Synthesis of analogues of griseusin A

Article abstract of DOI:10.1021/ol991020c

(equation presented) The synthesis of pyranonaphthoquinone-spiroacetals (3 and 4), which are synthetic analogues of the pyranonaphthoquinone antibiotic griseusin A (1) is reported. The oxygenated substituents on the spiroacetal ring were introduced onto the key naphthalene intermediate (5) using an anti asymmetric aldol reaction. The pyranonaphthoquinone skeleton was then assembled via furofuran annulation to naphthoquinone (22) to construct a furonaphthofuran ring followed by oxidative rearrangement to the furonaphthopyran ring.

Full text of DOI:10.1021/ol991020c

ORGANIC
LETTERS
1999
Vol. 1, No. 9
1459-1462
Synthesis of Analogues of Griseusin A
Margaret A Brimble,* Michael R. Nairn, and Josephine Park
School of Chemistry, F11, The UniVesity of Sydney,
Camperdown, NSW 2006, Australia
m.brimble@auckland.ac.nz
Received September 7, 1999
ABSTRACT
The synthesis of pyranonaphthoquinone-spiroacetals (3 and 4), which are synthetic analogues of the pyranonaphthoquinone antibiotic griseusin
A (1) is reported. The oxygenated substituents on the spiroacetal ring were introduced onto the key naphthalene intermediate (5) using an anti
asymmetric aldol reaction. The pyranonaphthoquinone skeleton was then assembled via furofuran annulation to naphthoquinone (22) to construct
a furonaphthofuran ring followed by oxidative rearrangement to the furonaphthopyran ring.
Griseusins A (1) and B (2) were isolated1 from a soil sample
collected in Peru which had been innoculated with Strepto-
myces griseus K-63 and are unique within the pyranonaph-
thoquinone family2 of antibiotics in that they contain a 1,7-
dioxaspiro[5.5]undecane ring system fused to a juglone
moiety. The absolute configuration of griseusin A (1) was
initially erroneously assigned by comparison of CD spectra
with other pyranonaphthoquinones of known absolute con-
figuration; however, X-ray crystallographic analysis of a 6,8-
dibromoderivative3 later established the absolute stereochem-
istry to be as depicted in structure (1).
only one total synthesis of griseusins A (1) and B (2) has
been reported to date.5 Yoshii et al.5 assembled the spiroacetal
ring of griseusin A (1) starting from an appropriate carbo-
hydrate precursor; however, the required functionalization
of the initial carbohydrate involved a lengthy process.
Our initial synthetic effort6 toward griseusin A (1) focused
on the hydroxylation of an unsaturated spiroacetal as a means
to introduce the oxygenated substituents onto the spiroacetal
ring. The basic griseusin A framework was assembled via
oxidative rearrangement of a furo[3,2-b]naphtho[2,1-d]furan
which in turn was assembled by addition of 2-[(trimethyl-
silyl)oxy]furan to a 1,4-naphthoquinone bearing an R,â-
unsaturated ketone at C-2. This approach was thwarted,
however, when hydroxylation of the final unsaturated
spiroacetal unexpectedly occurred on the C5a-C11a naph-
thoquinone double bond.
We herein report a synthesis of spiroacetals (3) and (4),7
adopting this furofuran annulation/oxidative rearrangement
strategy wherein the spiroacetal oxygenated substituents are
assembled onto an acyclic naphthalene intermediate (5) at
Despite their reported antimicrobial activity1 and their
proposed ability to act as bioreductive alkylating agents,4
(1) (a) Tsuji, N.; Kobayashi, M.; Wakisaka, Y.; Kawamura, Y.; Mayama,
M.; Matsumoto, K. J. Antibiot. (Tokyo) 1976, 29, 7. (b) Tsuji, N.; Kobayashi,
M.; Terui, Y.; Tori, K. Tetrahedron 1976, 32, 2207.
(2) Brimble, M. A.; Duncalf, L. J.; Nairn, M. R. Nat. Prod. Rep. 1999,
16, 267.
(3) Tsuji, N.; Kamagauchi, T.; Nakai, H.; Shiro, M. Tetrahedron Lett.
1983, 24, 389.
(4) (a) Moore, H. W. Science 1977, 197, 527. (b) Moore, H. W.; Czerniak,
R. Med. Res. ReV. 1981, 1, 249.
(5) Kometani, T.; Takeuchi, Y.; Yoshii, E. J. Org. Chem. 1983, 48, 2311.
(6) Brimble, M. A.; Nairn, M. R. Molecules 1996, 1, 3.
(7) All new compounds gave satisfactory spectroscopic and analytical
data.
10.1021/ol991020c CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/25/1999

an early stage in the synthesis. This approach provides a non-
carbohydrate-derived synthesis of analogues of griseusin A
(1).
similar to that observed in analogous aldol products.10,13
Furthermore the 3′,5′-syn stereochemistry of aldol adduct (10)
was confirmed by 13C NMR analysis14 of the acetonide
derivative (15) which was formed after removal of the chiral
auxiliary (Figure 1). The stereochemistry of the minor aldol
products (11 and 12) was established in a similar manner.
The functionality on the C3 side chain of the key naph-
thalene (5) was derived from aldehyde (6). In turn the re-
quired (2R,3R,5R)-aldehyde (6) was prepared via anti aldol
condensation of acyloxazolidinone (8) [derived from ox-
azolidinone (7)8] with (3R)-aldehyde (9) (Scheme 1). Alde-
Scheme 1
Figure 1.
Reductive removal of the chiral auxiliary from the triethyl-
silyl ether (13) of major aldol adduct (10) afforded alcohol
(14) which underwent oxidation to aldehyde (6) using TPAP/
NMO without epimerization.
Union of aldehyde (6) to a naphthalene fragment with the
oxygenation pattern required for assembly of naphthol (5),
initially focused on the use of the organometallic reagents
derived from 3-bromo-1,4,5-trimethoxynaphthalene. This
approach resulted in substantial quantities of 1,4,5-trimeth-
oxynaphthalene being recovered from the reaction together
with elimination of the â-triethylsilyloxy group from the
aldehyde. The three oxygenated substituents on the naph-
thalene ring resulted in a marked increase in the basic
character of the naphthyl anion15 such that protonation by
the aldehyde was occurring.
In light of the difficulties experienced with the above
approach, we next decided to effect C-arylation of aldehyde
(6) using a titanium naphtholate generated from naphthol
(16). This strategy was based on work by Bigi et al.16 and
Casiraghi et al.,17 who have effected regiospecific ortho-
arylation of R-alkoxy and R-amino carbonyl compounds.
hyde (9) was readily available from commercial (3R)-ethyl
3-hydroxybutanoate by protection of the hydroxyl group as
a tert-butyldimethylsilyl ether, lithium borohydride reduction
of the ester to an alcohol,9 followed by oxidation (TPAP,
NMO) to the aldehyde (9).10
(12) Compound 10 was obtained as a colorless oil. Rf: 0.56 (7:3 light
petroleum-ethyl acetate). Found: C, 66.0; H, 7.4; N, 2.6%. C29H41NO6Si
requires C, 66.0; H, 7.8; N, 2.65%. [R]D: -56.11 (c 1.788, CHCl3). υmax
(film), cm-1: 3589-3280 (m, OH), 1784 (s, OCdON), 1703 (s, NCd
OC), 1389 (m, C-N), and 1105 (m, C-O). δH (200 MHz, CDCl3): 0.08
(6H, s, SiMe2), 0.86 (9H, s, But), 1.18 (3H, d, J6′,5′ 6.2 Hz, H6′), 1.67 (1H,
ddd, Jgem 14.3, J4′A,3′ 9.7, and J4′A,5′ 9.7 Hz, H4′A), 1.94 (1H, ddd, Jgem
14.3, J4′B,3′ 3.8 or 1.6, and J4′B,5′ 1.6 or 3.8 Hz, H4′B), 2.60 (1H, dd, Jgem
13.6 and J 9.9 Hz, CHCHAPh), 3.15 (1H, dd, Jgem 13.6 and J 3.3 Hz,
CHCHBPh), 3.54 (1H, d, J 2.2 Hz, OH), 3.94-4.01 (1H, m, H3′), 4.01-
4.17 (3H, m, H5, H5′), 4.53-4.69 (1H, m, H4), 4.61 (2H, s, OCH2Ph),
5.31 (1H, d, J2′,3′ 7.7 Hz, H2′), and 7.17-7.41 (10H, m, Ph). δC (50 MHz,
CDCl3): -5.0, -4.2 (CH3, SiMe2), 17.6 (quat., CMe3), 24.2 (CH3, C6′),
25.6 (CH3, CMe3), 37.7 (CH2, CHCH2Ph), 42.2 (CH2, C4′), 55.2 (CH, C4),
66.2 (CH2, C5), 69.6 (CH, C5′), 72.6 (CH, C3′), 72.8 (CH2, OCH2Ph), 78.8
(CH, C2′), 127.0, 127.8, 128.1, 128.2, 128.6, 129.2 [CH, 2 × Ph, 135.1
(quat., CHCH2Ph), 137.1 (quat., OCH2Ph), 153.3 (quat., C2), and 172.1
(quat., C1′). m/z (LSIMS, NBA matrix): 528 (MH+, 18%).
Precedent for the desired anti aldol coupling between
oxazolidinone (8) and aldehyde (9) was based on work by
Evans et al.11 using tin(II) enolates of oxazolidinones in the
presence of TMEDA. Thus, the stannous enolate of oxazo-
lidinone (8) [generated using Et3N and Sn(OTf)2] was reacted
with aldehyde (9) in the presence of TMEDA to afford an
80% yield of the aldol products (10, 11, and 12) in a 12:3:1
ratio. The aldol products (10, 11, and 12) were separated by
flash chromatography and the 2′,3′-anti stereochemistry of
the major product (10)12 was supported by the magnitude of
the 2′,3′-vicinal coupling constant (J2′,3′ 7.7 Hz) which was
(13) Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem Soc. 1992,
114, 9434.
(14) Evans, D. A.; Rieger, D. L.; Gage, J. R. Tetrahedron Lett. 1990,
31, 7099.
(15) Jung, M. E.; Hagenah, J. A. J. Org. Chem. 1987, 52, 1889.
(16) (a) Bigi, F; Casnati, G.; Sartori, G.; Araldi, G. Gazz. Chim. Ital.
1990, 120, 413. (b) Bigi, F.; Casnati, G.; Sartori, G.; Araldi, G.; Bocelli,
G. Tetrahedron Lett. 1989, 30, 1121. (c) Bigi, F.; Casnati, G.; Sartori, G.;
Dalprato, C.; Bortolini, R. Tetrahedron Asymmetry 1990, 1, 861.
(8) Evans, D. A.; Weber, A. E. J. Am. Chem. Soc. 1986, 108, 6757.
(9) Mori, K.; Maemoto, S. Liebigs Ann. Chem. 1987, 863.
(10) Ohta, K.; Miyagawa, O.; Tsutsui, H.; Mitsunobu, O. Bull. Chem.
Soc. Jpn. 1993, 66, 523.
(11) Evans, D. A.; Gage, J. R.; Leighton, J. L.; Kim, A. S. J. Org. Chem.
1992, 57, 1961.
1460
Org. Lett., Vol. 1, No. 9, 1999

In the present work the desired benzylic alcohols (17 and
18) were prepared in moderate yield by addition of the
titanium naphtholate, generated from naphthol (16) and
TiCl3(OiPr), to aldehyde (6) (Scheme 2). Precise reaction
Scheme 3
Scheme 2
conditions were developed for this step to minimize forma-
tion of an unwanted biarylmethane byproduct.18
With alcohol (17) in hand, oxidation with manganese
dioxide provided ketone (19) which afforded acetates (5 and
20) and diacetate (21) upon treatment with Ac2O and Et3N.
Naphthyl acetate (20) isomerized to the desired alkyl acetate
upon treatment with guanidine in ethanol.
The key naphthol (5) underwent oxidation with CAN to
the sensitive naphthoquinone (22) which was treated directly
with 2-[(trimethylsilyl)oxy]furan (23) to afford furonaph-
thofuran (24) (Scheme 3). Characteristic doublets at δ 6.36
and δ 6.69 (both with J6b,9a 5.9 Hz) were assigned to the
bridgehead proton H-6b of the individual adduct isomers,
clearly establishing that furofuran annulation had taken place.
However, the 1:1 ratio of these two doublets indicated that
bulky benzyloxy group at C2′ on naphthoquinone (22) failed
to influence any stereocontrol in the ensuing annulation.
Addition of excess CAN to the isomeric mixture of adducts
(24) followed by immediate treatment with 5% HF effected
oxidative rearrangement and deprotection of the tert-butyl-
dimethylsilyl ether, affording lactol (25). The stereochemistry
assigned to lactol (25) was established by analogy to related
compounds19 wherein the hydroxyl group at C-5 is axial and
syn to the bridgehead proton H-3b. A more detailed assign-
ment of stereochemistry as either isomer 25a or 25b was
not made. In any event, the final cyclization to a spiroacetal
allowed a more detailed analysis of the stereochemistry.
Finally treatment of lactol (25) with a catalytic quantity
of camphorsulfonic acid in dichloromethane effected spiro-
cyclization to a 3.2:1 mixture of spiroacetals (3) and (4) in
52% yield.20 The magnitude of the vicinal coupling constant,
J3′,4′ 9.8 Hz, in both isomers clearly established that the
benzyloxy and acetate groups were diequatorial. An nOe
effect between H-4′ and 6′-Me was also observed in both
spiroacetals (3 and 4) (Figure 2).
Figure 2.
(17) (a) Casiraghi, G.; Cornia, M.; Rassu, G. J. Org. Chem. 1988, 53,
4919. (b) Cornia, M.; Casiraghi, G. Tetrahedron 1989, 45, 2869. (c)
Casiraghi, G.; Bigi, F.; Casnati, G.; Sartori, G.; Soncini, P.; Fava, G. G.;
Belichi, M. F. J. Org. Chem. 1988, 53, 1799.
(18) Brimble, M. A.; Oppen, E. Synth. Commun. 1997, 27, 989.
(19) Brimble, M. A.; Duncalf, L. J.; Phythian, S. J. J. Chem. Soc. Perkin
Trans. 1 1997, 1399.
The stereochemistry obtained for spiroacetals (3 and 4)
can be rationalized via epimerization at C-3′ which leads to
isomers in which the two bulky substituents at C-3′ and C-4′
can adopt more favorable equatorial positions. Assignment
Org. Lett., Vol. 1, No. 9, 1999
1461

of the stereochemistry at the spirocenter is mainly made on
the basis that the bridgehead proton H-11b of the major
isomer (3) is syn to O-1′ and is deshielded compared to the
same proton in the minor isomer (4). H-3′ is also more
deshielded in the minor isomer (4) due to the BnOC-H bond
being antiperiplanar to the C2′-O4 bond. Efforts to prevent
epimerization at C3′ in the spirocyclization step were
unsuccessful.
In summary, a synthesis of pyranonaphthoquinone-
spiroacetals (3 and 4) which are closely related to griseusin
A (1) and B (2) has been presented. The epimerization
observed in the final spirocyclization step demonstrates that
subtle stereoelectronic effects provide the driving force for
the stereochemistry observed in the final spiroacetals.
(20) Spiroacetals 3 and 4 were isolated as a 3.2:1 mixture of stereoisomers
as an oil. Found: M+H, 549.1747; C30H28O10 requires M+H, 549.1761. δH
(400 MHz, CDCl3): 1.37* (0.7H, d, J5′,4′ 5.8 Hz, Me), 1.42 (2.3H, d, J5′,4′
6.1 Hz, Me), 2.00, 2.03* (3H, s, COCH3), 2.00-2.03 (1H, m, H5′A), 2.10-
2.13 (1H, m, H5′B), 2.68* (0.24H, d, Jgem 17.6 Hz, H3A), 2.74 (0.76H d,
Jgem 17.6 Hz, H3A), 3.00 (1H, dd, Jgem 17.6 and J3B,3a 4.9 Hz, H3B), 3.47
(0.76H, d, J3′,4′ 9.8 Hz, H3′), 3.52* (0.24H, d, J3′,4′ 9.8 Hz, H3′), 3.98, 4.00*
(3H, s, OMe), 4.21-4.28 (1H, m, H4′), 4.67 (0.76H, d, Jgem 11.3 Hz,
OCHAPh), 4.68-4.70 (0.76H, m, H3a), 4.74* (0.24H, d, Jgem 11.1 Hz,
OCHAPh), 4.92 (0.76H, d, Jgem 11.3 Hz, OCHBPh), 4.94-4.96* (0.24H,
m, H3a), 4.95* (0.24H, d, Jgem 11.1 Hz, OCHBPh), 5.20-5.25 (1H, m,
H6′), 5.27* (0.24H, d, J11b,3a 2.8 Hz, H11b), 5.31 (0.76H, d, J11b,3a 2.8 Hz,
H11b), 7.30-7.36 (6H, m, H8, Ph), 7.47 (1H, t, J9,8 8.0 and J9,10 8.0 Hz,
H9), and 7.75 (1H, d, J10,9 8.0 Hz, H10). The asterisks (*) denote resonances
for the minor isomer 4.
Acknowledgment. This work was supported by an
Australian Research Council Small Grant and The University
of Sydney.
OL991020C
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Org. Lett., Vol. 1, No. 9, 1999