Diastereoselective access to the spirotetronate subunit of the quartromicins

Article abstract of DOI:10.1055/s-2005-872657

The agalacto-spirotetronate B subunit of quartromicins was synthesized in a predictible manner, following the Claisen-Ireland/metathesis approach (CIM strategy). Ene-yne ring-closure and selective mismatch Sharpless dihydroxylation are discussed as key st

Full text of DOI:10.1055/s-2005-872657

LETTER
2313
Diastereoselective Access to the Spirotetronate Subunit of the Quartromicins
D
iastereoselective
l
A
ccess
i
tothe
v
Spirotetrona
i
te Subu
e
nit of the
Q
r
uartromicins Bedel,*a Antoine Français,a Arnaud Haudrechyb
a
Laboratoire de Synthèse des Substances Naturelles, Associé au CNRS, Bât. 410, Université de Paris Sud, 91405 Orsay Cedex, France
b
Laboratoire de Glycosynthèse, UMR 6519, UFR Sciences Exactes et Naturelles, Bât. 18, BP 1039, 51687 Reims Cedex 2, France
Fax +33(3)26913166; E-mail: arnaud.haudrechy@univ-reims.fr
Received 27 June 2005
We have recently described a highly enantioselective
sequential Claisen–Ireland/metathesis process (CIM)
which allows the synthesis of cycloalkenes bearing two
contiguous highly functionalized asymmetric centers
(Scheme 1).12
Abstract: The agalacto-spirotetronate B subunit of quartromicins
was synthesized in a predictible manner, following the Claisen–
Ireland/metathesis approach (CIM strategy). Ene–yne ring-closure
and selective mismatch Sharpless dihydroxylation are discussed as
key steps, allowing an efficient approach to these structures.
Key words: quartromicin, ene–yne metathesis, Claisen–Ireland
rearrangement, asymmetric dihydroxylation, spirotetronate
R'
MeO2C
R
R'
R"
O
O
R
R"
CIM
n
In 1991, an impressively complex family of compounds,
the quartromicins, was isolated.1 They exhibit a large
spectrum of antiviral activity against herpes simplex virus
type I, influenza virus type A and human immunodefi-
ciency virus.2 The highly symmetrical structure results
from a junction between diastereoisomeric spirotetronate
subunits A and B (Figure 1).
n
Scheme 1 CIM: 1) KHMDS, PhMe, –78 °C; 2) TMSCl, –78 °C to
r.t.; 3) Grubbs’ I or II, CH2Cl2; 4) CH2N2, Et2O.
In this article we would like to present our work concern-
ing an approach to the type B backbone, using the follow-
ing retrosynthetic analysis (Scheme 2). The target
molecule 1 can be obtained through a Dieckmann reaction
of compound 2, with an in situ protection of the enolate.
Ester 2 is derived from diene 3, using a selective dihy-
droxylation and protecting group exchange. The key step
of our approach is a Claisen–Ireland rearrangement fol-
lowed by an ene–yne metathesis ring-closure to give 3
from the acyclic ester 4. Compound 4 is easily obtained
from allylic alcohol 5 and carboxylic acid 6.
RO
HO
M+
O
O–
B
A
O
-O
M+
O
O
O
O
M+
O
O
O
O-
O
O
A
OTBDPS
OMPM
COOMe
OR
OR
B
O
O
O–
M+
O
OAc
COOMe
OR
HO
B
Figure 1 Quartromicin A3 (R = a-D-galactosyl) and Quartromicin
OR'
D3 (R = H); M+ = Na+, K+, Ca2+.
R"O
R"O
3
1
2
Several natural products containing a quite similar central
subunit have been isolated, such as chlorothricolide,3
kijanolide,4 okilactomycin,5 tetronothiodin,6 tetronolide,7
ircinianin,8 pyrrolosporin A,9 PA-46101 A, A88696 C and
F.10
OTBDPS
OTBDPS
OH
5
O
O
+
O
OH
OMPM
Despite the exceptional work accomplished by Roush and
co-workers in establishing the relative configurations of
quartromicins,11 to the best of our knowledge, no total
synthesis has yet been published.
4
TMS
OMPM
6
Scheme 2
Synthesis of the Ester 4
Having previously prepared allylic alcohol 5,12 we turned
our efforts to the synthesis of the chiral alkyne 6. This
compound can be made from the known enantiomerically
SYNLETT 2005, No. 15, pp 2313–2316
Advanced online publication: 05.08.2005
DOI: 10.1055/s-2005-872657; Art ID: D17505ST
© Georg Thieme Verlag Stuttgart · New York
1
9
.0
9
.2
0
0
5

2314
O. Bedel et al.
LETTER
pure lactone 713 in six steps after DIBAL-H reduction. Esterification of 5 and 6 under classical conditions (DCC,
Treatment of the resulting lactol with trimethylsilyl diazo- DMAP) and subsequent alkyne protection furnished the
methane enolate14 gives the open chain alkyne. Overnight conveniently functionalized ester 4 (Scheme 4).16
reaction in a mild basic methanolic media was required to
isolate 8 in 39% overall yield.15 Hydroxyl MPM protec-
tion under acidic conditions, followed by smooth ammo-
nium fluoride deprotection gave the desired primary
alcohol 9 in 62% yield. The absolute configuration of the
Claisen–Ireland/Metathesis Sequence
The ester 4 was then submitted to the CIM process, using
as a last step, a Grubbs II ene–yne metathesis
(Scheme 5).17,18
MPM protected alcohol is not important at this stage, as it
is lost in the Claisen–Ireland deprotonation step. Oxida-
tion of the primary hydroxyl group in two steps with
OTBDPS
OMPM
TPAP, NMO and sodium chlorite under buffered condi-
1) KHMDS, Toluene, TMSCl
–78 °C –> r.t.
tions then afforded the carboxylic acid 6 in 81% yield
(Scheme 3).
4
COOMe
2) H2O then CH2N2
TMS
O
OTBDPS
OH
11
1) DIBAL-H, Toluene
–78 °C
O
1) K2CO3, MeOH
2) Grubbs II, toluene 80 °C
2) TMSCHN2, n-BuLi
THF, –78 °C to r.t.
then K2CO3, MeOH
8
OTBDPS
7
OTBDPS
39% yield
1) MPMOC(=NH)CCl3
CSA, CH2Cl2
OMPM
COOMe
2) excess NH4F, MeOH
62% yield
OH
1) TPAP, NMO
3
CH2Cl2, 0 °C
6
73% overall yield
OMPM
2) NaClO2, NaH2PO4
81% yield
9
Scheme 5
MPM = 4-MeOBn
As we have previously observed in our model study, when
the acetylenic moiety is unprotected, the diastereoselec-
tivity in the Claisen–Ireland rearrangement drops. This
particular behavior was tentatively explained by the
generation of a double-metallated species at the beginning
of the Claisen–Ireland process.12
Scheme 3
OTBDPS
O
O
DCC, DMAP
CH2Cl2, 0 °C
5
6
+
The transition state involved in the CIM process is shown
in Figure 2.
OMPM
10
LiHMDS / TMSCl
–78 °C
TBDPSO
R
OTBDPS
OMPM
O
TMSO
O
Me
OTMS
OMPM
Figure 2
TMS
AcOH, THF
–78 °C
Access to the Spirotetronate Subunit
In order to selectively oxidize the external double bond of
the cyclic derivative 3, we anticipated that a mismatch
Sharpless dihydroxylation with AD-mix reagent should
cleanly and selectively touch this alkene. This remarkable
transformation has already been observed19 and we have
applied it in a similar strategy during our total synthesis of
(–)fumagillol.20 The best result was obtained when 3 was
treated with AD-mix b giving the diastereoisomeric mix-
ture of 12a and 12b. Cleavage of the resulting 1,2-diol
OTBDPS
O
O
(1:1 ratio)
OMPM
4
TMS
69% overall yield
Scheme 4
Synlett 2005, No. 15, 2313–2316 © Thieme Stuttgart · New York

LETTER
Diastereoselective Access to the Spirotetronate Subunit of the Quartromicins
2315
with sodium periodate, direct sodium borohydride reduc-
tion, and protection of the primary alcohol resulted in the
formation of the compound 13 in a 48% overall yield
(Scheme 6).
OR
O
OH
OTBDPS
O
15
A
+
O
OH
OR'
OTBDPS
R"O
OMPM
OMPM
AD mix β, MeSO2NH2
COOMe
6
3
t-BuOH, H2O
HO
Scheme 8
OH
12a,b
R
O
OMPM
1) NaIO4, r.t.
2) NaBH4, 0 °C THF–H2O
3) TBDPSCl, Imidazole
CH2Cl2
TMSO
OTBDPS
OTBDPS
OMPM
COOMe
Figure 3
We are currently studying this new approach, as well as
the total synthesis of quatromicins and analogous com-
pounds.
TBDPSO
13
48% overall yield
Acknowledgment
Scheme 6
We would like to thank N. Blanchard, Y. Langlois and K. Plé for
helpful discussions.
Previous experience gained in the course of our fumagillol
synthesis20 showed that the deprotection of the MPM
group with this kind of structure under known conditions
(DDQ or CAN) can be problematic. The use of a strong
nucleophile with a Lewis acid activation has been found
to be a convenient solution. However, BF3·OEt2/PhSH re-
sulted in extensive deprotection of the TBDPS protecting
groups and we preferred a smoother method using AlCl3/
PhSH.21 The desired tertiary alcohol was obtained in 70%
yield. Finally, acetylation followed by Dieckmann cy-
clization using conditions already applied by Roush and
co-workers gave the quartromicins spirotetronate subunit
B 14 (Scheme 7).11a,c,d,22,23
References
(1) (a) Kusumi, T.; Ichikawa, A.; Kakisawa, H.; Tsunakawa,
M.; Konishi, M.; Oki, T. J. Am. Chem. Soc. 1991, 113,
8947. (b) Yoshii, E.; Takeda, K. Recent Prog. Chem. Synth.
Antibiot. Relat. Microb. Prod. 1993, 67.
(2) (a) Tsunakawa, M.; Tenmyo, O.; Tomita, K.; Naruse, N.;
Kotake, C.; Miyaki, T.; Konishi, M.; Oki, T. J. Antibiotics
1992, 45, 180. (b) Tanabe-Tochikura, A.; Nakashima, H.;
Murakami, T.; Tenmyo, O.; Oki, T.; Yamamoto, N.
Antiviral Chem. Chemother. 1992, 3, 345.
(3) Roush, W. R.; Sciotti, R. J. J. Am. Chem. Soc. 1998, 120,
7411.
(4) (a) Mallams, A. K.; Puar, M. S.; Rossman, R. R.; Mc Phail,
A. T.; Macfarlane, R. D.; Stephens, R. L. J. Org. Chem.
1992, 57, 2987. (b) Marshall, J. A.; Xie, S. J. Chem. Soc,
Perkin Trans. 1 1983, 1497.
1) PhSH, AlCl3, CH2Cl2
OTBDPS
O
70%
2) Ac2O, Sc(OTf)3, MeCN
72%
O
(5) Imai, H.; Kaniwa, H.; Tokunaga, T.; Fujita, S.; Furuya, T.;
Matsumoto, H.; Shimizu, M. J. Antibiot. 1987, 40, 1483.
(6) Ohtsuka, T.; Nakayama, N.; Itezono, Y.; Shimma, N.;
Kuwahara, T.; Yokose, K.; Seto, H. J. Antibiot. 1993, 46, 18.
(7) Hirayama, N.; Kasai, M.; Shirahata, K.; Ohashi, Y.; Sasada,
Y. Bull. Chem. Soc. Jpn. 1982, 55, 2984.
13
OMOM
3) LiHMDS, MOMCl, THF
94%
TBDPSO
14
(8) Takeda, K.; Sato, M.; Yoshii, E. Tetrahedron Lett. 1986, 33,
3903.
Scheme 7
(9) Schroeder, D. R.; Colson, K. L.; Klohr, S. E.; Lee, M. S.;
Matson, J. A.; Brinen, L. S.; Clardy, J. J. Antibiot. 1996, 49,
865.
(10) Bonjouklian, R.; Mynderse, J. S.; Hunt, A. H.; Deeter, J. B.
Tetrahedron Lett. 1993, 34, 7857.
(11) (a) Roush, W. R.; Barda, D. A. Tetrahedron Lett. 1997, 51,
8781. (b) Roush, W. R.; Barda, D. A. Org. Lett. 2002, 9,
1539. (c) Roush, W. R.; Limberakis, C.; Barda, D. A. Org.
Lett. 2002, 9, 1543. (d) Roush, W. R.; Barda, D. A.;
Limberakis, C.; Kunz, R. K. Tetrahedron 2002, 58, 6433.
In conclusion, we have shown that the CIM strategy can
be efficiently applied to the synthesis of the spirotetronate
subunit B of quartromicins. The subunit A is also accessi-
ble through the same CIM process by simply using the
modified alcohol 15,24 previously prepared in our labora-
tory (Scheme 8). The transition state in the Claisen–Ire-
land rearrangement is depicted in Figure 3.
Synlett 2005, No. 15, 2313–2316 © Thieme Stuttgart · New York

2316
O. Bedel et al.
LETTER
(12) Français, A.; Bedel, O.; Picoul, W.; Meddour, A.; Courtieu,
J.; Haudrechy, A. Tetrahedron: Asymmetry 2005, 16, 1141.
(13) (a) [a]D20 +37.5 (c 0.6, CHCl3) very close to the literature
{[a]D20 +37.7 (c 0.4, CHCl3)}. (b) Hanessian, S.; Murray, P.
J.; Sahoo, S. P. Tetrahedron Lett. 1985, 26, 5623.
(c) Herdeis, C.; Lütsch, K. Tetrahedron: Asymmetry 1993, 1,
121.
(14) Myers, A. G.; Goldberg, S. D. Angew. Chem. Int. Ed. 2000,
39, 2732.
(15) Ohira, S.; Okai, K.; Moritani, T. J. Chem. Soc., Chem.
Commun. 1992, 721.
(16) (a) O’Neil, S. V.; Quickley, C. A.; Snider, B. B. J. Org.
Chem. 1997, 62, 1970. (b) Rancourt, J.; Burke, S. D. J. Am.
Chem. Soc. 1991, 113, 2335.
(17) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H.
J. Am. Chem. Soc. 2000, 122, 3783.
H, J = 8.5 Hz), 6.74 (2 H, d, CMPMar–H, J = 8.5 Hz), 5.90–
6.05 (1 H, m, C4–CHCHMe), 5.74 (1 H, s, C3–H), 5.55–5.70
(1 H, m, C4–CHCHMe), 4.02–4.46 (2 H, AB syst., Ar–CH2),
3.95–4.10 (2 H, m, C2–CH2–OSi), 3.78 (3 H, s, OMe), 3.57
(3 H, s, COOMe), 2.71 (1 H, m, C5–H), 2.25–2.35 (1 H, m,
C6–Ha), 2.00–2.09 (1 H, m, C6–Hb), 1.78 (3 H, d, C4–
CHCHMe, J = 6.25 Hz), 1.16 (3 H, d, C5–Me, J = 7.25 Hz),
1.11 (9 H, s, t-Bu), 1.03 (3 H, s, C2–Me) ppm. 13C NMR
(62.5 MHz, CDCl3): d = 173.4 (COOMe), 158.6 (CqAr
–
OMe), 136.7 (C4), 135.7 (CAr), 134.0 (CMPMar–CH2O), 133.8
(CqAr), 132.7 (C3), 130.5 (C4–CHCHMe), 129.3 (CAr), 128.0
(CAr), 127.4 (CAr), 123.2 (C4–CHCHMe), 113.5 (CAr), 84.3
(C1), 67.6 (CMPMar–CH2O), 65.8 (C2–CH2–OSi), 55.2
(ArOMe), 51.3 (COOMe), 43.8 (C2), 30.7 (C5), 28.1 (C6),
26.9 (SiCMe3), 21.9 (C2–Me), 20.4 (C5–Me), 17.0 (SiCMe3)
ppm. [a]D20 +17.3 (c 1.2, CHCl3). HRMS (ES): m/z calcd
[M + Na]: 635.3169; found: 635.3183.
(18) Typical CIM Procedure.
Ester 4 (900 mg, 1.34 mmol) was dissolved in dry toluene
(17 mL) under argon and then cooled to –78 °C. A solution
of KHMDS in toluene (0.5 M) was added dropwise (4 mL, 2
mmol, 1.5 equiv) during 15 min. After 45 min, freshly
distilled TMSCl (540 mL) was added and the resulting
mixture was stirred for 5 min. Then, the mixture was
warmed to r.t. and stirred for additional 3 h. The mixture was
hydrolyzed with a 10% NH4Cl (aq) solution and the layers
were separated. The aqueous layer was extracted with Et2O
(3 × 20 mL), and the combined organic layers were dried,
filtered, and the solvent was removed under reduced
pressure. The crude product was esterified with
(19) (a) Sedrani, R.; Thai, B.; France, J.; Cottens, S. J. Org.
Chem. 1998, 63, 10069. (b) Andrus, M. B.; Lepore, S. D.;
Sclafani, J. A. Tetrahedron Lett. 1997, 38, 4043.
(c) Matsuo, G.; Miki, Y.; Nakata, M.; Matsumura, S.;
Toshima, K. J. Org. Chem. 1999, 64, 7101. (d) Andersson,
P. G.; Sharpless, K. B. J. Am. Chem. Soc. 1993, 115, 7047.
(20) Bedel, O.; Haudrechy, A.; Langlois, Y. Eur. J. Org. Chem.
2004, 3813.
(21) Bouzide, A.; Sauvé, G. Synlett 1997, 1153.
(22) Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto, H. J.
Am. Chem. Soc. 1995, 117, 4413.
(23) Data for compound 14: 1H NMR (250 MHz, CDCl3): d =
7.66 (4 H, m, CAr–H), 7.35 (6 H, m, CAr–H), 5.44 (1 H, br d,
C3–H), 5.16 (1 H, s, CO–CH), 5.01 (2 H, 2 collapsed d, O–
CH2–O), 4.25 (1 H, d, C4–CH2–OSi, J = 12.8 Hz), 4.08 (1 H,
d, C4–CH2–OSi), 3.73 (1 H, d, C2–CH2–OSi, J = 9.5 Hz),
3.63 (1 H, d, C2–CH2–OSi, J = 9.5 Hz), 3.37 (3 H, s, OMe),
2.77 (1 H, m, C5–H), 2.13 (1 H, dd, C6–Ha, J = 9.8 Hz,
J = 13.7 Hz), 1.89 (1 H, dd, C6–Ha, J = 7 Hz, J = 13.7 Hz),
1.05 (24 H, m, C5–Me, C2–Me, 2 t-Bu) ppm. 13C NMR (62.5
MHz, CDCl3): d = 182.7 (CO–CH2–O), 172.2 (CO), 139.9
(C4), 135.9 (CAr), 135.8 (CAr), 135.6 (CAr), 134.0 (CAr), 133.8
(CAr), 133.4 (CAr), 129.9 (CAr), 129.8 (CAr), 129.7 (CAr),
127.8 (CAr), 127.7 (CAr), 126.8 (C3), 96.9 (OMe), 91.2 (CO–
CH), 87.4 (O–CH2–O), 70.2 (C4–CH2–OSi),, 66.0 (C2–CH2–
OSi), 57.5 (C1), 42.5 (C2), 38.2 (C5), 29.8 (C6) 29.2 (C5–Me),
diazomethane, and after evaporation dissolved in MeOH (15
mL). Excess of solid K2CO3 (5.4 mmol, 630 mg, 4 equiv)
was added in one portion and this suspension was stirred
overnight at r.t. After evaporation under reduced pressure,
the product was dissolved in Et2O (30 mL) and washed with
H2O (15 mL). The layers were separated and the aqueous
one was extracted with Et2O (2 × 25 mL). The combined
organic layers were dried, filtered and concentrated.
The compound was dissolved in toluene (40 mL) under an
argon atmosphere, and a solution of second generation
Grubbs’ catalyst (90 mg, 0.105 mmol, 0.08 equiv) in toluene
(5 mL) was then added. This solution was heated to 80 °C for
1 h. After cooling down, the mixture was concentrated, and
the crude product was purified by silica gel column
chromatography (175 g SiO2, Et2O–n-pentane, 1:5) to afford
pure cyclized methyl ester 3 (747 mg, 73% yield for four
steps).
20
27.0 (C2–Me), 26.9 (2 SiCMe3), 19.5 19.4 (SiCMe3). [a]D
–3.2 (c 0.3, CHCl3). HRMS (ES): m/z calcd [M + H]:
775.3850; found: 775.3875.
Data for compound 3: 1H NMR (250 MHz, CDCl3): d = 7.66
(24) Bedel, O. PhD Thesis, personal results.
(4 H, m, CAr–H), 7.38 (6 H, m, CAr–H), 7.05 (2 H, d, CMPMar
–
Synlett 2005, No. 15, 2313–2316 © Thieme Stuttgart · New York