Synthesis of bridged oxafenestranes from pleuromutilin

Article abstract of DOI:10.1002/anie.201404765

Fenestranes are an intriguing class of highly strained molecules possessing a quaternary carbon with bonds that deviate from the canonical tetrahedral geometry. Herein we report the discovery that the natural product pleuromutilin can be used as a structurally complex starting material for the synthesis of a series of bridged cis,cis,cis,cis-[4.5.5.5]- and cis,cis,cis,cis-[4.5.7.5] oxafenestranes through a carbocation rearrangement cascade. X-ray crystallographic analysis of several cis,cis,cis,cis-[4.5.5.5]oxafenestranes shows a significant planarization of the central tetracoordinate carbon atom and demonstrates the influence of bridgehead substituents and bridging rings on planarity.

Full text of DOI:10.1002/anie.201404765

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Angewandte
Communications
DOI: 10.1002/anie.201404765
Strained Polycycles
Synthesis of Bridged Oxafenestranes from Pleuromutilin**
Robert W. Hicklin, Tania L. Lꢀpez Silva, and Paul J. Hergenrother*
[
3a]
Abstract: Fenestranes are an intriguing class of highly strained
molecules possessing a quaternary carbon with bonds that
deviate from the canonical tetrahedral geometry. Herein we
report the discovery that the natural product pleuromutilin can
be used as a structurally complex starting material for the
synthesis of a series of bridged cis,cis,cis,cis-[4.5.5.5]- and
cis,cis,cis,cis-[4.5.7.5]oxafenestranes through a carbocation
rearrangement cascade. X-ray crystallographic analysis of
several cis,cis,cis,cis-[4.5.5.5]oxafenestranes shows a significant
planarization of the central tetracoordinate carbon atom and
demonstrates the influence of bridgehead substituents and
bridging rings on planarity.
bridgehead atoms.
The potential for creating molecules
with highly planarized tetracoordinate carbon atoms and the
discovery of the fenestrane natural products laurenene 2,
penifulvins A–E (e.g. 3), and asperaculin A 4 have made
fenestranes appealing synthetic targets. Thus, several note-
worthy methods have been developed for the synthesis of
fenestranes with a full-carbon scaffold and fenestranes
containing heteroatoms (oxafenestranes and azafenestra-
nes). However, the synthesis of chiral nonracemic
fenestranes remains challenging, and only a few oxafenes-
[4]
[
5]
[6]
[
7]
[
8]
[8c,d,9]
[8a,b,e]
tranes have been synthesized as single enantiomers
no enantioselective methods for the synthesis of full-carbon
fenestranes have been reported.
and
[3a]
T
he tetrahedral four-coordinate carbon is one of the
Natural products are abundant sources of molecular
complexity and are attractive starting points for the synthesis
of enantioenriched complex molecules. Medicinally impor-
[
1]
fundamental structural features of organic molecules, thus
compounds possessing such carbon atoms but with altered
[2]
[10]
geometries have long been of interest. Fenestranes are
a class of compounds designed to deviate from the tetrahedral
tant but low abundant natural products, including taxol,
[11]
[12]
doxorubicin, and artemisinin, are derived semisyntheti-
cally from more easily available natural product precursors.
Semisynthesis is also used to access natural product deriva-
tives with improved efficacy and pharmacokinetic compe-
tence (e.g. camptothecin to topotecan, erythromycin to
[
3]
geometry by planarization of a four-coordinate carbon. The
fenestrane scaffold consists of four rings fused about a central
quaternary carbon, whose planarization can be measured by
two opposing bond angles, a and b (1, Figure 1). The
magnitudes of a and b are dependent on the ring size and
the relative configuration and substitution pattern of the
[
13]
azithromycin, and pleuromutilin to retapamulin). Further-
more, readily available natural products have been employed
as complex starting materials in the synthesis of numerous
classes of natural products and commodity chemicals (adre-
[
14]
nosterone to ouabagenin,
dehydroepiandrosterone to
[
15]
[16]
cyclopamine, and sclareol to ambroxan).
Complex natural products also provide a useful template
for the synthesis of novel molecular scaffolds of biological and
[17]
theoretical interest.
We have reported a strategy for
creating structurally diverse collections of complex small
molecules from readily available natural products, called
[18]
complexity-to-diversity. The key feature of our approach is
the systematic utilization of ring distortion reactions (i.e. ring
expansion, contraction, cleavage, and rearrangement) to
dramatically alter natural product ring systems and create
compounds that are structurally distinct from each other and
the starting natural product. In addition to the utility of such
molecules in drug discovery, the strategic application of ring
distortion reactions to complex natural products can facilitate
the creation of compounds to investigate unusual structural
phenomena, such as the planarization of four-coordinate
carbon atoms.
Figure 1. The structures of cis,cis,cis,cis-[4.5.5.5]fenestrane 1, laurenene
2, penifulvin B 3, asperaculin A 4, pleuromutilin 5, and bridged
cis,cis,cis,cis-[4.5.5.5]oxafenestrane 6.
[*] R. W. Hicklin, T. L. Lꢀpez Silva, Prof. P. J. Hergenrother
Department of Chemistry
University of Illinois at Urbana-Champaign
Pleuromutilin 5 (Figure 1) is a diterpene natural product,
first isolated from C. passeckerianus, that exhibits potent
antibacterial activity by binding to the bacterial 50S ribo-
261 RAL, Box 36-5, 600 S. Mathews, Urbana, IL 61801 (USA)
E-mail: hergenro@illinois.edu
[
19]
some.
semisynthesis of the approved antibiotics retapamulin, tia-
Due to its use as the starting material for the
[
**] We are grateful to the University of Illinois at Urbana-Champaign for
support of this work. We would like to thank Dr. Danielle Gray and
Dr. Jeffrey Bertke for X-ray analysis.
[20]
mulin, and valnemulin,
large quantities of 5 are readily
available from several commercial sources. The core ring
system of 5 is composed of 5-, 6-, and 8- membered rings
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201404765.
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containing a common CÀC bond and bears eight stereogenic
centers (Figure 1). The advantageous arrangement of oxygen-
containing functional groups (ketone, alcohol, and ester) on
the congested core scaffold of 5 facilitates the creation of
highly strained ring systems in short synthetic sequences
through ring distortion. As part of our ongoing studies on 5,
we have developed a method for the preparation of a unique
class of bridged cis,cis,cis,cis-[4.5.5.5]oxafenestranes that con-
tain highly planarized four-coordinate carbon atoms (e.g. 6,
Figure 1).
with potassium hydroxide provides the desired rearrange-
ment precursor, 9 (Scheme 2). Exposure of 9 to phosphorus
pentachloride results in cyclopropane opening and rearrange-
ment to the bridged cis,cis,cis,cis-[4.5.5.5]oxafenestrane 6 in
51% yield as a single diastereomer and single enantiomer.
Fenestrane 6 is one of the few examples of a chiral non-
racemic oxafenestrane that has been synthesized and suggests
the potential of pleuromutilin as the starting point for the
preparation of enantioenriched fenestranes.
From the X-ray crystal structure of 6, the degree of
planarization about the central carbon was assessed based on
the bond angles a and b (Scheme 2). Since 6 crystallized as
a hydrogen-bonded dimer, the bond angles about the central
carbon for each molecule of the dimer were measured. The
observed bond angles of a = 124.18, b = 119.18 and a = 123.68,
b = 118.48 show significant planarization of the central carbon
and the values for a are larger than any previously reported
Previous studies have shown that the treatment of 5 with
phosphorus pentachloride results in a carbocation-mediated
ring contraction of the 8-membered ring to form diene 7
[
21]
(
Scheme 1). Inspired by this result, we investigated carbo-
[3a]
for a cis,cis,cis,cis-[4.5.5.5]fenestrane. The large value for
a is likely due to the presence of the bridging 7-membered
ring, as bridged [4.6.4.6]- and [5.5.5.5]fenestranes exhibit
[
7h,8c]
similar increases in planarization for one bond angle.
However, the degree of planarization found in 6 is less than
the planarization possible in fenestranes with trans-bridge-
[
23]
[24]
Scheme 1. Ring contraction of pleuromutilin (5) developed by Birch
et al.
head substituents, fenestranes with bridgehead olefins, or
[
21]
[7c]
fenestranes with smaller ring sizes.
The crystal structure of 6 also provides insight into the
possible mechanism of this reaction (Scheme 3), as an
inversion of configuration occurs at carbon atoms C5, C11,
and C14 during the course of the reaction. The inversion at
C11 is indicative of a cyclopropyl bond migration to displace
the activated alcohol (10). Due to the proximity of the C4À
cation rearrangements as a late-stage ring distortion strategy
for the modification of structurally diverse compounds
originating from 5. We identified cyclopropane 8 as an
enticing potential scaffold for carbocation rearrangement due
to the possibility of cyclopropane ring opening (Scheme 2).
Cyclopropane 8 is readily accessible from 5 in three steps
C14 bond to C11 and the inversion of configuration at C14, it
is likely that migration of the C4ÀC14 bond occurs first to
(
(
41% overall yield) through modified literature procedures
form a carbocation at C14 (11). The newly-formed six-
membered ring then undergoes a ring flip to orient the empty
C14 p-orbital so that the Si face overlaps with the C4ÀC5
[
21,22]
see the Supporting Information).
Saponification of 8
bond, leading to the observed configuration at C14 upon
migration of the C4ÀC5 bond to form a tertiary carbocation at
C5 (12).
The C5 carbocation is geometrically constrained to only
react with the ketone from the Si face to form oxocarbenium
1
3 (Scheme 3). Addition of water upon completion of the
reaction results in the formation of the product hemiketal 6.
However, if the reaction mixture is quenched by addition of
an alternative nucleophile such as methanol, ethanol, or even
morpholine, the respective ketal or aminal is formed (14–16).
This result provides strong evidence for the presence of
a stable oxocarbenium under the reaction conditions.
The influence of substituents on the planarization of the
central carbon atom was studied with crystalline derivatives
of 6 (Scheme 4). Treatment of 6 with tribromoethanol and p-
toluenesulfonic acid gives tribromoethyl ketal 17. X-ray
crystallographic analysis of 17 reveals central bond angles of
a = 125.48 and b = 119.28, demonstrating that ketal substitu-
ents have a substantial impact on the bond angle a and
increase the planarization of the central carbon. Attempts to
introduce bridgehead olefins through hemiketal dehydration
Scheme 2. Synthesis of bridged cis,cis,cis,cis-[4.5.5.5]oxafenestrane 6:
a) KOH, EtOH, reflux, 12 h (71%); b) PCl , CH Cl , 08C to rt, 1 h
5
2
2
(
51%). The X-ray crystal structure shows that 6 exists as a hydrogen-
were hindered by the tendency of 6 to undergo S 1 reactions.
For example, tertiary alcohols and hemiketals typically
bonded dimer in the solid state and exhibits central bond angles with
significant planarization.
N
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undergo E1 elimination upon exposure to Martinꢀs sulfu-
[
25]
rane. Treatment of 6 with Martinꢀs sulfurane results in the
formation of ketal 18, in spite of the poor nucleophilicity of
1
,1,1,3,3,3-hexafluoro-2-phenyl-2-propanol (Scheme 4). Ketal
1
8 is highly crystalline and provides insight into the effects of
bulky ketal substituents on planarization of the central
carbon. The crystal structure of 18 shows that significant
steric bulk on one face of the molecule forces the fenestrane
skeleton toward the opposite face, leading to a large increase
in a and a modest decrease in b.
Further ring distortion of 6 was performed to assess the
influence of ring size on planarization. Reduction of 6 with
sodium borohydride provides the broken fenestrane 19
(Scheme 5). Exposure of 19 to triphosgene results in cyclic
Scheme 3. Proposed mechanism for the formation of 6: Alcohol
activation and displacement affords the secondary carbocation 11,
which undergoes a 1,2-migration to form the tertiary carbocation 12.
The tertiary carbocation is trapped by the carbonyl group to form
oxocarbenium 13, which forms hemiketal 6 upon quenching with
water. Quenching the reaction with methanol, ethanol, or morpholine
leads to the corresponding ketal or aminal (14–16).
Scheme 5. Synthesis of bridged cis,cis,cis,cis-[4.5.7.5]oxafenestrane 20
from 6: a) NaBH , MeOH, THF, 08C to rt, 6 h (87%); b) triphosgene,
4
pyridine, CH Cl , 08C to rt, 1 h (96%).
2
2
carbonate formation to provide bridged cis,cis,cis,cis-
4.5.7.5]dioxafenestrane 20. To our knowledge, this is the
[
first report of a [4.5.7.5]fenestrane. The X-ray crystal struc-
ture of 20 demonstrates the effects of increasing ring size on
the geometry of the central carbon atom (Scheme 5). While
[
4.5.5.5]oxafenestranes, such as 6, exhibit a high degree of
planarization and large values of a and b, [4.5.7.5]dioxafe-
nestrane 20 shows only modest planarization of the central
carbon (a = 113.48 and b = 116.88). Instead, the greater
flexibility of the 7-membered ring enables 20 to exhibit
[9c]
scissor-type distortion, a type of distortion commonly found
in molecules containing small rings characterized by one
angle contracting from the tetrahedral geometry and the
opposite angle enlarging to compensate (demonstrated by the
large difference between angles g and d).
In conclusion, the ring distortion of natural products
provides an advantageous method for the efficient prepara-
tion of molecules to investigate unusual structural phenom-
ena. Synthetic modification of the readily available diterpene
natural product pleuromutilin (5) enabled the synthesis of the
Scheme 4. Crystalline ketal derivatives of 6: a) 2,2,2-tribromoethanol,
pTsOH, DMF, 08C to rt, 17 h (37%); b) Martin’s sulfurane, CH Cl ,
2
2
0
8C to rt, 1 h (70%).
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highly complex bridged cis,cis,cis,cis-[4.5.5.5]oxafenestrane 6
in five synthetic steps and 15% overall yield. The key step of
this sequence was a phosphorus pentachloride-mediated
carbocation rearrangement cascade to create the fenestrane
scaffold. The X-ray crystal structure of 6 shows a high degree
of planarization of the central four-coordinate carbon as
evidenced by the large magnitude of the central bond angles
a and b. The presence of the bridging 7-membered ring leads
to a disproportionate increase in the value for one of the
central bond angles (a). X-ray crystallographic analysis of
ketal derivatives of 6 shows that increased steric bulk at the
bridgehead positions results in further increases in the value
of a but exceedingly bulky ketal substituents can decrease the
magnitude of the opposite bond angle b. Ring expansion of
the hemiketal of 6 to a cyclic carbonate enabled the synthesis
of the bridged cis,cis,cis,cis-[4.5.7.5]dioxafenestrane 20, which
predominately exhibits scissor type distortion of the central
four-coordinate carbon. Natural products continue to be
a convenient source of structural complexity that can rapidly
be converted to very diverse compounds.
[8] a) T. Gaich, J. Mulzer, J. Am. Chem. Soc. 2008, 130, 452 – 453;
b) T. Gaich, J. Mulzer, Org. Lett. 2009, 11, 272 – 275; c) C. S.
Penkett, J. A. Woolford, I. J. Day, M. P. Coles, J. Am. Chem. Soc.
2
010, 132, 4 – 5; d) N. Heinrich, A. C. Willis, I. A. Cade, J. Ho,
M. L. Coote, M. G. Banwell, Chem. Eur. J. 2012, 18, 13585 –
3588; e) W. Chen, J.-H. Tay, J. Ying, X.-Q. Yu, L. Pu, J. Org.
1
Chem. 2013, 78, 2256 – 2265.
[9] a) S. E. Denmark, L. A. Kramps, J. I. Montgomery, Angew.
Chem. 2002, 114, 4296 – 4299; Angew. Chem. Int. Ed. 2002, 41,
4122 – 4125; b) S. E. Denmark, J. I. Montgomery, Angew. Chem.
2005, 117, 3798 – 3802; Angew. Chem. Int. Ed. 2005, 44, 3732 –
3736; c) S. E. Denmark, J. I. Montgomery, L. A. Kramps, J. Am.
Chem. Soc. 2006, 128, 11620 – 11630.
[
10] D. Frense, Appl. Microbiol. Biotechnol. 2007, 73, 1233 – 1240.
[11] F.-M. Arcamone in Analogue-Based Drug Discovery II, Wiley-
VCH, Weinheim, 2010, pp. 217 – 241.
[
12] C. J. Paddon, P. J. Westfall, D. J. Pitera, K. Benjamin, K. Fisher,
D. McPhee, M. D. Leavell, A. Tai, A. Main, D. Eng, D. R.
Polichuk, K. H. Teoh, D. W. Reed, T. Treynor, J. Lenihan, M.
Fleck, S. Bajad, G. Dang, D. Dengrove, D. Diola, G. Dorin, K. W.
Ellens, S. Fickes, J. Galazzo, S. P. Gaucher, T. Geistlinger, R.
Henry, M. Hepp, T. Horning, T. Iqbal, H. Jiang, L. Kizer, B. Lieu,
D. Melis, N. Moss, R. Regentin, S. Secrest, H. Tsuruta, R.
Vazquez, L. F. Westblade, L. Xu, M. Yu, Y. Zhang, L. Zhao, J.
Lievense, P. S. Covello, J. D. Keasling, K. K. Reiling, N. S.
Renninger, J. D. Newman, Nature 2013, 496, 528 – 532.
Received: April 28, 2014
Published online: July 17, 2014
[
[
13] D. J. Newman, G. M. Cragg, J. Nat. Prod. 2012, 75, 311 – 335.
14] H. Renata, Q. Zhou, P. S. Baran, Science 2013, 339, 59 – 63.
Keywords: fenestranes · natural products ·
planar tetracoordinate carbon atom · strained molecules
.
[15] A. Giannis, P. Heretsch, V. Sarli, A. Stçßel, Angew. Chem. 2009,
21, 8052 – 8055; Angew. Chem. Int. Ed. 2009, 48, 7911 – 7914.
1
[
16] K.-G. Fahlbusch, F.-J. Hammerschmidt, J. Panten, W. Pickenha-
gen, D. Schatkowski, K. Bauer, D. Garbe, H. Surburg, Ullmannꢁs
Encyclopedia of Industrial Chemistry, Wiley-VCH, Weinheim,
[
[
[
1] a) J. H. van ꢁt Hoff, Arch. Neerl. Sci. Exactes Nat. 1874, 9, 44;
b) J. A. Le Bel, Bul. Soc. Chim. Fr. 1874, 22, 337.
2] V. I. Minkin, R. M. Minyaev, R. Hoffmann, Russ. Chem. Rev.
2
000, pp. 143 – 144.
17] K. C. Morrison, P. J. Hergenrother, Nat. Prod. Rep. 2014, 31, 6 –
4.
[
[
2002, 71, 869 – 892.
1
3] For reviews see: a) A. Boudhar, M. Charpenay, G. Blond, J.
Suffert, Angew. Chem. 2013, 125, 13020 – 13032; Angew. Chem.
Int. Ed. 2013, 52, 12786 – 12798; b) R. Keese, Chem. Rev. 2006,
18] a) R. W. Huigens III, K. C. Morrison, R. W. Hicklin, T. A.
Flood, Jr., M. F. Richter, P. J. Hergenrother, Nat. Chem. 2013,
5, 195 – 202; b) R. J. Rafferty, R. W. Hicklin, K. A. Maloof, P. J.
106, 4787 – 4808; c) D. Kuck, Chem. Rev. 2006, 106, 4885 – 4925;
Hergenrother, Angew. Chem. 2014, 126, 224 – 228; Angew.
Chem. Int. Ed. 2014, 53, 220 – 224.
d) B. R. Venepalli, W. C. Agosta, Chem. Rev. 1987, 87, 399 – 410.
4] R. E. Corbett, D. R. Lauren, R. T. Weavers, J. Chem. Soc. Perkin
Trans. 1 1979, 1774 – 1790.
[
[
[
[
[
19] a) F. Kavanagh, A. Hervey, W. J. Robbins, Proc. Natl. Acad. Sci.
USA 1951, 48, 570 – 574; b) Y.-Z. Tang, Y.-H. Liu, J.-X. Chen,
Mini-Rev. Med. Chem. 2012, 12, 53 – 61.
5] S. H. Shim, J. B. Gloer, D. T. Wicklow, J. Nat. Prod. 2006, 69,
1
601 – 1605.
6] N. Ingavat, C. Mahidol, S. Ruchirawat, P. Kittakoop, J. Nat. Prod.
011, 74, 1650 – 1652.
7] a) V. Georgian, M. Saltzman, Tetrahedron Lett. 1972, 13, 4315 –
317; b) M. N. Deshpande, M. Jawdosiuk, G. Kubiak, M.
Venkatachalam, U. Weiss, J. M. Cook, J. Am. Chem. Soc. 1985,
07, 4786 – 4788; c) V. B. Rao, C. F. George, S. Wolff, W. C.
[
[
20] R. Novak, Ann. N. Y. Acad. Sci. 2011, 1241, 71 – 81.
21] A. J. Birch, C. W. Holzapfel, R. W. Rickards, Tetrahedron 1966,
2
2
2, 359 – 387.
22] a) H. Wang, Y. W. Andemichael, F. G. Vogt, J. Org. Chem. 2008,
3, 478 – 481; b) G. Brooks, W. Burgess, D. Colthurst, J. D. Hinks,
[
4
7
E. Hunt, M. J. Pearson, B. Shea, A. K. Takle, J. M. Wilson, G.
Woodnutt, Bioorg. Med. Chem. 2001, 9, 1221 – 1231.
1
Agosta, J. Am. Chem. Soc. 1985, 107, 5732 – 5739; d) P. A.
Wender, T. W. Von Geldern, B. H. Levine, J. Am. Chem. Soc.
[
[
23] M. Thommen, R. Keese, M. Fortsch, Acta Crystallogr. Sect. C
1996, 52, 2051 – 2053.
1988, 110, 4858 – 4860; e) M. Thommen, P. Gerber, R. Keese,
24] M. Charpenay, A. Boudhar, G. Blond, J. Suffert, Angew. Chem.
Chimia 1991, 45, 21 – 24; f) X. Fu, G. Kubiak, W. Zhang, W. Han,
A. K. Gupta, J. M. Cook, Tetrahedron 1993, 49, 1511 – 1524; g) J.
Wang, R. Guidetti-Grept, R. Keese, H. Stoeckli-Evans, Helv.
Chim. Acta 1997, 80, 1169 – 1175; h) C. Hulot, G. Blond, J.
Suffert, J. Am. Chem. Soc. 2008, 130, 5046 – 5047; i) M. Thom-
men, L. Prevot, M. K. Eberle, P. Bigler, R. Keese, Tetrahedron
2
012, 124, 4455 – 4458; Angew. Chem. Int. Ed. 2012, 51, 4379 –
4382.
[
25] a) Z. Wang in Comprehensive Organic Name Reactions and
Reagents, Wiley, Hoboken, 2010; b) A. G. Myers, M. Siu, F. Ren,
J. Am. Chem. Soc. 2002, 124, 4230 – 4232.
2011, 67, 3868 – 3873.
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