(-)-Pseudodistomin E: First Asymmetric Synthesis and Absolute Configuration Assignment

Article abstract of DOI:10.1021/acs.orglett.7b00434

(-)-Pseudodistomin E has been prepared for the first time, allowing its structure and absolute configuration to be confirmed. The established conjugate addition of lithium (S)-N-allyl-N-(α-methyl-p-methoxybenzyl)amide to methyl (E,E)-hepta-2,5-dienoate generated the C(2)-stereocenter, and iodolactonisation of a derivative generated the remaining two stereogenic centers. Ensuing iodide displacement was achieved using a tethering strategy, to introduce the nitrogen atom to C(5). Decarboxylative coupling of a carboxylic acid with a dialkylzinc reagent completed construction of the tridecadienyl chain.

Full text of DOI:10.1021/acs.orglett.7b00434

Letter
pubs.acs.org/OrgLett
(−)-Pseudodistomin E: First Asymmetric Synthesis and Absolute
Configuration Assignment
Stephen G. Davies,* Ai M. Fletcher, Paul M. Roberts, James E. Thomson, and David Zimmer
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
S
* Supporting Information
ABSTRACT: (−)-Pseudodistomin E has been prepared for the first time,
allowing its structure and absolute configuration to be confirmed. The
established conjugate addition of lithium (S)-N-allyl-N-(α-methyl-p-
methoxybenzyl)amide to methyl (E,E)-hepta-2,5-dienoate generated the
C(2)-stereocenter, and iodolactonisation of a derivative generated the
remaining two stereogenic centers. Ensuing iodide displacement was achieved using a tethering strategy, to introduce the
nitrogen atom to C(5). Decarboxylative coupling of a carboxylic acid with a dialkylzinc reagent completed construction of the
tridecadienyl chain.
he pseudodistomin alkaloid family comprises six members
(Figure 1), isolated from the Okinawan tunicate
uniquely pseudodistomin E that remains to acquiesce to
laboratory synthesis, and hence receive confirmation of its
assigned structure and absolute configuration. The gross
structure of pseudodistomin E was assigned by Freyer et al.
using a combination of evidence, mainly gathered through NMR
T
spectroscopic investigations.3 1H NMR J coupling constant
3
analysis was used to assign the (E,E)-configuration to the diene
unit of the side chain, as well as the relative configurations of the
three stereogenic centers around the piperidine ring.3 This
analysis indicated that pseudodistomin E possessed the same
relative configuration of the three stereogenic centers as
pseudodistomin C. As the magnitudes of the specific rotation
values of pseudodistomin E {[α]D25 − 20.8 (c 0.39 in MeOH)}
and pseudodistomin C {[α]D24 − 24 (c 0.7 in MeOH)}18 were
similar and their signs the same, and given that their structures
differed only in the identity of the unsaturated hydrocarbon chain
at C(2), Freyer et al. reasoned that the two natural products
would be of the same enantiomeric form. As pseudodistomin C
had already been shown to possess the (2S,4S,5R) absolute
configuration by both degradation studies2 and total synthesis
from D-serine,10 Freyer et al. assigned the (2R,4S,5R) absolute
configuration to pseudodistomin E.3 Herein, we report the first
asymmetric synthesis of pseudodistomin E, which both confirms
its structure and enables the (2R,4S,5R) absolute configuration of
the three stereogenic centers of the piperidine ring to be assigned
unambiguously.
Figure 1. Structures of the pseudodistomin alkaloids.
Pseudodistoma kanoko by Kobayashi et al. in 1987 (pseudodis-
tomins A and B)1 and 1995 (pseudodistomin C),2 and from the
ascidian Pseudodistoma megalarva by Freyer et al. in 1997
(pseudodistomins D, E, and F).3,4 Unsurprisingly, there has been
interest in the development of syntheses of members of this
family of alkaloids in both racemic and enantiopure form, with
routes to pseudodistomins A,5 B,5−9 C,10−12 D,13,14 and F7
having been reported to date. These endeavors have enabled not
only the structures of the alkaloids to be confirmed (in fact, the
structures of pseudodistomins A and B originally proposed by
Kobayashi et al.15 were revealed to be erroneous and were thus
revised),6,16,17 but also their absolute configurations. It is
Our asymmetric synthesis of pseudodistomin D14 used the
diastereoselective conjugate addition of lithium (S)-N-allyl-N-
(α-methyl-p-methoxybenzyl)amide19 to methyl (E,E)-hepta-2,5-
dienoate 1 as a stereodefining step in the preparation of lactone 7.
Elaboration of 7 to pseudodistomin D involved formal
substitution of the iodide functionality by an amino functionality
with overall retention of configuration.14 We therefore envisaged
elaboration of 7 to pseudodistomin E via formal substitution of
Received: February 14, 2017
© XXXX American Chemical Society
A
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Letter
the iodide functionality by an amino functionality with overall
inversion of configuration; this obviously suggested an SN2-type
reaction. Lactone 7 was prepared as previously reported,14 in six
steps and 75% overall yield from methyl (E,E)-hepta-2,5-
dienoate. Attempted intermolecular displacement of the iodide
functionality within 7 by a range of nucleophilic nitrogen sources
(LiN3, NaN3, PhthNK, BnNH2, Bn2NH) was, however, thwarted
by either no reaction or the formation of N-Boc enamine 8, with
none of the corresponding substitution product 9 being observed
under any of the conditions investigated. This is consistent with
an E2-type elimination dominating, which is rendered a facile
process by the favorable antiperiplanar arrangement of the C(8)-
iodide functionality with one of the vicinal C(7)-protons on the
bicyclic framework of 7.20 In fact, treatment of 7 with DBU
provided 8 in 87% yield (Scheme 1).
analogous fashion to that of our pseudodistomin D synthesis]14
delivered a complex mixture of products from which 15 was
isolated in 33% yield (∼95% purity) and >95:5 dr [(Z):(E)
ratio]; the corresponding product 16 in which the oxazolidinone
ring had been cleaved was isolated as the only other identifiable
species in 3% yield (∼95% purity) and >95:5 dr [(Z):(E) ratio].
The geometries of the newly formed olefins were assigned from
the diagnostic values of the 1H NMR 3J coupling constants, with
3J < 11 Hz in both cases (Scheme 2).
Scheme 2. Attempted Preparation of 15
a
Scheme 1. Preparation of 7
a
Contaminated with ∼15% TsNH2.
In order to eradicate the competing dehydration pathway
(and, hence, formation of TsNH2), the possibility of effecting
olefination of the aldehyde functionality prior to isocyanate
trapping and oxazolidinone formation was considered. Although
reaction of 11 with Ph3PCH(CH2)3OBn resulted in
olefination and epoxide formation (undesired in this case),14
reaction of 11 with Ph3PCHCO2Me resulted in olefination
only, with 17 being isolated in 90% yield (from 7) and 68:32 dr
[(E):(Z) ratio]. Subsequent treatment of 17 with TsNCO gave
N-Ts carbamate 18 in 68:32 dr [(E):(Z) ratio], and then
exposure of 18 to Et3N gave N-Ts oxazolidinone 19 in 91% yield
(from 17) and 68:32 dr [(E):(Z) ratio]. Hydrogenation of 19
gave 20 in >95:5 dr, thus establishing conclusively that 68:32 dr
corresponds to the ratio of geometric olefin isomers for 17−19.
Methanolysis of the carbamate functionality within 20 using
K2CO3 in MeOH gave 21 in 77% yield (from 19). The relative
configuration of 21 was then assigned from 1H NMR 3J coupling
constant analysis, assuming a chair conformation. This not only
established the relative configurations within 19 and 20 but also
that the formal substitution of the iodide functionality by an
amino functionality had proceeded with inversion of config-
uration, as required for the synthesis of pseudodistomin E. With
this transformation (i.e., 7 to 19) established, an end-game for
the elaboration of lactone 7 into pseudodistomin E using the
decarboxylative coupling of a carboxylic acid and a dialkylzinc
reagent, recently reported by Baran et al.,23 was envisaged. Thus,
sequential treatment of lactone 7 with DIBAL-H, Ph3P
CHCO2Bn, TsNCO and Et3N gave N-Ts oxazolidinone 24 (the
a
PMP = p-methoxyphenyl. PhthNK = potassium phthalimide.
An alternative approach based upon tethered (i.e., intra-
molecular) delivery of the nucleophilic nitrogen atom was next
explored.21 Reduction of lactone 7 with DIBAL-H gave the
corresponding lactol 10, which existed mainly (∼90%) as the
open-chain form 1114 according to H NMR spectroscopic
1
analysis in CDCl3. Treatment of 11 with TsNCO gave a 5:88:7
mixture of unreacted 11, N-Ts carbamate 12, and vinyl ether 14,
along with TsNH2. Stirring this mixture with Et3N in acetone at
60 °C resulted in formation of a 10:81:9 mixture of unreacted 11,
N-Ts oxazolidinone 13, and vinyl ether 14, along with TsNH2.
Purification gave 11 in 10% yield (∼95% purity), 13 in 63% yield
(contaminated with ∼15% TsNH2), and 14 in 4% yield. These
product distributions suggest that a competing dehydration
process is occurring: reaction of the hydroxyl functionality within
the closed, lactol form 10 (rather than open-chain form 11) with
TsNCO followed by fragmentation gives 14 and N-tosylcarba-
mic acid, and decarboxylation of the latter gives TsNH2.22
Unfortunately, treatment of 13 with Ph3PCH(CH2)3OBn [to
subsequently facilitate C(2′) side-chain construction in an
B
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analogue of 19 with a pendant benzyl rather than methyl ester) in
77% overall yield and 68:32 dr [(E):(Z) ratio]. Tandem
hydrogenation/hydrogenolysis of 24 gave carboxylic acid 25
which was coupled with PhthNOH to give activated ester 26 in
96% yield and >95:5 dr (Scheme 3). The coupling partner, (E,E)-
and O-deprotection: the N-Ts group was removed from 30 upon
treatment with sodium naphthalenide to give 31 in 89% yield and
82:8:8:2 dr [(E,E):(6′E,8′Z):(6′Z,8′E):(Z,Z) ratio], the oxazo-
lidinone moiety within 31 was cleaved using KOH in hot MeOH
to give 32, and finally the N-Boc group was removed from 32
using HCl in hot MeOH to give synthetic pseudodistomin E 33
in 72% yield (from 31) and 82:8:8:2 dr [(E,E):(6′E,8′Z):
(6′Z,8′E):(Z,Z) ratio] after purification basification and by
chromatography; further separation of these olefin isomers was
not attempted. As the lithium amide reagent used for the
conjugate addition reaction was >99% ee, 33 was inferred as
being >99% ee, along with all intermediates en route (Scheme 5).
Scheme 3. Preparation of 26
a
Scheme 5. Preparation of Synthetic Pseudodistomin E 33
a
BBBPY = 4,4′-di-tert-butyl-2,2′-bipyridine.
3
1H NMR J coupling constant analysis of 33 was evincive of
the relative configuration around the piperidine ring [a chair
conformation with the C(2)- and C(4)-substituents equatorial,
and the C(5)-substituent axial], as well as the (E,E)-geometry of
the diene unit.25 As may be reasonably expected for a compound
containing two basic amino functionalities, the 1H and 13C NMR
spectroscopic data of 33 showed significant variance upon
introduction of trifluoroacetic acid (in 0.1 equiv portions) to the
sample (Figure 2 and Supporting Information). A similar effect
on the magnitude of the specific rotation value of 33 was also
noted: for example we obtained [α]D25 − 34.5 (c 1.0 in MeOH)
and [α]D25 − 9.2 (c 1.0 in 1.25 M methanolic HCl). Comparison
of our spectroscopic and physical data for 33 with those reported
by Freyer et al. for pseudodistomin E3 revealed excellent
agreement of the 1H NMR spectroscopic data of 33 (free base)
with those of the natural product (ΔδH ≤ 0.02 ppm).26
Meanwhile, the 13C NMR spectroscopic data of 33·0.1TFA
showed excellent parity with those reported for the natural
product (ΔδC ≤ 0.2 ppm),26 suggesting that traces of acid were
present in the sample of the natural product when the 13C NMR
spectrum was recorded. The specific rotation of 33·0.1TFA was
a
68.32 dr [(E):(Z) ratio]. PhthNOH = N-hydroxyphthalimide. DIC =
N,N′-diisopropylcarbodiimide.
1-bromodeca-3,5-diene 29, was prepared via 1,2-addition of
cyclopropylmagnesium bromide to (E)-2-heptenal 27 (>95:5
dr) and then rearrangement/substitution of the resultant
secondary alcohol 28 promoted by 48% aq HBr for 24 h24
which gave 29 in 86:7:7 dr [(E,E):(3E,5Z):(3Z,5E) ratio] and
91% isolated yield (Scheme 4).
Following Baran’s protocol,23 ester 26 was coupled with
bromide 29 to give 30 in 52% yield and 82:8:8:2 dr [(E,E):
(6′E,8′Z):(6′Z,8′E):(Z,Z) ratio]. The final stages involved N-
Scheme 4. Preparation of 29
25
measured as [α]D − 22.0 (c 0.5 in MeOH), which compares
25
favorably with [α]D − 20.8 (c 0.39 in MeOH)} reported by
Freyer et al. for pseudodistomin E.3 It can thus be concluded that
C
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Letter
ORCID
Stephen G. Davies: 0000-0003-3181-8748
Notes
The authors declare no competing financial interest.
REFERENCES
■
(1) Ishibashi, M.; Ohizumi, Y.; Sasaki, T.; Nakamura, H.; Hirata, Y.;
Kobayashi, J. J. Org. Chem. 1987, 52, 450.
(2) Kobayashi, J.; Naitoh, K.; Doi, Y.; Deki, K.; Ishibashi, M. J. Org.
Chem. 1995, 60, 6941.
(3) Freyer, A. J.; Patil, A. D.; Killmer, L.; Troupe, N.; Mentzer, M.;
Carte, B.; Faucette, L.; Johnson, R. K. J. Nat. Prod. 1997, 60, 986.
(4) Freyer et al. also isolated the known pseudodistomins B and C
alongside the new pseudodistomins D−F (see ref 3).
(5) Kiguchi, T.; Yuumoto, Y.; Ninomiya, I.; Naito, T. Chem. Pharm.
Bull. 1997, 45, 1212.
(6) Kiguchi, T.; Yuumoto, Y.; Ninomiya, I.; Naito, T.; Deki, K.;
Ishibashi, M.; Kobayashi, J. Tetrahedron Lett. 1992, 33, 7389.
(7) Ma, D.; Sun, H. J. Org. Chem. 2000, 65, 6009.
(8) Davis, F. A.; Zhang, J.; Li, Y.; Xu, H.; DeBrosse, C. J. Org. Chem.
2005, 70, 5413.
(9) Lee, J. H.; Jeong, W.; Rhee, Y. H. Synthesis 2014, 46, 2155.
(10) Doi, Y.; Ishibashi, M.; Kobayashi, J. Tetrahedron 1996, 52, 4573.
(11) Langlois, N. Org. Lett. 2002, 4, 185.
(12) Tanaka, K.; Maesoba, T.; Sawanishi, H. Heterocycles 2006, 68, 183.
(13) Trost, B. M.; Fandrick, D. R. Org. Lett. 2005, 7, 823.
(14) Davies, S. G.; Fletcher, A. M.; Lee, J. A.; Roberts, P. M.; Russell, A.
J.; Taylor, R. J.; Thomson, A. D.; Thomson, J. E. Org. Lett. 2012, 14,
1672.
(15) Pseudodistomin A was originally assigned as (2R,4R,5S,3′E,5′Z)-
2-(trideca-3′,5′-dien-1′-yl)-5-aminopiperidin-4-ol and pseudodistomin
B was originally assigned as (2R,4R,5S,E,E)-2-(trideca-3′,5′-dien-1′-yl)-
5-aminopiperidin-4-ol (see ref 1).
Figure 2. 1H (400 MHz) and 13C (100 MHz) NMR spectroscopic data
for pseudodistomin E and synthetic 33 in d4-MeOH. Values of ΔδC are
given in parentheses.
33 and pseudodistomin E are identical, hence establishing
unambiguously the structure and (2R,4S,5R) absolute config-
uration of the natural product.
(16) Naito, T.; Yuumoto, Y.; Kiguchi, T.; Ninomiya, I. J. Chem. Soc.,
Perkin Trans. 1 1996, 281.
(17) Ishibashi, M.; Deki, K.; Kobayashi, J. J. Nat. Prod. 1995, 58, 804.
(18) No specific rotation value for pseudodistomin C was reported in
either of the two publications detailing its isolation (see ref 2 and ref 3);
the value quoted is for the synthetic sample prepared by Kobayashi et al.
(see ref 10).
(19) For development of lithium N-allyl-N-(α-methylbenzyl)amide,
see: Davies, S. G.; Fenwick, D. R.; Ichihara, O. Tetrahedron: Asymmetry
1997, 8, 3387.
In conclusion, the first asymmetric synthesis of (−)-pseudo-
distomin E has been achieved in 16 steps from methyl (E,E)-
hepta-2,5-dienoate, and in 19% overall yield and >99% ee.
Conjugate addition of lithium (S)-N-allyl-N-(α-methyl-p-
methoxybenzyl)amide to methyl (E,E)-hepta-2,5-dienoate gen-
erated the C(2)-stereocenter of the target, with regioselective
iodolactonisation of a derivative being used to construct the
remaining C(4)- and C(5)-stereocenters. Iodide displacement
(with inversion of configuration) was achieved using a tethering
strategy, and set the absolute C(5)-stereochemistry required for
the target. The unsaturated C(2)-hydrocarbon chain was
constructed using a decarboxylative coupling of a carboxylic
acid with a dialkylzinc reagent. Comparison of NMR
spectroscopic and specific rotation data of our synthetic sample
with those of the natural product established conclusively both
the structure and (2R,4S,5R) absolute configuration of
pseudodistomin E.
(20) The solid state conformation of 7 (see ref 14) displays this
geometric arrangement.
(21) For examples of this tactic, see: (a) Knapp, S.; Kukkola, P. J.;
Sharma, S.; Pietranico, S. Tetrahedron Lett. 1987, 28, 5399. (b) Das, J.
Synth. Commun. 1988, 18, 907.
(22) The ratio of vinyl ether 14 to TsNH2 was ∼ 1:1 in the 1H NMR
spectrum of both of the relevant crude reaction mixtures.
(23) Qin, T.; Cornella, J.; Li, C.; Malins, L. R.; Edwards, J. T.;
Kawamura, S.; Maxwell, B. D.; Eastgate, M. D.; Baran, P. S. Science 2016,
352, 801.
(24) Svirskaya, P. I.; Maiti, S. N.; Jones, A. J.; Khouw, B.; Leznoff, C. C.
J. Chem. Ecol. 1984, 10, 795.
(25) 3J6′,7′ and 3J8′,9′ were discerned as > 15 Hz.
ASSOCIATED CONTENT
* Supporting Information
■
(26) ΔδX = |δX (synthetic) − δX (natural)|, where X = H or C.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00434.
Experimental details, characterization data, and copies of
1H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: steve.davies@chem.ox.ac.uk.
D
DOI: 10.1021/acs.orglett.7b00434
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