Harnessing glycal-epoxide rearrangements: The generation of the AB, EF, and IJ rings of adriatoxin

Article abstract of DOI:10.1002/anie.200803791

(Chemical Equation Presented) Climbing the ladder: The generation of three bicyclic subunits ofadriatoxin (see structure) was accomplished by using glycal-epoxide rearrangements, glycal-Claisen rearrangements, and C-glycoside-forming reactions.

Full text of DOI:10.1002/anie.200803791

Angewandte
Chemie
DOI: 10.1002/anie.200803791
Natural Product Synthesis
Harnessing Glycal-Epoxide Rearrangements: The Generation of the
AB, EF, and IJ Rings of Adriatoxin**
Clement Osei Akoto and Jon D. Rainier*
The marine ladder toxin class of natural products has
generated considerable interest from the synthetic and
biomedical communities because of their fascinating struc-
tures and biological activities.[1,2] This group includes a target
that has recently become of interest to us, adriatoxin
(Scheme 1), a polyether toxin isolated by Fattorusso and co-
(3).[6] Biologically, that adriatoxin had been implicated in
diarrhetic shellfish poisoning would allow us to continue our
collaborative studies which have been focused on the ability
of natural and non-natural polyethers to bind to ion
channels.[7] In addition to this, that Shimizu has identified
structurally related yessotoxin analogues as having excep-
tional cytotoxic activity against human cancer cell lines was
also intriguing.[8]
We had hoped to utilize iterative C-glycoside technology
to access the adriatoxin AB-ring subunit, starting from
2-deoxy-d-ribose (Scheme 2).[9] Conversion of this precursor
into olefinic alcohol 5 required four steps and was carried out
in a 64% overall yield.[10] Esterification with butanoic acid
derivative 6 and then olefinic ester cyclization, under our
recently disclosed reduced-titanium reaction conditions, gave
8 in 70% yield.[11] In contrast, the use of a more conventional
two-step enol ether–olefin ring-closing metathesis sequence
gave 8 in a 50% overall yield from 7.
Next, we needed to introduce an oxygen atom at C6 and to
reduce C7 of 8. In principle, these goals could be accom-
plished in a single flask by either subjecting the enol ether
to a hydroboration/oxidation reaction or by the use of a
2,2-dimethyldioxirane (DMDO)/diisobutylaluminum hydride
protocol.[12] However, because of the presence of the C3
angular methyl group in 8 we felt that both of these
procedures would generate the undesired stereochemistry at
both C6 and C7.[13] Whereas we believed that this problem
could be overcome by oxidizing the alcohol to the corre-
sponding ketone, equilibrating the C7 stereocenter to the
desired thermodynamically more stable isomer, and subse-
quently reducing the ketone, we sought a more direct
Scheme 1. Retrosynthetic analysis of adriatoxin. P=protectinggroup.
workers from the digestive gland of the Adriatic mussel
Mytilus galloprovincialis.[3–5] Synthetically, our fascination
with adriatoxin came out of an interest in determining
whether our recently described coupling protocol, which
leads to the pairing of two subunits and the generation of two
additional rings, would enable us to carry out a convergent
synthesis of the ten-ring system from three bicyclic precursors
representing the AB ring (1), the EF ring (2), and the IJ ring
[*] C. Osei Akoto, Prof. J. D. Rainier
Department of Chemistry, University of Utah
315 South 1400 East, Salt Lake City, UT 84112 (USA)
Fax: (+1)801-581-8433
E-mail: rainier@chem.utah.edu
Homepage: http://www.chem.utah.edu/faculty/rainier/group.html
Scheme 2. Synthesis of glycal 8. Reagents and conditions:
[**] We are grateful to the National Institutes of Health, General Medical
Sciences (GM56677) for support of this work. C.O.A. acknowledges
Pfizer for a graduate fellowship. We would like to thank the support
staff at the University of Utah and especially Dr. Charles Mayne
(NMR) and Dr. Jim Muller (MS) for their help in obtainingdata.
a) Ph3PMeBr, THF, tBuOK; b) PhCH(OMe)2, CSA (80% over two
steps); c) (COCl)2, DMSO, Et3N, À788C; d) MeMgBr, Et2O, À788C
(80% over two steps); e) HO2CCH2CH2CH(OMe)2 (6), DCC, DMAP,
CH2Cl2 (80%); f) TiCl4, TMEDA, Zn, PbCl2, THF, CH2Cl2, CH3CH2Br2
(70%). CSA=(+)-camphorsulfonic acid, DMSO=dimethylsulfoxide;
DCC=dicyclohexylcarbodiimide; DMAP=4-(dimethylamino)pyridine;
TMEDA=N,N,N’,N’-tetramethyl-1,2-ethanediamine.
Supportinginformation for this article is available on the WWW
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solution. We realized that we might be able to take advantage
of an epoxide rearrangement reaction that had, in the past,
been problematic for us.[14] The reaction is outlined in
Scheme 3 for 9 and involves a Lewis acid catalyzed pinacol-
type rearrangement to give 10. As illustrated, when the
rearrangement was induced with allyl Grignard, it resulted in
the generation of the corresponding tertiary alcohol (11) . Of
importance to our use of this reaction for the adriatoxin
AB subunit was that 11 was isolated as a single diastereomer,
implying that the rearrangement of 9 was stereoselective.
Scheme 5. Synthesis of adriatoxin AB-precursor 15. Reagents and
conditions: a) NaBH4, MeOH, À658C to RT (95%); b) PPTS, PhCl,
pyridine, 1358C (86%); c) DMDO, CH2Cl2, À608C to RT; propenyl
magnesium bromide, THF, À608C to RT (75%, 2.3:1 ratio of 15/16);
d) SO3·pyridine, DMSO, CH2Cl2, 08C to RT; e) DBU, PhCH3, 1108C;
f) NaBH4, MeOH, À658C to RT (60% over three steps). PPTS=pyr-
idinium para-toluenesulfonate; DBU=1,8-diazabicycloundec-7-ene.
using the three-step protocol mentioned earlier involving:
1)oxidation of the secondary alcohol, 2)equilibration of the
C10 stereocenter, and 3)reduction of the ketone. The syn-
thesis of AB subunit 15 was reasonably efficient in that it
required 13 steps (15% overall yield)and utilized d-ribose as
the sole source of chirality.
Intrigued by the reaction to access ketone 13, we
examined the scope of the rearrangement reaction by
exploring the effect of substitution in d-glucal model sub-
strates [Eq. (1); TBDPS = tert-butyldiphenylsilyl]. In these
studies we were somewhat disappointed to find that the
epoxides from 17 and 18 gave no rearranged products, but
instead gave only diols 19 and 20.
Scheme 3. Glycal epoxide rearrangement of 9. Reagents and condi-
tions: a) propenyl magnesium chloride, THF, 08C to RT (70%).
We recognized that if we were able harness the rearrange-
ment in a synthetic context, that it might prove to be a useful
solution for the adriatoxin A-ring problem and allow us to
avoid the equilibration sequence mentioned above. That is, if
the epoxidation of 8 was directed by the C3 angular methyl
group and if the subsequent rearrangement was stereoselec-
tive per our previous results, the reaction would deliver the
desired C7 stereochemistry along with a C6 ketone.
The oxidation of 8 using “acetone free” DMDO presum-
ably gave 12 (not isolated; Scheme 4),[15] which was then
directly subjected to Lewis acids in an attempt to induce the
rearrangement. We focused on Mg salts and examined
MgBr2·Et2O, an “aged” bottle of MeMgCl, and reagent
grade MgCl2. Pleasingly, because it was the simplest to use,
the MgCl2 worked best; upon exposure to MgCl2, 12
rearranged to ketone 13 in 82% yield. Extensive nOe
experiments indicated that 13 had the desired adriatoxin C7
stereochemistry, thus confirming our earlier hypothesis
regarding the stereoselectivity of the rearrangement.
Having successfully generated 13 we next focused our
attention on the C6 center and the B ring. To accomplish
these goals the ketone in 13 was reduced with NaBH4 to
obtain the desired equatorial alcohol (Scheme 5), which then
underwent acid-mediated cyclization and elimination to give
the adriatoxin B ring (14).[16] DMDO oxidation of 14 and
propenyl magnesium chloride addition to the resulting
epoxide provided a mixture of secondary alcohols 15 and
16. The undesired diastereomer (16)was converted into 15 by
In contrast to the results from 17 and 18, epoxides lacking
substitution at the allylic position gave the ketones in high
yield. Thus, when unsubstituted glycals 21 and 22 were
subjected to DMDO and subsequently reacted with MgCl2 we
isolated ketones 23 and 24, respectively [Eq. (2)]. As with the
rearrangement to 13, each of these compounds was isolated as
a single diastereomer. Although additional experiments on a
broader range of substrates are needed, our results imply that
less sterically hindered glycal epoxides are more likely to
undergo the rearrangement reaction, and are consistent with
previous results from our lab which described an inverse
dependence between epoxide reactivity and the steric bulk of
the allylic substituent.[17]
Seven-membered ring ketones can also be synthesized by
using the epoxide rearrangement reaction. When 25 was
subjected to DMDO and MgCl2 we isolated enol 26 as a single
diastereomer in 75% yield [Eq. (3)].[18]
Our efforts to access the adriatoxin EF ring began with
d-glyceraldehyde acetonide as a precursor to the E ring
(Scheme 6). The addition of homoallyl grignard in the
Scheme 4. Pinacol rearrangement of 12. Reagents and conditions:
a) DMDO, CH2Cl2, À608C to 08C; MgCl2, À608C to RT (82%).
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presence of ZnCl2 gave alcohol 27.[19] Methanolysis of the
acetonide and benzylidene acetal formation gave cyclization
precursor 30 after esterification with acetal 29. Olefinic ester
cyclization gave the adriatoxin E-ring subunit (31)in 65%
yield.
Scheme 7. Synthesis of adriatoxin EF-precursor 35. Reagents and
conditions: a) DMDO, iBu2AlH, CH2Cl2, À788C (80%);
b) SO3·pyridine, Et3N, DMSO (85%); c) MeMgBr, À788C (92%, 5:1);
d) PPTS, PhCl, pyridine, 1358C (75%); e) mCPBA, MeOH, À788C to
RT (88%); f) 3-bromo-1-propene, nBu4NI, DMF, 08C to 658C (85%).
mCPBA=3-chloroperbenzoic acid.
For the generation of the C23 stereocenter and the
completion of the adriatoxin F ring, we planned to employ a
Claisen rearrangement from an in situ generated allyl enol
ether (see 36, Scheme 8). Whereas Claisen rearrangements to
give C-glycosides are well precedented,[20] the proposed
reaction is somewhat unique in that the oxygen atom linking
the two alkenes is not in the allylic position on the pyran ring.
To the best of our knowledge there is only one other related
reaction and it was accomplished by us during our gambierol
work.[21] Oxidation of 33 with mCPBA in methanol gave 34 in
88% yield and then allyl ether formation gave rearrangement
precursor 35.
With the stage set for the rearrangement to the C23
stereocenter, we subjected 35 to PPTS, pyridine, and heat, and
isolated ketone 37 in 92% yield and as a greater than 10:1
mixture of diastereomers (Scheme 8). Presumably, the path to
37 proceeds through allyl enol ether 36 and, as mentioned
above, a stereoselective Claisen rearrangement. Having
successfully generated 37, all that remained to obtain EF-
ring precursor 38 was the reduction of the ketone, and this was
accomplished in 94% yield using NaBH4. Our synthesis of the
EF-ring precursor required 13 steps (11% overall yield)
utilizing d-glyceraldehyde acetonide as the precursor to the
remaining chiral centers.
Our synthesis of the IJ subunit is illustrated in Scheme 9.
From d-glucal derived C-glycoside 39,[22] vinyl ether forma-
tion and enol ether–olefin ring-closing metathesis, using the
second generation Grubbs catalyst (40), gave 41. The mCPBA
oxidation of the enol ether resulted in a 5.5:1 mixture of
anomeric acetals, both of which had the desired stereochem-
istry at C36. Here, we opted to invert the C32 stereocenter to
that required for the synthesis of adriatoxin.[23] This inversion
was accomplished in three steps: hydrogenolysis of 42 and
then oxidation of the resulting alcohol gave 43; reduction of
Scheme 6. Synthesis of adriatoxin E-ringprecursor 31. Reagents and
conditions: a) butenyl magnesium bromide, ZnCl2, Et2O, À908C (87%,
6:1); b) PPTS, MeOH, 658C (89%); c) PhCH(OMe)2, CSA (82%); 29,
DCC, DMAP, CH2Cl2 (85%); d) TiCl4, TMEDA, Zn, PbCl2, THF, CH2Cl2,
CH3CHBr2, 608C (65%).
Oxidation and reduction of the enol ether in 31 was
carried out using DMDO and iBu2AlH (Scheme 7). Addi-
tional oxidation of the resulting secondary alcohol gave
ketone 32. Notably, the reaction of 31 with DMDO and
iBu2AlH was stereoselective and ketone 32 existed as its keto
tautomer. In contrast, diastereomeric substrate 26 existed as
the enol tautomer [Eq. (3)]. Conversion of 32 into the
corresponding tertiary alcohol and cyclization/elimination
gave 33 in good yield.[16]
Two comments on the generation of 33 are worth noting.
First, we had hoped that the C19 angular methyl group would
ultimately dictate the stereochemistry at C23 (see below).
Thus, we were relieved that the formation of the C19 tertiary
alcohol was stereoselective. Second, whereas we have exam-
ined a number of related cyclization/elimination reactions,[16]
the cyclization to obtain 33 was the first in which a ketal was
employed, and we were pleased that the expected endocyclic
enol ether was the only isomer obtained from this reaction.
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Keywords: enols · epoxidation · metathesis · rearrangement ·
.
titanium
[1] For a recent review on the synthesis of polycyclic ethers, see: T.
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[2] For a recent review that discusses ion channel binding of ladder
toxins, see: G. M. Nicholson, R. J. Lewis, Mar. Drugs 2006, 4, 82.
[3] P. Ciminiellow, E. Fattorusso, M. Forino, S. Magno, R. Poletti, R.
Viviani, Tetrahedron Lett. 1998, 39, 8897.
[4] With the exception of the terminal K ring, adriatoxin shares a
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Lee, T. Yasumoto, Tetrahedron Lett. 1987, 28, 5869.
[5] For synthetic efforts to adriatoxin, see:a)N. Hiramatsu, Y. Mori,
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H. Hayashi, R. Noyori, J. Org. Chem. 2003, 68, 9050; e)K.
Suzuki, T. Nakata, Org. Lett. 2002, 4, 3943.
Scheme 8. Synthesis of adriatoxin EF-precursor 38. Reagents and
conditions: a) PPTS, PhCH3, pyridine, 1008C to 1208C (92%, >10:1);
b) NaBH4, MeOH À658C to RT (94%).
[6] H. W. B. Johnson, U. Majumder, J. D. Rainier, J. Am. Chem. Soc.
2005, 127, 848.
[7] a)E. Cuypers, Y. Abdel-Mottaleb, I. Kopljar, J. D. Rainier, A. L.
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[8] M. Konishi, X. Yang, B. Li, C. R. Fairchild, Y. Shimizu, J. Nat.
Prod. 2004, 67, 1309.
[9] S. P. Allwein, J. M. Cox, B. E. Howard, H. W. B. Johnson, J. D.
Rainier, Tetrahedron 2002, 58, 1997.
[10] K. C. Nicolaou, D. A. Nugiel, E. Couladouros, C.-K. Hwang,
Tetrahedron 1990, 46, 4517.
[11] K. Iyer, J. D. Rainier, J. Am. Chem. Soc. 2007, 129, 12604.
[12] U. Majumder, J. M. Cox, H. W. B. Johnson, J. D. Rainier, Chem.
Eur. J. 2006, 12, 1736.
[13] Alternatively, superhydride reduction of the glycal epoxide from
8 would potentially deliver the desired stereochemistry at C(7),
see: M. Inoue, S. Yamashita, A. Tatami, K. Miyazaki, M.
Hirama, J. Org. Chem. 2004, 69, 2797.
Scheme 9. Synthesis of adriatoxin IJ-precursor 44. Reagents and con-
ditions: a) Hg(OC(O)CF3)2, ethyl vinyl ether; b) 40 (20 mol%), PhH
(60% over 2 steps); c) m-CPBA, MeOH, À638C to RT (75%, 5.5:1);
d) Ac2O, DMAP, NEt3, CH2Cl2 (96%); e) H2, Pd(OH)2/C (90%);
f) SO3·pyridine, DMSO, CH2Cl2, NEt3 (90%); g) L-Selectride, THF,
À788C (90%). Mes=2,4,6-trimethylphenyl; Ac2O=acetic anhydride;
L-Selectride=lithium tri-sec-butylborohydride.
[14] J. D. Rainier, S. P. Allwein, J. M. Cox, J. Org. Chem. 2001, 66,
1380.
[15] M. Ferrer, M. Gibert, F. Sꢀnchez-Baeza, A. Messeguer, Tetrahe-
dron Lett. 1996, 37, 3585.
the ketone in 42 with L-Selectride gave the IJ subunit to
adriatoxin as 44.[24] The synthesis of IJ-precursor 44 was
efficient in that it required 12 steps (17% overall yield)from
d-glucal.
[16] J. D. Rainier, S. P. Allwein, Tetrahedron Lett. 1998, 39, 9601.
[17] S. W. Roberts, J. D. Rainier, Org. Lett. 2005, 7, 1141.
[18] That 23, 24, and 26 were isolated as single diastereomers implies
a stereoselective epoxidation. For a discussion of the reaction of
DMDO with cyclic enol ethers, see: A. M. Orendt, S. W.
Roberts, J. D. Rainier, J. Org. Chem. 2006, 71, 5565.
[19] J. S. Clark, J. G. Kettle, Tetrahedron Lett. 1997, 38, 127.
[20] For reviews, see: a)O. Arjona, A. M. Gomez, J. C. Lopez, J.
Plumet, Chem. Rev. 2007, 107, 1919; b)A. M. Martin Castro,
Chem. Rev. 2004, 104, 2939.
[21] J. M. Cox, J. D. Rainier, Org. Lett. 2001, 3, 2919.
[22] J. S. Clark, M. C. Kimber, J. Robertson, C. S. P. McErlean, C.
Wilson, Angew. Chem. 2005, 117, 6313; Angew. Chem. Int. Ed.
2005, 44, 6157.
[23] The stereochemistry at C32 was instrumental in setting the C33
and C34 stereocenters, see: reference [17] and U. Majumder,
J. M. Cox, J. D. Rainier, Org. Lett. 2003, 5, 913.
In summary, described herein is our synthetic strategy
toward the diarrhetic shellfish poison, adriatoxin, which
includes the use of a glycal-epoxide rearrangement to
obtain the AB subunit, a Claisen rearrangement to access
the EF subunit, and the use of C-glycoside-forming chemistry
to obtain the IJ subunit. This work expands the scope of glycal
epoxide chemistry by introducing epoxide rearrangements as
a viable synthetic reaction. Our future efforts will be focused
on the coupling of the subunits, the completion of the
synthesis of adriatoxin, and the study of its ability to interact
with biological receptors.
[24] Mitsunobu inversion of the C32 alcohol from 42 was slow and
gave low yields of the desired alcohol.
Received: August 1, 2008
Published online: September 10, 2008
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