The absolute configuration of the pyrrolosesquiterpenoid glaciapyrrol A

Article abstract of DOI:10.1002/chem.201101139

The total syntheses of the structurally unique and moderately cytotoxic pyrrolosesquiterpenoid glaciapyrrol A that has been isolated from a marine streptomycete by Macherla et al.1 and of seven of its stereoisomers have been performed from geraniol or nerol, respectively, using a known diastereoselective Ru-catalysed approach for the synthesis of tetrahydrofurans previously reported by Stark and co-workers.5 Comparison of ¹H and ¹³C NMR data unambiguously clarified the relative configuration of natural glaciapyrrol A that was previously only partly solved from the available NMR data. An enantioselective synthesis was carried out resulting in the unnatural enantiomer (11S,12R,15R)-(-)-glaciapyrrol A. These data establish the absolute configuration of the natural product as (11R,12S,15S)-(+)-glaciapyrrol A.

Full text of DOI:10.1002/chem.201101139

DOI: 10.1002/chem.201101139
The Absolute Configuration of the Pyrrolosesquiterpenoid Glaciapyrrol A
Ramona Riclea and Jeroen S. Dickschat*[a]
Abstract: The total syntheses of the
structurally unique and moderately cy-
totoxic pyrrolosesquiterpenoid glacia-
pyrrol A that has been isolated from a
marine streptomycete by Macherla
et al.[1] and of seven of its stereoiso-
mers have been performed from gera-
drofurans previously reported by Stark
and co-workers.[5] Comparison of 1H
and 13C NMR data unambiguously
clarified the relative configuration of
natural glaciapyrrol A that was previ-
ously only partly solved from the
available NMR data. An enantio-
selective synthesis was carried out
resulting in the unnatural enantio-
mer (11S,12R,15R)-(À)-glaciapyrrol A.
These data establish the absolute con-
figuration of the natural product as
(11R,12S,15S)-(+)-glaciapyrrol A.
Keywords: biosynthesis · glaciapyr-
rol A · heterocycles · natural prod-
ucts · terpenes
niol or nerol, respectively, using
a
known diastereoselective Ru-catalysed
approach for the synthesis of tetrahy-
Introduction
11,12-epoxide function that is fused to a pyrrol ring, while
glaciapyrrol B is the formal hydrolysis product derived by
nucleophilic attack of water to the epoxide of glacia-
Glaciapyrrols A (1), B (2), and C (3) are a family of pyrrolo-
sesquiterpenoids that have been purified from culture ex-
tracts of a marine Streptomyces sp. (NPS008187) isolated
from a sediment collected in Alaska.[1] The structurally most
complex compound within this family, glaciapyrrol A, exhib-
its moderate cytotoxic activity towards different tumor cell
lines such as the colorectal adenocarcinoma HT-29 and the
melanoma B16-F10 (IC50 =180 mmolLÀ1). However, during
fermentation all three compounds are produced in low
amounts of only 0.05–0.2 mgLÀ1 preventing extensive testing
for activity towards a broader range of eukaryotic cell lines
or prokaryotes, respectively. Glaciapyrrol A has a unique
structure composed of a tetrahydrofuran moiety as part of
an unsaturated sesquiterpenoid carbon backbone with
7Z,9E double bond geometry that is attached to the C-2 of a
pyrrol ring. Although the purified compound was extensive-
ly investigated by one- and two-dimensional NMR spectro-
scopic methods and the relative configuration of the sub-
stituents at the tetrahydrofuran ring was analysed by nuclear
Overhauser enhanced differential spectroscopy (NOEDS),
the relative configuration at C-11 and the absolute configu-
ration have not been established. For the related compounds
glaciapyrrol B and C only the planar structures have been
described. Glaciapyrrol C is similarly composed of an unsa-
turated 7Z,9E sesquiterpenoid carbon backbone with an
AHCTUNGTRENNUNG
curring terpenoids, whereas only very few pyrroloterpenoids
are known.[2] One other example from this compound class
is pyrrolostatin (4) that is a lipoxigenase inhibitor produced
by Streptomyces chrestomyceticus.[3] Due to its bioactivity to-
wards cancer cell lines in combination with the low yields
obtained from culture extracts, the unique structure, the
only partially resolved relative configuration, and the un-
known absolute stereostructure, we aimed at a total synthe-
sis of all four diastereoisomers of glaciapyrrol A with differ-
ent relative configurations at C-11, C-12 and C-15. These
syntheses were carried out from geraniol or nerol, respec-
tively, and resulted in the unambiguous elucidation of the
complete relative configuration of the natural compound. A
subsequent enantioselective synthesis of the correct
diastereo
glaciapyrrol A and established its absolute configuration as
(11R,12S,15S)-(+)-1.
G
AHCTUNGTRENNUNG
[a] R. Riclea, Dr. J. S. Dickschat
Technische Universitꢀt Braunschweig
Institut fꢁr Organische Chemie, Hagenring 30
38106 Braunschweig (Germany)
Fax : (+49)531-3915272
E-mail: j.dickschat@tu-bs.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101139.
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FULL PAPER
Results and Discussion
Epoxidation of the 11E double bond of 7a by an epoxi-
dase may occur from either face of the prochiral olefine and
can result in the formation of 3a or its enantiomer. Ring
opening by the attack of water likely at the sterically less
hindered carbon catalysed by an epoxide hydrolase yields
2a. A second epoxidation step from 3a, possibly catalysed
by the same epoxidase, can in principal again occur from
both faces of the olefinic double bond. One possibility is ep-
oxidation to 10aa. The tetrahydrofuran moiety of 1 can be
formed in a cascade of nucleophilic epoxide ring openings
as is known from the biosynthesis of polyether antibiotics
such as monensin.[4] This mechanism generates glacia-
The biosynthesis of the glaciapyrrols has not been studied,
but the biosynthetic relationship between the three com-
pounds is obvious. Unless several possibilities for the exact
biosynthetic pathway may exist, as discussed below, these
considerations were initially taken into account to predict
the most likely relative configurations of the natural glacia-
pyrrols (Scheme 1). Sesquiterpenes are usually derived from
(2E,6E)-farnesyl diphosphate (FPP, 5a) that could be fused
to pyrrol or another 5-membered N-heterocyclic precursor
resulting in 6a or its equivalent, respectively. Oxidation of
the sesquiterpenoid chain at C-6 (following the numbering
of glaciapyrrol A), introduction of an additional olefinic
double bond at C-9, and E/Z isomerisation of the C-7
double bond could generate 7a. Alternatively, a pyrrol-2-
carboxylic acid derivative likely formed from proline, e. g.
its coenzyme A ester, may be used to acylate a sesquiterpe-
noid building block such as (2E,6E)-farnesol (8) by nucleo-
philic attack of a C=C bond. The additional carbon of the
sesquiterpenoid moiety in 9 may then be lost by oxidation
to the carboxylic acid and decarboxylation. Farnesol could
also first be oxidised to farnesic acid prior to acylation.
AHCTUNGTREGpNNUN yrrol A with a relative configuration of 1aa that contradicts
the published relative configuration of natural 1. In fact,
four logical combinations of steps with different stereochem-
ical courses ending up at four stereoisomers of glaciapyrro-
l A are possible (Scheme 2). Scheme 2A briefly summarises
the important steps in the formation of 1aa from (2E,6E)-
5a as discussed above. Starting from the same precursor
Scheme 1. Proposed biosynthetic pathways to the glaciapyrrols from
Scheme 2. Alternative pathways with different stereochemical courses re-
(2E,6E)-FPP.
sulting in four different stereoisomers of 1.
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J. S. Dickschat and R. Riclea
(2E,6E)-5a the two epoxidation steps can also proceed to
10ab that is the precursor for 1ab (Scheme 2B). This path-
way is in agreement with the published relative configura-
tion of 1. If the rather unusual linear precursor (2E,6Z)-5b
is used, the subsequent steps lead via epoxidations to 10ba,
the precursor of 1ba (Scheme 2C). This molecule again
matches the published relative configuration of natural 1.
Alternative epoxidations result in the fourth possible stereo-
isomer 1bb via 10bb, again in contradiction to the published
relative configuration of 1 (Scheme 2D).
In summary, these considerations demonstrate that the
most likely biosynthetic pathways to the glaciapyrrols start-
ing from (2E,6E)-FPP open up two different possibilities for
the relative configuration of 1, depending on the stereo-
chemical course of the epoxidation steps, that may either
match or mismatch the published relative configuration of
the natural product, whereas the rather unusual (2E,6Z)-
FPP precursor can provide two further stereoisomers by ste-
reochemically different epoxidations. Since the relative con-
figuration of 1 was not fully known and our biosynthetic
considerations did not allow for a reliable prediction all four
stereoisomers were synthesised to unambiguously assign the
structure of the natural product.
from two acyclic terpenoid (E)- and (Z)-diastereoisomers,
similar as discussed above for the biosynthetic pathways to
the four isomers of 1. In this sense the Ru-catalysed cyclisa-
tion can be regarded as biomimetic.
Building block B was synthesised from ethyl 3-methylbut-
2-enoate (11) by radical bromination with NBS and AIBN[6]
resulting in required (Z)- and (E)-ethyl 4-bromo-3-methyl-
but-2-enoate (12, Scheme 4). These diastereomers could be
separated by repetitive column chromatography on silica gel
yielding 47% of (Z)-12 and 39% of (E)-12. The configura-
tions of both products were unambiguously assigned by
NOEDS. The pure (Z)-12 was converted into the phospho-
nate ester 13 in an Arbusov reaction in refluxing triethyl
phosphite.[6]
Scheme 4. Synthesis of building block B for the synthesis of four stereo-
isomers of glaciapyrrol A (1). a) NBS, AIBN, CCl4, reflux/3 h, 47% (Z)-
12 and 39% (E)-12; b) PACTHNUTRGNE(UNG OEt)3, 1708C/15 min, 76% from pure (Z)-12.
The retrosynthetic analysis of all four stereoisomers of 1
is presented in Scheme 3. The pyrrole moiety can be intro-
duced by an acylation of N-metallated pyrrole (A). The E
selective Horner–Wadsworth–Emmons (HWE) reaction can
be used to build up the 7Z,9E dienone portion of 1. For the
HWE reaction a phosphonate ester is required that can be
synthesised by radical bromination of ethyl 3-methylbut-2-
enoate followed by Arbusov reaction (B). The bis-protected
diol-aldehyde (C) for the HWE reaction contains all three
stereocentres of 1. Stark and co-workers described a Ru-cat-
alysed method for the synthesis of tetrahydrofurans that can
be used for the preparation of all four diastereomeric alde-
hydes from geraniol or nerol, respectively.[5] It is intriguing
that these four isomers are chemically accessible starting
The further synthesis of glaciapyrrol A was performed as
outlined in Scheme 5. The reported Ru-catalysed oxidative
cyclisation[5] of geranyl benzoate in THF/CH2Cl2 (9:1) selec-
tively yielded 14bb, whereas the same reaction in THF/
CH2Cl2 (1:1) resulted in a mixture of 14bb and 14ba
(d.r. 1.5:1) that can be separated by column chromatogra-
phy. Starting from neryl benzoate, the same reaction in
THF/CH2Cl2 (9:1) yielded 14aa, or 14aa and 14ab
(d.r. 1:1.6) in THF/CH2Cl2 (1:1), i. e. all four diastereomers
of 14 for the synthesis of the targeted glaciapyrrol A stereo-
isomers are available from geraniol or nerol, respectively.
TBS protection with TBSOTf[7] gave the bis-TBS ethers 15
in high yields (91–94%). Removal of the benzoate moiety
was performed with EtMgBr[8] to release the primary alco-
hols 16 (82–97%) that were oxidised to the aldehydes 17
with PCC (81–100%). Horner–Wadsworth–Emmons reac-
tion with the phosphonate 13 resulted in the esters 18 with
high E selectivity for the newly formed olefinic bond, but a
configurational isomerisation of the second double bond
was observed resulting in the formation of (2Z,4E)- and
(2E,4E)-18 with 2Z/2E ratios between 1.4:1 and 1:1.7 and
high yields of 84–94% (sum of 2Z and 2E isomers). The
(2Z,4E)- and (2E,4E)-stereoisomers could be separated by
column chromatography in all four cases, and all eight ob-
tained esters were saponified with NaOH to yield the E/Z-
configurationally stable carboxylic acids 19 (88–100%).
Their transformation with 2,2’-dipyridyl disulfide and PPh3
into the S-(2-pyridyl)thioate esters followed by a reaction
with pyrrol-1-ylmagnesium chloride[9] gave the bis-TBS pro-
tected glaciapyrrols A (20) with partial Z/E isomerisation
during the reaction in all eight cases. From the four stereo-
isomers of (2Z)-19 the compounds 20 were obtained in 73–
99% yield with Z/E isomerisation of about 25–75% of the
Scheme 3. Retrosynthetic analysis of four stereoisomers of glaciapyrrol A
(1). PG=protecting group.
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The Absolute Configuration of Glaciapyrrol A
FULL PAPER
Table 1. Comparison of 13C NMR data from natural and synthetic glacia-
pyrrol A stereoisomers.
Carbon No.
1[a]
1aa[b]
1ab[b]
1ba[b]
1bb[b]
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
135.4
117.5
111.2
126.6
182.2
123.5
149.7
131.2
138.0
78.9
86.7
34.7
27.8
88.6
72.3
26.3
21.4
23.9
135.4
117.5
111.3
126.7
182.2
123.6
149.6
131.5
137.6
79.3
86.9
33.7
27.6
86.2
72.7
27.3
21.4
24.2
135.4
117.5
111.3
126.7
182.2
123.5
149.7
131.2
138.0
78.9
86.7
34.7
27.8
88.6
72.3
26.3
21.4
24.0
135.4
117.5
111.3
126.7
182.2
123.6
149.6
131.4
137.6
79.3
86.6
35.0
27.9
88.1
72.3
26.3
21.4
23.7
135.4
117.5
111.3
126.7
182.2
123.7
149.7
131.5
137.8
79.5
86.6
35.4
27.6
86.9
72.7
27.3
21.4
23.6
25.1
25.9
25.1
25.0
25.6
[a] Chemical shifts d in ppm in the 13C NMR spectrum of natural glacia-
pyrrol A measured in [2H4]methanol as reported by Macherla et al.[1]
[b] Chemical shifts d in ppm in the 13C NMR spectrum of the synthetic
diastereomers of glaciapyrrol A measured in [2H4]methanol. Values that
deviate more than Æ0.2 ppm from the respective chemical shift of natural
glaciapyrrol A are in italics.
eral signals in the 13C NMR spectra of 1aa (carbons 9, 10,
11, 13, 15, 16, 17, 19 and 20), 1ba (carbons 10, 11, 13 and
15), and 1bb (carbons 9, 11, 13, 15, 16, 17, 19 and 20) exhib-
ited mismatches, all signals in the 13C NMR spectrum of 1ab
matched the chemical shifts of natural glaciapyrrol A and
showed maximum deviations of Æ0.1 ppm. Furthermore, the
1H NMR data of compound 1ab were in complete agree-
ment with the data from natural 1, whereas fundamental dif-
1
Scheme 5. Synthesis of glaciapyrrol A stereoisomers. a) TBSOTf, NEt3,
CH2Cl2, 08C/2 h; b) EtMgBr, Et2O, 0 8C/10 min, then RT/1 h; c) PCC,
CH2Cl2, RT/12 h; d) LDA, THF, 13, À908C/1 h, then À908C to RT/12 h;
e) NaOH, EtOH/H2O (12:1), reflux/2 h; f) 2,2’-dipyridyl disulfide, PPh3,
toluene, 258C/24 h, then pyrrol-1-ylmagnesium chloride, À788C/2 h; g)
ZrCl4, MeCN, RT/4 h.
ferences occurred between the H NMR data of the other
synthetic stereoisomers of 1 and natural glaciapyrrol A (for
complete NMR data of the synthetic stereoisomers of 1 see
the Supporting Information). In conclusion, natural glacia-
pyrrol A is identical with 1ab and has a relative configura-
tion of (11S*,12R*,15R*)-1. Therefore, the reported relative
configuration of the substituents at the THF moiety[1] is cor-
rect, and the previously unknown relative configuration at
C-11 was elucidated by our synthetic approach.
starting material. Starting from (2E)-19 similarly high yields
(74–86%) were obtained, but significantly less isomerisation
occurred resulting in mixtures of (7Z)-20 and (7E)-20 with
diastereomeric ratios of 1:8.2 to 1:1.6. After chromatograph-
ic separation of the (7ZE)-stereoisomers of 20 all eight com-
Subsequently, an enantioselective synthesis of glacia-
AHCTUNGTREGpNNNU yrrol A was carried out for the elucidation of its absolute
configuration (Scheme 6). Geraniol was converted into the
epoxide (2R,3S)-21 (99% ee determined by GC-MS analysis
of the (R)-Mosher ester, see the Supporting Information) by
Sharpless asymmetric epoxidation using l-(+)-diisopropyl
tartrate.[11,12] The epoxide was transformed into the benzoate
ester 22 followed by treatment with AD-mix b and metha-
nesulfonamide directly resulting in the formation of
(2S,3R,6R)-14ab. Such transformations of 2,7-dien-1-ols by a
combination of Sharpless epoxidation and conversion into
tetrahydrofuran-diols under Sharpless dihydroxylation con-
ditions have previously only been applied in a few total syn-
theses of natural products: the terpenoid (+)-tuberine[13]
[10]
pounds were deprotected with ZrCl4 to yield the desired
glaciapyrrols A (1). These reactions proceeded in moderate
yields (24–52%) with partial 7Z/7E double bond isomerisa-
tion (d.r. varying from 1:3.1 to 2.5:1).
1
The H and 13C NMR data of all synthetic (7Z)-stereoiso-
mers of 1 were compared to the reported NMR data of nat-
ural glaciapyrrol A to elucidate its full relative structure.
The 13C NMR data for natural glaciapyrrol A[1] and of all
four synthetic stereoisomers are summarised in Table 1.
Chemical shifts that deviate more than Æ0.2 ppm were re-
garded as inconsistent and are shown in italics. Whereas sev-
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J. S. Dickschat and R. Riclea
The enantioselective synthesis of glaciaACTHNUTRGNEpNUG yrrol A was carried
out from geraniol using a sequence of Sharpless asymmetric
epoxidation and dihydroxylation. The synthetic compound
(À)-1ab was found to be the optical antipode of the natural
product establishing its structure as (11R,12S,15S)-1. Future
experiments in our laboratory include the synthesis and
structure elucidation of the glaciapyrrols B and C. The syn-
thesis of several new derivatives of glaciapyrrol A in which
the pyrrol moiety is exchanged against other carbo- or het-
erocycles, and the application of the synthetic compounds in
screening experiments for their bioactivity against a broad
range of prokaryotic and eukaryotic targets will be per-
formed.
Scheme 6. Enantioselective synthesis of ent-glaciapyrrol A. a) BzCl, pyri-
dine, RT/12 h; b) AD-mix b, MeSO2NH2, tBuOH/H2O/acetone (1:1:1),
RT/2 days.
Acknowledgements
and the annonaceous acetogenins (+)-parviflorin,[14] corosso-
lins[15] and murisolins.[16] The same procedure as described
above for the synthesis of racemic 1ab (Scheme 5) was used
to obtain (11S,12R,15R)-1ab with an optical rotary power of
[a]2D0 =À9.2Æ1.9 (c=1.0 in MeOH, N=12). Since for natu-
ral glaciapyrrol A an optical rotary power of [a]2D2 = +16.8
(c=0.02 in MeOH) was reported, the synthetic compound is
the opposite enantiomer establishing the absolute configura-
tion of the natural product as (11R,12S,15S)-1. The numeral
deviation of the optical rotary powers of the synthetic and
the natural compound may in part be attributed to a fast
6Z/6E isomerisation that started immediately after purifica-
tion of the 6Z isomer (a solution of the pure 6Z isomer in
methanol exhibited an E/Z isomerisation of approximately
10% of the material within 2 h determined by NMR spec-
troscopy). Since the conformationally stable 6E isomer has a
lower optical rotary power of [a]2D3 =À7.2Æ3.7 (c=0.7 in
MeOH, N=10), the isomerisation process results in an over-
all decrease of the optical activity of a solution of enantio-
pure 1.
This work was funded by the Deutsche Forschungsgemeinschaft (DFG)
with an Emmy Noether fellowship to JSD. We thank Prof. Dr. Stefan
Schulz for excellent support.
[1] V. R. Macherla, J. Liu, C. Bellows, S. Teisan, B. Nicholson, K. S.
Lam, B. C. M. Potts, J. Nat. Prod. 2005, 68, 780–783.
[2] Y. Liu, S. Zhang, P. J. M. Abreu, Nat. Prod. Rep. 2006, 23, 630–651.
[3] S. Kato, K. Shindo, H. Kawai, A. Odagawa, M. Matsuoka, J. Mochi-
zuki, J. Antibiot. 1993, 46, 892–899.
[4] A. R. Gallimore, C. B. W. Stark, A. Bhatt, B. M. Harvey, Y. Demyd-
chuk, V. Bolanos-Garcia, D. J. Fowler, J. Staunton, P. F. Leadlay,
J. B. Spencer, Chem. Biol. 2006, 13, 453–460.
[5] S. Roth, S. Gçhler, H. Cheng, C. B. W. Stark, Eur. J. Org. Chem.
2005, 4109–4118.
[6] E. G. Mata, E. J. Thomas, J. Chem. Soc. Perkin Trans. 1 1995, 785–
799.
[7] E. J. Corey, H. Cho, C. Rꢁcker, D. H. Hua, Tetrahedron Lett. 1981,
22, 3455–3458.
[8] Y. Watanabe, T. Fujimoto, S. Ozaki, J. Chem. Soc. Chem. Commun.
1992, 681–683.
[9] K. C. Nicolaou, D. A. Claremon, D. P. Papahatjis, Tetrahedron Lett.
1981, 22, 4647–4650.
[10] G. V. M. Sharma, B. Srinivas, P. Radha Krishna, Tetrahedron Lett.
2003, 44, 4689–4691.
[11] K. B. Sharpless, W. Amberg, Y. L. Bennani, G. A. Crispino, J. Har-
tung, K. S. Jeong, H. L. Kwong, K. Morikawa, Z. M. Wang, D. Xu,
X. L. Zhang, J. Org. Chem. 1992, 57, 2768–2771.
[12] Y. Gao, R. M. Hanson, J. M. Klunder, S. Y. Ko, H. Masamune, K. B.
Sharpless, J. Am. Chem. Soc. 1987, 109, 5765–5780.
[13] D. F. Taber, R. S. Bhamidipati, M. L. Thomas, J. Org. Chem. 1994,
59, 3442–3444.
[14] T. R. Hoye, Z. Ye, J. Am. Chem. Soc. 1996, 118, 1801–1802.
[15] H. Makabe, H. Tanimoto, A. Tanaka, T. Oritani, Heterocycles 1996,
43, 2229–2248.
Conclusion
The total synthesis of all four stereoisomers of the pyrrolo-
terpenoid glaciapyrrol A with respect to the three stereogen-
ic centres, that is, the compounds (7Z)-1aa, (7Z)-1ab, (7Z)-
1ba, and (7Z)-1bb, and of the respective four (7E)-diaste-
reomers was performed from geraniol or nerol, respectively,
using a known diastereoselective Ru-catalysed method for
the synthesis of tetrahydrofurans reported by Stark and co-
workers.[5] Comparison of NMR spectroscopic data of the
synthetic materials to the natural compound clearly estab-
lished the identity of glaciapyrrol A and synthetic (7Z)-1ab.
[16] Y. Hattori, Y. Kimura, A. Moroda, H. Konno, M. Abe, H. Miyoshi,
T. Goto, H. Makabe, Chem. Asian J. 2006, 1, 894–904.
Received: April 13, 2011
Published online: September 7, 2011
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Chem. Eur. J. 2011, 17, 11930 – 11934