First enantioselective synthesis of (-)-(2s,6s)-(6-ethyltetrahydropyran-2- yl)formic acid

Article abstract of DOI:10.1055/s-2005-863744

We describe in this letter the first enantioselective synthesis of (-)-(2S,6S)-(6-ethyltetrahydropyran-2-yl)formic acid (2) in five steps (30% overall yield, 87% ee), from the commercial chiral template (R)-2,3- isopropylideneglyceraldehyde (4). The two stereogenic centers in 2 were controlled by diastereoselective Barbier allylation of 4 in aqueous media and an efficient Prins cyclization reaction between 5 with propanal.

Full text of DOI:10.1055/s-2005-863744

LETTER
869
First Enantioselective Synthesis of (–)-(2S,6S)-(6-Ethyltetrahydropyran-
2
-yl)formic Acid
a
a
a
a
E
L
nantioselective
e
Synthesis
a
of (–)-(2
S
,6
n
S
)-(6-Ethylt
d
etrahydropyr
r
an-2-yl)
o
formic
A
cid S. M. Miranda, Bruno A. Meireles, Jerônimo S. Costa, Vera. L. P. Pereira,
b
Mário L. A. A. Vasconcellos*
a
Núcleo de Pesquisas de Produtos Naturais, Universidade Federal do Rio de Janeiro, Bloco H, CCS, Ilha do Fundão, Rio de Janeiro, RJ,
1941-590, Brasil
2
b
Departamento de Química, Universidade Federal da Paraíba, Campus I, João Pessoa, PB, 58059-900, Brasil
Fax +55(83)2167413; E-mail: mlaav@quimica.ufpb.br
Received 22 December 2004
Abstract: We describe in this letter the first enantioselective syn-
thesis of (–)-(2S,6S)-(6-ethyltetrahydropyran-2-yl)formic acid (2)
in five steps (30% overall yield, 87% ee), from the commercial
chiral template (R)-2,3-isopropylideneglyceraldehyde (4). The two
stereogenic centers in 2 were controlled by diastereoselective
Barbier allylation of 4 in aqueous media and an efficient Prins
cyclization reaction between 5 with propanal.
H
H
H
H
HO
HO
HO
O
O
O
O
O
O
(
–)-(2S,6S)
(+)-(2R,6R)
(
±)-cis
1
2
3
Key words: enantioselective synthesis, antinociceptive activity,
tetrahydropyran, Prins cyclization, Barbier reaction, (R)-2,3-O-iso-
propylideneglyceraldehyde
Figure 1 Cis-(6-ethyl-tetrahydropyran-2-yl)formic acids.
hol 5 and propanal, through intermediate B, furnishing the
3
–5
cis-configuration between C -C . To the best of our
2
6
Six-membered ring saturated oxygen heterocycles are an knowledge the homoallylic alcohol 5 has never been used
1
integral part of many biologically active compounds. The as substrate on the Prins cyclization, probably due the
Prins cyclization of homoallylic alcohols with aldehydes
under strongly protic acidic conditions is an old reaction,2
that is now emerging as an efficient methodology for the
presence of a ketal moiety, which could lead to side reac-
tions in such an acidic media. However, the use the
homoallylic alcohol 5 in this synthesis leads to a few steps
procedure, avoiding deprotection–protection steps.
Finally the anti-5 could be prepared through a diastereo-
selective Barbier reaction between the synthon 4 and
3
preparation of substituted tetrahydropyran. In general,
2
,4,6-cis all equatorial substituted are obtained in high
4
,5
diastereoselectity.
In a recent paper, Rychnovsky
developed the first axial-selective Prins cyclization allylbromide.10
methodology to the heteroatom at the 4-position, expand-
6
ing the synthetic scope of this reaction.
Br
4
7
In our search for bioactive substances we have detected a
very active one, the (±)-cis-(6-ethyltetrahydropyran-2-
yl)formic acid (1), as a novel class of non-steroidal anal-
3
5
(R)
(S)
(S)
HO
(R)
2
O
6
O
(S) O (S)
1
8
gesic compound. In our previous paper, 1 was efficiently
O
O
A
2
prepared in the racemic form and showed important anal-
8
gesic properties in the tail flick model. In order to provide
Prins cyclization
this compound as a pure enantiomer for further pharmaco-
logical assays, we decided to create a fast enantioselective
synthesis of 2 which could be also appropriate to prepare
(R)
(
R)
(S) OH
+
O
3
. In this letter we described the first total enantioselective
(S) O
O
O
synthesis of 2 (Figure 1), based on the strategy of con-
structing the tetrahydropyran ring through an efficient
diastereoselective Prins cyclization.
O
O
5
B
In our retro-synthetic analysis of 2 (Scheme 1) the ketal A
OH
O
can be easily transformed to the carboxylic acid moiety of
Barbier reaction
Br
9
(R)
(R)
2
, trough a oxidative cleavage. The stereogenic carbon
(S)
+
O
O
on C (S) present in A could be controlled through a dia-
6
O
O
stereoselective Prins reaction, between homoallylic alco-
5
4
SYNLETT 2005, No. 5, pp 0869–0871
Advanced online publication: 09.03.2005
2
1.
0
3.
2
0
0
5
Scheme 1 Retro-synthetic analysis of 2.
DOI: 10.1055/s-2005-863744; Art ID: S11704ST
©
Georg Thieme Verlag Stuttgart · New York

8
70
L. S. M. Miranda et al.
LETTER
The (R)-2,3-isopropylideneglyceraldehyde (4) and its Then, compound 5 was treated with propanal and SnBr4,
enantiomer are commercially available and can be effi- and ethyl-ketal 8 was obtained subsequently in 66% yield
ciently prepared from D-mannitol and L-ascorbic acid, re- as a mixture of 4 diastereoisomers (Scheme 4).14
spectively. Both have been extensively used as starting
1
1
materials in enantioselective synthesis.
Br
The present synthesis of 2 starts with the allylation of the
non-distilled aldehyde 4 with allyl bromide under zinc-
mediated Barbier protocol in aqueous media, leading to
O
O
a
O
O
1
2
the formation of homoallylic alcohol 5 in 74% yield, as
an epimeric mixture (77:23, anti:syn, Scheme 2). It is im-
portant to note that the stereoselectivity using our protocol
was similar to that obtained in the literature, in which the
very expensive metallic indium in non-catalytic amounts
O
OH
5
8
b,c
9
is used as promoter.
We believe that the major anti-epimer could be obtained
through a chelated six-membered ring transition state,
where the allylzinc attacks the less hindered Si face of the
HO
O
1
1
OH
chiral aldehyde 4 (Scheme 2).
9
δ–
O
δ+
Zn
O
Scheme 4 Reagents and conditions: a) SnBr , propanal; CH Cl ,
4
2
2
Zn
O
-
0 °C, 66%; b) NaBH , DMSO, 80 °C; c) HCl, MeOH, 24 h, r.t., 88%
4
O
slow step
δ
(
two steps).
O
O
-
H
δ
H
H
H
Compound 8 was converted in the diol 9 (Scheme 5) in a
sequence concerning of debromination with sodium boro-
hydride followed by acidic ketal opening in 88% yield for
1
5
O
the two steps and 96% de measured by GC/MS. Finally,
O
O
(
s)
the oxidative cleavage of 9 with NaIO led to aldehyde 12
which was immediately converted to de desired (S,S)-cis-
Zn
4
water
O
OH
fast step
O
acid 2 through oxidation using NaClO –H O in 90%
H
2
2
2
H
5
yield and 87% ee (measured through chiral capillary gas
chromatography).16
Scheme 2
The separation of the anti-diastereoisomer of 5 from the
diastereoisomeric mixture was difficult to accomplish by
chromatographic methods. Thus, a selective transketaliza-
tion of the syn-isomer led to trans-ketal 6, which was eas-
ily separated by column chromatography, yielding the
a
HO
O
O
OH
O
9
12
1
3
desired anti-isomer in 92% de (Scheme 3).
b
HO
O
O
O
O
2
OH
5
anti/syn (96:4)
Scheme 5 Reagents and conditions: a) NaIO , MeOH–H O (1:3),
4 2
O
O
O
O
a
b
93%; b) NaClO , H O , 90%.
2 2 2
+
CHO
OH
O
O
In conclusion, we present in this letter the following
results: (1) the first example using the (R)-2,3-isopropyl-
idene glyceraldehyde (4) as an efficient chiron template in
an enantioselective strategy of construction of the tetrahy-
4
5
HO
anti/syn (77:23)
trans-6
Scheme 3 Reagents and conditions: a) Zn, allyl bromide; THF– dropyran ring through the Prins cyclization; (2) a fast and
NH Cl (1:5), 74%; b) acetone, p-TSA, 71%.
4
efficient first total enantioselective synthesis to the tet-
rahydropyran derivative (S,S)-2, a novel class of analgesic
Synlett 2005, No. 5, 869–871 © Thieme Stuttgart · New York

LETTER
Enantioselective Synthesis of (–)-(2S,6S)-(6-Ethyltetrahydropyran-2-yl)formic Acid
871
compound; (3) an efficient methodology to purify an
epimeric mixture of 5 through a selective transketalization
of the syn-isomer vs. the trans-isomer. Once the enantio-
mer (S)-2,3-isopropylidene glyceraldehyde is commercial
or easily prepared from L-ascorbic acid, our approach also
allows a fast and efficient synthesis of the enantiomer
Asymmetry 2004, 15, 2075. (d) Thijs, L.; Zwanenburg, B.
Tetrahedron 2004, 60, 5237. (e) Matsuya, Y.; Itoh, T.;
Nemoto, H. Eur. J. Org. Chem. 2003, 12, 2221. (f) Boyer,
S. H.; Ugarkar, B. G.; Erion, M. D. Tetrahedron Lett. 2003,
44, 4109.
(
12) (a) The diastereoisomeric purity of 5 was determined
13
9
through C NMR spectroscopy (ref. ), and its enantiomeric
purity through comparison of its optical rotation with
(
R,R)-3. Detailed pharmacological assays, comparing the
racemic (±)-1 with the enantiopure (S,S)-2 and (R,R)-3 is
now under investigation.
literature reference data: [a] 15.0 (92% de and 87% ee).
D
See: Roush, W. H.; Walts, A. E.; Hoong, L. K. J. Am. Chem.
1
Soc. 1985, 107, 8186. (b) Spectroscopical data of anti-5: H
NMR (200 MHz, CDCl ): d = 5.92–5.75 (m, 1 H), 5.20 (m,
3
References
1 H), 5.10 (m, 1 H), 4.05–3.87 (m, 3 H), 3.77 (dq, J = 8.8,
4
1
1
.4 Hz, 1 H), 2.43–2.10 (m, 2 H), 2.00 (d, J = 3.4 Hz, 1 H),
(1) (a) Class, Y. J.; DeShong, P. Chem. Rev. 1995, 95, 1843.
13
.43 (s, 3 H), 1.37 (s, 3 H). C NMR (50 MHz, CDCl ): d =
3
(
(
b) Norcross, R. D.; Paterson, I. Chem. Rev. 1995, 95, 2041.
c) Marko, I. E.; Bayston, D. J. Synthesis 1996, 297.
33.8, 118.1, 108.9, 77.9, 70.2, 65.0, 37.4, 26.3, 25.0. MS
(70 eV): m/z (%) = 59 (100), 73 (35), 101 (72), 114 (2.5), 131
(2) (a) Hanschke, E. Chem. Ber. 1955, 88, 1053. (b) Stapp, P.
R. J. Org. Chem. 1969, 34, 479.
(
1
7), 157 (45). IR (KBr, neat): 3444, 3078, 2987, 2936, 2899,
642, 1456, 1435, 1381, 1254, 1215, 1066, 917, 854 cm .
–1
(
3) (a) Arundale, E.; Mikeska, L. A. Chem. Rev. 1952, 52, 505.
(
13) Experimental Procedure for Diastereoisomeric
Enrichment of anti-5.
(
(
b) Adams, D. R.; Bhatnagar, S. P. Synthesis 1977, 661.
c) Snider, B. B. In The Prins Reaction and Carbonyl Ene
To a stirred solution of the diastereoisomeric mixture of 5
Reactions, Vol. 2; Trost, B. M.; Fleming, I.; Heathcock, C.
H., Eds.; Pergamon Press: New York, 1991, 527–561.
4) For recent work on the Prins cyclization, see: (a) Liu, J.;
Hsung, R. P.; Peters, S. D. Org. Lett. 2004, 6, 3989.
(
3.0 g, 17.4 mmol) in 45 mL of dry acetone, under Ar
atmosphere, is added in one portion 0.2 g of p-TSA (1.04
mmol). The reaction is left stirring at –15 °C for 48 h, then
the solvent is evaporated under reduced pressure and the
residue submitted to flash column chromatography yielding
(
(
b) Overman, L. E.; Velthuisen, E. J. Org Lett. 2004, 6,
853. (c) Hart, D. J.; Bennet, C. E. Org. Lett. 2003, 5, 1499.
d) Barry, C. S. J.; Crosby, S. R.; Harding, J. R.; Hughes, R.
A.; King, C. D.; Parker, G. D.; Willis, C. L. Org. Lett. 2003,
, 2429. (e) Miranda, P. O.; Diaz, D. D.; Padron, J. I.;
Bermejo, J.; Martin, V. S. Org. Lett. 2003, 5, 1979.
f) Lopez, F.; Castedo, L.; Mascarenas, J. L. J. Am. Chem.
3
(
1.6 g (71%) of diastereoisomeric enriched 5 (92% de).
(
14) To a stirred solution of 5 (0.5 g, 2.9 mmol) in dry CH Cl (5
2
2
mL), under an Ar atmosphere, is added propanal (0.5 mL, 6
mmol). The reaction mixture is cooled in an ice bath and
then a solution of SnBr (1.25 g in 3 mL of dry CH Cl ) is
5
4
2
2
(
slowly added. The reaction is monitored through TLC and
then quenched with 4 mL of a sat. solution of NaHCO3
followed by 5 mL of EtOAc. The mixture is left stirring for
more 40 min. The aqueous phase is then extracted with
EtOAc (3 ꢀ 5 mL). The combined organic phases are dried
Soc. 2002, 124, 4218. (g) Crosby, S. R.; Harding, J. R.;
King, C. D.; Parker, G. D.; Willis, C. L. Org. Lett. 2002, 4,
3407. (h) Crosby, S. R.; Harding, J. R.; King, C. D.; Parker,
G. D.; Willis, C. L. Org. Lett. 2002, 4, 577. (i) Cho, Y. S.;
Kim, H. Y.; Cha, J. H.; Pae, A. N.; Koh, H. Y.; Choi, J. H.;
Chang, M. H. Org. Lett. 2002, 4, 2025. (j) Yang, X. F.;
Mague, J. T.; Li, C. J. J. Org. Chem. 2001, 66, 739.
with anhyd NaSO and then concentrated. The crude product
4
is filtered through silica (eluted with 20% EtOAc–hexanes)
furnishing 0.55 g of 8 as a mixture of four diastereomers.
(
(
(
5) Alder, R. W.; Harvey, J. N.; Oakley, M. T. J. Am. Chem. Soc.
1
(
15) Spectroscopical data of 9: [a] –5.5 (c 2.9, CHCl ). H NMR
D
3
2
002, 124, 4960.
6) Jasti, R.; Vitale, J.; Rychnovsky, S. D. J. Am. Chem. Soc.
004, 126, 9904.
(
200 MHz, CDCl ): d = 3.8 (m, 2 H), 3.6 (m, 1 H), 3.4 (dq,
3
1
H, J = 11.09, 5.12, 1.83 Hz), 3.20 (m, 2 H), 2.40 (br s, 1
2
H), 1.90 (m, 1 H), 1.20–1.70 (m, 7 H), 0.90 (t, 3 H, J = 7.33
7) (a) de Souza, R. O. M. A.; Meireles, B. A.; Sequeira, L. S.;
13
Hz). C NMR (50 MHz, CDCl ): d = 79.9, 79.5, 73.5, 63.7,
3
Vasconcellos, M. L. A. A. Synthesis 2004, 1595.
3
1
3
0.9, 29.1, 27.2, 23.0, 9.7. MS (70 eV): m/z (%) = 143 (9),
(
2
b) Miranda, L. S. M.; Vasconcellos, M. L. A. A. Synthesis
004, 1767.
31 (4), 113 (57), 95 (98), 69 (61), 55 (100). IR (KBr, neat):
–1
390, 2934, 2856, 1460, 1441, 1085, 1045 cm .
(
(
8) Miranda, L. S. M.; Marinho, B. G.; Leitão, S. G.; Matheus,
E. M.; Fernandes, P. D.; Vasconcellos, M. L. A. A. Bioorg.
Med. Chem. Lett. 2004, 14, 1573.
(
16) Spectroscopical data of 2 [a] –45.2 (c 0.53, CHCl , 87%
D
3
1
ee). H NMR (200 MHz, CDCl ): d = 4.0 (dd, 1 H, J = 9.1,
3
2
.7 Hz), 3.4 (m, 1 H), 2.40 (m, 1 H), 2.00 (m, 2 H), 1.00–1.80
9) Dalcanalc, E.; Montanari, F. J. J. Org. Chem. 1986, 51, 567.
13
(
m, 6 H), 0.99 (t, 3 H, J = 7.2 Hz). C NMR (50 MHz,
(
(
10) (a) Paquette, L. A.; Mitzel, T. M. J. Am. Chem. Soc. 1996,
18, 1931. (b) Wang, Z. Y.; Pan, C. F.; Zhang, Z. H.; Sun,
G. J. Org. Lett. 2004, 6, 3059.
11) (a) Jurckak, J.; Pikul, S.; Bauer, T. Tetrahedron 1986, 42,
CDCl ): d = 147.3, 79.5 75.8, 29.9, 28.7, 28.3, 23.0, 9.6. MS
3
1
(
(
1
70 eV): m/z (%) = 129 (10), 113 (77), 101 (33), 95 (100). IR
KBr, neat): 3412, 2961, 2938, 2877, 2861, 1732, 1651,
–1
441, 1383, 1203, 1105, 918 cm .
1
0b
447. (b) For some recent examples see ref. (c) See also:
Wroblewski, A. E.; Halajewska-Wosik, A. Tetrahedron:
Synlett 2005, No. 5, 869–871 © Thieme Stuttgart · New York