Self-consistent synthesis of the squalene synthase inhibitor zaragozic acid C via controlled oligomerization

Full text of DOI:10.1021/ja808347q

Published on Web 12/03/2008
Self-Consistent Synthesis of the Squalene Synthase Inhibitor Zaragozic
Acid C via Controlled Oligomerization
David A. Nicewicz, Andrew D. Satterfield, Daniel C. Schmitt, and Jeffrey S. Johnson*
Department of Chemistry, UniVersity of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290
Received October 28, 2008; E-mail: jsj@unc.edu
In the realm of materials chemistry, selective repetitive incor-
poration of prochiral monomers is used to prepare production-scale
quantities of stereochemically defined polymers. Chiral natural
products such as polyketides, oligosaccharides, and peptides feature
repeating subunits, but the application of controlled oligomerization
for the concurrent creation of carbon skeletal frameworks and
tetrahedral stereochemistry is an undeveloped tactic in total
synthesis (Figure 1).1 The zaragozic acidsspicomolar inhibitors
of the enzyme catalyzing the first committed step in the production
of cholesterol2,3 and compounds that potentiate radiochemotherapy
in the destruction of acute myeloid leukemia (AML) cell
lines4sprovide the context for the development and implementation
of a new synthetic strategy that reduces this idea to practice. This
report discloses the conceptual framework and experimental details
for a short synthesis of zaragozic acid C (1). The brevity of the
sequence described herein is the consequence of a heretofore
unprecedented stereoselective oligomerization reaction and adher-
Figure 2. Retrosynthetic analysis.
ence to a synthetic plan predicated on the minimization of oxidation
state variance and protecting group manipulation.
grafting of complementary nucleophilic and electrophilic reagents
onto a protected glycolic acid.9-11 The reactivity pattern
exhibited by 4 is summarized in Figure 3. Nucleophilic attack
on the silyl glyoxylate facilitates CfO silicon migration (Brook
rearrangement)12 to form a stabilized carbanion. This nascent
enolate reacts with an electrophile giving rise to a product
wherein two new bonds have been formed at the same carbon
atom.
Figure 1
The highly oxygenated 2,8-dioxabicyclo[3.2.1]octane-3,4,5-tri-
carboxylic acid core of zaragozic acid C features six contiguous
asymmetric centers that comprise the principal obstacle to synthesis.
The two fully substituted hydroxy acids at C4 and C5 in the
hydrated acyclic precursor 2 have been particularly nettlesome in
extant syntheses5,6 and commonly require multistep oxidation state,
functional group, and/or protecting group adjustment. What we
found striking about zaragozic acid C was that the global complexity
masks a rather elementary composition of simple building blocks.
A retrosynthetic analysis of zaragozic acid C through bond
disconnection into its constituent synthons (Figure 2, blue arrows)
reveals a repeating series of glycolic acid fragments.
In contemplating efficient connections that would enable the
rapid construction of 2 or its equivalent, we were compelled to
consider a “self-consistent sequence,” one that concurrently
merges carbon skeletal buildup with the introduction of stere-
ochemistry, as a method that would be uniquely efficient.7,8 Thus,
a self-consistent synthesis of the zaragozic acid core would be
one with connection of the glycolic acid subunits in the correct
relative configuration (red arrows). The successful implementa-
tion of this strategy requires a synthetic equivalent to the unusual
geminal dipolar glycolic acid synthon 3. We recently developed
the silyl glyoxylate 4 to function as a reagent for the geminal
Figure 3. Silyl glyoxylate as a glycolic acid synthon.
Given the retrosynthetic analysis presented in Figure 2 and
the surrogacy of 4 for 3, we tested the hypothesis that
enchainment of >1 equivalent of 4 could be used to assemble
the zaragozic acid backbone in one step. The addition of 1 equiv
of vinylmagnesium bromide to 2 equiv of 4 at -78 °C initiated
the oligomerization detailed in Scheme 1. The initial adduct
rearranged to provide a new carbon nucleophile that enchained
a second equivalent of 4. A second Brook rearrangement
delivered the second magnesium enolate of the cascade. The
sequence was terminated via the introduction of tert-butyl
glyoxylate (6). The R-hydroxy ester 7 was obtained in 45-50%
yield on a 15 g scale as one diastereomer, the structure of which
9
10.1021/ja808347q CCC: $40.75
2008 American Chemical Society
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C O M M U N I C A T I O N S
Scheme 1
uration was advanced with the expectation that it could be
rectified later in the synthesis.
The racemic R-hydroxy ester (()-7 was subjected to a vanadium-
catalyzed oxidative kinetic resolution using O2 as the stoichiometric
oxidant (Scheme 2).15 The resolution yielded 48% (of a maximum
50%) of (-)-7 with an enantiomer ratio (er) of 90:10. In anticipation
of a projected intramolecular aldol reaction to introduce the C6/
C7 diol, the C3 hydroxyl group was converted to its derived ester
9 with R-benzyloxyacetyl chloride. Neither the resolution nor the
acylation was successful with epi-7. The requisite C6 electrophile
was then revealed through ozonolysis of the vinyl group to provide
aldehyde 10.
A completely diastereoselective intramolecular aldol reaction
under carefully prescribed conditions fashioned the C6-C7 bond
and led to ε-lactone 11. Aldolization to form ε-lactones is
unusual16,17 and this case may be assisted by the high level of
substitution in the connecting carbon atoms.18 The ring closure is
proposed to proceed via the illustrated transition structure (based
on the X-ray diffraction study of 11) and gives the correct
stereochemistry at C7 but the incorrect configuration at C6.
Epimerization of 11 was possible to correct the C3 stereochemistry
at this stage, but once again the correct C3 epimer was found to be
unsuitable in subsequent manipulations.
was determined from an X-ray diffraction study.13,14 Three
contiguous stereogenic centers of the carbon skeleton were
assembled in the correct oxidation state. The direct delivery of
the needed functional array meant that no oxidation state
adjustment was required in this domain for the remainder of the
synthesis. Beyond the native efficiency issues, this attribute was
unexpectedly critical for the successful completion of the
synthesis (Vide infra). Moreover, the reaction achieved its
secondary design purpose of providing an ideal protecting group
scheme that masked every functional group except the secondary
alcohol that would participate in the subsequent reaction. The
product obtained possessed the correct relative stereochemistry
for the challenging C4 and C5 tertiary alcohols, while the
stereocenter that would eventually become C3 of the core
required inversion. Epimerization of 7 with 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU) was possible at this stage (eq 1), but
multiple downstream operations were unsuccessful with epi-7.
For this reason, compound 7 bearing the incorrect C3 config-
The C1 side chain was appended by means of a nucleophilic
addition of the organolithium 1219 to the ε-lactone 11. The resulting
lactol/ketol mixture (13) was treated with p-toluenesulfonic acid
in methanol, affording three products that were easily converged
Scheme 2a
a Conditions: (a) V(O)(OiPr)3 (5 mol %), 8 (5.5 mol %), O2 (1 atm), toluene 23 °C; (b) EtMgBr, Et2O; BnOCH2C(O)Cl; (c) O3, CH2Cl2/MeOH/pyridine;
then Me2S; (d) LDA, LiBr, 2-MeTHF, -78 to -55 °C; TMSCl; (e) 12, Et2O, -78 °C; (f) TsOH, MeOH, reflux, 72 h (+1 recycle); (g) TBSOTf, Et3N,
CH2Cl2; (h) KOtBu, tamylOH; (i) 15, toluene; (j) NaOMe, MeOH; (k) Pd/C, H2; (l) Ac2O, DMAP; (m) K2CO3, MeOH; (n) (tBuO2C)2O, 4-pyrrolidinopyridine;
c
(o) HexNdCdNcHex, 19, CH2Cl2; (p) TFA.
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C O M M U N I C A T I O N S
to the desired tricyclic ketal 14. In addition to 14 (ca. 10-15%),
the acid-catalyzed ketalization yielded a tricyclic lactone lacking
the C4 silyl protecting group (ca. 45-55%) and an unidentified
isomeric ketal (ca. 15-20%). Resubmission of the isomeric ketal
to the TsOH/MeOH conditions, combination with the unprotected
tricyclic lactone, and silylation of the C4 hydroxyl group provided
an acceptable combined yield of 14.
stimulating discussions and Dr. Sheo Singh (Merck) for an authentic
natural sample of zaragozic acid C.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
The presence of the δ-lactone in 14 highlights the remaining
stereochemical problem: the incorrect configurations at C6 and C3.
The lactone was opened under unusual but uniquely effective
conditions (potassium tert-butoxide in tert-amyl alcohol) and
surprisingly occurred with concomitant inversion of the C6 ste-
reocenter.20 A retro-aldol/aldol sequence is the probable mechanism
accounting for this fortuitous stereochemical correction,21 the
occurrence of which would have been impossible in the absence
of functional groups in the correct oxidation state. The reaction
conditions resulted in partial saponification of the methyl esters
necessitating re-esterification with isourea 15.22 Epimerization of
the inconsequential mixture of esters (16) with NaOMe in MeOH
achieved the desired configuration of the C3 stereocenter. All of
the ester groups were unexpectedly cleaved in this reaction; re-
esterification of the resulting triacid using 15 gave the fully
functionalizedzaragozicacidcore17withtherequiredstereochemistry.
(1) For an approach directed toward polyacetate synthesis, see: Boxer, M. B.;
Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 48-49.
(2) 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–
647.
(3) 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.;
Hensens, O. D. Proc. Nat. Acad. Sci.U.S.A. 1993, 90, 80–84.
(4) Li, H. Y.; Appelbaum, F. R.; Willman, C. L.; Zager, R. A.; Banker, D. E.
Blood 2003, 101, 3628–3634.
(5) (a) Carreira, E. M.; Du Bois, J. J. Am. Chem. Soc. 1994, 116, 10825–
10826. (b) Carreira, E. M.; Du Bois, J. J. Am. Chem. Soc. 1995, 117, 8106–
8125. (c) Nicolaou, K. C.; Yue, E. W.; Naniwa, Y.; De Riccardis, F.; Nadin,
A.; Leresche, J. E.; La Greca, S.; Yang, Z. Angew. Chem., Int. Ed. Engl.
1994, 33, 2184–2187. (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, 2187–2190. (e) Nicolaou, K. C.; Nadin, A.; Leresche, J. E.; Yue,
E. W.; La Greca, S. Angew. Chem., Int. Ed. Engl. 1994, 33, 2190–2191.
(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.sEur. J.
1995, 1, 467–494. (g) Evans, D. A.; Barrow, J. C.; Leighton, J. L.;
Robichaud, A. J.; Sefkow, M. J. Am. Chem. Soc. 1994, 116, 12111–12112.
(h) Stoermer, D.; Caron, S.; Heathcock, C. H. J. Org. Chem. 1996, 61,
9115–9125. (i) Caron, S.; Stoermer, D.; Mapp, A. K.; Heathcock, C. H. J.
Org. Chem. 1996, 61, 9126–9134. (j) Sato, H.; Nakamura, S.; Watanabe,
N.; Hashimoto, S. Synlett 1997, 451–454. (k) Nakamura, S.; Sato, H.; Hirata,
Y.; Watanabe, N.; Hashimoto, S. Tetrahedron 2005, 61, 11078–11106. (l)
Armstrong, A.; Jones, L. H.; Barsanti, P. A. Tetrahedron Lett. 1998, 39,
3337–3340. (m) Armstrong, A.; Barsanti, P. A.; Jones, L. H.; Ahmed, G.
J. Org. Chem. 2000, 65, 7020–7032. (n) Tomooka, K.; Kikuchi, M.; Igawa,
K.; Suzuki, M.; Keong, P.-H.; Nakai, T. Angew. Chem., Int. Ed. 2000, 39,
4502–4505. (o) Freeman-Cook, K. D.; Halcomb, R. L. J. Org. Chem. 2000,
65, 6153–6159. (p) Nakamura, S.; Hirata, Y.; Kurosaki, T.; Anada, M.;
Kataoka, O.; Kitagaki, S.; Hashimoto, S. Angew. Chem., Int. Ed. 2003, 42,
5351–5355. (q) Hirata, Y.; Nakamura, S.; Watanabe, N.; Kataoka, O.;
Kurosaki, T.; Anada, M.; Kitagaki, S.; Shiro, M.; Hashimoto, S.
Chem.sEur. J. 2006, 12, 8898–8925. (r) Bunte, J. O.; Cuzzupe, A. N.;
Daly, A. M.; Rizzacasa, M. A. Angew. Chem., Int. Ed. 2006, 45, 6376–
6380.
Our synthesis differentiates the C6 and C7 alcohols in the key
intermediate 17, but installation of the C6 acyl side chain rendered
subsequent debenzylation impracticable in our hands. Instead,
debenzylation and acetylation were achieved under standard condi-
tions to give the triacetate 18, a compound utilized by Carreira in
the total synthesis of zaragozic acid C.5a,b The analytical data were
in full accord with those reported (1H NMR in CDCl3 and 13C NMR
in both CD3OD5b and CDCl3,5r IR, TLC, sign of rotation). The
preparation of 18 thus constitutes a formal synthesis of zaragozic
acid C. As illustrated in Scheme 2, we applied the Carreira protocol
to complete the synthesis of zaragozic acid C (1) in four steps from
triacetate 18. The synthetic material was identical to a sample of
natural material.
(6) Reviews: (a) Nadin, A.; Nicolaou, K. C. Angew. Chem., Int. Ed. Engl. 1996,
35, 1622–1656. (b) Jotterand, N.; Vogel, P. Curr. Org. Chem. 2001, 5,
637–661. (c) Armstrong, A.; Blench, T. J. Tetrahedron 2002, 58, 9321–
9349.
The zaragozic acid C synthesis was achieved with concurrent
creation of the carbon skeleton and tetrahedral stereochemistry with
only one oxidation state change (alkene ozonolysis) and no
functional group repair in the core synthesis. This study further
highlights the utility of silyl glyoxylates as geminal dipolar glycolic
acid synthons. Considering the ubiquity of this functional group in
organic chemistry, the applicability of reagents like 4 for a range
of efficient molecular constructions appears promising. More
broadly, given the common occurrence of natural products that
contain repeating subunits, the concept of controlled oligomerization
could have significant ramifications in small molecule synthesis.
The development of new reagents and attendant synthetic strategy
will be required for the full realization of this potential, but the
chemistry described herein provides a working blueprint for such
tactics.
(7) (a) Hendrickson, J. B. Top. Curr. Chem. 1976, 62, 49–172. (b) Hendrickson,
J. B. J. Am. Chem. Soc. 1977, 99, 5439–5450.
(8) For an excellent summary of metrics, see: Baran, P. S.; Maimone, T. J.;
Richter, J. M. Nature 2007, 446, 404-408.
(9) Nicewicz, D. A.; Johnson, J. S. J. Am. Chem. Soc. 2005, 127, 6170–6171.
(10) Linghu, X.; Satterfield, A. D.; Johnson, J. S. J. Am. Chem. Soc. 2006, 128,
9302–9303.
(11) Nicewicz, D. A.; Bre´te´che´, G.; Johnson, J. S. Org. Synth. 2008, 85, 278–
286.
(12) Brook, A. G. Acc. Chem. Res. 1974, 7, 77–84.
(13) The remainder of the mass balance was attributed to a product resulting
from γ addition of the initially formed enolate to the second equivalent
of 4.
(14) CCDC 694353 (7) and 694354 (11) contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.ca-
m.ac.uk/data_request/cif.
(15) Radosevich, A. T.; Musich, C.; Toste, F. D. J. Am. Chem. Soc. 2005, 127,
1090–1091.
(16) Molander, G. A.; Etter, J. B.; Harring, L. S.; Thorel, P. J. J. Am. Chem.
Soc. 1991, 113, 8036–8045.
(17) Marcos, I. S.; Garcia, N.; Sexmero, M. J.; Hernandez, F. A.; Escola, M. A.;
Basabe, P.; Diez, D.; Urones, J. G. Tetrahedron 2007, 63, 2335–2350.
(18) Jung, M. E.; Gervay, J. J. Am. Chem. Soc. 1991, 113, 224–232.
(19) The Supporting Information contains details of the syntheses of organo-
lithium 12 and the unsaturated acid 19.
Acknowledgment. Funding for this work was provided by the
National Institutes of Health (National Institute of General Medical
Sciences, Grant GM068443), Eli Lilly, Amgen, and GlaxoSmith-
Kline. D.A.N. acknowledges an ACS Division of Organic Chem-
istry Fellowship sponsored by Novartis. J.S.J. is an Alfred P. Sloan
Fellow and a Camille-Dreyfus Teacher Scholar. X-ray crystal-
lography was performed by Dr. Peter White. We acknowledge and
thank Dr. Victor Cee (Amgen) and Dr. Wes Trotter (Merck) for
(20) Although the silyl group is cleaved during this reaction, its presence is
essential for the success of the sequence.
(21) White, J. D.; Cutshall, N. S.; Kim, T. S.; Shin, H. J. Am. Chem. Soc. 1995,
117, 9780–9781.
(22) Mathias, L. J. Synthesis 1979, 561–576.
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