Total synthesis of (+)-apiosporamide: Assignment of relative and absolute configuration

Article abstract of DOI:10.1002/anie.200502015

Antipodal relationship: A convergent synthetic pathway leading to 4-hydroxy-2-pyridinones was involved in the synthesis of apiosporamide (1) and YM-215343 (2). Both have an antipodal relationship to the natural metabolites, whose relative and absolute configurations have been established. Activated β-alanine enolate equivalents derived from β-lactams were the key to the synthesis. (Chemical Equation Presented).

Full text of DOI:10.1002/anie.200502015

Angewandte
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challenging. Although homonuclear and heteronuclear
2D NMR spectroscopic experiments permitted the assign-
ment of the relative configuration of the decalin ring, the
configuration of the epoxydiol system could not be deter-
mined unambiguously. The latter moiety was tentatively
assumed to have an all-syn topology. Unfortunately, the
stereochemical features of the trans decalin portion present
an independent 1H NMR spectroscopic system relative to the
cyclohexanediol moiety owing to the planarity of the central
pyridinone linkage. Lastly, the substitution pattern of the
pyridinone ring was assumed by comparison with the
13C NMR spectroscopic chemical shifts of 1 with ilicicolin H,
which was previously described and confirmed by total
synthesis as a 5-aryl-4-hydroxy-3-acyl-2-pyridone.[3] Some
examples of this family include militarinone A,[4] oxysporidi-
none,[5] fischerin,[6] and funiculosin.[7] Herein, we report a
convergent total synthesis of (+)-apiosporamide (1) and its
subsequent oxidation to yield YM-215343 (2). Our efforts
have established the assignments of the relative and absolute
configurations, which confirm the antipodal relationship of
our synthetic materials with the naturally occurring metab-
olites.
Assignment of Configuration
DOI: 10.1002/anie.200502015
Total Synthesis of (+)-Apiosporamide:
Assignment of Relative and Absolute
Configuration**
To address the structural ambiguities of 1, we chose to
explore a convergent plan for stereocontrolled syntheses of
the trans-decalin and the epoxydiol components. This strategy
required appropriate functionalization of each subunit for the
late stage formation of the central pyridone. Additionally, we
sought to devise general, stereodivergent schemes that would
permit the flexibility necessary to examine the substantial
stereochemical issues previously outlined.
Studies of the cyclohexanediol portion of 1 began with the
synthesis of nonracemic 4-hydroxy-2-cyclohexenones. The
multigram preparation of 4 (Scheme 1) utilized (ꢀ)-quinic
acid as a chiral-pool precursor through formation of the pure
acetonide 3 as described by Danishefsky and co-workers.[8]
Consideration of the appropriate functionality for direct link-
age with the decalin component as well as subsequent pyridone
ring formation led us to examine the enolate condensation of
N-(4-methoxybenzyloxy)azetidin-2-one (5) with 4.
David R. Williams,* David C. Kammler,
Andrew F. Donnell, and William R. F. Goundry
Apiosporamide (1) was isolated from the fungus Apiospora
montagnei Saccardo (Amphisphaeriaceae) in 1994 by Gloer
and co-workers.[1] This unique 4-hydroxy-2-pyridinone exhib-
its potent antifungal activity against the coprophilous fungus
Ascobolus furfuraceus and exhibits antibacterial activity
against Bacillus subtilis and Staphylococcus aureus. Recently,
the corresponding ketone YM-215343 (2) was identified and
shown to demonstrate cytotoxicity against HeLa S3 cell
cultures.[2] Structural assignments of 1 (and 2) have proven
[*] Prof. D. R. Williams, D. C. Kammler, A. F. Donnell,
Dr. W. R. F. Goundry
Techniques for the incorporation of intact b-lactams are
rare.[9] Although the ring strain of 5 incorporates the desired
activation for coupling operations, the limited prospects for
addition reactions with unsubstituted b-lactams suggest issues
of incompatibility that arise from enolate instability, self-
condensation, and acylation of alkoxide intermediates. Thus,
we were gratified to find that the hydroxamic acid derivative 5
led to solutions of dependable enolates.[10] The starting b-
lactam 5 was readily obtained through procedures described
by Reinhoudt and van Elburg.[11] Complete deprotonation
was initially recorded through reaction with LiHMDS for 2 h
Department of Chemistry
Indiana University
800 East Kirkwood Avenue
Bloomington, IN 47405-7102 (USA)
Fax: (+1)812-855-8300
E-mail: williamd@indiana.edu
[**] We thank the National Institutes of Health (National Institute of
General Medical Sciences (GM41560)) for support of this research.
We also thank Professor Gloer for providing a 1H NMR spectrum of
authentic 1.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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use of KHMDS afforded diastereomers 6 and 7 (1.6:1 d.r.) in
97% yield. Although modest improvements in stereocontrol
were recorded,[13] the overall efficiency, scale, and ease of
separation for reactions with KHMDS proved most advanta-
geous for these efforts.
The relative stereochemistry within the cyclohexane ring
of 1 was investigated through the epoxidation of 6 and 7 with
catalytic molybdenum hexacarbonyl and tert-butylhydroper-
oxide,[14] to yield a single oxirane in each case. Coupling
constants derived from 1H NMR spectroscopic data for these
materials failed to provide a clear basis for stereochemical
assignments. However, mild hydrolysis of the TBS ethers gave
the crystalline diols 8 and 9, which were unambiguously
assigned by X-ray diffraction studies.[15] Internally directed
reactions were confirmed, and led to the use of the secondary
allylic alcohol derived from 10 for Henbest epoxidation and
silyl protection to yield diastereomer 11. Further studies to
prepare sufficient quantities of the remaining fourth diaster-
eomer that corresponds to the C4’ epimer of 11 encountered
several problems. Comparisons of 1H NMR spectroscopic
data for various derivatives of 8, 9, and 11 with the reported
1H NMR spectroscopic characteristics of apiosporamide were
not feasible. The presence of the pyridone ring of 1 effectively
inverts the relative positions of chemical shifts observed for
the hydrogen atoms of the neighboring oxirane moiety. Thus,
each b-lactam of Scheme 1 was independently advanced in
the synthetic pathway.
The decalin portion of 1 was prepared through an
intramolecular Diels–Alder reaction that began with (S)-
citronellol (12; Scheme 2). Oxidation[16] of 12 with TEMPO
Scheme 1. Formation of b-lactam diastereomers 8, 9, and 11. a) H2,
Pd(OH)2/C, 97%; b) DBU, TBSCl, heat, 72%; c) KHMDS, THF,
ꢀ788C, 2 h; then 4 at ꢀ788C; 97%, (d.r. 1.6:1); d) cat. [Mo(CO)6],
t-BuOOH, benzene/CH2Cl2 (5:1 by v/v), 808C, 2 h; 66%; e) cat. aq.
H2SiF6, CH3CN/tBuOH (9:1 by v/v), 228C, 80%; f) TBAF, 08C, 98%;
g) MCPBA, CH2Cl2, NaHCO3, 54%; h) TBSCl, imidazole, CH2Cl2,
100%. DBU=1,8-diazabicyclo[5.4.0]undec-7-ene; TBS=tert-butyldime-
thylsilyl; HMDS=1,1,1,3,3,3-hexamethyldisilazane; TBAF=tetrabutyl-
ammonium fluoride; MLPBA=meta-chloroperoxybenzoic acid.
at ꢀ788C. Although the enolate decomposed upon
warming to ꢀ408C, the addition of simple aldehydes
at ꢀ788C immediately led to the formation of addition
adducts in 80–95% yields.[12] In the case of cyclo-
hexenone 4, these experiments gave the two readily
separated b-lactam diastereomers 6 and 7 (1.2:1) in
high yields, (Scheme 1) without evidence of compet-
ing a deprotonation or conjugate addition. The ste-
reochemical features of 6 and 7 are rationalized by
arrangements A and B (Scheme 1), which illustrate
nucleophilic addition to either face of the carbonyl
group while minimizing nonbonded interactions with
the a-methylene of the starting ketone. Coordination
with the lithium cation is not essential as reactions in
the presence of 12[crown]-4 produced similar product
ratios. This conclusion was supported when the
reactions were increased to multigram levels, as the
Scheme 2. Formation of the trans-decalin 19. a) Cat. TEMPO, PhI(OAc)2,
CH2Cl2, 70%; b) 13, K2CO3, MeOH, RT, 82%; c) cat. OsO4, K3Fe(CN)6, K2CO3,
tBuOH/H2O (1:1 by v/v), 94%; then, NaIO4, aq. THF (1:1); then
H3CC(O)CH2P(O)(OMe)2, K2CO3, 91% (13:1 E/Z); d) [Cp2Zr(H)Cl], CH2Cl2, RT;
=
then I2, 77%; e) [Pd(PPh3)4] (5 mol%), (E)-BrZnCH CHCH3 (2.5 equiv), THF/
Et2O/pentane (4:4:1), ꢀ308C!RT; 74%; f) Dess–Martin periodinane, py,
CH2Cl2, 90%; g) EtAlCl2, toluene, ꢀ788C!RT, 72% (>97:3 d.r.); h) LiHMDS,
THF, ꢀ788C!08C; then HMPA at ꢀ788C; then MeOC(O)CN, 62%; i) KOH,
aq. MeOH, 08C, 81%. TEMPO=2,2,6,6-tetramethyl-1-piperidinyloxy radical,
Cp=cyclopentadienyl, HMPA=hexamethylphosphoric triamide.
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and treatment with the Ohira–Bestmann reagent 13[17]
provided a volatile alkyne. Selective oxidative cleavage of
the trisubstituted olefin followed by treatment with
H3CC(O)CH2P(O)(OMe)2 led to the conjugated enone in
14 (13:1 E/Z). The syn hydrozirconation of 14 followed by
treatment with iodine yielded the E alkenyl iodide 15 with
concomitant reduction of the ketone.[18] Facile Negishi
coupling[19] with (E)-prop-1-enylzinc(ii) bromide cleanly
delivered a single diene diastereomer without the need for
protection strategies to prevent the competing Heck reaction,
and subsequent mild oxidation recovered the intact enone of
16.
samarium diiodide yielded the dihydropyridone 22 with
ꢀ
selective N O bond cleavage. Subsequent oxidation with
bromotrichloromethane, based upon our previous studies,[22]
gave the expected 4-hydroxy-2-pyridinone for final depro-
tection to afford (+)-apiosporamide (1). The spectral data of
1 proved to be identical to that reported for the naturally
occurring 1, but the optical rotation was opposite.[1,23,24]
Further confirmation was obtained by the Dess–Martin
oxidation[25] of synthetic 1 to yield the antipode of 2,
(+)-YM-215343„ which was validated by comparison with
published data for the natural product.[2,26] Although the
structural homology of pyridones 1 and 2 suggest evidence of
a common biogenesis, we did not assume homochirality.
However, the characterization of these natural products
provides physical and spectral data that uniquely identify
the synthetic 1 and 2 compared to other diastereomers of this
series.
The Lewis acid mediated intramolecular Diels–Alder
reaction of 16 proceeded in toluene at ꢀ788C with subsequent
warming to 228C. Excellent stereoselectivity was observed,
1
and the trans decalin 17 was assigned by H NMR spectros-
copy. Decalin 17 arises through an exo bridging arrangement
with endo positioning of the ester function; a chairlike
conformation of the tether is adopted with a pseudoequatorial
disposition of the methyl substituent.[20] The corresponding
thermal cycloaddition (toluene, 1808C) occurred with poorer
stereocontrol (d.r. 70:30). Deprotonation of 17 under kinetic
conditions and C-acylation according to the Mander proto-
col[21] gave pure b-ketoester 18, which was then used to
produce the labile carboxylic acid 19 prior to coupling studies.
The synthesis of 1 was pursued from 11 (Scheme 3).
Although several pathways were examined, superior results
involved the initial nucleophilic opening of 11 to give the N-
alkoxyamine 20 for quantitative N-acylation with the carbox-
ylic acid 19. Subsequent acyl activation in the presence of
DBU resulted in ring closure to form 21. Reduction with
In conclusion, we have established the relative and
absolute configuration of apiosporamide and have illustrated
an efficient strategy for the synthesis of complex pyridinones.
The use of unsubstituted b-lactams as b-alanine enolate
equivalents has been demonstrated. Finally, the conversion of
synthetic (+)-apiosporamide into (+)-YM-215343 has been
described and has confirmed the antipodal relationship to the
natural products.
Received: June 10, 2005
Published online: September 27, 2005
Keywords: lactams · antifungal agents · antitumor agents ·
.
heterocycles · total synthesis
[1] A. A. Alfatafta, J. B. Gloer, J. A. Scott, D. Malloch, J.
Nat. Prod. 1994, 57, 1696.
[2] M. Shibazaki, M. Taniguchi, T. Yokoi, K. Nagai, M.
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[3] D. R. Williams, M. L. Bremmer, D. L. Brown, J.
D’Antuono, J. Org. Chem. 1985, 50, 2807, and refer-
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[4] K. Schmidt, W. Günther, S. Stoyanova, B. Schubert, Z.
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[6] H. Fujimoto, M. Ikeda, K. Yamamoto, M. Yamazaki, J.
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[8] J. E. Audia, L. Biosvert, A. D. Patten, A. Villalobos,
S. J. Danishefsky, J. Org. Chem. 1989, 54, 3738; see also:
B. M. Trost, A. G. Romero, J. Org. Chem. 1986, 51,
2332; J. B. Evarts, P. L. Fuchs, Tetrahedron Lett. 2001,
42, 3673.
Scheme 3. Synthesis of apiosporamide (1). a) Allyl alcohol, nBuLi (1 equiv);
then 11; ꢀ788C!RT; 80%; b) BOP, Et3N, MeCN, RT, 99%; c) [Pd(PPh3)4],
pyrrolidine, CH2Cl2, 85%; d) BOP, CH2Cl2, DBU, ꢀ208C, 56%; e) SmI2, THF,
98%; f) BrCCl3, TMG, 65%; then HF·pyr, THF, 75%; g) Dess–Martin period-
inane, CH2Cl2, 92%. BOP=benzotriazol-1-yloxy-tris(dimethylamino)phospho-
nium hexafluorophosphate, TMG=1,1,3,3-tetramethylguanidine.
[9] For some examples of enolate formation for addition
reactions of b-lactams, see: a) F. A. Bouffard, D. B. R.
Johnston, B. G. Christensen, J. Org. Chem. 1980, 45,
1130; b) F. A. Bouffard, T. N. Salzmann, Tetrahedron
Lett. 1985, 26, 6285, and references therein; c) I. Ojima,
Y. Pei, Tetrahedron Lett. 1990, 31, 977; d) E. J. Thomas,
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A. C. Williams, J. Chem. Soc. Perkin Trans. 1 1995, 351; e) B. J.
37.6, 36.7, 34.4, 32.5, 31.6, 31.0, 25.8, 23.0, 18.4 ppm; HRMS: m/z
calcd for C24H32NO6 [M + H]+ 430.2224; found: 430.2225.
Kim, Y. S. Park, P. Beak, J. Org. Chem. 1999, 64, 1705.
[10] For a review of N-alkoxy-b-lactams see: M. J. Miller, Acc. Chem.
Res. 1986, 19, 49.
[11] P. A. van Elburg, D. N. Reinhoudt, Heterocycles 1987, 26, 437.
[12] D. R. Williams, A. F. Donnell, D. C. Kammler, Heterocycles
2004, 62, 167.
[13] Studies of sparteine with various chiral boron enolates, Ti-based
complexes of (R)- and (S)-binol, and incorporation of non-
racemic amines in b-lactams will be described in the full account.
[14] K. B. Sharpless, R. C. Michaelson, J. Am. Chem. Soc. 1973, 95,
6136.
1
[24] Due to the anticipated similarities of H and 13C NMR spectro-
scopic data, and the discrepancy in the specific optical rotation in
1, the route was adapted for independent preparation of three
diastereomers with the syn relationship between the epoxide and
tertiary alcohol (as in 8 and 9). All of these isomers demon-
strated great instability and underwent opening of the oxirane, as
illustrated in the formation of 24 through directed oxidation of
23. Interestingly, five-membered-ring products were not
observed. Additional information will be provided in a full
account.
[15] a) Crystal data for 8: colorless plate, 0.50 ” 0.24 ”
0.08 mm3, C17H21N1O6, M = 335.35, orthorhombic,
space group P212121, a = 5.6693(2), b = 10.2239(3),
c = 28.4168(10) Š, V= 1647.10(10) Š3, T= 111(2) K,
Z = 4, 1calcd = 1.352 Mgmꢀ3, m = 0.1026 mmꢀ1, 2qmax
=
60.02, MoKa (l = 0.71073). A total of 23151 reflec-
tions were measured, of which 4801 were independ-
ent (Rint = 0.032). Final residuals were R1 = 0.0382
and wR1 = 0.0406 (for 4385 observed reflections with
I > 2s(I), 301 parameters, 0 restraints) with GOF =
1.029, Flack parameter ꢀ0.2(7), and largest residual
ꢀ3
peak 0.603 eŠ and hole ꢀ0.198 eŠꢀ3; b) crystal
data for 9: colorless plate, 0.20 ” 0.18 ” 0.10 mm3,
C17H21NO6, M = 1099.67, orthorhombic, space group
[25] D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277.
[26] Synthetic and natural 2 were identical in all respects, except for
rotation. Optical rotation for natural YM-215343 was recorded
P212121, a = 5.8978(2), b = 7.5734(3), c = 35.1598(13) Š, V=
1570.46(10) Š3, T= 112(2) K, Z = 4, 1calcd = 0.108 Mgmꢀ3, m =
as [a]2D5 = ꢀ448 (c = 0.10 MeOH), and synthetic 2 was [a]2D4
=
0.108 mmꢀ1
, 2qmax = 60.06, MoKa (l = 0.71073). A total of
+ 478 (c = 0.225 MeOH). Diastereoisomer 25 proved to be stable
and spectroscopically similar to apiosporamide. However, oxi-
dation gave ketone 26 which was clearly diastereomeric to 2.
16372 reflections were measured, of which 4597 were independ-
ent (Rint = 0.031). Final residuals were R = 0.0502 and wR2 =
0.1108 (for 4319 observed reflections with I > 2s(I), 247 param-
eters, 46 restraints) with GOF = 1.056, Flack parameter
ꢀ3
ꢀ0.1(10), and largest residual peak 0.388 eŠ
and hole
ꢀ0.415 eŠꢀ3. CCDC-274063 (8) and -274064 (9) contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from the Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[16] A. De Mico, R. Margarita, L. Parlanti, A. Vescovi, G. Piancatelli,
J. Org. Chem. 1997, 62, 6974.
[17] S. Müller, B. Liepold, G. J. Roth, H. J. Bestmann, Synlett 1996,
521; see also: S. Ohira, Synth. Commun. 1989, 19, 561.
[18] For a review, see: P. Wipf, H. Jahn, Tetrahedron 1996, 52, 12853.
[19] For examples of related couplings, see: P. Knochel, R. D. Singer,
Chem. Rev. 1993, 93, 2117.
[20] For a related intramolecular Dies–Alder reaction, see: D. J.
Witter, J. C. Vederas, J. Org. Chem. 1996, 61, 2613.
[21] L. N. Mander, S. P. Sethi, Tetrahedron Lett. 1983, 24, 5425.
[22] D. R. Williams, P. D. Lowder, Y.-G. Gu, D. A. Brooks, Tetrahe-
dron Lett. 1997, 38, 331; for an example in total synthesis, see:
D. R. Williams, R. A. Turske, Org. Lett. 2000, 2, 3217.
[23] Optical rotation data for naturally occurring apiosporamide was
recorded as [a]D = ꢀ97.48 (c = 0.0004 MeOH). Characterization
of synthetic 1: Rf = 0.12 (19:1 CH2Cl2/MeOH); [a]2D4 = + 1088
(c = 0.40, MeOH); IR (film): n˜ = 3248 (br), 3072, 3006, 2953,
2925, 1656, 1652, 1602, 1544, 1455, 1214, 1063, 1021, 964 cmꢀ1
;
1H NMR (400 MHz, CD3OD): d = 7.45 (s, 1H), 5.51 (m, 1H),
5.31 (d, J = 9.8, 1H), 4.30 (dd, J = 11.2, 5.7 Hz, 1H), 4.04 (ddd,
J = 5.9, 5.9, 3.1 Hz, 1H), 3.53 (d, J = 3.2 Hz, 1H), 3.32 (dd, J =
3.2, 3.1 Hz, 1H), 2.73 (m, 1H), 2.11 (dd, J = 13.0, 9.0, 1H), 1.85
(dd, J = 12.1, 2.5 Hz, 1H), 1.78–1.70 (m, 2H), 1.70–1.56 (m, 3H),
1.52–1.37 (m, 2H), 1.30–1.20 (m, 1H), 0.94 (ddd, J = 12.8, 12.1,
3.3 Hz, 1H), 0.87–0.76 (m, 1H), 0.84 (d, J = 6.5 Hz, 3H), 0.74 (d,
J = 7.2 Hz, 3H), 0.71 ppm (ddd, J = 12.4, 12.4, 12.4 Hz, 1H);
13C NMR (101 MHz, MeOH): d = 211.7, 179.5, 164.2, 139.9,
132.7, 131.7, 116.7, 108.8, 70.6, 67.1, 60.5, 57.6, 54.3, 43.3, 43.2,
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