Synthesis of (±)-epoxysorbicillinol using a novel cyclohexa-2,5-dienone with synthetic applications to other sorbicillin derivatives

Article abstract of DOI:10.1021/ol0155438

matrix presented A novel route to epoxysorbicillinol as well as dimers of sorbicillin is reported. The synthesis is - in principle - amenable to enantioselectivity. The key step is an oxidative dearomatization to produce a stable and highly malleable p-quinol intermediate, which undergoes a highly diastereoselective epoxidation.

Full text of DOI:10.1021/ol0155438

ORGANIC
LETTERS
2001
Vol. 3, No. 6
905-908
Synthesis of (±)-Epoxysorbicillinol Using
a Novel Cyclohexa-2,5-dienone with
Synthetic Applications to Other
Sorbicillin Derivatives
Liping H. Pettus, Ryan W. Van De Water, and Thomas R. R. Pettus*
Department of Chemistry and Biochemistry, UniVersity of California at Santa Barbara,
Santa Barbara, California 93106
pettus@chem.ucsb.edu
Received January 10, 2001
ABSTRACT
A novel route to epoxysorbicillinol as well as dimers of sorbicillin is reported. The synthesis issin principlesamenable to enantioselectivity.
The key step is an oxidative dearomatization to produce a stable and highly malleable p-quinol intermediate, which undergoes a highly
diastereoselective epoxidation.
Cyclohexanones 1-3 (Figure 1) belong to a family of
structurally diverse natural products isolated from both
marine and terrestrial sources that encompass a wide range
of biological activities.1 A highly functionalized tautomeric
cyclohexadienone, 4,2 has been proposed as the common
intermediate in the biosynthetic pathway.3b Indeed, several
dimeric members of this natural product family, 2-3 along
with trichodimerol, have yielded to synthesis by resolution
of the racemic precursor 5, followed by its saponification
and dimerization. These investigations3 testify to the dif-
ficulties that surround manipulating a ring system that
contains both a dienic and dienophilic segment, predisposed
toward dimerization.4
We were interested in developing a synthetic method that
avoided resolution of 5 and furnished a sturdier ring system
that was less prone toward dimerization. Such a process
might lead to both monomeric and dimeric members of the
(1) For isolation and medicinal value of sorbicillinoids, see: (a) Andrade,
R.; Ayer, W. A.; Mebe, P. P. Can. J. Chem. 1992, 70, 2526-2535. (b)
Andrade, R.; Ayer, W. A.; Trifonov, L. S. Can. J. Chem. 1996, 74, 371-
379. (c) Andrade, R.; Ayer, W. A.; Trifonov, L. S. Aust. J. Chem. 1997,
50, 255-257. (d) Sperry, S.; Samuels, G. J.; Crews, P. J. Org. Chem. 1998,
63, 10011-10014. (e) Abe, N.; Yamamoto, K.; Murata, T.; Hirota, A.
Tennen Yuki Kagobutsu Toronkai Koen Yoshishu 1999, 41, 553-558. (f)
Abe, N.; Murata, T.; Hirota, A. Biosci., Biotechnol., Biochem. 1998, 62,
661-666. (g) Shirota, O.; Pathak, V.; Hossain, C. F.; Sekita, S.; Takatori,
K.; Satake, M. J. Chem. Soc., Perkin Trans. 1 1997, 20, 2961-2964. (h)
Mazzucco, C. E.; Warr, G. J. Leukocyte Biol. 1996, 60, 271-277. (i) Warr,
G. A.; Veitch, J. A.; Walsh, A. W.; Hesler, G. A.; Pirnik, D. M.; Leet, J.
E.; Lin, P.-F. M.; Medina, I. A.; McBrien, K. D.; J. Antibiot. 1996, 49,
234-240. (j) Gao, Q.; Leet, J. E.; Thomas, S. T.; Matson, J. A.; Bancroft,
D. P. J. Nat. Prod. 1995, 58, 1817-1821.
(3) (a) Barnes-Seeman, D.; Corey, E. J. Org. Lett. 1999, 1, 1503-1504.
(b) Nicolaou, K. C.; Vassilikogiannakis, G.; Simonsen, K. B.; Baran, P. S.;
Zhong, Y.-L.; Vidali, V. P.; Pitsinos, E. N.; Couladouros, E. A. J. Am.
Chem. Soc. 2000, 122, 3071-3079. (c) Nicolaou, K. C.; Simonsen, K. B.;
Vassilikogiannakis, G.; Baran, P. S.; Vidali, V. P.; Pitsinos, E. N.;
Couladouros, E. A. Angew. Chem., Int. Ed. 1999, 38, 3555-3559. (d)
Nicolaou, K. C.; Jautelat, R.; Vassilikogiannakis, G.; Baran, P. S.; Simonsen,
K. B. Chem. Eur. J. 1999, 5, 3651-3665. (e) Wood, J. L.; Thompson, B.
D.; Yusuff, N.; Pflum, D. A. Abstracts of Papers, 219th National Meeting
of the American Chemical Society, San Francisco, CA, March 26-30, 2000;
American Chemical Society: Washington, DC, 2000; ORGN 848.
(4) A [4 + 2] cycloaddition of 4 produces bisorbicillinol 2, while a net
[4 + 4] cycloaddition of 4 results in trichodimerol, see refs 3a,b.
(2) Abe, N.; Sugimoto, O.; Tanji, K.-I.; Hirota, A. J. Am. Chem. Soc.
2000, 122, 12606-12607.
10.1021/ol0155438 CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/22/2001

could be incorporated in 7 that would promote stability,
govern the formation of a particular diastereomer in subse-
quent reactions, and expedite the eventual development of
an enantioselective method.
For these reasons the [P] and [R′] residues of 7 were to
be combined in a δ-lactone, 9, a structure we speculated
could be formed by electrophilic cyclization of an amide,
which was tethered ortho to a cationic site generated by
exposure of 6 [P ) -CH2C(O)NR2] or a similar resorcinol,
such as 12, to an oxidant [cf. Figure 3]. Scrutiny of the
Figure 1.
sorbicillin family of natural products and prove useful in the
synthesis of other complex molecules. Our plan entailed
developing an asymmetric oxidative dearomatization proce-
dure starting with the resorcinol derivative, 6,5 and affording
the chiral quinoid 7, which we anticipated would be more
manageable and therefore more synthetically useful than its
counterpart, the cyclohexa-2,4-dienone 5. The ultimate
synthetic value of 7, however, remained in doubt. The
adequacy of the 3°-alcoholic stereocenter in 7 to control the
formation of subsequent stereocenters was questionable and
potentially obviated efficient application of 7 to 1. Another
issue was the stability of 7. If the 3°-alcohol residue is
protected, the addition of certain nucleophilic reagents is
known to cause single electron transfer and elimination, re-
forming 6, rather than adding to the enone or ketone (Figure
2).6 In addition, in acidic media 7 is predisposed toward a
sigmatropic shift resulting in 8.7 Perhaps, a structural feature
Figure 3.
chemical literature for effective conditions for this intramo-
lecular oxidative cyclization revealed, however, that elec-
trophilic amide cyclizations generally yielded γ-lactones,8
while oxidative dearomatization usually involved an ipso
closure.9 Thus, precedent argued against the success of our
strategy for 1-3. Nevertheless, the oxidation was investi-
gated to test these notions in a racemic sense.
Coupling of sorbicillin 102b with the R-hydroxy amide 1110
using Mitsunobu’s conditions produces 12 (90%, Scheme
1). Oxidation of this resorcinol nucleus with 1 equiv of PhI-
(OCOCF3)2 followed by aqueous workup cleanly affords 9
(45%) along with epoxide 13 (5%). No other regioisomer
1
or derivative is apparent in H NMR spectra obtained for
the crude mixture. However, the mass transfer is inexplicably
low. The stability of 9 was remarkable, but not entirely
unexpected. The 3° [OR′] substituent disposed equatorially
in 9 is improperly aligned to eliminate, and being an electron-
deficient component of a lactone, a poor facilitator of a
(5) Van De Water, R. W.; Magdziak, D.; Chau, J.; Pettus, T. R. R. J.
Am. Chem. Soc. 2000, 122, 6502-6503.
(6) Morrow, G. W.; Schwind, B. Synth. Commun. 1995, 25, 269-276.
(7) Schultz, A. G.; Antoulinakis, E. G. J. Org. Chem. 1996, 61, 4555-
4559.
(8) Robin, S.; Rousseau, G. Tetrahedron 1998, 54, 13681-13736.
(9) There is but one example of an oxidative cyclization occurring with
an oxygen nucleophile tethered ortho to the site of cyclization, see: Pelter,
A.; Ward, R. S. Tetrahedron 2001, 57, 273-282. For an ipso example,
see: Wipf, P.; Kim, Y.; Fritch, P. C. J. Org. Chem. 1993, 58, 7195-7203.
(10) Antonsson, T.; Gustafsson, D.; Hoffmann, K.-J.; Nystrom, J.-E.;
Sorensen, H.; Sellen, M. PCT Int. Appl. WO 9723499 A1 19970703, 1997,
94 pp.
Figure 2.
906
Org. Lett., Vol. 3, No. 6, 2001

similar amount of PhIO affords 13 in almost quantitative
yield. Thus, we assume that 9 precedes 13 along the synthetic
pathway and further speculate that PhI(OCOCF3)2 in CH2-
Cl2 exists in equilibrium with PhIO. Epoxidation of 9 most
likely occurs by conjugate addition of PhIO to the activated
enone and cleavage of the [PhI-Osubstrate] bond by the
resulting enolate.12 The initial addition of PhIO occurs anti
to the angular methyl residue, which shields one side of the
enone and vinylogous ester from reaction. The relative
stereochemistry in 13 was assigned using NOE and com-
parison with 16, a structure that was rigorously established
using X-ray cystallography (Figure 4).13
Scheme 1a
Figure 4.
Vinyl ether 13 proved quite resistant to hydrolysis condi-
tions, which are usually employed with vinylogous esters
of this type.14 Therefore, the lactone was submitted to a
Weinreib procedure, which results in amide 14 (90%).15 This
material succumbs to SnCl4-mediated dealkylation of the
vinylogous ester and affords epoxysorbicillinol (1) (80%)
after acid cleavage of the tin enolate with 2 N HCl.
Access to the dimeric sorbicillinoids is achieved by
cleaving the tether to reveal the underlying cyclohexa-2,4-
dienone core. This is accomplished by treatment of 9 with
concentrated HCl, which contracts the lactone and produces
what we suppose is the mixed ketal 15.16 Subsequent addition
of aqueous KOH to the reaction mixture followed by acidic
workup produces bisorbicillinol (2) in 83% by the [4 + 2]
cycloaddition expected for these conditions.3b Synthesis of
2 also constitutes a formal synthesis of bisorbibutenolide (3).
The intramolecular cyclization leading to 9 should simplify
the development of an asymmetric oxidative dearomatization
procedure. During the conversion of 12 to 9, the oxygen atom
of the amide tether is restricted to two possible topologies
of closure, a compact transition state and a noncompact
a DEAD, PPh3, CH2Cl2 11, 90%; (b) 1.00 equiv of PhI(OCOCF3)
in CH2Cl2/CH3NO2 (3:1), 45%; (c) 2.2 equiv of PhI(OCOCF3)2 in
CH2Cl2/CH3NO2 (3:1), 40%; (d) 1.1 equiv of PhI(OCOCF3)2 in
CH2Cl2, 98%; (e) dimethylaluminum amide, CH2Cl2, 90%; (f)
SnCl4, CH2Cl2, 80%; (g) 8 equiv of concd HCl in THF, 15 not
isolated; (h) 15 equiv of KOH in H2O, 83%.
sigmatopic shift. Although the regiospecificity of the cy-
clization was predictable,11 the formation of epoxide 13 in
small quantities was quite surprising. We had anticipated that
formation of 13 would require a Julia epoxidation or some
similar type of procedure. However, treatment of 12 with
2.2 equiv of PhI(OCOCF3)2 exclusively affords the epoxide
13 as the sole diastereomer. Alternatively, treatment of 9
with 1.1 equiv of either PhI(OCOCF3)2 or treatment with a
(12) Moriarity, R. M.; Gupta, S. C.; Hu, H.; Berenschot, D. R.; White,
K. B. J. Am. Chem. Soc. 1981, 103, 686-688.
(13) Compound 16 was synthesized in a fashion analogous to that of
13. The X-ray data for 16 has been submitted to the Cambridge Crystal-
lographic database.
(14) (a) Obara, H.; Machida, Y.; Namazi, S.; Onodera, J. Chem. Lett.
1985, 1393-1394; (b) Johns, S. R.; Lamberton, J. A.; Morton, T. C.; Suars,
H.; Wiling, R. Aust. J. Chem. 1987, 40, 79-96.
(15) Basha, A.; Lipton, M.; Weinreb, S. Tetrahedron Lett. 1977, 4171-
4173.
(11) The coefficient of both the C-2 and C-4 sites in the cation are sizable
and within striking distance of the tether. However, the coefficient at C-2
is significantly reduced by its proximity to the adjacent carbonyl.
(16) We were unable to purify 15; however, replacing the sorbyl side
chain with an acetyl residue furnished a mixed ketal presumed to be an
analogue of 15.
Org. Lett., Vol. 3, No. 6, 2001
907

Although we have not yet completed satisfactory asym-
metric syntheses of 1, 2, and 3, similar treatment of 17, a
compound derived by Mitsunobu inversion of S-lactic acid
(Scheme 2), affords (+)-2 in 51% ee when the diastereomeric
mixture of analogues that corresponds to methylated deriva-
tives of 9 is carried forward without separation.17 We suspect
that A-1,3 strain between the chiral methyl residue and the
pyrrolidine ring restricts the cyclization to transition states
18aq and 18bq, where the methyl group is disposed in a
pseudo-axial orientation. These two transition states lead to
opposite enantiomers of 2. Because (+)-2 is obtained as the
major product, the pathway proceeding through the dipole-
stabilized intermediary 18bq appears to be the energetically
favored reaction coordinate for this transformation.18
Studies directed at optimizing the yield19 and enhancing
the enantioselectivity of the oxidative dearomatization are
underway. Applications to other natural products exhibiting
a highly oxidized core ring system such as manumycin,
scyphostatin, rishirilide B, and diazaphilonic acid are envi-
sioned.
Scheme 2a
a (i) 1.00 equiv of PhI(OCOCF3) in CH2Cl2/CH3NO2 (3:1); (ii)
8 equiv of concd HCl in THF, 15 not isolated; (iii) 15 equiv of
KOH in H2O, 30% overall with (+)-2 having 51% optical purity.
Acknowledgment. Support from the University of Cali-
fornia Cancer Research Coordinating Committee is greatly
appreciated.
Supporting Information Available: Spectral character-
ization for 9, 12, 13, 14, 16, 17, and 1. This material is
available free of charge via the Internet at http://pubs.acs.org.
transition state (cf. 18aq and 18bq for examples). In principle,
asymmetry can be induced during the cyclization by control-
ling both the reactive face of the amide carbonyl and the
topology of the cyclization. To this end, a stereocenter
installed in 12 at either one of two sites, between the carbonyl
and oxygen atoms in the tether moiety or adjacent to the
nitrogen atom in the pyrrolidine ring, may lead to optically
enriched products.
OL0155438
(17) The optical purity was determined by comparison of the [R]D of
synthetic and natural 2 at similar concentrations.
(18) Sevin, A. J. Org. Chem. 1986, 51, 2671-2675.
(19) Ley, S. V.; Finch, H.; Thomas, A. J. Chem. Soc., Perkin Trans. 1
1999, 10, 669-671.
908
Org. Lett., Vol. 3, No. 6, 2001