Novel approach to the Zaragozic acids. Enantioselective total synthesis of 6,7-dideoxysqualestatin H5

Article abstract of DOI:10.1021/jo011157s

The total synthesis of 6,7-dideoxysqualestatin H5 (3) has been completed by a concise approach that features the stereoselective intramolecular vinylogous aldol reaction of the furoic ester 25a to give 30 or its trimethylsilyl ether derivative 34, which possess the requisite absolute stereochemistry at C(3)-C(5) of 3. Compound 34 was reduced to the saturated bislactone 39, and the C(1) side chain subunit 47 was introduced leading to a mixture of the hemiacetals 48 and the corresponding ketone 49. When this mixture was stirred with methanolic acid, transketalization occurred to give a mixture of 50 and the spirocyclic methyl acetals 51a,b. Oxidation of the primary alcohol group in 50 followed by saponification of the two remaining ester groups gave 3. The longest linear sequence in the synthesis commences with commercially available erythronolactone (26) and requires 17 chemical steps with only 10 isolated intermediates.

Full text of DOI:10.1021/jo011157s

4200
J . Org. Chem. 2002, 67, 4200-4208
Novel Ap p r oa ch to th e Za r a gozic Acid s. En a n tioselective Tota l
Syn th esis of 6,7-Did eoxysqu a lesta tin H5
Satoru Naito, Maya Escobar, Philip R. Kym, Spiros Liras, and Stephen F. Martin*
Department of Chemistry and Biochemistry, The University of Texas, Austin, Texas 78712
sfmartin@mail.utexas.edu
Received December 18, 2001
The total synthesis of 6,7-dideoxysqualestatin H5 (3) has been completed by a concise approach
that features the stereoselective intramolecular vinylogous aldol reaction of the furoic ester 25a to
give 30 or its trimethylsilyl ether derivative 34, which possess the requisite absolute stereochemistry
at C(3)-C(5) of 3. Compound 34 was reduced to the saturated bislactone 39, and the C(1) side
chain subunit 47 was introduced leading to a mixture of the hemiacetals 48 and the corresponding
ketone 49. When this mixture was stirred with methanolic acid, transketalization occurred to give
a mixture of 50 and the spirocyclic methyl acetals 51a ,b. Oxidation of the primary alcohol group
in 50 followed by saponification of the two remaining ester groups gave 3. The longest linear
sequence in the synthesis commences with commercially available erythronolactone (26) and
requires 17 chemical steps with only 10 isolated intermediates.
In tr od u ction
isolated them from a soil sample from Portugal. These
compounds not only exhibit extraordinary potency as
inhibitors of squalene synthase, but they also are inhibi-
tors of farnesyl protein transferase.3 The first member
of this class was compound 1, which was named zaragozic
acid A by the Merck group and squalestatin S1 by the
Glaxo group. A large number of related compounds have
since been isolated, including zaragozic acid C (2) and
6,7-dideoxysqualestatin H5 (3).
The isolation and identification of natural products
having biological activity is an important undertaking
that has led to the discovery of numerous leads for new
drugs. One therapeutic area of particular importance is
the development of novel agents for treating cardiovas-
cular disease, which is among the leading causes of death
in developed countries. Antihypertensive agents have a
long and successful record of use for reducing high blood
pressure, and more recently hypercholesterolemic agents
have emerged as highly efficacious drugs for reducing
serum levels of cholesterol and the risk of coronary heat
disease. Many of the successful drugs in this latter area
are inhibitors of HMG CoA reductase. However, because
this enzyme plays a key role in the early steps of the
biosynthesis of cholesterol, the production of steroids
other than cholesterol may be affected, thereby leading
to side effects. Hence, there has been considerable
interest in finding agents that intervene at a latter stage
of the biosynthetic pathway, and attention has recently
focused on inhibiting squalene synthase, an enzyme that
catalyzes the first committed step in cholesterol biosyn-
thesis.
One of the most potent classes of such inhibitors was
discovered as a result of random screening procedures
that led to the discovery of a new family of fungal
metabolites. These compounds were named zaragozic
acids by Merck scientists,1 who isolated the compounds
from a fungus found in a river in the Zaragoza province
of Spain, and squalestatins,2 by Glaxo scientists who
The unusual structure of these highly functionalized
fungal metabolites coupled with their promising biologi-
(1) (a) Wilson, K. E.; Burk, R. M.; Biftu, T.; Ball, R. G.; Hoogsteen,
K. J . Org. Chem. 1992, 57, 7151-7158. (b) Dufresne, C.; Wilson, K.
E.; Zink, D.; Smith, J .; Bergstrom, J . D.; Kurtz, M.; Rew, D.; Nallin,
M.; J enkins, R., et al. Tetrahedron 1992, 48, 10221-10226. (c)
Bergstrom, J . D.; Kurtz, M. M.; Rew, D. J .; Amend, A. M.; Karkas, J .
D.; Bostedor, R. G.; Bansal, V. S.; Dufresne, C.; VanMiddlesworth, F.
L. et al. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 80-84. (d) Hensens,
O. D.; Dufresne, C.; Liesch, J . M.; Zink, D. L.; Reamer, R. A.;
VanMiddlesworth, F. Tetrahedron Lett. 1993, 34, 399-402. (e) Santini,
C.; Ball, R. G.; Berger, G. D. J . Org. Chem. 1994, 59, 2261-2266. (f)
Dufresne, C.; J ones, E. T. T.; Omstead, M. N.; Bergstrom, J . D.; Wilson,
K. E. J . Nat. Prod. 1996, 59, 52-54. (g) Tanimoto, T.; Hamano, K.;
Onodera, K.; Hosoya, T.; Kakusaka, M.; Hirayama, T.; Shimada, Y.;
Koga, T.; Tsujita, Y. J . Antibiot. 1997, 50, 390-394.
(2) (a) Dawson, M. J .; Farthing, J . E.; Marshall, P. S.; Middleton,
R. F.; O’Neil, M. J .; Shuttleworth, A.; Stylli, C.; Tait, R. M.; Tailor, P.
M.; Wildman, H. G.; Buss, A. D.; Langley, D.; Hayes, M. V. J . Antibiot.
1992, 45, 639-647. (b) Sidebottom, P. J .; Highcock, R. M.; Lane, S. J .;
Procopiou, P. A.; Watson, N. S. J . Antibiot. 1992, 45, 648-658. (c)
Hasumi, K.; Tachikawa, K.; Sakai, K.; Murakawa, S.; Yoshikawa, S.;
Kumazawa, S.; Endo, A. J . Antibiot. 1993, 46, 689-691. (d) Blows, W.
M.; Foster, G.; Lane, S. J .; Noble, D.; Piercey, J . E.; Sidebottom, P. J .;
Webb, G. J . Antibiot. 1994, 47, 740-754.
(3) For reviews, see: (a) Bergstrom, J . D.; Dufresne, C.; Bills, G. F.;
Nallin-Omstead, M.; Byrne, K. Annu. Rev. Microbiol. 1995, 49, 607-
639. (b) Nadin, A.; Nicolaou, K. C. Angew. Chem., Int. Ed. Engl. 1996,
35, 1622-1656. (c) Watson, N. S.; Procopiou, P. A. Prog. Med. Chem.
1996, 33, 331-378.
10.1021/jo011157s CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/10/2002

Novel Approach to the Zaragozic Acids
J . Org. Chem., Vol. 67, No. 12, 2002 4201
Sch em e 1
Sch em e 2
cal activities inspired numerous efforts directed toward
their synthesis. Consequent to these efforts, a variety of
ingenious approaches to the central 2,8-dioxabicyclo-
[3.2.1]octane core have been recorded,4 and total synthe-
ses of zaragozic acid A (squalestatin S1) (1), zaragozic
acid C (2), and other naturally occurring derivatives have
been reported.5,6 Despite these successes, we were at-
tracted to the considerable challenge of devising a more
concise and general approach to members of the zaragozic
acid family utilizing vinylogous aldol reactions as a key
construction. We now report the details of our work in
this area and a concise synthesis of 6,7-dideoxysqual-
estatin H5 (3).2d
a vinylogous aldol reaction of the furan 7 with the
dioxosuccinate 8.
In accordance with the above retrosynthetic analysis,
the requisite furan 10 was readily prepared by metalation
and carbomethoxylation of the known furan 9 (Scheme
2).7 The second building block, dimethyl dioxosuccinate
(8), was prepared in one step by the acid-catalyzed
dehydration of dihydroxytartrate according to the method
of Beak.8 With compounds 8 and 10 in hand, the stage
was set to examine the feasibility and the stereoselec-
tivity of the key vinylogous aldol reaction, but a series of
initial attempts to catalyze this reaction with a variety
of Lewis acids, including SnCl4, BF3‚OEt2, Me2AlCl, TiCl4,
and AlCl3 were unsuccessful. However, we were delighted
to discover that the vinylogous aldol addition could be
induced using excess HF‚pyridine to provide an insepa-
rable mixture (ca. 2.3:1) of the diastereomeric adducts
11a ,b in 91% yield. At this stage it was not possible to
assign the relative stereochemistry of the two adducts,
but subsequent experiments revealed that the major
isomer was in fact the desired 11a (vide infra). Unfor-
tunately, these adducts were extremely labile toward
retro-aldolization under both acidic and basic conditions.
The hydroxyl group at C(4) presumably serves as the
trigger for this reversal that is driven to relieve steric
congestion about the newly formed C(4)-C(5) bond. We
reasoned that reduction of the double bond of the buteno-
lide moiety in 11a ,b would stabilize the system and
indeed found that the mixture of saturated lactones
12a ,b, which were prepared in essentially quantitative
yield by catalytic hydrogenation of 11a ,b, were stable and
amenable to further manipulation.
Resu lts a n d Discu ssion
F ir st Gen er a tion Ap p r oa ch . In our first approach
to the various zaragozic acids 4, we targeted the bicyclic
lactone 5 as a potentially versatile gateway because it
contains the requisite absolute chirality at C(3)-C(5) as
well as appropriate functional handles for introducing the
remaining substituents and side chains of all the zara-
gozic acids (Scheme 1). We envisaged that this compact
intermediate might be assembled via reduction and
cyclization of 6, which would in turn be assembled using
(4) For some recent examples, see: (a) Koyama, H.; Ball, R. G.;
Berger, G. D. Tetrahedron Lett. 1994, 35, 9185-9188. (b) Hodgson, D.
M.; Bailey, J . M.; Harrison T. Tetrahedron Lett. 1996, 37, 4623-4626.
(c) Maezaki, N.; Gijsen, H. J . M.; Sun, L.; Paquette, L. A. J . Org. Chem.
1996, 61, 6685-6692. (d) Xu, Y.; J ohnson, C. R. Tetrahedron Lett. 1997,
38, 1117-1120. (e) Paterson, I.; Fessner, K.; Finlay, M. R. V.
Tetrahedron Lett. 1997, 38, 4301-4304. (f) Ito, H.; Matsumoto, M.;
Yoshizawa, T.; Takao, K.; Kobayashi, S. Tetrahedron Lett. 1997, 38,
9009-9012. (g) Hegde, S. G.; Myles, D. C. Tetrahedron 1997, 53,
11179-11190. (h) Brogan, J . B.; Zercher, C. K. Tetrahedron Lett. 1998,
39, 1691-1694. (i) Mann, R. K.; Parsons, J . G.; Rizzacasa, M. A. J .
Chem. Soc. Perkin Trans. 1 1998, 1283-1293. (j) Kataoka, O.; Kitagaki,
S.; Watanabe, N.; Kobayashi, J .; Nakamura, S.; Shiro, M.; Hashimoto,
S. Tetrahedron Lett. 1998, 39, 2371-2374. (k) Calter, M. A.; Zhu, C.;
Lachicotte, R. J . Org. Lett. 2002, 4, 209-212.
(5) (a) Carreira, E. M.; Du Bois, J . J . Am. Chem. Soc. 1995, 117,
8106-8125. (b) Evans, D. A.; Barrow, J . C.; Leighton, J . L.; Robichaud,
A. J .; Sefkow, M. J . Am. Chem. Soc. 1994, 116, 12111-12112. (c)
Nicolaou, K. C.; Yue, E. W.; La Greca, S.; Nadin, A.; Yang.; Z.;
Leresche.; J . E.; Tsuri T.; Naniwa, Y.; De Riccardis, F. Eur. J . Chem.
1995, 1, 467-494. (d) Stoermer, D.; Caron, S.; Heathcock, C. H. J . Org.
Chem. 1996, 61, 9115-9125. (e) Caron, S.; Stoermer, D.; Mapp, A. K.;
Heathcock, C. H. J . Org. Chem. 1996, 61, 9126-9134. (f) Sato, H.;
Nakamura, S.; Watanabe, N.; Hashimoto, S. Synlett. 1997, 451-454.
(g) Freeman-Cook, K. D.; Halcomb, R. L. J . Org. Chem. 2000, 65, 6153-
6159. (h) Armstrong, A.; Barsanti, P. A.; J ones, L. H.; Ahmed, G. J .
Org. Chem. 2000, 65, 7020-7032. (i) Tomooka, K.; Kikuchi, M.; Igawa,
K.; Suzuki, M.; Keong, P.-H.; Nakai, T. Angew. Chem., Int. Ed. 2000,
39, 4502-4505.
The stereoselectivity of the reduction of the carbonyl
group at C(3) of 12a ,b was then examined using a variety
of hydride reducing agents, but reduction with LiBH4 was
(7) Martin, S. F.; Barr, K. J .; Smith, D. W.; Bur, S. K. J . Am. Chem.
Soc. 1999, 121, 6990-6997.
(8) Song, Z.; Beak, P. J . Am. Chem. Soc. 1990, 112, 8126-8134.
(6) For a preliminary account of some of this work, see: Martin, S.
F.; Naito, S. J . Org. Chem. 1998, 63, 7592-7593.

4202 J . Org. Chem., Vol. 67, No. 12, 2002
Naito et al.
Sch em e 3
Sch em e 4
found to be the most diastereoselective giving an insepa-
rable mixture of 13 and 14 as the only identifiable
products. At this point, we were fortunate to find that
small quantities of crystals of the derived lactone 15
separated from the mixture of 13 and 14, and the
structure of this substance was unequivocally established
by X-ray analysis. When we attempted to convert 13 and
14 to their respective acetonides using camphorsulfonic
acid in 2,2-dimethoxypropane, we unexpectedly isolated
a mixture (ca. 2.2:1) of 15 together with the corresponding
lactone derived from 14. Pure 15 could thus be isolated
in 26% overall yield from furan 10 after crystallization
from chloroform.
The X-ray structure of 15 revealed that the vinylogous
aldol reaction had proceeded predominantly in the de-
sired stereochemical sense, but the hydride reduction of
the carbonyl group at C(3) proceeded with apparent
chelation control to give the incorrect relative stereo-
chemistry. We reasoned that it would either be possible
to reverse the stereochemistry of the reduction or to
invert this center later in the synthesis, so we examined
the feasibility of converting 15 into the 2,8-dioxabicyclo-
[3.2.1]octane system characteristic of the zaragozic acids.
Thus, selective reduction at C(1) of the less substituted
lactone ring of 15 using DIBAL proceeded smoothly to
give a mixture of hemiacetals, but subjecting this mixture
to refluxing methanolic HCl gave a mixture of methyl
acetals rather than the desired oxabicyclic core, presum-
ably because the ester group at C(3) would be axial in
such a product. It was thus apparent that an alternate
strategy that efficiently delivered an intermediate with
the correct configuration at all centers was needed.
Secon d Gen er a tion Ap p r oa ch . Inasmuch as the
bimolecular vinylogous aldol reaction of 8 and 10 pro-
ceeded with only modest selectivity, we queried whether
an intramolecular variant of this process might be more
stereoselective. Hence, a different entry to the zaragozic
acids was envisioned in which an intermediate such as
18, which has the requisite stereochemistry at C(3)-C(5),
might be formed by the cyclization of a furoic ester
related to 19 (Scheme 3). Preparation of 19 by esterifi-
cation of substituted furoic acids with the appropriate
alcohols was envisioned as being straightforward. The
activating group Z on the furan ring could be varied as a
tactical device to optimize the cyclization.
and 1,3-diols.9 After selective protection of the primary
alcohol as its TBDPS ether, the diprotected alcohol 22
was isolated in 50% yield by column chromatography. At
the outset of these studies, it was not clear what the
optimal nature of the activating group Z on the furan
ring would be, so the series of furoate esters 24a -c was
prepared by esterification of 22 with the known furoic
acids 23a -c10 in the presence of dicyclohexylcarbodimide
(DCC) and 4-(N,N-dimethylamino)pyridine (DMAP). The
tetrahydropyranyl group was removed from the esters
24a -c by the action of Me2AlCl.11 Because the interme-
diate secondary alcohols exhibited a tendency to suffer
an intramolecular 1,2-acyl transfer, they were typically
oxidized directly without extensive handling using Dess-
Martin periodinane to deliver the R-ketoesters 25a -c.12
While the above route to 25a -c could be used to make
the necessary quantities of material for cyclization stud-
ies, the problems associated with the somewhat inef-
ficient monoprotection of dimethyl tartrate coupled with
the modest regioselectivity in the hydride reduction of
21 persuaded us to examine other avenues to these R-keto
esters. In the event, erythronolactone (26)13 was selec-
tively protected in a modification of a literature procedure
by reacting the derived stannylidene acetal with p-
methoxybenzyl chloride to give a mixture of regioisomers
(6:1) that were readily separable by recrystallization to
give pure lactone 27.14 Protection of the remaining
secondary alcohol and methanolysis of the lactone under
basic conditions proceeded with migration of the silyl
protecting group to the primary alcohol to provide alcohol
28 in 78% yield over the two steps. The alcohol 28 was
coupled with furoic acid 23a as before, and subsequent
(9) (a) Saito, S.; Ishikawa, T.; Kuroda, A.; Koga, K.; Moriwake, T.
Tetrahedron 1992, 48, 4067-4086. (b) Saito, S.; Hasegawa, T.; Inaba,
M.; Nishida, R.; Fujii, T.; Nomizu, S.; Moriwake, T. Chem. Lett. 1984,
1389-1392. (c) Saito, S.; Nagao, Y.; Miyazaki, M.; Inaba, M.; Moriwake,
T. Tetrahedron Lett. 1986, 27, 5249-5252.
(10) (a) Torii, S.; Tanaka, H.; Okamoto, T. Bull. Chem. Soc. J pn.
1972, 45, 2783-2787. (b) Cella, J . A. J . Org. Chem. 1988, 53, 2099-
2103.
(11) Ogawa, Y.; Shibasaki, M. Tetrahedron Lett. 1984, 25, 663-664.
(12) (a) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155-
4156. (b) Meyer, S. D.; Schreiber, S. L. J . Org. Chem. 1994, 59, 7549-
7552.
Several routes to the alcohol component of the ester
generally represented by 19 were developed. In the first,
dimethyl tartrate (20) was protected as its mono-THP
derivative 21 (Scheme 4). Chemoselective reduction of the
ester moiety R to the hydroxy group in 21 was best
achieved using BH3‚SMe2 in the presence of catalytic
NaBH4 to give an inseparable mixture (3:1) of the 1,2

Novel Approach to the Zaragozic Acids
J . Org. Chem., Vol. 67, No. 12, 2002 4203
Sch em e 5
Sch em e 6
on the furan led to the formation of 32 as the major
product when TiCl4 was used as the catalyst, whereas
other acid catalysts led to mixtures of products. Activa-
tion of the furan ring with an electron-donating group
was clearly necessary, as when Z ) H or Br, no cycliza-
tion was observed.
To facilitate structure determination of the adducts
30-33, they were converted into their respective tri-
methylsilyl ethers 34-37. The structures of the adducts
34-37 were first tentatively assigned based upon the
observed NOEs as shown. However, it was not possible
to assign the stereochemistry at C(4) based upon NMR
alone. Consequently, the structures of 34, 36, and 37
were unequivocally established by X-ray crystallographic
analysis.
Ta ble 1. Ster eoch em istr y of Vin ylogou s Ald ol
Cycliza tion s of 25a -c
Lewis acid
(equiv)
isomer ratiob isolated isomer
compd
conditionsa
rt, 3 h
0 °Cfrt, 1.5 h
0 °Cfrt, 1.5 h
0 °Cfrt, 2 h
rt, 4 h
(30:31:32:33)
(%yield)b
25a TiCl4 (1.0)
TiCl4 (2.5)
6:2:1:0
30 (11)
14:1:1:0
>20:1:2:0
30 (33)
30 (42)
>20: 2:1:0 30 (43)
TiCl4 (3.0)
TiCl4 (5.0)
SnCl4 (2.0)
1:2:1:1
25b TiCl4 (3.0)
SnCl4 (1.0)
-78f0 °C, 2 h
0:0:2:1
32 (56), 33 (30)
-78 °Cfrt, 3 h trace:1:4:5
BF3‚OEt2 (1.0) rt, 3 h
0:1:0:3.4
0:3:0:1
1:1:>20:1
31 (19), 33 (40)
31 (39), 33 (12)
32 (65)
TMS-I (1.2) 0 °Cfrt, 1 h
25c TiCl4 (3.0)
-78f0 °C, 2 h
-78 °Cfrt, 2 h 2:1:5:6
SnCl4 (3.0)
BF3‚OEt2 (1.2) rt, 12 h
0:1:trace:3 31 (12), 33 (32)
a
The reactants were combined in dichloromethane at the lower
temperature and then stirred at the final temperature for the time
b
indicated. Ratio determined by 1H NMR of crude reaction
mixture.
deprotection of the resulting ester with DDQ and oxida-
tion with Dess-Martin periodinane gave 25a in 85%
yield. This route to 25a was both chemically and opera-
tionally more efficient than the previous one.
The intramolecular vinylogous aldol reactions of 25a -c
were then examined using different Lewis acids to
catalyze the addition (Table 1). When 25a was employed
as the starting material, Lewis acids as BF3‚OEt2, ZnCl2,
Sc(OTf)3, and TMS-I did not induce cyclization, and either
starting 25a or unidentified products were obtained.
However, both TiCl4 and SnCl4 effected cyclization al-
though the latter was not selective and gave a mixture
of all four possible diastereomers in approximately equal
amounts. The TiCl4-induced cyclization proceeded to give
the highest ratio of the desired adduct 30, and the
stereoselectivity was dependent upon the number of
equivalents of TiCl4. Poorer selectivities and lower yields
were observed when fewer than 3 equiv of TiCl4 were
employed, but use of larger quantities of catalyst had
little effect upon the reaction.
That the number of equivalents and the Lewis acid had
an effect upon the course of the cyclization was somewhat
expected, but it was surprising that the nature of the
activating group Z on the C(5) position of the furan had
a major impact upon the stereochemical outcome of the
reaction. For example, a methoxy group on the furan led
to the preferential formation of 32 and 33 in roughly
comparable amounts using TiCl4, but significant amounts
of 31 were isolated when TMS-I was employed to initiate
the reaction. The presence of a 4′-methylphenoxy group
Although the spirocyclic adducts 30-33 could be
isolated in pure form, they were somewhat unstable and
prone to suffer retroaldolization, especially in the pres-
ence of base. For example, if either pure 30 or 32 was
heated in pyridine at 50 °C, a mixture containing all four
diastereomers 30-33 was obtained in a ratio (5:10:5:1)
that reflects their corresponding relative stabilities in the
order 31>30 ) 32>33. When either pure 30 or 32 was
resubjected to the conditions of the initial cyclization, no
isomerization occurred, and hence we assume these
reactions were conducted under kinetically controlled
conditions.
Careful analysis of the reaction mixtures obtained in
the cyclizations of 25a revealed that the sulfide 38 was
formed in nearly 20% yield. Presumably the thiophenox-
ide anion that is released during the course of the
reaction adds in a 1,4-sense to the desired product 30 to
give 38. To circumvent this problem and to increase the
yield of 30, various thiophiles including Hg(II) and Cu-
(II) salts were added in hopes of trapping this anion prior
to its reaction with 30. Ultimately, all efforts to reduce
the amount of 38 formed during the reaction or workup
and increase the yield of 30 were unsuccessful, and a
modified protocol was developed for converting 38 into

4204 J . Org. Chem., Vol. 67, No. 12, 2002
Naito et al.
Sch em e 7
Sch em e 8
Sch em e 9
the more stable trimethylsilyl ether 34. In the event,
upon completion of the usual cyclization of 25a in the
presence of TiCl4, the crude product mixture was sequen-
tially treated with TMS-Cl and imidazole, MCPBA, and
then Et3N and TMS-Cl to give 34 in 54% overall yield
from 25a . It was necessary to add TMS-Cl in the last
step because some deprotection of the tertiary alcohol at
C(4) occurred during the sequence. Catalytic hydrogena-
tion of the butenolide 34 then gave 39, thereby setting
the stage for installation of the C(1) side chain. The
structure of 39 was also secured by X-ray crystallography.
In preliminary work directed toward introducing the
aliphatic side chain at C(1), we examined the additions
of various aliphatic Grignard, organolithium, and cerium
reagents to 39. However, starting 39 was typically
recovered, although low yields of the cyclic hemiacetals
arising from addition to the desired lactone carbonyl
group were sometimes obtained. Anions of phenyl sul-
fones are also known to react with lactones,15 and we
found that the monoanion of methyl phenyl sulfone added
cleanly to 39 providing 40. Reductive desulfonylation of
40 then furnished the desired lactol 41 in 61% overall
yield.16 When 41 was treated with methanolic sulfuric
acid, a mixture (2:1) of 42 and 43 was obtained, the latter
of which possesses the zaragozic acid core. That a mixture
of products was obtained in this model study occasioned
no serious alarm as the position of the equilibria in
related systems were known to be finely balanced and
dependent upon the specific substituents.4a,c,d,f,17 Indeed,
the equilibrium generally favors the desired dioxabicyclo-
[3.2.1]octane ring system in the natural series.5
known aldehyde 44 afforded alcohol 45.18 The optical
purity of 45 (>95% ee) was established by degradation
(NaIO4, RuO2‚xH2O) to the corresponding carboxylic acid
derivative of 44 and NMR analysis of its methyl (S)-(+)-
mandelate derivative.19 Mesylation of 45 followed by
reaction of the intermediate mesylate with NaBr gave
the allyl bromide 46. Initial attempts to convert 46 into
47 by alkylation of the lithiated monoanion of methyl
phenyl sulfone gave significant quantities of dialkylated
material. The potassium salts of sulfones were known to
undergo selective monoalkylation,20 and indeed we found
reaction of 46 with the potassium salt of methyl phenyl
sulfone proceeded cleanly to give 47 in 89% yield.
The spirobicycle 39 was then coupled with the C(1) side
chain by selective addition of the dianion of the sulfone
47 to the less hindered lactone moiety of 39. Reductive
desulfonylation with aluminum amalgam then gave a
mixture of hemiacetals 48 together with the ring opened
ketone 49. This mixture was then treated with metha-
nolic sulfuric acid to give a mixture (1:2.5) of the desired
bicyclic ketal 50 (25% yield) along with two methyl
acetals of formula 51 (1:1, 65% yield). Obtention of this
mixture was somewhat surprising inasmuch as all other
acid catalyzed transformations leading to natural zara-
gozic acids reportedly delivered either exclusively or
predominantly the desired 2,8-dioxabicyclo[3.2.1]octane
core.5 Thus, the presence of the hydroxyl groups at
C(6) and C(7) in synthetic intermediates leading to
In light of these positive results, we set to the task of
preparing the sulfone of the requisite C(1) side chain.
Thus, addition of 2-propenylmagnesium bromide to the
(13) Cohen, N.; Banner, B. L.; Laurenzano, A. J .; Carozza, L. Org.
Synth. 1985, 63, 127-135.
(14) Flasche, M.; Scharf, H. Tetrahedron: Asymmetry 1995, 6, 1543-
1546.
(15) (a) Thompson, C. M. Dianion Chemistry in Organic Synthesis;
CRC Press: Boca Raton, 1994; Chapter 2. (b) Mussatto, M. C.; Savoia,
D.; Tronbini, C.; Umani-Ronchi, A. J . Org. Chem. 1980, 45, 4002-
4005. (c) Cavicchioli, S.; Savoia, D.; Tronbini, C.; Umani-Ronchi, A. J .
Org. Chem. 1984, 49, 1246-1251. (d) Alze´rreca, A.; Avile´s, M.; Collazo,
L. J . Heterocycl. Chem. 1990, 27, 1729-1731. (e) Alze´rreca, A.;
Mart´ınez, J .; Vela´zquez, L.; Prieto, J . A.; Arias, L. J . Heterocycl. Chem.
1994, 31, 45-48.
(17) Dominey, A. P.; Goodman, J . M. Org. Lett. 1999, 1, 473-475.
(18) Myers, A. G.; Yang, B. H.; Gleason, J . L.; Chen, H. J . Am. Chem.
Soc. 1994, 116, 9361-9362.
(19) Tyrrel, E.; Tsang, M. W. H.; Skinner, G. A.; Fawcett, J .
Tetrahedron 1996, 52, 9841-9852.
(16) (a) Corey, E. J .; Chaykovsky, M. J . Am. Chem. Soc. 1964, 86,
1639-1640. (b) Wuonola, M. A.; Woodward, R. B. Tetrahedron 1976,
32, 1085-1095.
(20) Pine, S. H.; Shen, G.; Bautista, J .; Sutton, C. J r.; Yamada, W.;
Apodaca, L. J . Org. Chem. 1990, 55, 2234-2237.

Novel Approach to the Zaragozic Acids
J . Org. Chem., Vol. 67, No. 12, 2002 4205
Sch em e 10
Sch em e 11
cessful, frequently leading to mixtures of uncharacterized
compounds that were believed to arise from loss of the
TMS protecting group from the C(4) hydroxyl group of
34 and subsequent retroaldolization or attack upon one
or both the lactone carbonyl groups. To avoid such side
reactions, the two silyl protecting groups on the 1,3-diol
array in 34 were removed using HF‚pyridine and re-
placed with the more stable cyclic p-methoxybenzylidene
acetal to give 52. Although it was not possible to epoxidize
the double bond of 52, we found that 52 underwent 1,4-
addition of a dimethylphenylsilyl zincate to furnish the
silane 53,23 the structure of which was confirmed by X-ray
analysis. Unfortunately, all attempts to transform the
silyl moiety at C(6) in 53 into the requisite hydroxy group
to give 54 by applying a variety of known procedures were
unsuccessful,24 and either starting material or unidenti-
fied products were typically obtained. Hence, additional
studies directed toward functionalizing the double bond
of intermediates related to 34 must be pursued in order
to extend our approach to the syntheses of the more
complex zaragozic acids.
The total enantioselective synthesis of the natural
product 6,7-dideoxysqualestatin H5 (3) has been com-
pleted by a concise approach in which the longest linear
sequence is 17 steps from commercially available eryth-
ronolactone (26) and proceeds via only 10 isolated
intermediates. The synthesis highlights a novel strategy
for rapidly assembling the core of the zaragozic acids by
a stereoselective intramolecular vinylogous aldol reaction,
thereby providing a compelling example of the power and
versatility of such constructions in organic synthesis.
Other applications of this and related reactions are the
subjects of current investigations, the results of which
will be reported in due course.
zaragozic acids A and C may play an important role in
dictating the kinetic and/or the thermodynamic course
of these intramolecular transketalizations. In any event,
the mixture of 50 and 51 was readily separable by
chromatography, and the undesired ketals 51 could be
partially reequilibrated upon exposure to methanolic acid
to give additional quantities of 50. Oxidation of the
primary alcohol moiety in 50 with TPAP in the presence
of H2O and subsequent saponification of the methyl esters
gave 6,7-dideoxysqualestatin H5 (3) in 62% yield from
50.21 The synthetic 3 thus obtained gave 1H and 13C NMR
spectra identical with those of an authentic sample.22
Having successfully completed the enantioselective
total synthesis of 6,7-diedeoxysqualestatin H5, we turned
our attention to the possibility that the spirocyclic
intermediate 34 might be converted into other naturally
occurring zaragozic acids containing hydroxyl groups at
C(6) and C(7). We selected 7-deoxyzaragozic acid A as
our initial target as tactics developed for its synthesis
could be applied to the preparation of other zaragozic
acids. We envisioned that the C(6)-C(7) double bond in
34 would serve as a suitable functional handle for the
introduction of the requisite oxygen functionality at these
sites.
Exp er im en ta l Section
Gen er a l. Unless otherwise noted, solvents and reagents
were reagent grade and used without purification. Tetrahy-
drofuran (THF) was distilled from potassium/benzophenone
ketyl under nitrogen, and dichloromethane (CH2Cl2) was
(23) (a) Crump, R. A. N. C.; Fleming, I.; Urch, C. J . J . Chem. Soc.,
Perkin Trans. 1 1994, 701-706. (b) George, M. V.; Peterson, D. J .;
Gilman, H. J . Am. Chem. Soc. 1960, 82, 403-406.
Initial efforts directed toward oxidation of the buteno-
lide consisted of various attempts to epoxidize the double
bond. Unfortunately, all these experiments were unsuc-
(24) (a) Fleming, I.; Sanderson, P. E. J . Tetrahedron Lett. 1987, 28,
4229-4232. (b) Pearson, W. H.; Szura, D. P.; Postich, M. J . J . Am.
Chem. Soc. 1992, 114, 1329-1345. (c) Fleming, I.; Lawrence, N. J . J .
Chem. Soc., Perkin Trans. 1 1992, 3309-3326. (d) Lautens, M.; Zhang,
C. H.; Goh, B. J .; Crudden, C. M.; J ohnson, M. J . A. J . Org. Chem.
1994, 59, 6208-6222. (e) Fleming, I.; Henning, R.; Parker, D. C.; Plaut,
H. E.; Sanderson, P. E. J . J . Chem. Soc., Perkin Trans. 1 1995, 317-
337.
(21) Xu, Z.; J ohannes, C. W.; Houri, A. F.; La, D. S.; Cogan, D. A.;
Hofilena, G. E.; Hoveyda, A. H. J . Am. Chem. Soc. 1997, 119, 10302-
10316.
(22) We thank Dr. Philip J . Sidebottom (GlaxoWellcome, UK) for
1H and 13C NMR spectra of authentic 6,7-dideoxysqualestatin H5.

4206 J . Org. Chem., Vol. 67, No. 12, 2002
Naito et al.
distilled from calcium hydride prior to use. Reactions involving
air or moisture sensitive reagents or intermediates were
performed under an inert atmosphere of argon in glassware
that had been oven or flame dried. Melting points are uncor-
rected. Infrared (IR) spectra were recorded either neat on
sodium chloride plates or as solutions in CHCl3 as indicated
and are reported in wavenumbers (cm-1) referenced to the
1601.8 cm-1 absorption of a polystyrene film. 1H and 13C NMR
spectra were obtained as solutions in CDCl3 unless otherwise
indicated, and chemical shifts are reported in parts per million
(ppm, δ) downfield from internal standard Me4Si (TMS).
Coupling constants are reported in hertz (Hz). Spectral split-
ting patterns are designated as s, singlet; br, broad; d, doublet;
t, triplet; q, quartet; m, multiplet; and comp, complex multi-
plet. Flash chromatography was performed using Merck silica
gel 60 (230-400 mesh ASTM).25 Percent yields are given for
compounds that were g95% pure as judged by NMR.
layer was extracted with CH2Cl2 (2 × 50 mL). The combined
organic layers were dried (Na2SO4) and concentrated under
reduced pressure to give 10.84 g of a light yellow oil that was
purified by flash chromatography eluting with hexanes/EtOAc
(4:1) to afford 10.01 g (95%) of 28 as a colorless oil;1H NMR
(250 MHz) δ 7.65-7.62 (comp, 4 H), 7.44-7.35 (comp, 6 H),
7.19 (d, J ) 8.6 Hz, 2 H), 6.83 (d, J ) 8.6 Hz, 2 H), 4.57 (d,
J ) 11.1 Hz, 1 H), 4.34 (d, J ) 11.1 Hz, 1 H), 4.09 (d, J ) 6.9
Hz, 1 H), 3.98-3.94 (m, 1 H), 3.80-3.77 (m, 2 H), 3.79 (s, 3
H), 3.74 (s, 3 H), 2.56 (d, J ) 6.9 Hz, 1 H), 1.05 (s, 9 H); 13C
NMR (63 MHz) δ 171.6, 159.4, 135.5, 133.0, 132.9, 129.8, 129.8,
129.0, 127.8, 113.8, 78.3, 72.5, 72.3, 63.7, 55.2, 52.0, 26.8, 19.2;
IR (neat) 3490, 2952, 2932, 2856, 1750, 1611, 1513, 1427 cm-1
;
mass spectrum (CI) m/z 507.2203 [C29H36O6Si (M + 1) requires
507.2203] (base), 311, 251, 233.
Meth yl (2R,3R)-4-ter t-Bu tyld ip h en ylsiloxy-3-(5-p h en -
ylt h io-2-fu r oyloxy)-2-(4′-m et h oxyb en zyloxy)b u t a n oa t e
(29). A solution of 28 (10.01 g, 19.7 mmol), 23a (4.77 g, 21.6
mmol), DMAP (1.20 g, 9.8 mmol), and DCC (4.87 g, 23.6 mmol)
in CH2Cl2 (200 mL) was stirred at room temperature for 12 h.
The mixture was filtered, and the filtrate was concentrated
to give 16.4 g of a light tan oil that was purified by flash
chromatography eluting with hexanes/EtOAc (85:15) to afford
(3R,4R)-4-H yd r oxy-3-(4-m et h oxyb en zyloxy)d ih yd r o-
2(3H)-fu r a n on e (27). A suspension of erythronolactone (26)
(5.90 g, 50.0 mmol) and dibutyltin oxide (12.45 g, 50.0 mmol)
in toluene (250 mL) was heated at reflux for 6 h in an
apparatus equipped with a Dean-Stark trap. After cooling,
the solvent was removed under reduced pressure to give a tan
solid that was combined with CsF (14.43 g, 95.0 mmol) and
dried under reduced pressure. The solids were suspended in
DMF (150 mL), and KI (11.05 g, 66.5 mmol) and p-MeOC6H4-
CH2Cl (10.17 mL, 75.0 mmol) were added. The mixture was
stirred for 5 h at room temperature, EtOAc (350 mL) was
added, and the mixture was poured into H2O (300 mL). The
layers were separated, and the aqueous layer was extracted
with EtOAc (2 × 200 mL). The combined organic layers were
dried (Na2SO4) and concentrated under reduced pressure to
provide a yellow solid that was purified by column chroma-
tography eluting with hexanes/EtOAc (1:1-1:4) to afford 8.49
g of a mixture (6:1) of regioisomers. Recrystallization from hot
EtOAc provided 5.65 g (47%) of 27 as white needles: mp 100-
1
11.95 g (95%) of 29 as a colorless oil; H NMR (250 MHz) δ
7.64-7.60 (comp, 4 H), 7.42-7.21 (comp, 11 H), 7.11 (d, J )
3.4 Hz, 1 H), 6.79 (d, J ) 8.7 Hz, 2 H), 6.65 (d, J ) 3.4 Hz, 1
H), 5.45 (dt, J ) 4.5, 9.9 Hz, 1 H), 4.71 (d, J ) 11.5 Hz, 1 H),
4.46 (d, J ) 11.5 Hz, 1 H), 4.38 (d, J ) 5.4 Hz, 1 H), 3.99 (dd,
J ) 5.4, 11.1 Hz, 2 H), 3.93 (dd, J ) 4.5, 11.1 Hz), 3.76 (s, 3
H), 3.66 (s, 3 H), 1.00 (s, 9 H); 13C NMR (63 MHz) δ 170.2,
159.3, 156.6, 150.2, 146.4, 135.6, 135.5, 135.4, 133.4, 132.9,
132.8, 129.7, 129.6, 129.6, 129.2, 128.8, 127.6, 127.5, 127.5,
119.6, 118.5, 113.7, 75.7, 74.4, 72.5, 61.3, 55.1, 52.0, 26.6, 19.0;
IR (neat) 3070, 3012, 2931, 2856, 1731, 1612, 1577, 1513 cm-1
;
mass spectrum (CI) m/z 711.2459 [C40H43O8SSi (M + 1)
requires 711.2448] (base), 653, 302, 207.
1
Meth yl (2R,3R)-4-ter t-Bu tyld ip h en ylsiloxy-3-(5-p h en -
ylth io-2-fu r oyloxy)-2-h yd r oxybu ta n oa te. A solution of 29
(13.31 g, 18.7 mmol) and DDQ (8.50 g, 37.4 mmol) in CH2Cl2/
H2O (270 mL, 10:1) was stirred at 35 °C for 12 h. The solvent
was removed under reduced pressure, and the residue was
dissolved in Et2O (300 mL) and poured into saturated NaHCO3
(200 mL). The layers were separated, and the organic layer
was washed with saturated NaHCO3 (5 × 100 mL). The
organic layer was then stirred vigorously with saturated
NaHSO3 solution (500 mL) until no p-methoxybenzaldehyde
could be detected by TLC. The organic layer was dried (Na2-
SO4) and concentrated under reduced pressure to give 9.86 g
(89%) of alcohol as a yellow oil that was used in the next
reaction without further purification; 1H NMR (250 MHz) δ
7.69-7.63 (comp, 4 H), 7.44-7.22 (comp, 11 H), 7.17 (d, J )
3.5 Hz, 1 H), 6.63 (d, J ) 3.5 Hz, 1 H), 5.43 (dt, J ) 3.7, 9.4
Hz, 1 H), 4.58 (dd, J ) 3.7, 6.5 Hz, 1 H), 3.93 (dd, J ) 1.4, 5.8
Hz, 2 H), 3.72 (s, 3 H), 3.37 (d, J ) 6.5 Hz, 1 H), 1.03 (s, 9 H);
13C NMR (63 MHz) δ 172.3, 157.0, 150.5, 146.2, 135.4, 135.4,
133.3, 132.5, 129.7, 129.2, 127.7, 127.5, 119.9, 118.4, 74.8, 70.2,
61.5, 52.7, 26.7, 26.5, 19.0; IR (neat) 3489, 3070, 2953, 2856,
1736, 1566, 1463 cm-1; mass spectrum (CI) m/z 591.1883
[C32H35O7SSi (M + 1) requires 591.1873] (base), 513, 435, 302,
279.
Meth yl (3R)-4-ter t-Bu tyldiph en ylsiloxy-3-(5-ph en ylth io-
2-fu r oyloxy)-2-oxobu ta n oa te (25a ). Dess-Martin periodi-
nane (7.03 g, 16.6 mmol) was added to a stirred solution of
the preceding alcohol (6.53 g, 11.1 mmol) in CH2Cl2 (110 mL)
at 0 °C. After 10 min, wet CH2Cl2 (200 µL H2O in 200 mL CH2-
Cl2) was added dropwise, and stirring was continued for 2 h.
The solvents were removed under reduced pressure, and the
residue was dissolved in Et2O (200 mL). The solution was
washed with 10% NaHSO3 (100 mL) and saturated NaHCO3
(100 mL). The organic layer was dried (Na2SO4) and concen-
trated under reduced pressure to give 6.24 g (96%) of 25a as
a yellow oil; 1H NMR (300 MHz) δ 7.69-7.61 (comp, 4 H),
7.46-7.24 (comp, 11 H), 7.22 (d, J ) 3.4 Hz, 1 H), 6.66 (d, J )
3.4 Hz, 1 H), 5.99 (dd, J ) 3.4, 4.6 Hz, 1 H), 4.43 (dd, J ) 4.6,
11.4 Hz, 1 H), 4.09 (dd, J ) 3.4, 11.4 Hz, 1 H), 3.89 (s, 3 H),
103 °C; H NMR (250 MHz) δ 7.35 (dd, J ) 1.9, 6.6 Hz, 2 H),
7.32 (dd, J ) 2.0, 6.6 Hz, 2 H), 4.96 (d, J ) 11.6 Hz, 1 H), 4.76
(d, J ) 11.6 Hz, 1 H), 4.33-4.19 (comp, 3 H), 4.14 (d, J ) 4.8
Hz, 1 H), 3.81 (s, 3 H); 13C NMR (63 MHz) δ 173.5, 159.9, 130.1,
128.1, 114.1, 73.7, 72.6, 67.7, 55.3; IR (neat) 3462, 2958, 1781,
1612, 1514, 1465 cm-1; mass spectrum (CI) m/z 238.0846
[C12H15O5 (M + 1) requires 238.0841] (base), 161, 154, 149,
137.
(3R,4R)-4-ter t-Bu t yld ip h en ylsiloxy-3-(4-m et h oxyben -
zyloxy)d ih yd r o-2(3H)-fu r a n on e. A solution of 27 (5.65 g,
23.7 mmol) in CH2Cl2 (85.0 mL) containing imidazole (2.02 g,
29.6 mmol) and TBDPSCl (7.40 mL, 28.5 mmol) was stirred
for 5 h at room temperature. The mixture was poured into a
mixture of EtOAc (200 mL) and H2O (100 mL). The layers were
separated, and the aqueous layer was extracted with EtOAc
(2 × 50 mL). The combined organic layers were dried (Na2-
SO4) and concentrated under reduced pressure, and the
residual oil was purified by flash chromatography eluting with
hexanes/EtOAc (9:1) to afford 9.88 g (87%) of diprotected
lactone as a colorless oil; 1H NMR (250 MHz) δ 7.73-7.62
(comp, 4 H), 7.47-7.23 (comp, 6 H), 7.17 (d J ) 8.7 Hz, 2 H),
6.82 (d, J ) 8.7 Hz, 2 H), 4.67 (s, 2 H), 4.40 (ddd, J ) 1.1, 3.0,
4.4 Hz, 1 H), 4.13 (dd, J ) 1.1, 10.2 Hz, 1 H), 3.98 (dd, J )
3.0, 10.2 Hz, 1 H), 3.90 (d, J ) 4.4 Hz, 1 H), 3.77 (s, 3 H), 1.07
(s, 9 H); 13C NMR (63 MHz) δ 173.8, 159.4, 135.9, 135.6, 133.1,
132.5, 130.0, 129.9, 129.7, 128.6, 127.8, 127.6, 113.7, 74.0, 71.9,
71.5, 69.1, 55.1, 26.7, 19.2; IR (neat) 2333, 2858, 1790, 1613,
1514, 1464, 1428 cm-1; mass spectrum (CI) m/z 475.1932
[C28H32O5Si (M + 1) requires 475.1941] (base), 257, 241.
Meth yl (2R,3R)-4-ter t-Bu tyld ip h en ylsiloxy-3-h yd r oxy-
2-(4′-m eth oxyben zyoxy)bu ta n oa te (28). A solution of Cs2-
CO3 (0.4 g, 1.0 mmol) and the diprotected lactone from the
preceding experiment (9.88 g, 20.7 mmol) in MeOH (70 mL)
was stirred for 1 h at 0 °C. Brine (200 mL) and CH2Cl2 (100
mL) were added, and the layers were separated. The aqueous
(25) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2925.

Novel Approach to the Zaragozic Acids
J . Org. Chem., Vol. 67, No. 12, 2002 4207
0.99 (s, 9 H); 13C NMR (75 MHz) δ 187.1, 160.1, 156.9, 151.2,
145.7, 135.6, 135.4, 133.2, 132.6, 132.2, 130.0, 129.4, 127.9,
120.8, 118.6, 77.2, 63.2, 53.2, 26.5, 19.2; IR (CHCl3) 1736, 1577,
1463, 1296, 1114 cm-1; mass spectrum (CI) m/z 589.1720
[C32H33O7SiS (M + 1) requires 589.1716] (base), 511, 279, 177.
(5R,8R,9S)-8-ter t-Bu tyld ip h en ylsiloxym eth yl-9-m eth -
oxyca r bon yl-9-tr im eth ylsiloxy-1,7-d ioxa sp ir o[4.4]n on -3-
en e-2,6-d ion e (34). Neat TiCl4 (1.79 mL, 16.3 mmol) was
added dropwise to a stirred solution of R-ketoester 25a (3.20
g) in CH2Cl2 (25 mL) at 0 °C. The solution was stirred at 0 °C
for 30 min and then at room temperature for 2 h. The reaction
was cooled in an ice-H2O bath, and ice-cold H2O (100 mL) was
added. The layers were separated, and the aqueous layer was
extracted with CH2Cl2 (1 × 50 mL). The combined organic
layers were dried (Na2SO4), and the solvent was removed
under reduced pressure. The residue was dissolved in CH2Cl2
(25 mL) at 0 °C, and TMSCl (2.36 g, 2.76 mL, 21.7 mmol) and
imidazole (2.69 g, 43.4 mmol) were added with stirring. The
reaction was stirred at 0 °C for 1.5 h, and then EtOAc (50 mL)
was added. The mixture was washed with H2O (30 mL),
saturated NaHCO3 (30 mL), 1 M HCl solution (10 mL), and
brine (10 mL), dried (Na2SO4), and concentrated. The residue
was dissolved in CH2Cl2 (30 mL) at 0 °C, and NaHCO3 (1.82
g, 21.7 mmol) and MCPBA (3.90 g) were added. The mixture
was stirred at 0 °C for 30 min, whereupon EtOAc (100 mL)
and 10% Na2S2O3 (30 mL) were added. The layers were
separated, and the organic layer was washed with saturated
NaHCO3 (2 × 30 mL), dried (Na2SO4) and concentrated. The
residue was dissolved in EtOAc (25 mL) at 0 °C, and Et3N
(2.20 g, 3.0 mL 21.7 mmol) and TMSCl (0.69 mL, 5.43 mmol)
were added with stirring. The mixture was stirred at room
temperature for 30 min, and then EtOAc (50 mL) was added.
The reaction mixture was washed with H2O (30 mL), 1 M HCl
solution (20 mL), and brine (20 mL) and dried (Na2SO4). The
solvent was removed under reduced pressure, and the residue
was purified by flash chromatography eluting with hexanes/
EtOAc (6:1) to give 1.98 g of mixture of trimethylsilyl ethers.
Crystallization of the mixture from hexanes/EtOAc (4:1) (19
mL) gave 1.41 g (46%) of 34. The mother liquor was concen-
trated, and the residue was resubjected to chromatography
eluting with hexanes/EtOAc (5:1) to give 0.37 g of 34, which
was recrystallized from hexanes/EtOAc (5:1) (2 mL) to give
0.26 g of 34. The total recovery of 34 was 1.67 g (54%); mp
132-133 °C; 1H NMR (300 MHz) δ 7.68-7.65 (comp, 4 H), 7.54
(d, J ) 5.7 Hz, 1 H), 7.44-7.36 (comp, 6 H), 6.29 (d, J ) 5.7
Hz, 1 H), 4.96 (dd, J ) 4.5, 5.0 Hz, 1 H), 3.95-3.85 (m, 2 H),
3.75 (s, 3 H), 1.06 (s, 9 H), 0.02 (s, 9H); 13C NMR (75 MHz) δ
169.8, 167.5, 167.1, 150.4, 135.6, 132.4, 130.2, 128.0, 124.2,
90.1, 83.2, 83.0, 61.6, 53.6, 26.9, 19.3, 1.6; IR (CHCl3) 1798,
1770, 1102 cm-1; mass spectrum (CI) m/z 569.2037 [C29H37O8-
Si2 (M + 1) requires 569.2027] (base), 491.
(5R,8R,9S)-8-ter t-Bu tyld ip h en ylsiloxym eth yl-9-m eth -
oxycar bon yl-9-tr im eth ylsiloxy-1,7-dioxaspir o[4.4]n on an e-
2,6-d ion e (39). A mixture of butenolide 34 (1.28 g, 2.25 mmol)
in EtOAc (10 mL) containing 10% Pd/C (0.48 g, 0.45 mmol)
was stirred under H2 (1 atm) at room temperature for 15 h.
The catalyst was removed by filtration, and the filtrate was
concentrated under reduced pressure. The crude product was
purified by recrystallization from a mixture (1:1) of hexanes
and EtOAc (12 mL) to give 0.86 g of 39 as white crystals. The
filtrate was concentrated, and the residue was recrystallized
from a mixture (2:1) of hexanes and EtOAc (6 mL) to give an
additional 0.28 g of 39. The total recovery of 39 was 1.14 g
(89%); mp 142-145 °C; 1H NMR (300 MHz) δ 7.67-7.65 (comp,
4 H), 7.43-7.36 (comp, 6 H), 5.01 (dd, J ) 3.6, 7.5 Hz, 1 H),
3.89 (dd, J ) 3.6, 11.6 Hz, 1 H), 3.75 (dd, J ) 7.5, 11.6 Hz, 1
H), 3.74 (s, 3 H), 2.82-2.23 (comp, 2 H), 1.06 (s, 9 H), -0.02
(s, 9 H); 13C NMR (75 MHz) δ 174.2, 171.2, 168.1, 135.7, 135.6,
132.9, 132.6, 130.0, 127.9, 86.3, 83.5, 81.5, 62.5, 53.4, 27.2, 26.8,
23.4, 19.3, 1.4; IR (CHCl3) 1796, 1748, 1216, 1113 cm-1; mass
spectrum (CI) m/z 571.2179 [C29H39O8Si2 (M + 1) requires
571.2184] (base), 513, 493.
(152 mg, 6.25 mmol) in THF (3 mL) at room temperature. The
mixture was stirred at room temperature for 1 h and then
cooled to 0 °C, whereupon a solution of aldehyde 4418 (380 mg,
2.56 mmol) in THF (5 mL) was added. The mixture was stirred
at 0 °C for 10 min, at room temperature for 10 min and poured
into H2O (20 mL). The layers were separated, and the aqueous
layer was extracted with EtOAc (2 × 40 mL). The extracts
were dried (Na2SO4) and concentrated under reduced pressure.
The residue was purified by flash chromatography eluting with
hexanes/EtOAc (4:1) to give 366 mg (75%) of diastereomeric
mixture (∼1:1) of alcohols 45; 1H NMR (300 MHz) δ 7.31-
7.16 (comp, 5 H), 5.00-4.90 (comp, 2 H), 3.90-3.84 (comp, 1
H), 3.07 (dd, J ) 3.4, 13.2 Hz, 0.5 H), 2.76 (dd, J ) 6.0, 13.4
Hz, 0.5 H), 2.43 (dd, J ) 8.6, 13.4 Hz, 0.5 H), 2.29 (dd, J )
10.0, 13.2 Hz, 0.5 H), 2.00-1.86 (comp, 1 H), 1.75 (s, 1.5 H),
1.70 (s, 1.5 H), 1.59 (br s, 0.5 H), 1.58 (br d, J ) 4.1 Hz, 0.5
H), 0.84 (d, J ) 6.8 Hz, 1.5 H), 0.75 (d, J ) 6.8 Hz, 1.5 H); 13
C
NMR (75 MHz) δ 146.7, 146.5, 141.1, 141.0, 129.4, 129.1, 128.2,
128.1, 125.8, 125.7, 112.7, 111.3, 80.6, 77.9, 40.1, 38.2, 38.0,
37.6, 18.6, 17.4, 15.9, 13.4; IR (CHCl3) 3606, 1650, 1602, 1495,
1453, 1010, 907 cm-1; mass spectrum (CI) m/z 190.1352
[C13H18O (M+) requires 190.1358], 185, 173 (base), 153.
(2R,3E)-5-Br om o-2,4-d im eth yl-3-p en ten ylben zen e (46).
MsCl (223 µL, 2.88 mmol) was added to a stirred solution of
epimeric alcohols 45 (366 mg, 1.92 mmol) and Et3N (455 µL,
3.26 mmol) in dry CH2Cl2 (6 mL) at 0 °C. The reaction mixture
was stirred at room temperature for 1 h and then poured into
a mixture of EtOAc (50 mL) and H2O (50 mL). The layers were
separated, and the organic layer was washed with 1 M HCl
(10 mL), dried (Na2SO4), and concentrated under reduced
pressure to give 512 mg of crude mesylates. The mesylates
were dissolved in 2-butanone (10 mL) containing NaBr (395
mg, 3.84 mmol) and 18-crown-6 ether (50 mg, 0.19 mmol), and
the mixture was heated under reflux for 6 h. The mixture was
cooled to room temperature and poured into a mixture of
EtOAc (50 mL) and H2O (50 mL). The layers were separated,
and the organic layer was dried (Na2SO4) and concentrated
under reduced pressure. The residue was purified by flash
chromatography eluting with hexanes to give 395 mg (81%)
1
of bromide 46; H NMR (300 MHz) δ 7.28-7.11 (comp, 5 H),
5.43 (d, J ) 8.4 Hz, 1 H), 3.92 (s, 2 H), 2.65-2.54 (comp, 3 H),
1.54 (d, J ) 1.3 Hz, 3 H), 0.97 (d, J ) 6.4 Hz, 3 H); 13C NMR
(75 MHz) δ 140.3, 136.6, 131.2, 129.3, 128.2, 125.9, 43.4, 41.9,
35.0, 20.2, 14.7; IR (CHCl3) 1603, 1495, 1452 cm-1; mass
spectrum (CI) m/z 253.0592 [C13H18Br (M + 1) requires
253.0592], 173 (base).
(2R,3E)-2,4-Dim eth yl-6-p h en ylsu lfon yl-3-h exen ylben -
zen e (47). A solution of methylphenyl sulfone (244 mg, 1.56
mmol) in THF (2 mL) was added to a suspension of KH (57
mg, 1.42 mmol) in THF (2 mL) at 0 °C. The mixture was stirred
at 0 °C for 1 h, whereupon a solution of 46 (180 mg, 0.71 mmol)
in THF (1 mL) was added at 0 °C. The reaction mixture was
stirred at room temperature for 10 h and then saturated
aqueous NH4Cl (20 mL) was added. The layers were separated,
and the aqueous layer was extracted with EtOAc (2 × 30 mL).
The combined organic layers were dried (Na2SO4) and con-
centrated under reduced pressure. The residue was purified
by flash chromatography eluting with hexanes/EtOAc (5:1) to
give 208 mg (89%) of 47; 1H NMR (300 MHz) δ 7.93-7.25
(comp, 5 H), 7.24-7.05 (comp, 5 H), 4.95 (br d, J ) 8.9 Hz, 1
H), 3.14-2.98 (m, 2 H), 2.61-2.40 (comp, 3 H), 2.32-2.27 (m,
2 H), 1.31 (d, J ) 1.3 Hz, 3 H), 0.91 (d, J ) 6.2 Hz, 3 H); 13C
NMR (75 MHz) δ 140.7, 139.1, 133.7, 132.6, 130.0, 129.3, 129.2,
128.1, 128.0, 125.7, 55.2, 43.7, 34.6, 32.2, 20.6, 15.9; IR (CHCl3)
1603, 1495, 1448, 1307, 1151, 1086 cm-1; mass spectrum (CI)
m/z 329.1584 [C20H25O2S (M + 1) requires 329.1575], 187
(base), 143.
(1S,3R,4S,5R)-1-[(3E,5R)-3,5-Dim eth yl-6-p h en yl-3-h ex-
en yl]-4-h yd r oxy-3-h yd r oxym et h yl-4,5-b is(m et h oxyca r -
bon yl)-2,8-d ioxa bicyclo[3.2.1]octa n e (50) a n d (2R/S,5R,-
8R,9S)-2-[(3E,5R)-3,5-Dim eth yl-6-p h en yl-3-h exen yl]-9-h y-
dr oxy-8-(h ydr oxym eth yl)-2-m eth oxy-9-m eth oxycar bon yl-
1,7-dioxaspir o[4.4]n on an -6-on e (51a,b). A solution of n-BuLi
in hexanes (0.60 mL, 0.84 mmol) was added to a solution of
47 (138 mg, 0.42 mmol) in THF (1 mL) at -78 °C. The solution
(4R)-2,4-Dim eth yl-5-p h en yl-1-p en ten -3-ol (45). A solu-
tion of 2-bromopropene (605 mg, 5.00 mmol) in THF (2 mL)
was added slowly (ca 1 h) to a stirred suspension of magnesium

4208 J . Org. Chem., Vol. 67, No. 12, 2002
Naito et al.
was stirred at -78 °C for 1.5 h, and a solution of 39 (239 mg,
0.42 mmol) in THF (2 mL) was added. The reaction was stirred
at -78 °C for 1 h and then allowed to warm to 0 °C over 1 h.
Saturated aqueous NH4Cl (10 mL) was added at 0 °C, and the
layers were separated. The aqueous layer was extracted with
EtOAc (2 × 30 mL), and the combined organic layers were
dried (Na2SO4) and concentrated under reduced pressure. The
residue was dissolved in THF (8 mL), and the resulting
solution was added to aluminum amalgam, which was pre-
pared from small pieces of aluminum foil (1.56 g, 57.7 mmol)
and 2% aqueous HgCl2 (14 mL). HMPA (2 mL) and H2O (0.2
mL) were then added, and the reaction was stirred at room
temperature for 3 h, and the solids were removed by vacuum
filtration through a Celite pad, which was washed with Et2O
(1 × 50 mL). The combined filtrate and washings were washed
with H2O (2 × 50 mL), dried (Na2SO4), and concentrated under
reduced pressure. The residue was purified by flash chroma-
tography eluting with hexanes/EtOAc (3:1) to give 232 mg
(73%) of a mixture of epimeric hemiacetals 48 and ketone 49.
A portion of the above mixture of 48 and 49 (49 mg, 0.065
mmol) was dissolved in MeOH (5 mL) containing concentrated
H2SO4 (49 mg, 0.5 mmol), and the solution was stirred at room
temperature for 40 h. Pyridine (119 mg, 121 µL, 1.5 mmol)
was added, and the solvents were removed under reduced
pressure. The residue was dissolved in EtOAc (30 mL), and
the resulting solution was washed with H2O (10 mL), dried
(Na2SO4), and concentrated under reduced pressure. The
residue was purified by flash chromatography eluting with
hexanes/EtOAc (1:2) to give 7.6 mg (25%) of 50 and a total of
19.3 mg (65%) of the epimeric methyl acetals 51a and 51b.
6,7-Did eoxysqu a lesta tin H5 Dim eth yl Ester . N-Meth-
ylmorpholine N-oxide (25 mg, 0.22 mmol) and tetrapropylam-
monium perruthenate (2 mg, 0.005 mmol) were added to a
solution of alcohol 50 (25 mg, 0.05 mmol) in a mixture of CH3-
CN (1 mL) and H2O (2 mg, 0.11 mmol). The solution was
stirred at room temperature for 5 h, and then EtOAc (30 mL)
and 0.1 M HCl (10 mL) were added. The layers were separated,
and the organic layer was dried (Na2SO4) and concentrated
under reduced pressure. The residue was purified by flash
chromatography eluting with CH2Cl2/MeOH (5:1) to give 23
mg (88%) of 6,7-dideoxysqualestatin H5 dimethyl ester as a
1
glass; H NMR (300 MHz) δ 7.28-7.12 (comp, 5 H), 5.03 (d,
J ) 8.6 Hz, 1 H), 4.83 (s, 1 H), 3.94 (s, 3 H), 3.79 (s, 3 H),
3.12-3.01 (m, 1 H), 2.70-2.47 (m, 3 H), 2.22-1.96 (comp, 7
H), 1.46 (d, J ) 1.1 Hz, 3 H), 0.95 (d, J ) 6.6 Hz, 3 H); 13C
NMR (75 MHz) δ 169.8, 168.8, 165.9, 141.1, 132.9, 131.0, 129.3,
128.1, 125.8, 109.5, 88.1, 74.6, 53.8, 53.0, 44.0, 34.8, 34.5, 33.4,
31.4, 29.1, 20.9, 16.1; IR (CHCl3) 3525, 1740, 1603, 1439, 1271,
1124 cm-1; mass spectrum (CI) m/z 477.2107 [C25H33O9 (M +
1) requires 477.2125] (base), 459, 385.
6,7-Did eoxysqu a lesta tin H5 (3). 6,7-Dideoxysqualestatin
H5 dimethyl ester (10 mg, 0.021 mmol) was dissolved in
dioxane (1 mL) containing H2O (1.5 mg, 0.084 mmol), and
potasium tert-butoxide (24 mg, 0.21 mmol) was added. The
reaction mixture was heated at reflux for 1 d. The solvent was
evaporated, and H2O (10 mL) was added. The aqueous mixture
was washed with Et2O (1 × 10 mL), acidified with 0.1 M HCl
(4 mL), and extracted with EtOAc (2 × 20 mL). The combined
extracts were dried (Na2SO4) and concentrated under reduced
pressure. The residue was purified by reverse phase (C18)
HPLC eluting with MeOH/H2O/AcOH (850:150:2) to give 6.6
mg (70%) of 3; 1H NMR (500 MHz, CD3OD) δ 7.23-7.11 (comp,
5 H), 5.03 (d, J ) 9.0 Hz, 1 H), 4.87 (s, 1 H), 3.19-3.15 (m, 1
H), 2.68-2.60 (m, 1 H), 2.58 (dd, J ) 6.1, 13.0 Hz, 1 H), 2.47
(dd, J ) 8.3, 13.0 Hz, 1 H), 2.21-1.83 (comp, 7 H), 1.42 (d,
J ) 1.1 Hz, 3 H), 0.95 (d, J ) 6.6 Hz, 3 H); 13C NMR (125
MHz, CD3OD) δ 173.4, 172.4, 171.1, 142.4, 135.0, 131.7, 130.3,
129.0, 126.7, 109.9, 89.5, 76.2, 75.9, 45.1, 36.5, 35.9, 34.7, 32.2,
1
For 50: H NMR (300 MHz) δ 7.26-7.12 (comp, 5 H), 5.01
(d, J ) 9.1 Hz, 1 H), 4.28 (t, J ) 5.7 Hz, 1 H), 3.85 (s, 3 H),
3.79 (s, 3 H), 3.80-3.60 (m, 2 H), 3.12-3.03 (m, 1 H), 2.64-
2.51 (comp, 3 H), 2.21-1.85 (comp, 7 H), 1.44 (d, J ) 1.1 Hz,
3 H), 0.95 (d, J ) 6.4 Hz, 3 H); 13C NMR (75 MHz) δ 170.8,
169.4, 141.1, 133.2, 130.6, 129.3, 128.0, 125.7, 109.0, 88.1, 75.1,
74.1, 61.6, 53.2, 52.8, 44.0, 35.4, 34.5, 33.5, 31.6, 29.3, 20.9,
16.1; IR (CHCl3) 3538, 1737, 1439, 1268, 1229, 1124, 1036
cm-1; mass spectrum (CI) m/z 463.2323 [C25H35O8 (M + 1)
requires 463.2332] (base), 445.
30.3, 21.4, 16.1; IR (CHCl3) 3397, 1733, 1603, 1276, 1129 cm-1
;
For 51a : (less polar): mp, 100-102 °C; 1H NMR (300 MHz)
δ 7.25-7.11 (comp, 5 H), 4.98 (d, J ) 8.4 Hz, 1 H), 4.84 (t,
J ) 4.4 Hz, 1 H), 4.54 (s, 1 H), 4.10-4.07 (m, 2 H), 3.86 (s, 3
H), 3.22 (s, 3 H), 2.70-1.64 (comp, 11 H), 1.41 (d, J ) 1.2 Hz,
3 H), 0.96 (d, J ) 6.4 Hz, 3 H); 13C NMR (75 MHz) δ 173.9,
170.9, 141.1, 133.3, 130.6, 129.3, 128.0, 125.6, 112.4, 87.6, 81.0,
78.9, 60.9, 53.4, 48.9, 44.0, 35.7, 34.6, 33.0, 31.7, 27.7, 22.7,
14.2; IR (CHCl3) 3335, 1793, 1741, 1453, 1286, 1077, 1041,
1032 cm-1; mass spectrum (CI) m/z 463.2335 [C25H35O8 (M +
1) requires 463.2332], 431 (base), 403.
mass spectrum (FAB) m/z 447.1642 [C23H27O9 (M - 1) requires
447.1655] (base), 403.
Ack n ow led gm en t. We thank the National Insti-
tutes of Health, the Robert A. Welch Foundation, Pfizer,
Inc., and Merck Research Laboratories for their gener-
ous support of this research. We are also grateful to the
Sankyo Co., Ltd. (Tokyo, J apan) for financial support
for Dr. Satoru Naito.
For 51b: (more polar) 1H NMR (300 MHz) δ 7.26-7.12
(comp, 5 H), 4.99 (d, J ) 7.7 Hz, 1 H), 4.76 (t, J ) 5.0 Hz, 1
H), 4.11 (s, 1 H), 3.98-3.93 (m, 2 H), 3.92 (s, 3 H), 3.12 (s, 3
H), 2.75-1.70 (comp, 11 H), 1.43 (d, J ) 1.3 Hz, 3 H), 0.94 (d,
J ) 6.2 Hz, 3 H); 13C NMR (75 MHz) δ 174.2, 171.4, 141.1,
133.2, 130.6, 130.5, 129.3, 128.0, 125.7, 112.6, 87.0, 80.1, 79.4,
61.1, 53.8, 49.2, 44.0, 35.5, 34.6, 34.3, 32.8, 29.3, 20.8, 16.3;
Su p p or tin g In for m a tion Ava ila ble: Complete experi-
mental details and characterization (1H and 13C NMR spectra,
IR spectra, mass spectra) and copies of the 1H NMR spectra
of 10-17, 21, 22, 24a -c, 25a -c, 27-43, 45-47, 50-53 and
X-ray structural data for 15, 34, 36, 37, 39, and 53. This
material is available free of charge via the Internet at
http://pubs.acs.org.
IR (CHCl3) 3498, 1792, 1744, 1453, 1288, 1058, 1032 cm-1
;
mass spectrum (CI) m/z 463.2326 [C25H35O8 (M + 1) requires
463.2332], 431 (base), 403.
J O011157S