(-)-(2 S,3 R, Z)-nakinadine A: First asymmetric synthesis and absolute configuration assignment

Article abstract of DOI:10.1021/ol500096r

Mannich-type reaction of methyl phenylacetate with the N-tert-butylsulfinyl imine derived from (R)-tert-butylsulfinamide and (Z)-14-(pyridin-3′-yl) tetradec-11-enal has been used as the key step in the first asymmetric synthesis of (-)-nakinadine A. Both the 2,3-syn- and 2,3-anti-diastereoisomers were prepared; comparison of spectroscopic and specific rotation data facilitated assignment of the absolute (2S,3R,Z)-configuration within the natural product. (-)-(2S,3R,Z)-Nakinadine A was prepared in 10 steps from 11-bromoundecan-1-ol, in 10% overall yield, 97:3 dr [(Z):(E) ratio], and >98% ee.

Full text of DOI:10.1021/ol500096r

Letter
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(−)-(2S,3R,Z)‑Nakinadine A: First Asymmetric Synthesis and Absolute
Configuration Assignment
Stephen G. Davies,* Ai M. Fletcher, Paul M. Roberts, Rushabh S. Shah, Amber L. Thompson,
and James E. Thomson
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
S
* Supporting Information
ABSTRACT: Mannich-type reaction of methyl phenylacetate
with the N-tert-butylsulfinyl imine derived from (R)-tert-
butylsulfinamide and (Z)-14-(pyridin-3′-yl)tetradec-11-enal
has been used as the key step in the first asymmetric synthesis
of (−)-nakinadine A. Both the 2,3-syn- and 2,3-anti-
diastereoisomers were prepared; comparison of spectroscopic
and specific rotation data facilitated assignment of the absolute (2S,3R,Z)-configuration within the natural product.
(−)-(2S,3R,Z)-Nakinadine A was prepared in 10 steps from 11-bromoundecan-1-ol, in 10% overall yield, 97:3 dr [(Z):(E) ratio],
and >98% ee.
n 2007 and 2008, Kobayashi et al. reported the isolation of
cyanide (Strecker-type reaction),9 and ester enolates (Mannich-
Ithe nakinadine family of alkaloids from the Okinawan type reaction),10 that participate in this reaction manifold.7 We
sponge Amphimedon sp.1,2 Six members of the family were
envisaged that Mannich-type reaction of methyl phenylacetate
with N-tert-butylsulfinyl imine 5 [derived from condensation of
aldehyde 3 with (R)-4] would facilitate the synthesis of the
diastereoisomers of nakinadine A. Thus, 11-bromoundecan-1-ol
1 was elaborated to alcohol 2 in four steps via our previously
reported approach,4 in 53% overall yield and 97:3 dr [(Z):(E)
ratio],11 and oxidation of 2 with IBX in EtOAc12 gave the
requisite aldehyde 3. Condensation of 3 with (R)-4 (>98% ee)
gave N-tert-butylsulfinyl imine 5 in 80% yield (from 2) and 97:3
dr [(11Z):(11E) ratio],11 indicating that formation of the imine
functionality had occurred with complete (E)-selectivity7
(Scheme 1).
identified (nakinadines A−F), the common structural features
of which are an α-phenyl-β-amino acid moiety with a long-
chain aliphatic N-substituent capped by a pyridin-3-yl group
(Figure 1). As nakinadines A and D−F possess a similar long-
chain aliphatic substituent at the β-position, these members of
this alkaloid family can exist as one of four possible
stereoisomers (two pairs of enantiomers in each case, excluding
the possibility for geometric isomerism in nakinadines A and
F). Kobayashi et al. proposed their relative (RS,SR)-
configurations on the basis of 1H−13C coupling constant
analysis, but of all the nakinadine alkaloids a specific rotation
23
Treatment of methyl phenylacetate with LiHMDS gave an
85:15 mixture of the corresponding (E)- and (Z)-enolates,13
and reaction with imine 5 in the presence of MgBr2 gave an
approximate 80:20 mixture of α-phenyl-β-sulfinamido esters 7
and 8.14 In a separate experiment, use of MeMgBr as the base
under analogous conditions gave a similar, approximate 80:20
mixture of 7 and 8. Although the ratio of the diastereoisomeric
value for only nakinadine A was reported {[α]D −3 (c 1.0 in
CHCl3)},1 making this alkaloid a palpable target for asymmetric
synthesis to establish its absolute configuration. To date, we
have reported the only syntheses of any of these alkaloids: the
asymmetric syntheses of nakinadines B3 and C4 were achieved
via a common strategy using the conjugate addition of LiNBn2
to an N-α-phenylacryloyl SuperQuat derivative with diastereo-
selective enolate protonation as the key step;5 reductive N-
alkylation was then employed to introduce the requisite long-
chain aliphatic substituent.3,4 In continuation of our inves-
tigations within this area, we delineate herein the first
asymmetric synthesis of the (2S,3R,Z)- and (2R,3R,Z)-stereo-
isomers of nakinadine A and, through comparison of
spectroscopic and specific rotation data, assign the absolute
(2S,3R,Z)-configuration within natural (−)-nakinadine A.
Diastereoselective nucleophilic addition to an enantiopure N-
tert-butylsulfinyl imine (derived from condensation of enantio-
pure tert-butylsulfinamide 46 with the corresponding aldehyde
or ketone) has emerged as a powerful method for the
asymmetric synthesis of a range of amines7 owing to the
wide range of nucleophiles, including organometallic reagents,8
enolates could not be determined in the magnesium case,13
a
similar ratio to that obtained using LiHMDS may be assumed,
based upon the similar diastereoselectivities elicited by both of
these Mannich-type reactions. Purification of the crude reaction
mixture allowed isolation of 7 in 60% yield and 97:3 dr
[(Z):(E) ratio].11 Hydrogenation of this sample of 7 gave 9 as a
single diastereoisomer (>99:1 dr), thus unambiguously
establishing that the 97:3 dr of 7 represents the ratio of
geometric olefin isomers, consistent with the ratio of geometric
isomers of 5 (Scheme 2). Furthermore, the relative
configuration within 9 was unambiguously established by single
Received: January 11, 2014
Published: February 25, 2014
© 2014 American Chemical Society
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Scheme 2
Figure 1. Reported structures and assigned relative and absolute
configurations of the nakinadine alkaloids.
Scheme 1
Figure 2. X-ray crystal structure of (2S,3R,RS)-9 (selected H atoms are
omitted for clarity).
experiment and treatment of the crude reaction mixture
(approximate 80:20 mixture of 7 and 8, respectively) with
NaOMe in MeOH at 0 °C for 8 h resulted in formation of an
approximate 20:80 mixture of 7 and 8, respectively, showing
that 7 and 8 are related as epimers at C(2) and, hence,
establishing the absolute (2R,3R,RS,Z)-configuration within 8.
Purification gave a sample of 8 in 60% isolated yield (from 5)
and 94:3:3 dr [(2R,3R,RS,Z):(2R,3R,RS,E):(2S,3R,RS,Z) ratio]17
(Scheme 2).
Treatment of 7 (97:3 dr [(Z):(E) ratio]) with HCl in MeOH
effected hydrolysis of the N-tert-butylsulfinyl group to give the
corresponding primary amine and was followed by reductive N-
alkylation using 13-(pyridin-3′-yl)tridecanal 103 in the presence
of NaB(OAc)3H to give secondary amine 11 in 64% yield
(from 7) and 97:3 dr [(Z):(E) ratio].11 Finally, hydrolysis of 11
upon treatment with 3.0 M aq HCl at 70 °C18 followed by
sequential purification on Serdolit CG-400 I resin (OH− form)
and silica gel gave (2S,3R,Z)-12 in 60% yield and 97:3 dr
[(Z):(E) ratio].11 An analogous sequence of reactions applied
to 8 initially gave secondary amine 13 in 59% yield and 97:3 dr
[(Z):(E) ratio],11 with hydrolysis giving (2R,3R,Z)-14 in 62%
crystal X-ray diffraction analysis,15,16 with its absolute
(2R,3S,RS)-configuration following from the known (R)-
configuration of the sulfur atom (Figure 2). Thus, the absolute
(2R,3S,RS,Z)-configuration within 7 was also unambiguously
assigned. The formation of 7 as the major diastereoisomer from
this asymmetric Mannich-type reaction is entirely consistent
with the reaction proceeding via a chairlike transition state 6,
which has previously been proposed to rationalize the
diastereoselectivity of this class of reaction;7,10 the facial
selectivity for attack on the N-tert-butylsulfinyl imine may be
determined either by chelation or sterics (orientation of the S-
lone pair toward the approaching enolate). Repetition of this
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yield and 97:3 dr [(Z):(E) ratio].11 Given the known
enantiomeric purity of the (R)-tert-butylsulfinamide 4 (i.e.,
>98% ee) employed for the formation of imine 5, the
enantiomeric purities of 5, 7−9, and 11−14 can be confidently
inferred as >98% ee (Scheme 3).
Scheme 3
1
Comparison of the H and 13C NMR data reported for
natural nakinadine A by Kobayashi et al.1,19 with those of our
authentic samples of (2S,3R,Z)-12 and (2R,3R,Z)-14 (Figure 3)
revealed good agreement of the chemical shifts reported for the
natural product with those of 12 in particular in the key regions
of the spectra containing the resonances associated with the β-
amino acid moiety [C(21)H, C(22)H, C(21), C(22), and
C(24)], thus supporting the relative configuration assigment of
Kobayashi et al.1 For the natural product, Kobayashi et al.
Figure 3. 1H and 13C NMR spectroscopic data for “natural”
(−)-nakinadine A, “synthetic” (2S,3R,Z)-12, and “synthetic”
(2R,3R,Z)-14. The numbering convention adopted by Kobayashi et
1
al. (ref 1) has also been adopted here. * The (unassigned) H NMR
data for the natural product (C45H67N3O2) includes 69 protons in
total. Resonances corresponding to the protons of the long alkyl chains
are reported at 1.0−1.4 (34H, m), 1.42 (2H, m), 1.43 (2H, m), 1.54
(2H, m), 1.57 (2H, m); the midpoint of these has been quoted here
for purposes of comparison.
reported the specific rotation [α]D −3 (c 1.0 in CHCl3),1
23
while our sample of (2S,3R,Z)-12 has a specific rotation of
20
[α]D −15.7 (c 1.0 in CHCl3). Although the magnitudes of
these specific rotation values do not match closely, their
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303. (e) Pflum, D. A.; Krishnamurthy, D.; Han, Z.; Wald, S. A.;
Senanayake, C. H. Tetrahedron Lett. 2002, 43, 923. (f) Almansa, R.;
Guijarro, D.; Yus, M. Tetrahedron: Asymmetry 2008, 19, 2484.
(9) For example, see: (a) Davis, F. A.; Lee, S.; Zhang, H.; Fanelli, D.
L. J. Org. Chem. 2000, 65, 8704. (b) Mabic, S.; Cordi, A. A.
Tetrahedron 2001, 57, 8861. (c) Avenoza, A.; Busto, J. H.; Corzana, F.;
Peregrina, J. M.; Sucunza, D.; Zurbano, M. M. Synthesis 2005, 575.
(d) Wang, H.; Zhao, X.; Li, Y.; Lu, L. Org. Lett. 2006, 8, 1379.
(e) Plant, A.; Thompson, P.; Williams, D. M. J. Org. Chem. 2008, 73,
3714. (f) Luo, Y.-C.; Zhang, H.-H.; Xu, P.-F. Synlett 2009, 833.
(10) For example, see: (a) Tang, T. P.; Ellman, J. A. J. Org. Chem.
1999, 64, 12. (b) Tang, T. P.; Ellman, J. A. J. Org. Chem. 2002, 67,
7819. (c) Sun, S.; Guo, P. Patent CN102134208, 2011.
identical signs suggest that natural (−)-nakinadine A is the
(2S,3R,Z)-stereoisomer 12. The absolute (2S)-configuration is
also in accordance with the absolute (2S)-configurations
assigned by Kobayashi et al.2 to nakinadines B and C. On
this basis, it seems likely that this family of alkaloids are
homochiral at C(2); in turn, considering the relative (RS,SR)-
configurations assigned to nakinadines D−F by Kobayashi et
al.,2 it is thus proposed that these family members also share the
absolute (2S,3R)-configuration.
In conclusion, the first asymmetric syntheses of both possible
diastereoisomers (excluding geometric isomers) of the reported
structure of the marine alkaloid nakinadine A has been
achieved. These syntheses rely on the asymmetric Mannich-
type reaction of methyl phenylacetate with the sulfinimide
derived from (R)-tert-butylsulfinamide and (Z)-14-(pyridin-3′-
yl)tetradec-11-enal as the key stereodefining step. The synthesis
of the (2S,3R,Z)-stereoisomer proceeded in 10 steps and 10%
overall yield, while the synthesis of the (2R,3R,Z)-stereoisomer
(11) The (Z):(E) ratio was assigned from integration of the
resonances associated with the allylic protons [C(10)H2 or C(10′)H2]
1
in the 700 MHz H NMR spectrum.
(12) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001.
(13) In the case of the lithium enolates (generated from treatment
with LiHMDS), the (E):(Z) ratio was determined by trapping with
TMSCl at −78 °C to give a mixture of the corresponding silyl enol
1
1
proceeded in 11 steps and 9% overall yield. Comparison of H
ethers, which was analyzed by H NMR spectroscopy. In the case of
and 13C NMR spectroscopic and specific rotation data for these
synthetic samples with those reported for the natural product
allowed assignment of the absolute (2S,3R,Z)-configuration
within natural (−)-nakinadine A. Further application of this
methodology to facilitate the asymmetric synthesis of the
remaining members of the nakinadine alkaloid family is
currently under investigation within our laboratory.
the magnesium enolates (generated from treatment with MeMgBr),
several attempts at this trapping procedure consistently returned only
starting material.
(14) A more accurate ratio of (2S,3R,RS,Z)-7:(2R,3R,RS,Z)-8 could
1
not be determined from the H NMR spectrum of the crude reaction
mixture due to peak overlap, the presence of the corresponding
(2S,3R,RS,E)- and (2R,3R,RS,E)-diastereoisomers, and other minor
impurities.
(15) Crystallographic data (excluding structure factors) have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 977827. See the
Supporting Information for further details.
ASSOCIATED CONTENT
* Supporting Information
■
S
1
Experimental procedures, characterization data, copies of H
(16) Analysis of the crystal used for the X-ray structure determination
and 13C NMR spectra, and crystallographic information file (for
structure CCDC 977827). This material is available free of
charge via the Internet at http://pubs.acs.org.
1
by H NMR spectroscopy (on a 500 MHz instrument fitted with a 1
mm microprobe) confirmed that it was representative of the bulk
sample.
(17) A sample of 7 was also isolated from this rection, in 10% yield
and 97:3 dr [(Z):(E) ratio].
(18) Attempted use of a higher temperature (and hence shorter
reaction time) to effect the ester hydrolysis led to competing hydration
of the olefin.
(19) Unfortunately, Professor Kobayashi was unable to provide either
an authentic sample of the natural product or copies of the original
characterization data for comparison.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: steve.davies@chem.ox.ac.uk.
Notes
The authors declare no competing financial interest.
REFERENCES
■
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