Total synthesis of pteridic acid A

Article abstract of DOI:10.1021/ol9026842

(Figure presented) A convergent approach to the total synthesis of pteridic acid A, having potent plant growth regulator activity, Is described. Key steps include the desymmetrization of bicyclic olefin with Brown's chiral hydroboration, acid-mediated spiroketalization, and zirconium-catalyzed ethylmagnesation protocol to Install the ethyl stereocenter at C14.

Full text of DOI:10.1021/ol9026842

ORGANIC
LETTERS
2010
Vol. 12, No. 2
348-350
Total Synthesis of Pteridic Acid A
J. S. Yadav,* V. Rajender, and Y. Gangadhara Rao
Organic Chemistry DiVision-1, Indian Institute of Chemical Technology,
Hyderabad 500 007, India
yadaVpub@iict.res.in
Received November 21, 2009
ABSTRACT
A convergent approach to the total synthesis of pteridic acid A, having potent plant growth regulator activity, is described. Key steps include
the desymmetrization of bicyclic olefin with Brown’s chiral hydroboration, acid-mediated spiroketalization, and zirconium-catalyzed
ethylmagnesation protocol to install the ethyl stereocenter at C14.
Pteridic acid A, a spirocyclic polyketide natural product, was
isolated by the Igarashi group1 from the fermentation broth
of Streptomyces hygroscopicus TP-A0451 obtained from the
stems of the bracken Pteridium aquilinum, collected in
Toyama, Japan. It induces the formation of adventitious roots
in hypocotyls of kidney beans (at 1 nM concentration) as
effectively as auxins2 (indole-3-acetic acid), a natural phy-
tohormone. The structure of pteridic acid was determined
to be a spiroketal from extensive spectroscopic studies
including HMBC and NOESY experiments. Structurally,
pteridic acids A and B are epimers, differing at the C11 spiro
center, and possess a highly substituted dioxaspiro[5.5]unde-
cene ring system comprising seven stereo centers along with
a conjugated diene carboxylic acid side chain at C7, which
accommodates one more chiral center.
mediated aldols to construct the polyketide core, Frater or
Seebach alkylation, and boron-mediated aldols to install the
ethyl-bearing C14 stereocenter. As part of our studies on
the synthesis of spirocyclic natural products6 and macrolides
containing polyketide units by exploiting a desymmetrization
strategy,7 we present a novel strategy for pteridic acid A,
radically different from those reported so far.
Scheme 1. Retrosynthetic Analysis of Pteridic Acid A (1)
First total synthesis of pteridic acid A was reported by
Kuwahara et al.3 in 2005 followed by the Paterson group4
and recently by the Dias group.5 The earlier synthetic efforts
toward pteridic acid syntheses relied on auxiliary/boron-
(1) Igarashi, Y.; Iida, T.; Yoshida, R.; Furumai, T. J. Antibiot. 2002,
55, 764–767.
(2) (a) Igarashi, Y.; Yoshida, R.; Furumai, T. Shokubutsu no Seicho
Chosetsu 2002, 37, 63–68. (b) Igarashi, Y.; Iida, T.; Sasaki, T.; Saito, N.;
Yoshida, R.; Furumai, T. Actinimycetologica 2002, 16, 9–13.
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(b) Nakahata, T.; Fujumura, S.; Kuwahara, S. Chem.sEur. J. 2006, 12,
4584–4593.
Retrosynthetically (Scheme 1), we envisaged that 1 could
be prepared by short sequential manipulations of diol 16,
embedded with all of the required stereocenters, and the diol
16 in turn could be generated by acid-mediated spiroketal-
(4) Paterson, I; Anderson, E. A.; Findlay, A. D.; Knappy, C. S.
Tetrahedron 2008, 64, 4768–4777.
(5) Dias, L. C.; Salles Jr, A. G. J. Org. Chem. 2009, 74, 5584–5589.
10.1021/ol9026842  2010 American Chemical Society
Published on Web 12/18/2009

ization of hemiacetal 13. Intermediate 13 could be ob-
tained by assembling lactone 2 (C5-C11) and alkyne 3
(C12-C15).
Scheme 3. Synthesis of Alkyne 3
Scheme 2. Synthesis of Lactone 2
for 12 h followed by quenching of the ethylmagnesation
product with O2 resulted in the formation of alcohol 9 (72%)
as a single diastereomer. Though terminal alkenes are not
subject to strict conformational control, exclusive formation
of the diastereomer is due to bulky cyclohexylidene protec-
tion adjacent to the site of addition in olefin 8. Having
successfully installed the C14 ethyl center using an efficient
protocol, we next proceeded to synthesize the alkyne
functionality by oxidation of alcohol 9 with BAIB-TEMPO
to afford aldehyde 10 (91% yield), which was converted to
alkyne 3 (72%) by employing Ohira-Bestmann reagent.13
As our initial objective to synthesize the pteridic acid A
through the assemble of the lactone 2 with vinyl iodide 11
(prepared from aldehyde 10 using Stork and Zhao protocol)
using n-BuLi and i-PrMgBr14 met with failure and ended
up with doubly vinylated product (in minor quantities) along
with unsaturated lactone (in major quantities). When we tried
the coupling by transmetalation of Li to Mg using t-BuLi-
As outlined in Scheme 2, the C5-C11 segment 2 was
prepared mainly on the basis of desymmetrization of bicyclic
olefin using Brown’s chiral hydroboration via known triol
4, which was extensively utilized as a building block for
the synthesis of many natural products containing polypro-
pionate units in our laboratory.7 Synthesis of lactone 2 was
commenced with the conversion of triol 4 to acetal 5 using
anisaldehyde dimethyl acetal8 and catalytic CSA. Reductive
opening of acetal with NaBH3CN9 led to the 1,5-diol 6 (71%
yield). The resulting 1,5-diol was subjected to oxidative
lactonization in the presence of BAIB-TEMPO10 to obtain
lactone 7 (87% yield). Epimerization of lactone 7 at the C2
position by exposure to a stoichiometric amount of DBU7b
completed the construction of the key Prelog-Djerassi-type
lactone 2.
15
MgBr2 at -136 °C (Liq N2-pentane bath), it resulted in
dehydrohalogenation of vinyl iodide along with unreacted
lactone (Scheme 4).
The failures of our initial attempts forced us to revise the
coupling strategy (Scheme 5) in which the alkyne 3 was
chosen as a coupling partner. Thus, treatment of lactone 2
with lithium acetylide16 of 3 at -78 °C afforded lactol.
Exposure of this crude lactol to a catalytic amount of CSA
in MeOH resulted in the formation of hemiacetal 12 with
concomitant deprotection of the cyclohexylidene acetal.
Next the hemiacetal 12 was subjected to partial hydroge-
nation using Lindlar’s catalyst to establish the Z-alkene
functionality in 13 (92%). Our next key task en route to the
synthesis of pteridic acid A, spiroketalization was achieved
under mild acidic conditions. To our delight, the NMR
The synthesis of the C12-C15 segment (Scheme 3) began
with the installation of the crucial ethyl center at C14 by
employing a zirconium-catalyzed carbomagnesation protocol
developed by Hoveyda.11 Thus the treatment of olefin12
8
with EtMgCl and 5 mol % of Cp2ZrCl2 at room temperature
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Org. Lett., Vol. 12, No. 2, 2010
349

Scheme 4
.
Initial Attempt To Couple Fragments 2 and 11
Scheme 5. Synthesis of Pteridic Acid A (1)
sample of hemiacetal 13 in CDCl3 completely converted to
1
spiro compound 14, which was confirmed by H and 13C
NMR. Thus, treatment of 13 in 1% HCl in CHCl3 resulted
in the formation of spiro compound 14 as a single diaste-
reomer (96%), which can be explained through double
anomeric effect,17 and appearance of the 13C signal (96.89
ppm) of the spiro carbon comparable to that of natural
pteridic acid A (96.86 ppm) confirmed the required stereo-
chemical outcome.
At this juncture, it is necessary to establish the methyl
chiral center at C15. To this end, the primary alcohol in
spiroketal 14 was transformed to a methyl group by a
tosylation-reductive elimination sequence to furnish deoxy-
genated spiroketal 15. The deprotection of both PMB and
benzyl ethers by using excess Li-naphthalenide18 (20 equiv)
afforded diol 16 (91%) and minor product epimerized at the
spirocyclic carbon to an extent of 2-3%.3b Selective
oxidation of primary alcohol in diol 16 to aldehyde 17 was
achieved with BAIB-TEMPO in CH2Cl2 at room temperature
(89% yield), and appendage of the conjugated diene ester to
the aldehyde using known phosphonate ester through HWE
olefination furnished the corresponding conjugate ester 18
(88% yield). Finally, saponification of ethyl ester 18 with
KOH in EtOH accomplished the synthesis of pteridic acid
A (96%), whose spectral and analytical data were in good
agreement with the reported values.
In conclusion, the total synthesis of pteridic acid A has
been achieved. Key features of this synthesis are efficient
desymmetrization strategy to construct the polyketide core,
zirconium-catalyzed carbomagnesation protocol to install the
C14 ethyl stereocenter, and an effective spiroketalization
under mild acidic conditions. The 13-step longest linear
sequence proceeding from triol 4 gave an overall yield of
17.4%.
Acknowledgment. V.R. and Y.G.R. thank UGC and
CSIR-New Delhi for the award of fellowships.
Supporting Information Available: Experimental pro-
cedures and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
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J. K. Can. J. Chem. 1981, 59, 1105–1122.
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