Total synthesis of natural (+)-membrenone C and its 7-epimer

Article abstract of DOI:10.1016/j.tetlet.2005.12.129

Highly stereoselective asymmetric total syntheses of the polypropionate marine defense substance (+)-membrenone C and its 7-epimer have been achieved. Highlights of the strategy include the utilization of a desymmetrization technique to create five contig

Full text of DOI:10.1016/j.tetlet.2005.12.129

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1603–1606
Total synthesis of natural (+)-membrenone C and its 7-epimerq
J. S. Yadav,* R. Srinivas and K. Sathaiah
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 2 August 2005; revised 12 December 2005; accepted 22 December 2005
Dedicated to Professor S. Chandrasekaran, IISc, Bangalore on his 60th birthday
Abstract—Highly stereoselective asymmetric total syntheses of the polypropionate marine defense substance (+)-membrenone C
and its 7-epimer have been achieved. Highlights of the strategy include the utilization of a desymmetrization technique to create
five contiguous chiral centres from a single bicyclic precursor.
Ó 2006 Elsevier Ltd. All rights reserved.
During the course of our ongoing programme of synthe-
sis of biologically potent natural products we selected
(+)-membrenone C, the polypropionate marine defense
natural product as a synthetic target. Membrenone C
was first isolated along with membrenone A and mem-
brenone B from a Mediterranean mollusc Pleurobran-
chus membranaceus by Ciavatta et al.1 Membrenones
A–C were found to afford protection for the mollusc
from potential predators in the hostile marine environ-
ment. Ciavatta and co-workers assigned structures to
the membrenones by extensive NMR analysis, the rela-
tive and absolute stereochemistry of the natural prod-
ucts was confirmed by synthesis.2,3
disconnection between the C4–C5 and C11–C12 bonds
via double aldol reactions as reported by Perkins and
co-workers.3 The dialdehyde could be derived from a
single bicyclic precursor 6 which in turn is easily synthe-
sized, and was earlier used by our group towards the
synthesis of rifamycin S,4 discodermolide,5 scytophycin
C6 and prelactone B.7
The required lactone5,6 7 was prepared from 6 by a pro-
tocol we had developed and utilized for a number of
syntheses wherein we had exploited a desymmetrization
technique to create six stereogenic centres at once.
Alkylation of the lactone 7 with LHMDS/MeI afforded
compound 54 as the only product which on reductive
opening with LAH furnished the triol 8 (Scheme 2).
The triol 8 on dibenzyl ether protection followed by
PMB8 ether deprotection afforded diol 9. Protection of
the diol as its di-tert-butyl silyl ether 10 was achieved
by using di-tert-butyl silyl bis[trifluoromethanesulfonate]
The exceptional bioactivity and extreme scarcity of the
natural material together with the novel structure
prompted us to attempt the total synthesis of (+)-mem-
brenone C 1. It was envisioned that (+)-membrenone C
could be obtained from tetraketone 3 as shown in
Scheme 1. The construction of 3 was to be based on a
9
O
O
O
O
O
8
10
O
O
O
O
OR
O
O
membrenone A (R=(
membrenone B (R=propionyl)
R)-2-methylbutyryl)
(+)-membrenone C
(+)-7-epi-membrenone C
2
1
Keywords: (+)-Membrenone C and its 7-epimer; Desymmetrization technique.
q IICT Communication No. 050801.
*
Corresponding author. Fax: +91 40 27160512; e-mail: yadavpub@iict.res.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.129

1604
J. S. Yadav et al. / Tetrahedron Letters 47 (2006) 1603–1606
O
O
11
5
4
12
O
O
O
O
O
O
O
O
Si
3
(+)-membrenone C
1
O
O
O
H
H
+
O
O
O
O
O
Si
O
OPMB
OPMB
6
5
4
Scheme 1. Retrosynthetic strategy for (+)-membrenone C.
O
O
O
O
O
O
°
LAH, THF, 25 C
LHMDS, MeI
HO
OH
4 h, 90%
OH
°
-78 C, THF,1 h
PMBO
94%
OPMB
OPMB
8
7
5
Scheme 2.
and 2,6-lutidine. Debenzylation of 10 using a cata-
PCC oxidation gave dialdehyde 11. Next, the bidirec-
lytic amount of Pd/C and H2 afforded a diol which on
tional chain extending double aldol reaction was
1) NaH, BnBr, THF
)
2 Si(OTf)2
°
25 C, 4 h, 95%
BnO
OBn
HO
OH
2,6-lutidine, DCM
2) TFA, Anisole, DCM
OH OH
OH
°
PMBO
8 h, 65 C, 90%
°
25 C, 2 h, 83%
8
9
3-pentanone
1) H2/Pd-C(10%)
H
H
TiCl4 / iPr2NEt
4 h, 83%
°
EtOH, 25 C,
°
O
DCM, -78 C
O
O
O
Si
OBn O
O
OBn
2) PCC, DCM
3 h, 90%
Si
°
25 C, 3 h, 62%
11
10
(COCl)2, DMSO
OH
O
OH
O
O
O
°
Et3N, -78 C,
O
Si
O
O
O
O
O
Si
12
13
O
O
1) HF-Py, pyridine, THF
2) TFA, DCM
O
O
(+)-7-epi-membrenone C
2
Scheme 3.

J. S. Yadav et al. / Tetrahedron Letters 47 (2006) 1603–1606
1605
°
DMP, DCM, 25 C
BnO
OBn
PTSA, DCM: MeOH (1:3)
4 h, 90%
BnO
OBn
O
OTBS
15
OH OTBS
1 h, 94%
14
)2 Si(OTf)2
1)
2,6-lutidine, DCM,
70%
DIBAL (4 eq), Et2O
BnO
OBn
BnO
HO
OBn
OH
°
OH OH
H2/Pd-C(10%)
-100 C, 2 h
2)
O
OH
°
EtOH, 25 C, 4 h,
17
16
80%
1) 3-pentanone
PCC, DCM
TiCl4/iPr2NEt, DCM
°
25 C, 3 h, 62%
H
H
°
-78 C, 3 h, 90%
O
O
O
O
O
O
O
Si
2) (COCl)2, DMSO
Si
°
Et3N, -78 C, 90%
4
18
1) HF-Py, pyridine,
THF
O
O
O
O
O
O
O
O
O
Si
2) TFA, DCM
(+)-membrenone C
3
1
Scheme 4.
achieved by reacting with the Ti(IV) enolate of 3-penta-
none in DCM at ꢀ78 °C, as previously reported by Per-
kins et al. and Evans et al.9,10 to yield compound 12 with
high diastereoselectivity (Scheme 3). Since the four ste-
reocentres produced in the formation of 12 are not pres-
ent in the final product, we proceeded with the
diastereomeric mixture.
high diastereoselectivity (>90% ds). The protection of
diol 17 as the di-tert-butyl silylene15 followed by debenz-
ylation gave the diol 18 (Scheme 4). PCC oxidation of
18 gave the compound 4 which on double aldol chain
extension followed by Swern oxidation gave compound
3. Deprotection of the di-tert-butyl silylene group fol-
lowed by cyclization/dehydration then gave 1 in 35%
overall yield from 3 in two steps (Scheme 4).
Swern oxidation of 12 gave a quantitative yield of tet-
raketone 13. Since the tetraketone was very sensitive
having readily epimerisable centres, we proceeded with
the crude product. The di-tert-butyl silyl group of 13
was removed by treatment with HFÆPy buffered with ex-
cess pyridine, to give a mixture of diols and hemiacetals.
Rapid acid catalyzed cyclization/dehydration gave a sin-
gle product 2 in 52% overall yield in three steps from 12
(Scheme 3). The synthetic material exhibited the desired
The synthetic material exhibited spectral properties16
25
and a specific rotation, ½aꢁD +23.6 (c 0.38, CHCl3)
{lit.3 [a]D +23.5 (c 0.63, CHCl3)}, in agreement with
those reported earlier by the Marshall group.2
In summary, the highly stereoselective synthesis of (+)-
membrenone C and its 7-epimer illustrates the utility of
the bicyclic precursor 6 and the desymmetrization ap-
proach control for the five required stereocentres. This
is the first report of the total synthesis of (+)-7-epi-mem-
brenone C.
spectral properties of (+)-7-epi-membrenone C and a
25
specific rotation of ½aꢁD +110.6 (c 1.81, CHCl3).
The synthesis of (+)-membrenone C 1, our target mole-
cule was achieved directly from 8 which on di-O-benzyl
protection of the primary alcohols followed by TBS pro-
tection of the secondary alcohol and deprotection of the
PMB ether using DDQ in aqueous DCM11 gave com-
pound 14 in 90% overall yield in three steps. Dess–Mar-
tin oxidation (DMP)12 of the secondary alcohol in 14
gave the ketone 15 which was subjected to desilylation
using 2 equiv of PTSA in methanolic DCM13 to afford
the hydroxy-ketone 16. Our subsequent task was the
1,3-syn-selective reduction of 16 which was achieved
by using DIBAL-H in diethyl ether14 at ꢀ100 °C to give
the desired product 17 as the major diastereoisomer with
Acknowledgements
The authors R.S. and K.S. thank CSIR and UGC, India,
respectively, for the award of research fellowships.
References and notes
1. Ciavatta, L. M.; Trivellone, E.; Villani, G.; Cimino, G.
Tetrahedron Lett. 1993, 34, 6791–6794.
2. Marshall, J. A.; Elic, K. C. Org. Lett. 2003, 5, 1729–1732.

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13. Thomas, E. J.; Williams, A. C. J. Chem. Soc., Chem.
3. (a) Sampson, R. A.; Perkins, M. V. Org. Lett. 2002, 4,
1655–1658; (b) Sampson, R. A.; Perkins, M. V.; Taylor,
M. R. Acta Crystallogr. 2003, E59, 1867–1868; (c) Perkins,
M. V.; Sampson, R. A. Org. Lett. 2001, 3, 123–126; (d)
Perkins, M. V.; Sampson, R. A. Tetrahedron Lett. 1998,
39, 8367–8370.
Commun. 1987, 992–994.
14. Kiyooka, S.; Kuroda, H.; Shimasaki, Y. Tetrahedron Lett.
1986, 27, 3009–3012.
15. (a) Sampson, R. A.; Perkins, M. V. Org. Lett. 2002, 4,
1655–1658; (b) Trost, B. M.; Caldwell, C. G. Tetrahedron
Lett. 1981, 22, 4999–5002; (c) Corey, E. J.; Hopkins, P. B.
Tetrahedron Lett. 1982, 23, 4871–4874; (d) Trost, B. M.;
Caldwell, C. G.; Murayama, E.; Heissler, D. J. Org.
Chem. 1983, 48, 3252–3265.
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16. Spectral data of compound 1: Low melting solid, 1H NMR
(300 MHz, CDCl3): d 4.24 (dd, 1H, J = 10.4, 2.4 Hz), 3.90
(dd, 1H, J = 13.6, 2.4 Hz), 2.51 (m, 1H), 2.46–2.22 (m,
5H), 2.19 (m, 1H), 1.71 (s, 3H), 1.69 (s, 3H), 1.19 (d, 3H,
J = 7.5 Hz), 1.18 (t, 3H, J = 8.0 Hz), 1.11 (d, 3H,
J = 8.0 Hz), 1.07 (t, 3H, J = 7.2 Hz), 1.02 (d, 3H, J =
7.2 Hz); 13C NMR (50 MHz, CDCl3): d 197.0, 194.3,
173.5, 172.3, 108.4, 107.5, 83.2, 81.6, 80.8, 40.2, 39.8, 34.5,
25.3, 10.8, 10.7, 9.6, 9.4, 9.2, 9.1, 9.0; IR (Neat): 1721,
1662, 1615 cmꢀ1
;
FAB Mass: m/z 335 [M+H]+,
25
½aꢁD +23.6 (c 0.38, CHCl3); Spectral data of compound 2:
liquid, 1H NMR (300 MHz, CDCl3): d 4.22 (dd, 1H,
J = 8.6, 4.3 Hz), 4.13 (dd, 1H, J = 12.16, 1.43 Hz), 2.48
(m, 1H), 2.42–2.34 (m, 5H), 2.18 (m, 1H), 1.75 (s, 3H),
1.71 (s, 3H), 1.25 (d, 3H, J = 7.2 Hz), 1.16 (t, 3H,
J = 7.8 Hz), 1.13 (t, 3H, J = 7.2 Hz), 1.01 (d, 3H,
J = 7.2 Hz), 1.00 (d, 3H, J = 7.2 Hz); 13C NMR (75
MHz, CDCl3): d 195.2, 194.8, 172.6, 170.4, 108.2, 107.5,
84.3, 82.5, 80.8, 40.7, 40.0, 34.0, 25.4, 15.4, 10.9, 10.7, 9.5,
9.2, 9.1, 8.8; IR (Neat) : 1739, 1658, 1615 cmꢀ1; FAB
Mass: m/z 335 [M+H]+, HRMS calcd for C20H30O4:
11. Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.;
Yonemitsu, O. Tetrahedron 1986, 42, 3021–3028.
12. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277–7287.
25
335.2222. Found: 335.2251. ½aꢁD +110.6 (c 1.81, CHCl3).