Enantioselective total synthesis of avarol and avarone

Article abstract of DOI:10.1002/(SICI)1521-3773(19991018)38:20<3089::AID-ANIE3089>3.0.CO;2-W

Formation of the C11-C1' bond through application of Barton's radical decarboxylation and quinone addition is the cornerstone of a new convergent and concise synthesis of the marine metabolites avarol (1) and avarone (2; see scheme), for which antimitotic, antileukemic, and antiviral effects have been reported.

Full text of DOI:10.1002/(SICI)1521-3773(19991018)38:20<3089::AID-ANIE3089>3.0.CO;2-W

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5
0.6, 48.7, 46.6, 43.7, 38.9, 34.4, 33.0, 29.7, 26.7, 26.1, 25.4, 21.2, 17.3, 12.2, 9.6;
MS (CI, NH ) calcd for
): 356 [M‡1], 373 [M‡18]; HR-MS (CI, CH
[M‡H]: 355.2723, found: 355.2715.
Enantioselective Total Synthesis of Avarol and
Avarone**
3
4
20 4
C H37NO
Taotao Ling, Alan X. Xiang, and
Emmanuel A. Theodorakis*
Received: April 1, 1999 [Z13238IE]
German version: Angew. Chem. 1999, 111, 3274 ± 3277
In memory of Sir Derek H. R. Barton
Keywords: aldol reactions ´ antifungal agents ´ asymmetric
synthesis ´ macrocycles ´ total synthesis
Quinone and hydroquinone subunits are featured in a
variety of natural products,[ including a family of marine
1]
[
1] a) V. R. Hegde, M. G. Patel, V. P. Gullo, A. K. Ganguly, O. Sarre, M. S.
Puar, A. T. McPhail, J. Am. Chem. Soc. 1990, 112, 6403 ± 6405; b) V. R.
Hegde, M. G. Patel, V. P. Gullo, M. S. Puar, J. Chem. Soc. Chem.
Commun. 1991, 810 ± 812.
[2]
[2]
metabolites represented by avarol (1), avarone (2), ili-
[3]
[4]
maquinone (3), smenospongine (4), and mamanuthaqui-
none (5).[ Among the exciting and diverse biological proper-
ties exhibited by all members of this family, the antimitotic,
antileukemic, and antiviral effects reported for 1 and 2 are
5]
[
2] a) N. Naruse, O. Tenmyo, K. Kawano, K. Tomita, N. Ohgusa, T.
Miyaki, M. Konishi, T. Oki, J. Antibiot. 1991, 44, 733 ± 740; b) K.
Tomita, N. Oda, Y. Hoshino, N. Ohkusa, H. Chikazawa, J. Antibiot.
[6]
particularly noteworthy. Although the chemical origins of
1991, 44, 940 ± 948, and references therein.
[
[
3] H. Ui, M. Imoto, K. Umezawa, J. Antibiot. 1995, 48, 387 ± 390.
4] Apart from the substituents on the macrolactam ring, the congeners
differ in the aminosaccharide that is linked to the hydroxyl group:
Me
Me
Me
Me
Me
1
Sch 38516, Sch 39185, and fluvirucin A contain 3-amino-3,6-dideoxy-
a-l-talopyranose; Sch 38518 is a mycosamine glycoside; etc.[1, 2]
5] a) Antibiotics and Antiviral Compounds (Eds.: K. Krohn, H. A. Kirst,
H. Maag), VCH, Weinheim, 1993; b) M. Bartra, F. Urpí, J. Vilarrasa in
Recent Progress in the Chemical Synthesis of Antibiotics and Related
Microbial Products, Vol. 2 (Ed.: G. Lukacs), Springer, Berlin, 1993,
pp. 1 ± 65.
9
9
9
Me
Me
Me
[
H
H
H
Me
Me
O
Me
1
1
'
11
11
1
1'
1'
OH
O
HO
O
HO
O
OMe
[
6] a) A. F. Houri, Z. Xu, D. A. Cogan, A. H. Hoveyda, J. Am. Chem. Soc.
1
1
2
3
995, 117, 2943 ± 2944; b) Z. Xu, C. W. Johannes, A. F. Houri, D. S. La,
D. A. Cogan, G. E. Hofilena, A. H. Hoveyda, J. Am. Chem. Soc. 1997,
19, 10302 ± 10316.
7] B. M. Trost, M. A. Ceschi, B. König, Angew. Chem. 1997, 109, 1562 ±
564; Angew. Chem. Int. Ed. 1997, 36, 1486 ± 1489.
8] D. A. Evans, D. L. Rieger, T. K. Jones, S. W. Kaldor, J. Org. Chem.
990, 55, 6260 ± 6268.
Me Me
1
Me
H
[
[
[
6
5
10
1
8
9
9
Me
Me
H
Me
Me
11
11
1
1'
1'
HO
O
HO
O
9] The auxiliaries of Evans et al. do not work with nonactivated
substrates such as 9. The camphorsultam-derived auxiliary (W.
Oppolzer, Tetrahedron 1987, 43, 1969 ± 2004) afforded the desired
alkylation product in only 39% yield, and, moreover, cleavage of the
chiral auxiliary turned out to be troublesome.
O
NH2
O
OMe
4
5
[
10] A. G. Myers, B. H. Yang, H. Chen, L. McKinstry, D. J. Kopecky, J. L.
Gleason, J. Am. Chem. Soc. 1997, 119, 6496 ± 6511, and references
therein.
these biological properties remain obscure, the redox proper-
ties of the hydroquinone ± quinone system present in 1 and 2
may be held accountable for such a profile.[
The combination of attractive structure and biological
activity displayed by the above family has spurred the
[
11] For leading references on chiral boron enolates, see a) P. V. Ram-
achandran, W. Xu, H. C. Brown, Tetrahedron Lett. 1996, 37, 4911 ±
7]
4914; b) I. Paterson, K. R. Gibson, R. M. Oballa, Tetrahedron Lett.
1996, 37, 8584 ± 8588.
[
12] a) C. Gennari, C. T. Hewkin, F. Molinari, A. Bernardi, A. Comotti,
J. M. Goodman, I. Paterson, J. Org. Chem. 1992, 57, 5173 ± 5177; b) C.
Gennari, D. Moresca, S. Vieth, A. Vulpetti, Angew. Chem. 1993, 105,
development of multiple syntheses for some of these com-
[8, 9]
pounds.
A common element in all reported strategies is the
1
717 ± 1719; Angew. Chem. Int. Ed. 1993, 32, 1618 ± 1621; c) A.
Gonz a lez, J. Aiguad e , F. Urpí, J. Vilarrasa, Tetrahedron Lett. 1996, 37,
949 ± 8952.
early assembly of the entire skeleton of the natural products
8
[
13] The absolute configuration of 12 (and that of its epimer) was
[
*] Prof. Dr. E. A. Theodorakis, T. Ling, A. X. Xiang
Department of Chemistry and Biochemistry
University of California, San Diego
1
established by
H NMR spectroscopy (cf. W. R. Roush, T. D.
Bannister, M. D. Wendt, Tetrahedron Lett. 1993, 34, 8387 ± 8390) and
1
was confirmed by comparing the Dd( H) values of the diastereomeric
9
500 Gilman Drive #0358, La Jolla, CA 92093 ± 0358 (USA)
Mosher esters arising from (R)- and (S)-a-methoxy-a-(trifluorome-
thyl)phenylacetyl chloride (cf. I. Ohtani, T. Kusumi, Y. Kashman, H.
Kakisawa, J. Am. Chem. Soc. 1991, 113, 4092 ± 4096).
Fax: (‡1)858-822-0386
E-mail: etheodor@ucsd.edu
[
**] Dedicated with respect and appreciation to the memory of Professor
Sir Derek H. R. Barton. Financial support from the Cancer Research
Coordinating Committee, the American Cancer Society (RPG CDD-
[
14] For leading references on the preparation of thiopyridyl esters, see
a) T. Mukaiyama, R. Matsueda, M. Suzuki, Tetrahedron Lett. 1970, 1901±
1904; b) E. J. Corey, D. A. Clark, Tetrahedron Lett. 1979, 2875 ± 2878.
9
922901), the NSF (Shared Instrumentation Grant CHE-9709183),
[
15] For the reduction of azides with tin(ii) ± thiolate complexes, see a) M.
Bartra, F. Urpí, J. Vilarrasa, Tetrahedron Lett. 1987, 28, 5941 ± 5944;
b) M. Bartra, P. Romea, F. Urpí, J. Vilarrasa, Tetrahedron 1990, 46,
and the Hellman Foundation (Faculty Research Fellowship to E.A.T.)
is gratefully acknowledged. We also thank Professor D. John Faulkner
(
Scripps Insitute of Oceanography) for a sample of natural avarol and
5
87 ± 594.
16] a) D. H. R. Barton, S. W. McCombie, J. Chem. Soc. Perkin Trans. 1
975, 1574 ± 1585; b) H. Ishiwata, H. Sone, H. Kigoshi, K. Yamada,
Tetrahedron 1994, 50, 12853 ± 12882.
avarone and for critical suggestions.
[
1
Supporting information for this article is available on the WWW
under http://www.wiley-vch.de/home/angewandte/ or from the author.
Angew. Chem. Int. Ed. 1999, 38, No. 20
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
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COMMUNICATIONS
by constructing the C9�C11 bond. This is generally achieved
by allowing the C9 enolate (formed by in situ reduction of
enone 8, see Scheme 1) to react with a suitably substituted
benzyl bromide. While this regime has allowed the syn-
thesis of the natural products, it consistently suffers from low
yields during the final deprotection of the masked quinone.
In considering the above observations, we sought to
develop a method for constructing the entire framework by
forming the C11�C1' carbon ± carbon bond (Scheme 1). If
O
O
O
Me
Me
c) O3; LiAlH4
d) TIPSOTf
a) (CH2OH)2, H+
4
4
[
10]
8
b) Li, NH3,
H2C=CHCH2Br
O
O
e) Dess-
Martin
H
Me
Me
(55%)
(70%)
8
(>95% ee)
13
O
O
O
O
i) 0.1N HCl
j) [CH2=PPh3]
k) I2, ∆
Me
Me
g) H , Pd/C
2
4
h) TBAF•THF
8
8
Me
Me
X
Me
Me
H
H
(8:1 ratio at C8)
(95%)
Me
(
76%)
O
Me
Me
Me
H
OH
16
OTIPS
9
Me
14: X = O
15: X = CH2
H
f)
Me
O
1
1
9
S
N
O
Me
[
radical
addition
Me
Me
Me
Me
Me 11
Me
8
O
1
'
4
3
HS
8
8
l) Dess-Martin
O]
Me
Me
Me
Me
6
H
H
O N
m) NaH2PO4,
NaClO2
O
1
and 2
OH
OH
18
1'
(86%)
O
O
17
19
7
n) DCC
(91%)
Me
Me
H
Scheme 1. Strategy for the synthesis of avarol (1) and avarone (2).
Me
Me
9
Me
successful, this strategy could allow for the rapid construction
of several analogues of 1 and 2 differing only in the quinone
moiety, which could be used to address the significance of the
redox chemistry of these molecules during a biological event.
In addition, this strategy could circumvent the low-yielding
deprotection steps toward 1 or 2. To this end, application of
Bartonꢁs radical decarboxylation and quinone addition ap-
peared to be the best reaction candidate (Scheme 2).[
Me
9
1
1
'
o)
7
Me
Me
1
H
HO
S
N
1
1
hν
81%)
S
N
(
O
OH
O
20
7
6
Me
Me
11]
p) Raney Ni
84%)
q) MnO2
(97%)
9
Me
1
2
H
(
Me
O
1
1
'
1
S
N
21
O
Scheme 3. Synthesis of avarol (1) and avarone (2). a) (CH
2
OH)
2
Scheme 2. Use of Bartonꢁs radical decarboxylation and addition to
quinones for the synthesis of 12. py ˆ 2-pyridyl.
(1.0 equiv), TsOH (0.1 equiv), 808C, benzene, 12 h, 90%; b) Li (5.0 equiv),
NH
3
, � 80 ! � 308C, H
308C, 5 h, 78%; c) O
! 258C, 1 h, 65%; d) TIPSOTf (1.0 equiv), 2,6-lutidine (1.3 equiv),
Cl
, � 808C, 0.5 h, 98%; e) Dess ± Martin periodinane (1.6 equiv),
CH Cl , 1 h, 258C, 87%; f) CH PPh Br (3.0 equiv), NaHMDS (2.5 equiv),
2
O (1.0 equiv), CH
2
ˆ
CHCH Br (5.0 equiv), � 80 !
2
�
3
, CH Cl
2
2
, � 788C, then LiAlH
4 2
(3.0 equiv), Et O,
0
Conceptually, this reaction involves photochemical activation
of a thiohydroxamic ester 9 and in situ trapping of the
generated carbon-centered radical 10 with a quinone radi-
CH
2
2
2
2
3
3
THF, 658C, 10 h, 89%; g) Pd/C (10%, 0.1 equiv by weight), H
258C, 12 h, 95%; h) TBAF ´ THF (1n, 1.3 equiv), THF, 258C, 0.5 h, 100%;
i) 0.1n HCl, THF, 3 h, 258C, 93%; j) CH PPh Br (3.0 equiv), NaHMDS
2.5 equiv), THF, 658C, 10 h, 92%; k) I (0.01 equiv), xylenes, 1508C, 12 h,
9%; l) Dess ± Martin periodinane (1.2 equiv), CH Cl , 1 h, 258C, 96%;
m) NaClO2 (2.0 equiv), NaH PO4 (2.0 equiv), CH CHˆC(CH )
2 3 2
, CH CO Et,
[
12]
cophile (such as benzoquinone (7)). In accordance with a
radical chain mechanism, this conjugate-type addition was
expected to furnish initially the 1,2 substituted quinone 11,
which could rapidly tautomerize to hydroquinone 12. Further
manipulation of 12 could produce avarol (1) and avarone (2).
3
3
(
2
8
2
2
2
3
3 2
(
2.0 equiv), tBuOH/H
(1.0 equiv), DCC (1.0 equiv), CH
3.0 equiv), CH Cl , hn (300 W), 2 h, 08C, 81%; p) Raney nickel (excess),
CH Cl , 458C, 10 min, 84%; q) MnO (5.0 equiv), Et O, 258C, 0.5 h, 97%.
2
O (2/1), 258C, 1 h, 90%; n) 19 (1.0 equiv), 18
[
13]
2
Cl 12 h, 258C, dark, 91%; o) 7
2
,
Execution of this strategy is shown in Scheme 3.
(
2
2
Our synthetic approach began with optically pure enone 8,
which was readily available through an l-phenylalanine-
mediated asymmetric Robinson annulation (60 ± 65% yield,
2
2
2
2
DCC ˆ dicyclohexylcarbodiimide,
HMDS ˆ hexamethyldisilylamide,
TBAF ˆ tetrabutylammonium fluoride, TIPSOTf ˆ triisopropylsilyl tri-
fluoromethanesulfonate, TsOH ˆ p-toluenesulfonic acid.
[
14]
>
95% ee). Selective protection of the C4 ketone group
followed by reductive alkylation with allyl bromide afforded
ketone 13 in 70% overall yield. Transformation of alkene 13
to silyl ether 14 was accomplished in 64% combined yield by
ozonolysis, reduction, and silylation of the resulting alcohol.
The C8 ketone functionality that also suffered reduction
during the above procedure was subsequently restored upon
treatment with Dess ± Martin periodinane (87% yield). Ma-
nipulation of the C8 stereocenter was attained by Wittig
olefination of the C8 ketone followed by a Pd-catalyzed
3
090
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Angew. Chem. Int. Ed. 1999, 38, No. 20

COMMUNICATIONS
hydrogenation of the exocyclic methylene unit. This proce-
dure installed the methyl group at the C8 carbon atom in 85%
combined yield, as an unseparable mixture of stereoisomers
Keywords: natural products ´ quinones ´ radical reactions ´
synthetic methods ´ total synthesis
(
8:1 in favor of the desired b epimer). The stereoisomers were
easily separated after a fluoride-induced deprotection of the
primary silyl ether, and alcohol 16 was furnished in 75%
overall yield (starting from 14). Acid-catalyzed deprotection
of the C4 ketal of 16 followed by a second Wittig methyle-
nation provided the exo-alkene, which was isomerized to the
C3�C4 endocyclic olefin 17 upon treatment with iodine (76%
[1] Recent reviews: a) The Chemistry of the Quinonoid Compounds,
Vol. 1, 2 (Eds.: S. Patai, Z. Rappoport), Wiley, New York, 1988;
b) Naturally Occuring Quinones IV: Recent Advances (Ed.: R. H.
Thomson), 4th ed., Blackie Academic & Professional, London, 1997.
[2] a) L. Minale, R. Riccio, G. Sodano, Tetrahedron Lett. 1974, 3401 ±
3404; b) R. Puliti, S. De Rosa, C. A. Mattia, Acta Crystallogr. Sect. C
1
994, 50, 830 ± 833.
[
3] a) R. T. Luibrand, T. R. Erdman, J. J. Vollmer, P. J. Scheuer, J. Finer,
J. C. Clardy, Tetrahedron 1979, 35, 609 ± 612; b) R. J. Capon, J. K.
MacLeod, J. Org. Chem. 1987, 52, 5059 ± 5060.
yield over three steps).
The stage was now set for the attachment of the aromatic
residue on the avarol core. This was accomplished by a two-
step oxidation of primary alcohol 17 to carboxylic acid 18 with
Dess ± Martin periodinane and sodium chlorite (86% overall
yield). DCC-induced esterification of 18 with commercially
available 2-sulfanylpyridine N-oxide (19) furnished the pho-
[4] M. L. Kondracki, M. Guyot, Tetrahedron 1989, 45, 1995 ± 2004.
[5] J. C. Swersey, L. R. Barrows, C. M. Ireland, Tetrahedron Lett. 1991,
6
687 ± 6690.
[6] a) W. E. G. Müller, D. Sladic, R. K. Zahn, K. H. Bässler, N. Dogovic,
H. Gerner, M. J. Gasic, H. C. Schröder, Cancer Res. 1987, 47, 6565 ±
6
571; b) M. L. Ferrandiz, M. J. Sanz, G. Bustos, M. Paya, M. J. Alcaraz,
[
12]
tolabile ester 6 (91% yield). Light-induced decarboxylation
350 nm) of 6 in the presence of benzoquinone (7, 3.0 equiv)
S. de Rosa, Eur. J. Pharmacol. 1994, 253, 75 ± 82; c) S. Loya, A. Hizi,
FEBS Lett. 1990, 269, 131 ± 134; d) H. C. Schröder, M. E. Begin, R.
Klocking, E. Matthes, A. S. Sarma, M. Gasic, W. E. G. Müller, Virus
Res. 1991, 21, 213 ± 223.
(
produced the substituted quinone 21 in 81% yield. The
structure of 21 can be mechanistically rationalized by consid-
ering an initial formation of the hydroquinone adduct 20,
[7] M. A. Belisario, M. Maturo, R. Pecce, S. de Rosa, G. R. D. Villani,
Toxicology, 1992, 72, 221 ± 233.
[
12, 15, 16]
which is further oxidized in situ with excess 7.
An
[8] Three different syntheses of 1 and 2 have been reported to date:
a) A. S. Sarma, P. Chattopadhyay, J. Org. Chem. 1982, 47, 1727 ± 1731;
b) E. P. Locke, S. M. Hecht, Chem. Commun. 1996, 2717 ± 2718; c) J.
An, D. F. Wiemer, J. Org. Chem. 1996, 61, 8775 ± 8779.
additional remarkable feature of this radical addition is its
efficiency, especially when considering the presumed steric
hindrance of the intermediate neopentylic carbon-centered
radical at C11.
For the transformation of 21 to 1 a reductive desulfurization
procedure was sought. To this end, brief treament of 20 with
Raney nickel produced synthetic avarol (1) in high yield.
Avarone (2) was produced from 1 in 97% yield by hetero-
geneous oxidation with MnO2.
[
9] For syntheses of 3, see a) S. D. Bruner, H. S. Radeke, J. A. Tallarico,
M. L. Snapper, J. Org. Chem. 1995, 60, 1114 ± 1115; b) H. S. Radeke,
C. A. Digits, S. D. Bruner, M. L. Snapper, J. Org. Chem. 1997, 62,
2
823 ± 2831; c) S. Poigny, M. Guyot, M. Samadi, J. Org. Chem. 1998, 63,
5
890 ± 5894.
[
10] A noteworthy exception to this strategy is the exo-Diels ± Alder
approach employed to the synthesis of 5: T. Yoon, S. J. Danishefsky, S.
de Gala, Angew. Chem. 1994, 106, 923 ± 925; Angew. Chem. Int. Ed.
Engl. 1994, 33, 853 ± 855.
11] Selected reviews: a) D. Crich, Aldrichimica Acta 1987, 20, 35 ± 49; b) D.
Crich, L. Quintero, Chem. Rev. 1989, 89, 1413 ± 1432; c) D. H. R.
Barton, Tetrahedron 1992, 48, 2529 ± 2544.
In conclusion, we have developed an enantioselective
synthesis of avarol (1) and avarone (2) that departs from the
readily available Wieland ± Miesher-type enone 8 and pro-
[
[
17]
ceeds in 16 steps and 12% overall yield. Essential to our
strategy is the application of Bartonꢁs radical decarboxylation
and quinone addition reaction employed to install the
quinone nucleus during the last steps of the synthesis. Our
strategy provides the first application of the above method-
ology to natural products synthesis and clearly demonstrates
its power and versatility. Our strategy also paves the way for
the construction of designed analogues of 1 and/or 2 that
could be used to address biologically relevant issues.
[12] a) D. H. R. Barton, D. Bridon, S. Z. Zard, Tetrahedron 1987, 43, 5307 ±
314; b) D. H. R. Barton, W. Sas, Tetrahedron 1990, 46, 3419 ± 3430.
5
[
13] All new compounds exhibited satisfactory spectroscopic and analyt-
ical data (see the Supporting Information). Yields refer to spectro-
scopically and chromatographically homogeneous materials.
[14] H. Hagiwara, H. Uda, J. Org. Chem. 1988, 53, 2308 ± 2311.
[15] Alkyl-substituted quinones have lower oxidation potentials than the
nonsubstituted counterparts. See reference [1a] for more precise data.
[
16] Compound 20 was independently produced by reduction of 21 with
Na and was quantitatively reoxidized to 21 upon treatment with
2 2 4
S O
benzoquinone (7).
[
17] For a recent application of 8 to natural products synthesis, see A. X.
Xiang, D. A. Watson, T. Ling, E. A. Theodorakis, J. Org. Chem. 1998,
63, 6774 ± 6775.
Received: April 29, 1999 [Z13347IE]
German version: Angew. Chem. 1999, 111, 3277 ± 3279
Angew. Chem. Int. Ed. 1999, 38, No. 20
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1433-7851/99/3820-3091 $ 17.50+.50/0
3091