Total synthesis of pteridic acids A and B

Article abstract of DOI:10.1021/jo9010365

(Chemical Equation Presented) The total synthesis of pteridic acids A and B is reported. The convergent asymmetric synthesis involved the use of a diastereoselective ethyl ketone aldol reaction followed by an efficient spiroketalization and provided pteri

Full text of DOI:10.1021/jo9010365

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Total Synthesis of Pteridic Acids A and B†
Luiz C. Dias* and Airton G. Salles Jr.
Institute of Chemistry, University of Campinas, UNICAMP, P.O. Box 6154 13084-971,
Campinas, SP, Brazil
ldias@iqm.unicamp.br
Received May 18, 2009
The total synthesis of pteridic acids A and B is reported. The convergent asymmetric synthesis
involved the use of a diastereoselective ethyl ketone aldol reaction followed by an efficient
spiroketalization and provided pteridic acids A and B in 2.9% and 2.8% overall yield, respectively.
Introduction
plex molecular architecture comprises a highly substituted
[6,6]-spiroketal motif, which bears seven stereocenters, an
unsaturated side chain appended at C7 that incorporates
another stereocenter, and a terminal carboxylic acid.2,3 In a
recent paper, Paterson et al.2c showed that the spiroketal unit
of pteridic acid A presents a double anomeric effect, which is
counterbalanced by pseudoaxial ethyl and methyl groups at
C14 and C15, respectively. On the other hand, pteridic acid B
displays only a single anomeric effect with pseudoequatorial
alkyl substituents at C14 and C15.2c Applying molecular
modeling (Macro Model, MM2), these authors found that
the global minima of 1 and 2 are of similar energies, accounting
for the existence of both as secondary metabolites.2c
Pteridic acids A and B (1 and 2) are spirocyclic polyketides
isolated in minor amounts by Igarashi and co-workers1 from
the fermentation broth of Streptomyces hygroscopicus TP-
A0451 (Figure 1). These compounds exhibit potent plant
growth promoter properties with auxin-like activity, indu-
cing the formation of adventitious roots in kidney beans at
1 nM concentrations. The structures of pteridic acids have
been suggested by spectroscopic studies including HMBC
and NOESY experiments, and the absolute configuration
has been determined by total synthesis.2 Their com-
†Dedicated to Prof. Vítor Francisco Ferreira (Universidade Federal Flumine-
nese - RJ) for his outstanding contributions to the field of synthetic organic
chemistry in Brazil.
*To whom correspondence should be addressed. Fax: þ55-19-3521-3023.
(1) Igarashi, Y.; Iida, T.; Yoshida, R.; Furumai, T. J. Antibiot. 2002, 55,
764.
(2) Total synthesis of pteridic acids A and B: (a) Nakahata, T.; Fujimura,
S.; Kuwahara, S. Chem. Eur. J. 2006, 12, 4584. (b) Nakahata, T.; Kuwahara,
S. Chem. Commun. 2005, 1028. (c) Paterson, I.; Anderson, E. A.; Findlay, A.
D.; Knappy, C. S. Tetrahedron 2008, 64, 4768.
As limited amounts of pteridic acids A and B are available
from nature, we initiated a project directed toward their total
synthesis. In addition, attracted by their promising anticancer
activities, we intend to provide material for more extensive
biological studies, along with access to novel analogues.
Results and Discussion
(3) Reviews about spiroketals: (a) Aho, J. E.; Pihko, P. M.; Rissa, T. K.
Chem. Rev. 2005, 105, 4406. (b) Perron, F.; Albizati, K. F. Chem. Rev. 1989,
89, 1617. (c) Vaillancourt, V.; Pratt, N. E.; Perron, F; Albizati, K. F. In The
Total Synthesis of Natural Products; Apsimon, J., Ed.; John Wiley & Sons,
1992; Vol. 8, p 533. (d) Mead, K. T.; Brewer, B. N. Curr. Org. Chem. 2002, 6, 1.
Spiroketals in insects: (e) Francke, W.; Kitching, W. Curr. Org. Chem. 2001,
5, 233. Bis-spiroketals: (f) Brimble, M. A. Molecules 2004, 9, 394. (g) Brimble,
Our synthetic planning revealed that the unsaturated side
chain at C7 could be undertaken via a Horner-Wads-
worth-Emmons reaction with triethyl-4-phosphonocroto-
nate (Scheme 1).4 Further dissection provides the possibility
€
M. A.; Furkert, D. P. Curr. Org. Chem. 2003, 7, 1. (h) Francke, W.; Schroder, W.
(4) The numbering of pteridic acids A and B as well as of each inter-
mediate follows that suggested in ref 1.
Curr. Org. Chem. 1999, 3, 407.
5584 J. Org. Chem. 2009, 74, 5584–5589
Published on Web 07/02/2009
DOI: 10.1021/jo9010365
r
2009 American Chemical Society

Dias and Salles
JOCArticle
SCHEME 1. Retrosynthetic Analysis
FIGURE 1. Pteridic acids A and B.
of spiroketalization of 3 preceded by late-stage aldol addi-
tion of aldehyde 4 with ethyl ketone 5 in a convergent route.
Aldehyde 4 may be obtained by exploiting the Evans asym-
metric aldol reaction between aldehyde 6 and N-propiony-
loxazolidinone 7. By employing an asymmetric Frater
alkylation on commercially available (R)-methyl-3-hydro-
xybutanoate 8, we planned to establish the stereocenter at
C14 in ethyl ketone 5. We anticipated the aldol reaction
between the (Z)-metal enolate derived from ethyl ketone 5
and aldehyde 4 to proceed with an anti-Felkin addition.5
The synthesis commenced with an asymmetric aldol addition
of the boron enolate derived from oxazolidinone (R)-7 with
aldehyde 6 to give aldol adduct 98 in 75% yield, exhibiting
excellent diastereoselectivity (ds>95:5) (Scheme 2).6-8 Removal
of the oxazolidinone auxiliary in the syn-aldol 9 with N,O-
dimethylhydroxylamine generated the Weinreb amide 10 (85%
yield).9 The oxazolidinone chiral auxiliary was recovered by
crystallization from the reaction mixture. Protection of the OH
function as its TBS ether cleanly provided Weinreb amide 118
(89% yield), which was smoothly reduced to the aldehyde 48
(used in the next step without further purification), correspond-
ing to the C(5)-C(9) fragment, on treatment with diisobutyla-
luminum hydride in THF at -78 °C, in 90% yield (Scheme 2).8,10
We next moved to the preparation of ethylketone 5,
corresponding to the C(10)-C(16) fragment, necessary to
couple with fragment C(5)-C(9) (Scheme 3). As shown in
Scheme 3, the synthesis of the C(10)-C(16) fragment began
from commercially available hydroxyester 8. Frater alkyla-
tion11 of hydroxyester 8 provided the 1,2-anti ester 1212 in
89% yield (95:5 diastereoselectivity).12 Protection of the OH
function as its TBS ether (87% yield), followed by DIBAL-H
reduction of ester 13,12 gave primary alcohol 1412 in 86%
yield.12 Exposure of alcohol 14 to the Swern13 oxidation
protocol provided aldehyde 1512 which was treated with
ketophosphonate 16 under Ando’s14 conditions to give
(Z)-R,β-unsaturated ester 17 (Z/E=95:5) in 79% yield over
the two-step sequence. Ester 17 was converted to the Wein-
reb amide 18, which was followed by treatment of 18 with
EtMgBr to give the (Z)-R,β-unsaturated ketone 5 in excellent
yields for the two-step sequence.15
With the successful synthesis of fragments C(5)-C(9) and
C(10)-C(16) (4 and 5, respectively) in hand, we proceeded to
assemble both the segments (Scheme 4). After considerable
experimentation, this was accomplished by an aldol reaction
of 5 with aldehyde 4 in 70% yield and 80:20 diastereoselec-
tivity favoring the 1,2-syn anti-Felkin adduct 19 (Scheme 4).5
The optimized conditions involved treatment of ethyl ketone
5 with LiHMDS in THF/HMPA followed by slow addition
of aldehyde 4. The 80:20 ratio was determined after separa-
tion of the diastereoisomers by flash column chromatogra-
phy, which afforded 56% isolated yield of pure 19. The
relative stereochemistry for the major 1,2-syn anti-Felkin
aldol adduct 19 was determined initially by vicinal coupling
(5) (a) Gustin, D. J.; VanNieuwenhze, M. S.; Roush, W. R. Tetrahedron
Lett. 1995, 36, 3443. (b) Roush, W. R. J. Org. Chem. 1991, 56, 4151. (c)
Evans, D. A.; Dart, M. J.; Duffy, J. L.; Rieger, D. L. J. Am. Chem. Soc. 1995,
117, 9073. (d) Wu, B.; Liu, Q.; Jin, B.; Qu, T.; Sulikowski, G. A. Eur. J. Org.
Chem. 2006, 277. (e) Lister, T.; Perkins, M. V. Org. Lett. 2006, 8, 1827. (f)
Gillingham, D. G; Hoveyda, A. H. Angew. Chem. Int. Ed 2007, 46, 3860. (g)
Evans, D. A.; Yang, M. G.; Dart, M. J.; Duffy, J. L. Tetrahedron Lett. 1996,
37, 1957. (h) Ghidu, V. P.; Wang, J; Wu, B.; Liu, Q.; Jacobs, A.; Marnett, L.
J.; Sulikowiski, G. A. J. Org. Chem. 2008, 73, 4949.
1
constant analysis as showed in Figure 2.16 The H NMR
spectra (250 MHz, in CDCl3) exhibit Hb at 2.64 ppm as a
(6) Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 83.
(7) (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127. (b) Evans, D. A.; Taber, T. R. Tetrahedron Lett. 1980, 21, 4675.
(8) (a) Dias, L. C.; Lima, D. J. P.; Gonc-alves, C. C. S.; Andricopulo, A.
D. Eur. J. Org. Chem. 2009, 1491. (b) Smith, A. B. III; Beauchamp, T. J.;
LaMarch, M. J.; Kaufman, M. D.; Qiu, Y.; Arimoto, H.; Jones, D. R.;
Kobayashi, K. J. Am. Chem. Soc. 2000, 122, 8654. (c) Dias, L. C.; de Sousa,
M. A. Tetrahedron Lett. 2003, 44, 5625.
quartet of doublets with coupling constants 1.6 Hz (JHb-Ha
and 7.3 Hz (JHb-Me). Hydrogen Ha appears at 4.0 ppm as a
doublet of doublets with coupling constants 1.6 Hz (JHb-Ha
)
)
and 7.2 Hz (JHa-Hc). This assignment was subsequently
(9) Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982, 12, 989.
(10) (a) Dias, L. C.; de Oliveira, L. G.; de Sousa, M. A. Org. Lett. 2003, 5,
265. (b) Dias, L. C.; Meira, P. R. R. Tetrahedron Lett. 2002, 43, 185. (c) Dias,
L. C.; Meira, P. R. R. J. Org. Chem. 2005, 70, 4762. (d) Dias, L. C.; de
Oliveira, L. G.; Vilcachagua, J. D.; Nigsch, F. J. Org. Chem. 2005, 70, 2225.
(e) Dias, L. C.; de Oliveira, L. G. Org. Lett. 2001, 3, 3951.
(13) Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
(14) (a) Ando, K. Tetrahedron Lett. 1995, 36, 4105. (b) Ando, K. J. Org.
Chem. 1997, 62, 1934. (c) Ando, K. J. Org. Chem. 2000, 65, 4745.
(15) (a) Francavilla, C.; Chen, W.; Kinder, F. R. Jr. Org. Lett. 2003, 5,
1233. (b) Tsuchiya, Y; Hamashima, Y.; Sodeoka, M. Org. Lett. 2006, 8, 4851.
(16) (a) Heathcock, C. H.; Pirrung, M. C.; Sohn, J. E. J. Org. Chem. 1979,
44, 4294. (b) Evans, D. A.; Nelson, J. V.; Taber, T. Top. Stereochem. 1982, 13,
1. (c) Dias, L. C.; Aguilar, A. M.; Salles, A. G. Jr.; Steil, L. J.; Roush, W. R.
J. Org. Chem. 2005, 70, 10461.
(11) (a) Seebach, D.; Chow, H. F.; Jackson, R. F. W.; Sutter, M. A.;
Thaisrivongs, S.; Zimmerman, J. Liebigs Ann. Chem. 1986, 1281. (b) Frater,
€
€
G.; Muller, U.; Gunther, W. Tetrahedron 1984, 40, 1269.
(12) Evans, D. A.; Fitch, D. M. J. Org. Chem. 1997, 62, 454.
J. Org. Chem. Vol. 74, No. 15, 2009 5585

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SCHEME 2. Preparation of Aldehyde 4
SCHEME 3. Preparation of (Z)-R,β-Unsaturated Ethylketone 5
SCHEME 4. Synthesis of Spiroketals 21 and 22
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FIGURE 2. Assignment of the relative stereochemistry for aldol adduct 19.
SCHEME 5. Total Synthesis of Pteridic Acid A
SCHEME 6. Total Synthesis of Pteridic Acid B
confirmed by correlation with the spectroscopic data of
esters 25 and 27, as well as pteridic acids A and B, known
in the literature.1,2
As illustrated in Scheme 5, spiroketal 21 was converted to
pteridic acid A (1). Oxidation of the primary alcohol 21 to
aldehyde 23 was accomplished with TEMPO and BAIB in
CH2Cl2 at rt.18 At this stage, Horner-Wadsworth-
Emmons homologation of aldehyde 23 with ketophosphonate
24 occurred readily to give the corresponding R,β-unsaturated
ester 25 in 60% overall yield (two steps).2c Conclusion of the
synthesis required hydrolysis of ester 25 with aqueous KOH in
EtOH at rt to provide pteridic acid A in 70% yield. The
spectroscopic and physical data [1H and 13C NMR,
IR, [R]D, Rf] were identical in all respects with the published
data for both natural and synthetic pteridic acid A (see the
Supporting Information for comparison of natural and our
synthetic pteridic acid A).1,2 The 13-step sequence (longest
linear sequence) starting from 8 proceeded in 2.9% overall
yield and is amenable to a gram scale-up.
Treatment of pure 19 with DDQ in CH2Cl2 at 0 °C
provided primary alcohol 20, a key synthetic intermediate,
in 64% yield. Subsequent efficient removal of the TBS
protecting groups positioned at C7 and C15 with concomi-
tant spiroketalization was achieved upon treatment of 20
with HF-pyr in THF/H2O (10/1) to give a 50:50 mixture of
spiroketals 21 and 22 in 80% isolated yield, which were
separated by careful silica gel column chromatography
(Scheme 4).18
(17) (a) Dias, L. C.; de Oliveira, L. G. Org. Lett. 2004, 6, 2587. (b) de
Oliveira, L. G.; Dias, L. C.; Sakauchi, H.; Kiyota, H. Tetrahedron Lett. 2006,
47, 2413. (c) Dias, L. C.; Correia, V. G.; Finelli, F. G. Tetrahedron Lett. 2007,
48, 7683.
(18) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N.
J. Am. Chem. Soc. 2001, 123, 9535.
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The same sequence applied to spiroketal 22 provided
pteridic acid B (2) in 2.8% overall yield for the 13-step linear
sequence (Scheme 6). The spectroscopic and physical data
[1H and 13C NMR, IR, [R]D, Rf] were identical in all respects
with the published data for both natural and synthetic
pteridic acid B (see the Supporting Information for compar-
ison of natural and our synthetic pteridic acid B).1,2
separated, and the aqueous phase was washed with CH2Cl2
(3ꢀ10 mL). The combined organic phases were then dried
(Na2SO4) and concentrated in vacuo. Flash chromatography
(40% EtOAc/Hex) afforded spiroketals 21 (9 mg, 0.03 mmol,
40%) and 22 (9 g, 0.03 mmol, 40%) as colorless oils.
1
Spiroketal (21):. Rf 0.31 (40% EtOAc in hexane); H NMR
(500 MHz, C6D6) δ 5.62 (dd, J 10.2, 5.5 Hz, 1H), 5.33 (dd, J 10.2,
1.3 Hz, 1H), 3.85-3.90 (q, J 7.1 Hz, 1H þ dd, J 10.1, 2.2 Hz, 1H),
3.77 (dd, J 11.0, 4.8 Hz, 1H), 3.72 (dd, J 10.7, 7.8 Hz, 1H), 3.57
(dd, J 10.7, 3.8 Hz, 1H), 1.90-2.00 (m, 2H), 1.70-1.79 (m, 2H),
1.52-1.61 (m, 2H), 1.38 (d, J 6.8 Hz, 3H), 0.98 (d, J 6.7 Hz, 3H),
0.92 (d, J 6.9 Hz, 3H), 0.74 (t, J 7.4 Hz, 3H), 0.56 (d, J 6.9 Hz,
3H); 13C NMR (125 MHz, C6D6) δ 4.9, 11.8, 12.9, 13.0, 21.6,
26.4, 37.01, 37.02, 40.7, 41.0, 68.3, 71.7, 71.9, 77.1, 97.2, 128.3,
130.4; [R]23D þ2.8 (c 0.4, CH2Cl2); HRMS (ESI TOF-MS) calcd
for C17H31O4 299.2222, found 299.2192.
Conclusions
In summary, we have achieved the total synthesis of
pteridic acids A and B. Notable features of this approach
include convergence, a lithium enolate-mediated aldol reac-
tion to set up the desired C9 and C10 stereocenters, and a
spiroketalization reaction. This approach compares very
well with previously published routes and, in principle, is
readily applicable for the preparation of additional novel
structural analogues. Further optimization of the synthesis
as well as application of this strategy to the synthesis of
pteridic acid analogues is underway and the results will be
described in due course.19
1
Spiroketal (22):. Rf 0.20 (40% EtOAc in hexane); H NMR
(500 MHz, C6D6) δ 5.73 (ap t, J 11.6 Hz, 1H þ d, J 11.9 Hz, 1H),
3.96 (dq, J 9.8, 6.1 Hz, 1H), 3.72 (ap t, J 11.1, 10.8 Hz, 1H), 3.61
(dd, J 10.6, 6.8 Hz, 1H), 3.25 (dd, J 11.4, 4.7 Hz, 1H), 3.18 (dd, J
9.8, 2.0 Hz, 1H), 2.01-1.85 (m, 2H), 1.70-1.60 (m, 2H), 1.32-
1.17 (m, 2H), 1.12 (d, J 6.2 Hz, 3H), 1.02 (d, J 6.7 Hz, 3H), 0.91
(d, J 6.9 Hz, 3H), 0.76 (t, J 7.5 Hz, 3H), 0.56 (d, J 6.9 Hz, 3H); 13
C
NMR (125 MHz, C6D6) δ 5.0, 10.2, 11.9, 12.8, 19.5, 23.5, 36.85,
D
36.92, 41.0, 42.7, 68.4, 69.0, 73.7, 77.9, 98.6, 124.0, 133.7; [R]23
Experimental Section
-2.0 (c 0.3, CH2Cl2); HRMS (ESI TOF-MS) calcd for
C17H31O4 299.2222, found 299.2198.
(5R,6S,10S,11R,12S,13S,Z)-6-Ethyl-11-hydroxy-13-((S)-
1-(4-methoxybenzyloxy)propan-2-yl)-2,2,3,3,5,10,12,15,15,-
16,16-undecamethyl-4,14-dioxa-3,15-disilaheptadec-7-en-9-one
(19). To a solution of LHMDS (0.94 mL, 0.94 mmol, 1 M in
THF/ethylbenzene, 1.2 equiv) in THF (6.5 mL) at -78 °C was
added a solution of ethyl ketone 5 (0.221 g, 0.78 mmol) and
HMPA (0.42 mL, 2.37 mmol, 3 equiv) in THF (16 mL). The
reaction mixture was stirred at -78 °C for 2 h before a solution
of aldehyde 4 (0.296 g, 0.78 mmol, 1 equiv) in THF (2.9 mL)
was added dropwise. The solution was stirred at -78 °C for 2 h,
quenched with saturated NH4Cl (50 mL), and warmed to room
temperature. The aqueous layer was extracted with Et2O/
EtOAc (1:1, 3ꢀ15 mL), and the combined organic layers were
dried (MgSO4), filtered, and concentrated in vacuo. The
residue was purified by flash chromatography (10% hexanes/
EtOAc) to afford 0.293 g (0.44 mmol) of aldol 19 as a colorless
oil (56% yield), together with a second diastereoisomer tenta-
tively assigned as the corresponding syn aldol with Felkin
addition (0.073 g, 0.11 mmol, 14% yield). Aldol 19: Rf 0.45
(10% EtOAc in hexane); 1H NMR (250 MHz, CDCl3) δ 7.25
(br d, J 8.6 Hz, 2H), 6.86 (br d, J 8.7 Hz, 2H), 6.32 (br d, J 11.7
Hz, 1H), 6.14 (ap t, J 10.5 Hz, 1H), 4.41 (br s, 2H), 4,00 (dd,
J 7.2, 1.5 Hz, 1H), 3.82-3.92 (m, 2H), 3.80 (s, 3H), 3.58 (dd,
J 8.9, 4.3 Hz, 1H), 3.35-3.15 (m, 3H), 2.64 (qd, J 7.3, 1.6 Hz,
1H), 1.91-2.01 (m, 1H), 1.62-1.19 (m, 3H), 1.08 (d þ m, J 7.2
Hz, 3H þ 1H), 1.04 (d, J 6.3 Hz, 3H), 0.96 (d, J 6.8 Hz, 3H),
0.88 (s, 9H), 0.86 (s þ t, 12H), 0.77 (d, J 6.9 Hz, 3H), 0.07 (s,
3H), 0.05 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (62.5
MHz, C6D6) δ -4.7, -4.1, -3.9, -3.7, 8.3, 9.8, 12.1, 14.7, 18.3,
18.8, 22.3, 25.0, 26.1, 26.5, 38.4, 39.3, 47.2, 47.8, 54.7, 70.6, 71.1,
72.5, 73.1, 73.3, 114.0, 129.4, 131.4, 151.0, 159.6, 207.6; IR νmax
(film) 3472, 3053, 2959, 2932, 2856, 1674, 1612, 1514, 1462, 1265,
1036, 837; [R]23D þ21.0 (c 1.4, CH2Cl2); HRMS (ESI TOF-MS)
calcd for C37H69O6Si2 665.4633, found 665.4546.
Ester 25. To a solution of triethyl 4-phosphonocrotonate
(31 mg; 0.123 mmol) in THF (0.5 mL) at -78 °C was added
LiHMDS (0.12 mL, 1 M in THF/ethylbenzene, 0.120 mmol)
and the resultant solution stirred for 10 min. A solution of
aldehyde 23 (0.050 mmol) in THF (0.25 mL) was then added
slowly and the reaction mixture allowed to warm to -25 °C and
stirred for 1.5 h. The reaction was then allowed to warm to rt and
quenched by the addition of saturated aqueous NH4Cl (1 mL).
The aqueous phase was extracted with Et2O (3ꢀ5 mL), and the
combined organic phases were dried (MgSO4) and concentrated
in vacuo. Flash chromatography (20% EtOAc/Hex) afforded
ester 25 (12 mg, 0.031 mmol, 60% for two steps) as a colorless
oil: Rf 0.30 (30% EtOAc/40-60 petroleum ether); 1H NMR
(400 MHz, C6D6) δ 7.53 (dd, J 15.4, 10.3 Hz, 1H), 6.06 (dd,
J 15.4, 7.5, 1H), 5.97 (dd, J 15.4, 10.4 Hz, 1H), 5.90 (d, J 15.6 Hz,
1H), 5.65 (ddd, J 10.3, 5.6, 1.1 Hz, 1H), 5.42 (dd, J 10.3, 0.8 Hz,
1H), 4.06 (q, J 7.0, 2H), 3.85 (br q, J 6.9, 1H), 3.78 (dt, J 10.9, 4.7,
1H), 3.66 (dd, J 9.8, 2.2 Hz, 1H), 2.38-2.27 (m, 1H), 1.79-1.72
(m, 1H), 1.61-1.53 (m, 1H), 1.39-1.27 (m, 3H), 1.21 (d, J 6.9
Hz, 3H), 1.01 (d, J 6.4 Hz, 3H), 0.99 (t, J 7.3 Hz, 3H), 0.93 (d, J
6.7 Hz, 3H), 0.77 (t, J 7.5 Hz, 3H), 0.71 (d, J 6.9 Hz, 3H); 13C
NMR (100 MHz, C6D6) δ 4.8, 11.9, 12.9, 14.4, 15.1, 23.1, 26.7,
36.8, 38.8, 40.7, 41.1, 59.9, 71.7, 72.2, 74.7, 97.0, 120.0, 127.3,
127.8-128.8 (obs), 129.6, 145.3, 148.7, 166.8; IR νmax (film)
3454, 2964, 2928, 1713, 1641, 1618, 1460, 1421, 1265, 1144, 1030,
1003; [R]23 þ20.5 (c 0.14, MeOH); HRMS (ESI TOF-MS)
D
calcd for C23H37O5 393.2641, found 393.2593.
Ester 27. To a solution of triethyl-4-phosphonocrotonate
(9.3 g, 0.037 mmol) in THF (0.3 mL) at -78 °C was added
LiHMDS (0.035 mL, 1 M in THF/ethylbenzene, 0.035 mmol)
and the resultant solution stirred for 10 min. A solution of
aldehyde 26 (0.015 mmol) in THF (0.1 mL) was then added
slowly and the reaction mixture allowed to warm to -25 °C and
stirred for 1.5 h. The reaction was then allowed to warm to rt and
quenched by the addition of saturated aqueous NH4Cl (0.5 mL).
The aqueous phase was extracted with Et2O (3ꢀ5 mL), and the
combined organic phases were dried (MgSO4) and concentrated
in vacuo. Flash chromatography (20% EtOAc/Hex) afforded
ester 27 (3,5 g; 0.009 mmol, 62% for two steps) as a colorless oil:
Spiroketals 21 and 22. To a solution of aldol 20 (42 mg,
0.08 mmol) in THF/H2O (10:1, 9.3 mL) in a polypropylene
vessel at 0 °C was added HF-pyridine (1.70 mL). After 8 h at rt,
the reaction mixture was partitioned between saturated aqueous
NaHCO3 (20 mL) and CH2Cl2 (10 mL). The phases were
(19) New compounds and the isolatable intermediates gave satisfactory
1H and 13C NMR, IR, HRMS, and analytical data. Yields refer to chroma-
tographically and spectroscopically homogeneous materials.
1
Rf 0.20 (30% EtOAc/40-60 petroleum ether); H NMR (400
MHz, C6D6) δ 7.54 (dd, J 15.4, 10.6 Hz, 1H), 6.05 (dd, J 15.4,
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Dias and Salles
JOCArticle
10.6 Hz, 1H), 5.96 (d, J 15.2 Hz, 1H), 5.91 (dd, J 14.5, 6.2 Hz,
1H), 5.67 (br d, J 10.3 Hz, 1H), 5.65 (ddd, J 10.3, 5.6, 1.1 Hz,
1H), 4.13 (dd J 9.8, 6.1 Hz, 1H), 4.07 (q, J 7.0 Hz, 2H), 3.29 (dt,
J 11.2, 5.0, 1H), 2.97 (dd, J 9.8, 2.2 Hz, 1H), 2.36-2.26 (m, 1H),
1.78-1.63 (m, 3H), 1.32-1.23 (m, 1H), 1.15-1.09 (obs, 1H),
1.14 (d, J 6.2 Hz, 3H), 1.05 (d, J 6.7 Hz, 3H), 0.99 (t, J 7.0 Hz,
3H), 0.92 (d, J 6.9 Hz, 3H), 0.82 (t, J 7.5 Hz, 3H), 0.76 (d, J 6.2
Hz, 3H); 13C NMR (100 MHz, C6D6) δ 4.9, 10.1, 11.8, 14.3,
15.3, 19.6, 23.6, 36.7, 38.7, 41.0, 42.6, 60.0, 68.0, 73.9, 75.7, 98.1,
(10%, 0.10 mL) dropwise. After 24 h at rt, the reaction mixture
was partitioned between pH 4 buffer (1 mL) and CH2Cl2 (3 mL).
The phases were separated and the aqueous phase washed with
CH2Cl2 (5 ꢀ 4 mL). The combined organic phases were then
dried (Na2SO4) and concentrated in vacuo. Flash chromato-
graphy (8% MeOH/CH2Cl2) afforded pteridic acid A (6.6 mg,
0.018 mmol, 70%) as a white solid: Rf 0.54 (8% MeOH/
CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.23 (dd, J 15.1, 10.3
Hz, 1H), 6.24 (dd, J 15.2, 6.6 Hz, 1H), 6.17 (dd, J 15.4, 10.0 Hz,
1H), 5.95 (dd, J 10.3, 5.6 Hz, 1H), 5.77 (d, J 15.1 Hz, 1H), 5.50
(dd, J 10.3, 1.2 Hz, 1H), 3.90 (q, J 6.6 Hz, 1H), 3.83 (dd J 10.9,
4.9 Hz, 1H), 3.74 (dd, J 10.0, 2.2 Hz, 1H), 2.50 (m, 1H), 2.05 (m,
1H), 1.63 (q, J 6.7 Hz, 1H), 1.60 (dq, J 11.0, 6.4 Hz, 1H), 1.44
(quint, J 7.6 Hz, 2H), 1.23 (d, J 7.0 Hz, 3H), 0.99 (d, J 6.8 Hz,
3H), 0.92 (t, J 7.4 Hz, 3H), 0.91 (d, J 6.8 Hz, 3H), 0.90 (d, J 6.8
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 4.5, 11.9, 12.5, 15.2,
22.8, 26.2, 36.3, 38.5, 40.4, 40.9, 71.6, 72.4, 74.5, 96.8, 118.2,
119.9, 124.6, 128.5, 133.8, 145.6, 148.2, 166.9; [R]23 -18.7
D
(c 0.12, MeOH); HRMS (ESI TOF-MS) calcd for C23H37O5
393.2641, found 393.2598.
Pteridic Acid B. Toa solutionofester 27 (12.5mg, 0.031mmol)
in EtOH/H2O (2:1, 1.5 mL) at rt was added aqueous KOH (10%,
0.12 mL) dropwise. After 24 h at rt, the reaction mixture was
partitioned between pH 4 buffer (1 mL) and CH2Cl2 (3 mL). The
phases were separated, and the aqueous phase was washed with
CH2Cl2 (5ꢀ4 mL). The combined organic phases were then dried
(Na2SO4) and concentrated in vacuo. Flash chromatography
(8% MeOH/ CH2Cl2) afforded pteridic acid B (7.5 mg, 0.020
mmol, 65%) as a white solid: Rf 0.52 (8% MeOH/CH2Cl2); 1H
NMR (500 MHz, CDCl3) δ 7.26 (1H, obscured), 6.23 (dd, J 15.2,
10.5Hz, 1H), 6.14 (dd, J 15.3, 7.1 Hz, 1H), 5.92 (dd, J 10.5, 1.8 Hz,
1H), 5.89 (br d, J 11.1 Hz, 1H), 5.76 (d, J 15.3 Hz, 1H), 3.89 (dq,
J 10.0, 6.1 Hz, 1H), 3.69 (dd J 11.2, 4.8 Hz, 1H), 3.26 (dd, J 10.0,
1.8 Hz, 1H), 2.53 (m, 1H), 2.05 (m, 1H), 1.85 (m, 1H), 1.76 (m,
1H), 1.48 (m, 1H), 1.21 (d, J 6.1 Hz, 3H), 1.20 (m, 1H), 0.96 (d,
126.8, 127.5, 130.2, 147.4, 150.1, 171.5; [R]23 þ 19.1 (c 0.10,
D
CHCl3); HRMS (ESI TOF-MS) calcd for C21H33O5 365.2328,
found 365.2291.
1
For H and 13C NMR analysis of pteridic acids A and B,
deuterated CDCl3 has been passed through a plug of basic
alumina and stored in K2CO3 just before use.
Acknowledgment. We are grateful to FAEP-UNICAMP,
~
ꢀ
FAPESP (Fundac-ao de Amparo a Pesquisa do Estado de
Sao Paulo), CNPq (Conselho Nacional de Desenvolvimento
~
J 6.9 Hz, 6H), 0.92 (d, J 6.7 Hz, 3H), 0.87 (t, J 7.5 Hz, 3H); 13
C
ꢁ
Cientıfico e Tecnologico), and INCT-INOFAR Proc. CNPq
´
NMR (125 MHz, CDCl3) δ 4.9, 10.0, 11.5, 15.3, 19.6, 23.4, 36.3,
38.4, 40.8, 42.3, 68.1, 74.3, 75.6, 97.9, 118.1, 123.5, 127.4, 134.0,
573.564/2008-6 for financial support. We thank also Prof.
Carol H. Collins for helpful suggestions about English
grammar and style.
147.5, 149.4, 171.3; [R]23 -20.0 (c 0.10, CHCl3); HRMS (ESI
D
TOF-MS) calcd for C21H33O5 365.2328, found 365.2295. For 1H
and 13C NMR analysis of pteridic acids A and B, deuterated
CDCl3 has been passed through a plug of basic alumina and
stored in K2CO3 just before use.
Supporting Information Available: Experimental proce-
dures and spectral data for the prepared compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Pteridic Acid A. To a solution of ester 25 (10 mg, 0.025 mmol)
in EtOH/H2O (2:1, 1.2 mL) at rt was added aqueous KOH
J. Org. Chem. Vol. 74, No. 15, 2009 5589