Enantioselective synthesis of the sporolide quinone acid fragment

Article abstract of DOI:10.1055/s-0029-1217963

The sporolide quinone acid is a key fragment in the biosynthesis of the complex heptacyclic marine metabolite sporolide. We report a concise enantioselective route to this fragment, which is obtained in seven steps with 65% overall yield from trimethoxybe

Full text of DOI:10.1055/s-0029-1217963

LETTER
2849
Enantioselective Synthesis of the Sporolide Quinone Acid Fragment
Synthesis
e
of the
S
por
a
olide Quino
n
ne Acid Fra
-
Swiss Federal Institute of Technology (EPFL), Chemical Synthesis Laboratory (ISIC-LSYNC), 1015 Lausanne, Switzerland
Fax +41(21)6939700; E-mail: karl.gademann@epfl.ch
Received 10 July 2009
OH
R2
Abstract: The sporolide quinone acid is a key fragment in the bio-
synthesis of the complex heptacyclic marine metabolite sporolide.
We report a concise enantioselective route to this fragment, which
is obtained in seven steps with 65% overall yield from trimethoxy-
benzene. The enantioselective transfer reduction is achieved by
Ipc2BCl, and the absolute configuration of the product secured by
X-ray analysis of its cinchonine salt. The target fragment is then ob-
tained by methylation and oxidation to the quinone by AgO.
OH
OH
O
O
R1
Me
O
O
MeO
O
HO
O
OH
sporolide A: R1 = Cl, R2 = H
sporolide B: R1 = H, R2 = Cl
Key words: asymmetric synthesis, natural products, biosynthesis,
transfer hydrogenation, quinones
CO2H O
The marine natural products sporolides A and B
(Equation 1), isolated in 2005 by Fenical and coworkers,1
display a complex heptacyclic framework involving a
chlorinated cyclopenta[a]indene ring and hydrated quino-
ne hydroxy acid fused in a macrocyclic ansa-type struc-
ture. This densely functionalized and compact
architecture is built from 24 C atoms, out of which 22 are
either oxygenated or sp2 hybridized. Due to its complex
structure and unsolved biosynthesis, several research
groups embarked on studies on this marine metabolite,2
and, recently, sporolide had succumbed to total synthesis
by Nicolaou and co-workers earlier this year.3 From a
structural point of view, this intramolecularly hydrated
macrolide could be degraded by hydrolysis into two key
components, the cyclopenta[a]indene fragment and a
chiral a-methoxy quinone acid. This analysis is also sup-
ported by biosynthetic investigations, which demonstrat-
ed separate biogenesis of the two fragments.2b,d
Me
MeO
O
OH
O
sporolide quinone acid
Equation 1
O
CO2H
CO2H
SpoT1
HO
OH
p-hydroxyphenylpyruvate
OH
(S)-p-hydroxymandelic acid
racemization?
oxidation?
epoxydation?
methylation?
MeO2C
MeO
O
HO2C
MeO
O
This hypothesis highlights the importance of the ep-
oxyquinone acid as a key precursor in the biosynthesis of
sporolide. The first step in the quinone biosynthesis via
(S)-p-hydroxy mandelic acid [(S)-HMA] was recently
demonstrated in vitro,2d and the putative enzymes
(SpoT1-T9) for sporolide quinone acid generation in Sali-
nospora tropica have been postulated (Scheme 1). Re-
Me
Me
OH
O
OH
O
O
sporolide quinone acid
1
Scheme 1 Postulated biosynthesis of the sporolide quinone acid ac-
maining questions in the biosynthesis of this sporolide cording to Moore and co-workers2d and target fragment 1
acid involve the racemization step of (S)-HMA to the final
R-configured sporolide quinone acid, the sequence of ox-
idation reactions, and the postulated S-adenosyl methion-
ine dependent O- and C-methylations. These open
biogenetic questions, as well as its utility in a total synthe-
sis campaign towards the sporolides, renders the sporolide
quinone acid fragment 1 a key target. In this letter, we re-
port an efficient stereoselective preparation of this quino-
ne fragment of sporolide.
The synthesis started with commercially available 1,2,4-
trimethoxybenzene, which was metalated with n-BuLi
and quenched with MeI to give 2 in 99% yield
(Scheme 2).4 The pyruvate derivative 3 was directly ob-
tained via Friedel–Crafts acylation5 in 98% yield and no
SYNLETT 2009, No. 17, pp 2849–2851
Advanced online publication: 09.09.2009
DOI: 10.1055/s-0029-1217963; Art ID: G22409ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
9
regioisomer could be detected by NMR analysis. The
enantioselective reduction of the keto group was exam-
ined next, and catalytic enantioselective reductions such

2850
J.-Y. Wach, K. Gademann
LETTER
as Corey–Itsuno6 or the enantioselective Friedel–Crafts the installment of the stereogenic center was a transfer hy-
hydroxyalkylation developed by Jørgensen7 have not been drogenation with (–)-Ipc2BCl, and the absolute configura-
successful on this substrate. Gratifyingly, transfer reduc- tion was secured by X-ray crystallographic analysis of the
tion with chlorodiisopinocampheylborane (Ipc2BCl)8 was cinchonine salt. Further elaboration to the quinone was
identified as the method of choice.
achieved by deprotection and oxidation with Ag(II) oxide.
This fragment and its derivatives can now be utilized in
further synthetic studies on the sporolides as well as in
biosynthetic investigations.
OMe
OMe
1. n-BuLi, MeI
2. ethyl chloroglyoxylate,
OMe
OMe
Me
O
TiCl4
97% over 2 steps
EtO
Acknowledgment
OMe
O
OMe
3
K.G. is a European Young Investigator (EURYI). We thank the
Schweizerischer Nationalfonds zur Förderung der wissenschaftli-
chen Forschung (200021-115918/1 and PE002-117136/1) for sup-
port. We thank Dr. Rosario Scopelliti (ISIC-EPFL) for X-ray crystal
structure analysis.
2
1. LiOH, H2O
2. (–)-Ipc2BCl, Et3N
3. recryst with CyNH2
77% over 3 steps
OMe
OMe
OMe
OMe3BF4
proton sponge
4 Å MS
OMe
Me
O
O
References and Notes
MeO
HO
Me
99%
(1) Buchanan, G. O.; Williams, P. G.; Feling, R. H.; Kauffman,
C. A.; Jensen, P. R.; Fenical, W. Org. Lett. 2005, 7, 2731.
(2) (a) Oh, D. C.; Williams, P. G.; Kauffman, C. A.; Jensen, P.
R.; Fenical, W. Org. Lett. 2006, 8, 1021. (b) Udwary, D.
W.; Zeigler, L.; Asolkar, R. N.; Singan, V.; Lapidus, A.;
Fenical, W.; Jensen, P. R.; Moore, B. S. Proc. Natl. Acad.
Sci., U.S.A. 2007, 104, 10376. (c) Perrin, C. L.; Rodgers,
B. L.; O’Connor, J. M. J. Am. Chem. Soc. 2007, 129, 4795.
(d) McGlinchey, R. P.; Nett, M.; Moore, B. J. Am. Chem.
Soc. 2008, 130, 2406. (e) Review: Fenical, W.; Jensen,
P. R. Nature Chem. Biol. 2006, 2, 666.
OMe OMe
OH OMe
5
4 (98% ee)
AgO, HNO3
89%
O
O
OH
Cl
oxalyl chloride
DMF
O
O
MeO
Me
MeO
Me
84%
OMe
O
OMe O
(3) (a) Nicolaou, K. C.; Wang, J.; Tang, Y. Angew. Chem. Int.
Ed. 2008, 47, 1432. (b) Nicolaou, K. C.; Tang, Y.; Wang, J.
Angew. Chem. Int. Ed. 2009, 48, 3449.
1
6
Scheme 2 Synthesis of the sporolide quinone fragment 1
(4) Carmen Carreno, M.; Garcia Ruano, J. L.; Toledo, M. A.;
Urbano, A. Tetrahedron: Asymmetry 1997, 8, 913.
(5) Yoshikawa, N.; Doyle, A.; Tan, L.; Murry, J. A.; Akao, A.;
Kawasaki, M.; Sato, K. Org. Lett. 2007, 9, 4103.
(6) (a) Itsuno, S.; Kito, K.; Hirao, A.; Nakahama, S. J. Chem.
Soc., Chem. Commun. 1983, 469. (b) Corey, E. J.; Shibata,
S.; Bakshi, R. K. J. Org. Chem. 1988, 53, 2861.
(7) Gathergood, N.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem.
Soc. 2000, 122, 12517.
(8) (a) Brown, H. C.; Ramachandran, P. V. Acc. Chem. Res.
1992, 25, 16. (b) Ramachandran, P. V.; Brown, H. C.; Pitre,
S. Org. Lett. 2001, 3, 17.
After saponification of the ethylester 3 by LiOH and H2O,
the resulting carboxylic acid was deprotonated (Et3N) and
the B reagent was slowly added at low temperature. The
a-hydroxy 410 acid was obtained in high enantiomeric pu-
rity after a single recrystallization with cyclohexylamine
(98% ee and 77% yield over 3 steps), as determined by
HPLC on chiral stationary phases. The absolute configu-
ration of the newly formed stereogenic center was unam-
biguously established by X-ray diffraction of the
cinchonine salt (CCDC 742509). Moreover, CH2Cl2 was
present in the crystal structure, thus providing additional
confirmation of the correct configuration.
(9) (a) Snyder, C. D.; Rapoport, H. J. Am. Chem. Soc. 1972, 94,
227. (b) Hauser, F. M.; Rhee, R. P. J. Org. Chem. 1980, 45,
3061.
(10) Preparation and Selected Data for Compound 4
A solution of 2-oxo-2-(2,4,5-trimethoxy-3-methylphenyl)-
acetic acid (300 mg, 1.18 mmol, 1.0 equiv) in THF (6 mL) at
–40 °C was treated with Et3N (164 mL, 1.18 mmol, 1.0
equiv) and stirred for 5 min followed by the slow addition of
(–)-Ipc2BCl (417 mg, 1.30 mmol, 1.1 equiv) in THF (2 mL).
The reaction mixture was gradually warmed up to r.t. and
stirred at r.t. for 3 h. The reaction was quenched with H2O,
treated with NaOH (10%) to pH >12, extracted with Et2O,
and the organic layers were combined and washed with H2O
(25 mL). The aqueous layers were then combined and
acidified with 1 N HCl to pH 2 and extracted with EtOAc.
The combined organic layers were washed with brine and
dried over Na2SO4. Once concentrated, the crude hydroxy
acid was purified by recrystallization from hot EtOH as its
cyclohexylammonium salt. The title compound was then
obtained (233 mg, 0.909 mmol, 77%) as a white crystalline
The R-configured hydroxy acid 4 was then reacted with
Meerwein’s salt to provide the doubly methylated hydro-
quinone ester 5. An acidic solution of Ag(II) oxide9 gave
the target sporolide fragment 111 in 89% yield. In addition,
this hydroxyquinone can be readily transformed to the
chloro-paraquinone 6.12 This activated vinylogous acyl
chloride can be utilized in further synthetic studies by
coupling to the cyclopenta[a]indene fragment of
sporolide.
In conclusion, we report here a short, enantioselective
route to the sporolide quinone acid fragment 1, which is
obtained in seven steps with an overall yield of 65% from
commercially available 1,2,4-trimethoxybenzene. Key for
Synlett 2009, No. 17, 2849–2851 © Thieme Stuttgart · New York

LETTER
solid by extraction with Et2O of the aqueous acid solution of
Synthesis of the Sporolide Quinone Acid Fragment
2851
128.88, 118.02, 76.81, 59.37, 53.25, 1.45. IR: n = 3352 (w),
2955 (m), 2920 (s), 2851 (m), 1744 (s), 1659 (s), 1643 (s),
1620 (m), 1458 (w), 1393 (m), 1346 (m), 1269 (m), 1196 (s),
1157 (m), 1107 (m), 1045 (w), 1011 (w) cm–1.
the salt. Rf = 0.21 (CH2Cl2–MeOH–AcOH = 9:1:0.05);
[a]D25 –81.6 (c 0.2325, CHCl3). 1H NMR (400 MHz,
CDCl3): d = 6.89 (s, 1 H), 5.36 (s, 1 H), 3.84 (s, 6 H), 3.80
(s, 3 H), 2.24 (s, 3 H). 13C NMR (100 MHz, CDCl3):
d = 193.66, 174.75, 150.16, 148.35, 125.78, 125.41, 107.98,
68.61, 61.33, 60.33, 55.99, 9.71. ESI-HRMS (TOF): m/z
calcd for C12H16O6 [M + Na]+: 279.0845; found: 279.0834.
IR: n = 3429 (br m), 2994 (m), 2940 (m), 2858 (w), 1728 (s),
1597 (w), 1489 (s), 1462 (m), 1420 (m), 1335 (m), 1242 (s),
1123 (s), 1084 (s), 1007 (m) cm–1.
(12) Preparation and Selected Data for Compound 6
To a solution of (R)-methyl 2-(4-chloro-5-methyl-3,6-
dioxocyclohexa-1,4-dienyl)-2-methoxyacetate (1, 46 mg,
0.193 mmol, 1.0 equiv) in dry CH2Cl2 (1.9 mL) at 0 °C was
added oxalyl chloride (33 mL, 0.387 mmol, 2.0 equiv)
followed by one drop of DMF. The reaction mixture was
stirred for 1 h at 0 °C and 16 h at r.t. The reaction was
quenched with H2O (3 mL), and the aqueous layer was
extracted with CH2Cl2. The combined organic layers were
dried over Na2SO4 and concentrated to afford the crude
product, which was purified by chromatography using
hexane–EtOAc (9:1) as eluent. The analytically pure product
(42 mg, 0.162 mmol, 84%) was obtained as a red viscous oil.
Rf = 0.71 (hexane–EtOAc = 1:1); [a]D25 –48.0 (c 0.27,
CHCl3). 1H NMR (400 MHz, CDCl3): d = 7.00 (d, J = 1.2
Hz, 1 H), 4.88 (d, J = 1.2 Hz, 1 H), 3.80 (s, 3 H), 3.54 (s, 3
H), 2.24 (s, 3 H). 13C NMR (100 MHz, CDCl3): d = 183.56,
178.92, 173.23, 168.85, 143.69, 142.41, 132.61, 76.27,
59.05, 52.88, 13.75. ESI-HRMS (TOF): m/z calcd for
C11H11ClO5 [M + Na]+: 281.0187; found: 281.0189. IR: n =
2955 (w), 2924 (w), 2847 (w), 2361 (w), 2338 (w), 1748 (s),
1670 (s), 1605 (w), 1439 (w), 1373 (w), 1277 (m), 1246 (m),
1204 (m), 1165 (w), 1111 (m), 1015 (w) cm–1.
(11) Preparation and Selected Data for Compound 1
To a stirred solution of (R)-methyl 2-methoxy-2-(2,4,5-
trimethoxy-3-methylphenyl)acetate (5, 250 mg, 0.879
mmol, 1.0 equiv) in dioxane (4 mL) was added AgO (545
mg, 4.397 mmol, 5.0 equiv) followed by 4 N HNO3 until the
silver oxide was completely dissolved. The resulting
solution was stirred for 30 min and then diluted with CH2Cl2.
The organic layer was washed with H2O, brine, dried over
Na2SO4, and the solvent was evaporated under reduced
pressure to afford the crude product, which was purified by
chromatography using hexane–EtOAc (8:2) as eluent. The
analytically pure product (188 mg, 0.782 mmol, 89%) was
obtained as a red viscous oil. Rf = 0.50 (hexane–EtOAc =
1:1); [a]D25 –33.0 (c 0.36, CHCl3). 1H NMR (400 MHz,
CDCl3): d = 6.85 (d, J = 1.3 Hz, 1 H), 4.90 (d, J = 1.3 Hz, 1
H), 3.77 (s, 3 H), 3.51 (s, 3 H), 1.96 (s, 3 H). 13C NMR (100
MHz, CDCl3): d = 186.63, 183.06, 169.48, 151.73, 146.22,
Synlett 2009, No. 17, 2849–2851 © Thieme Stuttgart · New York

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