Total synthesis of goniocin and cyclogoniodenin T. Unique biosynthetic implications [2]

Full text of DOI:10.1021/ja973696d

J. Am. Chem. Soc. 1998, 120, 4017-4018
4017
This biogenetic issue recently became even more intriguing
when goniodenin, 2, was isolated from the same plant.6 The
structure of 2 was found to be closely related to that of 1. In
fact, nonstereoselective epoxidation of 2 with m-chloroperoxy-
benzoic acid (m-CPBA) followed by acid-catalyzed ring closure
afforded two new stereoisomers of 1.6 One of them, 3, containing
an all-trans tris-THF structure, was named cyclogoniodenin T. It
has been reported that compounds 1 and 3 are different from one
Total Synthesis of Goniocin and Cyclogoniodenin T.
Unique Biosynthetic Implications
Santosh C. Sinha,†,‡,§ Anjana Sinha,†,‡
Subhash C. Sinha,*,† and Ehud Keinan*,†,‡,§
Department of Molecular Biology and The Skaggs
Institute for Chemical Biology, The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, California 92037
Department of Chemistry, Technion-Israel Institute
1
another on the basis of the H and 19F NMR spectra of their
Mosher’s esters. Yet, their biological activity was found to be
similar. Hence, before drawing any further conclusions from a
seemingly extraordinary biogenetic event, where two structurally
similar but stereochemically very different natural products, 1 and
2, coexist in the same plant, it became necessary to verify the
absolute configuration of 1 and 3 by total synthesis.
Clearly, the main challenge in the synthesis of 1 and 3 is the
construction of the trans-tris-THF fragment with the appropriate
configuration of the seven stereogenic carbinol centers. In our
earlier efforts to employ the tandem oxidative cyclization reactions
with rhenium(VII) reagents using trienol substrates, we discovered
that this highly stereospecific method produces the trans-threo-
cis-threo-cis-threo-tris-THF system rather than the all-trans system
required here.7 Therefore, we employed alternative synthetic
methods, including the Sharpless asymmetric dihydroxylation
(AD)8 and epoxidation (AE)9 reactions as well as the Williamson
etherification reaction (Schemes 1 and 2).
of Technology, Technion City, Haifa 32000, Israel
ReceiVed October 24, 1997
The growing interest in Annonaceous acetogenins1,2 arises from
their antimalarial, immunosuppressive, pesticidal, and antifeedant
activities and particularly from their remarkable antitumor activ-
ity.3
Goniocin, which has been recently isolated from Goniothala-
mus giganteus,4 represents the first, and so far the only, example
of a new subgroup of the Annonaceous acetogenins which
possesses three adjacent THF rings. Structure 1 was proposed
1
for goniocin on the basis of its MS and H and 13C NMR data.4
Our synthesis of 1 (Scheme 1) started with trienol 4 which is
obtained from ethyl heptadec-4-enoate using AD-mix-â10 followed
by a sequence of reactions similar to that described in ref 7 (see
the Supporting Information). Asymmetric epoxidation of 4 using
(-)-DET produced epoxide 5 in more than 95% enantiomeric
excess (ee). Reductive cleavage of 5 with Red-Al gave the
corresponding 1,3-diol, whose primary hydroxyl group was
protected in the form of a tert-butyldiphenylsilyl (BPS) ether 6.
Oxidative cyclization of the latter with CF3CO2ReO3 and lutidine
produced the trans-THF derivative, whose spectral characteristics
(1H and 13C NMR) were found to be very similar to those of
other trans-THF analogues.11 Protection of the free hydroxyl
group as a tert-butyldimethylsilyl (BMS) ether afforded 7.
Asymmetric dihydroxylation of 7 using AD-mix-R followed by
double mesylation produced 8. Acidic cleavage of the acetonide
and the silyl ethers followed by heating of the resultant tetrol in
pyridine produced the desired all-trans tris-THF diol 9. The
primary alcohol was protected in the form of a BPS ether and
the secondary alcohol in the form of a MOM ether. The silyl
ether was then hydrolyzed, and the resultant primary alcohol was
converted to an iodide and then to the phosphonium salt 10. The
latter was converted to the corresponding Wittig reagent and then
reacted with aldehyde 117 to produce alkene 12. Finally, catalytic
hydrogenation and deprotection of both MOM and BPS groups
afforded goniocin, 1.
The all-trans geometry of the THF rings as well as the (R,R)
configuration of carbon atoms 21 and 22 was determined on the
basis of the NMR spectra of the natural product and of its Mosher
esters.4 On the basis of these data, an (S) configuration was as-
signed for the carbon atom 10. From a biosynthetic standpoint,
this assignment is remarkable, due to the fact that in almost all
of the other structurally related acetogenins isolated from G.
giganteus to date carbon atom 10 was assigned an (R) configu-
ration.1,5
† Department of Molecular Biology.
‡ The Skaggs Institute for Chemical Biology.
§ Technion-Israel Institute of Technology.
(1) Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z.-M.; He, K.;
McLaughlin, J. L. Nat. Prod. Rep. 1996, 275.
Cyclogoniodenin-T, 3, was synthesized (Scheme 2) using a
strategy that is very similar to the above-described synthetic
(2) For synthesis, see: (a) Sinha, S. C.; Keinan, E. J. Am. Chem. Soc. 1993,
115, 4891. (b) Naito, H.; Kawahara, E.; Maruta, K.; Maeda, M.; Sasaki, S. J.
Org. Chem. 1995, 60, 4419. (c) Sinha, S. C.; Sinha-Bagchi, A.; Yazbak, A.;
Keinan, E. Tetrahedron Lett. 1995, 36, 9257. (d) Yao, Z. J.; Wu, Y. L. J.
Org. Chem. 1995, 60, 1170. (e) Franck, X.; Figadere, B.; Cave´, A. Tetrahedron
Lett. 1996, 37, 1593. (f) Hoye, T. R.; Ye, Z. J. Am. Chem. Soc. 1996, 118,
1801. (g) Konno, H.; Makabe, H.; Tanaka, A.; Oritani, T. Tetrahedron 1996,
52, 9399. (h) Sinha, S. C.; Sinha, A.; Yazbak, A.; Keinan, E. J. Org. Chem.
1996, 61, 7640. (i) Marshall, J. A.; Hinkle, K. W. J. Org. Chem. 1997, 62,
5989. (j) Trost, B. M.; Calkins, T. L.; Bochet, C. G. Angew. Chem., Int. Ed.
Engl. 1997, 36, 2632.
(5) (a) Zafra-Polo, M. C.; Gonzalez, M. C.; Estornell, E.; Sahpaz, S.; Cortes,
D. Phytochemistry 1996, 42, 253. (b) Zeng, L.; Zhang, Y.; Ye, Q.; Shi, G.;
He, K.; McLaughlin, J. L. Bioorg. Med. Chem. 1996, 4, 1271.
(6) Zhang, Y.; Zeng, L.; Woo, M.-H.; Gu, Z.-M.; Ye, Q.; Wu, F.-E.;
McLaughlin, J. L. Heterocycles 1995, 41, 1743.
(7) Sinha, S. C.; Sinha, A.; Sinha, S. C.; Keinan, E. J. Am. Chem. Soc.
1997, 119, 12014.
(8) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV. 1994,
(3) (a) Ahammadsahib, K. I.; Hollingworth, R. M.; McGovren, J. P.; Hui,
Y.-H.; McLaughlin, J. L. Life Sci. 1993, 53, 1113. (b) Gu, Z.-M.; Zhao, G.-
X.; Oberlies, N. H.; Zeng, L.; McLaughlin, J. L. in Recent AdVances in
Phytochemistry; Arnason, J. T., Mata, R., Romeo, J. T., Eds.; Plenum Press:
New York, 1995; Vol. 29, pp 249-310. (c) Oberlies, N. H.; Croy, V. L.;
Harrison, M. L.; McLaughlin, J. L. Cancer Lett. 1997, 115, 73.
(4) Gu, Z.-M.; Fang, X.-P.; Zeng, L.; McLaughlin, J. L. Tetrahedron Lett.
1994, 35, 5367.
94, 2483.
(9) (a) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; VCH Publishers, Inc.: New York, 1993; p 103. (b) Gao, Y.;
Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J.
Am. Chem. Soc. 1987, 109, 5765.
(10) Wang, Z.-M.; Zhang, X.-L.; Sharpless, K. B.; Sinha, S. C.; Sinha-
Bagchi, A.; Keinan, E. Tetrahedron Lett. 1992, 33, 6407.
(11) Sinha, S. C.; Sinha, S. C.; Keinan, E. Submitted for publication.
S0002-7863(97)03696-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/14/1998

4018 J. Am. Chem. Soc., Vol. 120, No. 16, 1998
Communications to the Editor
Scheme 1a
a Key: (a) Ti-i-(OPr)4, (-)-DET, TBHP, molecular sieves, CH2Cl2; (b) i. Red-Al, THF, 0 °C, 4 h; ii. TBDPSCl, diisopropylethylamine, CH2Cl2, rt,
16 h; (c) i. CF3CO2ReO3, lutidine, CH2Cl2, 16 h; ii. TBDMSCl, imidazole, DMF, rt, 16 h; (d) i. AD-mix-R, t-BuOH-H2O, 0 °C, 16 h; ii. MsCl, Et3N,
CH2Cl2, 0 °C, 2 h; (e) i. TsOH, H2O-MeOH, then pyridine, reflux, 2 h; (f) i. TBDPSCl, diisopropylethylamine, CH2Cl2, rt, 16 h, then MOMCl,
diisopropylethylamine, CH2Cl2, 0 °C to rt, 16 h; ii. TBAF, THF, 0 °C to rt, 2 h; iii. I2, PPh3, imidazole, 0 °C to rt, 2 h; iv. PPh3, NaHCO3, CH3CN, 45
°C, 48 h; (g) BuLi, THF, 0 °C, then aldehyde 11; (h) i. H2, Wilkinson’s catalyst (20%, w/w), C6H6-EtOH (4:1), rt, 4 h; ii. 4% AcCl in MeOH-CH2Cl2
(1:1, v/v), rt, 16 h.
1
Scheme 2a
As both the H and 13C NMR spectra of 1 and 3 are virtually
indistinguishable from one other, the absolute stereochemistry of
our synthetic 1 and 3 was proved by comparison of the 1H NMR
spectra of their (R) and (S) bis Mosher esters with the original
spectra of the esters of the naturally occurring 1 and the
semisynthetic 3.12
It is remarkable that the two nearly enantiomeric natural
products, 1 and 2, occur in the same plant. Although the co-
existence of both enantiomers of simple natural products having
one or two asymmetric centers have been reported, there are very
few such cases with more complex structures. The co-occurrence
of both enantiomers of nonactic acid, which has four asymmetric
carbon atoms, is probably the closest case to our findings.13 It
has been postulated that the biosynthesis of the poly-THF structure
in most Annonaceous acetogenins involves a polyepoxide precur-
sor that undergoes sequential ring closure reactions.1 Thus, one
can envision a common intermediate in the biosynthesis of both
1 and 2. Theoretically, either of the two pentaepimeric precursors
(II and V, Scheme 3) may lead to 2, depending on the direction
of the tandem epoxide opening cascade. Similarly, either of the
two heptaepimeric precursors, III and VI, may lead to 1. If III
is the precursor of 1, then the original 10(R) hydroxyl group must
be a good leaving group, e.g., by protonation (as shown in Scheme
3), acetylation, phosphorylation, etc.
In conclusion, the first asymmetric total syntheses of goniocin,
1, and cyclogoniodenin T, 3, have been achieved in 17 steps from
4 and ent-4, respectively. The synthetic materials, 1 and 3, were
found to be identical to the naturally occurring compounds,
thereby confirming their proposed absolute configurations. We
interpret the remarkable coexistence of nearly enantiomeric natural
products, 1 and 2, in the same organism to be a result of two
alternative modes of tandem ring-closure routes, both starting with
a common polyepoxide intermediate. Feeding experiments with
isotopically labeled precursors could verify this biosynthetic
hypothesis.
a Key: (a) The same set of reactions described in Scheme 1 (a-f)
was used here except that (+)-DET and AD-mix-â were used instead of
(-)-DET and AD-mix-R; (b) the same reactions described in Scheme 1
(g-h) were used here.
Scheme 3
approach. Ethyl heptadec-4-enoate was dihydroxylated with AD-
mix-R10 and converted to the allylic alcohol ent-4 (see the
Supporting Information). Asymmetric epoxidation using (+)-
DET produced ent-5 in more than 95% ee. The latter was reduced
to ent-6 which was oxidatively cyclized to ent-7 as described
above for the enantiomeric system. Dihydroxylation with AD-
mix-â followed by double mesylation afforded ent-8 which
underwent Williamson-type ring closure to ent-9. The latter was
converted to the phosphonium salt ent-10. The synthesis was
completed as described in Scheme 1 to give 3.
(12) We found that the most significant differences were observed in the
signals of the methoxy hydrogens in the spectra of the Mosher’s bis-esters of
1 and 3. For the (R) bis-esters of both the synthetic and the naturally occurring
1, the two methoxy signals appear at 3.63 and 3.49 ppm. For the (S) bis-
esters, they appear at 3.55 and 3.50 ppm. With both synthetic and authentic
samples of 3, the methoxy signals of the (R) bis-esters appear at 3.55 and
3.49 ppm. For the (S) bis-esters of 3, these signals appear at 3.63 and 3.50
ppm. Although this information is not given in ref 4, we compared our data
directly with the original spectra provided by Prof. J. L. McLaughlin (see the
Supporting Information). An intrinsic signature of the (R) and (S) configura-
tions of the Mosher esters is evident from the following: The two protons at
Acknowledgment. We thank the US-Israel Binational Science
Foundation, the Israel Cancer Research Fund, PharMore Biotechnologies,
and the Skaggs Institute for Chemical Biology for financial support. E.K.
is the incumbent of the Benno Gitter & Ilana Ben-Ami chair of
Biotechnology. We thank Prof. J. L. McLaughlin, Dr. Z.-M. Gu, and F.
Alali for copies of the NMR spectra of 1 and 3 as well as those of their
Mosher esters.
Supporting Information Available: The synthetic schemes of 4 and
1
position 3 of the bis-Mosher esters of 1 and 3 exhibit very characteristic H
1
ent-4; spectral data for 4-10 (or ent-4-10); H and 13C NMR spectra
NMR signals: for the (S) ester, these protons appear as a narrow multiplet at
2.58 ppm, and for the (R) ester, they appear as an ABX system 2.66 (dd) and
2.58 (dd) ppm.
1
of 1 and 3-10; H NMR apectra of (R) and (S) Mosher bis-esters of 1
and 3 (27 pages, print/PDF). See any current masthead page for ordering
(13) (a) Ashworth, D. M.; Robinson, J. A. J. Chem. Soc., Chem. Commun.
1983, 1327. (b) Spavold, Z. M.; Robinson, J. A. J. Chem. Soc., Chem.
Commun. 1988, 4.
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