Synthetic study of macquarimicins: Highly stereoselective construction of the AB-ring system

Article abstract of DOI:10.1021/ol016449u

matrix presented The highly stereoselective synthesis of the AB-ring system of macquarimicins, a novel class of microbial metabolites with inhibitory activity for neutral sphingomyelinase, has been achieved. The present synthesis features the highly stere

Full text of DOI:10.1021/ol016449u

ORGANIC
LETTERS
2001
Vol. 3, No. 19
3029-3032
Synthetic Study of Macquarimicins:
Highly Stereoselective Construction of
the AB-Ring System
Ryosuke Munakata, Tatsuo Ueki, Hironori Katakai, Ken-ichi Takao, and
Kin-ichi Tadano*
Department of Applied Chemistry, Keio UniVersity, Hiyoshi, Kohoku-ku,
Yokohama 223-8522, Japan
tadano@applc.keio.ac.jp
Received July 18, 2001
ABSTRACT
The highly stereoselective synthesis of the AB-ring system of macquarimicins, a novel class of microbial metabolites with inhibitory activity
for neutral sphingomyelinase, has been achieved. The present synthesis features the highly stereocontrolled construction of the
cis-tetrahydroindan structure via the intramolecular Diels−Alder reaction of an (E,Z,E)-1,6,8-nonatriene derived from D-glyceraldehyde acetonide.
The macquarimicins A-C (1-3, Figure 1) were isolated
from the fermentation broths of Micromonospora chalcea
by a group at Abott Laboratories in 1995.1 Macquarimicins
B and C were found to display cytotoxicity against the
leukemia cell line P388. Later, researchers at Sankyo Co.,
Ltd. discovered that macquarimicin A is a selective inhibitor
of membrane-bound neutral sphingomyelinase (N-SMase)
from rat brain.2 Inhibitors of N-SMase recently have been
stimulating considerable interest since it has been suggested
that they might have clinical potential in pathologies such
as inflammatory and autoimmune diseases.3 The unique
structures of the macquarimicins comprise a cis-tetra-
hydroindanone ring, a â-keto-δ-lactone ring, and (for mac-
quarimicins A and B) a 10-membered carbocycle (the CD-
ring). Closely related antibiotics called cochleamycins have
(1) (a) Jackson, M.; Karwowski, J. P.; Theriault, R. J.; Rasmussen, R.
R.; Hensey, D. M.; Humphrey, P. E.; Swanson, S. J.; Barlow, G. J.;
Premachandran, U.; McAlpine, J. B. J. Antibiot. 1995, 48, 462-466. (b)
Hochlowski, J. E.; Mullally, M. M.; Henry, R.; Whittern, D. M.; McAlpine,
J. B. J. Antibiot. 1995, 48, 467-470.
(2) Tanaka, M.; Nara, F.; Yamasato, Y.; Masuda-Inoue, S.; Doi-Yoshioka,
H.; Kumaura, S.; Enokita, R.; Ogita, T. J. Antibiot. 1999, 52, 670-673.
(3) (a) Tanaka, M.; Nara, F.; Suzuki-Konagai, K.; Hosoya, T.; Ogita, T.
J. Am. Chem. Soc. 1997, 119, 7871-7892. (b) Nara, F.; Tanaka, M.;
Masuda-Inoue, S.; Yamasato, Y.; Doi-Yoshioka, H.; Suzuki-Konagai, K.;
Kumakura, S.; Ogita, T. J. Antibiot. 1999, 52, 531-535. (c) Uchida, R.;
Tomoda, H.; Dong, Y.; Omura, S. J. Antibiot. 1999, 52, 572-574. (d)
Tanaka, M.; Nara, F.; Yamasato, Y.; Ono, Y.; Ogita, T. J. Antibiot. 1999,
52, 827-830. (e) Arenz, C.; Giannis, A. Angew. Chem., Int. Ed. 2000, 35,
1440-1442. (e) Hakogi, T.; Monden, Y.; Iwama, S.; Katsumura, S. Org.
Lett. 2000, 2, 2627-2629.
Figure 1. Structures of macquarimicins.
10.1021/ol016449u CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/30/2001

been discovered, and their biosynthesis via an intramolecular
Diels-Alder (IMDA) reaction has been proposed.4 The
intriguing biological activity and structures of macquari-
micins have prompted us to work toward their total synthesis
and determination of their unknown absolute configuration.
Herein, we report the synthesis of the AB-ring system of
macquarimicins, featuring the highly stereoselective con-
struction of the framework through the IMDA reaction of
an (E,Z,E)-1,6,8-nonatriene derivative. Compared to (E,E,E)-
or (Z,E,E)-trienes, (E,Z,E)-trienes have been far less utilized
in IMDA reactions due to their lower reactivity and the
possibility of a side reaction such as olefin isomerization.5,6
Despite these drawbacks, we considered the IMDA reactions
of (E,Z,E)-trienes to be synthetically valuable as they are
known to attain only the endo-transition state, leading to cis-
fused cycloadducts.7 In our study, we anticipated that the
reaction would be effected by designing appropriate sub-
strates.
The synthesis of alkyne 6 was accomplished as illustrated
in Scheme 2.8 The crotylboration of D-glyceraldehyde
Scheme 2a
Our retrosynthetic analysis for macquarimicins is shown
in Scheme 1. It was expected that 4, an advanced intermedi-
Scheme 1
a Reagents and conditions: (a) MPMCl, NaH, DMF (93%); (b)
BH3‚SMe2, THF, then H2O2, aqueous NaOH (77%); (c) (COCl)2,
DMSO, Et3N, CH2Cl2, -78 °C to room temperature; (d) Ph3-
PdCHCO2Et, benzene (84% for 2 steps); (e) DIBALH, CH2Cl2,
-78 °C (97%); (f) PivCl, Et3N, pyr. (97%); (g) AcOH-THF-
H2O (3:1:1), 40 °C (95%); (h) NaIO4, MeOH-H2O (2:1); (i) CBr4,
PPh3, CH2Cl2, -78 °C (82% for 2 steps); (j) DIBALH, CH2Cl,
-78 °C (97%); (k) TBDPSCl, imidazole, DMF (97%); (l) BuLi,
THF, -78 °C (80%).
acetonide 8 with pinacol (Z)-crotylboronate was conducted
as described by Roush et al.,9 affording 9 diastereoselectively.
The alcohol 9 was protected as a (4-methoxyphenyl)methyl
(MPM) ether, giving 10. Treatment of 10 with borane-Me2S
followed by oxidation with H2O2 provided 11 regioselec-
tively.10 The Swern oxidation of 11 and the Wittig olefination
of the resultant aldehyde provided the R,â-unsaturated ester
12. Reduction of 12 with diisobutylaluminum hydride
(DIBALH) followed by esterification of the resultant allylic
alcohol 13 provided pivalate 14. The acetal group in 14 was
then deprotected by acidic hydrolysis to afford diol 15. The
oxidative cleavage of the diol in 15 with sodium periodate
and the Corey-Fuchs homologation11 of the resultant alde-
hyde provided dibromoalkene 16. Reductive removal of the
pivaloyl group in 16 with DIBALH provided 17, which was
protected as a tert-butyldiphenylsilyl (TBDPS) ether, giving
18.12 Treatment of 18 with BuLi11 afforded the alkyne 6,
the substrate for the Sonogashira coupling.
ate for the macquarimicin synthesis, would be synthesized
through the diastereoselective IMDA reaction of (E,Z,E)-
triene 5. The triene 5 could become available from alkyne 6
and (E)-vinyl iodide 7 via Sonogashira coupling followed
by semi-hydrogenation of the triple bond.
(4) (a) Shindo, K.; Matsuoka, M.; Kawai, H. J. Antibiot. 1996, 49, 241-
243. (b) Shindo, K.; Iijima, H.; Kawai, H. J. Antibiot. 1996, 49, 244-248.
(c) Shindo, K.; Sakakibara, M.; Kawai, H. J. Antibiot. 1996, 49, 249-252.
(5) For some recent reviews on the IMDA reactions, see: (a) Roush,
W. R. In AdVances in Cycloaddition; Curran, D. P., Ed.; JAI Press:
Greenwich, CT, 1990; Vol. 2, pp 91-146. (b) Carruthers, W. Cycloaddition
Reactions in Organic Synthesis; Pergamon Press: Oxford, 1990. (c) Roush,
W. R. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I.,
Paquette, L. A., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, pp 513-
550. (d) Kappe, C. O.; Murphree, S. S.; Padwa, A. Tetrahedron 1997, 53,
14179-14233. (e) Fallis, A. G. Acc. Chem. Res. 1999, 32, 464-474.
(6) For some IMDA reactions using (E,Z,E)-trienes, see: (a) House, H.
O.; Cronin, T. H. J. Org. Chem. 1965, 30, 1061-1970. (b) Borch, R. F.;
Evans, A. J.; Wade, J. J. J. Am. Chem. Soc. 1975, 97, 6282-6284. (c)
Boeckman, R. K., Jr.; Alessi, T. R. J. Am. Chem. Soc. 1982, 104, 3216-
3217. (d) Pyne, S. G.; Hensel, M. J.; Fuchs, P. L. J. Am. Chem. Soc. 1982,
104, 5719-5728. (e) Yoshioka, M.; Nakai, H.; Ohno, M. J. Am. Chem.
Soc. 1984, 106, 1133-1135. (f) Wattanasin, S.; Kathawala, F. G.;
Boeckman, R. K., Jr. J. Org. Chem. 1985, 50, 3810-3815. (g) Diedrich,
M. K.; Kla¨rner, F.-G. J. Am. Chem. Soc. 1998, 120, 6212-6218. (h) Back,
T. G.; Payne, J. E. Org. Lett. 1999, 1, 663-665. (i) Back, T. G.; Nava-
Salgado, V. O.; Payne, J. E. J. Org. Chem. 2001, 66, 4361-4368.
(7) Very recently, effective utilization of Lewis acid catalysts in the
IMDA reactions of (Z)-substituted diene has been reported, see: Yakelis,
N. A.; Roush, W. R. Org. Lett. 2001, 3, 957-960.
We investigated another synthetic route to the alkyne 6
(Scheme 3). The second-generation synthesis of 6 com-
(8) All new compounds were characterized by 1H and 13C NMR, IR,
and HRMS. Yields refer to isolated, chromatographically purified products.
(9) Roush, W. R.; Adam, M. A.; Walts, A. E.; Harris, D. J. J. Am. Chem.
Soc. 1986, 108, 3422-3434.
(10) A diastereomeric mixture (1:1) of the secondary alcohols was also
isolated (10%).
(11) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769-3772.
3030
Org. Lett., Vol. 3, No. 19, 2001

periodinane20 and the treatment of the resultant aldehyde with
Corey-Fuchs conditions11 provided the dibromoalkene 18,
the precursor of the alkyne 6, as shown in Scheme 2.21
The vinyl iodide 7, a coupling partner of the expected
Sonogashira reaction, was derived from the known com-
pound 29E22 (Scheme 4). We developed a modified proce-
Scheme 3a
Scheme 4a
a Reagents and conditions: (a) Bu3SnH, AIBN, benzene, 80 °C;
(b) I2, CH2Cl2, 0 °C; (c) MeONa, MeOH, reflux (74% for 3 steps);
(d) TrCl, DMAP, pyr., 60 °C (100%).
a Reagents and conditions: (a) LiAlH4, Et2O, 0 °C (96%); (b)
PCC, NaOAc, MS4A, CH2Cl2 (76%); (c) (EtO)2P(O)CH2CO2Et,
NaH, THF (80%); (d) DIBALH, CH2Cl2, -78 °C; (e) Amberlyst
15, MeOH-H2O (1:1), 40 °C; (f) p-anisaldehyde dimethyl acetal,
TsOH‚H2O, DMF, reduced pressure; (g) DIBALH, CH2Cl2, -78
°C (80% for 4 steps); (h) TBDPSCl, Et3N, DMAP, CH2Cl2, -78
to -20 °C (73%); (i) Dess-Martin periodinane, CH2Cl2; (j) CBr4,
PPh3, CH2Cl2, -78 °C (77% for 2 steps).
dure for a more convenient way to prepare 29E.23 Thus,
3-butyn-1-ol (27) was hydrostannylated to give a mixture
of 28E and 28Z.22b The mixture was immediately treated
with iodine in CH2Cl2 to give a mixture of vinyl iodide 29E
and 29Z. After most tin byproducts were separated by an
aqueous KF workup, the mixture of 29E and 29Z was treated
with MeONa (1.5 molar equiv) in refluxing MeOH. Under
these conditions, only the Z-isomer was susceptible to an
elimination reaction, which gave 27.24 Isomerically pure 29E
was obtained in an overall yield of 74% from 27. The vinyl
iodide 29E was treated with trityl chloride in pyridine to
give trityl ether 7.
menced with the diastereoselective conjugate addition of
MeLi to 19, as reported by Leonard et al.13 Thus, the known
R,â-unsaturated ester 1914 was exposed to MeLi in diethyl
ether at -78 °C to give the syn-adduct 20 as a single
diastereomer.15 The ester group in 20 was reduced with
LiAlH4, giving the primary alcohol 21.16 Oxidation of 21
with pyridinium chlorochromate (PCC), followed by Hor-
ner-Wadsworth-Emmons olefination, provided the unsatur-
ated ester 22 with an E-selectivity greater than 20:1.
Reduction of 22 with DIBALH gave allylic alcohol 23.
Through the following conventional steps, 23 was converted
into 26. Namely, the acetonide in 23 was hydrolyzed to give
triol 24, in which the secondary alcohol was selectively
protected as an MPM ether, giving 25 by the formation of
methoxybenzylidene acetal17 followed by regioselective
cleavage with DIBALH.18 The less-hindered primary allylic
alcohol in 25 was selectively protected with 0.85 equiv of
TBDPSCl to afford 26 in a 73% yield with 13% of recovered
25.19 The oxidation of primary alcohol 26 with Dess-Martin
The desired AB-ring was constructed as illustrated in
Scheme 5. The Sonogashira coupling between 6 and 7 was
Scheme 5a
(12) Hydrolytic removal of the isopropylidene group in the TBDPS ether
derived from 13 provided the corresponding diol in an unacceptable low
yield.
(13) Leonard, J.; Mohialdin, S.; Reed, D.; Ryan, G.; Swain, P. A.
Tetrahedron 1995, 51, 12843-12858.
a Reagents and conditions: (a) Pd(PPh3)4, CuI, Et3N (91%); (b)
H2, Lindlar catalyst, quinoline, 1-hexene (66%, 31% recovery of
30); (c) Bu4NF, THF (100%); (d) MnO2, CH2Cl2 (83%); (e) 0.01
M, toluene, BHT (catalytic), 150 °C, in a sealed tube (75%); (f)
NaBH4, EtOH (99%).
(14) Takano, S.; Kurotaki, A.; Takahashi, M.; Ogasawara, K. Synthesis
1986, 403-406.
(15) In our hands, the yield of 20 increased when the reaction was
conducted on a larger scale. Consequently, we were able to prepare 20 on
a 15 g scale with complete diastereoselectivity.
(16) Compound 21 had been synthesized by Boeckman et al. using a
different route, see: Boeckman, R. K., Jr.; Charette, A. B.; Asberom, T.;
Johnston, B. H. J. Am. Chem. Soc. 1991, 113, 5337-5353.
(17) Johansson, R.; Samuelsson, B. J. Chem. Soc., Perkin Trans. 1 1984,
2371-2374.
(18) Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett. 1983,
1593-1596.
conducted in the presence of a catalytic amount of Pd(PPh3)4
and CuI in triethylamine, efficiently providing 30 in 91%
yield. Semi-hydrogenation of 30 in 1-hexene with Lindlar
catalyst25 afforded 31 in a 66% yield, along with recovered
Org. Lett., Vol. 3, No. 19, 2001
3031

30 (31%). Treatment of 31 with Bu4NF in THF gave primary
allylic alcohol 32, which was oxidized with MnO2, affording
5, the substrate for the IMDA reaction. On heating to 150
°C in a sealed tube, the IMDA reaction of 5 proceeded
smoothly, without isomerization of the diene moiety, to
produce the desired cycloadduct 4 in a 75% yield as a single
isomer.
The stereochemistry of 4 was determined by NOE experi-
ments of 4 and 33 as shown in Figure 2. Compound 33 was
Figure 3. Plausible mechanism for diastereoselection.
because of the severe steric interaction between the (4-
methoxyphenyl)methoxy group and the vinylic hydrogen
atom existing in transition state B. Consequently, the
configuration of the MPMO group is believed to affect
significantly the π-facial selection of the cycloaddition.
Figure 2. NOE experiments on 4 and 33.
obtained by NaBH4 reduction of 4. The stereochemical
outcome of the IMDA reaction is rationalized by considering
the transition states illustrated in Figure 3. Since the exo-
mode is sterically inaccessible in the IMDA reactions of
(E,Z,E)-1,6,8-nonatrienes, only two endo-transition states, A
or B, are possible. Compared with B, transition state A,
which leads to 4, seems to be substantially more favorable
In conclusion, a stereoselective synthesis of the AB-ring
system of macquarimicins using an IMDA approach has been
achieved. The present work has demonstrated the effective-
ness of the use of an (E,Z,E)-1,6,8-nonatriene as the substrate
for an IMDA reaction. The key steps in the present work
are the Sonogashira coupling of the alkyne 6 derived from
D-glyceraldehyde acetonide and (E)-vinyl iodide 7, as well
as the highly diastereoselective IMDA reaction of the
(E,Z,E)-triene 5. We are currently investigating the total
synthesis of macquarimicins.
(19) The reductive opening of the TBDPS-protected acetal, prepared from
24 [(1) MPM acetal formation, (2) silyl ether (OTBDPS) formation], with
DIBALH was accompanied by cleavage of the silyl ether.
(20) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.
(c) Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
(21) The overall yield of 6 from 8 was 23% and that from 19 was 16%.
We prefer the second route because the isolation of 9 from other
diastereomers by chromatographic separation on silica gel was problematic
in our case on a large-scale experiment.
Acknowledgment. This research was supported by a
Grant-in-Aid for Scientific Research on Priority Areas (A)
from the Ministry of Education, Culture, Sports, Science,
and Technology of Japan.
(22) (a) Nicolaou, K. C.; Stylianides, N. A.; Ramphal, J. Y. J. Chem.
Soc., Perkin Trans. 1 1989, 2131-2132. (b) Pilli, R. A.; de Andrade, C. K.
Z.; Souto, C. R. O.; de Meijere, A. J. Org. Chem. 1998, 63, 7811-7819.
(c) Chong, J. M.; Heuft, M. A. Tetrahedron 1999, 55, 14243-14250. (d)
Germain, J.; Deslongchamps, P. Tetrahedron Lett. 1999, 40, 4051-4054.
(23) During a large-scale preparation of 29E, we encountered a tedious
chromatographic separation of 28E and 28Z.
Supporting Information Available: Experimental pro-
cedures and spectroscopic characterization (1H and 13C NMR,
IR, and HRMS) of all new compounds. This information is
available free of charge via the Internet at http://pubs.acs.org.
(24) Schlosser, M.; Ladenberger, V. Chem. Ber. 1971, 104, 2873-2884.
(25) Ho, T.-L.; Liu, S.-H. Synth. Commun. 1987, 17, 969-973.
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