A diastereoselective route to 2,6-syn-disubstituted tetrahydropyrans: Synthesis of the civet compound (+)-2-((2S,6S)-6-methyltetrahydro-2H-pyran-2-yl) acetic acid

Article abstract of DOI:10.1039/b810231g

A diastereoselective synthesis of 2,6-syn-disubstituted tetrahydropyrans has been developed based on the ability of furanyl-ether chiral centres to epimerise readily under acidic conditions. This novel methodology was applied to the synthesis of (+)-2-((2S,6S)-6-methyltetrahydro-2H-pyran-2-yl) acetic acid, a component of the African civet cat's glandular marking secretion. The Royal Society of Chemistry.

Full text of DOI:10.1039/b810231g

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A diastereoselective route to 2,6-syn-disubstituted tetrahydropyrans:
synthesis of the civet compound (+)-2-((2S,6S)-6-methyltetrahydro-
2H-pyran-2-yl) acetic acid
Matthew O’Brien,*a Shane Cahillb and Lyndsay A. Evansb
Received (in College Park, MD, USA) 17th June 2008, Accepted 1st September 2008
First published as an Advance Article on the web 30th September 2008
DOI: 10.1039/b810231g
A diastereoselective synthesis of 2,6-syn-disubstituted tetrahydro-
pyrans has been developed based on the ability of furanyl–ether
chiral centres to epimerise readily under acidic conditions. This
novel methodology was applied to the synthesis of (+)-2-
((2S,6S)-6-methyltetrahydro-2H-pyran-2-yl) acetic acid, a com-
ponent of the African civet cat’s glandular marking secretion.
Many natural products of biological and pharmacological
significance contain the 2,6-syn disubstituted tetrahydropyran
moiety.1 An example is (+)-2-((2S,6S)-6-methyltetrahydro-
2H-pyran-2-yl) acetic acid (1), which was isolated by Maurer
and coworkers in 1978 from civet—the perianal glandular
pheromone secretion of the African civet cat (Viverra civetta).2
Scheme 1 Retrosynthesis of 2,6-syn tetrahydropyrans.
amide leads to the d-valerolactones 7, several of which are
commercially available in racemic form.
Treatment of morpholine with aluminium chloride in
dichloromethane followed by addition of the lactones 7a–e
afforded the corresponding morpholine amides 6a–e in high
yield (Scheme 2).6 We initially decided to protect the second-
ary alcohol in 6a as the trimethylsilyl ether (8) prior to
furanylation (Scheme 3). Treatment of a tetrahydrofuran
As both substituents in 2,6-syn disubstituted tetrahydro-
solution of furan with n-butyllithium at ꢀ10 1C followed by
pyrans are in equatorial positions, this configuration is
thermodynamically favoured with respect to the 2,6-anti. Under
conditions where one chiral centre readily epimerises, its
the addition of 8 led to furanyl ketone 9 in high yield.
Exposure of 9 to a catalytic amount of hydrochloric acid in
methanol at room temperature effected the smooth cleavage of
configuration should be controlled by the other, configura-
the trimethylsilyl group (by TLC analysis). The reduction of
tionally more stable chiral centre. We have recently exploited
the ketone group was carried out in the same pot by the
the tendency of furanyl–ether chiral centres to epimerise under
addition of sodium borohydride to furnish the diol 4a as an
acidic conditions in a diastereoselective synthesis of 6,6-spiro-
approximately 1 : 1 mixture of diastereomers (by NMR
ketals3 and we sought to extend this methodology to the
analysis). Although the overall yield of this sequence was
tetrahydropyran system. Our plan is outlined retrosyntheti-
acceptable, we decided to investigate a more direct approach,
cally in Scheme 1.
which avoided the protection step. Accordingly, amide 6a was
The equilibrating mixture of syn and anti tetrahydropyrans
added to a solution of furanyl lithium. After the coupling was
2 and 3 will result from the cyclisation of the configurationally
stable secondary alcohol at C1 onto a cation formed at the C5
position of diol 4 under acidic conditions.4 This cation
formation (and the equilibration of 2 and 3) will be facilitated
by the electron donating ability of the adjacent furan group.
Diol 4 will be formed as a mixture of C5 epimers by means of a
non-selective reduction of the carbonyl group in 5, which in
turn will result from the coupling of a suitable furanyl–metal
reagent with morpholine amide 6.5 Disconnection of this
a Whiffen Laboratory, University Chemical Laboratory, Cambridge
University, Lensfield Road, Cambridge, UK CB2 1EW.
E-mail: mo263@cam.ac.uk
b School of Chemistry, Trinity College Dublin, College Green, Dublin,
D2, Republic of Ireland
Scheme 2 Reagents and conditions: (a) morpholine, AlCl3, DCM,
ꢀ10 1C - rt, then 7, DCM, ꢀ10 1C - rt.
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Table 2 Results of tetrahydropyran syntheses
Entry
Diol Product
R
R0
Yield (%)a syn–anti
1
2
3
4
5
6
7
8
9
10
4a
4b
4c
4d
4e
4f
4g
4h
4i
2a
2b
2c
2d
2e
2f
2g
2h
2i
Me
H
H
H
H
H
Me
90
95
91
89
93
92
90
88
94
90
95 : 5
93 : 7
94 : 6
94 : 6
94 : 6
95 : 5
93 : 7
91 : 9
94 : 6
94 : 6
C5H11
C6H13
C7H15
C9H19
Me
C5H11 Me
C6H13 Me
C7H15 Me
C9H19 Me
4j
2j
a
Scheme 3 Reagents and conditions: (a) TMSCl, imidazole, DCM,
0 1C; (b) nBuLi, furan, THF–hexanes, ꢀ10 1C, then 8; (c) HCl (2N aq.,
cat.), MeOH, then NaBH4; (d) nBuLi, furan or methylfuran,
THF–hexanes, ꢀ10 1C, then 6a–e, then MeOH, then NaBH4, 0 1C.
Isolated as a syn–anti mixture after column chromatography on
silica gel.
approximately 2 : 1 in favour of the 2,6-syn tetrahydropyrans
(stereochemistry determined by NOE) but equilibration led to
an increase in the diastereomeric ratio. The reaction mixtures
were monitored periodically by NMR analysis. After stirring
at room temperature for 7 days, the diastereomeric ratios
remained constant (d.r. greater than 10 : 1 in all cases, Table 2)
and the reactions were worked up to afford products 2a–j
in high yield (Scheme 4, Table 2). Having established the
diastereoselectivity of the tetrahydropyran formation, we
commenced the synthesis of the civet cat secretion compound
(+)-2-((2S,6S)-6-methyltetrahydro-2H-pyran-2-yl) acetic acid
1. Racemic 6a was exposed to an excess of vinyl acetate in
toluene in the presence of catalytic Candida antarctica lipase B
(CALB) supported on acrylic resin to afford a 1 : 1 mixture of
the (5R)-acetate 10 and the (5S)-alcohol (5S)-6a, which were
separated by column chromatography (Scheme 5).
Table 1 Results of one-pot diol formation
Entry
Amide
Diol
R
R0
Yield (%)a
1
2
3
4
5
6
7
8
9
10
6a
6b
6c
6d
6e
6a
6b
6c
6d
6e
4a
4b
4c
4d
4e
4f
4g
4h
4i
Me
H
H
H
H
79
88
91
88
94
85
93
89
90
91
C5H11
C6H13
C7H15
C9H19
Me
C5H11
C6H13
C7H15
C9H19
H
Me
Me
Me
Me
Me
4j
a
Isolated yield after column chromatography over silica gel.
complete (by TLC analysis), the reaction was quenched with
methanol. Subsequent addition of sodium borohydride
afforded the desired diol 4a in good yield (79%).
The ee of (5S)-6a was determined to be at least 95% by com-
1
parison of the H NMR spectra of its (S)-acetoxymandelate
Using this direct one-pot approach, we synthesised ten
different 1,5-diol substrates, coupling the amides 6a–e to either
furan or 2-methylfuran. All diols were formed as approxi-
mately 1 : 1 mixtures of diastereomers in high yield (Table 1).
With the substrates 4a–j in hand, we turned our attention to
the acid catalysed cyclisation–epimerisation. When the diols
were taken up in deuterochloroform and exposed to catalytic
amounts of para-toluenesulfonic acid, they rapidly cyclised to
give a mixture of tetrahydropyrans (as monitored by TLC
and/or NMR analysis), presumably by a mechanism similar to
that shown in Scheme 4. The initial ratio of stereoisomers was
ester 11 (single set of peaks) with that of the (S)-acetoxy-
mandelate esters (11 and 5-epi-11) of rac-6a (two sets of
peaks), Scheme 6. Inspection of these spectra also confirmed
the 5S stereocentre.7 Cyclisation to the tetrahydropyran (S,S)-
2a was carried out in a likewise fashion to the racemate 2a
(Scheme 5). The furan group in (S,S)-2a was cleaved to
the carboxylic acid 12 using sodium periodate and catalytic
ruthenium trichloride (Scheme 7).8
Both (R) and (S) 10-phenylethylamides (16 and 10-epi-16) of
12 were formed as single diastereoisomers with distinct 1H
NMR spectra, indicating that 12 was formed as a single
Scheme 5 Reagents and conditions: (a) Candida antarctica lipase B on
acrylic resin, vinyl acetate, toluene, rt, 18 h; (b) i. nBuLi, furan,
THF–hexanes, ꢀ10 1C, then (5S)-6a, then MeOH, then NaBH4, 0 1C;
ii. pTSA, CDCl3, rt, 7 d, then hexane, silica gel chromatography.
Scheme 4 Reagents and conditions: (a) pTSA, CDCl3, rt, 7 d, then
hexane, silica gel chromatography.
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without isolating 13 by the addition of triethylamine and
trimethylsilyl-diazomethane to afford 14 in good yield. Wolff
rearrangement10 followed by saponification afforded the
natural product 111 whose spectral data and optical rotation
were consistent with those reported in the literature.2,12
Further exploration of the scope of this methodology is
underway and will be published in due course.
We gratefully acknowledge Professor Steven V. Ley for
his support of this work and Trinity College Dublin for a
scholarship (SC).
Scheme 6 Reagents and conditions: (a) (S)-acetylmandelic acid,
EDCI, DMAP, DCM, rt.
Notes and references
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D. E. Williams, R. A. Keyzers, K. Warabi, K. Desjardine, J. L.
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2 (a) B. Maurer and W. Thommen, Helv. Chim. Acta, 1979, 62,
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Scheme 7 Reagents and conditions: (a) RuCl3ꢂH2O (cat.), NaIO4,
DCM, MeCN, H2O; (b) oxalyl chloride, DMF (cat.), DCM or
N,N-dimethyl(1-chloro-2-methyl-propenyl)amine; (c) TMSCHN2,
Et3N, Et2O, DCM; (d) AgOBz, Et3N, MeOH, 80 1C, then NaOH,
H2O, 60 1C then HCl.
8 P. H. J. Carlsen, T. Katsuki, V. S. Martin and K. B. Sharpless,
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10 M. S. Newman and P. F. Beal, J. Am. Chem. Soc., 1950,
5163–5165.
11 The intermediates in this sequence were carried through as a 95 : 5
mixture of diastereomers. 1 was isolated as a single diastereomer
after column chromatography on silica gel.
12 (a) M. F. Semmelhack and C. Bodurow, J. Am. Chem. Soc., 1984,
106, 1496–1498; (b) E. Keinan, K. K. Seth and R. Lamed, J. Am.
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9660–9661; (e) V. Ragoussis and V. Theodorou, Synthesis, 1993,
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Scheme
8
Reagents and conditions: (a) (R)-1-phenylethylamine,
EDCI, DMAP, DCM, 0 1C; (b) (S)-1-phenylethylamine, EDCI,
DMAP, DCM, 0 1C.
enantiomer and proving that the stereochemical integrity of
the (S)-methyl carbinol centre from (5S)-6a was still intact
(Scheme 8).
Arndt–Eistert homologation began with the conversion of
12 to the corresponding acid chloride 13 (Scheme 7) using
Ghosez’s reagent.9 Diazoketone formation was carried out
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Chem. Commun., 2008, 5559–5561 | 5561