PdII-catalyzed stereospecific formation of tetrahydro- and 3,6-dihydro[2H]pyran rings: 1,3-Chirality transfer by intramolecular oxypalladation reaction

Article abstract of DOI:10.1016/j.tetasy.2005.02.006

The stereospecific synthesis of 2,6-disubstituted tetrahydropyran and 3,6-dihydro[2H]pyran is described. The Pd^II-catalyzed cyclization of the hydroxy nucleophile to the allylic alcohol takes place efficiently under mild conditions, with the st

Full text of DOI:10.1016/j.tetasy.2005.02.006

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1299–1303
PdII-Catalyzed stereospecific formation of tetrahydro- and
3,6-dihydro[2H]pyran rings: 1,3-chirality transfer by
intramolecular oxypalladation reaction
Junꢀichi Uenishi,* Masashi Ohmi and Atsushi Ueda
Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8412, Japan
Received 10 January 2005; accepted 4 February 2005
Abstract—The stereospecific synthesis of 2,6-disubstituted tetrahydropyran and 3,6-dihydro[2H]pyran is described. The PdII-cata-
lyzed cyclization of the hydroxy nucleophile to the allylic alcohol takes place efficiently under mild conditions, with the stereogenic
center on the secondary allylic alcohol transfers to a newly generated stereogenic center on pyran ring via a syn-SN20 type process.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
OH
X
O
Tetrahydro- and 3,6-dihydro[2H]pyran rings bearing
substituents at the 2- and/or 6-positions are often ob-
served in many biologically important natural products,
such as phorboxazole,1a zampanolide,1b lasonolide,1c
ratjadone,1d leucascandrolide,1e swinholides,1f misaki-
nolides,1g sorangicin A,1h scytophycins,1i,j laulimalide1k
and so on. The cis or trans configuration of the 2,6-sub-
stituents on the rings can influence both the three dimen-
sional molecular configuration and biological activity of
these natural products. Therefore, the stereocontrolled
synthesis of 2,6-disubstituted tetrahydro- and 3,6-dihy-
dro[2H]pyrans is an important task for synthetic organic
chemistry. Although a number of methods for hydropy-
ran synthesis have been reported,2a–k an efficient and
highly stereocontrolled method for rings construction
is still in need.
PdII
X-
- Pd0
- H+
PdII
- PdII
- OH-
H
X
X
HO
Scheme 1.
an exo- or endo-trigonal fashion, an oxygen heterocycle
would be formed, as shown in Scheme 2.4,5
n-exo-trig
*
OH
*
n
PdII
O
O
H
Nucleophilic attack of heteroatoms to Pd p-complexes is
well known in Pd-catalyzed reactions.3 When the reac-
tion occurs to an allyl alcohol, as shown in Scheme 1,
an SN20-type replacement takes place to give an a-het-
eroatom-substituted alkene by addition of PdII and Xꢀ
to alkene and elimination of hydroxide anion and PdII,
while it also gives the b-heteroatom-substituted ketone
by the Wacker type process. If the former reaction can
occur intramolecularly with the hydroxy nucleophile in
OH
*
n-endo-trig
*
n
O
PdII
H
O
Scheme 2.
In addition, if a stereogenic center of a secondary alco-
hol is designed properly, a stereospecific intramolecular
oxypalladation and elimination can take place to give
stereodefined tetrahydro- and 3,6-dihydro[2H]pyran
rings by a 1,3-chirality transfer process. Therefore, we
chose substrates 1 and 10 for the synthesis of tetrahydro-
pyran 2 via 6-exo-trig cyclization and 3 and 30 for that of
*
Corresponding author. E-mail: juenishi@mb.kyoto-phu.ac.jp
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.02.006

1300
J. Uenishi et al. / Tetrahedron: Asymmetry 16 (2005) 1299–1303
HO
OH
ζ
ε
δ
H
H
H
H
H
H
H
H
O
1
6-exo-trig
O
O
O
PdII
HO
OH
trans-2E
trans-2Z
cis-2E
cis-2Z
1'
Ph
Ph
OH
δ
β
γ
Ph
Ph
OH
H
H
6-endo-trig
H
H
O
O
3
PdII
OH
OH
cis-4
trans-4
3'
Scheme 3.
3,6-dihydro[2H]pyran 4 via 6-endo-trig cyclization. The
expected products for these reactions are cis- and
trans-2 and 4, as shown in Scheme 3.
pated to be difficult, an enantioselective synthesis has
been undertaken. Racemic 6-hepten-2-ol 5 was prepared
from 5-hexen-1-ol by Swern oxidation and Grignard
addition of the resultant aldehyde with MeMgI. The
racemic alcohols were subjected to lipase catalyzed
kinetic acetylation by Candida antarctica lipase (Cal)
with vinyl acetate.6 An (S)-alcohol (S)-5 was recovered
in 45% yield with >98% ee along with (R)-acetate (R)-6
in 49% yield with >98% ee. Silylation of (S)-5 with
TBDMSCl gave 7 in 78% yield. Ozonolysis and Wittig
reaction with triphenylphospholideneacetone gave
(S)-8-TBDMSoxy-3-nonen-2-one 8 in 79% yield in two
steps. Reduction of the carbonyl group with NaBH4 in
the presence of CeCl3 heptahydrate gave diastereomeric
alcohols in a 1:1 ratio in 91% yield, which was acetylated
again with vinyl acetate in the presence of lipase Cal to
Herein we report a novel stereospecific ring construction
for tetrahydro- and 3,6-dihydro[2H]pyrans by the
PdCl2(MeCN)2 catalyzed cyclization of f-hydroxy-d,e-
unsaturated and b-hydroxy-c,d-unsaturated alcohols.
2. Results and discussion
2.1. Synthesis of the starting materials
The synthesis of 1 and 10 is described in Scheme 4. Since
the separation of remote diastereomeric diols is antici-
OH
OH
OAc
a, b
c
HO
3
3
3
3
5
(R)-6
(S)-5
OTBDMS
OTBDMS
O
OTBDMS OH
e
f
d
3
3
3
8
9
7
TBDMSO
OH
g
1
3
(S)-9
OAc
c
TBDMSO
g, h
1'
3
10
i
˚
Scheme 4. Reagents and conditions: (a) Swern oxidation (80%); (b) MeMgI, Et2O, 0 °C–rt (75%); (c) Cal, vinyl acetate, MS 4 A, PrO2, rt [(S)-5: 45%,
(R)-6: 49%]; (d) TBDMSCl, imidazole, DMF, rt (78%); (e) ozonolysis then Ph3P@CHCOMe, CH2Cl2, ꢀ78 °C to rt (79%); (f) NaBH3, CeCl3Æ7H2O,
MeOH, 0 °C–rt (91%); (g) TBAF, THF, rt (95–98%); (h) K2CO3, MeOH, rt (88%).

J. Uenishi et al. / Tetrahedron: Asymmetry 16 (2005) 1299–1303
1301
give the (R)-acetate 10 in 45% yield and the (S)-alcohol
(S)-9 in 48% yield. After desilylation of (S)-9, diol 1 was
obtained in 95% yield. On the other hand, treatment of
10 with TBAF followed by methanolysis with K2CO3 in
methanol gave 10 in 86% yield (Scheme 5).
reactions proceeded very smoothly to completion within
30 min under the mild reaction conditions employed, in
nearly quantitative yield.9 The results indicate that the
1,3-chirality transfer of the starting allylic alcohol to
the tetrahydropyran ring is perfectly controlled, in
which a syn-SN20 type cyclization takes place stereospe-
cifically by PdII-promoted 6-exo-trig cyclization. This
stereochemical outcome is more interesting in compari-
son with the case of the nitrogen nucleophile in the
piperidine synthesis (Scheme 6).10
Ph
Ph
OR
O
a
OH
O
b
Ph
O
H
HO
12
H
H
O
11
10% PdCl2(MeCN)2
THF, 0 ˚C, 30 min
O
OH
R = TBDMS
Ph
Ph
1
trans-2E
O
OR
HO
OH
d
e
H
O
3
H
H
O
10% PdCl2(MeCN)2
THF, 0 ˚C, 30 min
H
OH
c
14
cis-2E
13
1'
Scheme 6.
Ph
Ph
O
OR
OH
On the other hand, when diol 3 was subjected to the
above conditions at rt, cis-4 was obtained as a single dia-
stereoisomer in 68% yield after 7 h.11 The reaction of 30
with PdCl2(MeCN)2 under the same reaction conditions
was completed in 23 h to give trans-4 in 60% yield.11
Both reactions afford a syn-SN20 type product, the same
as that in the above 6-exo-trig cyclizations. Although
6-endo-trig cyclization is allowed in Baldwinꢀs rule,12
the reaction rate for the 6-endo-type cyclization is slower
than that in the exo-type (Scheme 7).
d
e
H
3'
O
H
14'
13'
Scheme 5. Reagents and conditions: (a) LDA, THF, ꢀ78 °C (79%); (b)
TBDMSCl, imidazole, DMF, rt (82%); (c) NaBH4, CeCl3Æ7H2O,
MeOH, 0 °C–rt (13: 48%, 130: 45%); (d) TBAF, THF, rt (3: quant., 30:
quant.); (e) 2,2-dimethoxypropane, CSA, rt (14: 86%, 140: 86%).
The synthesis of 3 and 30 was performed in four steps.
The lithium salt of 5-methyl-3-hexen-2-one, generated
with LDA in THF, was quenched with 3-phenylprop-
anal to give 7-hydroxy-2-methyl-9-phenyl-3-nonen-5-
one 11 in 79% yield. Silylation of the secondary alcohol
gave silyl ether 12 in 82% yield, whose reduction with
NaBH4 in the presence of CeCl3 heptahydrate gave a
mixture of 13 and 130. These were separable by flash col-
umn chromatography on silica gel affording the less
polar isomer 13 in 48% yield and polar isomer 130 in
45% yield. Deprotection of silyl ether 13 and 130 with
TBAF gave 3 and 30, respectively, in quantitative yields.
The relative structures were determined by NOE exper-
Ph
Ph
OH
OH
H
H
20% PdCl2(MeCN)2
THF, rt, 7 hr
O
3
cis-4
Ph
Ph
OH
OH
H
H
20% PdCl2(MeCN)2
THF, rt, 23 hr
O
3'
trans-4
1
iments with H NMR after the formation of acetonides
14 and 140. Thus, the polar isomer was identified to be a
syn diol when the carbon chain was described in
extended structure and while the less polar was an anti
diol.
Scheme 7.
In the case of the 6-exo-trig cyclization of 1, we consid-
ered its mechanism as shown in Scheme 8. If the chiral
secondary allylic alcohol controls the initial formation
of the Pd-complex I with the b-face of the olefinic plane,
it is in equilibrium with complex II by a ligand exchange.
A syn-attack of the hydroxy nucleophile to the carbon of
II occurs from the same side of the Pd-complex in a
6-exo-trig fashion to give the r-Pd complex III. Subse-
quently, syn-elimination of PdCl(OH) afforded trans-
pyran trans-2E with an (E)-olefinic substituent.13,14
2.2. Pd-Catalyzed 6-exo-trigonal and 6-endo-trigonal
cyclizations
When diol
1
was treated with 10% mol of
PdCl2(MeCN)2 in THF at 0 °C, trans-(E)-tetrahydropy-
ran trans-2E was obtained as a single stereoisomer in
71% yield.7 Meanwhile, that of 10 under the same condi-
tions gave cis-(E)-tetrahydropyran cis-2E8 as a single
isomer in 78% yield. The structures of the products were
identified by NOE experiments with 1H NMR. Both
On the other hand, as in the case of the 6-endo-trig
cyclization of 3 or 30, the mechanism cannot be fully

1302
J. Uenishi et al. / Tetrahedron: Asymmetry 16 (2005) 1299–1303
14, 1905–1908; (e) Hayakawa, H.; Iida, K.; Miyazawa, M.;
1
trans-2E
Miyashita, M. Chem. Lett. 1999, 601–602; (f) Hartung, J.;
Drees, S.; Greb, M.; Schmidt, P.; Svoboda, I.; Fuess, H.;
Murso, A.; Stalke, D. Eur. J. Org. Chem. 2003, 2388–2408;
(g) Smith, A. B., III; Safonov, I. G.; Corbett, R. M. J. Am.
Chem. Soc. 2002, 124, 11102–11113; (h) Fettes, A.;
Carreira, E. M. J. Org. Chem. 2003, 68, 9274–9283; (i)
Aubele, D. L.; Lee, C. A.; Floreancig, P. E. Org. Lett.
2003, 5, 4521–4523; (j) Nakamura, R.; Tanino, K.;
Miyashita, M. Org. Lett. 2003, 5, 3579–3582; (k) Chakra-
borty, T. K.; Reddy, V. R.; Reddy, T. J. Tetrahedron 2003,
59, 8613–8622.
PdCl2
- PdCl(OH)
H
O
H
O
Pd
HO
Pd
Cl
Cl
Cl
Cl
H
Pd
Cl
O
H
- HCl
H
H
O
O
I
III
II
3. Henry, P. The Wacker Oxidation and Related Asymmetric
Syntheses. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E.-i., Ed.; John Wiley and
Sons: New York, 2002; Vol. 2, pp 2119–2139.
Scheme 8.
4. Hosokawa, T.; Murahashi, S. Intramolecular Oxypalla-
dation In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E.-i., Ed.; John Wiley and
Sons: New York, 2002; Vol. 2, pp 2169–2192.
elucidated at this point.15 Further studies are currently
in progress.
5. No 6-endo-trigonal type intramolecular oxypalladation for
chiral allylic alcohol substrate with hydroxy nucleophile
has been reported so far. 6-exo-Trigonal cyclization to
allylic alcohol without a stereogenic center has been
reported very recently by Miyazawa, M.; Hirose, Y.;
Narantsetseg, M.; Yokoyama, H.; Yamaguchi, S.; Hirai,
Y. Tetrahedron Lett. 2004, 45, 2883–2886.
6. (a) Faber, K. Biotransformations in Organic Chemistry;
Springer: Berlin, 1992; (b) Chen, C.-S.; Sih, C. J. Angew.
Chem., Int. Ed. Engl. 1989, 28, 695–707; (c) Klibanov, A.
M. Acc. Chem. Res. 1990, 23, 114–120; (d) Santaniello, E.;
Ferraboschi, P.; Grisenti, P.; Manzocchi, A. Chem. Rev.
1992, 92, 1071–1140.
3. Conclusion
2,6-Disubstituted tetrahydro- and 3,6-dihydro[2H]-
pyrans were synthesized stereospecifically by intra-
molecular PdII-catalyzed cyclization of allylic alcohol
with a hydroxy nucleophile under mild conditions. This
result should be useful not only for the synthesis of
these hydrated pyran rings, but also to give further
mechanistic insights into the intramolecular oxypallada-
tion reaction.
7. Typical experiment. A mixture of diol 1 or 10 (1 mmol)
and PdCl2(MeCN)2 (0.1 mmol) in THF (10 mL) was
stirred at 0 °C for 30 min. The mixture was diluted and
carefully purified by silica gel column chromatography
(10% ether in pentane) to give trans- or cis-2E. trans-2E;
1H NMR (300 MHz, CDCl3): d 1.16 (3H, d, J = 6.4 Hz),
1.19–1.32 (2H, m), 1.59–1.68 (4H, m), 1.71 (3H, dd,
J = 6.1 and 1.3 Hz), 3.91 (1H, dqd, J = 7.5, 6.4, and
2.8 Hz), 4.25–4.29 (1H, m), 5.62–5.66 (2H, m); 13C NMR
(75 MHz, CDCl3): d 17.9, 18.6, 20.4, 29.6, 32.1, 67.0, 71.9,
Acknowledgements
This research was supported (in part) by the 21st COE
Program from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan.
References
1
127.2, 131.4. cis-2E; H NMR (300 MHz, CDCl3): d 1.19
1. (a) Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995,
117, 8126–8131; (b) Tanaka, J.; Higa, T. Tetrahedron Lett.
1996, 37, 5535–5538; (c) Horton, P. A.; Koehn, F. E.;
Longley, R. E.; McConnell, O. J. J. Am. Chem. Soc. 1994,
116, 6015–6016; (d) Schummer, D.; Gerth, K.; Reichen-
bach, H.; Hofle, G. Liebigs Ann. 1995, 685–688; (e)
DꢀAmbrosio, M.; Guerriero, A.; Debitus, C.; Pietra, F.
Helv. Chim. Acta 1996, 79, 51–60; (f) Carmely, S.;
Kashman, Y. Tetrahedron Lett. 1985, 26, 511–514; (g)
Tanaka, J.; Higa, T.; Kobayashi, M.; Kitagawa, I. Chem.
Pharm. Bull. 1990, 38, 2967–2970; (h) Jansen, R.; Wray,
V.; Irschik, H.; Reichenbach, H.; Hofle, G. Tetrahedron
Lett. 1985, 26, 6031–6034; (i) Moore, R. E.; Patterson, G.
M. L.; Mynderse, J. S.; Barchi, J., Jr. Pure Appl. Chem.
1986, 58, 263–271; (j) Ishibashi, M.; Moore, R. E.;
Patterson, G. M. L.; Xu, C.; Clardy, J. J. Org. Chem.
1986, 51, 5300–5306; (k) Jefford, C. W.; Bernardinelli, G.;
Tanaka, J.; Higa, T. Tetrahedron Lett. 1996, 37, 159–162.
2. (a) Recent syntheses of pyran ring Ghosh, A. K.; Wang,
Y. J. Am. Chem. Soc. 2000, 122, 11027–11028; (b) Anada,
M.; Washio, T.; Shimada, N.; Kitagaki, S.; Nakajima, M.;
Shiro, M.; Hashimoto, S. Angew. Chem., Int. Ed. 2004, 43,
2665–2668; (c) Hansen, E. C.; Lee, D. Tetrahedron Lett.
2004, 45, 7151–7155; (d) Joo, J. M.; Kwak, H. S.; Park, J.
H.; Song, H. Y.; Lee, E. Bioorg. Med. Chem. Lett. 2004,
(3H, d, J = 6.2 Hz), 1.25–1.35 (2H, m), 1.46–1.60 (3H, m),
1.68 (3H, ddd, J = 6.4, 1.5, and 0.7 Hz), 1.78–1.85 (1H,
m), 3.48 (1H, dqd, J = 11.0, 6.2, and 1.6 Hz), 3.77 (1H, br
dd, J = 11.3 and 6.6 Hz), 5.51 (1H, ddq, J = 15.4, 6.6, and
1.5 Hz), 5.69 (1H, dqd, J = 15.4, 6.4, and 0.9 Hz); 13C
NMR (75 MHz, CDCl3): d 17.8, 22.2, 23.5, 31.4, 33.0,
73.7, 78.3, 126.7, 132.7.
8. The synthesis of racemic cis-2E has been reported, see
Semmelhack, M. F.; Kim, C. R.; Dobler, W.; Meier, M.
Tetrahedron Lett. 1989, 30, 4925–4928.
9. The quantitative conversion was observed in an NMR
tube experiment. Since products 2 are volatile liquid, some
technical loss occurs during the work-up and purification
process in the above scale of the reaction.
10. The reaction with a nitrogen nucleophile for piperidine
synthesis has been reported, in which an opposite stereo-
chemical result was described, see Hirai, Y.; Nagatsu, M.
Chem. Lett. 1994, 21–22.
11. Their stereochemistries were determined by NOE exper-
iments with their H NMR.
1
12. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734–
736.
13. Alternatively, a chloride intermediate generated by the
addition of PdII and a chloride anion can be considered,3
this idea could be eliminated because of the low concen-

J. Uenishi et al. / Tetrahedron: Asymmetry 16 (2005) 1299–1303
1303
tration of chloride ion under these reaction conditions and
poor SN2 reactivity of the oxygen nucleophile to second-
ary alkyl chlorine in the absence of base.
15. Although the 5-endo-trig cyclization is disfavored accord-
ing to the Baldwinꢀs rule (Baldwin, J. E.; Cutting, J.;
Dupont, W.; Kruse, L.; Silberman, L.; Thomas, R. C. J.
Chem. Soc., Chem. Commun. 1976, 736–739); An example
for the synthesis of the dihydrofuran was reported, in
which a syn-SN20 type product was obtained. See Saito, S.;
Hara, T.; Takahashi, N.; Hirai, M.; Moriwake, T. Synlett
1992, 237–238.
14. The recent intramolecular syn-oxypalladation in 5-exo-
trigonal type cyclization reaction via phenoxy(p-alken-
yl)palladium(II) species, see Hayashi, T.; Yamasaki, K.;
Mimura, M.; Uozumi, Y. J. Am. Chem. Soc. 2004, 126,
3036–3037.