Asymmetric synthesis of N,O-diacetyl-3-epi-xestoaminol C: Structure and absolute configuration confirmation of 3-epi-xestoaminol C

Article abstract of DOI:10.1016/j.tetlet.2016.02.021

The asymmetric synthesis of N,O-diacetyl-3-epi-xestoaminol C is reported. The synthesis employs diastereoselective aminohydroxylation of tert-butyl crotonate [conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)amide, then in situ enolate oxidati

Full text of DOI:10.1016/j.tetlet.2016.02.021

Accepted Manuscript
Asymmetric synthesis of N,O-diacetyl-3-epi-xestoaminol C: structure and ab-
solute configuration confirmation of 3-epi-xestoaminol C
Susanna G. Archer, Kristína Csatayová, Stephen G. Davies, Ai M. Fletcher, Paul
M. Roberts, James E. Thomson
PII:
S0040-4039(16)30131-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.02.021
TETL 47294
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
27 January 2016
2 February 2016
3 February 2016
Please cite this article as: Archer, S.G., Csatayová, K., Davies, S.G., Fletcher, A.M., Roberts, P.M., Thomson, J.E.,
Asymmetric synthesis of N,O-diacetyl-3-epi-xestoaminol C: structure and absolute configuration confirmation of
3-epi-xestoaminol C, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.02.021
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Asymmetric synthesis of N,O-diacetyl-
3-epi-xestoaminol C: structure and absolute
configuration confirmation of
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3-epi-xestoaminol C
Susanna G. Archer, Kristína Csatayová,† Stephen G. Davies,* Ai M. Fletcher, Paul M. Roberts, and James E.
Thomson

1
Tetrahedron Letters
journal homepage: www.els evier.com
Asymmetric synthesis of N,O-diacetyl-3-epi-xestoaminol C:
structure and absolute configuration confirmation of 3-epi-xestoaminol C
Susanna G. Archer, Kristína Csatayová,† Stephen G. Davies,* Ai M. Fletcher, Paul M. Roberts, James E.
Thomson
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
ARTICLE INFO
ABSTRACT
Article history:
Received
The asymmetric synthesis of N,O-diacetyl-3-epi-xestoaminol C is reported. The synthesis
employs diastereoselective aminohydroxylation of tert-butyl crotonate [conjugate addition of
lithium (S)-N-benzyl-N-(α-methylbenzyl)amide, then in situ enolate oxidation with (+)-
camphorsulfonyloxaziridine (CSO)] and a diastereoselective reduction protocol as the key
stereodefining steps. The synthetic sample of the natural product was isolated as its N,O-diacetyl
derivative for ease of purification; this material was prepared in ten steps and 17% overall yield
from commercially available tert-butyl crotonate. This synthesis confirms unambiguously both
the assigned structure and absolute (S,S)-configuration of the natural product.
Received in revised form
Accepted
Available online
Keywords:
xestoaminol C
3-epi-xestoaminol C
natural product
conjugate addition
2009 Elsevier Ltd. All rights reserved
.
The vicinal amino alcohol motif is a common sub-structure of
a range of biologically active natural and non-natural products.
For example in 1990, Jiménez and Crews reported the isolation
of xestoaminol C from a Fijian sponge, Xestospongia sp., and
found that it displayed reverse transcriptase inhibition.1,2 In 2014,
Keyzers and co-workers reported the isolation of the
diastereoisomeric compound, 3-epi-xestoaminol C, from the New
Zealand brown alga Xiphophora chondrophylla, and found that it
displayed broad spectrum antimicrobial activity.3 The structure
and relative configuration of 3-epi-xestoaminol C was assigned
by a combination of NMR spectroscopic and mass spectrometric
analyses, chemical derivatisation, and comparison with data
reported for xestoaminol C, whilst its absolute (S,S)-
configuration was assigned by a derivatisation method2 (Figure
1). Since its isolation, several syntheses of xestoaminol C have
been reported,4-7 including our synthesis which employed the
aminohydroxylation of tert-butyl crotonate as the key
stereodefining step.5 The first synthesis of 3-epi-xestoaminol C
was reported in early 2015.8 Herein we report the application of
our highly enantio- and diastereoselective aminohydroxylation
reaction,5 together with a diastereoselective reduction,9 as the key
stereodefining steps in an asymmetric synthesis of N,O-diacetyl-
3-epi-xestoaminol C. Our synthesis also confirms the structure of
the natural product and its absolute (S,S)-configuration.
syn-α-Hydroxy-β-amino ester 4 was prepared from tert-butyl
crotonate 1 (which is commercially available) using established
procedures.5,9 Diastereoselective aminohydroxylation of 1,
employing the conjugate addition of lithium (S)-N-benzyl-N-(α-
methylbenzyl)amide followed by in situ enolate oxidation with
(+)-camphorsulfonyloxaziridine (CSO), gave anti-α-hydroxy-β-
amino ester 2 in 64% yield and >99:1 dr.5,9 Oxidation of 2 under
Swern conditions gave complete conversion to ketone 3, which
was reduced diastereoselectively using NaBH4 in MeOH at −20
°C to give syn-α-hydroxy-β-amino ester 4 in 94% yield (from 2)9
and in >99:1 dr (Scheme 1).
Ph
(i)
Ph
N
CO2tBu
Me
CO2tBu
Me
OH
1
2, 64%, >99:1 dr
(ii)
Ph
Ph
NH2
3
(iii)
2
Ph
N
Ph
N
Me
CO2tBu
CO2tBu
xestoaminol C
OH
Me
Me
NH2
OH
4, 94%, >99:1 dr
O
3
Me
3-epi-xestoaminol C
OH
Scheme 1. Reagents and conditions: (i) lithium (S)-N-benzyl-N-(α-
methylbenzyl)amide, THF, −78 °C, 2 h, then (+)-CSO, −78 °C to rt, 12 h; (ii)
Figure 1. Structures of xestoaminol C and 3-epi-xestoaminol C.
−78
DMSO, (ClCO)2, Et3N, CH2Cl2,
°C to rt, 1 h; (iii) NaBH4, MeOH, −20
* Corresponding author. Tel.: +44 (0)1865 275646.
E-mail address: steve.davies@chem.ox.ac.uk (S. Davies).
°C, 2 h.

2
Tetrahedron
Based on our previously reported synthesis of xestoaminol C,5
protecting group manipulation of 4 was next undertaken:
hydrogenolysis of 4 with in situ N-Boc protection gave 5,9 and
subsequent treatment of 5 with 2,2-dimethoxypropane and cat.
BF3·Et2O in acetone gave trans-oxazolidine 6 in 55% yield (from
4). Reduction of 6 with LiAlH4 then provided alcohol 7 in quant.
yield, and of sufficient purity to use directly in the next step
(Scheme 2). Recrystallisation of an aliquot enabled the identity of
and relative configuration within alcohol 7 to be established
unambiguously via single crystal X-ray diffraction analysis,10
with the absolute (4S,5R)-configuration following from the
determination of a Flack x parameter11,12 of −0.08(16) for the
structure (Figure 2). The long alkyl chain was then introduced
using a Wittig olefination: oxidation of alcohol 7 via a Swern
protocol gave the corresponding aldehyde 8, which was
immediately treated with the ylide derived from deprotonation of
commercially available (1-decyl)triphenylphosphonium bromide
with BuLi to give (Z)-alkene 9 in 94:6 dr [(Z):(E) ratio], isolated
in 75% yield (and 94:6 dr). Hydrogenation of 9 under acidic
conditions also effected global N,O-deprotection to give 3-epi-
xestoaminol C as its hydrochloride salt 10. In order to facilitate
purification and isolation, 10 was treated with Ac2O in pyridine
to effect N- and O-acetylation, giving N,O-diacetyl-3-epi-
xestoaminol C 11 in 67% yield (from 9). This corresponds to an
overall yield of 17% in ten steps from tert-butyl crotonate 1
(Scheme 2).
Boc
Me
N
O
4
5
OH
Figure 2. Single crystal X-ray structure of 7 (selected H atoms are omitted
for clarity).
O
15
NH
16
4
6
8
10
12
14
1
3
5
7
9
11
13
2
17
O
O
18
Keyzers and co-workers
δ
This study
H (500 MHz)
proton #
1
H (600 MHz)
δ
1.10
(1H, d, J = 6.8)
1.11
(3H, d, J = 6.8)
Ph
Boc
4.20
(1H, dqd, J = 9.3, 6.8, 4.1)
4.21
(1H, dqd, J = 9.2, 6.8, 4.1)
(i)
Ph
N
NH
2
3
CO2tBu
CO2tBu
4.85
(1H, ddd, J = 7.6, 5.9, 4.1)
4.87
(1H, ddd, J = 7.1, 5.9, 4.1)
Me
Me
OH
4, >99:1 dr
OH
1.52
(2H, m)
1.53
(2H, m)
4
5, 72%, >99:1 dr
(ii)
1.26
(18H, m)*
1.28
(18H, m)
5–13
14
16
18
NH
Boc
Boc
N
N
0.87
(3H, d, J = 7.0)
0.88
(3H, d, J = 7.0)
(iii)
O
O
Me
1.99
(3H, s)
2.00
(3H, s)
Me
t
OH
CO2 Bu
2.09
(3H, s)
2.10
(3H, s)
7, quant, >99:1 dr
6, 77%, >99:1 dr
5.53
(1H, d, J = 9.3)
5.53
(1H, d, J = 9.2)
(iv)
Boc
Boc
N
Keyzers and co-workers
This study
C (125 MHz)
N
(v)
carbon #
δC (150 MHz)
δ
O
O
Me
1
2
18.7
47.4
18.5
Me
94:6 dr
[( ):( )]
Z
E
C9H19
47.2
CHO
3
76.6
76.5
8
9, 75% 94:6 dr [(Z):(E)]
4
31.7
31.6
(vi)
5
25.4
25.3
Ac
NH HCl
•
2
6–11
12
13
14
15
16
17
18
29.5–29.8
32.1
29.3–29.6
31.9
NH
(vii)
C11H23
C11H23
OAc
Me
Me
22.8
22.7
OH
14.3
14.1
N,O-diacetyl-3-epi-xestoaminol C 11
67%, >99:1 dr
10
169.6
23.6
169.4
23.4
Scheme 2. Reagents and conditions: (i) H2, Pd(OH)2/C, Boc2O, EtOAc, rt, 12
h; (ii) 2,2-dimethoxypropane, BF3·Et2O, acetone, rt, 12 h; (iii) LiAlH4, THF,
171.7
21.2
170.9
21.0
−78
0 ºC to rt, 12 h; (iv) DMSO, (ClCO)2, Et3N, CH2Cl2,
°C to rt, 1 h; (v)
[C10H21PPh3]+[Br]−, BuLi, THF, hexane, −78 ºC to rt, 12 h; (vi) H2,
Pd(OH)2/C, HCl (3.0 M, aq), MeOH, rt, 12 h; (vii) Ac2O, DMAP, pyridine, rt,
12 h.
Figure 3. H and 13C NMR spectroscopic data (in CDCl3) for the samples of
11 derived from the natural source and the synthetic material. The numbering
convention adopted by Keyzers and co-workers (Ref. 3) has also been
adopted here. *Resonances corresponding to the protons of the long alkyl
chain are reported at 1.24 (12H, m), 1.25 (2H, m), 1.27 (2H, m), 1.28 (2H,
m); the mid-point of these has been quoted here for purposes of comparison.
1
Excellent agreement was noted between both the H and 13C
1
NMR spectroscopic data reported by Keyzers and co-workers3
for their sample of 11 derived from the natural source with those
for our synthetic sample of 11, thus unambiguously confirming

3
both the structure of and relative configuration within the natural
product. Furthermore, comparison of the specific rotation values
for these two samples of 11 {[α]D25 −23 (c 0.1 in CHCl3) for the
25
sample derived from the natural source3 versus [α]D −22.6 (c
0.5 in CHCl3) for our synthetic sample} showed identical sign
and very close magnitude, thus confirming unambiguously the
absolute (S,S)-configuration originally assigned to the natural
product by Keyzers and co-workers3 (Figure 3).
In conclusion, we have completed an asymmetric synthesis
which unambiguously confirms both the structure and absolute
configuration of 3-epi-xestoaminol C. The synthesis employs the
enantio- and diastereoselective aminohydroxylation of tert-butyl
crotonate and a diastereoselective reduction as the key steps to
install the stereogenic centers present within the target, which
was isolated as the N,O-diacetyl derivative for ease of
purification. The overall yield of N,O-diacetyl-3-epi-xestoaminol
C obtained via this method was 17% over ten steps from tert-
butyl crotonate (which is commercially available). Comparison
of the 1H and 13C NMR spectroscopic data of this synthetic
sample of N,O-diacetyl-3-epi-xestoaminol C with those reported
for the material derived from the natural source revealed
excellent agreement, thus serving to confirm both the structure
and relative configuration of the natural product. Furthermore,
comparison of the specific rotation values for these two samples
revealed them to be of identical sign and very close in magnitude,
thus enabling the absolute (S,S)-configuration of 3-epi-
xestoaminol C, originally assigned to the natural product upon its
isolation by means of a derivatisation method, to be confirmed
unambiguously.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.XXXX.
References and notes
1. Jiménez, C.; Crews, P. J. Nat. Prod. 1990, 53, 978.
2. Xestoaminol C was also subsequently isolated from the ascidian
Pseudodistoma obscurum; see: Garrido, L.; Zubia, E.; Ortega, M. J.;
Naranjo, S.; Salva, J. Tetrahedron 2001, 57, 4579.
3. Dasyam, N.; Munkacsi, A. B.; Fadzilah, N. H.; Senanayake, D. S.;
O’Toole, R. F.; Keyzers, R. A. J. Nat. Prod. 2014, 77, 1519.
4. Ichihashi, M.; Mori, K. Biosci. Biotech. Biochem. 2003, 67, 329.
5. Abraham, E.; Davies, S. G.; Millican, N. L.; Nicholson, R. L.;
Roberts, P. M.; Smith, A. D. Org. Biomol. Chem. 2008, 6, 1655.
6. Uraguchi, D.; Nakamura, S.; Ooi, T. Angew. Chem. Int. Ed. 2010,
49, 7562.
7. Chen, B.-S.; Yang, L.-H.; Ye, J.-L.; Huang, T.; Ruan, Y.-P.; Fu, J.;
Huang, P.-Q. Eur J. Med. Chem. 2011, 46, 5480.
8. Choi, J.; Ha, H.-J. J. Korean Chem. Soc. 2015, 59, 203.
9. Davies, S. G.; Fletcher, A. M.; Frost, A. B.; Lee, J. A.; Roberts, P.
M.; Thomson, J. E. Tetrahedron 2013, 69, 8885.
10. Crystallographic data (excluding structure factors) have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 1450195.
11. Flack, H. D. Acta Crystallogr., Sect. A 1983, 39, 876.
12. Flack, H. D.; Bernardinelli, G. J. Appl. Crystallogr. 2000, 33, 1143.