Studies of novel cyclitols. A synthesis of 3'O,4'O-dimethylfuniculosin

Article abstract of DOI:10.1016/S0040-4039(00)01496-9

A synthesis of funiculosin dimethyl ether (2) is described. Methodologies for an asymmetric conjugate addition to establish the 1,3-anti dimethyl array, stereocontrolled formation of the Z,E-bis-allylic C-11 alcohol, and interception of a reactive pyridin

Full text of DOI:10.1016/S0040-4039(00)01496-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9397–9401
Studies of novel cyclitols. A synthesis of
3%O,4%O-dimethylfuniculosin†
David R. Williams,* Patrick D. Lowder and Yu-Gui Gu
Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, IN 47405-7102, USA
Received 31 August 2000; accepted 7 September 2000
Abstract
A synthesis of funiculosin dimethyl ether (2) is described. Methodologies for an asymmetric conjugate
addition to establish the 1,3-anti dimethyl array, stereocontrolled formation of the Z,E-bis-allylic C-11
alcohol, and interception of a reactive pyridinone methide are examined. © 2000 Published by Elsevier
Science Ltd.
Funiculosin (1) is isolated as a unique metabolite from the fermentation broth of Penicillium
funiculosium (Thom Iam 7013).1 Significant biological activity is exhibited as a potent, broad-
spectrum antifungal with activities comparable to griseofulvin. Most notably, funiculosin shows
consistently excellent results against Trichophyton asteroide, T. mentagrophytes and T. yubrum.
The natural product also demonstrates in vitro activity against Herpes simplex virus (Strain HF)
and Newcastle disease virus with modest antitumor effects. The structural characterization of 1
was disclosed in 1978 upon hydrogenation to yield 9,10,12,13-tetrahydrofuniculosin, which
provided for unambiguous assignment via a single-crystal X-ray diffraction study.1b The
structure displays an unusual all syn-cyclopentanetetrol as a rare example of a substituted cyclitol
that is directly C-linked to the 5-position of the heterocyclic nucleus.2 In fact, the presence of the
3,5-disubstituted-4-hydroxy-2-pyridinone in naturally occurring secondary metabolites is also
unusual. Recent representatives of this family, including pyridomacrolidin,3a oxysporidinone,3b
apiosporamide,3c fischerin,3d and sambutoxin,3e possess a range of biological properties.
RO
9
CH3
OH
OH
10
12
RO
4
7
18
CH3
3
14
16
O
H
H
H
HO
1
N
CH3 CH3 CH3
6
O
CH3
1 (Funiculosin) R = H
2 (3'O,4'O-Dimethylfuniculosin) R = CH3
* Corresponding author. E-mail: williamd@indiana.edu
†
Dedicated as a tribute to Professor Harry H. Wasserman in recognition of his statesmanship, his leadership, and his
unwavering passion in support of excellence in our science.
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01496-9

9398
Our earlier efforts toward tenellin and ilicicolin H provided the first examples of total
syntheses within this class of natural products.4 Additional advances in these laboratories, as
well as others, have underscored interest in the fundamental chemistry of these heterocyclic
systems.5 Herein we have described the first synthesis pathway leading to the enantiocontrolled
construction of the intact funiculosin nucleus with the stereoselective preparation of funiculosin
dimethyl ether 2.
Our synthesis strategy recognized the meso plane of symmetry in the all-syn-cyclopen-
tanetetrol portion of 1, greatly simplifying issues of stereochemistry for a convergent pathway.
In fact, we have studied intramolecular enolate condensations using stable carboxamidimida-
zolides as a general preparation of functionalized 4-hydroxy-2-pyridinones incorporating the
cyclitol fragment.5a Pattenden has also described a route to the all-syn-cyclopentanetetrol.6
However, we were unable to utilize intermediates containing the intact pyridone to further
synthesis efforts toward 1. Therefore, we have explored formation of the heterocyclic system as
a late-stage event after stereocontrolled assembly of the intact carbon backbone. These efforts
began with the asymmetric conjugate addition utilizing the Hruby 4-phenyloxazolidinone
auxiliary7 as shown in Scheme 1.
O
N
Ph
O
O
O
L
L
O
BnO
Br
Ph
O
1) LiBH4, wet Et2O, (84%)
2) Ph3P, I2, imid., (96%)
Mg
CH3
4
H
O
O
N
CH3
N
H
BnO
Mg° / THF
CuBr•DMS (1 equiv)
at –78 °C
H3C
O
3) LiEt3BH then
O
Ph
3
CH3 CH3
Cu
H2O2, NaOH, (98%)
5a
Bn
H
(75%)
5
H
CH3
O
1) HC≡CMgBr
1) Swern oxidation; then add
Ph3P=C(CH3)CO2Et, (82%)
THF; 0 °C
RO
CH3
O
CH3
H
CH3
CH3 CH3
CH3 CH3 CH3
CH3 CH3 CH3
2) MnO2, CH2Cl2
(88% for two steps)
2) DIBAL, CH2Cl2, –78 °C, (97%)
3) MnO2, CH2Cl2, (91%)
10% Pd/C
10% HCO2H
9
8
6 R = Bn
7 R = H
in MeOH, (93%)
COOCH3
1) Me2CuLi, THF
at –78 °C
1) LAH, ether, –78 °C
X
CH3
(+)-Chirald®, (2.3 equivs) (75%)
quench NH4Cl (98%)
RO
CH3
RO
CH3
H
H
2) Et3SiCl, pyridine
2) DIBAL, CH2Cl2
–78 °C (97%)
CH3 CH3 CH3
CH3 CH3 CH3
10 R = Et3Si
catalytic DMAP, 22 °C
3) nBuLi (2 equiv), THF
then ClCO2CH3, –78 °C
(95% over two steps)
11 R = Et3Si; X = OH
CBr4; CH2Cl2
Ph2PCH2CH2PPh2
Et3N, 0 °C
12 R = Et3Si; X = Br
Scheme 1.
Addition of the Yamamoto organocopper reagent derived from bromide 48 provided the
1,3-anti-dimethyl array in 5 with complete diastereofacial selectivity. Chelation in the S-syn-con-
former as depicted in 5a facilitated a process of double stereodifferentiation, and benzyl ether 6
was obtained in 79% overall yield following reductive removal of the chiral auxiliary.9 Subse-
quent conversion to the enal 8 proceeded in straightforward fashion.
Selective construction of the C9ꢀC10 Z-trisubstituted alkene offered the additional challenge
for the introduction of the desired (S)-stereochemistry of the bis-allylic C11-alcohol. This was
resolved by production of the acetylenic a,b-unsaturated enone 9, and successful deployment of
the Mosher asymmetric reduction,10 resulting in remarkably high facial selectivity for this

9399
modified hydride reagent.13 Thus, the addition of an ethereal solution of 2.3 equivalents of
(2S,3R)-(+)-4-dimethylamino-1,2-diphenyl-3-methyl-2-butanol((+)-Chirald®)10c to a suspension
of LiAlH4 (1 equiv.) in ether at 0°C resulted in a thick precipitate which was cooled to −78°C.
Slow addition of an ether solution of ketone 9 over 1.5 h and continued stirring for 4.5 h
provided an 88% yield of acetylenic alcohols (85:15 dr).11 This stereoselective reduction of
acyclic, cross-conjugated alkynones is notable in light of reported results for steric recognition
of unsaturated aromatic, acetylenic, or vinylic substitution versus larger sp3 aliphatic substitu-
tion. In our case, the modified aluminum hydride is capable of steric discrimination between the
smaller alkyne unit and the adjacent, conjugated alkenyl residue.12 Silyl ether formation led to
the separation of diastereomers by silica gel chromatography, and C-acylation gave the
acetylenic ester 10. Finally, the syn-addition of dimethylcuprate at low temperature was
followed by DIBAL reduction to yield the doubly unsaturated Z,E-allylic alcohol 11.
In order to explore our carbonyl condensation strategy for formation of the pyridone ring, a
three-carbon extension of the acyclic chain was required. Conversion to the allylic bromide 12
(Scheme 1) permitted nucleophilic displacement with Grignard reagent 13 (Scheme 2) prepared
from 3-chloro-1-propanol via initial deprotonation with ethylmagnesium chloride (1 equiv.)
yielding 14 (65%).13 Oxidation and transformation to the desired methyl ester 15 was uneventful.
Production of the lithium enolate of 15 and low temperature aldol condensation with aldehyde
1614 was immediately followed by Moffat oxidation of the crude product mixture and removal
of Fmoc protection to produce the 5,6-dihydropyridinone 17 in 73% yield.15 Mild oxidation with
BrCCl3 and DBU16 and desilylation gave the penultimate intermediate 18. Our plans for the
formation of the 2,6-cis-dihydropyranyl system of 2 required the generation of a highly reactive
pyridone methide to effect spontaneous intramolecular conjugate addition of the bis-allylic (C11)
hydroxyl group.17 In the event, our application of Saguesa oxidation conditions18 afforded a
48% yield of two novel products, which were separated by flash silica gel chromatography (2:1
HMPA; THF
1)
(excess)
13
MgBr2
–40 °C → 22 °C (65%)
X
CH3
1) LDA, THF
at –78 °C
Mg
O
12
MeO
Et3SiO
CH3
OMOM
CHO
H
Add:
2) Dess-Martin oxidation
3) NaClO2, NaH2PO4, 0 °C
tBuOH, aqu. CH3CN
CH3CH=C(CH3)2
CH3 CH3 CH3
MeO
14 X = CH2OH
15 X = COOCH3
H
16
MOMO
CH3
N
Fmoc
2) HMPA, –78 °C
3) DMSO, DCC oxid.
then piperidine (73%)
4) CH2N2; ether, 0 °C
(93% over 3 steps)
MeO
MeO
MeO
MOMO
OMOM
O
OMOM
OH
CH3
CH3
1) CBrCl3, DBU
MeO
RO
CH3
HO
CH3
CH2Cl2, 0 °C
2) Et3N•HF
H
H
H
H
MOMO
CH3 CH3 CH3
CH3 CH3 CH3
N
O
N
O
17 R = Et3Si
18
CH3
CH3
Pd(OAc)2
CH3CN/K2CO3
rt (5 hr)
O
N
MeO
OR
OH
CH3
H3C
OH
H
MeO
O
CH3
MeO
H
O
CH3
H
H
H
RO
OR
CH3 CH3 CH3
CH3 CH3
19 R = MOM
H
N
O
MeO
OR
CH3
2a R = MOM
R = H
H
H
BCl3, CH2Cl2 at –78 °C
2
Scheme 2.

9400
ratio). Upon deprotection at −78°C, funiculosin dimethyl ether (2) was isolated as the product
of palladium-induced allylic oxidation. The major component of the cyclization reaction was the
unique C-linked glycoside 19, rationalized as the product of competing p-palladium complexa-
tion, initiating a formal 6-exo-trig etherification followed by palladium hydride elimination.19
The structural assignment of funiculosin dimethyl ether (2) was confirmed by direct spectral
comparisons of carbon and proton NMR data obtained from a sample of the natural product
1.20 Further efforts will be reported in due course.
Acknowledgements
This work was supported by a grant from the National Institutes of Health (GM41560).
References
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Chem. 1996, 61, 2839. (c) Rigby, J. H.; Qabar, M. J. J. Org. Chem. 1989, 54, 5852.
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J. Tetrahedron Lett. 1998, 39, 8593 and references cited therein.
8. Bromide 4 and its corresponding Grignard reagent were prepared from (2R)-methyl-3-hydroxy-2-methylpropi-
onate (Aldrich) via reaction with benzyl 2,2,2-trichloroacetimidate, LiAlH4 reduction, tosylation and exchange
with LiBr in DMF at 50°C (J. Earley, Ph.D. Thesis, Indiana University 1996).
9. Confirmation of our 1,3-stereochemistry was established by an independent synthesis using asymmetric allylation
methodology to produce a homochiral allylic alcohol. (Roush, W. R.; Palkowitz, A. D.; Palmer, M. A. J. Org.
Chem. 1987, 52, 316.) Conversion to alcohol 7 was accomplished in four steps (65% overall yield).
t
1) H2, Rh/Al2O3
in EtOAc
HO
Me2 BuSiO
OH
CH3
S
CH3 CH3
CH3 CH3
N
N
2)
N
7
N
105 °C in toluene
3) n-Bu3SnH; tol.; 110 °C
4) TBAF, THF
10. (a) Yamaguchi, S.; Mosher, H. S. J. Org. Chem. 1973, 38, 1870. Brinkmeyer, R. S.; Kapoor, V. M. J. Am. Chem.
Soc. 1977, 99, 8339. (b) Somers, P. K.; Wandless, T. J.; Schreiber, S. L. J. Am. Chem. Soc. 1991, 113, 8045. (c)
Also known as Darvon alcohol, (+)-Chirald® (Aldrich) is readily available.

9401
11. The diastereomer ratio was determined by 1H NMR integration of chemical shifts of bis-allylic methine
hydrogens and Mosher ester analysis (see Ref. 10b). Conversion to 2 attests to the S-assignment.
12. Such examples are rare: Okamura, W. H.; Peter, R.; Rieschl, W. J. Am. Chem. Soc. 1985, 107, 1034.
13. Sarkar, T. K.; Ghosh, S. K.; Satapathi, T. K. Tetrahedron 1990, 46, 1885.
14. Aldehyde 16 was prepared by an extension of previous studies (Ref. 5a) as summarized below.
MeO
MeO
MOMO
MeO
MeO
MOMO
1) LAH, THF
(83%)
1) H2/Pd-C, MeOH
2)
OMOM
COOCH3
OMOM
COOCH3
16
(R = 9-fluorenylmethyl)
2) Dess-Martin Ox.
(95%)
H
H
CH3
OR
COOBn
N
N
OCOCl
CH3
O
pyr, CH2Cl2, 0 °C (88%)
15. Crude products of intermediate steps stemming from the aldol reaction contain N-protected and cyclized
materials from partial loss of the Fmoc unit. Lactam 17 is a mixture of diastereomers, existing as keto tautomers,
1
whereas H NMR evidence describes 18 as completely enolic at C-4.
16. Williams, D. R.; Lowder, P. D.; Gu, Y.-G.; Brooks, D. A. Tetrahedron Lett. 1997, 38, 331.
17. Examples of pyridinone methides as reactive intermediates; (a) Girotra, N. N.; Wendler, N. L. Heterocycles 1978,
9, 417. (b) Tietze, L. F.; Brand, S.; Brumby, T.; Fennen, J. Angew. Chem., Int. Ed. Engl. 1990, 29, 665. See also
Refs. 5b and 16.
18. Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
19. The C-9 stereochemistry of 19 cannot be unambiguously assigned from H NMR data.
1
20. We thank Dr. P. Bollinger (Sandoz AG, Basel) for a generous sample of funiculosin to assist our studies.
.