Remarkable control of radical cyclization processes of cyclic enyne: Total syntheses of (±)-methyl gummiferolate, (±)-methyl 7β-hydroxykaurenoate, and (±)-methyl 7-oxokaurenoate and formal synthesis of (±)-gibberellin A12 from a common synthetic precursor

Article abstract of DOI:10.1021/ja0035506

Total syntheses of (±)-methyl gummiferolate (13b), (±)-methyl 7β-hydroxykaurenoate (14b), and (±)-methyl 7-oxokaurenoate (14d) and a formal synthesis of (±)-gibberellin A₁₂ (15) have been accomplished through the common synthetic precursor, (3aR*,7aR*)-3,3-dimethyl-7a-(2-propynyl)-3a,4,7,7a- tetrahydroisobenzofuranone (16). The homoallyl - homoallyl radical rearrangement reaction of the monocyclic enyne 25, derived from 16 in two steps, afforded the bicyclo[2,2,2]octane compound 26, which was converted to (±)-methyl gummiferolate (13b). In contrast, the radical cyclization of the bicyclic enyne 16 gave the tricyclic lactone 19, leading to (±)-methyl 7β-hydroxykaurenoate (14b) and (±)-methyl 7-oxokaurenoate (14d). Transformation of 14d into lactone 20 was carried out in a single step under bromination conditions. This constitutes a formal total synthesis of gibberellin A₁₂ (15).

Full text of DOI:10.1021/ja0035506

1856
J. Am. Chem. Soc. 2001, 123, 1856-1861
Remarkable Control of Radical Cyclization Processes of Cyclic
Enyne: Total Syntheses of (()-Methyl Gummiferolate, (()-Methyl
7â-Hydroxykaurenoate, and (()-Methyl 7-Oxokaurenoate and Formal
Synthesis of (()-Gibberellin A12 from a Common Synthetic Precursor
Masahiro Toyota,* Masahiro Yokota, and Masataka Ihara*
Contribution from the Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku UniVersity, Aobayama, Sendai 980-8578, Japan
ReceiVed September 29, 2000
Abstract: Total syntheses of (()-methyl gummiferolate (13b), (()-methyl 7â-hydroxykaurenoate (14b), and
(()-methyl 7-oxokaurenoate (14d) and a formal synthesis of (()-gibberellin A12 (15) have been accomplished
through the common synthetic precursor, (3aR*,7aR*)-3,3-dimethyl-7a-(2-propynyl)-3a,4,7,7a-tetrahydroisoben-
zofuranone (16). The homoallyl-homoallyl radical rearrangement reaction of the monocyclic enyne 25, derived
from 16 in two steps, afforded the bicyclo[2.2.2]octane compound 26, which was converted to (()-methyl
gummiferolate (13b). In contrast, the radical cyclization of the bicyclic enyne 16 gave the tricyclic lactone 19,
leading to (()-methyl 7â-hydroxykaurenoate (14b) and (()-methyl 7-oxokaurenoate (14d). Transformation
of 14d into lactone 20 was carried out in a single step under bromination conditions. This constitutes a formal
total synthesis of gibberellin A12 (15).
Introduction
ring in 11. Attack by tributyltin hydride on the less hindered
convex face of the more abundant conformation 12 provided
the tricyclic compound as a major product (Scheme 2).5
Having successfully developed a flexible methodology for
the selective formation of bicyclo[2.2.2]octane or bicyclo[3.2.1]-
octane derivatives, our efforts were next focused on the total
synthesis of plant growth-regulators, such as gummiferolic acid
(13a) and gibberellin A12 (15), from a common starting material.
Plant Growth-Regulators. Interestingly, some tetracyclic
diterpenoids, which have bicyclo[2.2.2]octane or bicyclo[3.2.1]-
octane ring systems as their CD rings, exhibit considerable plant
growth-regulatory activity. Gummiferolic acid (13a), which was
isolated from Margotia gummifera by Pinar et al.,6 possesses
six contiguous stereogenic centers and a bicyclo[2.2.2]octane
ring system as the CD part. In addition, 13a shows plant growth-
regulatory activity similar to or greater than that displayed by
gibberellic acid.7 Although kaurenoic acid and its derivatives,
such as 14, are biosynthetic intermediates for gibberellins,
grayanotoxins, and stevioside, little is known about activities
worthy of special mention.8 Gibberellin A12 (15), isolated from
Gibberella fujikuroi and whose structure was elucidated by
Cross et al.,9 has a trans-hydrindane AB ring system and a spiro-
fused bicyclo[3.2.1]octane moiety that comprises the C and D
rings (Figure 1).
Radical reactions have evolved as a powerful methodology
for the synthesis of biologically active organic compounds
during the last two decades, and many elegant total syntheses
of structurally complicated natural products have been realized
employing radical cyclizations and cascade radical reactions.1
Some of the attractive features of the radical reactions include
high functional group tolerance, mild reaction conditions, and
regio- and stereoselectivity. To prepare moderately functional-
ized bicyclo[2.2.2]- or bicyclo[3.2.1]octane ring compounds,
both of which are crucial carbon frameworks for many biologi-
cally active natural products, we envisioned novel synthetic
routes to these bicyclic compounds from a common intermediate
by using radical cyclizations. The synthetic design is depicted
in Scheme 1; the initially generated vinyl radical 3 from
acetylene 1 or vinyl halide 2 was expected to cyclize to afford
the bicyclic radical 5.2 The resulting radical 5 would undergo
3-exo-trig cyclization to give the unstable cyclopropylcarbinyl
radical 7, which would rearrange to the thermodynamically more
stable homoally radical 8.3
After extensive investigation, it was found that the homoallyl
radical 10 with a methyl group in the R2 position gave good
selectivity for the bicyclo[2.2.2]octane since the 3-exo-trig
cyclization proceeds smoothly, probably due to the nonbonding
interaction between the R2 substituent and Bu3Sn•.4 In contrast,
avoidance of strain of the furanone ring in 11 can be important
in bringing about conformational inversion of the six-membered
Synthetic Plans for Gummiferolic Acid and Gibberellin
A12. In an effort to synthesize structurally different plant growth-
regulators, 13 and 15, through the use of radical cyclization
reactions, we envisaged (3aR*,7aR*)-3,3-dimethyl-7a-(2-pro-
pynyl)-3a,4,7,7a-tetrahydroisobenzofuranone (16) as a common
(1) (a) Giese, B.; Kopping, B.; Gobel, T.; Dickhaut, J.; Thoma, G.;
Kulicke, K. J.; Trach, F. Org. React. 1996, 48, 301-856. (b) Curran, D.
P.; Porter, N. A.; Giese, B. Stereochemistry of Radical Reactions; VCH:
Weinheim, New York, Basel, Cambridge, Tokyo, 1995.
(5) Toyota, M.; Yokota, M.; Ihara, M. Tetrahedron Lett. 1999, 40, 1551-
1554.
(2) (a) Curran, D. P.; Chang, C.-T. J. Org. Chem. 1989, 54, 3140-3157.
(b) Yadav, V.; Fallis, A. G. Tetrahedron Lett. 1989, 30, 3283-3286.
(3) (a) Beckwith, L, J.; O’Shea, D. M. Tetrahedron Lett. 1986, 27, 4525-
4528. (b) Stork, G.; Mook, R., Jr. Tetrahedron Lett. 1986, 27, 4529-4532.
(4) Damm, W.; Giese, B.; Hartung, J.; Hasskerl, T.; Houk, K. N.; Huter,
O.; Zipse, H. J. Am. Chem. Soc. 1992, 114, 4067-4079.
(6) Pinar, M.; Rodriguez, B.; Alemany, A. Phytochemistry 1978, 17,
1637-1640.
(7) Villalobos, N.; Martin, L.; Macias, M. J.; Mancheno, B.; Grande,
M. Phytochemistry 1994, 37, 635-639.
(8) MacMillan, J. Nat. Prod. Rep. 1997, 14, 221-243.
(9) Cross, B. E.; Norton, K. J. Chem. Soc. 1965, 1570-1572.
10.1021/ja0035506 CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/10/2001

Radical Cyclization Processes of Cyclic Enyne
J. Am. Chem. Soc., Vol. 123, No. 9, 2001 1857
Scheme 1
Scheme 2
Scheme 3
intermediate. First, we planned to synthesize gummiferolic acid
(13a) by means of homoallyl-homoallyl radical rearrangement.
Thus, we designed the alcohol 17 as an appropriate precursor
for vinyl radical assisted homoallyl-homoallyl radical rear-
rangement. Compound 17 has a tertiary alcohol, which should
be bulky enough to control the radical cyclization and is easily
convertible to isopropenyl group.5 After construction of the
bicyclo[2.2.2]octane compound 18, the trans-decalin structure
that corresponds to the AB ring system of gummiferolic acid
(13a) could be prepared by an intramolecular Diels-Alder
reaction.10 On the other hand, the bicyclo[3.2.1]octane 19 would
be synthesized through intramolecular vinyl radical-promoted
cyclization. The trans-decalin part of the pentacyclic compound
20 could be prepared by intramolecular Diels-Alder reaction
as described above. The lactone 20 had already been transformed
into GA12.9,11,12
Total Synthesis of (()-Methyl Gummiferolate by Homoal-
lyl-Homoallyl Radical Rearrangement. Since it was found
that monocyclic enynes such as 1 and 2, bearing bulky R2
substituents, gave better selectivity for bicyclo[2.2.2]octanes in
the preliminary studies,5 substrates 24 and 25 were prepared as
depicted in Scheme 4. Thus, commercially available cis-1,2,3,6-
tetrahydrophthalic anhydride (21) was submitted to methanolysis
to give the corresponding half ester, which was treated with
excess methylmagnesium iodide to afford the lactone 22 in 76%
overall yield from 21 after acid treatment. The vinyl bromide
24 was synthesized in three steps from 22 through alkylation
(92%), LiAlH4 reduction (82%) of the lactone moiety, followed
by monoacetylation (93%) of the primary alcohol. Meanwhile,
the cyclic enyne 25 was prepared in 84% overall yield in a
manner similar to that described above.
Refluxing a solution of 24 in benzene with tributyltin hydride
and AIBN afforded the desired bicyclo[2.2.2]octane compound
26. However, chromatographic purification of 26 was very
difficult due to contamination by nonpolar byproducts. The
isolation problem was solved by using acetylene 25 as a
substrate for the key reaction. Thus, reaction of 25 under
optimized conditions furnished the bicyclic acetate 26 (32%)
together with the bicyclo[3.2.1]octane derivative 27 (50%).
(10) (a) Ciganek, E. Org. React. 1984, 32, 1-374. (b) Roush. W. R.
AdVances in Cycloaddition; JAI Press Inc.: Greenwich, CT, London, 1990;
Vol. 2, pp 91-146. (c) Roush, W. R. ComprehensiVe Organic Synthesis;
Pergamon Press: Oxford, New York, Seoul, Tokyo, 1991; Vol. 5, pp 513-
550.
(11) (a) Cross, B, E.; Galt, R. H. B.; Hanson, J. R. J. Chem. Soc. (C)
1963, 2944-2961. (b) Galt, R. H. B.; Hanson, J. R. J. Chem. Soc. (C)
1965, 1565-1570.
(12) Mori, K.; Takemoto, I.; Matsui, M. Tetrahedron 1976, 32, 1497-
1502.

1858 J. Am. Chem. Soc., Vol. 123, No. 9, 2001
Toyota et al.
Scheme 4a
Scheme 7a
a Reagents and conditions: (a) MeOH, reflux, 100%. (b) MeMgI,
Et2O; H2SO4, 76%. (c) LDA, THF, -78 °C; HMPA, 2,3-dibromopro-
pene, 92%. (d) LAH, Et2O, 82%. (e) Ac2O, pyridine, 93%. (f) LDA,
THF, -78 °C; HMPA, propargyl bromide, 85%. (g) LAH, Et2O, 99%.
(h) Ac2O, pyridine, 100%.
Scheme 5a
a Reagents and conditions: (a) Aqueous NaOH, MeOH, reflux. (b)
Liquid NH3, Na; 10% HCl. (c) DCC, DMAP, CH2Cl2, 77% for 3 steps.
(d) NaBH4, MeOH. (e) MeMgI, Et2O. (f) PDC, Florisil, CH2Cl2, 38%
for 3 steps. (g) LDA, THF, -78 °C; HMPA; propargyl bromide, 67%.
(h) LAH, Et2O, 84%. (i) Ac2O, pyridine, 100%. (j) Bu3SnH, AIBN,
benzene, reflux; SiO2, Ch2Cl2.
Scheme 8a
a Reagents and conditions: (a) Bu3SnH, AIBN, benzene, reflux. (b)
Bu3SnH, AIBN, benzene, reflux; SiO2, CH2Cl2.
Scheme 6
a Reagents and conditions: (a) POCl3, pyridine, 99%. (b) K2CO3,
MeOH, 100%. (c) SO3‚Py, DMSO, Et3N, CH2Cl2, 97%. (d) s-BuLi,
THF, 3-triethylsilyloxy-1,4-pentadiene, -78 °C.
to large-scale synthesis was prepared from phthalide 31 as
depicted in Scheme 7. Thus, hydrolysis of 31 followed by Birch
reduction provided the cyclohexadiene derivative 32, which was
subjected to lactonization reaction by the use of the Steglich
protocol14 to afford the lactone 33 in 77% overall yield from
31. Conjugate reduction with NaBH4 furnished the tetrahydro-
phthalide 34 (92%) as a 2:1 mixture of diastereoisomers. Treat-
ment of 34 with excess methylmagnesium iodide followed by
PDC oxidation of the resulting diol produced lactone 35 as a
single stereoisomer. After alkylation (67%) of 35, the resulting
lactone 36 was converted to the acetate 37 via LiAlH4 reduction
Generation of 27 from 25 can be explained by 1,5-radical
translocation (28 f 29) of the initially formed vinyl radical
28 followed by a 5-exo-trig cyclization process (29 f 30) as
shown in Scheme 6. On the basis of our model studies,5 the
formation of the bicyclo[3.2.1]octane ring system was not
anticipated.13
To overcome this drawback, many approaches were surveyed.
The substrate 37 that eventually proved to be most amenable
(13) A part of this work was published as a preliminary communica-
tion: Toyota, M.; Yokota, M.; Ihara, M. Org. Lett. 1999, 1, 1627-1629.
(14) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17,
522-524.

Radical Cyclization Processes of Cyclic Enyne
J. Am. Chem. Soc., Vol. 123, No. 9, 2001 1859
Scheme 9a
a Reagents and conditions: (a) Ac2O, DMAP, CH2Cl2, 99%. (b)
toluene, 200 °C, sealed tube. (c) Bu4NF, THF, 92% for 2 steps.
Figure 1.
Scheme 10a
Figure 2.
a Reagents and conditions: (a) Me3S+OI-, NaH, DMSO, 50 °C, 73%.
(b) BF3‚Et2O, toluene, -20 °C. (c) NaClO2, KH2PO4, 2-methyl-2-butene,
t-BuOH-H2O. (d) DBU, MeI, MeCN. (e) K2CO3, MeOH, 50 °C, 65%
for 4 steps. (f) TMSOTf, lutidine, CH2Cl2, 96%. (g) LDA, THF, -78
°C; HMPA; MeI, 94%. (h) Bu4NF, THF, 94%. (i) angelic acid, 2,4,6-
trichlorobenzoyl chloride, Et3N, toluene, 80 °C, 55%.
Figure 3.
(84%) and acetylation (100%). Homoallyl-homoallyl radical
rearrangement of 37 was conducted under the same reaction
conditions as described above to yield the crude products, which
were submitted to protodestannylation15 to lead to the desired
acetate 26 in 47% overall yield as well as 38 (26%) and 39
(17%). The structures of 26, 38, and 39 were unambiguously
determined by NMR spectroscopy.
With the required bicyclo[2.2.2]octane compound 26 in hand,
we turned to the next phase of our scheme. The tetraene 43 for
intramolecular Diels-Alder reaction was constructed as depicted
in Schemes 8 and 9. The isopropenyl group (dienophile) was
prepared by the treatment of 26 with POCl3 in pyridine, and
the diene part was synthesized by hydrolysis of 40 followed by
Parikh oxidation and alkylation with ((triethylsilyloxy)penta-
dienyl)lithium according to Oppolzer’s method.16 The stereo-
selectivity of this process could be explained by a Cram
model17 (Figure 2). Finally, the alcohol 42a was acetylated to
furnish 43.
Tetraene 43 was next subjected to intramolecular Diels-Alder
reaction10 to provide a 7.5:1 regioisomeric mixture of the
tetracyclic silyl enol ethers 44 in quantitative yield. Although
these regioisomers were not separable at this stage, ketone 45
was obtained as a sole product after treatment with tetrabutyl-
ammonium fluoride. Under such reaction conditions, the
thermodynamically more stable 45 was isolated (Scheme 9).
The high stereoselectivity observed for the present cycloaddition
may be attributed to the fixed conformation of the isopropenyl
group, in which 1,3-allylic strain18 between the olefinic hydrogen
(15) Stork, G.; Mook, R., Jr. J. Am. Chem. Soc. 1987, 109, 2829-2831.
(16) Oppolzer, W.; Snowden, R. L.; Briner, P. H. HelV. Chim. Acta 1981,
64, 2002-2022.
(17) Cram, D. J.; Abd Elhafez, F. A. J. Am. Chem. Soc. 1952, 74, 5828-
5835.
(18) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841-1860.

1860 J. Am. Chem. Soc., Vol. 123, No. 9, 2001
Toyota et al.
Scheme 11a
Scheme 12a
a Reagents and conditions: (a) Me3S+OI-, NaH, DMSO, 50 °C, 72%.
(b) BF3‚Et2O, toluene, -20 °C. (c) NaClO2, KH2PO4, 2-methyl-2-
butene, t-BuOH-H2O. (d) DBU, MeI, MeCN, 78% for 3 steps. (e)
K2CO3, MeOH, 50 °C, 87%. (f) TMSOTf, 2,6-lutidine, CH2Cl2, 98%.
(g) LDA, THF, -78 °C; HMPA; MeI, 81%. (h) Bu4NF, THF, 100%.
(i) PCC, Florisil, NaOAc, CH2Cl2, 100%. (j) CuBr2, LiCl, DMF, reflux,
51%.
a Reagents and conditions: (a) Bu3SnH, AIBN, benzene, reflux; SiO2,
CH2Cl2. (b) LAH, Et2O, 97%. (c) Ac2O, pyridine, 100%. (d) POCl3,
pyridine, 96%. (e) K2CO3, MeOH, 96%. (f) SO3‚Py, DMSO, Et3N,
CH2Cl2, 99%. (g) s-BuLi, THF, 3-triethylsilyloxy-1,4-pentadiene, -78
°C, 96%. (h) Ac2O, DMAP, CH2Cl2, 98%. (i) Toluene, 200 °C, sealed
tube. (j) Bu4NF, THF.
methylation followed by deprotection furnished the correspond-
ing alcohol, which was finally transformed into (()-methyl
gummiferolate (13b). The synthetic 13b thus obtained was
spectroscopically identical with that reported.6
and C-2 hydrogen is minimun in both conformers 43a and 43b.
However, the interaction of the silyloxy group of the diene part
with the acetoxy group of the methylene would disfavor the
conformer 43b. In contrast, this interaction is absent in the
conformer 43a, which affords the desired cycloadduct 44. On
the other hand, conformers 43c and 43d suffer from severe
interactions between the olefinic hydrogen and the ethano bridge
as shown in Figure 3.
Introduction of a C1 unit at the C-4 position of 45 proved to
be rather difficult, and a variety of attempts to achieve the
required homologation were unsuccessful. Ultimately, it was
found that the Corey-Chaykovsky reaction19 of ketone 45 gave
rise to epoxide 46 in 73% yield as a single stereoisomer. This
stereochemical outcome can be elucidated by nucleophilic attack
from the face opposite to the angular methyl group at C-10.
BF3‚Et2O promoted rearrangement of the epoxide group of 46,
followed by oxidation of the resulting aldehyde 47, esterification,
and chemoselective hydrolysis of the acetyl group provided
methyl ester 48 in 65% overall yield as an 84:16 mixture of
stereoisomers. After protection of the hydroxyl group of 48,
Total Syntheses of (()-Methyl 7â-Hydroxykaurenoate and
(()-Methyl 7-Oxokaurenoate and Formal Synthesis of Gib-
berellin A12. With the total synthesis of (()-methyl gummif-
erolate (13b) accomplished, our attention turned to the synthesis
of (()-gibberellin A12 (15) from the same intermediate 16 by
the route shown in Scheme 3. The pivotal radical cyclization
reaction of 16 followed by protodestannylation led to the desired
bicyclo[3.2.1]octane compound 19 and the bicyclo[2.2.2]octane
derivative 50 in 93% yield as an 18:1 separable mixture. A small
amount of 51 (5%) was also obtained. The structures of the
cyclized products (19, 50, and 51) were determined by NMR
spectroscopy. Furthermore, the structure of 50 was confirmed
by the transformation of the bicyclic acetate 26 into 50 through
hydrolysis followed by PCC oxidation. Successive treatment
of 19 with LiAlH4 and acetic anhydride in pyridine effected
conversion to hydroxy acetate 52, which was subjected to
dehydration followed by hydrolysis to give rise to alcohol 53.
The diene moiety of 54 was installed in two steps by applying
the same protocol described above for conversion of 41 to 42.
After protection of the hydroxyl group of 54, the resulting
tetraene was heated at 200 °C in a sealed tube to provide the
tetracyclic silyl enol ether 55, which was treated with tetrabu-
(19) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353-
1364.

Radical Cyclization Processes of Cyclic Enyne
J. Am. Chem. Soc., Vol. 123, No. 9, 2001 1861
tylammonium fluoride to yield a chromatographically separable
mixture of the 7â-acetoxy ketone 56 (57% overall yield from
the tetraene acetate) together with the 7R-isomer 57 (19%).
Functional group manipulation at the C-4 position in 56 was
first carried out by using dimethyloxosulfonium methylide to
give the epoxide 58 (72% yield). This intermediate was
converted to an 84:16 mixture of stereoisomeric ester 59 in 78%
overall yield via Lewis acid treatment, followed by oxidation
and esterification. After changing the protective group of 59
from an acetate to a trimethysilyloxy group, the resulting
compound 60 was successively submitted to methylation and
desilylation to provide (()-methyl 7â-hydroxykaurenoate (14b)20
in 81% overall yield. Oxidation of 14b afforded (()-methyl
7-oxo-kaurenoate (14d)21 in quantitative yield. The spectral data
of both 14b and 14d were identical with those of the corre-
sponding natural products. Intriguingly, keto lactone 20 was
synthesized from 14d by using bromination conditions. Thus,
treatment of 14d with copper(II) bromide in the presence of
lithium chloride produced 20 in 51% yield. Since the keto
lactone 20 has been transformed into gibberellin A12 (15),9,11,12
the present work constitutes a formal total synthesis. In
summary, total syntheses of (()-methyl gummiferolate (13b),
(()-methyl 7â-hydroxykaurenoate (14b), and (()-methyl 7-ox-
okaurenoate (14d) and a formal synthesis of (()-gibberellin A12
(15) have been achieved via the common intermediate, (3aR*,-
7aR*)-3,3-dimethyl-7a-(2-propynyl)-3a,4,7,7a-tetrahydroisoben-
zofuranone (16). The salient steps include homoallyl-homoallyl
radical rearrangement of monocyclic enyne derivatives, 25 and
37, to generate the bicyclo[2.2.2]octane compound 26 and vinyl
radical-promoted 5-exo-trig cyclization of the bicyclic lactone
16 to form the bicyclo[3.2.1]octane framework 19. The present
synthetic design should be readily amenable to the construction
of other polycyclic natural products that contain a bicyclo[2.2.2]-
octane ring system or bicyclo[3.2.1]octane carbon framework.
Experimental Section
See Supporting Information.
Acknowledgment. This work is supported by a Grant-in-
Aid (No. 11672097) from the Ministry of Education, Science,
Sports and Culture, Japan.
Supporting Information Available: Experimental details
involving synthetic procedures and spectroscopic data (PDF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
(20) Quesne, P. W.; Honkan, V.; Onan, K. D.; Morrow, P. A.; Tonkyn,
D. Phytochemistry 1985, 24, 1785-1787.
(21) Hasan, C. W.; Healey, T. M.; Waterman, P. G. Phytochemistry 1982,
21, 1365-1368.
JA0035506