, J . E.; Yue, E. W.; La Greca, S.
Angew. Chem., Int. Ed. Engl. 1994, 33, 2190. (f) Nicolaou, K. C.; Yue,
E. W.; La Greca, S.; Nadin, A.; Yang, Z.; Leresche, J . E.; Tsuri, T.;
Naniwa, Y.; De Riccardis, F. Chem. Eur. J . 1995, 1, 467. (g) Evans, D.
A.; Barrow, J . C.; Leighton, J . L.; Robichaud, A. J .; Sefkow, M. J . Am.
Chem. Soc. 1994, 116, 12111. For reviews of the syntheses of the
zaragozic acids, see: (h) Koert, V. Angew. Chem., Int. Ed. Engl. 1995,
34, 773. (i) Nadin, A.; Nicolaou, K. C. Angew. Chem., Int. Ed. Engl.
1996, 35, 1623.
(3) Blows, W. M.; Foster, G.; Lane, S. J .; Noble, D.; Piercey, J . E.;
Sidebottom, P. J .; Webb, G. J . Antibiot. 1994, 47, 740.
(4) (a) Dufresne, C.; Turner J ones, E. T.; Nallin Omstead, M.;
Bergstrom, J . D.; Wilson, K. E. J . Nat. Prod. 1996, 59, 52. (b) Dufresne,
C.; Wilson, K. E.; Singh, S. B.; Zink, D. L.; Bergstrom, J . B.; Rew, D.;
Polishook, J . D.; Meinz, M.; Huang, L.; Silverman, K. C.; Lingham, R.
B.; Mojena, M.; Cascales, C.; Pelae´z, F.; Gibbs, J . B. J . Nat. Prod. 1993,
56, 1923.
(5) For a review of the zaragozic acids, see: Bergstrom, J . D.;
Dufresne, C.; Bills, G. F.; Nallin Omstead, M.; Byrne, K. Annu. Rev.
Microbiol. 1995, 49, 607.
(7) Caron, S.; Stoermer, D.; Mapp, A. K.; Heathcock, C. H. J . Org.
Chem. 1996, 61, 9126.
S0022-3263(96)01533-2 CCC: $12.00 © 1996 American Chemical Society

9116 J . Org. Chem., Vol. 61, No. 26, 1996
Stoermer et al.
Sch em e 1a
a
Reagents and conditions: (a) i-PrNdC(O-t-Bu)NH-i-Pr, CH2Cl2, reflux; (b) HONH2‚HCl, NaOAc, MeOH; (c) EtMgBr, CeCl3, -78 °C;
(d) (i) O3, CH2Cl2, -78 °C; (ii) Me2S; (e) NaBH4, MeOH, 0 °C; (f) Pb(OAc)4, benzene, 10 °C; (g) MeOH, (MeO)3CH, PPTS rt, 3 h.
Sch em e 2a
a
Reagents and conditions: (a) (i) LDA, THF -78 °C; (ii) (S)-1-iodo-2-methylbutane, DMPU, -78 °C to -45 °C to rt; (b) CF3CO2H; (c)
(i) (COCl)2, DMF (cat.), CH2Cl2; (ii) (S)-3-lithio-4-benzyl-2-oxazolidinone, THF; (d) (i) NaHMDS, THF, -78 °C; (ii) CH3I, -78 °C to rt; (e)
LiBH4, MeOH, Et2O, 0 °C to rt; (f) (COCl)2, DMSO, Et2N, CH2Cl2; (g) Ph3PdCHCO2Me, CH2Cl2, rt; (h) LiOH, H2O, THF.
The degradation of zaragozic acid A into the relay
compound 2 is summarized in Scheme 1. As reported
by Ponpipom and co-workers,8 tri-tert-butyl ester 3 is
formed in excellent yield when zaragozic acid A is treated
with O-tert-butyl-N,N′-diisopropylisourea in methylene
chloride at reflux. The selective cleavage of the C6 R,â-
unsaturated ester was readily effected by treatment of 3
with hydroxylamine,8,9 providing 4 as a crystalline solid
in virtually quantitative yield. Removal of the acetate
from 4 was also accomplished by using the general
method of Ponpipom and co-workers.8 Thus, treatment
of 4 with ethylmagnesium bromide and cerium(III)
chloride at low temperature afforded the desired tetrol
5 in good yield. This method was superior to transes-
terification or hydrolysis of the acetate under basic
conditions because of the lability of the C3 tert-butyl ester
under these conditions.10 Ozonolytic cleavage of the
double bond afforded ketone 6, which was reduced with
methanolic sodium borohydride to yield the diol 7 as a
3:2 mixture of diastereomers. Selective cleavage of the
side chain glycol over the trans glycol on the core using
Pb(OAc)4 next provided aldehyde 8; the isomeric cyclic
hemiacetal of 8 was never observed by NMR spectros-
copy. Treatment of 8 with methanol and trimethyl
orthoformate in the presence of pyridinium p-toluene-
sulfonate afforded acetal 2.
For the reconstitution of zaragozic acid A, it was first
necessary to prepare R,â-unsaturated acid 14. This was
accomplished as shown in Scheme 2. Alkylation of the
lithium enolate of tert-butyl acetate with (S)-1-iodo-2-
methylbutane11 followed by treatment of the resulting
tert-butyl ester with trifluoroacetic acid afforded (S)-4-
methylhexanoic acid (9).12 This acid was converted into
the corresponding acyl chloride and used to acylate (S)-
3-lithio-4-benzyl-2-oxazolidinone. The resulting imide 10
was methylated by the method of Evans13 to obtain 11
and its C2 diastereomer in a 17:1 ratio. The diastereo-
mers were readily separable by column chromatography,
and 11 could be obtained in high yield and diastereomeric
purity. An alternative approach, which involved alky-
lation of the mixed lithium-potassium enolate of (R)-1-
propanoyl-2-pyrrolidinemethanol14 with (S)-1-iodo-2-
methylbutane, gave the two C2 diastereomers in a ratio
(11) (S)-1-Iodo-2-methylbutane (>99% ee) was prepared (I2, PPh3,
imidazole, Et2O/CH3CN, 0 °C) from the corresponding alcohol derived
from methyl (R)-3-hydroxy-2-methylpropanoate (Aldrich, >99% ee) as
described by Mori and Wu: Mori, K.; Wu, J . Liebigs Ann. Chem. 1991,
213.
(12) An alternative three-step preparation of this acid using diethyl
malonate and (S)-1-bromo-2-methylbutane has been reported by
Volger: Volger, K.; Chopard-dit-J ean, L. H. Helv. Chim. Acta 1960,
36, 279.
(8) Ponpipom, M. M.; Girotra, N. N.; Bugianesi, R. L.; Roberts, C.
D.; Berger, G. D.; Burk, R. M.; Marquis, R. W.; Parsons, W. H.; Bartizal,
K. F.; Bergstrom, J . D.; Kurtz, M. M.; Onishi, J . C.; Rew, D. J . J . Med.
Chem. 1994, 37, 4031.
(9) Panfil, I.; Maciejewski, S.; Belzecki, C.; Chmielewski, M. Tetra-
hedron Lett. 1989, 30, 1527.
(10) The carboxy group attached to C3 of the zaragozic acid core
has been shown to be more reactive than those attached to C4 and
C5. See ref 8 and: Kuo, C. H.; Plevyak, S. P.; Biftu, T.; Parsons, W.
H.; Berger, G. D. Tetrahedron Lett. 1993, 34, 6863.
(13) Evans, D. A.; Ennis, M. D.; Mathre, J . D. J . Am. Chem. Soc.
1982, 104, 1737.

Total Synthesis of Zaragozic Acid A
J . Org. Chem., Vol. 61, No. 26, 1996 9117
Sch em e 3
of 17-19:1. This approach was abandoned because the
diastereomers were separable only with difficulty and in
rather low yield by column chromatography.15 Reduction
of 11 with lithium borohydride in a mixture of methanol
and ether16 typically afforded alcohol 12 in greater than
80% yield, accompanied by about 65% of recovered
oxazolidinone. Oxidation of 12 under standard Swern
conditions17 gave an aldehyde that was immediately
condensed with Ph3PdCHCO2Me to yield exclusively the
(E)-R,â-unsaturated ester 13. Saponification of 13 with
lithium hydroxide in aqueous THF afforded acid 14. The
saponification was initially carried out with lithium
hydroxide in aqueous methanol. However, the product
obtained using those conditions was contaminated with
a small amount of the â,γ-isomer, which was difficult to
separate from 14. The overall yield for the eight-step
sequence leading to 14 was 35%.18 The synthetic side
chain was identical in all respects to that obtained by
degradation of zaragozic acid A.1b
C7 hydroxyl group. These results prompted us to revise
our strategy so that the labile C7-OH would first be
protected, leaving the C6-OH free for acylation with 14.
Compound 4 was again used as a model for 2 and was
treated with tert-butyldimethylsilyl chloride and imida-
zole in DMF. To our surprise, the C6 silyl ether 16a was
produced in good yield. Only 3% of the desired product
16b was isolated, along with 10% of recovered starting
material.19,20
Having completed the synthesis of 2 and 14, we were
prepared to begin the reconstruction of zaragozic acid A
by attaching acid 14 to the C6 hydroxyl group of 2. We
had originally thought that the C6-OH, syn to the one-
atom bridge, would be less hindered and therefore more
reactive than the C7-OH, syn to the three-atom bridge.
However, preliminary esterifications of diol 4 with
various derivatives of acid 14 showed that this was not
the case. For example, activation of acid 14 with dicy-
clohexylcarbodiimide and catalytic 4-(dimethylamino)-
pyridine (DMAP) in the presence of diol 4 gave a 6:1
mixture of the C7- and C6-acylated products 15 and 3
(Scheme 3). Treatment of 4 with the acid chloride
derived from 14 in the presence of triethylamine and
catalytic DMAP also led to preferential acylation of the
These seemingly contradictory results may be rational-
ized by the difference in steric accessibility and acidity
of the C6 and C7 hydroxyl groups. It has been shown
that the mechanism of silylation of an alcohol involves
attack on silicon by the neutral hydroxyl group.21 Thus,
the preferential formation of 16a presumbably reflects
the greater steric accessibility of the C6 hydroxyl group.
However, the C7-OH is expected to be more acidic than
the C6-OH because of the electron-withdrawing effect of
the two acetal oxygens. If acylation involves prior
deprotonation of the alcohol and attack on the activated
acid by an alkoxide ion, it is reasonable that 15 is the
major monoester formed in this reaction. In DMAP-
catalyzed acylations, the counterion associated with the
activated N-acyl-4-(dimethylamino)pyridinium ion par-
ticipates in general base catalysis.22
(14) (a) Evans, D. A.; Takacs, J . M. Tetrahedron Lett. 1980, 21, 4233.
(b) Sonnet, P. E.; Heath, R. R. J . Org. Chem. 1980, 45, 3137.
(15) This alkylation has also been investigated by White and
J ohnson, who obtained similar diastereomeric ratios. (a) White, J . D.;
J ohnson, A. T. J . Org. Chem. 1994, 59, 3347. (b) White, J . D.; J ohnson,
A. T. J . Org. Chem. 1990, 55, 5938.
(16) Penning, T. D.; Djuric, S. W.; Haack, R. A.; Kalish, V. J .;
Miyashiro, J . M.; Rowell, B. W.; Yu, S. S. Synth. Commun. 1990, 20,
307.
(19) Other researchers have reported studies dealing with the
relative reactivity of the C6 and C7 hydroxyl groups of the zaragozic
acid core; see refs 6b and 6f.
(20) The structure assignments of 16a and 16b were confirmed by
an unambiguous synthesis of 16b. Treatment of 3 with TBDMSCl and
imidazole followed by HONH2‚HCl and NaOAc‚3H2O in methanol
afforded 16b.
(17) Swern, D.; Mancuso, A. J . Synthesis 1981, 165.
(18) The C6 acyl side chain has also been synthesized by Nicolaou
and co-workers by a different route; see refs 6d and 6f.
(21) Chaudhary, S. K.; Hernandez, O. Tetrahedron Lett. 1979, 99.
(22) Ho¨fle, G.; Steglich, W.; Vorbru¨ggen, H. Angew. Chem., Int. Ed.
Engl. 1978, 17, 569.

9118 J . Org. Chem., Vol. 61, No. 26, 1996
Stoermer et al.
Sch em e 4a
a
Reagents and conditions: (a) PPTS, benzene, reflux, 4 Å sieves; (b) 14, DCC, DMAP, CH2Cl2, 0 °C to rt; (c) H2O acetone, PPTS, 50
°C; (d) Et3SiCl, pyridine, rt.
26
Sch em e 5a
treated with anhydrous CeCl3 to obtain the R-alkoxy-
organocerium(III) reagent. Addition of aldehyde 20 to
the organocerium reagent afforded alcohols 24a ,b as a
15:1 diastereomeric mixture in 87% yield (Scheme 6).27
Use of the organocerium reagent in this procedure was
found to be crucial. If the addition was carried out with
the R-alkoxyorganolithium reagent, much enolization
occurred and 24a ,b was obtained in only 27% yield, with
about 70% recovery of aldehyde 20 after aqueous workup.
The diastereomeric ratio when using the organolithium
reagent was 1:1. We did not determine the relative
configuration of the major and minor diastereomers of
24. However, on the basis of a previous study dealing
with additions of chiral R-alkoxyorganometal reagents to
aldehydes, we would expect that the major diastereomer
has a syn relationship between the alcohol and [(p-
methoxybenzyl)oxy]methoxy group.28 Oxidation of the
mixture of diastereomeric alcohols with Dess-Martin
reagent29 provided ketone 25 in an overall yield for the
two steps of about 80%. For introduction of the final
carbon, we first explored the use of the Wittig reaction.
However, treatment of 25 with methylenetriphenylphos-
phorane30 gave 26 in only low yield, accompanied by
recovered starting material. The highly selective, non-
basic Zn/TiCl4/CH2Br2 methylenation procedure of Lom-
bardo31 also proved ineffective, giving only recovered
starting material. On the other hand, the Tebbe reaction,
using the procedure of Pine and co-workers,32 served
admirably, affording 26 in 77% yield along with 15% of
recovered starting material. Removal of the [(p-meth-
a
Reagents and conditions: (a) (COCl)2, DMSO, Et3N, CH2Cl2;
(b) Bu3SnLi, THF, -78 °C; (c) p-MeOC6H4CH2OCH2Cl, Hu¨ing’s
base, CH2Cl2; (d) HPLC separation.
The problem of regiocontrol in the acylation was nicely
solved when we discovered that treatment of 2 with
pyridine p-toluenesulfonate in refluxing benzene in the
presence of 4 Å molecular sieves resulted in smooth
transformation to a 6:1 diastereomeric mixture of cyclic
methyl acetals, 17a ,b (Scheme 4). Acylation of the free
hydroxyl group gave 18a ,b and a small amount (2-3%)
of side products arising from the acylation of 17a ,b with
the â,γ-unsaturated isomer of 14. We speculated that
this side product was the result of deprotonation of the
activated acid intermediate by DMAP. Reduction of the
amount of DMAP from 0.1-0.4 to 0.03-0.05 equiv led
to the formation of 18a ,b only. The diastereomers were
hydrolyzed to hydroxy aldehyde 19. Treatment of this
material with triethylsilyl chloride provided 20.
(25) A model study of the C1 side chain was used to tentatively
assign the configuration at C1 of the diastereomers 23a ,b. Model
compounds A and B were synthesized in three steps from 23a ,b and
nonanal. The 1H NMR spectrum of A more closely resembled that of
the C1 alkyl side chain in 26, prepared from natural zaragozic acid
(Scheme 6).
To reinstall the full C1 side chain, we elected to use
the R-alkoxystannane methodology of Still23 (Scheme 5).
To this end, (R)-2-methyl-3-phenylpropanol13 (21) was
oxidized using the Swern procedure17 and the resulting
aldehyde immediately treated with (tributylstannyl)-
lithium at low temperature. The resulting diastereo-
meric mixture of hydroxy stannanes (22) was alkylated
with p-methoxybenzyl chloromethyl ether,24 and the
mixture of diastereomeric ethers was separated by
preparative HPLC to obtain the pure diastereomers 23a
and 23b in yields of about 30% each.25
(26) Imamoto, T.; Sugiura, Y.; Takiyama, N. Tetrahedron Lett. 1984,
25, 4233.
(27) Before purification the ratio of diastereomeric alcohols 24 was
10:1.
(28) McGarvey, G. J .; Kimura, M. J . Org. Chem. 1982, 47, 5420.
(29) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155.
(30) Fitjer, L.; Quabeck, U. Synth. Commun. 1985, 855.
(31) (a) Lombardo, L. Tetrahedron Lett. 1982, 23, 4293. (b) Lom-
bardo, L. Org. Synth. 1987, 65, 81.
Stannane 23a was transmetalated with n-butyllithium
at -78 °C, and the resulting R-alkoxyorganolithium was
(23) (a) Still, W. C.; Sreekumar, C. J . Am. Chem. Soc. 1980, 102,
1201. (b) Still, W. C. J . Am. Chem. Soc. 1978, 100, 1481.
(24) Benneche, T.; Strande, P.; Undheim, K. Synthesis 1983, 762.
(32) Pine, S. H.; Kim, G.; Lee, V. Org. Synth. 1990, 69, 72.

Total Synthesis of Zaragozic Acid A
J . Org. Chem., Vol. 61, No. 26, 1996 9119
Sch em e 6a
a
Reagents and conditions: (a) (i) n-BuLi, THF; (ii) CeCl3; (iii) 20; (b) Dess-Martin periodinane, pyridine, CH2Cl2; (c) Tebbe reagent,
THF, 0 °0; (d) DDQ, CH2Cl2, H2O; (e) (CH3CO)2O, DMAP, Et3N, CH2Cl2, 0 °C; (f) HF, pyridine, THF, 0 °C; (g) CF3CO2H, CH2Cl2, rt; (h)
Et3SiCl, imidazole, DMF, rt; (i) EtMgBr, CeCl3, THF, -78 °C; (j) p-MeOC6H4CH2OCH2Cl, Hu¨ing’s base, CH2Cl2, rt.
values are in Hertz. For 13C NMR spectra, carbon type is
oxybenzyl)oxy]methyl protecting group was smoothly
defined as 3 (CH3), 2 (CH2), 1 (CH), or 0 (C) on the basis of
DEPT experiments. Melting points were determined in Pyrex
effected by treatment of 26 with 2,3-dichloro-5,6-di-
cyano-1,4-benzoquinone (DDQ) in methylene chloride.
capillaries open to air. IR spectra were recorded as solutions
The resulting alcohol 27 was acetylated in quantitative
in the solvent indicated or as thin films on NaCl plates. The
yield to obtain 28. The synthesis of zaragozic acid A was
completed by removal of the triethylsilyl group (HF and
pyridine in THF) followed by cleavage of the three tert-
CHCl3 used to measure optical rotations was filtered through
alumina, basic Brockman activity I, 60-325 mesh.
[1S-[1r(4S,5R),3r,4â,5r ,6r(2E,4S,6S),7â]]-1-[4-Acetyloxy-
butyl esters (trifluoroacetic acid in methylene chloride).
The resulting material was identical in all spectral and
chromatographic aspects to an authentic sample of
zaragozic acid A (1). Intermediates 26, 27, and 28 were
also prepared by degradation of 1, as shown in the
retrograde reaction arrows in Scheme 6.
In summary, we have developed a seven-step degrada-
tion of zaragozic acid A (1) into dimethyl acetal 2; the
optimized process provides 2 in 52% overall yield. In
addition, intermediate 2 has been converted back into 1
by a 10-step route that proceeds in 27% yield.
5-m eth yl-3-m eth ylen e-6-p h en ylh exyl]-6-(4,6-d im eth yl-2-
octen oyl)-4,6,7-tr ih yd r oxy-2,8-d ioxa bicyclo[3.2.1]octa n e-
3,4,5-tr icar boxylic Acid 3,4,5-Tr is(1,1-dim eth yleth yl) Ester
(3). A. F r om Za r a gozic Acid (1). This compound was
prepared by a procedure similar to one described by Ponpi-
pom.8 Zaragozic acid A (1) (634.2 mg (e89% pure), 0.821
mmol) was dissolved in CH2Cl2 (8 mL), and O-tert-butyl-N,N′-
diisopropylisourea (0.58 mL, 2.46 mmol) was added at rt. The
resulting solution was heated at reflux for 2 h, and additional
isourea was added (0.6 mL). The solution was allowed to cool
to rt and stir overnight (14 h). The mixture was again warmed
to reflux, and more isourea (two 0.6-mL portions) was added
over 6 h. An aqueous acetic acid solution (pH 5) was added,
and the mixture was extracted with EtOAc (4 × 40 mL). The
combined organic extracts were washed with saturated aque-
ous NaHCO3 (2 × 80 mL), water (80 mL), and brine (80 mL),
dried over MgSO4, filtered, and concentrated. To the crude
residue was added 1:5 EtOAc/hexanes. Following filtration
and concentration of the filtrate, the crude product was
subjected to chromatography on SiO2 (1:5 EtOAc/hexanes). The
product 3 was isolated as a white foam (610.7 mg, 87%).
TLC: Rf 0.27 (1:3 EtOAc/hexanes). [R]D: +15.3 (c 4.8, CHCl3).
Exp er im en ta l Section
Gen er a l. Unless otherwise indicated, all starting materials
were obtained from commercial suppliers and used without
further purification. Benzene, toluene, pyridine, Et3N, i-Pr2-
NH, i-Pr2NEt, and CH2Cl2 were distilled under N2 from CaH2,
and THF was distilled under N2 from sodium/benzophenone
prior to use. Dimethyl sulfoxide (DMSO) was distilled from
CaH2 and stored over 4 Å molecular sieves. All reactions were
conducted under a N2 atmosphere. Flash chromatography was
performed according to the procedure of Still33 using Merck
60 230-400 mesh silica gel. Reaction mixtures and chroma-
tography fractions were analyzed using Merck silica gel 60
F-254 TLC plates. 1H NMR and 13C NMR spectra were
measured in CDCl3 unless otherwise stated. Chemical shifts
are expressed in ppm relative to internal CHCl3 (7.26 ppm). J
IR (CDCl3): 3550, 3450, 1735, 1655 cm-1
.
1H NMR (500
MHz): δ 0.80-0.85 (m, 9), 1.03 (d, 3, J ) 6.7), 1.09-1.14 (m,
2), 1.26-1.41 (m, 3), 1.44 (s, 9), 1.48 (s, 9), 1.59 (s, 9), 2.07-
2.15 (m, 3), 2.09 (s, 3), 2.29-2.37 (m, 2), 2.41-2.49 (m, 2), 2.69
(dd, 1, J ) 13.5, 5.5), 2.98 (br s, 1), 4.02 (dd, 1, J ) 3.1, 2.1),
4.07 (s, 1), 4.95 (s, 1), 4.97 (s, 1), 5.05 (s, 1), 5.10 (d, 1, J )
4.8), 5.76 (dd, 1, J ) 15.7, 0.9), 6.01 (d, 1, J ) 1.9), 6.90 (dd, 1,
J ) 15.6, 8.4), 7.13-7.26 (m, 5). 13C NMR (100 MHz): δ 10.85
(3), 13.40 (3), 18.63 (3), 20.00 (3), 20.78 (3), 25.32 (2), 27.79
(3), 27.90 (3), 29.46 (2), 31.62 (1), 34.01 (2), 34.23 (1), 36.37
(33) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

9120 J . Org. Chem., Vol. 61, No. 26, 1996
Stoermer et al.
(1), 39.80 (2), 42.97 (2), 74.03 (0), 75.15 (1), 78.74 (1), 80.36
(1), 82.09 (1), 82.69 (0), 83.45 (0), 85.38 (0), 88.91 (0), 104.18
(0), 110.93 (2), 118.16 (1), 125.64 (1), 128.02 (1), 128.93 (1),
140.12 (0), 145.70 (0), 156.85 (1), 163.88 (0), 165.55 (0), 166.10
4.10 (d, 1, J ) 1.7), 4.96 (s, 1), 5.00 (s, 1), 5.08 (s, 1), 5.13 (s,
1), 7.15-7.28 (m, 5). 13C NMR (100 MHz): δ 13.88, 25.82,
27.99, 28.11, 28.23, 33.94, 38.23, 40.10, 74.39, 75.23, 78.38,
78.72, 82.81, 83.43, 84.43, 84.84, 91.20, 104.95, 112.10, 125.72,
128.20, 129.20, 141.16, 150.81, 165.96, 166.21, 168.06. Anal.
Calcd for C35H52O12: C, 63.23; H, 7.88. Found: C, 62.88; H,
7.98.
1
(0), 168.47 (0), 169.99 (0). The H NMR data agrees with that
published by Ponpipom.8
B. F r om 28. To a solution of the triethylsilyl ether 28 (29.2
mg, 30.0 µmol) in THF (0.3 mL) at 0 °C was added two drops
of hydrogen fluoride-pyridine complex from a disposable
Pasteur pipet (ca. 70 µL). The solution was stirred at 0 °C
under N2 for 6 h. During this time the septum was removed
three times and additional hydrogen fluoride-pyridine com-
plex (a total of 7 drops) was added. The cold solution was
diluted with Et2O (5 mL) and neutralized with saturated
aqueous NaHCO3 (5 mL). The mixture was poured into a
separatory funnel, the phases were separated, and the aqueous
phase was extracted with Et2O (2 × 10 mL). The combined
organic phases were washed with water (5 mL) and brine (5
mL), dried over MgSO4, filtered, and concentrated in vacuo.
The residue was concentrated twice from toluene (2 × 10 mL)
to remove residual pyridine and purified by flash chromatog-
raphy on SiO2 (gradient elution, 1:7 to 1:3 EtOAc/hexanes) to
provide 3 (22.4 mg, 87%). The 1H NMR spectrum of this
material was identical to that obtained by procedure A.
[1S-(1r(4S,5R),3r,4â,5r,6r,7â)]-1-[4-(Acetyloxy)-5-m eth -
yl-3-m e t h yle n e -6-p h e n ylh e xyl)]-4,6,7-t r ih yd r oxy-2,8-
d ioxa bicyclo[3.2.1]octa n e-3,4,5-tr ica r boxylic Acid 3,4,5-
Tr is(1,1-d im eth yleth yl) Ester (4). To 5 mL of a methanol
solution 0.2 M in HONH2‚HCl and 0.2 M in NaOAc‚3H2O was
added 3 (75.8 mg, 88.0 µmol). The solution was heated at
reflux for 2.5 h, concentrated in vacuo, diluted with EtOAc
(20 mL), washed with H2O (15 mL), and dried over MgSO4.
Evaporation of the solvent yielded a colorless oil which was
purified by flash chromatography on SiO2 (1:2 EtOAc/hexanes)
to afford 4 (60.1 mg, 97%) as an analytically pure white solid.
A sample was crystallized (EtOAc/hexanes) to give white
crystals, mp 135.0-135.5 °C. TLC: Rf 0.15 (2:3 EtOAc/
hexanes). [R]D: +9.2 (c 1.06, CHCl3). IR (CHCl3): 3600-3400
[1S-(1r(4S,5R),3r,4â,5r,6r,7â)]-1-(4-Hyd r oxy-5-m eth yl-
3-oxo-6-p h en ylh exyl)-4,6,7-tr ih yd r oxy-2,8-d ioxa bicyclo-
[3.2.1]oct a n e-3,4,5-t r ica r b oxylic Acid 3,4,5-Tr is(1,1-d i-
m eth yleth yl) Ester (6). Ozone was bubbled through a
solution of 5 (72.0 mg, 0.108 mmol) in CH2
Cl2 (2 mL) at -78
°C until the solution turned pale blue. Dimethyl sulfide (1
mL) was added, and the solution was stirred for 10 min at
-78 °C, warmed to rt, and concentrated in vacuo. Purification
by flash chromatography on SiO2 (1:1 EtOAc/hexanes) provided
6 (68.0 mg, 94%) as a white foam. TLC: Rf 0.12 (3:2 EtOAc/
hexanes). [R]D: +25.2 (c 0.50, CHCl3). IR (CH2Cl2): 3585,
3473, 3258, 1725 cm-1
.
1H NMR (400 MHz): δ 0.72 (d, 3, J )
6.8), 1.43 (s, 9), 1.47 (s, 9), 1.58 (s, 9), 2.13-2.21 (m, 1), 2.25-
2.34 (m, 2), 2.60-2.71 (m, 2), 2.82-2.87 (m, 2), 2.92-3.00 (m,
1), 3.22 (d, 1, J ) 4.3), 3.59 (d, 1, J ) 4.5), 3.98 (s, 1), 4.09 (m,
1), 4.18 (m, 1), 4.92 (s, 1), 5.00 (m, 1), 7.18-7.31 (m, 5). 13C
NMR (100 MHz): δ 12.80 (3), 27.96 (3), 28.01 (3), 28.17 (3),
30.18 (2), 31.81 (2), 38.17 (1), 40.19 (2), 74.08 (0), 75.10 (1),
78.42 (1), 78.68 (1), 83.35 (0), 83.45 (1), 84.32 (0), 85.38 (0),
91.32 (0), 104.03 (0), 126.03 (1), 128.30 (1), 129.31 (1), 140.30
(0), 165.98 (0), 166.06 (0), 168.75 (0), 214.08 (0). Anal. Calcd
for C34H50O13: C, 61.24; H, 7.56. Found: C, 60.94; H, 7.55.
[1S-(1r,3r,4â,5r,6r,7â)]-1-(3-Oxopr opyl)-4,6,7-tr ih ydr oxy-
2,8-dioxabicyclo[3.2.1]octan e-3,4,5-tr icar boxylic Acid 3,4,5-
Tr is(1,1-d im eth yleth yl) Ester (8). Sodium borohydride
(25.7 mg, 0.679 mmol) was added to a solution of 6 (70.0 mg,
0.105 mmol) in methanol (1 mL) at 0 °C. The mixture was
stirred for 5 min, and additional NaBH4 (30 mg) was added.
The mixture was stirred an additional 1 min, and then water
(10 mL) was added. The mixture was extracted with EtOAc
(4 × 20 mL). The combined organic extracts were washed once
with water (30 mL), dried over MgSO4, filtered, and concen-
trated to provide 62.2 mg (89%) of a 1.5:1 mixture of diaster-
eomeric alcohols 7.
(br), 1730 cm-1 1H NMR (500 MHz): δ 0.84 (d, 3, J ) 6.8),
.
1.45 (s, 9), 1.50 (s, 9), 1.59 (s, 9), 2.04-2.16 (m, 3), 2.11 (s, 3),
2.20-2.28 (m, 1), 2.32 (d, 1, J ) 4.7), 2.41 (dd, 1, J ) 13.4,
8.9), 2.40-2.48 (m, 1), 2.47 (d, 1, J ) 5.1), 2.69 (dd, 1, J )
13.5, 5.7), 3.93 (s, 1), 4.07 (dd, 1, J ) 4.7, 2.1), 4.91 (s, 1), 4.97
(s, 1), 5.01 (s, 1), 5.02 (dd, 1, J ) 5.1, 2.1), 5.09 (d, 1, J ) 4.5),
7.13-7.28 (m, 5). 13C NMR (100 MHz): δ 13.51 (3), 21.06 (3),
25.77 (2), 27.95 (3), 28.01 (3), 28.14 (3), 33.29 (2), 36.60 (1),
40.02 (2), 74.28 (0), 75.14 (1), 78.78 (1), 78.90 (1), 82.39 (1),
83.08 (0), 83.98 (0), 84.97 (0), 91.23 (0), 104.65 (0), 110.97 (2),
125.95 (1), 128.30 (1), 129.07 (1), 140.30 (0), 145.85 (0), 165.98
(0), 166.21 (0), 168.65 (0), 170.64 (0). Anal. Calcd for
C37H54O13: C, 62.87; H, 7.68. Found: C, 62.55; H, 7.80.
[1S-(1R(4S,5R),3R,4â,5R,6R,7â)]-1-(4-Hyd r oxy-5-m eth yl-
3-m e t h yle n e -6-p h e n ylh e xyl)-4,6,7-t r ih yd r oxy-2,8-d i-
oxa b icyclo[3.2.1]oct a n e-3,4,5-t r ica r b oxylic Acid 3,4,5-
This material was dissolved in benzene (0.8 mL) and cooled
to ∼10 °C. Lead tetraacetate (85.9 mg, 0.194 mmol) was
added, and the mixture was stirred for 17 min. After addition
of saturated aqueous NaHCO3 (10 mL), the mixture was
extracted with EtOAc (3 × 30 mL). The combined organic
extracts were washed with water, dried over MgSO4, filtered,
and concentrated. Purification of the crude product by flash
chromatography on SiO2 (gradient elution, 1:1 to 3:2 EtOAc/
hexanes) provided aldehyde 8 (39.7 mg, 73%) as a white solid,
mp 160 °C dec. TLC: Rf 0.32 (4:1 EtOAc/hexanes). [R]D: -1.9
(c 2.21, CH2Cl2). IR (CHCl3): 3450 (br), 1730 cm-1 1H NMR
.
(500 MHz): δ 1.45 (s, 9), 1.48 (s, 9), 1.58 (s, 9), 2.21 (dt, 1, J )
14.7, 6.9), 2.33 (dt, 1, J ) 14.5, 7.2), 2.75 (dtd, 1, J ) 18.3, 7.0,
1.2), 2.79 (d, 1, J ) 5.1), 2.92 (dtd, 1, J ) 18.3, 7.1, 1.3), 3.11
(d, 1, J ) 4.3), 3.95 (s, 1), 4.10-4.12 (m, 1), 4.93 (s, 1), 5.02
(dd, 1, J ) 5.0, 2.0), 9.83 (t, 1, J ) 1.3). 13C NMR (100 MHz):
δ 27.89, 27.93, 28.12, 28.53, 37.75, 74.14, 75.19, 78.64, 82.99,
83.30, 84.02, 85.11, 91.23, 104.13, 165.80, 166.13, 168.62,
26
Tr is(1,1-d im eth yleth yl) Ester (5). Dry CeCl3 (626 mg,
2.54 mmol) was stirred in THF (4 mL) for 2 d to yield a thick
white paste. THF (2 mL) was added to form a slurry which
was cooled to -78 °C. A solution of ethylmagnesium bromide
in THF (1.9 mL, 1.9 mmol) was added. After 20 min, 4 (103.6
mg, 146.5 µmol) in THF (2 mL) at -78 °C was added via
cannula to the slurry, and the mixture was stirred for 20 min
at -78 °C. Saturated aqueous NH4Cl (15 mL) was added, and
the mixture was allowed to warm to rt and was extracted with
EtOAc (3 × 25 mL). The combined organic extracts were
washed with water (30 mL) which was back-extracted with
EtOAc (25 mL). The organic extracts were dried over MgSO4,
filtered, and concentrated. Extensive purification by flash
chromatography on SiO2 (performed three times, 2:3 EtOAc/
hexanes) provided 5 (78.8 mg, 81%) as a white foam and
recovered starting material (13.8 mg, 13%). TLC: Rf 0.11 (1:1
EtOAc/hexanes). [R]D: +2.1 (c 0.52, CHCl3). IR (CDCl3):
203.24. Anal. Calcd for C24H38O12
Found: C, 55.86; H, 7.10.
: C, 55.59; H, 7.39.
[1S-(1r,3r,4â,5r,6r,7â)]-1-(3,3-Dim eth oxyp r op yl)-4,6,7-
tr ih yd r oxy-2,8-d ioxa bicyclo[3.2.1]octa n e-3,4,5-tr ica r box-
ylic Acid 3,4,5-Tr is(1,1-d im eth yleth yl) Ester (2). Pyri-
dinium p-toluenesulfonate (66.0 mg, 0.263 mmol) was added
to a solution of aldehyde 8 (193.9 mg, 0.374 mmol) and
trimethyl orthoformate (2 mL) in methanol (8 mL) at rt.
Saturated aqueous K2CO3 (20 mL) was added after 3 h, and
the mixture was extracted with EtOAc (4 × 30 mL). The
combined organic layers were washed with saturated aqueous
NH4Cl (30 mL) and water (30 mL), dried over MgSO4, filtered,
and evaporated. Purification of the crude product by flash
chromatography on SiO2 pretreated with Et3N (1:1 EtOAc/
hexanes) provided 2 (200.1 mg, 95% yield) as a white solid,
mp 141 °C dec. TLC: Rf 0.31 (4:1 EtOAc/hexanes). [R]D: +1.8
3600-3460 (br), 1735 cm-1
.
1H NMR (400 MHz): δ 0.85 (d,
3, J ) 6.6), 1.46 (s, 9), 1.49 (s, 9), 1.58 (s, 9), 1.92-1.99 (m, 1),
2.14 (t, 2, J ) 7.3), 2.32 (dd, 1, J ) 13.5, 9.4), 2.29-2.36 (m,
1), 2.47 (m, 1), 2.73-2.78 (br s, 1), 2.75 (dd, 1, J ) 13.4, 5.0),
2.82-2.84 (m, 1), 3.07 (br s, 1), 3.89 (s, 1), 4.02 (d, 1, J ) 6.0),
(c 0.50, CH2Cl2). IR (CDCl3): 3600-3400 (br), 1760, 1730 cm-1
.

Total Synthesis of Zaragozic Acid A
J . Org. Chem., Vol. 61, No. 26, 1996 9121
1H NMR (400 MHz): δ 1.45 (s, 9), 1.48 (s, 9), 1.58 (s, 9), 1.89-
1.92 (m, 1), 1.95-2.01 (m, 2), 2.04-2.09 (m, 1), 2.59 (m, 1),
3.29 (m, 1), 3.343 (s, 3), 3.345 (s, 3), 3.92 (s, 1), 4.10 (s, 1), 4.48
(t, 1, J ) 5.0), 4.96 (s, 1), 5.02 (s, 1). 13C NMR (100 MHz): δ
26.46, 27.99, 28.07, 28.18, 31.04, 53.21, 74.35, 75.11, 78.92,
82.57, 83.09, 84.14, 84.93, 91.15, 104.77, 104.87, 165.93,
166.38, 168.57. Anal. Calcd for C26H44O13: C, 55.31; H, 7.85.
Found: C, 55.65; H, 7.64.
2.88 (ddd, 1, J ) 15.8, 9.8, 5.8), 2.99 (ddd, 1, J ) 15.6, 10.0,
5.5), 3.29 (dd, 1, J ) 13.4, 3.2), 4.14-4.21 (m, 2), 4.67 (m, 1),
7.20-7.34 (m, 5). 13C NMR (100 MHz): δ 11.12, 18.76, 29.04,
30.70, 33.18, 33.82, 37.69, 54.93, 65.94, 127.10, 128.72, 129.24,
135.21, 153.24, 173.45. Anal. Calcd for C17H23NO3: C, 70.56;
H, 8.01; N, 4.84. Found: C, 70.39; H, 8.08; N, 4.83.
[3(2S,4S),4S]-3-(2,4-Dim et h yl-1-oxoh exyl)-4-(p h en yl-
m eth yl)-2-oxa zolid in on e (11). To a solution of imide 10
(2.82 g, 9.75 mmol) in THF (10 mL) at -78 °C was added a
solution of sodium bis(trimethylsilyl)amide in THF (14.6 mL,
14.6 mmol) over 20 min. The solution was stirred at -78 °C
for 1 h, and iodomethane (2.50 mL, 40.2 mmol) was added over
5 min. After being stirred for 1.5 h at -78 °C, the reaction
mixture was allowed to warm to rt and the reaction was
quenched with saturated aqueous NH4Cl (30 mL). The THF
was evaporated in vacuo. The mixture was transferred to a
separatory funnel and extracted with CH2Cl2 (2 × 50 mL). The
combined organic layers were washed with water (50 mL) and
brine (50 mL), dried over MgSO4, filtered, and evaporated to
leave a yellow oil which was purified by flash chromatography
on SiO2 (1:12 EtOAc/hexanes). Imide 11 was isolated as a
clear, colorless oil (2.54 g, 86%). TLC: Rf 0.38 (1:5 EtOAc/
hexanes). [R]D: +86.9 (c 4.4, CH2Cl2). IR (thin film): 1781,
(S)-4-Meth ylh exa n oic Acid (9). A solution of diisoprop-
ylamine (3.88 mL, 29.6 mmol) in THF (26 mL) was cooled to
-78 °C, and n-BuLi in hexanes (11.0 mL, 28.3 mmol) was
added. The resulting pale yellow solution was stirred in an
ice bath for 10 min and cooled to -78 °C. To the solution was
added slowly tert-butyl acetate (3.63 mL, 26.9 mmol). The
solution was stirred for 50 min at -78 °C and cooled to -100
°C. In a separate flask, a solution of (S)-1-iodo-2-methyl-
butane11 (8.28 g, 41.8 mmol) in THF (46 mL) and N,N′-
dimethylpropyleneurea (23 mL) was stirred and cooled to -78
°C. The tert-butyl lithioacetate solution was added via Teflon
cannula over 2 min to the alkyl iodide. After 5 min, the milky
white reaction mixture was warmed to -42 °C, stirred for 3
h, and warmed slowly to rt. The mixture was poured into
saturated aqueous NH4Cl (50 mL) and extracted with ether
(150 mL). The organic phase was washed with water (2 × 50
mL) and brine (50 mL), dried over MgSO4, filtered, and
concentrated in vacuo. Excess alkyl iodide was separated from
the product, (S)-tert-butyl-4-methylhexanoate, by flash chro-
matography on SiO2 (pentane followed by 1:4 ether/pentane).
Concentration of the appropriate fractions yielded recovered
iodide (1.83 g) and tert-butyl ester (4.36 g, 87%). The ester
was found to be approximately 90% pure by 1H NMR analysis
and was used directly in the following step. Further purifica-
tion of the ester on SiO2 (1:100 ether/pentane) provided a clear,
colorless liquid for characterization. TLC: Rf 0.45 (1:20
EtOAc/hexanes). [R]D: +8.67 (c 2.03, CH2Cl2). IR (neat): 1732
1698 cm-1 1H NMR (400 MHz): δ 0.85 (d, 3, J ) 6.5), 0.86 (t,
.
3, J ) 7.1), 1.08-1.19 (m, 2), 1.20 (d, 3, J ) 6.9), 1.25-1.43
(m, 2), 1.85 (ddd, 1, J ) 13.6, 8.6, 5.4), 2.75 (dd, 1, J ) 13.4,
9.4), 3.20 (dd, 1, J ) 13.4, 3.2), 3.82-3.90 (m, 1), 4.10-4.16
(m, 2), 4.62-4.67 (m, 1), 7.17-7.31 (m, 5). 13C NMR (100
MHz): δ 11.00, 18.11, 19.10, 29.17, 32.00, 35.08, 37.50, 40.16,
54.97, 65.68, 127.00, 128.59, 129.21, 135.10, 152.72, 177.06.
Anal. Calcd for C18H25NO3: C, 71.25; H, 8.31; N, 4.62.
Found: C, 71.10; H, 8.43; N, 4.51.
(2S,4S)-2,4-Dim eth ylh exa n ol (12). A stirred solution of
imide 11 (1.7032 g, 5.614 mmol) in Et2O (112 mL) was cooled
to 0 °C. Methanol (250 µL, 6.18 mmol) was added followed by
a solution of LiBH4 in THF (3.09 mL, 6.18 mmol). The reaction
was allowed to warm to rt. After 1 h, 1.5 M NaOH (10 mL)
was added and stirring was continued until both phases were
clear. The mixture was poured into a separatory funnel and
washed with water (30 mL) and brine (40 mL). The organic
phase was dried over MgSO4, filtered, and concentrated in
vacuo. Purification by flash chromatography on SiO2 (gradient
elution, 1:9 to 1:7 followed by 3:2 EtOAc/hexanes) yielded
alcohol 12 (601.4 mg, 84%) as a clear, colorless liquid and
recovered oxazolidinone (671.7 mg, 68%). TLC: Rf 0.24 (1:5
EtOAc/hexanes). [R]D: -3.9 (c 1.63, CHCl3) [lit.15a [R]D +3.7
(c 1.67, CHCl3) for the antipode of 12]. IR (thin film): 3620-
cm-1 1H NMR (400 MHz): δ 0.84-0.88 (m, 6), 1.11-1.22 (m,
.
1), 1.27-1.40 (m, 3), 1.43 (s, 9), 1.56-1.66 (m, 1), 2.13-2.27
(m, 2). 13C NMR (100 MHz): δ 11.28, 18.83, 28.08, 29.17,
31.59, 33.40, 33.99, 79.84, 173.55. Anal. Calcd for C11H22O2:
C, 70.92; H, 11.90. Found: C, 71.05; H, 12.19.
A solution of 4.36 g of ester, prepared as described above,
in CH2Cl2 (30 mL) was cooled to 0 °C, and trifluoroacetic acid
(10 mL) was added. The solution was stirred at 0 °C for 2.5
h. Additional trifluoroacetic acid (10 mL) was added, and the
solution was warmed to rt, stirred for 2.5 h, concentrated in
vacuo, and distilled (128 °C, 29 mmHg) to yield acid 9 (2.31 g,
66%) as a clear, colorless liquid. [R]D: +12.09 (neat) [lit.12 [R]D
+11.80 (neat)]. IR (neat): 3470-2600 br, 1711 cm-1
.
1H NMR
3040 (br) cm-1 1H NMR (400 MHz): δ 0.85 (t, 3, J ) 7.5),
.
(400 MHz): δ 0.88 (t, 3, J ) 7.3), 0.88 (d, 3, J ) 6.4), 1.12-
1.23 (m, 1), 1.30-1.50 (m, 3), 1.64-1.73 (m, 1), 2.28-2.43 (m,
2). 13C NMR (100 MHz): δ 11.08 (3), 18.59 (3), 29.02 (2), 31.13
(2), 31.85 (2), 33.84 (1), 180.95 (0).
0.86-0.96 (m, 1), 0.87 (d, 3, J ) 6.6) , 0.91 (d, 3, J ) 6.7),
1.02-1.13 (m, 1), 1.24-1.47 (m, 4), 1.65-1.76 (m, 1), 3.37 (dd,
1, J ) 10.5, 6.8), 3.51 (dd, 1, J ) 10.5, 5.2). 13C NMR (100
MHz): δ 11.04 (3), 17.24 (3), 19.72 (3), 28.96 (2), 31.54 (1),
33.08 (1), 40.58 (2), 68.24 (2). These data agree with the
literature data.15a,b
[3(4S),4S]-3-(4-Meth yl-1-oxoh exyl)-4-(p h en ylm eth yl)-2-
oxa zolid in on e (10). Oxalyl chloride (0.59 mL, 6.81 mmol)
was added to a solution of acid 9 (0.739 g, 5.68 mmol) and
N,N-dimethylformamide (1 µL) in CH2Cl2 (5 mL). The solution
was stirred for 2 h at rt and concentrated in vacuo to provide
the acid chloride (0.835 g) in 99% crude yield. In a separate
flask, a solution of n-BuLi in hexanes (2.24 mL, 5.68 mmol)
was added slowly to a -78 °C solution of (S)-(-)-4-benzyl-2-
oxazolidinone (1.006 g, 5.68 mmol) in THF (20 mL). The
solution was stirred for 20 min, and the acid chloride was
added via cannula followed by two THF (0.5 mL) rinses. The
reaction mixture was stirred at -78 °C for 2.5 h and allowed
to warm slowly to rt. Saturated aqueous NH4Cl (10 mL) was
added, and the THF was removed in vacuo. The mixture was
poured into a separatory funnel and extracted with CH2Cl2 (3
× 20 mL). The combined organic extracts were washed with
saturated aqueous NaHCO3 (30 mL), water (30 mL), and brine
(30 mL), dried over MgSO4, filtered, and concentrated. Puri-
fication of the crude product by flash chromatography on SiO2
(1:5 EtOAc/hexanes) provided 10 (1.48 g, 90%) as a clear,
colorless oil. TLC: Rf 0.34 (1:5 EtOAc/hexanes). [R]D: +74.2
(2E,4S,6S)-4,6-Dim eth yl-2-octen oic Acid Meth yl Ester
(13). To a stirring solution of oxalyl chloride (0.18 mL, 2.06
mmol) in CH2Cl2 (6 mL) at -78 °C was added slowly dimethyl
sulfoxide (0.262 mL, 3.69 mmol). After 20 min, alcohol 12
(0.200 g, 1.54 mmol) in CH2Cl2 (1 mL followed by 2 × 0.5 mL
rinses) was added via cannula over 5 min. The cloudy white
mixture was stirred at -78 °C for 40 min, and triethylamine
(1.07 mL, 7.68 mmol) was added. The thick slurry was stirred
for 1.5 h at -78 °C, diluted with CH2Cl2 (20 mL), and washed
with 10% aqueous NaHSO4 (12 mL), saturated aqueous
NaHCO3 (10 mL), water (2 × 10 mL), and brine (10 mL). The
organic layer was dried over MgSO4, filtered, concentrated to
∼2 mL, and filtered through a plug of cotton into a 25-mL
round bottomed flask. The cotton was rinsed with dry CH2-
Cl2 (4 mL) which was also collected in the same flask. To this
solution was added methyl (triphenylphosphoranylidene)-
acetate (0.6738 g, 2.015 mmol). The reaction mixture was
stirred under N2 for 18 h at rt, during which time additional
methyl (triphenylphosphoranylidene)acetate (0.400 g) was
added. The solution was concentrated to ∼2.5 mL and filtered
through a column of SiO2 (1:40 Et2O/hexanes). The eluent was
concentrated, and 13 (0.2830 g, 86%) was isolated after
(c 4.1, CH2Cl2). IR (thin film): 1783, 1700 cm-1 1H NMR (500
.
MHz): δ 0.88-0.92 (m, 6), 1.16-1.25 (m, 1), 1.36-1.47 (m, 2),
1.49-1.56 (m, 1), 1.68-1.75 (m, 1), 2.76 (dd, 1, J ) 13.4, 9.6),

9122 J . Org. Chem., Vol. 61, No. 26, 1996
Stoermer et al.
purification by HPLC (1:30 Et2O/hexanes) as a clear, colorless
d ioxa bicyclo[3.2.1]octa n e-3,4,5-tr ica r boxylic Acid 3,4,5-
Tr is(1,1-d im eth yleth yl) Ester (16b). To a solution of 4 (23.0
mg, 32.5 mmol) in N,N-dimethylformamide (0.3 mL) at rt were
added imidazole (49 mg, 0.72 mmol) and tert-butyldimethylsilyl
chloride (54 mg, 0.36 mmol). The solution was stirred for 6 h,
diluted with EtOAc (15 mL), and washed with saturated
aqueous NH4Cl (5 mL), saturated aqueous NaHCO3 (5 mL),
water (5 mL), and brine (5 mL). The organic phase was dried
over MgSO4, filtered, and evaporated in vacuo. The crude
product was subjected to flash chromatography on SiO2 (1:5
EtOAc/hexanes) to provide 16a (20.9 mg, 78%), recovered 4
(2.4 mg, 10%), and 16b (0.8 mg, 3%).
liquid. TLC: Rf 0.23 (1:20 EtOAc/hexanes). [R]D: +53.2 (c
1.48, CH2Cl2). IR (CH2Cl2): 1716, 1656 cm-1 1H NMR (400
.
MHz): δ 0.83-0.87 (m, 6), 1.03 (d, 3, J ) 6.7), 1.09-1.14 (m,
2), 1.26-1.40 (m, 3), 2.41 (m, 1), 3.73 (s, 3), 5.79 (d, 1, J )
15.7), 6.82 (dd, 1, J ) 15.7, 8.5). 13C NMR (100 MHz): δ 11.11,
18.79, 20.34, 29.80, 31.86, 34.26, 43.36, 51.33, 119.18, 155.01,
167.30. Anal. Calcd for C11H20O2: C, 71.69; H, 10.94.
Found: C, 71.63; H, 10.88. The NMR data agrees with that
published by Nicolaou et. al.6f
(2E,4S,6S)-4,6-Dim eth yl-2-octen oic Acid (14). A mix-
ture of methyl ester 13 (228.0 mg, 1.237 mmol), lithium
hydroxide monohydrate (58.0 mg, 1.38 mmol), THF (0.9 mL),
and water (0.3 mL) was stirred for 22 h at rt. Additional
lithium hydroxide monohydrate (103.8 mg, 2.47 mmol) was
added, and stirring was continued for 2 d. The mixture was
added to water (10 mL) and washed with Et2O (20 mL). The
organic layer was extracted with saturated aqueous NaHCO3
(5 mL). The aqueous layers were combined and acidified with
6 M HCl and extracted with Et2O (3 × 25 mL). The combined
organic layers were washed with H2O (20 mL) and brine (20
mL), dried over MgSO4, filtered, and concentrated in vacuo.
The crude acid was purifed by flash chromatography on silver
Ma jor P r od u ct 16a . White solid, mp 164-164.5 °C.
TLC: Rf 0.29 (1:3 EtOAc/hexanes). [R]D: -0.9 (c 0.34, CH2-
Cl2). IR (CH2Cl2): 3550, 3450, 1740 cm-1
.
1H NMR (500
MHz): δ 0.12 (s, 3), 0.19 (s, 3), 0.83 (d, 3, J ) 6.8), 0.92 (s, 9),
1.44 (s, 9), 1.47 (s, 9), 1.61 (s, 9), 1.97-2.25 (m, 5), 2.10 (s, 3),
2.39 (dd, 1, J ) 13.4, 8.9), 2.43-2.51 (m, 1), 2.69 (dd, 1, J )
13.4, 5.7), 3.98-4.00 (m, 2), 4.90 (s, 1), 4.96 (s, 1), 5.00 (s, 1),
5.01 (d, 1, J ) 1.3), 5.08 (d, 1, J ) 4.8), 7.12-7.28 (m, 5). 13C
NMR (100 MHz): δ -4.65, -4.38, 13.71, 17.98, 21.04, 25.82,
28.06, 28.12, 28.19, 33.65, 36.70, 40.03, 74.51, 75.57, 78.77,
79.33, 82.96, 83.00, 84.55, 84.82, 91.98, 104.54, 111.33, 125.96,
128.32, 129.08, 140.33, 145.79, 164.97, 166.10, 168.98, 170.30.
Anal. Calcd for C43H68O13Si: C, 62.90; H, 8.35. Found: C,
62.94; H, 8.56.
34
impregnated SiO2 (gradient elution, 1:20 to 1:7 Et2O/pen-
tane). The product was isolated as a clear, colorless liquid
(200.1 mg, 95%). [R]D: +58.2 (c 0.067, CHCl3). IR (neat):
3414-3278 (br), 1697, 1650 cm-1
.
1H NMR (400 MHz): δ
Min or P r od u ct 16a . Colorless oil. TLC: Rf 0.19 (1:3
EtOAc/hexanes). [R]D: +9.4 (c 1.45, CH2Cl2). IR (thin film):
0.85-0.88 (m, 6), 1.05 (d, 3, J ) 6.7), 1.11-1.17 (m, 2), 1.22-
1.43 (m, 3), 2.42-2.49 (m, 1), 5.80 (dd, 1, J ) 15.6, 0.8), 6.94
(dd, 1, J ) 15.6, 8.4). 13C NMR (100 MHz): δ 11.14, 18.86,
20.20, 29.79, 31.93, 34.40, 43.29, 119.00, 157.64, 172.26. These
data are in excellent agreement with those published for the
acid side chain obtained from the natural product.1b
3463 (br), 1737 cm-1 1H NMR (500 MHz): δ 0.11 (s, 3), 0.17
.
(s, 3), 0.80 (d, 3, J ) 6.7), 0.91 (s, 9), 1.44 (s, 9), 1.49 (s, 9),
1.58 (s, 9), 1.93-2.17 (m, 3), 2.09 (s, 3), 2.26-2.43 (m, 3), 2.43
(d, 1, J ) 5.1), 2.72 (dd, 1, J ) 13.3, 5.0), 3.91 (s, 1), 4.00 (d, 1,
J ) 1.9), 4.90 (s, 1), 4.90 (dd, 1, J ) 5.2, 1.9), 4.98 (s, 1), 4.99
(s, 1), 5.13 (d, 1, J ) 5.4), 7.12-7.27 (m, 5). 13C NMR (100
MHz): δ -5.23, -4.65, 13.77, 17.81, 21.09, 25.18, 25.65, 27.99,
28.05, 28.20, 33.83, 36.64, 39.93, 74.36, 74.88, 79.18, 79.72,
82.68, 82.82, 84.08, 84.60, 91.12, 104.70, 111.61, 125.91,
128.26, 129.15, 140.36, 145.84, 166.08, 166.62, 168.69, 170.13.
Anal. Calcd for C43H68O13Si: C, 62.90; H, 8.35. Found: C,
63.21; H, 8.52.
[1S-[1r(4S,5R),3r,4â,5r,6r,7â(2E,4S,6S)]]-1-[4-Acetyloxy-
5-m eth yl-3-m eth ylen e-6-p h en ylh exyl]-7-(4,6-d im eth yl-2-
octen oyl)-4,6,7-tr ih yd r oxy-2,8-d ioxa bicyclo[3.2.1]octa n e-
3,4,5-tr icar boxylic Acid 3,4,5-Tr is(1,1-dim eth yleth yl) Ester
(15). Triol 4 (18.2 mg, 25.7 µmol) and acid 14 (4.4 mg, 25.7
µmol) were dissolved in CH2Cl2 (0.1 mL) containing 4-di-
methylaminopyridine (DMAP, 0.094 mg, 0.77 µmol). The
solution was cooled to 0 °C, and 1,3-dicyclohexylcarbodiimide
(DCC, 7.1 mg, 34 µmol) was added. The reaction mixture was
allowed to warm to rt and was stirred for 12 h. The CH2Cl2
was evaporated under a flow of N2. The resulting residue was
diluted with 1:5 EtOAc/hexanes and filtered through a plug
of Celite. The filtrate was concentrated in vacuo. Purification
by flash chromatography on SiO2 (gradient elution, 1:5 to 2:3
EtOAc/hexanes) provided a 5.6:1 mixture of 15 and 3 (12.7
mg, 58%) in addition to the C6-OH and C7-OH diacylated
derivative of 4 (1.2 mg, 4%) and recovered 4 (7.0 mg, 38%).
The major product 15 was further purified for characterization
using HPLC and was isolated as a colorless oil. TLC: Rf 0.14
(1:3 EtOAc/hexanes). [R]D: +23.0 (c 0.94, CH2Cl2). IR (thin
[1R,3R,8S-(1r,2r,5r,10r,11â)]-5-Meth oxy-2,11-dih ydr oxy-
4,9,12-t r ioxa t r icyclo[6.3.1.03,8]d od eca n e-1,10,11-t r ica r -
boxylic Acid 1,10,11-Tr is(1,1-d im eth yleth yl) Ester (17a )
a n d [1R,3R,8S-(1r,2r,5â,10r,11â)]-5-Meth oxy-2,11-d ih y-
d r oxy-4,9,12-tr ioxa tr icyclo[6.3.1.03,8]d od eca n e-1,10,11-tr i-
ca r b oxylic Acid 1,10,11 Tr is(1,1-d im et h ylet h yl) E st er
(17b). Benzene (8 mL) was heated at reflux for 1 h in a 25-
mL flask equipped with a small Soxhlet extractor filled with
activated 4 Å molecular sieves. Dimethyl acetal 2 (20.5 mg,
0.036 mmol) was added to the flask, and the solution was
heated at reflux for 30 min to remove any trace amount of
H2O. Anhydrous pyridinium p-toluenesulfonate (ca. 4 mg,
0.016 mmol) was added to the hot solution, which was then
heated at reflux for 7 min. After the solution had cooled
slightly, triethylamine (1 mL) was added and the reaction was
allowed to cool to rt. Ethyl acetate (15 mL) was added, and
the solution was washed with saturated aqueous NH4Cl (3 ×
10 mL), water (10 mL), and brine (10 mL). The aqueous layers
were back-extracted with EtOAc (20 mL). The organic phases
were combined, dried over MgSO4, filtered, and concentrated
in vacuo. After purification by flash chromatography on SiO2
(gradient elution, 1:5 to 1:1 EtOAc/hexanes), a 6:1 mixture of
diastereomers 17a and 17b (19.2 mg, 99%) was isolated as a
white foam. Anal. Calcd for C25H40O12: C, 56.38; H, 7.57.
Found: C, 56.37; H, 7.86. The diastereomers were separated
by HPLC for full characterization.
film): 3469 (br), 1761, 1728, 1648 cm-1 1H NMR (500 MHz):
.
δ 0.81 (d, 3, J ) 6.7), 0.84-0.87 (m, 6), 1.05 (d, 3, J ) 6.7),
1.08-1.19 (m, 2), 1.25-1.44 (m, 3), 1.46 (s, 9), 1.50 (s, 9), 1.56
(s, 9), 2.09 (s, 3), 2.05-2.18 (m, 3), 2.31-2.47 (m, 4), 2.71 (dd,
1, J ) 13.4, 5.3), 2.90 (d, 1, J ) 3.5), 3.97 (s, 1), 4.74 (s, 1),
4.84 (d, 1, J ) 2.0), 4.97 (s, 2), 5.09-5.12 (m, 2), 5.89 (d, 1, J
) 15.7), 6.94 (dd, 1, J ) 15.7, 8.4), 7.13-7.29 (m, 5). 13C NMR
(100 MHz): δ 11.14, 13.68, 18.91, 20.13, 21.05, 25.40, 27.99,
28.06, 28.09, 29.71, 31.94, 33.94, 34.43, 36.63, 40.02, 43.25,
74.05, 75.43, 76.84, 79.21, 83.32, 83.68, 83.89, 85.08, 90.90,
104.06, 111.41, 118.07, 125.93, 128.27, 129.14, 140.39, 145.57,
157.65, 165.07, 165.83, 166.93, 168.48, 170.16. Anal. Calcd
for C47H70O14: C, 65.71; H, 8.21. Found: C, 65.47; H, 8.28.
[1S-[1r(4S,5R),3r,4â,5r,6r,7â]]-1-[4-(Acetyloxy)-5-m eth -
yl-3-m eth ylen e-6 p h en ylh exyl]-6-[d im eth yl(1,1-d im eth -
ylet h yl)silyl]-4,6,7-t r ih yd r oxy-2,8-d ioxa b icyclo[3.2.1]-
octa n e-3,4,5-tr ica r boxylic Acid 3,4,5-Tr is(1,1-d im eth yl-
eth yl) Ester (16a ) a n d [1S-[1r(4S,5R),3r,4â,5r,6r,7â]]-1-
[4-(Acetyloxy)-5-m eth yl-3-m eth ylen e-6 p h en ylh exyl]-7-
[d im et h yl(1,1-d im et h ylet h yl)silyl]-4,6,7-t r ih yd r oxy-2,8-
Ma jor Dia ster eom er 17a . White solid, mp 137-139 °C.
TLC: Rf 0.37 (1:1 EtOAc/hexanes). [R]D: +57.7 (c 1.19, CH2-
Cl2). IR (CH2Cl2): 3570, 3455, 1755, 1726 cm-1 1H NMR (500
.
MHz): δ 1.44 (s, 9), 1.50 (s, 9), 1.59 (s, 9), 1.76-1.79 (m, 1),
2.09-2.22 (m, 3), 2.58 (d, 1, J ) 3.4), 3.40 (s, 3), 3.94 (s, 1),
4.06 (d, 1, J ) 5.2), 4.66 (s, 1), 4.80 (d, 1, J ) 3.0), 5.18 (dd, 1,
J ) 5.1, 3.5). 13C NMR (100 MHz): δ 27.29, 27.97, 28.09,
28.20, 29.53, 54.83, 72.43, 74.45, 74.76, 78.86, 83.13, 84.56,
85.04, 91.44, 99.82, 100.06, 165.71, 166.53, 168.36.
(34) Morris, L. J . Chem. Ind. 1962, 1238.
Min or Dia ster eom er 17b. White solid, mp 151-152 °C

Total Synthesis of Zaragozic Acid A
J . Org. Chem., Vol. 61, No. 26, 1996 9123
.
1651 cm-1 1H NMR (500 MHz): δ 0.82-0.85 (m, 6), 1.02 (d,
dec. TLC: Rf 0.29 (1:1 EtOAc/hexanes). [R]D: -29.7 (c 0.64,
CH2Cl2). IR (CH2Cl2): 3582, 3455, 1756, 1725 cm-1
.
1H NMR
3, J ) 6.7), 1.08-1.14 (m, 2), 1.23-1.38 (m, 3), 1.45 (s, 9), 1.46
(s, 9), 1.59 (s, 9), 2.20-2.25 (m, 1), 2.32-2.38 (m, 1), 2.38-
2.43 (m, 1), 2.76-2.81 (m, 1), 2.90-2.95 (m, 1), 3.10 (d, 1, J )
3.1), 4.06-4.07 (m, 2), 5.05 (s, 1), 5.74 (dd, 1, J ) 15.7, 0.9),
6.01 (d, 1, J ) 2.0), 6.88 (dd, 1, J ) 15.7, 8.5), 9.83 (t, 1, J )
1.1). 13C NMR (100 MHz): δ 11.09, 18.81, 20.22, 27.99, 28.01,
28.15, 28.87, 29.70, 31.84, 34.50, 37.83, 43.17, 74.09, 75.33,
80.66, 82.62, 83.33, 84.04, 85.89, 88.92, 103.84, 118.17, 157.45,
163.85, 165.57, 166.57, 168.64, 202.16. Anal. Calcd for
C34H54O13: C, 60.88; H, 8.11. Found: C, 60.83; H, 8.11.
[1S-(1r,3r,4â,5r,6r(2E,4S,6S),7â)]-1-(3-Oxop r op yl)-6-
(4,6-dim eth yl-2-octen oyl)-7-(tr ieth ylsilyl)-4,6,7-tr ih ydr oxy-
2,8-dioxabicyclo[3.2.1]octan e-3,4,5-tr icar boxylic Acid 3,4,5-
Tr is(1,1-d im eth yleth yl) Ester (20). Aldehyde 19 (48.2 mg,
71.9 µmol) was dissolved in pyridine (2.50 mL). The solution
was cooled to 0 °C, and a solution of triethylsilyl chloride (0.40
mL, 2.4 mmol) in pyridine (2.0 mL) was added over 5 min.
The ice bath was removed, and the solution was stirred at rt
for 22 h, diluted with Et2O (30 mL), and washed with 0.5 M
HCl (2 × 30 mL), saturated aqueous NaHCO3 (20 mL), water
(20 mL), and brine (20 mL). The aqueous layers were back-
extracted with Et2O (30 mL). The combined organic layers
were dried over MgSO4, filtered, and evaporated. The crude
product was purified by flash chromatography on SiO2 (gradi-
ent elution, 1:7 to 1:5 EtOAc/hexanes) to yield 20 (46.3 mg,
82%). TLC: Rf 0.49 (2:3 EtOAc/hexanes). [R]D: +33.0 (c 3.58,
(500 MHz): δ 1.42 (s, 9), 1.49 (s, 9), 1.57 (s, 9), 1.82-1.91 (m,
2), 1.96-2.04 (m, 1), 2.30-2.33 (m, 1), 2.66 (d, 1, J ) 3.1), 3.58
(s, 3), 3.66 (d, 1, J ) 5.1), 3.95 (s, 1), 4.62 (dd, 1, J ) 9.2, 2.6),
4.75 (s, 1), 5.22 (dd, 1, J ) 5.1, 3.1). 13C NMR (100 MHz): δ
27.98, 28.07, 28.19, 28.27, 30.94, 57.29, 72.13, 74.19, 74.77,
83.02, 84.70, 85.04, 85.20, 92.20, 99.44, 105.70, 165.48, 166.55,
168.37.
[1R,3R,8S-(1r,2r(2E,4S,6S),5r,10r,11â)]-2-(4,6-Dim eth yl-
2 -o c t e n o y l )-5 -m e t h o x y -2 ,1 1 -d i h y d r o x y -4 ,9 ,1 2 -t r i -
oxa tr icyclo[6.3.1.03,8]d od eca n e-1,10,11-tr ica r boxylic Acid
1,10,11-Tr is(1,1-dim eth yleth yl) Ester (18a) an d [1R,3R,8S-
(1r,2r(2E,4S,6S),5â,10r,11â)]-2-(4,6-Dim eth yl-2-octen oyl)-
5-m eth oxy-2,11-d ih yd r oxy-4,9,12-tr ioxa tr icyclo[6.3.1.03,8]-
d od eca n e-1,10,11-t r ica r b oxylic Acid 1,10,11-Tr is(1,1-
d im eth yleth yl) Ester (18b). Acid 14 (28.5 mg, 167 µmol),
17a ,b (50.9 mg, 95.6 µmol), and 10 µL of a 0.286 M solution of
DMAP in CH2Cl2 (2.86 µmol) were combined, concentrated
three times from benzene, and diluted with CH2Cl2 (0.25 mL).
The solution was cooled to 0 °C, and DCC (35.5 mg, 172 µmol)
was added. The resulting cloudy white mixture was stirred
at 0 °C for 2 h and at rt for 12 h. Additional 14 (16.7 mg, 98.1
µmol) and DCC (20.8 mg, 101 µmol) were added, and stirring
was continued for another 12 h. The solvent was evaporated
under a flow of N2, and the residue was diluted with 1:7 EtOAc/
hexanes and filtered through a plug of Celite. The filtrate (15
mL) was washed with saturated aqueous NaHCO3 (5 mL),
saturated aqueous NH4Cl (5 mL), water (5 mL), and brine (5
mL), dried over MgSO4, filtered, and concentrated. The
product was purified by flash chromatography on SiO2 (gradi-
ent elution, 1:7 to 1:5 EtOAc/hexanes), and the product 18a ,b
(63.0 mg, 96%) was isolated as a clear, colorless oil. IR (CH2-
CH2Cl2). IR (thin film): 3459, 1762, 1730 cm-1 1H NMR (400
.
MHz): δ 0.60 (q, 6, J ) 7.9), 0.81-0.84 (m, 6), 0.93 (t, 9, J )
7.9), 1.00 (d, 3, J ) 6.7), 1.07-1.13 (m, 2), 1.24-1.35 (m, 3),
1.38 (s, 9), 1.45 (s, 9), 1.64 (s, 9), 2.07 (m, 1), 2.30 (m, 1), 2.39
(m, 1), 2.80 (m, 1), 2.98 (m, 1), 4.06 (s, 1), 4.11 (d, 1, J ) 1.4),
5.07 (s, 1), 5.75 (d, 1, J ) 15.7), 6.35 (d, 1, J ) 1.2), 6.89 (dd,
1, J ) 15.7, 8.4), 9.87 (s, 1). 13C NMR (100 MHz): δ 4.59 (2),
6.57 (3), 11.11 (3), 18.74 (3), 20.15 (3), 27.95 (3), 28.05 (3), 28.75
(2), 29.72 (2), 31.87 (1), 34.39 (1), 37.99 (2), 43.23 (2), 73.92
(0), 75.12 (1), 78.50 (1), 83.02 (1), 83.14 (0), 84.07 (0), 86.07
(0), 89.91 (0), 103.71 (0), 118.58 (1), 156.65 (1), 163.93 (0),
164.49 (0), 165.96 (0), 168.98 (0), 202.15 (1). Anal. Calcd for
C40H68O13Si: C, 61.20; H, 8.73. Found: C, 61.48; H, 8.84.
(1R,2R)-1-[[(p-Meth oxyben zyl)oxy]m eth oxy]-2-m eth yl-
3-ph en yl-1-(tr i-n -bu tylstan n yl)pr opan e (23a) an d (1S,2R)-
1-[[(p-Meth oxyben zyl)oxy]m eth oxy]-2-m eth yl-3-p h en yl-
1-(tr i-n -bu tylsta n n yl)p r op a n e (23b). Dimethyl sulfoxide
(0.28 mL, 3.95 mmol) was added slowly to a solution of oxalyl
chloride (0.19 mL, 2.18 mmol) in CH2Cl2 (6 mL) at -78 °C.
The solution was stirred for 15 min at -78 °C. Alcohol 2113
(250.0 mg, 1.66 mmol) in CH2Cl2 (1 mL) was added, followed
by two CH2Cl2 rinses (1 mL and 0.5 mL) via cannula over 10
min. The cloudy white reaction mixture was stirred for 1 h,
and triethylamine (1.16 mL, 8.32 mmol) was added. The
resulting thick white mixture was stirred for 1.5 h at -78 °C
and then poured while still cold into 10% NaHSO4 (7 mL). The
mixture was immediately extracted with 20% Et2O in hexanes
(20 mL). The organic phase was washed with saturated
aqueous NaHCO3 (7 mL), water (7 mL), and brine (7 mL), dried
over MgSO4, filtered, and concentrated in vacuo to afford a
yellow liquid (0.260 g). The crude aldehyde was concentrated
twice from benzene (3 mL) and used directly in the next step.
To a solution of diisopropylamine (262 µL, 2.00 mmol) in
THF (5 mL) at 0 °C was added n-BuLi in hexanes (0.88 mL,
1.83 mmol) over 3 min. The solution was stirred for 30 min,
and tributylstannane (0.54 mL, 2.00 mmol) was added. The
solution was stirred for 30 min and then cooled to -78 °C,
and the aldehyde was added in THF (1 mL, followed by 2 × 1
mL rinses) via cannula over 10 min. After 45 min, the reaction
was quenched with 5% NH4Cl solution (3 mL) and allowed to
warm up. The cold mixture was extracted with Et2O (2 × 8
mL). The combined organic extracts were washed with water
(2 × 6 mL), dried over Na2SO4, filtered, and concentrated. The
crude hydroxy stannane 22 was diluted with CH2Cl2, filtered
through a plug of cotton to remove the small amount of water
still present, and then concentrated again and taken directly
onto the next step.
Cl2): 3450, 1762, 1737, 1733, 1652 cm-1
. Anal. Calcd for
C35H56O13: C, 61.38; H, 8.24. Found: C, 61.62; H, 8.30. The
diastereomers were separated by flash chromatography for
further characterization.
Ma jor Dia ster eom er 18a . White foam. TLC: Rf 0.46 (2:3
EtOAc/hexanes). [R]D: +80.5 (c 0.84, CH2Cl2). 1H NMR (500
MHz): δ 0.81-0.84 (m, 6), 1.02 (d, 3, J ) 6.7), 1.08-1.13 (m,
2), 1.24-1.39 (m, 3), 1.45 (s, 9), 1.47 (s, 9), 1.60 (s, 9), 1.75-
1.78 (m, 1), 2.13-2.25 (m, 3), 2.37-2.42 (m, 1), 3.27 (s, 3), 4.12
(s, 1), 4.15 (d, 1, J ) 4.8), 4.76 (s, 1), 4.82 (d, 1, J ) 3.1), 5.74
(dd, 1, J ) 15.7, 0.9), 6.40 (d, 1, J ) 4.8), 6.87 (dd, 1, J ) 15.7,
8.3). 13C NMR (100 MHz): δ 11.11, 18.87, 20.16, 27.24, 27.99,
28.06, 28.08, 29.68, 29.78, 31.87, 34.38, 43.23, 54.61, 72.66,
74.43, 74.64, 78.70, 83.26, 83.86, 86.02, 90.22, 99.84, 100.14,
118.52, 156.35, 163.98, 164.76, 165.58, 168.71.
Min or Dia ster eom er 18b. White foam. TLC: Rf 0.38 (2:3
EtOAc/hexanes). [R]D: +30.6 (c 0.51, CH2Cl2). 1H NMR (500
MHz): δ 0.83-0.86 (m, 6), 1.02 (d, 3, J ) 6.7), 1.08-1.16 (m,
2), 1.25-1.39 (m, 3), 1.43 (s, 9), 1.44 (s, 9), 1.62 (s, 9), 1.83-
1.87 (m, 1), 1.90-1.96 (m, 1), 2.00-2.06 (m, 1), 1.34-2.43 (m,
2), 3.57 (s, 3), 3.77 (d, 1, J ) 4.6), 4.14 (s, 1), 4.60 (dd, 1, J )
9.8, 2.7), 4.87 (s, 1), 5.74 (dd, 1, J ) 15.7, 1.0), 6.51 (d, 1, J )
4.6), 6.89 (dd, 1, J ) 15.7, 8.2). 13C NMR (100 MHz): δ 11.07,
18.86, 20.14, 27.98, 28.00, 28.07, 28.30, 29.65, 31.10, 31.78,
34.32, 43.23, 57.26, 71.71, 74.22, 74.62, 83.14, 84.12, 84.77,
86.33, 91.45, 99.35, 105.78, 118.67, 156.38, 163.78, 164.39,
165.52, 168.78.
[1S-(1r,3r,4â,5r,6r(2E,4S,6S),7â)]-1-(3-Oxop r op yl)-6-
(4,6-d im e t h yl-2-oct e n oyl)-4,6,7-t r ih yd r oxy-2,8-d ioxa -
bicyclo[3.2.1]octa n e-3,4,5-tr ica r boxylic Acid 3,4,5-Tr is-
(1,1-d im eth yleth yl) Ester (19). The combined diastereomers
18a ,b (36.3 mg, 53.0 µmol) were dissolved in acetone (1 mL).
To the solution were added 1 drop of water from a Pasteur
pipet and pyridinium p-toluenesulfonate (14 mg, 56 µmol). The
solution was heated at 50 °C for 7 h, cooled to rt, poured into
saturated aqueous NaHCO3 (5 mL), and extracted with EtOAc
(3 × 15 mL). The combined organic layers were washed with
saturated aqueous NH4Cl (10 mL), water (10 mL), and brine
(10 mL), dried over MgSO4, filtered, and concentrated. The
crude product was subjected to flash chromatography on SiO2
(1:4 EtOAc/hexanes). Aldehyde 19 was isolated as a white
foam (33.3 mg, 97%). TLC: Rf 0.19 (2:3 EtOAc/hexanes). [R]D:
+15.5 (c 1.4, CH2Cl2). IR (thin film): 3459 (br), 1755, 1732,
Hydroxy stannane 22 was dissolved in CH2Cl2 (2.8 mL) and
cooled to 0 °C. Diisopropylethylamine (1.16 mL, 6.66 mmol)

9124 J . Org. Chem., Vol. 61, No. 26, 1996
Stoermer et al.
and p-methoxybenzyl chloromethyl ether24 (0.932 g, 4.99 mmol,
slightly contaminated with p-methoxybenzyl chloride) were
added. The reaction mixture was stirred at 0 °C for 2 d, during
which time additional diisopropylethylamine and p-methoxy-
benzyl chloromethyl ether were added until the hydroxy
stannane was no longer visible by TLC analysis of the reaction.
The solution was diluted with 20% Et2O in hexanes (20 mL),
washed with 0.5 M HCl solution (10 mL), water (2 × 10 mL),
and brine (10 mL), then dried over MgSO4, filtered, and
concentrated. Purification of the product was accomplished
by first performing flash chromatography on SiO2 (1:90 EtOAc/
hexanes). The isolated product was contaminated with p-
methoxybenzyl chloride, which was subsequently removed by
heating the product at 50 °C under high vacuum. The two
diastereomers were separated by HPLC (1% EtOAc in hex-
anes) to afford 23a (321.0 mg, 32%) and 23b (269.3 mg, 28%)
as colorless liquids. Anal. Calcd for C31H50O3Sn: C, 62.20;
H, 8.55. Found: C, 62.34; H, 8.70.
1, J ) 11.5), 4.68 (d, 1, J ) 11.6), 4.75 (d, 1, J ) 6.8), 4.95 (d,
1, J ) 6.7), 5.08 (s, 1), 5.76 (dd, 1, J ) 15.7, 1.0), 6.34 (d, 1, J
) 1.8), 6.86-6.92 (m, 3), 7.13-7.31 (m, 7).
To alcohol 24a ,b (11.6 mg, 10.7 µmol) was added a hetero-
geneous mixture of Dess-Martin periodinane29 (22.6 mg, 53.4
µmol) and pyridine (21.6 µL, 268 µmol) in CH2Cl2 (0.9 mL).
The mixture was stirred for 40 min at rt. A solution of 1:1
saturated aqueous NaHCO3 and saturated aqueous Na2S2O3
(4 mL) was added, and the mixture was stirred for 5 min,
diluted with Et2O (15 mL), and washed with saturated aqueous
NaHCO3 (2 × 5 mL) and brine (5 mL). The organic layer was
dried over MgSO4, filtered, and concentrated. Ketone 25 was
isolated after flash chromatography on SiO2 (gradient elution,
1:7 to 1:5 EtOAc/hexanes) as a colorless oil (10.7 mg, 92%).
TLC: Rf 0.51 (1:2 EtOAc/hexanes). [R]D: +22.0 (c 0.75,
CH2Cl2). IR (thin film): 3481 (br), 1759, 1727 cm-1 1H NMR
.
(500 MHz): δ 0.60 (q, 6, J ) 7.9), 0.81-0.84 (m, 9), 0.92 (t, 9,
J ) 7.9), 1.00 (d, 3, J ) 6.7), 1.07-1.14 (m, 2), 1.24-1.38 (m,
3), 1.38 (s, 9), 1.42 (s, 9), 1.65 (s, 9), 1.99 (m, 1), 2.25 (m, 1),
2.35-2.44 (m, 2), 2.58 (dd, 1, J ) 13.5, 9.1), 2.84 (dd, 1, J )
13.5, 5.7), 2.90 (ddd, 1, J ) 18.4, 10.9, 5.2), 3.03 (ddd, 1, J )
18.5, 10.4, 4.5), 3.79 (s, 3), 4.09-4.10 (m, 2), 4.19 (d, 1, J )
3.3), 4.57 (d, 1, J ) 11.6), 4.66 (d, 1, J ) 11.6), 4.71 (d, 1, J )
7.0), 4.78 (d, 1, J ) 7.0), 5.07 (s, 1), 5.76 (dd, 1, J ) 15.7, 1.0),
6.36 (d, 1, J ) 1.8), 6.86-6.92 (m, 3), 7.17-7.21 (m, 3), 7.25-
7.28 (m, 4).
23a : TLC: Rf 0.17 (1:20 EtOAc/hexanes). IR (neat): 1613,
1514, 1248, 1031 cm-1 1H NMR (500 MHz): δ 0.87 (d, 3, J )
.
6.6), 0.90 (t, 9, J ) 7.3), 0.91-0.95 (m, 6), 1.31 (m, 6, J ) 7.2),
1.48-1.54 (m, 6), 2.25 (m, 1), 2.32 (dd, 1, J ) 12.8, 9.8), 3.02
(dd, 1, J ) 12.8, 4.4), 3.81 (s, 3), 4.16 (m, 1), 4.53 (d, 1, J )
11.5), 4.61 (d, 1, J ) 11.5), 4.68 (d, 1, J ) 6.6), 4.76 (d, 1, J )
6.6), 6.87 (m, 2), 7.14-7.19 (m, 3), 7.5-7.28 (m, 4). 13C NMR
(100 MHz): δ 10.07, 13.67, 16.85, 27.53 (3J (119Sn-13C) ) 28
Hz), 29.22 (3J (119Sn-13C) ) 10 Hz), 40.46, 41.86, 55.25, 69.29,
80.50, 94.79, 113.77, 125.67, 128.18, 129.11, 129.37, 130.08,
141.53, 159.17.
13C NMR (100 MHz): δ 4.59, 6.59, 11.11, 13.62,
18.74, 20.17, 27.97, 28.05, 29.69, 29.73, 31.88, 33.51, 34.39,
37.49, 40.08, 43.25, 55.23, 69.69, 73.99, 75.10, 78.43, 82.87,
83.26, 83.98, 85.23, 85.96, 90.00, 94.54, 103.81, 113.76, 118.66,
126.02, 128.32, 129.25, 129.44, 129.95, 140.23, 156.56, 159.14,
164.02, 164.54, 166.01, 169.01, 210.58. Anal. Calcd for
C59H90O16Si: C, 65.40; H, 8.37. Found: C, 65.14; H, 8.39.
[1S-[1r(4S,5R),3r,4â,5r,6r(2E,4S,6S),7â]]-1-[4-[[(p-Meth -
o x y b e n z y l)o x y ]m e t h o x y ]-5-m e t h y l-3-m e t h y le n e -6-
ph en ylh exyl]-6-(4,6-dim eth yl-2-octen oyl)-7-(tr ieth ylsilyl)-
4,6,7-t r ih yd r oxy-2,8-d ioxa b icyclo[3.2.1]oct a n e -3,4,5-
t r ica r b oxylic Acid 3,4,5-Tr is(1,1-d im et h ylet h yl) E st er
(26). A. F r om 25. Tebbe reagent was prepared following
the procedure of Pine et al.32 and added dropwise to a stirred
solution of ketone 25 (7.5 mg, 6.9 µmol) in THF (0.8 mL) at 0
°C over 4.5 h. The reaction was monitored carefully by TLC
and stopped when overmethylenated product was observed.
Approximately 0.5 mL of 0.1 M NaOH was added slowly, and
23b: TLC: Rf 0.17 (1:20 EtOAc/hexanes). IR (neat): 1613,
1514, 1248, 1031 cm-1 1H NMR (400 MHz): δ 0.89-0.99 (m,
.
18), 1.34 (m, 6, J ) 7.4), 1.50-1.61 (m, 6), 2.30-2.37 (m, 2),
2.79 (d, 1, J ) 8.7), 3.81 (s, 3), 4.16 (d, 1, J ) 4.6), 4.50 (d, 1,
J ) 11.4), 4.59 (d, 1, J ) 11.4), 4.66 (d, 1, J ) 6.7), 4.74 (d, 1,
J ) 6.7), 6.88 (d, 2, J ) 8.7), 7.16-7.31 (m, 7). 13C NMR (100
MHz): δ 10.10, 13.67, 18.22, 27.55 (3J (119Sn-13C) ) 29 Hz),
29.25 (3J (119Sn-13C) ) 10 Hz), 40.06, 40.69, 55.25, 69.27, 81.40,
94.62, 113.76, 125.77, 128.22, 128.99, 129.41, 130.07, 141.14,
159.17.
[1S-[1r(4S,5R),3r,4â,5r,6r(2E,4S,6S),7â]]-1-[4-[[(p-Meth -
oxyben zyl)oxy]m eth oxy]-5-m eth yl-3-oxo-6-p h en ylh exyl]-
6-(4,6-d im et h yl-2-oct en oyl)-7-(t r iet h ylsilyl)-4,6,7-t r ih y-
d r oxy-2,8-d ioxa b icyclo[3.2.1]oct a n e-3,4,5-t r ica r b oxylic
Acid 3,4,5-Tr is(1,1-d im eth yleth yl) Ester (25). The reaction
was carried out in a flask shaped like an inverted “Y” with
the mixture was stirred for 10 min and added to H2
O (5 mL).
The mixture was extracted with Et2O (2 × 15 mL). The
organic layer was washed with brine and dried over MgSO4.
After extensive purification by flash chromatography on SiO2
(gradient elution, 1:9 to 1:5 EtOAc/hexanes), 26 was isolated
as a colorless oil (5.8 mg, 77%). In addition, 1.1 mg (15%) of
26
the volume of each arm approximately 0.8 mL. Dry CeCl3
(35.0 mg, 142 µmol) was added to one arm of the flask, and
organostannane 23a (36.3 mg, 61.6 µmol) was added to the
other. THF (0.2 mL) was added to the CeCl3, and the white
slurry was stirred for 5 h at rt, during which time additional
THF was added to keep the volume at 0.2-0.3 mL. THF (0.3
mL) was added to 23a to yield a clear, colorless solution. The
flask was cooled to -78 °C. A solution of n-BuLi in hexanes
(21 µL, 51 µmol) was added to the solution of 23a , and after
being stirred for 5 min, the resulting yellow solution was added
to the CeCl3 slurry by quickly tipping the flask. After 0.5 min,
a 0.124 M solution of aldehyde 20 in THF (100 µL, 12.4 µmol)
was added to the organocerium reagent. The reaction mixture
was stirred for 5 min and then the reaction quenched with
saturated aqueous NH4Cl (3 mL) and the mixture warmed to
rt. The mixture was diluted with EtOAc (15 mL) and washed
with 0.5 M HCl (7 mL), saturated aqueous NaHCO3 (7 mL),
water (7 mL), and brine (7 mL). The aqueous layers were
back-extracted with EtOAc (15 mL). The combined organic
phases were dried over MgSO4, filtered, evaporated in vacuo,
and purified by flash chromatography on SiO2 (gradient elution
1:7 to 1:3 EtOAc/hexanes) to provide a 15:1 mixture of alcohols
24a ,b (11.6 mg, 87%). TLC (24a ,b): Rf 0.43 (2:3 EtOAc/
hexanes).
1
25 was recovered. The optical rotation and H NMR spectrum
were identical to those obtained for 26 when synthesized from
27.
B. F r om 27. N,N-Diisopropylethylamine (0.15 mL, 0.86
mmol) and p-methoxybenzyl chloromethyl ether24 (6 drops
from a disposable Pasteur pipet, ca. 75 mg, 0.402 mmol) were
added to a solution of alcohol 27 (61.3 mg, 65.8 µmol) in
CH2Cl2 (0.3 mL) at 0 °C. The reaction mixture was stirred at
rt for 36 h. During this time additional N,N-diisopropylethyl-
amine and p-methoxybenzyl chloromethyl ether were added
to drive the reaction to completion. The yellow solution was
diluted with EtOAc (20 mL) and washed with 10% aqueous
NaHSO4 (10 mL), saturated aqueous NaHCO3 (10 mL), H2O
(10 mL), and brine (10 mL). The organic layer was dried over
MgSO4, filtered, and concentrated in vacuo. The product was
isolated as a clear, colorless oil (68.6 mg, 96%) after purification
by flash chromatography on SiO2 (1:8 EtOAc/hexanes). TLC:
Rf 0.64 (1:2 EtOAc/hexanes). [R]D: -2.4 (c 0.67, CH2Cl2). IR
(thin film): 3476, 1761, 1735 cm-1
.
1H NMR (500 MHz): δ
0.57 (q, 6, J ) 7.9), 0.81-0.84 (m, 6), 0.86 (d, 3, J ) 6.6), 0.90
(t, 9, J ) 7.9), 1.00 (d, 3, J ) 6.7), 1.07-1.13 (m, 2), 1.24-1.40
(m, 3), 1.39 (s, 9), 1.43 (s, 9), 1.65 (s, 9), 1.93-1.99 (m, 1), 2.05-
2.10 (m, 1), 2.12-2.18 (m, 1), 2.27-2.33 (m, 2), 2.37-2.43 (m,
1), 2.49-2.54 (m, 1), 2.80 (dd, 1, J ) 13.5, 4.1), 3.79 (s, 3),
3.96 (d, 1, J ) 6.5), 4.03 (s, 1), 4.12 (d, 1, J ) 1.8), 4.45 (d, 1,
J ) 11.3), 4.65 (d, 1, J ) 6.9), 4.68 (d, 1, J ) 6.9), 4.70 (d, 1,
J ) 11.4), 5.06-5.07 (m, 2), 5.07 (s, 1), 5.78 (dd, 1, J ) 15.7,
Ma jor Dia ster eom er 24a . 1H NMR (400 MHz): δ 0.59
(q, 6, J ) 8.0), 0.81-0.85 (m, 6), 0.89-0.94 (m, 12), 1.00 (d, 3,
J ) 6.7), 1.07-1.14 (m, 2), 1.25-1.42 (m, 3), 1.39 (s, 9), 1.42
(s, 9), 1.57-1.71 (m, 1), 1.64 (s, 9), 1.85-1.98 (m, 2), 2.04-
2.18 (m, 2), 2.40 (m, 1), 2.56 (dd, 1, J ) 13.5, 8.5), 2.80 (dd, 1,
J ) 13.5, 6.5), 3.27 (dd, 1, J ) 6.4, 2.9), 3.46 (d, 1, J ) 4.3),
3.80 (s, 3), 3.89 (m, 1), 4.01 (s, 1), 4.08 (d, 1, J ) 1.7), 4.62 (d,

Total Synthesis of Zaragozic Acid A
J . Org. Chem., Vol. 61, No. 26, 1996 9125
0.9), 6.36 (d, 1, J ) 1.7), 6.86 (dm, 2, J ) 8.7), 6.90 (dd, 1, J )
15.7, 8.4), 7.13-7.28 (m, 7). 13C NMR (100 MHz): δ 4.62, 6.58,
11.09, 14.37, 18.78, 20.15, 24.55, 27.98, 28.06, 29.71, 31.88,
34.26, 34.38, 37.20, 40.25, 43.26, 55.24, 69.39, 74.18, 75.15,
78.62, 82.67, 82.80, 83.75, 83.94, 85.73, 89.97, 91.88, 104.27,
113.11, 113.79, 118.71, 125.61, 128.11, 129.25, 129.47, 130.15,
141.05, 146.51, 156.44, 159.17, 164.15, 164.57, 166.11, 168.96.
Anal. Calcd for C60H92O15Si: C, 66.63; H, 8.58. Found: C,
66.56; H, 8.75.
[1S-[1r(4S,5R),3r,4â,5r,6r(2E,4S,6S),7â]]-1-[4-Hyd r oxy-
5-m eth yl-3-m eth ylen e-6-p h en ylh exyl]-6-(4,6-d im eth yl-2-
o c t e n o y l)-7-(t r i e t h y ls i ly l)-4,6,7-t r i h y d r o x y -2,8-d i -
oxa b icyclo[3.2.1]oct a n e-3,4,5-t r ica r b oxylic Acid 3,4,5-
Tr is(1,1-d im eth yleth yl) Ester (27). A. P r ep a r a tion fr om
26. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 6.3 mg,
0.028 mmol) was added to ether 26 (25.1 mg, 23.2 µmol) and
H2O (5 µL) in CH2Cl2 (0.1 mL) at 0 °C. The ice bath was
removed, and the mixture was stirred at rt. After 1 h,
additional DDQ (1.8 mg) was added. The mixture was stirred
for 1.5 h more and then was diluted with CH2Cl2 (20 mL) and
washed with saturated aqueous NaHCO3 (10 mL), H2O (10
mL), and brine (10 mL). The organic phase was dried over
MgSO4, filtered, concentrated in vacuo, and purified by flash
chromatography on SiO2 (1:7 EtOAc/hexanes). Allylic alcohol
27 was obtained as a clear, colorless oil (19.6 mg, 91%). The
1H and 13C NMR spectra and [R]D value were identical to that
obtained for 27 when synthesized from 28.
at 0 °C was added acetic anhydride (16 µL, 0.165 mmol). The
solution was stirred for 1 h at 0 °C, and saturated aqueous
NaHCO3 (2 mL) was added. The mixture was extracted with
CH2Cl2 (3 × 7 mL). The combined organic extracts were
washed with saturated aqueous NH4Cl (7 mL), water (7 mL),
and brine (7 mL), dried over MgSO4, filtered, and concentrated.
After purification by flash chromatography on SiO2 (1:7 EtOAc/
hexanes), 28 was isolated as a colorless oil (64.0 mg, 100%).
1
The H NMR spectrum and [R]D value were identical to those
obtained for 28 when synthesized from 3.
P r ep a r a tion fr om 3. To a solution of 3 (0.427 g, 0.497
mmol) in DMF (1.65 mL) at rt were added imidazole (88 mg,
1.29 mmol) and triethylsilyl chloride (108 µL, 0.647 mmol).
The solution was stirred, and additional imidazole (88 mg) and
triethylsilyl chloride (108 mL) were added after 18 h. After
another 10 h, saturated aqueous NH4Cl (8 mL) was added,
and the mixture was extracted with EtOAc (3 × 15 mL). The
combined organic extracts were washed with saturated aque-
ous NaHCO3 (30 mL) and water (30 mL), dried over MgSO4,
filtered, and concentrated. After purification by flash chro-
matography on SiO2 (1:7 EtOAc/hexanes), 0.450 g (93%) of 28
was obtained. TLC: Rf 0.70 (1:2 EtOAc/hexanes). [R]D: +35.1
(c 1.1, CH2Cl2). IR (CDCl3): 3455, 1738, 1650 cm-1 1H NMR
.
(500 MHz): δ 0.59 (q, 6, J ) 7.9), 0.81-0.85 (m, 9), 0.92 (t, 9,
J ) 7.9), 1.02 (d, 3, J ) 6.6), 1.07-1.16 (m, 2), 1.26-1.41 (m,
3), 1.41 (s, 9), 1.45 (s, 9), 1.66 (s, 9), 1.90-1.96 (m, 1), 2.06-
2.20 (m, 2), 2.09 (s, 3), 2.32-2.43 (m, 3), 2.50-2.56 (m, 1), 2.73
(dd, 1, J ) 13.4, 5.1), 4.05 (s, 1), 4.10 (d, 1, J ) 1.7), 4.97 (s, 1),
4.98 (s, 1), 5.08 (s, 1), 5.14 (d, 1, J ) 5.1), 5.79 (dd, 1, J ) 15.7,
0.9), 6.36 (d, 1, J ) 1.8), 6.91 (dd, 1, J ) 15.7, 8.4), 7.15-7.17
(m, 3), 7.24-7.27 (m, 2). 13C NMR (100 MHz): δ 4.54, 6.50,
11.02, 13.55, 18.69, 20.11, 20.96, 25.30, 27.90, 27.96, 27.98,
29.65, 31.81, 34.21, 34.33, 36.42, 39.91, 43.18, 74.04, 75.04,
78.54, 79.35, 82.71, 82.77, 83.63, 85.72, 89.91, 104.11, 111.23,
118.64, 125.75, 128.14, 129.11, 140.30, 146.05, 156.36, 164.10,
164.45, 166.02, 168.93, 169.97. Anal. Calcd for C53H84O14Si:
C, 65.40; H, 8.70. Found: C, 65.44; H, 8.75.
B. P r ep a r a tion fr om 28. A slurry of dry CeCl326 (650 mg,
2.64 mmol) in THF (2 mL) was stirred at rt for 22 h under N2.
More THF (1.25 mL) was added, and the slurry was cooled to
-78 °C. A solution of ethylmagnesium chloride in THF (0.75
mL, 1.51 mmol) was added, and the flask was put in an ice
bath for 20 min and then recooled to -78 °C. To the slurry
was added 28 (58.8 mg, 60.4 µmol) in THF (1 mL, then 2 ×
0.5 mL rinses) at -78 °C via cannula over 10 min. The
reaction mixture was stirred for 15 min at -78 °C and then
the reaction quenched with 1 M HCl (2 mL). The mixture was
warmed to rt, diluted with EtOAc (20 mL), and washed with
1 M HCl (8 mL), saturated aqueous NaHCO3 (8 mL), water (8
mL), and brine (8 mL). The aqueous phases were back-
extracted with EtOAc (20 mL). The combined organic phases
were dried over MgSO4, filtered, and concentrated. Purifica-
tion of the resulting yellow residue by flash chromatography
on SiO2 (1:5 EtOAc/hexanes) provided 27 (55.1 mg, 98%) as a
clear, colorless oil. TLC: Rf 0.54 (1:2 EtOAc/hexanes). [R]D:
Za r a gozic Acid A (1). A solution of 3 (16.6 mg, 19.3 µmol)
and trifluoroacetic acid (0.35 mL) in CH2Cl2 (1.0 mL) was
stirred for 11 h at rt and then concentrated in vacuo. The
crude product was concentrated from toluene (4 × 4 mL) to
remove residual trifluoroacetic acid and purified using reverse
phase HPLC (semipreparative C18 column, 7:3 CH3CN/0.1%
aqueous H3PO4, flow rate: 3 mL/min, Rt ) 13.7 min) to afford
zaragozic acid A (1) (9.9 mg, 74%) as a white film in g95%
+36.7 (c 3.72, CH2Cl2). IR (thin film): 3458, 1736 cm-1
.
1H
purity by H NMR analysis. IR (thin film): 3458 (br), 1721,
1
NMR (400 MHz): δ 0.58 (q, 6, J ) 7.9), 0.82-0.85 (m, 9), 0.93
(t, 9, J ) 7.9), 1.01 (d, 3, J ) 6.7), 1.04-1.14 (m, 2), 1.26-1.38
(m, 3), 1.40 (s, 9), 1.45 (s, 9), 1.65 (s, 9), 1.91-2.04 (m, 2), 2.13
(ddd, 1, J ) 14.5, 9.0, 5.9), 2.32-2.50 (m, 5), 2.81 (dd, 1, J )
13.5, 5.4), 3.96 (s, 1), 4.09 (m, 2), 5.01 (s, 1), 5.07 (s, 1), 5.13 (s,
1), 5.77 (dd, 1, J ) 15.7, 0.9), 6.35 (d, 1, J ) 1.8), 6.90 (dd, 1,
J ) 15.7, 8.4), 7.14-7.27 (m, 5). 13C NMR (100 MHz): δ 4.62,
6.58, 11.09, 13.21, 18.76, 20.16, 26.52, 27.98, 28.08, 28.11,
29.72, 31.88, 34.27, 34.39, 38.03, 40.28, 43.25, 74.19, 75.11,
77.31, 78.47, 82.93, 83.08, 83.98, 85.57, 89.85, 104.37, 110.72,
118.67, 125.59, 128.11, 129.22, 141.39, 151.23, 156.48, 164.10,
164.52, 166.10, 168.31. Anal. Calcd for C51H82O13Si: C, 65.77;
H, 8.88. Found: C, 66.00; H, 8.96.
1648 cm-1 1H NMR (CD3OD, 500 MHz): δ 0.84-0.89 (m, 9),
.
1.02 (d, 3, J ) 6.6), 1.10-1.16 (m, 2), 1.28-1.41 (m, 3), 1.96-
2.07 (m, 2), 2.09 (s, 3), 2.22-2.45 (m, 5), 2.68 (dd, 1, J ) 13.4,
6.3), 4.03 (d, 1, J ) 1.7), 4.96 (s, 1), 5.01 (s, 1), 5.06 (d, 1, J )
4.7), 5.26 (s, 1), 5.79 (d, 1, J ) 15.7), 6.30 (d, 1, J ) 1.7), 6.84
(dd, 1, J ) 15.6, 8.5), 7.12-7.26 (m, 5). 13C NMR (CD3OD,
100 MHz): δ 11.52, 14.23, 19.30, 20.59, 20.97, 26.57, 30.86,
33.23, 35.05, 35.65, 37.79, 40.99, 44.46, 75.65, 76.69, 80.23,
81.11, 82.61, 91.18, 106.95, 111.62, 119.92, 126.99, 129.39,
130.27, 141.69, 147.84, 157.63, 166.59, 168.48, 170.16, 172.18,
172.55. The spectra are identical with those obtained with
an authentic sample of zaragozic acid A obtained from Glaxo,
U.K.
[1S-[1r(4S,5R),3r,4â,5r,6r(2E,4S,6S),7â]]-1-[4-(Acet y-
loxy)-5-m eth yl-3-m eth ylen e-6-p h en ylh exyl]-6-(4,6-d im e-
t h yl-2-oct e n oyl)-7-(t r ie t h ylsilyl)-4,6,7-t r ih yd r oxy-2,8-
d ioxa bicyclo[3.2.1]octa n e-3,4,5-tr ica r boxylic Acid 3,4,5-
Tr is(1,1-d im eth yleth yl) Ester (28). P r ep a r a tion fr om 27.
To a solution of 27 (61.4 mg, 65.9 µmol), triethylamine (32 µL,
0.23 mmol), and DMAP (1.2 mg, 9.8 µmol) in CH2Cl2 (0.33 mL)
Ack n ow led gm en t. We thank the National Science
Foundation for a research grant and FCAR and Pfizer
for awarding a fellowship to S.C. We thank Dr. Barry
C. Ross of Glaxo, U.K. for a supply of squalestatin S1.
J O961533M