Asymmetric synthesis of the putative structure of (-)-oryzoxymycin.

Article abstract of DOI:10.1021/ol0269704

[reaction: see text] A short asymmetric synthesis of (2'S,5R,6R)-2'-[6-amino-5-hydroxy-1,3-cyclohexadiene-1-carbonyloxy]propionic acid, the enantiomer of the reported structure of (+)-oryzoxymycin is described. The reported spectral data does not match that obtained for synthetic "oryzoxymycin".

Full text of DOI:10.1021/ol0269704

ORGANIC
LETTERS
2003
Vol. 5, No. 3
239-242
Asymmetric Synthesis of the Putative
Structure of (−)-Oryzoxymycin
Mark E. Bunnage,† Thota Ganesh,‡ Ishmael B. Masesane,‡ Darren Orton,‡ and
,‡
Patrick G. Steel*
Department of Chemistry, UniVersity of Durham, South Road, Durham DH1 3LE, U.K.,
and Pfizer Global Research and DeVelopment, Sandwich, Kent CT13 9NJ, U.K.
p.g.steel@durham.ac.uk
Received September 26, 2002
ABSTRACT
A short asymmetric synthesis of (2′S,5R,6R)-2′-[6-amino-5-hydroxy-1,3-cyclohexadiene-1-carbonyloxy]propionic acid, the enantiomer of the
reported structure of (+)-oryzoxymycin is described. The reported spectral data does not match that obtained for synthetic “oryzoxymycin”.
In 1968, Hashimoto et al. reported the isolation of a novel
metabolite, oryzoxymycin, from a soil sample of a Strepto-
myces strain, exhibiting moderate in vitro activity against
Xanthomonas oryzae.1,2 The structure 1 was subsequently
determined to be that shown in Figure 1 by a combination
of spectroscopic, analytical, and degradation studies.3 As
such, the structure is closely related to intermediates in the
biosynthesis of anthranilate, e.g., 2.4,5,6 The principal differ-
ence in the compounds appears in the position of the lactate
or enoylpyruvate moiety, which is more commonly coupled
through the C-5 hydroxyl group.
this context, the interesting structure of 1 represented an
attractive target and prompted us to pursue its synthesis.
Reflecting the importance of these biosynthetic pathways,
the syntheses of a number of related structures have been
published.8 However, to date, neither a synthetic approach
to oryzoxymycin nor an asymmetric synthesis of the dihy-
drohydroxyanthranilate core has been reported.9 In this paper,
we describe our approach to these two goals.
Our retrosynthetic analysis for oryzoxymycin disconnected
the lactate unit, leaving the dihydroanthranilate ester 3, Figure
2. This could be generated from the base induced fragmenta-
tion of the bicyclic amino ester 4, derived from a Diels-
Alder reaction between furan and a â-nitroacrylate 5.10
As part of a broader synthetic program, we have been
exploring the use of substituted nitroacrylates as versatile
synthetic reagents to provide access to a range of confor-
mationally restricted functionalized â-amino acids.7 Within
† Pfizer Global Research and Development.
‡ University of Durham.
(1) Hashimoto, T.; Kondo, S.; Takita, T.; Hamada, M.; Takeuchi, T.;
Okami, Y.; Umezawa, H. J. Antibiot. 1968, 21, 653-658.
(2) Hashimoto, T.; Takahashi, S.; Naganawa, H.; Takita, T.; Maeda, K.;
Umezawa, H. J. Antibiot. 1972, 25, 350-355.
(3) Hashimoto, T.; Kondo, S.; Naganawa, H.; Takita, T.; Maeda, K.;
Umezawa, H. J. Antibiot. 1974, 27, 86-87.
(4) Walsh, C. T.; Erion, M. D.; Walts, A. E.; Delany, J. J.; Berchtold,
G. A. Biochemistry 1987, 26, 4734-4745.
(5) Morollo, A. A.; Finn, M. G.; Bauerle, R. J. Am. Chem. Soc. 1993,
115, 5, 816-817.
(6) Anderson, K. S.; Kati, W. M.; Ye, C. Z.; Liu, J.; Walsh, C. T.; Benesi,
A. J.; Johnson, K. A. J. Am. Chem. Soc. 1991, 113, 3198-3200.
Figure 1. Reported structure of oryzoxymycin and related com-
pounds.
10.1021/ol0269704 CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/09/2003

Scheme 1. Preparation of Dihydroanthranilate Core 10a
Figure 2. Retrosynthetic analysis for oryzoxymycin.
Efficient access to 5 was achieved through a modification
of the McMurry method11,12 involving the reaction of an
acrylate with N2O4 and I2 followed by careful elimination
of HI with Hunig’s base in ether. With this sequence, we
can routinely generate 10-20 g batches of this versatile
reagent in 70-80% overall yield, Scheme 1. Following
literature precedents,13 the furan Diels-Alder reaction with
nitroacrylate 5 occurred rapidly at room temperature to give
a mixture of cycloadducts favoring the required endo nitro
isomer 8. Enhanced selectivity could be obtained by running
the reaction in CHCl3 at -20 °C to give a separable 4:1
mixture of the two isomers in >90% yield. Attempts to
further improve this selectivity with Lewis acids were not
successful affording, instead, the substituted furan 11 in
moderate yields. Subsequent selective conversion to the
protected aminoester 9 was then achieved in a single pot by
reduction with Zn/HCl followed by addition of a large excess
i
a Reagents: (i) I2, N2O4, Et2O, 91%; (ii) Pr2NEt, Et2O, 84%;
(iii) furan, CHCl3, -20 °C, 120 h, 90% 8/7 81:19); (iv) chroma-
tography; (v) Zn, HCl, EtOH; (vi) Pr2NEt, (Boc)2O, 77%; (vii)
KHMDS, THF, -50 to +25 °C, 71%; (viii) KOH, THF, H2O, 68%;
(ix) CsF, (S)-MsOCH(CH3)CO2Me 13, DMF, 50 °C, 83%.
i
However, on workup considerable amounts of the starting
ester were recovered.15 Attempts to enhance the fragmenta-
tion by various rapid, mildly acidic, inverse quenches were
partially successful albeit only on very small scale. Finally,
the use of a less coordinating potassium counterion (KH-
MDS) allowed the isolation of the ester 10 in a reproducible
70% yield together with variable amounts of ethyl 3-hy-
droxybenzoate.
Preliminary attempts to protect the 5-hydroxyl group as a
silyl ether proved difficult and although this has subsequently
been achieved in high yield, the resultant ether is not
particularly stable to acidic or basic conditions undergoing
ready aromatization to give 3-hydroxybenzoate esters.16
Consequently, following routine hydrolysis of the ester group
we explored selective coupling of the resultant acid with
various lactate derivatives. Initial attempts to achieve this
transformation using a large number of classical coupling
reagents resulted in extensive decomposition. Believing this
to be due to a problem of steric hindrance to nucleophilic
attack at the activated carbonyl group we considered other
approaches involving nucleophilic displacement of an acti-
i
of Pr2NEt and Boc2O.
With this intermediate in hand, our attention turned to the
key fragmentation reaction. Related base promoted trans-
formations have been reported in the literature and our initial
experiments followed these precedents.14 With a variety of
lithium bases the reaction appeared, by TLC, to be extremely
rapid giving complete conversion of starting material.
(7) For a recent review of this field, see: Fu¨lo¨p, F. Chem. ReV. 2001,
101, 2181-2204.
(8) See, for example: (a) Teng, C. Y. P.; Ganem, B.; Doktor, S. Z.;
Nichols, B. P.; Bhatnagar, R. K.; Vining, L. C. J. Am. Chem. Soc. 1985,
107, 5008-5009. (b) Teng, C. Y. P.; Ganem, B. J. Am. Chem. Soc. 1984,
106, 2463-2464. (c) Policastro, P. P.; Au, K. G.; Walsh, C. T.; Berchtold,
G. A. J. Am. Chem. Soc. 1984, 106, 2443-2444. (d) Kozlowski, M. C.;
Tom, N. J.; Seto, C. T.; Sefler, A. M.; Bartlett, P. A. J. Am. Chem. Soc.
1995, 117, 2128-2140.
(9) Enantiomerically pure DHAA has been isolated from a fermantation
culture (McCormick, J. R. D.; Reichenthal, J.; Hirsch, U.; Sjolander, N. O.
J. Am. Chem. Soc. 1962, 84, 3711) and subsequently used in asymmetric
syntheses of related structures; see ref 8b. For an alternative approach to
DHAA, see: Fukuyama, T.; Nakatsuka, S.; Kishi, Y. Tetrahedron 1981,
37, 2045-2078 references therein.
(10) Just, G.; Martel, A. Tetrahedron Lett. 1973, 1517-1520.
(11) McMurry, J. E.; Musser, J. H. Org. Synth. 1977, 56, 65-68.
(12) Jew, S. S.; Kim, H. D.; Cho, Y. S.; Cook, C. H. Chem. Lett. 1986,
1747-1748.
(13) Itoh, K.; Kitoh, K.; Sera, A. Heterocycles 1999, 51, 243-248.
(14) (a) Brion, F. Tetrahedron Lett. 1982, 23, 5299-5302. (b) Rajapaksa,
D.; Keay, B. A.; Rodrigo, R. Can. J. Chem. 1984, 62, 826-827. (c)
Campbell, M. M.; Sainsbury, M.; Searle, P. A. Synthesis 1993, 179-193.
(d) Evans, D. A.; Barnes, D. M. Tetrahedron Lett. 1997, 38, 57-58 and
references therein.
(15) Similar observations have been noted elsewhere. See, for example,
ref 8d and: Couche, E.; Deschatrettes, R.; Poumellec, K.; Bortolussi, M.;
Mandville, G.; Bloch, R. Synlett 1999, 87-89.
(16) The relatively high stability of the free hydroxy compound relative
to substituted analogues has been noted in similar systems and can be
attributed to a conformational effect that places both heteroatom substituent
in a different plane to both the diene p-system and the neighboring H atoms.
For similar observations, see ref 8d.
240
Org. Lett., Vol. 5, No. 3, 2003

vated lactate derivative by a carboxylate anion. In this
context, Otera has reported that lactyl esters can be prepared
by SN2 displacement of the corresponding mesylate with
carboxylates in the presence of CsF.17 Consequently, an-
thranilate ester 10 was hydrolyzed with KOH and the
resultant acid treated with CsF and mesylate 13 in DMF to
give the desired lactate coupled product 12 as a mixture of
two diastereoisomers. Separation of the diasteroisomers
proved impossible, and we therefore sought an enantiose-
lective preparation of ester 10.
Scheme 2 a
Preliminary attempts to prepare and use chiral nitroacry-
lates did not prove to be viable and consequently we
considered resolution.18 A considerable body of literature has
reported on enzymatic hydrolysis of bicyclic esters related
to 9.19 Following these precedents, we screened a number
of different enzyme systems for selectivity. Ultimately, the
use of PLE in pH 8 phosphate buffer/ether for 4 days
afforded a very effective kinetic resolution, Figure 3. At the
a Reagents: (i) KHMDS, THF, -50 to +25 °C, 71%; (ii) KOH,
t
THF, H2O, 68%; (iii) CsF, (R)-MsOCH(CH3)CO2 Bu 19, DMF,
50 °C, 83%; (iv) TFA, DCM, 89%; (v) H2, Pd-C, MeOH, 98%
([R]D values in parentheses are derived from the enantiomeric
bicyclic ester 9b).
achieved with TFA to provide the enantiomer of natural
“oryzoxymycin” in good yield as the TFA salt 17a. In an
identical fashion, treatment of enantiomeric bicyclic ester
9b led to the C5,C6 diastereoisomer 17b. The absolute
stereochemistry of 15 and hence synthetic “oryzoxymycin”
17a was confirmed by reproducing the literature reduction
of 15b to known (1R,2S,3S)-2-tert-butoxycarbonylamino-3-
Figure 3. Enzymatic resolution of (()-9.
hydroxycyclohexanecarboxylic acid 18 [R]21 -37 (c ) 1,
D
H2O) (lit.9 [R]21 -35 (c ) 0.5, H2O). Interestingly, unlike
D
same time, a preparative chiral HPLC method (Chiralpak
AD, heptane/ethanol 95:5) was found to be equally effective
giving both enantiomers of the bicyclic ester with good
recovery. With the chiral esters in hand, a similar sequence
to that described above was followed, Scheme 2.
the free natural product, these “oryzoxymycin” salts show
appreciable stability when stored at 0 °C, and this has allowed
us to obtain satisfactory spectroscopic and analytical data to
support our assignment. In particular, HMBC correlations
between the cyclohexadienylcarboxylate carbonyl carbon and
H-2′ and H-2 confirmed the correct point of attachment of
the lactate unit. At this stage several differences between
our observed data and that reported in the original isolation
of oryzoxymycin became apparent. Namely, the optical
rotation [17a [R]21D -199 (c ) 1, H2O); lit.2 [R]21D +349 (c
) 1, H2O)] and significant differences in the infrared
spectrum both in the carbonyl region and characteristic bands
in the fingerprint region. This suggests that the correct
structure for oryzoxymycin may be the isomeric C-5 lactate
ester 20.20 Efforts to prepare this compound and verify this
Repeating the fragmentation-coupling sequence starting
from enantiomer 9a, using the mesylate 19, derived from
tert-butyl (R)-lactate, afforded protected “ent-oryzoxymycin”
16a as a single diastereoisomer as ascertained by high-field
NMR. With this substrate complete, deprotection could be
(17) Otera, J.; Nakazawa, K.; Sekoguchi, K.; Orita, A. Tetrahedron 1997,
53, 13633-13640.
(18) Nitroacrylates bearing chiral auxiliaries have been successfully
prepared and used in asymmetric Diels-Alder reactions. See: Clive, D. L.
J.; Bo, Y. X.; Selvakumar, N.; McDonald, R.; Santarsiero, B. D. Tetrahedron
1999, 55, 3277-3290.
(19) See, for example: Bloch, R.; Guibejampel, E.; Girard, C. Tetra-
hedron Lett. 1985, 26, 4087-4090. Schueller, C. M.; Manning, D. D.;
Kiessling, L. L. Tetrahedron Lett. 1996, 37, 8853-8856 and references
therein.
(20) In this context, it is relevant to note that corresponding C-5
acetate derivative of ester 10 has CdO stretches at 1737, 1717, and 1679
-1
cm
.
Org. Lett., Vol. 5, No. 3, 2003
241

hypothesis are in progress. These results will be reported in
detail in due course.
D.O.), and the University of Botswana (Scholarship to
I.B.M.). Mr. Steve Jackson (GlaxoSmithKline) for help with
the preparative HPLC, Dr. A. M. Kenwright for assistance
with NMR experiments, and Dr. M. Jones for mass spectra.
Supporting Information Available: Experimental sec-
tion containing procedures and characterization of key
compounds 10a, 16a,b, and 17a,b. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the EPSRC (support for
T.G. and studentship to D.O.), Pfizer Ltd (CASE award to
OL0269704
242
Org. Lett., Vol. 5, No. 3, 2003