Asymmetric Total Synthesis of (+)-Neooxazolomycin Using a Chirality-Transfer Strategy

Article abstract of DOI:10.1002/anie.201906158

The total synthesis of (+)-neooxazolomycin was achieved from the amino-acid d-serine. The efficiency of this approach is derived from the use of principles of memory of chirality and dynamic kinetic resolution in the intramolecular aldol reaction of a serine derivative to build the densely functionalized lactam framework and to install three contiguous stereocenters. The key intermediate was readily elaborated to the target natural product.

Full text of DOI:10.1002/anie.201906158

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Accepted Article
Title: Asymmetric Total Synthesis of (+)-Neooxazolomycin Using a
Chirality Transfer Strategy
Authors: Jae Hyun Kim, Illan Kim, Yeonghun Song, Min Jung Kim, and
Sanghee Kim
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201906158
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10.1002/anie.201906158
Angewandte Chemie International Edition
COMMUNICATION
Asymmetric Total Synthesis of (+)-Neooxazolomycin Using a
Chirality Transfer Strategy
Jae Hyun Kim, Illan Kim, Yeonghun Song, Min Jung Kim and Sanghee Kim*
Abstract: The total synthesis of (+)-neooxazolomycin was achieved
from the amino acid D-serine. The efficiency of our approach is
derived from the use of principles of memory of chirality and dynamic
kinetic resolution in the intramolecular aldol reaction of a serine
derivative to build the densely functionalized lactam framework and to
install three contiguous stereocenters. The key intermediate was
readily elaborated to the target natural product.
Oxazolomycins are structurally unique natural products that are
characterized by fused or spiro bicyclic lactam-lactone systems
as well as
a polyene subunit. Since the isolation of
neooxazolomycin (1, Scheme 1) in 1985,[1] a number of members
of this family have been identified, including oxazolomycins A–C,[2]
oxazolomycin A2, bisoxazolomycin A,[3] 16-methyloxazolomycin,[4]
curromycins A–B,[5] KSM-2690 B–C,[6] and lajollamycins A–D.[7]
These oxazolomycins exhibit a wide range of potent antibacterial
and antiviral activities as well as in vivo antitumor activity.[8]
Because of their structural complexity and potent biological
activities, considerable attention has been paid to their
synthesis.[9] However, there are only a few reports on the
successful total syntheses of oxazolomycins.[10]
Structurally, neooxzolomycin (1) is comprised of a left-hand
fragment 2 containing oxazole triene and right-hand fragment 3
containing a densely functionalized fused lactam-lactone ring
system. A major challenge in the synthesis of this complex natural
product is the stereocontrolled installation of six stereocenters in
the right-hand fragment 3. Kende et al. achieved the total
synthesis by employing
amidomalonate dianion with
a
cyclocondensation of an
a functionalized galactoside
Scheme 1. Retrosynthetic analysis of (+)-neooxazolomycin (1).
derivative, albeit with the undesired diastereoselectivity.[10a]
Hatakeyama et al. reported an elegant total synthesis using a
stereoconvergent approach by connecting chiral building blocks
Our retrosynthetic analysis is shown in Scheme 1. An obvious
disconnection of the amide linkage of 1 gave two fragments, 2 and
3. The amide form of left-hand fragment 2 is a naturally occurring
compound named inthomycin A.[12] We envisaged that the
(Z,Z,E)-configured triene unit of 2 could be constructed from (Z)-
unsaturated aldehyde 4. The Z configuration of the trisubstituted
double bond in 4 was expected to be installed by a 1,4-addition of
methyl cuprate to alkynoic ester 5. In turn, alkynoic ester 5 could
be accessible from hydroxypivalic acid.
We envisioned that the exocyclic stereocenters and the dienyl
amine moiety of right-hand fragment 3 would be installed from the
hydroxyl methyl group in 6 in a substrate-controlled manner
utilizing the stereochemical features of the fused bicyclic lactam
system. We planned to conduct an intramolecular aldol reaction
of oxaproline derivative 7 to construct the lactam ring of 6 and to
install the three contiguous stereocenters. This type of aldol
reaction has been proposed as a plausible step in the biosynthetic
pathway towards oxazolomycins.[13] In turn, it was envisioned that
7 could be traced back to known-keto acid 8[9c] and D-serine. If
the principles of “memory of chirality” (MOC) and “dynamic kinetic
and
a substrate controlled installation of the remaining
stereocenters.[10b,c]
Given our interest in the asymmetric total synthesis with chirality
conservation,[11] we sought a retrosynthetic scheme that would
lead to simple D-serine as the only chiral source in the preparation
of stereochemically enriched right-hand fragment 3. Herein we
report the asymmetric total synthesis of (+)-neooxazolomycin (1)
from D-serine through a strategy that features a number of novel
chirality transfer processes.
[*]
Dr. J. H. Kim, I. Kim, Y. Song, M. J. Kim, Prof. Dr. S. Kim
College of Pharmacy, Seoul National University
1 Gwanak-ro, Gwanak-gu, Seoul 08826 (Korea)
E-mail: pennkim@snu.ac.kr
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201906158
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COMMUNICATION
resolution” (DKR) were applied to the aldol reaction of serine
derived oxaproline amide 7,[14] as in our previous total synthesis
of (–)-penibruguieramine starting from L-proline,[11a] the
asymmetric synthesis of right-hand fragment 3 could be achieved
from D-serine without the aid of external chiral influences. If
successful, this approach would complete the total synthesis of
the natural product with high chiral economy and might also have
implications in the biosynthesis of the oxazolomycin family
of natural products.
of the chirality of serine and the stereochemical outcome at C2
indicated that MOC and DKR were active during the reaction.
Notably, in the previous reports by Moloney,[9c] similar aldol
reactions of Seebach's oxazolidine substrates 14 (Scheme 2)
proceeded with low stereoselectivity, which highlights the
efficiency of our MOC aldol ring closure of oxaproline substrate 7.
Our synthesis commenced with the preparation of aldol
substrate 7, which could be obtained by coupling serine derivative
9 with -keto acid 8 (Scheme 2). Starting from D-serine, Cbz-
protected oxaproline t-butyl ester 10 was obtained in two steps.[15]
Under hydrogenolysis conditions, the Cbz moiety was removed to
provide oxaproline 9. Meanwhile, the reaction of ethyl 4-
chloroacetoacetate (11) with sodium benzyloxide, and
subsequent monomethylation afforded 12. The hydrolysis of 12
afforded 8. Because both coupling partners (8 and 9) are unstable,
the amide coupling was conducted immediately after the
preparation of these species, and aldol reaction substrate 7 was
obtained in a good overall yield as an inseparable 1.4:1 mixture
of C2 diastereomers (neooxazolomycin numbering).
Scheme 3. Construction of the exocyclic carbon chain. Reagents and
conditions: a) Pd/C, H2, MeOH/AcOH (2:1), RT, 16 h, 97%; b) TEMPO, TCCA,
CH2Cl2, 0 °C, 1 h, 84%; c) i. 16, In, TBAI, water, RT, 5 h; ii. EtOAc, 50 °C, 4 h,
79%, 12:1 d.r.; d) Pd/C, H2, MeOH/AcOH (2:1), RT, 16 h, 99%; e) N,O-
dimethylhydroxylamine hydrochloride, iPrMgCl, THF, –78 °C to RT, 30 min,
92%; f) NMO, TPAP, CH2Cl2, 0 °C to RT, 2 h, 90%; g) CeCl3·7H2O, NaBH4,
MeOH, 0 °C, 1 h, 85%, 15:1 d.r.; h) HMDS, TMSCl, pyridine, RT, 16 h, 94%.
TEMPO: 2,2,6,6-tetramethyl-1-piperidinyloxy; TCCA: trichloroisocyanuric acid;
TBAI: tetrabutylammonium iodide; NMO: N-methylmorpholine N-oxide; TPAP:
tetrapropylammonium perruthenate; HMDS: hexamethyldisilazane; TMSCl:
chlorotrimethylsilane.
To introduce the exocyclic carbon chain, the benzyl protecting
group of 13 was removed, and the resulting hydroxyl group was
oxidized (Scheme 3). With aldehyde 15 in hand, various
nucleophilic addition reactions, such as a Grignard reaction, an
NHK reaction, and a Barbier-type addition, were examined.
Among them, only the Barbier-type addition with allyl bromide
16[17] was successful. The best result was obtained when the
Barbier reaction was conducted in water using indium and TBAI
to give 17 in 12:1 d.r. and 79% yield after spontaneous
lactonization in EtOAc (see the Supporting Information for
optimizations).[18] The newly generated stereocenter at the C4
position is epimeric to that of target natural product 1. However,
this stereochemistry was useful in the induction of the desired C6
stereocenter by hydrogenation.[19] The stereochemistry of 18,
obtained from 17 under hydrogen atmosphere with Pd/C as the
catalyst, was confirmed by XRD analysis.[16] The lactone ring of
18 was opened to Weinreb amide 19, and the resulting C4
secondary hydroxyl group was then inverted by a sequential
oxidation and stereoselective reduction (15:1 d.r.) to give 20.
Protection of the secondary hydroxy group of 20 required careful
selection of the reaction conditions because of the facile
lactonization with the nearby carbonyl groups. TMS protection
Scheme 2. Synthesis of MOC aldol reaction product 13. Reagents and
conditions: a) 2 N NaOH, 37% aqueous HCHO, 0 °C, 16 h, then CbzCl, NaHCO3,
acetone, 0 °C, 1 h; b) Boc2O, DMAP, THF, RT, 1 h, 72% for 2 steps; c)
Pd(OH)2/C, H2, Et3N, EtOAc, RT, 20 min, 99%; d) NaH, BnOH, THF, 0 °C to RT,
16 h, 86%; e) K2CO3, MeI, acetone, 0 °C to RT, 16 h, 88%; f) KOH, H2O/MeOH
(2:1), RT, 2 h, 98%; g) DCC, DMAP, CH2Cl2, RT, 2 h, 76%, 1.4:1 d.r.; h) NaOEt,
EtOH, –20 °C, 12 h, 92%, 10:1:1 d.r., >99% e.e. DMAP: 4-
(dimethylamino)pyridine;
dicyclohexylcarbodiimide.
THF:
tetrahydrofuran;
DCC:
N,N'-
For the intramolecular aldol reaction, 7 was treated with NaOEt
at room temperature. Desired aldol product 13 was obtained as a
single diastereomer in 61% yield with perfect enantioselectivity
(>99% e.e.). The only noticeable side product was the C2,C3
dehydrated product (20%). Dehydration of 13 was suppressed at
lower temperatures. For example, the reaction at –20 °C provided
the essentially enantiomerically pure aldol product 13 in 76% yield
without the formation of the dehydrated side product, but two
minor diastereomers were formed in a 10:1:1 ratio. The
configuration of the three contiguous stereocenters of 13 was
unambiguously confirmed by XRD analysis.[16] The preservation
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10.1002/anie.201906158
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COMMUNICATION
using HMDS and TMSCl in pyridine gave 21 without undesired
lactonization.
Scheme 5. Preparation of the left-hand fragment. Reagents and conditions: a)
(COCl)2, pyridine, DMF, CH2Cl2, RT, 2 h; b) CuI, DIPEA, methyl propiolate,
CH2Cl2, RT, 16 h, 86% for 2 steps; c) (+)-DIPCl, RT, 16 h, 72%, 93% e.e.; d)
BzCl, Et3N, DMAP, CH2Cl2, 0 °C to RT, 20 min, 98%; e) CuI, MeLi, THF, –78 °C,
30 min, 89%; f) DIBAL-H, THF, –78 to –20 °C, 1 h, 83%; g) NMO, TPAP, CH2Cl2,
RT, 30 min, 98%; h) CBr4, PPh3, Et3N, CH2Cl2, 0 °C to RT, 16 h, 99%; i)
Pd(PPh3)4, Bu3SnH, toluene, RT, 16 h, 99%; j) 36, PEPPSI-iPr, DMF, 55 °C, 36
h, 70%; k) HF·pyridine, THF/pyridine (5:3), 0 °C to RT, 20 h, 90%; l) (COCl)2,
DMSO, Et3N, –78 °C to RT, 1 h, 96%; m) NaClO2, NaH2PO4·H 2O, 2-methyl-2-
Scheme 4. Preparation of right-hand fragment. Reagents and conditions: a)
dimethyl methylphosphonate, nBuLi, THF, –78 °C to 0 °C, 30 min, 82%; b) TBAF,
THF, –10 °C, 2 h, 80%; c) FeCl3, Et3SiH, CH2Cl2, RT, 3 h, 51% (60% brsm); d)
Si(iPr)2(OTf)2, 2,6-lutidine, 0 °C, 20 min, 99%; e) Ba(OH)2, 26, THF/H2O (40:1),
–30 °C, 16 h, 75%; f) L-selectride, THF, –95 °C, 20 min; g) Ac2O, pyridine, RT,
3 h, 75% for 2 steps, 4:1 d.r. TBAF: tetrabutylammonium fluoride.
butene, tBuOH/water (1:1),
dimethylformamide; DIPEA:
chlorodiisopinocampheylborane; DIBAL-H: diisobutylaluminum hydride.
PEPPSI-iPr: [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-
0
°C to RT, 30 min, 84%. DMF: N,N-
N,N-diisopropylethylamine; DIPCl:
chloropyridyl)palladium(II) dichloride.
We employed a Horner–Wadsworth–Emmons (HWE) reaction
to install the dienyl amine moiety. In this regard,
lithiomethylphosphonate was added to Weinreb amide 21 to give
-keto phosphonate 22. Prior to the HWE reaction, construction
of the N-methylated fused lactam-lactone system of the natural
product was accomplished as follows. Desilylation of 22
proceeded with concomitant lactonization to give 23. The
The synthesis of the left-hand fragment commenced with known
TBS-protected hydroxypivalic acid 29[24] (Scheme 5). The copper
acetylide of propiolate was reacted with the acyl chloride of 29 to
afford 30.[25] To install the required (R)-configuration at C3’, (+)-
DIP-chloride[26] was used for the asymmetric reduction of prochiral
ketone to give 31 in 93% e.e. and 72% yield. The resulting
hydroxyl group was protected with BzCl to provide 32. With
careful selection of the copper salt and methyl anion, the Z-
selective 1,4-addition of methyl cuprate to alkynoic ester 32 was
achieved to afford 33 with complete stereoselectivity.[27] The
methyl ester of 33 was selectively reduced to the hydroxyl group
without affecting the benzoate protecting group,[28] and this
species was then oxidized to aldehyde 34.
reductive ring opening of the oxaproline moiety of 23 with
[21]
Et3SiH/FeCl3
provided N-methylated product 24.[16] The
hydroxyl groups in 24 were protected as dioxasilinane to give
25.[10b,22]
After extensive experiments,[23] we found that the HWE reaction
of 25 with aldehyde 26 proceeded in good yield when
substoichiometric amounts of Ba(OH)2 were employed at –30 °C
(see the Supporting Information for optimizations). During the
HWE reaction, the dioxasilinane group was partially hydrolyzed to
give 27 in 75% yield. Under these reaction conditions, no
isomerization at C6 was observed. Ketone 27 was reduced with
L-selectride and immediately acetylated to produce 28 in a ratio
of 4:1. Notably, no diastereoselectivity was observed in the
formation of C7 stereocenter when the primary hydroxy group was
not protected.
Attempts to construct the (Z,Z,E)-configured triene unit from (Z)-
configured unsaturated aldehyde 34 by
a
Wittig-type
condensation were not successful mainly because of poor Z/E
selectivity. Attempts towards the preparation of geometrically
pure Z,Z-1-halodienes or Z,Z-1-boryldienes in a single step from
34 also failed. However, Z,Z-1-bromodiene 35 was selectively
obtained in two steps using Uenishi's protocol[29] which involves a
Corey–Fuchs
dibromoolefination
and
Pd-catalyzed
hydrogenolysis. The stille coupling of 35 with known vinyl
stannane 36[30] successfully provided oxazole triene 37 without
significant isomerization of any of the double bonds.[31] The TBS
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10.1002/anie.201906158
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COMMUNICATION
protecting group was removed, and the resulting alcohol was
oxidized to the acid by a Swern oxidation followed by a Pinnick
oxidation to provide 38.
2019R1A2C2009905) of the National Research Foundation of
Korea (NRF) grant funded by the Government of Korea (MSIP).
Keywords: alkaloids • asymmetric synthesis •
diastereoselectivity • natural products • total synthesis
[1]
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Scheme 6. Completion of the total synthesis of (+)-neooxazolomycin (1).
Reagents and conditions: a) i. 38, BOPCl, Et3N, CH2Cl2, RT, 2 h; ii. 28, DBU,
CH2Cl2, RT, 30 min; iii. The reaction mixture of ii. was added to the reaction
mixture of i., RT, 2 h, 51%; b) i. K2CO3, MeOH, RT, 16 h; ii. Amberlyst IRC-86,
MeOH, RT, 16 h, 90%. BOPCl: bis(2-oxo-3-oxazolidinyl)phosphinic chloride;
DBU: 1,8-diazabicyclo(5.4.0)undec-7-ene.
[8]
[9]
For selected examples, see: a) K. Eto, J. Ishihara, S. Hatakeyama,
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Pattenden, Tetrahedron 2007, 63, 6216–6231.
With left-hand fragment 38 and right-hand fragment 28 in hand,
we connected these parts to complete the total synthesis
(Scheme 6). The BOP-mediated coupling between acid 38 and
the free amine generated in situ from 28 furnished amide 39. The
silyl protecting group was also removed during the reaction.
Obtained coupling product 39 was treated with K2CO3 in MeOH to
cleave the benzoate and acetate protective groups. The required
reaction conditions led to partial lactone ring opening. However,
relactonization was achieved simply by treatment with acidic resin
to give neooxazolomycin (1). The spectral data and optical
rotation of synthetic 1 were in good agreement with those
previously reported.
In summary, we have accomplished the asymmetric total
synthesis of (+)-neooxazolomycin (1) using a minimum number of
chiral sources. The right-hand fragment with six stereocenters
was synthesized from D-serine as the only chiral source. Several
chirality propagation processes were employed, including MOC,
DKR and substrate-controlled asymmetric inductions. The only
chirality present in the left-hand fragment was installed by the
asymmetric reduction of a ketone. The (Z,Z,E)-configured triene
unit was stereoselectively constructed using metal-assisted
[10] a) A. S. Kende, K. Kawamura, R. J. DeVita, J. Am. Chem. Soc. 1990,
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reactions such as
a
cuprate addition,
a
Pd-catalyzed
hydrogenolysis of a dibromoalkene, and a Stille reaction. This
synthesis is an exceptionally attractive strategy in terms of its
chiral economy. The use of this efficient strategy for the synthesis
of other oxazolomycins is currently under investigation.
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not applicable has been reported, albeit with very low diastereoselectivity
and yield. See: A. G. Brewster, J. Jayatissa, M. B. Mitchell, A. Schofield,
R. J. Stoodley, Tetrahedron Lett. 2002, 43, 3919–3922.
Acknowledgements
This work was supported by the Mid-Career Researcher
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and
NRF-
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COMMUNICATION
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10.1002/anie.201906158
Angewandte Chemie International Edition
COMMUNICATION
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COMMUNICATION
Chirality Transfer: The total
synthesis of (+)-neooxazolomycin was
achieved with excellent stereocontrol.
The six stereocenters in the right-hand
fragment were derived from D-serine
by a series of chirality transfer
processes.
Jae Hyun Kim, Illan Kim, Yeonghun
Song, Min Jung Kim and Sanghee Kim*
Page No. – Page No.
Asymmetric Total Synthesis of (+)-
Neooxazolomycin Using a Chirality
Transfer Strategy
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