Total synthesis of (+)-pyrenolide D

Article abstract of DOI:10.1002/1521-3773(20010316)40:6<1128::AID-ANIE11280>3.0.CO;2-J

The direct stereoselective I¹¹¹-mediated ocidative ring contraction of a protected 6-deoxy-D-gulal substrate to form a highly functinalized tetrahydrofurfural intermediate is a key step in the first total synthesis of (+)-pyrenlide D (see scheme; R = TBS = tert-butyldimethylsilyl).

Full text of DOI:10.1002/1521-3773(20010316)40:6<1128::AID-ANIE11280>3.0.CO;2-J

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[26] K. Kawamura, M. Shang, O. Wiest, T. P. Fehlner, Inorg. Chem. 1998,
37, 608.
[27] G. E. Herberich in Comprehensive Organometallic Chemistry II,
Vol. 1 (Eds.: E. Abel, F. G. A. Stone, G. Wilkinson), Pergamon,
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[28] G. E. Herberich, B. Hessner, G. Huttner, L. Zsolnai, Angew. Chem.
1981, 93, 471; Angew. Chem. Int. Ed. Engl. 1981, 20, 472.
[29] E. D. Jemmis, A. C. Reddy, Organometallics 1988, 7, 1561.
[30] A. S. Weller, M. Shang, T. P. Fehlner, Chem. Commun. 1998, 1787.
struction of highly oxygenated tetrahydrofurans from glycal
starting materials is reported.
Initial retrosynthetic disconnection of 1 (Scheme 1) leads
back to a 2-alkoxyfuran 2 and the highly oxygenated
tetrahydrofurfural derivative 3 as viable synthetic precursors.
Scheme 1. Retrosynthetic analysis.
Although a number of synthetic strategies to prepare 3 can be
envisioned through the synthesis and cyclization of acyclic
polyol precursors, we reasoned that a more efficient approach
might arise from a stereoselective oxidative ring contraction
of a glycal substrate such as 6-deoxy-d-gulal (4), incorporating
three of the four stereocenters within 3. For such an oxidative
ring contraction process to be feasible, an appropriate
electrophilic oxidant 6 (Scheme 2) is required. Not only must
Total Synthesis of (‡)-Pyrenolide D**
Kenneth M. Engstrom, Mario R. Mendoza,
Mauricio Navarro-Villalobos, and David Y. Gin*
The phytogenic fungus Pyrenophora teres has been a source
of a number of fungal metabolites of interesting and varying
biological activities. These metabolites include the pyrenoli-
des A ± C,[1] simple macrocyclic lactones that exhibit potent
Scheme 2. Oxidative ring contraction of glycals.
this reagent efficiently perform an electrophilic activation of
the glycal substrate (5 !7), but it must also concomitantly
install a potent leaving group at the C2 position of the
activated pyranoside intermediate 7. This would hopefully
allow 1,2-migration of the endocyclic C O bond in a displace-
ment of the C2 leaving group, resulting in a net oxidative ring
contraction of the glycal substrate to form the C-furanoside
product 8, an intermediate that directly maps onto the
proposed synthetic intermediate 3 (Scheme 1). Given our
interest in glycal activation processes,[4] we sought to establish
the means to effect the conversion of 5 into 8 as one of the key
steps in the synthesis of 1.
Based on this strategy, the initial synthetic target involved
the preparation of 2,3-di-O-protected-6-deoxy-d-gulal (4) as
the desired substrate for the formation of the C-furanoside 3.
The synthesis commenced (Scheme 3) with the preparation of
the pseudoglycal 10 from commercially available tri-O-acetyl-
d-galactal (9) through a three-step sequence that included:
SnCl4-catalyzed Ferrier-type glycosylation of thiophenol
(84%), acetate hydrolysis and selective tosylation of the C6-
hydroxy group (78%), and hydride displacement of the C6-
sulfonate functionality (86%).[5] Subsequent oxidation of the
allylic sulfide in 10 with m-chloroperoxybenzoic acid led to
the formation of the corresponding anomeric sulfoxide, which
underwent an Evans ± Mislow [2,3]-sigmatropic rearrange-
ment. Subsequent aminolysis of the sulfenate functionality
installed the a-C3-OH group (89%).[6] The resulting 6-deoxy-
d-gulal diol 11 was protected as the bis(tert-butyldimethylsil-
growth-inhibitory and morphogenic activities toward fungi. A
fourth metabolite, pyrenolide D (1),[2] is structurally distinct
from the other members of this family in that it incorporates a
highly oxygenated tricyclic spiro-g-lactone structure related
to certain members of the cephalosporolide class of natural
products.[3] Moreover, pyrenolide D is further distinguished
from the other pyrenolides in that it is not active toward fungi,
but rather that it exhibits significant cytotoxic activity toward
HL-60 cells. This biological profile, in combination with its
densely functionalized polycyclic structure, spawned our
efforts to develop a synthetic approach to 1 that would also
establish the absolute configuration of the natural product.
We report herein the first total synthesis of 1 by a very short
sequence. In this context, a method for the efficient con-
[*] Prof. D. Y. Gin, K. M. Engstrom, M. R. Mendoza,
Dr. M. Navarro-Villalobos
Department of Chemistry, University of Illinois
Urbana, IL 61801 (USA)
Fax : (‡1)217-244-8024
E-mail: gin@scs.uiuc.edu
[**] This research was supported by the National Institutes of Health,
Glaxo Wellcome Inc., the Alfred P. Sloan Foundation, and the Arnold
and Mabel Beckman Foundation.
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
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Scheme 3. a) PhSH, SnCl4 (cat.), CH2Cl2,
108C, 84%; b) NaOMe,
MeOH, 238C; Bu2SnO, MeOH, reflux; p-toluenesulfonyl chloride,
Bu4NBr, CHCl3, 78%; c) LiAlH4, THF, reflux, 86%; d) m-CPBA, CH2Cl2,
408C; Et2NH, THF, 238C, 89%; e) tert-butyldimethylsilyl trifluorome-
thane sulfonate, 2,4,6-(tri-tert-butylpyridine, DMF, 238C, 76%; TBS ˆ tert-
butyldimethylsilyl.
yl) ether to afford 12 (76%), the desired glycal precursor for
stereoselective oxidative ring contraction.
Reports on the direct oxidative ring contraction of glycals
have been scarce,[7] with only a few examples of this process
proceeding efficiently with stoichiometric quantities of
Tl(NO3)3 as the oxidant. To avoid the use of highly toxic
heavy metal salt oxidants, we focused on the use of hyper-
valent iodine reagents[8] (i.e., Scheme 2, 6, X ˆ PhI) to execute
this transformation. Studies involving the reaction of hyper-
valent iodine reagents with glycal substrates have also been
limited, except for the pioneering work of Kirschning who
employed various IIII reagents to effect efficient allylic 3-O-
oxidations of protected glycals.[9] In their allylic oxidation
studies, a few examples were reported in which the action of
the Koser reagent (PhI(OH)(OTs)) on a glycal substrate led
not only to allylic oxidation, but also to the formation of small
quantities of tetrahydrofuran by-products (ꢀ35%).[10] Thus,
the key challenges in employing IIII reagents for glycal
oxidative ring contraction in the context of the synthesis of
1 include: 1) the development of a reagent combination that
would favor the ring contraction of 12 over the reaction
manifold involving C3 oxidation, and 2) the generation of the
corresponding C-furanoside 3, in which the resulting C1-
acetal functionality is cis to the C3 O-substituent, with high
stereoselectivity.
Scheme 4. Oxidative ring contraction.
tion,[13] the half-chair conformational states are dynamic, and
it is likely that the observed stereoselective formation of 15a
in the ring contraction arises from glycal activation via its 5H4
conformation (i.e., Curtin ± Hammett situation, Scheme 4). In
this hypothesis, the favored approach of the IIII oxidant should
occur on the a-face (12 !13), an approach that would not
only avoid steric interactions with the C6-methyl group, but
would also lead to a chairlike transition state in the activation
step to form 13.[14] Following a conformational chair flip
(13 !14) that orients the migrating C1 O bond antiperipla-
nar to the equatorial C2 I bond, ring contraction would ensue
by means of the displacement of iodobenzene with inversion
to provide 15a as the major diastereomer. Conversely, b-
approach of the oxidant onto 12 (4H5) would also result in a
chairlike transition structure; however, a higher energy
transition structure might result as a consequence of a
developing syn-pentane-like (i.e., 1,3-diaxial) interaction
between the C4 O TBS group and the C2 IIII substituent.
Following a conformational chair flip (16 !17), ring contrac-
tion would lead to the minor diastereomer 15b.[15, 16]
With an efficient synthetic route to the C-furanoside 15a,
introduction of the butenolide fragment and formation of the
spiroketal functionality comprised the remaining steps in the
synthesis of 1 (Scheme 5). The dimethyl acetal functionality in
the a-epimer of 15 was hydrolyzed in the presence of TiCl4 at
08C. This mild deprotection protocol afforded the tetrahy-
drofurfural intermediate 18 (88%) without epimerization of
the C2 stereocenter and with the TBS protecting groups
intact. Addition of commercially available 2-(trimethylsilyl-
oxy)furan to the aldehyde 18 in the presence of BF3 ´ OEt2
at 788C afforded a diastereomeric mixture of alcohols
After screening a number of hypervalent iodine reagents,
we converted the 6-deoxy-d-gulal derivative 12 into the
corresponding C-furanoside 15 (Scheme 4) in high yield
(88%) by using the reagent combination of iodosylbenzene
and trifluoromethane sulfonic (triflic) anhydride (Tf2O) in a
solution of methanol and dichloromethane. In this reaction,
dimethoxyiodosylbenzene[11] and triflic acid are presumably
generated as the active reagents in situ under anhydrous
conditions. The presence of triflic acid is required for efficient
ring contraction; the incorporation of an acid scavenger such
as 2,4,6-tri-tert-butylpyridine rendered the reagent combina-
tion unreactive towards 12.[12] Moreover, the oxidative ring
contraction proceeds with good stereoselectivity, yielding a
5:1 mixture of 15 in favor of the desired a-epimer (Scheme 4).
Although 1H NMR spectroscopic analysis of the 6-deoxygulal
4
substrate 12 suggests that it approximates the H5 conforma-
Angew. Chem. Int. Ed. 2001, 40, No. 6
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[4] a) V. Di Bussolo, Y.-J. Kim, D. Y. Gin, J. Am. Chem. Soc. 1998, 120,
13515 ± 13516; b) V. DiBussolo, J. Liu, L. G. Huffman, Jr., D. Y. Gin,
Angew. Chem. 2000, 112, 210 ± 213; Angew. Chem. Int. Ed. 2000, 39,
204 ± 207; c) J.-Y. Kim, V. Di Bussolo, D. Y. Gin, Org. Lett. 2001, 3,
303 ± 306.
[5] R. L. Halcomb, S. H. Boyer, M. D. Wittman, S. H. Olson, D. J.
Denhart, K. K. C. Liu, S. J. Danishefsky, J. Am. Chem. Soc. 1995,
117, 5720 ± 5749.
[6] a) P. Bickart, F. W. Carson, J. Jacobus, E. G. Miller, K. Mislow, J. Am.
Chem. Soc. 1968, 90, 4869 ± 4876; b) D. A. Evans, G. C. Andrews, Acc.
Chem. Res. 1974, 7, 147 ± 154.
[7] a) A. Kaye, S. Neidle, C. B. Reese, Tetrahedron Lett. 1988, 29, 1841 ±
1844; b) E. Bettelli, P. DꢁAndrea, S. Mascanzoni, P. Passacantilli, G.
Piancatelli, Carbohydr. Res. 1998, 306, 221 ± 230.
[8] a) A. Varvoglis, The Organic Chemistry of Polycoordinated Iodine,
VCH, New York, 1992; b) R. M. Moriarity, O. Prakash, Org. React.
1999, 54, 273 ± 418.
[9] A. Kirschning, Eur. J. Org. Chem. 1998, 2267 ± 2274.
[10] A. Kirschning, Liebigs Ann. 1995, 2053 ± 2056.
[11] R. M. Moriarty, O. Prakash, M. P. Duncan, R. K. Vaid, N. Rani, J.
Chem. Res. Synop. 1996, 432 ± 433.
[12] It is likely that the triflic acid serves to activate the PhI(OMe)2 reagent
generated in situ.
Scheme 5. a) TiCl4, Et2O, 0 8C, 88%; b) 2-(trimethylsilyloxy)furan, BF3 ´
OEt2, CH2Cl2, 788C; c) Burgess reagent, PhH, 558C, 80% (two steps);
[13] 1H NMR analysis shows a relatively small H3 H4 proton coupling
constant (J3,4 ˆ 2.8 Hz). This is consistent with previous observations
in other pyranosides incorporating vicinal tert-butyldimethylsilyl
ethers in which gauche interactions between the bulky protective
groups are minimized. See, for example: a) M. A. Tius, J. Busch-
Peterson, Tetrahedron Lett. 1994, 35, 5181 ± 5184; b) W. A. Roush,
C. E. Bennett, J. Am. Chem. Soc. 1999, 121, 3541 ± 3542.
[14] This rationale assumes, among other things, that the activation of gulal
12 proceeds irreversibly through a relatively late (i.e., C2-pyramidal-
ized) transition state. For some discussions on the conformational
flexibility of glycals, see: a) J. Thiem, P. Ossowski, J. Carbohydr. Chem.
1984, 3, 287 ± 313; b) W. R. Roush, D. P. Sebesta, C. E. Bennett,
Tetrahedron 1997, 53, 8825 ± 8836.
d) 1n LiOHaq, 238C; 16% HFaq, 238C, 93% (1:1.4, 1/21); e) 8n HClaq
THF, 238C, quant.
,
19, which was directly treated with the Burgess dehydrating
agent (MeO2CNSO2NEt3) to afford the unsaturated g-lactone
20 (80%, two steps) as a mixture of stereoisomers (2:1, E/Z).
Formation of the spiroketal functionality and completion of
the synthesis proceeded in a two-step, one-pot transformation
from 20, involving initial hydrolysis of the lactone (1n
LiOHaq), followed by acid-mediated (HFaq) TBS-deprotection
and spiroketalization to form a diastereomeric mixture of
pyrenolide D (1) and its spiroketal epimer 21 in a 1:1.4 ratio
(93% total). Although the thermodynamic distribution of 1
and 21 exhibits essentially no selectivity, separation of the
epimers by chromatography is trivial, allowing the quantita-
tive iterative re-equilibration of 21 (8n HClaq, THF) to
enhance the production of the natural product 1. The spectral
data (1H and 13C NMR, FTIR) of synthetic 1 derived from tri-
O-acetyl-d-galactal coincide with those reported by Nukina
and Hirota ([a]2D3 ˆ ‡64.3 (c ˆ 0.4, CHCl3), lit.: [a]2D3 ˆ ‡79.5
(c ˆ 0.9, CHCl3)).
[15] The employment of the tert-butyldimethylsilyl protecting groups was
crucial in achieving the desired stereoselectivity. The use of dibenzyl-
d-gulal with the identical oxidative ring contraction procedure led to
indiscriminate facial approach of the IIII reagent, affording a 1:1 (a/b)
mixture of the corresponding tetrahydrofurfural acetals in 82% yield.
[16] Formation of the minor diastereomer 15b might also arise from the b-
approach of the oxidant onto 12 (5H4), leading to a higher energy
twist-boatlike transition state. Following a conformational half-chair
flip, ring contraction would lead to the minor diastereomer 15b.
In summary, the first synthesis of pyrenolide D (1) is
described, involving a short sequence beginning with tri-O-
acetyl-d-galactal. A key feature in the synthesis includes the
efficient formation of highly functionalized tetrahydrofurfural
intermediates directly from glycal substrates, by employing
the reagent combination of iodosylbenzene and triflic anhy-
dride in a mixture of methanol and dichloromethane. Not only
did this process lead to the efficient synthesis and absolute
stereochemical assignment of 1, but it also highlights this
oxidative ring contraction strategy as one that holds promise
in both natural product and C-nucleoside synthesis.
Crown-Ether-Directed Assembly of Discrete
and One-Dimensional Silver Aggregates
Containing Embedded Acetylenediide**
Quan-Ming Wang and Thomas C. W. Mak*
In memory of Daniel Y. Chang
Recent studies have shown that the coordination modes of
2
the acetylide dianion (C2 , IUPAC name acetylenediide) can
be classified into three categories: 1) linear end-to-end
[*] Prof. T. C. W. Mak, Q.-M. Wang
Department of Chemistry
Received: November 30, 2000 [Z16202]
The Chinese University of Hong Kong
Shatin, New Territories, Hong Kong SAR (PR China)
Fax : (‡852)26035057
[1] M. Nukina, M. Ikeda, T. Sassa, Agric. Biol. Chem. 1980, 44, 2761 ±
2762.
[2] M. Nukina, H. Hirota, Biosci. Biotechnol. Biochem. 1992, 56, 1158 ±
1159.
E-mail: tcwmak@cuhk.edu.hk
[**] Financial support from the Hong Kong Research Grants Council
Earmarked Grant (CUHK 4268/00P) is gratefully acknowledged.
[3] M. J. Ackland, J. R. Hanson, P. B. Hitchcock, A. H. Ratcliffe, J. Chem.
Soc. Perkin Trans. 1 1985, 843 ± 847.
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