Diastereoselective synthesis of functionalized 2-methyltetrahydropyran-4- ones

Article abstract of DOI:10.1016/j.tetlet.2011.05.022

A simple procedure for the synthesis of functionalized 2-methyl-2,3- dihydropyran-4-ones, based on the Maitland-Japp reaction, and their diastereoselective conversion into functionalized 2-methyltetrahydropyran-4-ones has been developed. This allows acces

Full text of DOI:10.1016/j.tetlet.2011.05.022

Tetrahedron Letters 52 (2011) 3654–3656
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Diastereoselective synthesis of functionalized 2-methyltetrahydropyran-4-ones
⇑
Paul A. Clarke , Philip B. Sellars, Nimesh Mistry
Department of Chemistry, University of York, Heslington, York, North Yorks YO10 5DD, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple procedure for the synthesis of functionalized 2-methyl-2,3-dihydropyran-4-ones, based on the
Maitland–Japp reaction, and their diastereoselective conversion into functionalized 2-methyltetrahydro-
pyran-4-ones has been developed. This allows access to a structural unit present in a large number of bio-
logically active natural products, and has been successfully applied to the synthesis of the molecule found
in Civet cat secretion.
Received 7 February 2011
Revised 18 April 2011
Accepted 6 May 2011
Available online 13 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
2-Methyldihydropyrans
2-Methyltetrahydropyrans
Maitland–Japp reaction
Civet cat secretion
2-Methyltetrahydropyrans are present in a large number of bio-
logically active natural products, including molecules such as ophi-
ocerins (1a–c),1 pederin (2),2 lasalocid acid (3),3 and the active
constituent in civet cat secretion 44 (Fig. 1). These molecules have
a wide spectrum of biological activity ranging from anti-feedant
activity (pederin), to antibiotic activity (lasalocid acid) to being a
constituent of fragrances (civet cat secretion), thus making them
important targets for synthetic chemists. Despite the popularity
of targets of this type, there are no general procedures for the syn-
thesis of functionalized 2-methyltetrahydropyrans. Rather, each
synthesis relies on an individual and specific strategy for the syn-
thesis of this structural unit.
For example, ophiocerins (1a–c) have been made by the modi-
fication of a carbohydrate in 10 steps,5a and via ring-closing
metathesis,5b the 2-methyltetrahydropyran in pederin (2) (pederic
acid) has been constructed several times by a variety of different
strategies.6 For lasalocid acid (3) the tetrahydropyran ring has been
constructed by ring expansion of tetrahydrofurans7a and by manip-
ulation of a carbohydrate,7b and civet cat secretion 4 has been con-
structed by a plethora of alternative routes.8
tionalized 2-methyltetrahydropyran-4-ones. Precedents from our
earlier work suggested that these could be readily converted into
a variety of functionalized 2-methyltetrahydropyrans by means
of manipulation of the ester and ketone functionalities.10–12
The first challenge that had to be overcome was the propensity
for the Maitland–Japp reaction to deliver mixtures of 2,6-cis and
2,6-trans diastereomers which interconvert under the reaction
conditions.9b,c Additionally, when acetaldehyde had been em-
ployed as one of the aldehydes, the yields of the cyclized products
were always lower than expected. This is presumably due to the
ease with which the aldol dimerization of acetaldehyde occurs un-
der the Lewis acid conditions of the reaction. We wondered if it
would be possible to modify the Maitland–Japp reaction to gener-
ate 2,6-disubstitued 2,3-dihydropyran-4-ones, which could then
be reduced diastereoselectively to provide the desired tetrahydro-
OMe
OH
OH
OMe
OH
OH
We have an interest in the development of new methods for the
synthesis of tetrahydropyrans and wished to include as our targets
some of these natural products. Therefore we decided to extend
our general existing strategy for the synthesis of 2,6-disubstituted
tetrahydropyran-4-ones to include the synthesis of substituted tet-
rahydropyran-4-ones containing a 2-methyl group. We thought
that with suitable modification, our Maitland-Japp procedure
(Scheme 1)9 would provide access to diastereomerically pure func-
OH
O
MeO
O
H
N
O
1a
O
OH
1b
OH
OH
O
OMe
2
O
1c
CO2H
O
4
OH
O
H
O
H
O
OH
CO2H
3
OH
⇑
Corresponding author. Tel.: +44 1904 322614; fax: +44 1904 322516.
E-mail addresses: paul.clarke@york.ac.uk, pac507@york.ac.uk (P.A. Clarke).
Figure 1. Representative 2-methyltetrahydropyran-containing natural products.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.022

P. A. Clarke et al. / Tetrahedron Letters 52 (2011) 3654–3656
3655
Table 2
O
TiCl4, RCHO
Formation of 2-methyltetrahydropyran-4-ones
O
O
OH
O
O
O
HO
MeOH, -78 oC
MeO
R
R1O2C
R1O2C
R1O2C
L-selectride, THF,
O
O
OH
-78 oC
R1CHO
R
O
R
R
O
7
O
MeO2C
R1
MeO2C
R1
6
8
R
R
O
Entry
R
R1
Ratio (7-keto:7-enol:8)
Yield (%)
Scheme 1. The Maitland–Japp reaction.
a
b
c
d
e
f
g
h
i
Ph
Pr
i-Pr
2-Furyl
BnOCH2
BnOCH2CH2
CH3CH@CH
Cy
Me
1:0.34:0
1:0.13:0
1:0.13:0
1:0.2:0
1:0.15:0
1:0.19:0
1:0.15:0
1:0.25:0.35
1:0.14:0
69
61
67
84
62
67
51
83
49
Me
Me
Me
Me
Me
i-Pr
i-Pr
i-Pr
pyran-4-ones. In order to do this we investigated the use of the di-
methyl acetal of N,N-dimethyl acetamide as an alternative to the
second aldehyde partner.
As can be seen from Table 1, a range of d-hydroxy-b-ketoesters
bearing aryl, heteroaryl, alkyl, alkenyl and oxygenated substituents
can be employed, generating the desired 2-methyl-2,3-dihydropy-
ran-4-ones 6 in moderate to good yields.13 The reactions proceed
simply by mixing the reagents together in toluene for between
2 h and 16 h. The work-up consists of removal of the solvent in va-
cuo followed by flash column chromatography, eluting with
EtOAc–petroleum ether mixtures.
Pr
to the literature.9c The trace amounts of enol-trans products could
be separated from the major cis-diastereomers by flash column
chromatography using cyclohexane–EtOAc mixtures as the mobile
phase. An exception to this was 2-methyl-2,3-dihydropyran-4-one
6h which generated a significant amount of the 2,6-trans-tetrahy-
dropyran-4-one 8h as the enol-tautomer; which could not be sep-
arated from the 2,6-cis-tetrahydropyran by chromatography. We
believe that the trans-diastereomer exists solely as the enol-tauto-
mer as this removes unfavorable interaction between the methyl
group at C2 and the equatorial ester group at C3, which would
be present in the keto-tautomer. Additionally the flattening of
the ring by the enol-double bond will also reduce any 1,3-diaxial
interactions present in the trans-diastereomer.
We rationalize the sense of diastereoselectivity as being due to
pseudo-axial addition of a hydride to the double bond of the 2-
methyl-2,3-dihydropyran-4-one followed by pseudo-axial trap-
ping of the resultant enolate from the conformation of the ring
where the R group is in an equatorial position. Thus the addition
of the hydride nucleophile and the proton electrophile occurred
anti to each other (Fig. 2). It is possible that the trans-diastereomers
such as 8h are formed by a retro-Michael/Michael equilibration
which has been shown to occur in these systems under Brønsted
and Lewis acid conditions.9
With a general and viable procedure for the diastereoselective
construction of 2-methyl substituted 2,6-cis-tetrahydropyran-4-
ones we turned our attention to using it for the synthesis of the
natural civet cat secretion product 4 (Scheme 2). Our synthesis
began with 7f, which was transformed into 9 quantitatively by
heating in wet DMF in a microwave for 10 min.15 Tetrahydropy-
ran-4-one 9 was converted into tetrahydropyran 10, quantita-
tively, by the formation of dithiolane and removal of the benzyl
group. Reduction of the dithiolane with Raney Ni and H2 revealed
alcohol 11 in 52% yield. Alcohol 11 was then oxidized with Jones’
reagent to give the carboxylic acid8c in 63% yield, thus completing
With 2-methyl-2,3-dihydropyran-4-ones 6 in hand we next
looked at their conversion into 2,6-functionalized tetrahydropy-
ran-4-ones 7. After screening a number of reducing agents includ-
ing Stryker’s reagent, hydrogenation over 10% Pd/C and Lewis acids
with triethylsilane, all to no effect, we discovered that L-selectride
performed the desired conjugate reduction of 2-methyl-2,3-dihyd-
ropyran-4-ones 6 (Table 2).14 All of the 2-methyl-2,3-dihydropy-
ran-4-ones 6 underwent smooth conjugate reduction to yield
2,6-cis-tetrahydropyran-4-ones in moderate to good yields. In gen-
eral, the 2,6-cis-tetrahydropyran-4-ones existed as a mixture of
keto-/enol-tautomers with the keto-tautomer predominating in a
ratio of approx 10:1. In all cases the stereochemistry of the keto-
tautomers was determined from the magnitudes of the trans-diax-
ial coupling constants between H2–H3 of about 10 Hz and between
H5ax–H6 of about 10 Hz. This assignment was confirmed by NOE
enhancements between the protons at the 2- and 6-positions with
values ranging from 1.7% to 2.6%.14 Additionally, for all the 2,6-cis-
tetrahydropyran-4-one enol-tautomers, the stereochemistry was
elucidated by the presence of NOE enhancements between the pro-
tons at the 2- and 6-positions with values ranging from 1.0% to
1.5%.14 Trace amounts of the 2,6-trans-tetrahydropyran-4-ones
were also formed. The stereochemistry of these products was
determined by the presence of NOE enhancements between H6
and the methyl group at C2 of around 2.4%, and by comparison
Table 1
Formation of 2-methyl-2,3-dihydropyran-4-ones
O
MeC(OMe)2NMe2
PhMe
O
O
OH
R1O2C
R1O
R
R
O
5
6
H
Entry
R
R1
Yield (%)
R
a
b
c
d
e
f
g
h
i
Ph
Pr
i-Pr
2-Furyl
BnOCH2
BnOCH2CH2
CH3CH@CH
Cy
Pr
Me
Me
Me
Me
Me
Me
i-Pr
i-Pr
i-Pr
60
70
70
40
61
72
69
81
75
H
O
O
Me
O
R
R1O2C
H
O
R1O2C
Me
H
H
Figure 2. Explanation of the diastereoselectivity.

3656
P. A. Clarke et al. / Tetrahedron Letters 52 (2011) 3654–3656
6465; (c) Wilson, T.; Kocienski, P.; Faller, A.; Campbell, S. J. Chem. Soc., Chem.
O
O
O
O
Commun. 1987, 106; (d) Jarowicki, K.; Kocienski, P.; Marczak, S.; Wilson, T.
Tetrahedron Lett. 1990, 31, 3433; (e) Jewett, J. C.; Rawal, V. H. Angew. Chem., Int.
Ed. 2007, 46, 6502.
i
ii, iii
MeO2C
OBn
OBn
7. (a) Nakata, T.; Schmid, G.; Vranesic, B.; Okigawa, M.; Smith-Palmer, T.; Kishi, Y.
J. Am. Chem. Soc. 1978, 100, 2933; (b) Ireland, R. E.; Thaisrivongs, S.; Wilcox, C. S.
J. Am. Chem. Soc. 1980, 102, 1155.
7f
9
8. (a) Kim, Y.; Mundy, B. P. J. Org. Chem. 1982, 47, 3556; (b) Semmelhack, M. F.;
Bodurow, C. J. Am. Chem. Soc. 1984, 106, 1496; (c) Jones, J. B.; Hinks, R. S. Can. J.
Chem. 1987, 65, 704; (d) Wei, Z. Y.; Wang, D.; Li, J. S.; Chan, T. H. J. Org. Chem.
1989, 54, 5768; (e) Ragoussis, V.; Theodorou, V. Synthesis 1993, 84; (f)
Edmunds, A. J. F.; Trueb, W. Tetrahedron Lett. 1997, 38, 1009; (g) Banwell, M. G.;
Bissett, B. D.; Bui, C. T.; Pham, H. T.; Simpson, G. W. Aust. J. Chem. 1998, 51, 9; (h)
O’Brien, M.; Cahill, S.; Evans, L. A. Chem. Commun. 2008, 5559; (i) Zhou, H.; Loh,
T.-P. Tetrahedron Lett. 2009, 50, 4368.
S
S
iv
v
O
O
OH
OH
10
11
9. (a) Clarke, P. A.; Martin, W. H. C. Org. Lett. 2002, 4, 4527; (b) Clarke, P. A.;
Martin, W. H. C.; Hargreaves, J. M.; Wilson, C.; Blake, A. J. Chem. Commun. 2005,
1061; (c) Clarke, P. A.; Martin, W. H. C.; Hargreaves, J. M.; Wilson, C.; Blake, A. J.
Org. Biomol. Chem. 2005, 3, 3551; (d) Clarke, P. A.; Santos, S.; Martin, W. H. C.
Green Chem. 2007, 9, 438.
CO2H
O
4
10. Santos. S. Ph.D. Thesis, University of York, 2008.
11. (a) Clarke, P. A.; Martin, W. H. C. Tetrahedron Lett. 2004, 45, 9061; (b) Clarke, P.
A.; Martin, W. H. C. Tetrahedron 2005, 61, 5433.
12. Clarke, P. A.; Hargreaves, J. M.; Woollaston, D. J.; Rodriguez Sarmiento, R. M.
Tetrahedron Lett. 2010, 51, 4731.
Scheme 2. Reagents and conditions: (i)
l-wave, DMF/H2O, 10 min, 100%; (ii)
HSCH2CH2SH, BF3ÁOEt2, CH2Cl2, rt, 100%; (iii) BCl3ÁSMe2, CH2Cl2, rt, 100%; (iv) Raney
Ni, H2, EtOH, 50 °C, 52%; (v) Jones’ reagent, acetone, 63%.
13. General procedure for the formation of 2-methyl-2,3-dihydropyran-4-ones: N,N-
a total synthesis of the civet cat secretion natural product 4 in 5
steps from 7f.
dimethylacetamide dimethyl acetal (1.37 mL, 9.39 mmol) was added to
a
stirred solution of methyl 5-hydroxy-3-oxooctanoate (353 mg, 1.88 mmol) in
anhydrous toluene (12 mL) at room temperature, under nitrogen. The solution
was stirred at room temperature and monitored by TLC. Upon completion of
the reaction, the solvent was removed in vacuo. Purification by flash column
chromatography (petroleum ether–EtOAc) afforded the product, 6b.Yellow oil,
In summary we have developed a general procedure for the
synthesis of 2-methyl-2,3-dihydropyran-4-ones and their diaste-
reoselective reduction to 2-methyl-2,6-cis-tetrahydropyran-4-ones
in moderate to good yields. The utility of this approach has been
demonstrated by a short synthesis of the civet cat secretion natural
product 4. Further investigations into extending the scope of both
the amide acetal coupling partner and the nature of the electro-
philic trap will be reported in due course.
yield: 70%. m
max/cmÀ1 (film) 2960, 2875, 1772, 1700, 1684, 1576, 1559, 1457,
1399, 1340, 1265, 1207, 1084; dH (400 MHz, C6D6) 3.51 (1H, m), 3.47 (3H, s),
1.88 (1H, dd, J = 16.5, 3.7 Hz), 1.80 (3H, s), 1.79 (1H, dd, J = 16.5, 13.1 Hz), 1.14–
0.77 (4H, m) and 0.54 (3H, t, J = 7.3 Hz) ppm; dC (100 MHz, C6D6) 187.0, 175.2,
166.5, 113.3, 79.9, 51.6, 40.9, 36.1, 19.6, 18.0 and 13.7 ppm; m/z (ES+) 235
(M+Na+), 213 (M+H+), 181 (M+ÀCH3OH). (Found 235.0937 M+Na+. C11H16O4
requires 235.0941).
14. General procedure for the formation of 2-methyl-2,6-cis-tetrahydropyran-4-ones:
To
a stirred solution of 2-methyl-4-oxo-6-propyl-5,6-dihydro-4H-pyran-3-
Acknowledgements
carboxylic acid methyl ester (50 mg, 0.24 mmol) in THF (5 mL) at À78 °C,
under nitrogen, was added a 1.0 M solution of L-selectride in THF (0.24 mL,
0.24 mmol). The mixture was stirred for 30 min, then partitioned between Et2O
(15 mL) and saturated aqueous NH4Cl (15 mL). The aqueous layer was washed
with Et2O (3 Â 15 mL) and the combined organic extracts were washed with
brine (15 mL), dried over MgSO4 and concentrated in vacuo. Purification by
flash column chromatography (cyclohexane–EtOAc) afforded the product, 7b.
We thank the University of York (P.B.S.) and the EPSRC/DTA
(N.M.) for funding.
References and notes
Yellow oil, isolated yield: 61%. m
max/cmÀ1 (film) 2959, 2933, 2873, 1747, 1718,
1657, 1618, 1438, 1335, 1261, 1126, 1035; NOE H-2–H-6 1.8%, H-3–H-5ax
0.7%, H-3–H-7 0.9%, enol H-2–H-6 1%; dH (400 MHz, C6D6) 12.64 (0.13H, s,
enol), 4.46 (0.13H, m, enol), 3.91 (1H, dq, J = 10.4, 5.8 Hz), 3.41 (3H, s), 3.25
(0.39H, s, enol), 3.10 (1H, m), 3.00 (1H, dd, J = 10.4, 0.9 Hz), 2.18 (0.13H, m,
enol), 2.04 (1H, dd, J = 14.0, 2.4 Hz), 1.96 (0.13H, m, enol), 1.68 (1H, ddd,
J = 14.0, 11.6, 0.9 Hz), 1.47 (0.39H, d, J = 6.1 Hz, enol), 1.33–0.98 (4H, m), 1.19
(3H, d, J = 6.1 Hz), 0.79 (0.39H, t, J = 7.0 Hz, enol) and 0.72 (3H, d, J = 7.0 Hz)
ppm; dC (100 MHz, C6D6) 201.4, 171.5, 168.8, 102.5, 77.4, 76.6, 75.1, 72.2, 68.9,
64.8, 51.8, 51.0, 47.0, 38.6, 38.0, 35.7, 22.7, 21.0, 18.8, 18.7, 14.3 and 14.2. ppm;
m/z (ES+) 237 (M+Na+), 215 (M+H+), 171. (Found 237.1095 M+Na+. C11H18NaO4
requires 237.1097).
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