Silyl migrations in d-xylose derivatives: Total synthesis of a marine quinoline alkaloid

Article abstract of DOI:10.1021/ol402760p

A versatile method for the synthesis of orthogonally protected d-xylose 1-thioethers is described using unusual silyl group migrations which were pivotal in the synthesis of 4,8-dimethyl-6-O-(2′,4′-di-O-methyl- β-d-xylopyranosyl)hydroxyquinoline confirming the structure and absolute configuration of the natural product.

Full text of DOI:10.1021/ol402760p

ORGANIC
LETTERS
2013
Vol. 15, No. 22
5734–5737
Silyl Migrations in D‑Xylose Derivatives:
Total Synthesis of a Marine Quinoline
Alkaloid
Anuchit Phanumartwiwath, Thomas W. Hornsby, Joazaizulfazli Jamalis,
Christopher D. Bailey, and Christine L. Willis*
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, U.K.
Chris.willis@bristol.ac.uk
Received September 24, 2013
ABSTRACT
A versatile method for the synthesis of orthogonally protected D-xylose 1-thioethers is described using unusual silyl group migrations which were
pivotal in the synthesis of 4,8-dimethyl-6-O-(20,40-di-O-methyl-β-D-xylopyranosyl)hydroxyquinoline confirming the structure and absolute
configuration of the natural product.
Given the many biological events being uncovered in
which carbohydrates play an integral part including the
importance of glycosylated secondary metabolites as leads
in the pharmaceutical industry, the development of strat-
egies for the synthesis of carbohydrate building blocks
remains an important goal. In nature, glycosylation with
D-xylose dimethyl ethers occurs on a wide variety of structural
frameworks including, for example, the cytotoxic macro-
lactones ankaraholides A and B from the cyanobacteria
Geitlerima sp1 and polycavernoside A from the red alga
Polycavernosa tsudai,2 the macrodilactones clavosolides B
and C from Myristra clavosa,3 a series of steroid derivatives
from the starfish Henricia leviuscula,4 and the aromatic
antitumor compound cleistanthins A.5 Herein we report a
versatile method for the synthesis of orthogonally protected
D-xylose thioethers 1 and 2 using unusual migrations of
triisopropylsilyl (TIPS) groups (Figure 1). The value of the
methodology is demonstrated in the first total synthesis
of 4,8-dimethyl-6-O-(20,40-di-O-methyl-β-D-xylopyranosyl)-
hydroxyquinoline 3, a natural product isolated from ex-
tracts of the cyanobacterium Lyngbya majuscula6 thus
confirming the structure and absolute configuration of
the natural product.7
Figure 1. Target compounds.
The substrate diols 9 and 10 required for the pivotal silyl
migrations were prepared as shown in Scheme 1. D-Xylose
was readily converted to the known thioether 48 in three
(1) Andrianasolo, E. H.; Goss, H.; Geoger, D.; Girt, M. M.;
McPhail, K.; Leal, R. M.; Mooberry, S. L.; Gerwick, W. H. Org. Lett.
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M. R. J. Nat. Prod. 2002, 65, 1303.
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(5) Ramesh, C.; Ravindranath, N.; Ram, T. S.; Das, B. Chem. Pharm.
Bull. 2003, 51, 1299.
(6) Orjala, J.; Gerwick, W. H. Phytochemistry 1997, 45, 1087.
(7) Previous methods for the synthesis of D-xylose 2,4-dimethyl ether
derivatives include: (a) Ferrier, R. J.; Prasad, D.; Rudowski, A.;
Sangster, I. J. Chem. Soc. 1964, 3330. (b) Paquette, L. A.; Barriault,
L.; Pissarnitski, D. J. Am. Chem. Soc. 2000, 122, 619. (c) Fujiwara, K.;
Murai, A. J. Am. Chem. Soc. 1998, 120, 10770.
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(9) (a) Toyooka, N.; Nakazawa, A.; Hirniyama, T.; Nemoto, H.
Heterocycles 2003, 59, 75. (b) Stick, R. V.; Stubbs, K. A.; Watts, A. G.
Aust. J. Chem. 2004, 57, 779.
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10.1021/ol402760p
Published on Web 10/28/2013
2013 American Chemical Society

steps and 70% overall yield, and then reaction of 4 with
2-methoxypropane gave a 4:1 mixture of acetals 5 and 6.9
The major product 5 could be isolated in 65% yield by
careful SiO2 column chromatography. However it proved
more efficient to convert the mixture toTIPS ethers 7 and 8
and then selectively deprotect the acetals with pTsOH
giving diols 9 and 10 which were readily separated. The
structure of the major product 9 was confirmed by HMBC
studies as well as by conversion to diacetate 11. The
400 MHz 1H NMR spectrum in CDCl3 showed downfield
shifts of the signals assigned to 2-H and 3-H from δ3.48
and δ3.62 respectively in diol 9 to δ4.85 and δ5.06 in
diacetate 11. The structure of the minor product diol 10
was similarly confirmed by NMR studies and by conver-
sion to diacetate 12.
Scheme 2. Migration of the TIPS Group and X-ray Structure of
Silyl Ether 1
3-silyl ether 1 exists in the chair conformation in the solid
state, the 400 MHz 1H NMR spectrum in CDCl3 indicated
that a conformational change had occurred by comparison
with 4-silyl ether 13. All vicinal coupling constants in 1 were
significantly smaller (J ca. 5 Hz) than in 13 (J ca. 9 Hz), and
there was a downfield shift of 1-H from δ4.52(d, J9.3 Hz) in
13 to δ5.16 (d, J 5.2 Hz) in the silyl migrated product 1. The
different conformations of dimethyl ethers 1 and 13 in
CDCl3 were confirmed by NOE studies (Figure 2). These
changes in the spectral properties of 3- versus their 4-silyl
ether counterparts in CDCl3 proved to be general and were
empirically useful to analyze reaction mixtures prior to
purification and full characterization of the products as
discussed later.
Scheme 1. Preparation of Protected D-Xylose Phenyl Thioether 9
The pivotal step in the preparation of 2,4-dimethyl ether
1 was treatment of diol 9 with NaH, MeI in DMF for 24 h
to give 1, in which the TIPS group had migrated from the
4- to the 3-position, in 74% yield (Scheme 2). In addition a
minor product 13 (25% yield) arising from simple methyl-
ation was isolated. The same mixture of products was
formed using THF as the solvent, but the reaction was
complete in just 3 h. Dimethyl ether 1 was recrystallized
from dichloromethane, and X-ray crystallography con-
firmed the proposed structure.
Whilst silyl migrations are known in carbohydrate
chemistry10 to the best of our knowledge this is the first
example of migration of a silyl group from the 4-position in
a xylose derivative to the apparently more sterically con-
strained 3-position. During studies on the reactivity of
glycosyl donors, Bols and co-workers reported that bulky
silyl groups change the pyranoside conformation to a more
“axial-rich” conformer.11 Interestingly, in our case, whilst
Figure 2. Conformations of diol 9 (left) and silyl ether 1 (right)
showing important NOEs.
We propose that migration occurs via attack of alkoxide
I on silicon to give the five-membered silyl intermediate II
(Scheme 3). Subsequent reaction of II with an electrophile
such as methyl iodide occurs preferentially from the less
sterically hindered trajectory giving the migrated silyl ether
1 as the major product.
To explore the generality of this transformation for the
preparation of orthogonally protected D-xylose deriva-
tives, diol9 wastreated with NaH inDMF and the reaction
was quenched with methanol rather than methyl iodide
(Scheme 4). A 4:1 mixture of inseparable diols 14 and 9 was
formed. Inthe 400 MHz 1H NMR spectrum in CDCl3, 1-H
of the major isomer 14 resonated at δ5.16 (d, J 3.9 Hz)
(10) See for example: (a) Lassaletta, J. M.; Meichle, M.; Weiler, S.;
Schmidt, R. R. J. Carbohydr. Chem. 1996, 15, 241. (b) Faghih, R.; Reid,
B. F. Carbohydr. Res. 1987, 169, 247. (c) Teranishi, K.; Ueno, F.
Tetrahedron Lett. 2003, 44, 4843. (d) Furegati, S.; White, A. J. P.; Miller,
A. D. Synlett 2005, 2385. (e) Lassaletta, J. M.; Schmidt, R. R. Synlett
1995, 925.
(11) (a) Pedersen, C. M.; Marcinscu, L. G.; Bols, M. Chem. Commun.
2008, 2465. (b) Jensen, H. H.; Pedersen, C. M.; Bols, M. Chem.;Eur. J.
2007, 13, 7576.
Org. Lett., Vol. 15, No. 22, 2013
5735

Scheme 3. Proposed Mechanism of Silyl Migration
Scheme 5. Synthesis of 2,3-Dimethyl Ethers
compared with the minor product 9 δ4.69 (d, J 8.0 Hz) in
accord with our earlier observations. The mixture of diols
14 and 9 was acetylated giving diacetates 2 and 11 which
were readily purified by SiO2 column chromatography.
The major product diacetate 2 (79% yield over the two
steps) was generated via migration of the TIPS group from
the 4- to the 3-position in accord with protonation of
intermediateII(R = H, Scheme 3) occurring preferentially
from the less hindered trajectory.
3-Silyl ether 14 was also obtained as the major product
on treatment of 2-silyl ether 10 with NaH in DMF and the
reaction quenched with methanol. Since the NMR data for
10 in CDCl3 were in accord with a boat conformation with
the silyl group axial, it is likely that migration occurs to the
axial 4-hydroxyl prior to further migration to the 3-posi-
tion. From these studies it is apparent that it is unnecessary
to separate diols 9 and 10 (Scheme 1) prior to the silyl
migration and quenching with an appropriate electrophile.
Monomethyl ether 15 was readily acetylated to 16. An
alternative approach to a 3,4-dimethyl ether was via methyla-
tion of the known 4-benzyloxy diol 17.9b,12 Thus we have
established a versatile approach for the synthesis of differen-
tially protected D-xylose 1-thioethers including 2,4-dimethyl
ether 1 and diacetate 2as well as 2,3-dimethyl ethers 13 and 18
and 2,3-diacetate 11.
Turning to glycosylated quinoline 3, the structure of the
natural product was elucidated by spectroscopic methods
and the absolute configuration assumed on the basis of the
more usual D-xylose.6 To confirm the structure and abso-
lute stereochemistry we embarked on the total synthesis
using 2,4-dimethyl thioether 1 prepared as described
above. Two different routes to the synthesis of hydroxy-
quinoline 20 were investigated (Scheme 6). The first ap-
proach was based on the method of Madugula and co-
workers for the preparation of substituted quinolines.13
Scheme 6. Synthesis of Hydroxyquinoline 20
Scheme 4. Silyl Migrations Give 3-Silyl Ether 14 as the Major
Product
Treatment of 4-hydroxy-2-methylaniline 19 with methyl-
vinyl ketone (MVK) in the presence of activated iron(III)
chloride followed by addition of zinc chloride gave 20
in 23% yield. However, the reaction was capricious and
could not be reproduced reliably. Similar problems were
Since silyl migration is dependent upon formation of
alkoxide I and hence the pentacoordinate intermediate II
(Scheme 3), the reaction conditions may be readily mod-
ified for the synthesis of 2,3- rather than 2,4-dimethyl
ethers. For example, reaction of diol 9 with silver oxide,
MeI in CH2Cl2 gave dimethyl ether 13 and 2-monomethyl
ether 15 in 49% and 51% yield respectively confirming that no
silyl migration occurred under these conditions (Scheme 5).
(12) The known benzyl ether 17 was prepared via benzylation of
alcohol 5 followed by deprotection of the acetonide with TsOH in
MeOH.9b
(13) Madugula, S. R. M.; Thallapelly, S.; Bandarupally, J.; Yadav,
J. S. U.S. Patent 2007123708, May 2007.
(14) Beight, D. W.; Bonjouklian, R.; Liao, J.; Mcmillen, W. T.;
Parkhurst, B. L.; Sawyer, J. S.; Yingling, J. M.; York, J. S. U.S. Patent
WO2004026971, April 2004.
5736
Org. Lett., Vol. 15, No. 22, 2013

encountered using sulfuric acid rather than iron(III)
chloride.14 In contrast, with the less activated 4-bromo-2-
methylaniline, 21, reaction with MVK and sulfuric acid
under reflux gave bromoquinoline 22 consistently in 70%
yield. Bromide 22 was converted to the required hydroxy
quinoline 20 via formation of a boronic ester followed by
oxidation.15 The spectroscopic data of 20 were in accord
with the aglycone isolated in very low yields from extracts
of L. majuscula.6
Scheme 8. Completing the Synthesis of Natural Product 3
Scheme 7. Model Glycosylations Using 2-Naphthol
In conclusion, migration of silyl ethers in xylose deriva-
tives occurs readily giving the 3-silyl ether as the major
product. Evidence is presented for a mechanism involving
generation of a five-membered silyl intermediate preferen-
tially followed by reaction with electrophiles from the less
hindered trajectory. This rearrangement was pivotal in the
preparation of 2,4-dimethyl-3-triisopropylsilyl-D-xylose
thioether 1 used for the synthesis of glycosylated quinoline
3 confirming the structure and absolute configuration of
the natural product.
To optimize the glycosylation conditions, model studies were
conducted using 2-naphthol as the acceptor (Scheme 7).16
Reaction of naphthol with 1, NIS, TMSOTf in CH2Cl2/
CH3CN at ꢀ42 °C showed the most promise giving a 1:1
mixture of R:β anomers 23 in 51% yield. Interestingly
when the same conditions were used with the 3-acetoxy
analogue 24,17 the R-anomer 25 was isolated as the sole
product in 89% yield.
These reactions conditions were used for the coupling of
thioether 1 with hydroxyquinoline 20 giving a 1.4:1 mix-
ture of R:β-anomers 26 (Scheme 8). The products were
inseparable by column chromatography, but on removal
of the TIPS group with TBAF both the β- and R-anomers 3
and 27 were isolated. The spectroscopic data and optical
rotation of synthetic 3 were in accord with those reported
for the natural product6 isolated from Lyngbya majuscula
confirming the structure of the natural product.
Acknowledgment. We are grateful to the following for
funding: The Development and Promotion of Science
Technology Talents Project (DPST) Thailand (to A.P.);
the Bristol Chemical Synthesis Centre for Doctoral Train-
ing, funded by EPSRC (EP/G036764/1), AstraZeneca,
GlaxoSmithKline, Novartis, Pfizer, Syngenta, and the
University of Bristol for a studentship to T.W.H.; the
Malaysian Government and Universiti Teknologi Malaysia
(to J.J.). We thank Dr. Mairi Haddow, School of Chem-
istry, University of Bristol for X-ray crystallography and
Professor Roger Alder FRS, School of Chemistry, Uni-
versity of Bristol for useful discussions.
(15) (a) McCubbin, J. A.; Tong, X.; Wang, R.; Zhao, Y.; Snieckus,
V.; Lemieux, R. P. J. Am. Chem. Soc. 2004, 126, 1161. (b) Bunt, A. J.;
Bailey, C. D.; Cons, B. D.; Edwards, S. J.; Elsworth, J. D.; Pheko, T.;
Willis, C. L. Angew. Chem., Int. Ed. 2012, 51, 3901.
(16) For previous studies on the synthesis of aryl glycosides, see: Paul,
S.; Jayaraman, N. Carbohydr. Res. 2007, 342, 1305.
(17) Acetate 24 was prepared from silyl ether 1 by deprotection with
TBAF and acetylation of the resultant 3-alcohol in 78% yield over the
two steps.
Supporting Information Available. Preparation and
characterization of the compounds described in this
paper. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 22, 2013
5737