Template-directed C-H insertion: synthesis of the dioxabicyclo[3.2.1]octane core of the zaragozic acids.

Article abstract of DOI:10.1021/ol0158361

[reaction: see text] The preparation of (+/-)-24, a model for the core of the zaragozic acids, is reported. The pivotal reaction in this endeavor is the dirhodium(II)-catalyzed intramolecular C-H bond insertion of 2-diazoacetyl-1,3-dioxane 4, a transforma

Full text of DOI:10.1021/ol0158361

ORGANIC
LETTERS
2001
Vol. 3, No. 15
2261-2264
Template-Directed C−H Insertion:
Synthesis of the
Dioxabicyclo[3.2.1]octane Core of the
Zaragozic Acids
Duncan J. Wardrop,* Adriana I. Velter, and Raymond E. Forslund
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
wardropd@uic.edu
Received March 13, 2001 (Revised Manuscript Received June 20, 2001)
ABSTRACT
The preparation of (±)-24, a model for the core of the zaragozic acids, is reported. The pivotal reaction in this endeavor is the dirhodium(II)-
catalyzed intramolecular C−H bond insertion of 2-diazoacetyl-1,3-dioxane 4, a transformation which generates four of the six stereocenters
present in the core structure. A novel method for the diastereoselective synthesis of pyruvic acid acetals was also developed and employed
in the preparation of 4 from xylitol derivative 7.
During the past two decades, the dirhodium(II)-catalyzed
decomposition of R-diazocarbonyl compounds and intra-
molecular C-H insertion of the resulting Rh carbenoids has
emerged as a particularly powerful methodology for the
construction of carbocyclic and heterocyclic rings.1 Herein
we report a method for the preparation of 2,8-dioxabicyclo-
[3.2.1]octanones involving the C-H insertion of 2-diazo-
acetyl-1,3-dioxanes. We also report the application of this
insertion strategy to the synthesis of the acetal core of the
zaragozic acids (squalestatins). This family of fungal me-
tabolites, first isolated in 1992 by groups at Merck2 and
Glaxo,3 respectively, share a common 2,8-dioxabicyclo[3.2.1]-
octane-3,4,5-tricarboxylic acid core which houses an array
of six contiguous stereocenters. Since the zaragozic acids
are potent inhibitors of mammalian squalene synthase, the
enzyme responsible for the first committed step of cholesterol
biosynthesis, they are potential therapeutic agents for the
treatment of hypercholesterolaemia.2
The unique structure and potent biological activities
associated with the zaragozic acids have, not surprisingly,
stimulated intense synthetic interest.4,5 A widely used strategy
has been the preparation and acetalization of highly func-
tionalized ketone polyols which contain up to five of the six
stereocenters present in the natural product. Unfortunately,
this bicyclization strategy has, in some cases, been compli-
(1) Reviews: (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern
Catalytic Methods for Organic Synthesis with Diazo Compounds: from
Cyclopropanes to Ylides; Wiley-Interscience: New York, 1998. (b) Padwa,
A.; Austin, D. J. Angew. Chem., Int. Ed. Engl. 1994, 33, 1797-1815. (c)
Taber, D. F. Methods of Organic Chemistry (Houben-Weyl); Helmchen,
G., Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.; Georg Thieme
Verlag: Stuttgart, 1995; Vol. E21a, pp 1127-1148. (d) Ye, T.; McKervey,
A. Chem. ReV. 1994, 94, 1091-1160. (e) Sulikowski, G. A.; Cha, K. L.;
Sulikowski, M. M. Tetrahedron: Asymmetry 1998, 9, 3145-3169.
(2) For a review of the discovery, biosynthesis, and mechanism of action
of the zaragozic acids, see: Bergstrom, J. D.; Dufresne, C.; Bills, G. F.;
Nallinomstead, M.; Byrne, K. Annu. ReV. Microbiol. 1995, 49, 607-639
and references therein.
(3) 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, 11705-11708.
(4) Review: Nadin, A.; Nicolaou, K. C. Angew. Chem., Int. Ed. Engl.
1996, 35, 1622-1656.
(5) For a review of work not covered in ref 4, see: Armstrong, A.;
Barsanti, P. A.; Jones, L. H.; Ahmed, G. J. Org. Chem. 2000, 65, 7020-
7032 and references therein.
10.1021/ol0158361 CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/27/2001

cated by formation of isomeric bicyclic acetals.4,5 Intrigued
by the pseudo C2-symmetrical nature of the acetal core of 1
(Figure 1), we believed that a synthetic strategy centered
Before embarking on the synthesis of 24, our investigation
began with the preparation of a range of simple 2-diazo-
acetyl-1,3-dioxanes 11. Following a protocol reported by
Ziegler,9 treatment of a solution of 8a-d (Table 1, entries
Table 1. Preparation 2-Diazoacetyl-1,3-dioxanes 11a
Figure 1.
upon formation of the 5/6 C-C bond would enable us to
set four of the six asymmetric centers within the acetal core
in a single transformation since this disconnection would
generate a meso precursor.6 The retrosynthetic disconnections
which form the basis of this planned synthesis of zaragozic
acid A (1) are illustrated in Scheme 1.
entry
8
R1
R2
Me Me
Et Et
(CH2)4
R3
R4 methoda
11
yield (%)b
1
2
3
4
5
8a
8b
8c
8d Me
8e
H
H
H
H
a, b, d
a, b, d
a, b, d
a, b, d
c, d
11a
11b
11c
11d
11e
61
60
68
80
49
H
H
H
H
H
Me
H
H
H
a Methods: (a) MeCOCO2Me, BF3‚Et2O, CH3CN, rt, 16 h; (b) NaOH,
THF, H2O, reflux, 5 h; (c) (i) MeCOCO2H, Amberlite IR-120, PhH, reflux
16 h; (ii) NaOH, H2O, reflux, 2 h. (d) (i) Et3N, CH2Cl2, -20 °C; (ii)
i-BuOCOCl, -20 °C, 5 min; (iii) CH2N2, Et2O, -20 °C f rt, 16 h. b Overall
yield of 11 from 8 after purification by flash chromatography.
Scheme 1. Retrosynthetic Analysis
1-4) in acetonitrile with BF3‚Et2O (2 equiv) and methyl
pyruvate (2 equiv) gave 9 which were then saponified to
furnish the corresponding carboxylic acids 10. On the other
hand, substrate 10e (entry 5) was prepared by acid-catalyzed
acetalization of 1,3-propanediol (8e) (1.5 equiv) and pyruvic
acid (1.0 equiv) followed by saponification of the resulting
mixture of ester products.10 Encouragingly, in the case of
8d (entry 4), acetalization provided a single diastereomer in
which the C-2 carboxylate group was found to be in the axial
orientation, trans to the equatorial ring substituents. The
relative configuration of the acetal stereocenter in this case
was determined using 13C NMR spectroscopy, examining
the C-2 methyl group (δ 26.8 ppm) which is known to be
sensitive to the relative configuration of the adjoining acetal.11
Treatment of 10 with Et3N and isobutyl chloroformate now
generated the corresponding mixed anhydrides which, upon
treatment with an ethereal solution of diazomethane, provided
the R-diazo ketones 11 in good yield.12 With a protocol for
the preparation of 11 established, attention now turned to
the C-H insertion. Thus, slow addition of 11a to dirho-
dium(II) tetraacetate (Rh2(O2CCH3)4) (2 mol %) in CH2Cl2
afforded 12a, the product of transannular C-H insertion, in
52% yield together with a small amount of 13a (4%) (Table
2, entry 1). This bicyclic enol ether proved to be rather
Removal of the C-6 O-acyl side chain and disconnection
at C-3/4′ of 1 (Figure 1) leads to 2 which is the relay
compound in Heathcock’s synthesis of 1.7 Further discon-
nection of 2 generates 3 which could be obtained from 4 by
transannular C-H insertion. From this point, the synthetic
problem is now reduced to an exercise in the stereocontrolled
preparation of a symmetrical 1,3-dioxane. Under thermody-
namically controlled conditions, acetalization of 6 or 7 with
pyruvate derivative 5 should favor the diastereomer in which
the C-2 carboxylate group adopts the axial position.8 While
the synthesis of 1 will require us to prepare 6 and address
the introduction of a C-1 side chain other than methyl, our
initial studies have been directed toward the preparation of
24 (Scheme 3) from xylitol derivative 7 and methyl pyruvate
5 (R2 ) Me).
(6) While this work was in progress, Wills and co-workers reported a
related approach to the zaragozic acids based on alkylidene carbene
insertion: Walker, L. F.; Connolly, S.; Wills, M. Tetrahedron Lett. 1998,
39, 5273-5276.
(7) Stoermer, D.; Caron, S.; Heathcock, C. H. J. Org. Chem. 1996, 61,
9115-9125.
(8) 2-Carboxy-1,3-dioxanes display a pronounced preference (∼4 kcal/
mol) for the axially oriented 2-carboxylate group: Bailey, W. F.; Eliel, E.
L. J. Am. Chem. Soc. 1974, 96, 1798-1806.
(9) Ziegler, T. Tetrahedron Lett. 1994, 35, 6857-6860.
(10) Newman, M. S.; Chen, C. C. J. Org. Chem. 1973, 38, 1173-1177.
(11) Gorin, P. A. J.; Mazurek, M.; Iacomini, M.; Duarte, J. H. Carbohydr.
Res. 1982, 100, 1-15.
(12) Plucinska, K.; Liberek, B. Tetrahedron 1987, 43, 3509-3517.
2262
Org. Lett., Vol. 3, No. 15, 2001

R′-diazoketones 11 are more resistant to diazo decomposition
than other R-diazo ketones and may be due to the electron-
withdrawing effect of the acetal group adjoining the diazo
center.1a
Table 2. Preparation of 2,8-Dioxabicyclo[3.2.1]octanones 12a
Our synthesis of the zaragozic acetal core itself com-
menced from 3,5-O-benzylidene xylitol (17)14 which was
O-alkylated (NaH, BnBr, DMF) to provide the corresponding
tribenzyl ether in 51% yield (Scheme 3). Removal of the
entry
11
methoda
yield (%) of 12b
yield (%) of 13b
1
2
3
4
5
6
11a
11a
11b
11c
11d
11e
a
b
a
a
a
a
52
45
42
50
50
44
4
5
12
11
Scheme 3. Synthesis of the Zaragozic Core Acetal 24a
a Methods: (a) a solution of 11 in CH2Cl2 was added via syringe pump
to a solution of Rh2(O2CCH3)4 (2 mol %) in CH2Cl2 (0.023 M), over 20 h;
(b) a solution of 11 in CH2Cl2 was added via syringe pump to a solution of
Rh2(cap)4 (2 mol %) in CH2Cl2, at reflux, over 72 h. b Yields of 12 and 13
after purification by flash chromatography.
unstable to silica gel chromatography in addition to being
volatile. Cyclization of substrates 12b-e (entries 3-6) under
these conditions provided similar yields of 12, while 13 was
isolated from the reactions of 11b and 11c only.
With regard to the formation of 13, Clark and co-workers
recently reported the formation of analogous products during
the diazo decomposition of R-diazo-R′-alkoxy ketones.13
According to Clark’s mechanistic rationale, the rhodium
carbenoid species generated upon diazo decomposition of
11a faces two possible fates: (i) concerted C-H insertion
to form 12a or (ii) oxygen-assisted hydride transfer to the
electron-deficient carbene center, generating oxonium ion-
rhodium enolate species 15. Cyclization of 15, or its enol
tautomer 16, could then generate 12a or 13a (Scheme 2).
Scheme 2
a Reagents and conditions: (a) NaH, BnBr, Bu4NI, DMF, rt, 20
h; (b) EtSH, p-TsOH, CHCl3, rt, 48 h; (c) (i) MeC(OMe)3, p-TsOH,
4 Å molecular sieves, CH2Cl2, rt, 30 min; (ii) Na2CO3; (d)
Me3SiCN, SnCl2, 4 Å molecular sieves, CH2Cl2, reflux, 1.5 h; (iii)
K2CO3; (e) NaOH, H2O2, EtOH, reflux, 1 h; (f) DMF-DMA (3.5
equiv), MeOH, 100 °C, 72 h; (g) LiOH, THF, H2O, 4 h, reflux; (h)
(i) Et3N, rt, 30 min; (ii) i-BuOCOCl, CH2Cl2, -30 °C, 30 min;
(iii) CH2N2, 0 °C, 1 h; (i) Rh2(OAc)4, CH2Cl2, rt, 8 h; (j) (i)
KHMDS, THF, -78 °C, 40 min; (ii) TIPSCl, -78 °C, 30 min; (k)
(i) BH3‚Me2S, THF, reflux, 5 h; (ii) H2O2, 0.6 M NaOH, rt, 48 h.
Hydride transfers have also been reported by Doyle and
White,13b,c who note that this process becomes prevalent
when the oxonium ion species 15/16 are stabilized. Reason-
ing that a less electrophilic catalyst might suppress hydride
transfer and favor insertion, dirhodium(II) tetra(caprolac-
tamate) (Rh2(cap)4) was examined as a catalyst. However,
decomposition of 11a was prohibitively slow at room
temperature and only proceeded upon heating for 72 h. The
yields of 12a and 13a in this case were similar to those found
with Rh2(O2CCH3)4 (entry 2). It appears that bis-R-alkoxy-
benzylidene acetal proceeded smoothly to provide 7 upon
treatment with ethanethiol and a catalytic amount of p-TsOH
in chloroform. With the precedent gained in our initial study,
it was now anticipated that acetalization of 7 with methyl
pyruvate would provide 1,3-dioxane 21. All attempts to effect
this transformation using Ziegler’s protocol, however, re-
sulted in the decomposition of 7. In view of the centrality
of this transformation to our synthesis, it was decided to
(13) (a) Clark, J. S.; Dossetter, A. G.; Russel, C. A.; Whittingham, W.
G. J. Org. Chem. 1997, 62, 4910-4911. (b) Doyle, M. P.; Dyatkin, A. B.;
Autry, C. L. J. Chem. Soc., Perkin Trans. 1 1995, 619-621. (c) White, J.
D.; Hrnciar, P. J. Org. Chem. 1999, 64, 7271-7223.
(14) Hann, R. M.; Ness, A. T.; Hudson, C. S. J. Am. Chem. Soc. 1946,
68, 1769-1774.
Org. Lett., Vol. 3, No. 15, 2001
2263

develop an alternative pyruvate acetal synthesis which would
be compatible with the labile O-benzyl protecting groups.
To this end, ortho ester 18 was prepared as a single isomer
by treating 7 with trimethyl orthoacetate in the presence of
a catalytic amount of p-TsOH.15 The relative stereochemistry
of 18 was established by examination of the NOESY
spectrum which showed correlations between the axially
positioned C-2 methoxyl group and the adjacent C-4/6
hydrogens. Since 18 proved to be susceptible to hydrolysis,
it was immediately treated with trimethylsilyl cyanide
(Me3SiCN) and SnCl2 in CH2Cl2.16 Upon heating to reflux
for 1.5 h, cyanation proceeded to give 19 as a single isomer
in high yield.17 Hydrolysis of this material with alkaline
hydrogen peroxide then gave 20 in 73% overall yield from
7. Following a method recently reported by Brocchetta,18
20 was now converted to the corresponding methyl ester 21
in 73% yield by heating with dimethylformamide dimethyl
acetal (DMF-DMA) in methanol at 90 °C (sealed tube) for
72 h.
With 21 secured, R-diazo ketone 4 was now prepared in
88% yield by a sequence of saponification, mixed anhydride
formation, and in situ treatment with diazomethane. Upon
slow addition of 4 to a solution of Rh2(OAc)4 (2 mol %) in
CH2Cl2 at room temperature, diazo decomposition proceeded
smoothly to afford 22 in 49% yield. Prompted by a report
from Brown19 describing the regioselective hydroboration
of 3-methoxy-2,5-dihydrofuran, we now decided to inves-
tigate the hydroboration of 23 as means of installing the
C-6/7 trans diol moiety in a single operation. Deprotonation
of 22 with KHMDS in THF and addition of TIPSCl furnished
23 which smoothly underwent hydroboration (BH3‚Me2S)
in THF upon heating at reflux for 5 h. Oxidation of the
resulting borane with alkaline hydrogen peroxide proved to
be rather slow, taking 48 h to reach completion, but
ultimately provided the differentially protected diol 24 in
81%. The relative stereochemistry of 24 was confirmed by
measurement of scalar couplings and NOESY correlations:
H-7 (δ 4.06 ppm) appeared as a doublet (J ) 2.2 Hz) while
H-6 (δ 4.00 ppm), a multiplet, displayed NOESY correlations
to H-3 (δ 4.38 ppm) and H-4 (δ 3.50 ppm). The 2.2 Hz
coupling constant between the C-6 and C-7 hydrogens is
diagnostic of their anti relationship5 and confirms that
hydroboration proceeded from the exo face of 23.
In summary, the acetal core of the zaragozic acids 24 has
been prepared in 11 steps from 17 using a C-H bond
insertion strategy which sets four of the six stereocenters of
the natural product. Investigations of the asymmetric de-
symmetrization of 4 and installation of the C-1 side chain
present in 1 are now in progress and will be reported in due
course.
Acknowledgment. We thank the National Institutes of
Health (GM59157-01), the National Science Foundation
(NSF-DUE-98-562167), and the University of Illinois at
Chicago for financial support. A.I.V. thanks the Fulbright
Commission for generous support in the form of a scholar-
ship. We are indebted to Professor Mike Doyle of the
University of Arizona for generously providing a sample of
Rh2(cap)4. We also thank Mateusz Cebula for his initial
investigations of the ortho ester chemistry reported herein.
(15) Eliel, E. L.; Nader, F. W. J. Am. Chem. Soc. 1970, 92, 584-589.
(16) Utimoto, K.; Wakabayashi, Y.; Horiie, T.; Inoue, M.; Shishiyama,
Y.; Obayashi, M.; Nozaki, H. Tetrahedron 1983, 39, 967-973.
(17) Axially orientated 2-methoxy-1,3-dioxanes are known to undergo
nucleophilic substitution with retention at C-2: (a) Eliel, E. L.; Nader, F.
W. J. Am. Chem. Soc. 1970, 92, 584-590. (b) Rychnovsky, S. D.; Kim, J.
Tetrahedron Lett. 1991, 32, 7223-7224.
(18) Anelli, P. L.; Brocchetta, M.; Palano, D.; Visigalli, M. Tetrahedron
Lett. 1997, 38, 2367-2368.
(19) Brown, H. C.; Murali, D.; Singaram, B. J. Organomet. Chem. 1999,
581, 116-121.
Supporting Information Available: Full experimental
procedures and spectral data for compounds 4, 7, 9-13, and
17-24. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0158361
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Org. Lett., Vol. 3, No. 15, 2001