Stereochemical Determination of Tuscolid/Tuscorons and Total Synthesis of Tuscoron D and E: Insights into the Tuscolid/Tuscoron Rearrangement

Article abstract of DOI:10.1002/anie.201906166

The stereochemistry of the structurally unique myxobacterial polyketides tuscolid/tuscorons was determined by a combination of high-field NMR studies, molecular modeling, and chemical derivatization and confirmed by a modular total synthesis of tuscorons D and E. Together with the discovery of three novel tuscorons, this study provides detailed insight into the chemically unprecedented tuscolid/tuscoron rearrangement cascade.

Full text of DOI:10.1002/anie.201906166

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Stereochemical Determination of Tuscolid/Tuscorons and Total
Synthesis of Tuscoron D and E: Insights into the Tuscolid/
Tuscoron Rearrangement
Authors: Björn Göricke, Michelle Fernandez Bieber, Kathrin E. Mohr,
and Dirk Menche
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201906166
Angew. Chem. 10.1002/ange.201906166
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10.1002/anie.201906166
Angewandte Chemie International Edition
COMMUNICATION
Stereochemical Determination of Tuscolid/Tuscorons and Total
Synthesis of Tuscoron D and E: Insights into the
Tuscolid/Tuscoron Rearrangement
Björn Göricke,[a,c] Michelle Fernandez Bieber,[a,c,d] Kathrin E. Mohr,[b] and Dirk Menche*[a]
Abstract: The stereochemistry of the structurally unique
HO2C
*
*
1
myxobacterial polyketides tuscolid/tuscorons was determined by a
combination of high field NMR studies, molecular modeling and
chemical derivatization and confirmed by a modular total synthesis
of tuscorons D and E. Together with the discovery of three novel
tuscorons, this study enables detailed insights into the chemically
unprecedented tuscolid/tuscoron rearrangement cascade.
a)
H
OH OMe
O
O
O
9
5
17
S
*
O
*
*
*
*
*
*
18
18
17
21
HO
*
*
*
OH
O
O
O
*
*
HO2C
OH
22
O
*
*
Tuscoron A
2
( )
1
*
MeO
H
*
*
1
5
OH OH OMe
O
*
12
O
O
9
6
17
5
*
*
*
*
*
*
OH
*
*
18
Tuscolid (1) and tuscorons A and B (2, 3, Figure 1)1 present
structurally unique and stereochemically elaborate polyketides
from Sorangium cellulosum, which hold a special place among
myxobacterial natural products2 and polyketides3,4 as they
originate from one joint biosynthesis. While tuscolid is
characterized by a 22-membered macrolactone ring with an
uncommon chiral furan-one bearing a bridgehead double bond,5
the tuscorons present linear compounds with a related furan-one
and polypropionate, however, the appending diene is connected
to a different dihydropyran by an sp2-sp3 fusion. While an
interconversion has been tentatively proposed,1 proof or details
have remained elusive1 and further studies have been hampered
by the lack of full stererochemical knowledge and a missing
synthetic approach to resolve the supply issue of these scarce
metabolites. Herein, we report full stereochemical assignment of
the tuscolid/tuscorons, the discovery of three novel tuscorons (4-
6) and the total synthesis of tuscorons D and E, which
unequivocally confirms our stereo-chemical proposal. In
combination, these results enable detailed molecular insights
into the unprecedented tuscolid/tuscoron rearrangement
cascade.
OH
O
Tuscolid
1
( )
Tuscoron B
3
( )
22
b)
OH OMe
OH OH
O
7
18
*
CO2H
*
*
*
*
*
*
2
12
OH
3
OH
O
22
OH OH OMe
*
O
7
*
1
Tuscoron C (4)
9
5
18
*
*
*
*
*
*
*
O
O
12
*
O
OH
3
22
OH OH OMe
O
Tuscoron E
6
( )
7
9
5
1
18
*
*
*
*
*
*
12
*
O
O
*
O
OH
22
Tuscoron D
5
( )
S
* : configuration assigned herein
: derived by Mosher ester analysis
Figure 1. The tuscolid/tuscorons, biosynthetically interconverting polyketides
from Sorangium cellulosum: a) known representatives and b) novel
intermediates of the tuscolid/tuscorons rearrangement reported herein.
C-17 and C-12 to C-18 subunits of 4 and 5 confirmed by C,H-
coupling data. HMQC- and HMBC-correlations, together with the
double bond equivalents from HRMS analyses, defined the C-7
to C-12 and the C-18 to C-22 subunits of 4 and 5. The
corresponding data for the C-1 to C-9 fragment of 5 suggested a
cyclic lactone resembling the analogous subunit of tuscolid,
however lacking one H2O equivalent. For tuscolid C, HMBC-
correlations from H-4 and H-6 to C-1 were missing, which
together with its molecular formula lead to the assignment of an
open chain analog. In combination, these data lead to
assignment of the planar structures of tuscorons C and D, which
was further corroborated by close spectral similarities with the
respective data for tuscorons A and B. For tuscoron E (6) 2D-
C,H-coupling and 13C-NMR experiments could not be obtained
with sufficient quality due to the very low amounts available and
its structure could only be derived by comparison with the
tuscolid/tuscoron data. In detail, signals for the C-18 to C-22
subunit were very similar to those of tuscolid and tuscoron B,
while the C1 to C-5 data resembled those of tuscolid and
tuscoron C. Since the remaining signals corresponded to those
observed for all tuscolid/tuscorones the planar structure of
tuscoron E was tentatively assigned.
Sorangium cellulosum strain So ce1401 was identified as an
efficient tuscolid/tuscoron producing myxobacterium, leading to
the discovery of the three novel tuscorons C, D and E (4, 5, 6,
Figure 2). The planar structures of 4 and 5 were assigned by
extensive 1D and 2D-NMR analyses. In detail, characteristic
1H,1H-COSY- correlations allowed for identification of the C-12 to
[a]
[b]
B. Göricke, M. F. Bieber, Prof. Dr. D. Menche,
Kekulé-Institut für Organische Chemie und Biochemie
Universität Bonn
Gerhard-Domagk-Str. 1
D-53121 Bonn, Germany
E-mail: dirk.menche@uni-bonn.de
Dr. K. E. Mohr
Helmholtz Centre for Infection Research (HZI): Microbial Drugs
Inhoffenstr. 7
D-38124 Braunschweig, Germany
[c]
[d]
These authors contributed equally to this work. M.F.B.: structure
elucidation, stereochemical determination and significant synthetic
studies; B.G.: total synthesis of Tuscoron D and E.
Present address: Molitor Solutions, Germany.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201906166
Angewandte Chemie International Edition
COMMUNICATION
between Me-2 and H4a and H4b. Finally, the the relative
configuration of the lactone fragments of 1 and 5 were deduced
by strong NOE correlations between H-5 and H-4b, H-6 and H-7,
and H-4a to Me-2 in combination with a small coupling from H-5
to H-4b and a large coupling from H-5 to H-4a (9, Figure 3c,
data for 1 given), leading to an assignment as shown, in
agreement with the Höfle proposal.1
H
OH OMe
H
H
OH OH
O
O
5
3
1
16
13
20
8
CH2
OH
H
24
HO CH3
O
H
CH3
25
H
H3C
4
Tuscoron C ( )
22
H
3
CH3
O
OH OH
H
H
CH2
O
H
13
OMe
CH2
5
16
18
1
20
O
8
H
24
25
H
Me
H14
HO CH
O
3 CH3
H
H14
a) C-12 to C-21 subunit
HO
C13
H13
HO
OMe
H16
H3C
22
OH
3
Tuscoron D (5)
Me
H15
H-15
Me
Me
H
H
18
C12
H15
H-13
OH OH OMe
O
HO
O
H
16
14
5
1
13
H
H-14
H-14
18
19
16
15
H17
OH
MeO
H-14 (3.7) H-13 (3.7) H-15 (10.7) H-14 (10.7)
O
O
O
20
22
8
Me
13
H-15 (10.7)
H-16 (2.4)
24
H
HO
Tuscoron E (6)
: HMBC-correlation : H,H-COSY-correlation
O
12CH2
25
H18
Me
Me
H18
7
H17
C16
RO
H17
HO
C14
H16
H16
H16
additional NOESY
correlations
R
H17
C15
H15
H-16
H-13 to H-15
Me-14 to H-15
H-13 to OH-15
O
OH
HO
OH
Figure 2. Planar structures of novel tuscorons C, D and E.
H-15
H-16
H-17
H-17
H-18
H-16 (2.4) H-15 (2.4) H-17 (9.3) H-16 (9.3) C-18 (~0.3) C-17 (1.1)
H-17 (9.3)
H-18 (0.9)
C-16 (1.8)
: NOESY correlation
b) C-1 to C-9 subunit of 2
The constitutions of tuscolid and tuscorons A/B had been
H-2
H-3 (8.9)
H-3
H-2 (8.9)
H-4a (6.8)
H-4b (6.8)
HO2C
O
Et
H2
H
H
H
7
elucidated by the Höfle group and also
a
relative
Me
RH2C4
OR
2
3
H2C
Me
HO2C
H
7
H
stereochemistry within the C-13 to C-17 of 1 and the pyranes of
1 and 2 was tentatively assigned.1 For full stereochemical
determination, optimal NMR resolutions were obtained in
CD3OD and CDCl3, allowing for determination of the relevant
3JH,H coupling constants. These data and ROESY correlations
suggested the C-12 to C-21 subunits to be relatively rigid. For
tuscolid and tuscoron D, large homonuclear coupling constants
between H-14 and H-15 as well as H-16 and H-17 indicated
antiperiplanar relationships between these protons (Figure 3a,
data for 1 given). Small vicinal couplings between H-13 and H-
14, H-15 and H-16, and H-17 and H-18 together with strong
NOE correlations between H-11 and H-14, H-15 and H-16, H-17
and H18, and H-15 and OH-17 and C-12 CH2-protons and H-15
suggested this subunit to reside in conformation 7. Three further
key NOESY correlations, OMe-13 to Me-14, H-14 to Me-16 and
Me-14- to H-16, supported the relative assignment, in full
agreement with a previous analysis of Höfle for 1. Following
Murata’s method6 assignment of a syn-relationship between the
adjacent oxygen substituents at C-17 and C-18 was based on
small heteronuclear coupling constants observed from H-17 to
C-18, and from H-18 to C-16 and C17, in combination with a
small coupling constant from H-17 to H-18. This assignment was
in agreement with a characteristic low-field shift of H-17 as
compared to H-14 and H-15, caused by the carbonyl residing on
the same side, subsequently confirmed by modeling, and
characteristic coupling constants of synthetic material (vide infra).
Based on a common biogenesis and close similarity of the
spectral data, the stereochemistry of the C-12 to C-21 subunits
of all tuscorons was assigned accordingly. In contrast to Höfle,1
detailed analysis of the 3JH,H coupling couplings observed for the
C-1 to C-9 segment of 2 suggested the contribution of two or
more rapidly interconverting conformations (Figure 3b). Identical
couplings from H-3 to H-4a and H-4b together with a medium
value from H-6 to H-7 (3.4 Hz) supported considerable
conformational flexibility. With strong NOE-contacts between H-
3 and H-9 and H-2 to H-7, two interconverting conformers 8a
and 8b were proposed and a relative anti-configuration between
H-3 and H-7 was suggested, which was further supported by the
absence of a significant NOE contact between these two protons,
leading to a reassignment of this segment.1 The relative
configuration between C-2 and C-3 in turn was based on a large
coupling between H- 2 and H-3 and a strong NOE-contact
2
3 H
H
Me
Me
CO2H
9
H2C
Et
H3
O
8a
8b
d)
c) C-1 to C-6 subunit of 1
17
18
7
H
H
6
14
O
H
13
2
5
Et
Hb
O
H
3
2
OR
Ha
3
Me
7
5
9
H-2
H-3 (6.2)
H-3
H-2 (6.2)
H-4a (13.0)
H-4b (3.8)
6
H3
H2
C1
H4b
C5
H4a
RO
MMFS-
conformation
Me
10
Figure 3. Key data for stereochemical assignment of the tuscolid/tuscorons
(data for 1 given in Figures 3a and 3c, except for heteronuclear couplings,
given for 6). Abbreviation: MMFS = Merck molecular force field static.
Finally, correlation of these subunits and the centers at C-10
and C-18 was effectuated by molecular modeling (Macromodel:
Monte Carlo searches using a generalized water solvent model)
of the possible stereochemical permutations. The calculated
conformation 10 of tuscolid isomer 1 resulted in a close match of
calculated and observed NMR data. No low energy conformers
for other C17,C18 configurations were found in accordance with
the spectral data, thus confirming this assignment. Finally, the
absolute configuration was derived by Mosher ester analysis of
the OH-15 of tuscoron A (2) (Figure 1). Structure 1 summarizes
the assignment of the full relative and absolute configuration for
tuscolid. Based on a common biogenesis and close similarity of
the spectral data, the stereochemistry of tuscorons A-E (3-6)
was assigned accordingly (all Figure 1).
For validation of our proposal, key biosynthetic intermediate
tuscoron E was selected together with tuscoron D as synthetic
targets. A synthesis of tuscoron E was also required for definite
structural proof. Our synthetic approach relied on three building
blocks, i.e. furanone 11, polypropionate 12 as well as lactones
13 and 14 for construction of tuscorons D and E, respectively
(Scheme 1). For connection, a challenging cross coupling to
forge the hindered C-7, C-8 bond and a modular Mukaiyama
aldol reaction was planned for attachment of the Western
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10.1002/anie.201906166
Angewandte Chemie International Edition
COMMUNICATION
fragment to enable
a
stereodivergent access to all
zirconium-carboalumination presents an extension of this
method. For tuscoron D fragment 13, 24 was deprotected,
oxidized and elongated by a Still-Gennari-olefination13 with
phosphonate 27.14 After saponification, both resulting
diastereomers 29 (E/Z = 2.1:1) were cyclized by a Yamaguchi
protocol, involving a dynamic E/Z isomerization.15 Finally, iodide
13 was obtained by hydrostannylation and tin-iodine exchange.
For tuscoron E fragment 14 joint intermediate 24 was protected
and oxidized to aldehyde 25, which was homologated by a
Masamune anti-aldol16 reaction with 26 proceeding with high
selectivity (dr 19:1) towards 28,17 after auxiliary removal and
protecting group manipulations. Finally, oxidative lactonization18
and hydrostannylation/ tin-iodine exchange gave building block
14.
stereoisomers for further stereochemical proof.
Mukaiyama aldol
OH OH OMe
R
O
Stille
cross coupling
O
18
O
OH
O
R: H Tuscoron D (5)
R: OH Tuscoron E (6)
OH
O
TES
O
OTBS
OH
OMe
I
O
O
+
+
I
O
O
OTES
11
12
13
14
Scheme 1. Retrosynthetic analysis of Tuscoron D and E.
1. (+)-DIPT, Ti(OiPr)4
OTBS
OH
1. TBSCl (98%)
TBHP (82%, 75%ee)
HO
3. BuLi
(94%)
2. PPh3, CCl4
(91%)
As shown in Scheme 2, synthesis of the central
polypropionate fragment 12, started by early introduction of the
C-10 tertiary allylic alcohol. It was generated from geraniol (15)
by a sequence involving Sharpless epoxidation, Appel reaction,
double elimination of resulting chloride 16, with subsequent
methylation of resulting alkyne and TBS protection.7 Inspired by
a related transformation,8 it proceeded in a reliable fashion
giving 17 in high yields (64% from 15). After quantitative
Sharpless dihydroxylation and solid supported periodate
cleavage,9 resulting aldehyde 18 was elongated by an anti-aldol
coupling with Roche ester derived ketone 19, giving 20 with high
selectivity (dr 96:4), purely based on substrate control. After 1,3-
syn reduction and OH-13 methylation, the hydoxyl at C-15 was
protected as an acetate (21). Ester migration to the primary
during TBAF mediated TBS-deprotection was then effectively
used for selective introduction of a TES ether at OH-15, followed
by liberation of primary acohol giving 12 in a reliable sequence.
2. i. Et3Al, Cp2ZrCl2
ii. (HCHO)n (44%)
23
22
1. PMBCl (51%)
2. CSA (72%)
O
OTBS
PMBO
HO
H
3. IBX (86%)
25
24
1.
Ph
2. TBSOTf
(91%)
3. DIBAL-H
4. DDQ
(76%
O
1. CSA (92%)
3.
2. IBX
(77%)
, Et3N
O
O
O
4. NaOH
(CF3CH2)2P
N
OMe
27
Bn
SO2Mes
26
(75%
2 steps)
KHMDS
(43%, dr 19:1)
2 steps)
1. TBAF (98%)
TBS
1. TCBC
(92%)
2. TEMPO
BAIB (46%)
HO
O
OH
HO
14
13
3. HSnBu3
(47%)
4. I2 (74%)
2. Bu3SnH
(53%)
3. I2 (98%)
HO
O
28
29
Scheme 3. Synthesis of Eastern building blocks. Abbreviations: TBS = tert-
butyldimethylsilyl, (+)-DIPT (+)-diisopropyl -tartrate, PMB p-
=
L
=
methoxybenzyl, CSA = campher sulfonic acid, IBX = 2-iodoxybenzoic acid,
DIBAL-H = diisobutylaluminum hydride, DDQ = 2,3-dichloro-5,6-dicyano-p-
Notably, introduction of
stereochemical control in the Mukaiyama coupling.
a
TES-ether was required for
benzoquinone, TEMPO
=
2,2,6,6-tetramethyl-1-piperidinyloxy, BAIB
=
bisacetoxyiodobenzene, TCBC = 2,4,6-trichlorobenzoyl chloride.
1. BuLi, MeI
(85%)
O
ref. [7]
OH
O
Cl
2. TBSOTf
(quant)
15
16
TBSO
Et3N
O
Fragment fusion was initiated by a Mukaiyama aldol reaction
between ether 11 and aldehyde 31, which were obtained by TBS
protection of furanone 3019 and IBX oxidation of polypropionate
12 (Scheme 4). After considerable experimentation, useful
selectivity towards desired isomer 32 was obtained with Me2AlCl
in non-polar DCM, presumably by enforcing an OTES-chelation
the aldehyde 31, together with minimization of steric interactions
of the α- and β-center,20 and favorable dipole-dipole
interactions.21 TES-deprotection of sensitive 32 proved delicate,
giving decomposition under various methods. Finally, traces of
CSA in DCM targeted triol 32 in acceptable yield, considering its
lability. Comparison of the spectral data of all isomers with the
natural tuscorons revealed only for the major isomer a close
match, while considerable deviations were observed for all other
isomers were observed.22 Finally, hydrostannylation and cross
coupling with either 13 or 14, by a protocol by Fürstner,23 gave
tuscorons D (5) and E (6). All spectroscopic data (1H-NMR, 13C-
NMR, MS) and CD spectra of authentic and synthetic material of
1. AD-mix-α
(quant)
19
H
2. NaIO4/SiO2
(99%)
OTBS
OTBS
(cHex)2BCl
18
17
(94%, dr 94:6)
TBSO
O
OH
1. Et2BOMe, NaBH4 (84%)
2. MeI (44%)
3. Ac2O (98%)
OAc OMe
OTBS
20
TBSO
1. TBAF (73%)
2. TESOTf; Mg(OMe)2 (81%)
12
OTBS
21
Scheme 2. Synthesis of central polypropionate 12. Abbreviations: TBSOTf =
tert-butyldimethylsilyl trifluoromethanesulfonate, AD-mix-α asymmetric
dihydroxylation mixture alpha, (cHex)2BCl = dicyclohexylboron chloride, TBAF
tetra-n-butyl ammonium fluoride, TESOTf triethylsilyl
trifluoromethanesulfonate.
=
=
=
Joint synthesis of Eastern fragments 13 and 14 was
accomplished by a diversification of common precursor 24
(Scheme 3). Zirconium induced carboalumination10–12 of
commercial 22 with addition of formaldehyde gave allylic alcohol
23 and the tertiary alcohol was obtained by an analogous
sequence as above. Notably, innovative use of Et3Al in the initial
5
were in agreement, thus confirming their architectures,
including that of key biosynthetic intermediate 6 and also verified
the stereochemical proposals of all tuscolid/tuscorons.
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10.1002/anie.201906166
Angewandte Chemie International Edition
COMMUNICATION
TES
O
O
TBSO
stage highly hindered and protective group free Stille cross
coupling. This first total synthesis of the tuscolid/tuscoron family
should be applicable also for synthesis of other members of this
class and enable biological studies of these scarce metabolits.
Furthermore, this study enables detailed insights into the
biosynthetically and chemically unprecedented tuscolid/tuscoron
rearrangement cascade, which should be further investigated.
O
OMe
TBSCl
(quant)
IBX
12
+
H
O
O
(88%)
OTES
30
11
31
2. CSA
(27%, 2 steps)
1. Me2AlCl
dr (5.2/1.7/1.6/1.0)
OH OH OMe
O
16
18
17
15
OH
O
OH
32
1. HSnBu3
2. CuTC, Ph2PO2NBu4
Pd(PPh3)4
Acknowledgements
I
O
O
I
O
O
Funding by the DFG (ME 2756/7-1) is gratefully acknowledged.
We thank Andreas J. Schneider for excellent HPLC-support,
Hendrik Schnepel for modeling support, Jutta Niggemann (HZI)
for preparation of an extract and the fermentation service of the
HZI.
13
(10%, 2 steps) (5%, 2 steps)
14
5
6
Scheme 4. Completion of the total synthesis of tuscoron D and E.
Abbreviation: CuTC = Copper(I) thiophene-2-carboxylate.
Keywords: total synthesis • polyketides • rearrangements •
These results allow for
a detailed formulation of the
natural products • myxobacteria
tuscolid/tuscorone rearrangement. In contrast to a tentative
previous hypothesis a concerted action ca be ruled out,1 and a
stepwise mechanism has to be formulated. Also, full
stereochemical knowledge is now available. The chemicall
[1]
J. Niggemann, M. Herrmann, K. Gerth, H. Irschik, H. Reichenbach, G.
Höfle, Eur. J. Org. Chem. 2004, 487.
[2]
[3]
[4]
[5]
K. J. Weissman, R. Müller, Nat. Prod. Rep. 2010, 27, 1276.
E. J. N. Helfrich, J. Piel, Nat. Prod. Rep. 2016, 33, 231.
C. Hertweck, Angew. Chem. Int. Ed. 2008, 48, 4688.
J. Y. W. Mak, R. H. Pouwer, C. M. Williams, C. M. Angew. Chem. Int.
Ed. 2014, 53, 13664.
unprecedented cascade is initiated by
a decarboxylative
macrolactone opening followed by a vinylogous retro-Claisen
condensation towards tuscoron E (Scheme 5). The δ-lactone
may then be cleaved to give 33, in agreement with the discovery
of dehydrated tuscoron C. Finally, an intramolecular SN2’-type
endo-cyclisation would close the dihydropyran to tuscoron B (3).
Tuscorons A and D (2, 5), in turn are derived by water
elimination from tuscorons B and E.
[6]
a) N. Matsumori, D. Kaneno, M. Murata, H. Nakamura, K. Tachibana, J.
Org. Chem. 1999, 64, 866. b) D. Menche Nat. Prod. Rep. 2008, 25,
905-918; heteronuclear coupling data were obtained for tuscoron D in
CH2Cl2 due to optimal resolution.
[7]
[8]
[9]
J. S. Yadav, P. K. Deshpande, G. V. M. Sharma, Tetrahedron 1990, 46,
7033.
D. K. Mohapatra, C. Pramanik, M. S. Chorghade, M. K. Gurjar, Eur. J.
Org. Chem. 2007, 5059.
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O
O
[10] E. Negishi, C. L. Rand, K. P. Jadhav, J. Am. Chem. Soc. 1981, 46,
5041.
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Am. Chem. Soc. 1996, 118, 9577.
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2586.
[17] Small amounts of minor diastereomers originating from the Sharpless
or the aldol coupling were removed at this stage. _The absolute
configuration at C3 was assigned by Mosher ester analysis, while the
relative configuration within the Eastern fragment was confirmed by
NOE data, see SI section.
[18] T. M. Hansen, G. J. Florence, P. Lugo-Mas, J. Chen, C. J. Forsyth,
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Soc. 2001, 123, 10840.
Nu-
(1) decarboxylative
Tuscoron D 5
( )
HO
O
O
O
H
OH
vinylogous retro-Claisen
MeO
-H2O
-CO2
O
OH
OH
Tuscolid
2
( )
OH OH OMe
O
(2) lactone
opening
O
O
OH
O
H2O
Tuscoron E
6
( )
(3) endo
cyclization
OH OH OMe
OH OH
O
CO2H
H
OH
O
CO2H
H
33
OH OH OMe
O
O
[21] J. D. Winkler, K. Oh, S. M. Asselin, Org. Lett. 2005, 7, 387.
[22] Configurational assignment at C17 was based on the acetonide
method. S. D. Rychnovsky, B. Rogers, G. Yang, J. Org. Chem. 1993,
58, 3511, while the relative C17C18 configuration was confirmed by
characteristic coupling constants, i.e. 3.7 and 3.7 Hz for the two syn-
diastereomers and 7.3 and 7.9 Hz for the anti-isomers and the
expected selectivity of the aldol coupling: see Ref. [20]. The main
product resulted from the expected selectivity
-H2O
OH
O
Tuscoron C (4)
-H2O
Tuscoron B (3)
Scheme 5. Proposed tuscolid/ tuscoron rearrangement.
Tuscoron A (2)
[23] A. Fürstner, J. Funel, M. Tremblay, L. C. Bouchez, C. Nevado, M.
Waser, J. Ackerstaff, C. C. Stimson. Chem. Commun. 2008, 2873.
In summary, full stereochemical assignment of the
tuscolid/tuscorons has been accomplished by a combination of
high field NMR studies, modeling and chemical derivatization.
This proposal was unambiguously confirmed by a joint total
synthesis of tuscorons D and E by a versatile strategy, which
proceeds in 18 steps from geraniol. Key steps involve highly
stereoselective aldol reactions,
a
challenging, modular
Mukaiyama coupling on highly elaborate fragments and a late-
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10.1002/anie.201906166
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Björn Göricke, Michelle Fernandez
Bieber, Kathrin E. Mohr, and Dirk
Menche*
Page No. – Page No.
Stereochemical Determination of
Tuscolid/Tuscorons and Total
Synthesis of Tuscoron D and E:
Insights into the Tuscolid/Tuscoron
Rearrangement
for Table of Contents
Insights into an unprecedented rearrangement: stereochemical determination,
total synthesis and discovery of novel tuscorons reveal mechanistic insights into the
biosynthetic tuscolid/tuscoron reaction cascade.
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