An expeditious enantiospecific total synthesis of (+)-7-epi-goniofufurone

Article abstract of DOI:10.1055/s-2005-871965

Stereoselective synthesis of styryl lactone, (+)-7-epi-goniofufurone was achieved in high yield via simple transformations from tartaric acid. The key step involves the successive stereoselective reduction of ketones with borohydride and selectride. Georg

Full text of DOI:10.1055/s-2005-871965

2260
LETTER
An Expeditious Enantiospecific Total Synthesis of (+)-7-epi-Goniofufurone
Total
S
ynthesis of
a
(+)-7-epi
-
G
v
oniofufuroneirayani R. Prasad,* Shivajirao L. Gholap
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
Fax +91(80)23600529; E-mail: prasad@orgchem.iisc.ernet.in
Received 27 April 2005
O
Abstract: Stereoselective synthesis of styryl lactone, (+)-7-epi-go-
niofufurone was achieved in high yield via simple transformations
from tartaric acid. The key step involves the successive stereoselec-
tive reduction of ketones with borohydride and selectride.
H
H
H
HO
Ph
O
HO
Ph
O
OH
O
O
O
O
Ph
O
H
HO
OH OH
HO
Key words: styryl lactones, (+)-goniofufurone, stereoselective re-
duction
(+)-7-epi-Goniofufurone (1)
(+)-Goniofufurone (2)
(+)-Goniotriol (3)
O
H
H
O
O
OH
O
Trees of genus Goniothalamus of the plant family Annon-
aceae have been known for a long time as a source of po-
tent biologically active styryl lactones.1 Due to their
proven use in folk medicine in Taiwan, Malaysia, and In-
dia to treat rheumatism, edema, as an abortifacient, and as
a mosquito repellant, there has been an interest in the ac-
tive ingredients as potential therapeutic targets. This re-
sulted in the isolation by McLaughlin et al. of a series of
styryl lactones which were reported to show cytotoxic, an-
titumor, pesticidal, ratogenic, and embryotoxic activities.2
The styryl lactones isolated can be mainly classified into
two groups related to the size of the lactone ring. The first
group consists of the five-membered lactone moiety for
e.g. 7-epi-(+)-goniofufurone (1) and goniofufurone (2).
The second group consists of the six-membered lactones
such as, goniotriol (3), etharvendiol (4), altholactone (5),
and goniopyrone (6). Amongst these, goniofufurones con-
taining a furanofurone bicyclic structure has exhibited
significant cytotoxic activities against several human tu-
mor cell lines.3 Coupled with their unique and intriguing
structures as well as their broad spectrum of activity, these
compounds have attracted the attention of several synthet-
ic groups.4
Ph
HO
O
O
Ph
O
O
Ph
H
HO
HO
H
OH OEt
Etharvendiol (4)
(+)-Goniopypyrone (6)
(+)-Altholactone (5)
Figure 1 Bioactive styryllactones
recently disclosed a multi-step synthesis starting from a
chiral aldehyde derived from D- and L-tartaric acid.10
During the course of the synthesis of symmetrical 1,4-di-
aryl diones from 7, we observed that careful addition of
Grignard reagent furnished the mono-addition product,
keto amide 8, which can be further elaborated. Thus, we
envisaged that the known intermediate 14 for the synthe-
sis of 7-epi-gonifufurone can easily be accessed via the re-
duction of the keto amide, as depicted in the retrosynthesis
(Scheme 1).
H
OH OH
HO
Ph
O
O
Ph
O
OH
O
H
HO
14
O
1
Of the several syntheses reported for 7-epi-goniofufurone
and its derivatives, most of them utilized carbohydrates
such as D-glucose and D-mannose, as well as other chiral
pool sources. For example Shing et al. reported the first
synthesis of the title compound from D-glycero-D-gulo-
heptano-g-lactone.5 An elegant strategy involving a Wit-
tig reaction of a lactol derived from glucose was described
by Prakash and Rao.6 Mukai et al.7 utilized a chiral arene
chromium(0) complex, while unstable chiral lactonic al-
dehydes as the key intermediates were employed by Tsu-
buki et al8 in their synthesis. Mereyala et al.9 described the
synthesis of 7-epi-goniofufurone and its analogues in-
volving a Pd(0)-mediated cyclization. Recently Su et al.
Ph
O
Ph
O
O
O
NMe2
R3SiO
R3SiO
O
OH
O
O
O
O
O
O
NMe2
NMe2
Me2N
Ph
O
7
8
O
Scheme 1 Retrosynthesis for (+)-epi-goniofufurone
Our synthesis of 1 began with the D-(–)-isopropylene-
dioxy tartaric amide 7,11 which on reaction with two
equivalents of PhMgBr cleanly produced the mono-addi-
tion product keto amide 8 in 92% yield along with traces
of the diketone. Stereoslective reduction of ketone 8 with
SYNLETT 2005, No. 14, pp 2260–2262
0
2
.0
9
.2
0
0
5
Advanced online publication: 13.07.2005
DOI: 10.1055/s-2005-871965; Art ID: D11205ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Total Synthesis of (+)-7-epi-Goniofufurone
2261
NaBH4/CeCl3 resulted in the alcohols forming in a 94:6 general and is quite suitable for creating a pool of ana-
ratio, with 9 being the major isomer.12 Protection of the logues in addition to the synthesis of other bioactive sty-
benzylic alcohol 9 as the corresponding TBDMS ether ryllactones. Further work in this direction is currently in
was realized in almost quantitative yield. Addition of 4- progress.
butenylmagnesium bromide13 proceeded smoothly to give
the ketone 10 in 91% yield. Stereoselective reduction of
ketone 10 was accomplished with L-selectride to furnish
Acknowledgment
We thank DST, New Delhi for funding of this project. SLG thanks
IISc, Bangalore and CSIR, New Delhi for a research fellowship.
the alcohol 11 in 86% yield after flash chromatography.
Ozonolysis of alcohol 11 produced the corresponding lac-
tol, which was oxidized to lactone 12 in 92% combined
yield. Phenylselenation of the lactone followed by elimi-
nation of the phenylselenyl moeity furnished a,b-unsatur-
ated ketone 13 in 65% isolated yield. On treatment with
HCl/AcOH in THF the known triol 14 {[a]D –83 (c 0.3,
MeOH) [lit.5 –85 (c 0.3, MeOH)]}, was obtained in 70%
yield, which upon treatment with DBU in THF produced
7-epi-(+)-goniofufurone (Scheme 2). All the physical
constants and spectral data14 are in complete agreement
with those reported in the literature. Similarly, starting
from L-(+)-isopropylenedioxy tartaric amide (7), we syn-
thesized the corresponding (–)-enantiomer in 19% overall
yield.
References
(1) For a review on styryllactones from Goniothalamus species
see: Blàzquez, M. A.; Bermejo, A.; Zafra-Polo, M. C.;
Cortes, D. Phytochem. Anal. 1999, 10, 161.
(2) (a) Fang, X. P.; Anderson, J. E.; Chang, C. J.; Fanwick, P. E.;
McLaughlin, J. L. J. Chem. Soc., Perkin. Trans. 1 1990,
1655. (b) Fang, X. P.; Anderson, J. E.; Chang, C. J.;
McLaughlin, J. L.; Fanwick, P. E. J. Nat. Prod. 1991, 54,
1034. (c) Fang, X. P.; Anderson, J. E.; Chang, C. J.;
McLaughlin, J. L. Tetrahedron 1991, 47, 9751.
(3) For a review on the cytotoxic activity and other bioactivity
of styryl lactones, see: Mereyala, H. B.; Joe, M. Curr. Med.
Chem.: Anti-Cancer Agents 2001, 1, 293.
(4) (a) Ye, J.; Bhatt, R. K.; Falck, J. R. Tetrahedron Lett. 1993,
34, 8007. (b) Murphy, P. J.; Dennison, S. T. Tetrahedron
1993, 49, 6695. (c) Gracza, T.; Jäger, V. Synthesis 1994,
1359. (d) Xu, D.; Sharpless, K. B. Tetrahedron Lett. 1994,
35, 4685. (e) Yang, Z. C.; Zhou, W. S. Tetrahedron 1995,
51, 1429. (f) Ko, S. Y.; Lerpiniere, J. Tetrahedron Lett.
1995, 36, 2101. (g) Yi, X.-H.; Meng, Y.; Hua, X.-G.; Li, C.-
J. J. Org. Chem. 1998, 63, 7472. (h) Fernandez de la
Pradilla, R.; Montero, C.; Priego, J.; Martinez-Cruz, L. A.
J. Org. Chem. 1998, 63, 9612. (i) Bruns, R.; Wernicke, A.;
Koll, P. Tetrahedron 1999, 55, 9793. (j) Surivet, J.-P.;
Vatele, J.-M. Tetrahedron 1999, 55, 13011.
(5) Shing, T. K. M.; Tsui, H. C.; Zhou, Z. H. J. Org. Chem.
1995, 60, 3121.
(6) (a) Prakash, K. R. C.; Rao, S. P. Tetrahedron 1993, 49,
1505. (b) Prakash, K. R. C.; Rao, S. P. Synlett 1993, 123.
(7) Mukai, C.; Kim, I. J.; Kido, M.; Hanaoka, M. Tetrahedron
1996, 52, 6547.
In summary, we have shown that the rapid assembly of the
pivotal intermediate containing four contiguous stereo-
genic centers en route to (+)-7-epi-goniofufurone is
achieved in a short synthetic sequence. The strategy is
O
O
O
Ph
Ph
O
O
O
b
a
NMe2
NMe2
Me2N
Ph
90% for
92%
two steps
O
8
O
O
7
O
Ph
O
O
O
d
c
NMe2
RO
RO
RO
91%
86%
9
O
10
(8) Tsubuki, M.; Kanai, K.; Nagase, H.; Honda, T. Tetrahedron
1999, 55, 2493.
O
Ph
O
O
O
(9) (a) Mereyala, H. B.; Gadikota, R. R. Indian J. Chem., Sect.
B: Org. Chem. Incl. Med. Chem. 2000, 39, 166.
(b) Mereyala, H. B.; Gadikota, R. R.; Joe, M.; Arora, S. K.;
Dastidar, S. G.; Agarwal, S. Bioorg. Med. Chem. 1999, 7,
2095.
f
e
RO
65%
92%
O
OH
12
11
O
(10) Su, Y.-L.; Yang, C.-S.; Teng, S.-J.; Zhao, G.; Ding, Y.
Tetrahedron 2001, 57, 2147.
(11) (a) Toda, F.; Tanaka, K. J. Org. Chem. 1988, 53, 3607.
(b) Seebach, D.; Hidber, A. Org. Synth., Coll. Vol. 7; Wiley:
New York, 1990, 447.
OH OH
Ph
O
O
g
h
Ph
1
RO
70%
55%
OH
O
O
13
14
O
(12) The minor isomer was removed by simple crystallization
from hexane–EtOAc.
O
Scheme 2 Stereoselective synthesis of (+)-7-epi-goniofufurone a)
PhMgBr (2 equiv), THF, –10 °C, 0.5 h; b) (i) NaBH4 (1.2 equiv)/
CeCl3 (1.2 equiv), –78 °C, 2 h; (ii) TBDMSCl (1.5 equiv), imidazole
(3 equiv), DMAP (20 mol%), DMF, r.t., 6 h; c) butenylMgBr (2
equiv), THF, –10 °C, 0.5 h; d) L-Selectride (1.2 equiv), THF, –78 °C,
1 h; e) (i) O3/Me2S, MeOH–CH2Cl2, –78 °C to 0 °C, 4 h; (ii) PCC (2
equiv)/NaOAc/Celite/CH2Cl2, 1 h; f) (i) LiHMDS (2.5 equiv)/THF,
–78 °C to –50 °C; PhSeCl (1.5 equiv) or PhSeSePh (1.5 equiv); (ii)
30% H2O2, CH2Cl2, 0 °C, 0.5 h; g) HCl–THF–AcOH (1:1:1), r.t., 6 h);
cat. DBU/THF, r.t., 24 h.
(13) We anticipated that the addition of vinyl magnesiumbromide
to 9 followed by a stereoselective reduction of the ketone
and RCM would yield the intermediate 14. However,
addition of vinyl magnesium bromide to 9 proceeded with
low yield. Full details of this strategy will be discussed in a
future article.
(14) All new compounds exhibited satisfactory spectral data. 8:
[a]D +23 (c 1, CHCl3). 1H NMR (300 MHz, CDCl3): d = 1.41
(s, 3 H), 1.50 (s, 3 H), 3.00 (s, 3 H), 3.17 (s, 3 H), 5.16 (d,
J = 5.7 Hz, 1 H), 5.934 (d, J = 5.4 Hz, 1 H), 7.40–7.65 (m,
Synlett 2005, No. 14, 2260–2262 © Thieme Stuttgart · New York

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K. R. Prasad, S. L. Gholap
LETTER
3 H), 8.05–8.15 (m, 2 H). 13C NMR (75 MHz): d = 26.40,
35.97, 37.13, 75.04, 76.59, 77.43, 79.45, 112.56, 128.55,
129.41, 133.69, 134.94, 168.25, 196.38. Anal. calcd for
C21H34NO4Si: C, 64.97; H, 6.91. Found: C, 65.28; H, 7.02.
9: [a]D +67.5 (c 1, CHCl3). 1H NMR (300 MHz, CDCl3): d =
–0.14 (s, 3 H), –0.04 (s, 3 H), 0.84 (s, 9 H), 1.26 (s, 3 H), 1.34
(s, 3 H), 2.84 (s, 3 H), 2.99 (s, 3 H), 4.44 (d, J = 6.6 Hz, 1 H),
4.72–4.88 (m, 2 H), 7.15–7.40 (m, 5 H). 13C NMR (75
MHz): d = –5.15, –4.85, 18.21, 25.71, 26.43, 26.71, 35.78,
36.96, 73.23, 74.14, 82.03, 110.97, 127.29, 127.52, 127.71,
140.59, 169.04. Anal. calcd for C21H35NO4Si: C, 64.08; H,
8.96. Found: C, 64.10; H, 9.21. 11: [a]D +38.9 (c 1.5,
CHCl3). 1H NMR (300 MHz, CDCl3): d = –0.12 (s, 3 H),
0.00 (s, 3 H), 0.82 (s, 9 H), 1.10 (s, 3 H), 1.32 (s, 3 H), 1.33–
1.50 (m, 1 H), 1.85–2.15 (m, 3 H), 3.09 (br s, 1 H), 3.64 (dd,
J = 8.1 Hz, 2.4 Hz 1 H), 4.10 (dd, J = 8.1 Hz, 5.4 Hz 1 H),
4.76 (d, J = 5.1 Hz, 1H), 4.80–5.00 (m, 2 H), 5.67 (ddt,
J = 16.8 Hz, 10.2 Hz, 6.9 Hz, 1 H), 7.15–7.30 (m, 5 H). 13
NMR (75 MHz): d = –4.99, –4.85, 18.26, 25.79, 27.04,
27.39, 29.87, 33.87, 69.33, 75.54, 79.25, 80.57, 109.13,
114.79, 127.40, 127.78, 127.88, 138.14, 139.97. 13: [a]D
C
+11.7 (c 0.6, CHCl3). 1H NMR (300 MHz, CDCl3): d = 0.00
(s, 3 H), 0.11 (s, 3 H), 0.90 (s, 9 H), 1.17 (s, 3 H), 1.34 (s, 3
H), 3.87 (dd, J = 8.1, 2.4 Hz, 1 H), 4.46 (dd, J = 8.1, 5.7 Hz,
1 H), 4.52 (q, J = 2.0 Hz, 1 H), 4.94 (d, J = 5.7 Hz, 1 H), 6.07
(dd, J = 5.7 Hz, 1.8 Hz, 1 H), 7.26 (dd, J = 5.7, 1.8 Hz, 1 H),
7.25–7.45 (m, 5 H). 13C NMR (75 MHz): d = –4.97, –4.94,
18.27, 25.79, 26.27, 26.99, 75.08, 75.11, 80.03, 81.47,
110.23, 122.14, 127.27, 128.03, 139.38, 153.10, 172.82.
Anal. calcd for C22H33O5Si: C, 65.31; H, 7.97. Found: C,
65.26; H, 7.80.
Synlett 2005, No. 14, 2260–2262 © Thieme Stuttgart · New York