A three-step entry to the aspirochlorine family of antifungal agents

Full text of DOI:10.1002/1521-3773(20001103)39:21<3866::AID-ANIE3866>3.0.CO;2-E

COMMUNICATIONS
lem, by a route quite different than that used in the previous
synthesis, arose from a provocative, albeit unsupported,
conjecture 9Scheme 1). The thought was that the ring-
enlarged dithio system present in 1 could arise from the
rearrangement[7] of a more typical type of EDKP precursor
A.[8] The electrophilic character that promotes rearrangement
to C might arise directly upon heterolysis of the leaving group
9OL) in A. Alternatively, loss of HOL from A might give rise
to quinomethide B, which could serve as the active electro-
A Three-Step Entry to the Aspirochlorine
Family of Antifungal Agents**
Zhicai Wu, Lawrence J. Williams, and
Samuel J. Danishefsky*
Dedicated to Professor Yoshito Kishi
Our laboratory has been studying a variety of natural
products containing diketopiperazines 9DKP) in the setting of
indole alkaloid structures.[1] It was in this context that
aspirochlorine 91), a bacterially derived metabolite isolated
from various Aspergillus species, first caught our attention.[2]
While initial reports on the biological properties of aspiro-
chlorine had not been particularly encouraging, a recent
disclosure from the Lepetit Research Center[3] indicated that
this compound is a rather selective and potent inhibitor of
fungal protein synthesis.
R1
OH
R1
O
O
N
O
N
R2
N
R2
N
O
S
S
O
LO
S
S
R
R
R
R
A
C
R1
R2
O
1
O
N
MeO
8 N
O
R1
O
O
1
HO
13
O O
R2
N
O
N
7
8
S
H
N
S
9
N
R
R
Cl
7
11
B
S
S
S
S
Scheme 1. Proposed sulfur rearrangement.
1
2
phile.[9] The ultimate hope in this case was that the sulfur
migration step, though in principle reversible, might be
followed by attack of the oxygen attached at position C91)
upon the now electrophilic C98) bridgehead, thereby giving
rise to the dihydrobenzofuran core of our target, C. While
direct rearrangement of A to C, or rearrangement of A to C
via B, implicitly raises issues of stereoselectivity at the
migration terminus C97), we postpone consideration of this
interesting question until the results of the research are
presented.
In addition to its increasingly attractive biological profile,
aspirochlorine exhibits several structural features of partic-
ular interest. The epidithiodiketopiperazine 9EDKP) moiety
2 is certainly well known in other natural products.[4] How-
ever, in the case of aspirochlorine one of the sulfur atoms is
anchored not to the piperazine, but to the C97) position of a
spiro-fused dihydrobenzofuran substructure. Moreover, the
two nitrogens of the DKP present novel structural character-
istics as well. One of these nitrogens, N913), bears a most
unusual N-methoxy substituent, which is rarely present in
DKP natural products. The other nitrogen atom is present in
the form of a free NH linkage bearing a geminal sulfur atom.
As such, there could well be concern over the possibility of a
low energy, but destabilizing, pathway leading to acyl iminium
character at C911).[5]
To evaluate the feasibility of such a functional group
reorganization in a model system, we synthesized the known
bicyclic thioacetal 3 9Scheme 2).[10] We were well aware of the
R
OTBS
Path II
a
O
N
H3C
S
N
H
OTBS
CHO
S
N
H3C
O
O
These structural complexities notwithstanding, a total syn-
thesis of aspirochlorine was accomplished by Williams and
Miknis.[6] Our interest in revisiting the aspirochlorine prob-
CH3
O
S
HO
S
N
CH3
H
4
R
Path I
5 (1:1)
3
[*] Prof. S. J. Danishefsky, Dr. L. J. Williams
Laboratory for Bioorganic Chemistry
Sloan ± Kettering Institute for Cancer Research
1275 York Avenue, New York, NY 10021 9USA)
Fax : 9‡1)212-772-8691
HO
Cl
MOMO
Cl
OH
OMOM
CHO
b
CHO
6
7
E-mail: s-danishefsky@ski.mskcc.org
Prof. S. J. Danishefsky, Dr. Z. Wu
Department of Chemistry, Columbia University
Havemeyer Hall, 3000 Broadway, New York, NY 10024 9USA)
MOMO
Cl
OMOM
O
N
H3C
c
N
3
CH3
S
7
O
[**] This work was supported by the National Institutes of Health 9grant
numbers: AI16943/CA28824/HL25848). L.J.W. gratefully acknowl-
edges the NIH for a Postdoctoral Fellowship Grant 9grant number:
NIHF32CA79120). Prof. Gerard Parkin and Mr. Brian M. Bridge-
water of Columbia University are gratefully acknowledged for the
X-ray analysis.
HO
S
R
R = C6H4OCH3
8 (1:1)
Scheme 2. Preparation of alcohols 5 and 8. Conditions: a) BuLi, THF, then
4, À788C, 40%; b) MOMCl, iPr2NEt, DMF, 08C !RT, 95%; c) BuLi,
THF, then 7, À788C, 67%. MOM ˆ methoxymethyl, TBS ˆ tert-butyldi-
methylsilyl, RTˆ room temperature.
Supporting information for this article is available on the WWW under
http://www.wiley-vch.de/home/angewandte/ or from the author.
3866
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1433-7851/00/3921-3866 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2000, 39, No. 21

COMMUNICATIONS
penetrating studies of Kishi and co-workers[11] which served to
demonstrate that, in a system of this sort, deprotonation of the
seemingly similar bridgehead protons may well occur with
high diastereotopic selectivity. Indeed, based on the prece-
dents of Kishi et al., it might be expected that deprotonation
would follow the course suggested by Path I in preference to
Path II. For our purposes it would be necessary to extend such
findings to aldol-like reactions of such anions.[12]
Accordingly, we wondered about base-induced condensa-
tion of 3 with substituted benzaldehydes, such as 4, with the
expectation of reaching precursors of type A. Indeed,
exposure of 3 to butyl lithium, at low temperature, followed
disulfide formation in a protected EDKP could be effected
from a p-methoxybenzylidene dithioacetal by oxidation of
one of the sulfur atoms to a sulfoxide. The conversion of a
non-EDKP thioacetal of type 9 however, was not precedent-
ed. Happily, the action of meta-chloroperoxybenzoic acid
followed by treatment of the monosulfoxide with perchloric
acid cleanly converted 9 into the corresponding disulfide 10.
It was important to test the applicability of this chemistry in
a more realistic scenario. Upon applying anhydrous acid
conditions to benzylic alcohols 8, the rearranged product 11
was obtained as a single diastereomer. Moreover, application
of the thioacetal deprotection sequence to produce 12 also
proceeded smoothly, to give an advanced model of the natural
product, which differs from aspirochlorine only in the
substituents on the nitrogen atoms.[15]
by addition of
4 gave the corresponding alcohols 5
9Scheme 2). In a similar vein, a more realistic aldehyde 7
was prepared by protection of 6[13] as the bis methoxymethyl
ether. The condensation procedure was then executed to
combine the anion of 3 with 7 and give the expected alcohols
8. In each of these cases, NMR analysis indicated the
formation of a two-component 91:1) mixture of products. At
the time, we could not be certain whether the components of
the mixture reflected stereochemical randomness in the
Clearly the stereochemical outcomes at position C97) in the
rearrangements are independent of the configurations at this
center in the starting alcohols 5 and 8 9Scheme 4). This finding
rules out obligatory inversion at the migration terminus in the
R1
R2
OH
R1
R2
O
H3C
O
O
13
N
À
deprotonation or in the C C bond formation process. None-
H3C
N
11
8
N
theless, we moved to the next phase of the synthesis.
CH3
N
O
S
CH3
7
9
H2O+
O
S
S
We chose to start with simple acidolysis of the benzylic
alcohol 9Scheme 3). Remarkably, the action of anhydrous
trifluoromethanesulfonic acid in acetonitrile on 5 furnished
S
R
R
5 or 8
13
R3
H3C
R1
R2
CH3
N
R1
R2
CH3
N
CH3
R1
R2
O
R1
R2
O
O
N
O
O
O
O
O
N
a
O
CH3
N
O
CH3
13
N
S
CH3
N
S
N
CH3
O
S
HO
S
S
S
S
S
R
R
R
R
15 (not observed)
5: R1 = R2 = H, R3 = OTBS
8: R1 = R3 = OMOM, R2 = Cl
9: R1 = R2 = H, 98%
11: R1 = OH, R2 = Cl, 61%
14
Scheme 4. Mechanistic rationalization of the stereoselective rearrange-
ment of 5 and 8.
CH3
N
R1
R2
O
O
CH3
N
R1
R2
rearrangement but does not go into the question of the
intermediacy of quinomethide 9see 13). We also note that the
preference for sulfur migration to the b-face[16] of position
C97) 9that is, syn to C99)) cannot easily be interpreted as a
consequence of least-motion considerations,[17] since the plane
containing the bridgehead carbons C98) and C911), as well as
the two sulfur atoms, appears to bisect the median plane of the
DKP ring. Hence, the observed stereospecificity reflects an
inherent preference of the sulfur to migrate syn to position
C99) rather than N913). A possible, though certainly unpro-
ven, interpretation is that in the operative b-face pathway
leading to 14, the sulfur atom can maintain a favorable long-
range interaction with the C99) carbonyl center.[18] By
contrast, movement from the a-face 9leading to unobserved
product 15) might incur relatively unfavorable electronic or
steric interactions with the N913) methyl function.[19] Thus, it
will be of interest, and of importance to the total synthesis, to
learn whether this face selectivity is responsive to the nature
of the substituent at position N913).[20]
O
O
O
CH3
N
S
O
b
CH3
N
S
S
S
R
10: R1 = R2 = H, 85%
12: R1 = OH, R2 = Cl, 75%
9: R1 = R2 = H
11: R1 = OH, R2 = Cl
R = C6H4OCH3
Scheme 3. Rearrangement of EDKPs 9 and 11. Conditions: a) CF3SO3H,
CH3CN, RT; b) mCPBA, CH2Cl2, 08C; then Me2S, then HClO4 in MeOH,
08C !RT. mCPBA ˆ meta-chloroperoxybenzoic acid.
exclusively a dehydration product as a single diastereomer
and in near quantitative yield. We concluded that 5 was
indeed a 1:1 mixture of hydroxy epimers. These had con-
verged to a single product by sulfur migration and associated
formation of the spiro linkage. That this product was in fact
the desired compound 9 with the relative stereochemistry
required for aspirochlorine was unequivocally established by
crystallographic analysis.[14]
Having effected the desired rearrangement there remained
the issue of removing the thioacetal and forming the disulfide
bridge, as it is present in the natural product. Following the
precedent of Kishi and co-workers[11] it might be expected that
In summary, we have demonstrated an unprecedented
sulfur migration in a protected EDKP. This rearrangement
occurs in a highly stereoselective manner and in high yield.
The amenability of this chemistry to produce structural
Angew. Chem. Int. Ed. 2000, 39, No. 21
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1433-7851/00/3921-3867 $ 17.50+.50/0
3867

COMMUNICATIONS
[15] Stereochemical assignments of compounds 11 and 12 were based upon
similarity of spectroscopic data in comparison to compounds 9 and 10,
respectively. See the Supporting Information.
diversity in a quest for superior antifungal agents is apparent
on inspection. Efforts to implement this rearrangement as a
key simplifying transformation in the total synthesis of the
fully elaborated aspirochlorine system will be reported in due
[16] We use the expression b-face migration as referring to establishment
À
of the S C97) bond syn to position C99) of the spiro diketopiperazine
course.
substructure.
[17] J. Hine, Adv. Phys. Org. Chem. 1977, 15, 1; see also: K. B. Carpenter, J.
Am. Chem. Soc. 1985, 107, 5730; R. H. Newman-Evans, R. J. Simon,
B. K. Carpenter, J. Org. Chem. 1990, 55, 695.
Received: July 4, 2000 [Z15385]
[18] A similar stabilizing interaction between a sulfur atom and a carbonyl
group was invoked in Ref. [11b].
[19] The arguments advanced above focus on the migrating sulfur atom
[1] Spirotryprostatin A: S. Edmondson, S. J. Danishefsky, L. Sepp-Lor-
enzino, N. Rosen, J. Am. Chem. Soc. 1999, 121, 2147; himastatin: T. M.
Kamenecka, S. J. Danishefsky, Angew. Chem. 1998, 110, 3166; Angew.
Chem. Int. Ed. 1998, 37, 2995; 5-N-acetylardeemin and amauromine:
K. M. Depew, S. P. Marsden, D. Zatorska, A. Zatorski, W. G.
Bornmann, S. J. Danishefsky, J. Am. Chem. Soc. 1999, 121, 11953;
gypsetin, deoxybrevianamide E, brevianamide E, and tryprostatin:
J. M. Schkeryantz, J. C. G. Woo, P. Siliphaivanh, K. M. Depew, S. J.
Danishefsky, J. Am. Chem. Soc. 1999, 121, 11964; spirotryprostatin B:
F. von Nussbaum, S. J. Danishefsky, Angew. Chem. 2000, 112, 2259;
Angew. Chem. Int. Ed. 2000, 39, 2175.
À
wherein the sense of rotation around the C97) C98) bond accom-
modates the preferred modality of sulfur migration. Alternatively, it
À
could be that a preferred sense to the C C rotation itself serves to
determine the face of the sulfur migration.
[20] We note that the observed rearrangement process is suggestive of a
possible biosynthesis of aspirochlorine.
[2] A. Kato, T. Saeki, S. Suzuki, K. Ando, G. Tamura, J. Antibiot. 1969, 22,
322; D. H. Berg, R. P. Massing, M. M. Hoehn, L. D. Boeck, R. L.
Hamill, J. Antibiot. 1976, 29, 394; K. Sakata, A. Masago, A. Sakurai, N.
Takahashi, Tetrahedron Lett. 1982, 23, 2095; K. Sakata, T. Kuwatsuka,
A. Sakurai, N. Takahashi, G. Tamura, Agric. Biol. Chem. 1983, 47,
2673; K. Sakata, M. Maruyama, J. Uzawa, A. Sakurai, H. S. M. Lu, J.
Clardy, Tetrahedron Lett. 1987, 28, 5607; for structurally related
gliovirin and FA-2097, see: R. D. Stipanovic, C. R. Howell,J. Antibiot.
1982, 35, 1326 9gliovirin); C. Miyamoto, K. Yokose, T. Furumai, H. B.
Maruyama, J. Antibiot. 1982, 35, 376 and K. Yokose, N. Nakayama, C.
Miyamoto, T. Furumai, H. B. Maruyama, R. D. Stipanovic, C. R.
Howell, J. Antibiot. 1984, 37, 6679FA-2097).
Ion-Specific Aggregation in Conjugated
Polymers: Highly Sensitive and Selective
Fluorescent Ion Chemosensors**
Jinsang Kim, D. Tyler McQuade, Sean K. McHugh, and
Timothy M. Swager*
[3] F. Moonti, F. Ripamonti, S. P. Hawser, I. Khalid, J. Antibiot. 1999, 52,
311.
Conjugated polymers are emerging as versatile elements
for the design of chemical sensors.[1, 2] An expansive range of
structures is known, and thus the facile tuning of properties by
modification of the polymer backbone or the introduction of
side groups is possible. A variety of transduction methods that
modify the emission and conductivity of a conjugated polymer
is available, these include photochemically induced electron
transfer, doping, conformational changes, and metal liga-
tion.[1±3] Interchain interactions play a decisive role in
controlling the conductive and emissive properties of con-
jugated polymers in the bulk material.[4] Nevertheless, no
sensory system which directly exploits interchain interactions
in conjugated polymers has been reported. Herein, we report
a new transduction mechanism based on the aggregation of
[4] A. W. Braithwaite, R. D. Eichner, P. Waring, A. Mullbacher, Mol.
Immunol. 1987, 24, 47; P. Waring, R. D. Eichner, A. Mullbacher, Med.
Res. Rev. 1988, 8, 499; R. D. Eichner, P. Waring, A. M. Geue, A. W.
Braithwaite, A. Mullbacher, Med. Res. Rev. 1988, 8, 499.
[5] H. Hiemstra, W. N. Speckamp in Comprehensive Organic Synthesis,
Vol. 2 9Eds: B. M. Trost, I. Fleming), Pergamon, Oxford, 1991,
pp. 1047± 1082; H. De Koning, W. N. Speckamp, Methods Org. Chem.
2Houben-Weyl) 4th ed., 1952 ± , Vol. E21, 1995, p. 1953; W. N.
Speckamp, M. J. Moolenaar, Tetrahedron 2000, 56, 3817.
[6] a) R. M. Williams, G. F. Miknis, Tetrahedron Lett. 1990, 30, 42997;
b) G. F. Miknis, R. M. Williams, J. Am. Chem. Soc. 1993, 115, 536.
[7] For recent examples of sulfanyl migrations, see: L. Djakovitch, J.
Eames, D. J. Fox, F. H. Sansbury, S. Warren, J. Chem. Soc. Perkin
Trans. 1 1999, 2771; J. Eames, S. Warren, J. Chem. Soc. Perkin Trans. 1
1999, 2783; J. Eames, D. J. Fox, M. A. D. L. Haras, S. Warren, J. Chem.
Soc. Perkin Trans. 1 2000, 1903; and references therein.
[8] At this stage we leave unspecified the nature of the R---R insert in
structures A ± C. The sulfur groups may be separated, directly
connected, or connected through a linker.
[*] Prof. T. M. Swager
[9] It is recognized that the species produced from protonation of the
ketonic oxygen of quinomethide B formally converges with the
product of A upon acid-induced heterolysis of OL.
[10] For the preparation of 3, see Ref. [11a], and references therein.
[11] a) Y. Kishi, T. Fukuyama, S. Natatsuka, J. Am. Chem. Soc. 1973, 95,
6490; b) T. Fukuyama, S. Natatsuka, Y. Kishi, Tetrahedron 1981, 37,
2045.
[12] Refs. [11a] and [11b] include the addition of nucleophiles derived
from 3 to primary halides and acid chlorides.
[13] Several preparations of 6 exist; see, for example, Ref. [6b], and
references therein.
[14] All new compounds display satisfactory spectroscopic and analytical
data consistent with the assigned structures. Crystallographic data
9excluding structure factors) for compound 9 reported in this paper
have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication no. CCDC-147018. Copies of the
data can be obtained free of charge on application to CCDC, 12 Union
Road, Cambridge CB21EZ, UK 9fax: 9‡44)1223-336-033; e-mail:
deposit@ccdc.cam.ac.uk).
Department of Chemistry and Center for Materials Science and
Engineering
Massachusetts Institute of Technology
Cambridge, MA 02139 9USA)
Fax : 9‡1)617-253-7929
E-mail: tswager@mit.edu
J. Kim
Department of Materials Science and Engineering
Department of Chemistry and Center for Materials Science and
Engineering
Dr. D. T. McQuade, S. K. McHugh
Department of Chemistry
[**] The authors thank the Office of Naval Research, the Defense
Advanced Research Projects Agency, and the Draper Laboratory
for generous financial support. D.T.M. thanks the National Institute of
Health for a post-doctoral fellowship through NIGMS.
Supporting information for this article is available on the WWW under
http://www.wiley-vch.de/home/angewandte/ or from the author.
3868
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1433-7851/00/3921-3868 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2000, 39, No. 21