CLUSTER
Isolation of Intermediary anti-Aldol Adducts of the Horner–Wadsworth–Emmons Reaction
131
to the hydroxyl group but to the (EtO)2P(=O) moiety of
anti-2, followed by the formation of anti-TBSO-oxaphos-
phetane intermediate 9. Successive elimination of TBS-
O-P(=O)(OEt)2 (10) from 9 gives the desired Z-a,b-unsat-
urated ester 8.17
References and Notes
(1) (a) Horner, L.; Hoffman, H.; Wippel, H. G.; Klahre, G.
Chem. Ber. 1959, 92, 2499. (b) Wadsworth, W. S.;
Emmons, W. D. J. Am. Chem. Soc. 1961, 83, 1733.
(2) For a book and reviews: (a) Wadsworth, D. H. Org. React.
1977, 25, 73. (b) Boutagy, J.; Thomas, R. Chem. Rev. 1974,
74, 87. (c) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989,
89, 863. (d) Nicolaou, K. C.; Harter, M. W.; Gunzner, J. L.;
Nadin, A. Liebigs Ann./Recl. 1997, 1283. (e) Motoyoshiya,
J. Trends Org. Chem. 1998, 7, 63. (f) Thirsk, C.; Whiting,
A. J. Chem. Soc., Perkin Trans. 1 2002, 999.
(3) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
(4) (a) Ando, K. Tetrahedron Lett. 1995, 36, 4105. (b) Ando,
K. J. Org. Chem. 1997, 62, 1934. (c) Ando, K. J. Org.
Chem. 1998, 63, 8411. (d) Ando, K. J. Org. Chem. 1999, 64,
6815. (e) Ando, K.; Oishi, T.; Hirama, M.; Ohno, H.; Ibuta,
T. J. Org. Chem. 2000, 65, 4745. (f) Ando, K. Synlett 2001,
1272.
In conclusion, we achieved the first isolation of interme-
diary aldol adducts and their TMS ethers of the HWE re-
action. These anti-adducts underwent subsequent
stereoselective elimination using TBS-BEZA–PyH+·OTf–
to afford less accessible Z-a,b-unsaturated esters. The
present method will provide a new insight into the widely
used HWE reaction.
Table 4 Preparation of Z-Alkenes from 2 Using TBS-BEZA–
PyH+·OTf–a
OTBS
O
OH
(5) (a) Sano, S.; Yokoyama, K.; Fukushima, M.; Yagi, T.;
Nagao, Y. Chem. Commun. 1997, 559. (b) Sano, S.;
Teranishi, R.; Nagao, Y. Tetrahedron Lett. 2002, 43, 9183.
(c) Sano, S.; Saito, K.; Nagao, Y. Tetrahedron Lett. 2003,
44, 3987.
Ph
Ph
N
(TBS-BEZA)
EtO
R
EtO2C
R
cat. PyH+ TfO–
P(O)(OEt)2
·
THF, 20–25 °C
2
8
(6) (a) Mukaiyama, T.; Banno, K.; Narasaka, K. Chem. Lett.
1973, 1011. (b) Mukaiyama, T.; Banno, K.; Narasaka, K. J.
Am. Chem. Soc. 1974, 96, 7503. (c) Mukaiyama, T.
Organic Reactions, Vol. 28; Wiley: New York, 1982, 203.
(7) (a) Evans, D. A.; Clark, J. S.; Metternich, R.; Novack, V. J.;
Sheppard, G. S. J. Am. Chem. Soc. 1990, 112, 866.
(b) Evans, D. A.; Urpi, F.; Somers, T. C.; Clark, J. S.;
Bilodeau, M. T. J. Am. Chem. Soc. 1990, 113, 8215.
(c) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J.
Am. Chem. Soc. 1991, 112, 1047. (d) Crimmins, M. T.;
King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem.
2001, 66, 894.
Entry
1
R
Product
Yield (%)b E:Zc
8a
Ca. 100d
10:90
2
8c
86
13:87
3
4
8e
8g
98
97
24:76
22:78
(8) (a) Tanabe, Y. Bull. Chem. Soc. Jpn. 1988, 62, 1917.
(b) Misaki, T.; Nagase, R.; Matsumoto, K.; Tanabe, Y. J.
Am. Chem. Soc. 2005, 127, 2854; and other references cited
therein.
(9) (a) Tanabe, Y.; Matsumoto, N.; Higashi, T.; Misaki, T.; Itoh,
T.; Nishii, Y. Tetrahedron 2002, 58, 8269. (b) Tanabe, Y.;
Matsumoto, N.; Funakoshi, S.; Manta, N. Synlett 2001,
1959. (c) Tanabe, Y.; Mitarai, K.; Higashi, T.; Misaki, T.;
Nishii, Y. Chem. Commun. 2002, 2542.
a Crude compounds 2 were used without any purification.
b Isolated.
c Determined by 1H NMR analyses of the crude products.
d Due to a volatile product, conversion yields of crude products based
on 1H NMR.
–
Py
N
(10) Typical Procedure (Table 2, Entry 1).
⋅ OTf
H
+
Ph
TiCl4 (neat, 132 mL, 1.20 mmol) and Et3N (142 mg, 1.40
mmol) in CH2Cl2 (0.5 mL) were successively added to a
stirred solution of (EtO)2P(O)CH2CO2Et (1; 224 mg, 1.00
mmol) in CH2Cl2 (3.5 mL) at –20 °C under an Ar
atmosphere. After 15 min, i-PrCHO (110 mL, 1.20 mmol)
was added and the reaction mixture was stirred for 2 h. Then,
H2O was added to the mixture, which was extracted twice
with Et2O. The combined organic phase was washed with
H2O, brine, dried (Na2SO4) and concentrated to give the
desired product 2a (281 mg, 95%). 1H NMR (300 MHz,
CDCl3): d = 0.91 (syn, 3 H, d, J = 6.5 Hz), 0.93 (anti, 3 H, d,
J = 6.9 Hz), 1.02 (anti, 3 H, d, J = 6.9 Hz), 1.08 (syn, 3 H, d,
J = 6.5 Hz), 1.27–1.38 (9 H, m), 1.72–1.88 (1 H, m), 3.20
(syn, 1 H, dd, J = 9.3, 20.6 Hz), 3.27 (anti, 1 H, dd, J = 3.8,
23.4 Hz), 3.80–3.87 (1 H, m), 4.08–4.30 (6 H, m). 13C NMR
(75 MHz, CDCl3): d = 13.99, 16.27, 17.99, 19.39, 32.71,
32.85, 48.45 [d, 1J (13C, 31P) = 132.9 Hz], 62.50 [d, 2J (13C,
31P) = 7.2 Hz], 63.18 [d, 2J (13C, 31P) = 7.2 Hz], 74.75 [d,
2J (13C, 31P) = 4.3 Hz], 163.68 [d, 2J (13C, 31P) = 4.3 Hz].
(11) Among several attempts of O-acetylation procedures, use of
Ac2O (2.0 equiv)–cat. Ph2N+H2·OTf– (0.1 equiv) in toluene
at r.t. resulted in nearly quantitative conversion yields.
Ph
O
O
Si t-Bu
t-Bu SiO
O
P(OEt)2
(EtO)2P
R
EtO2C
R
EtO2C
H
R
H
CO2Et
OH
8
O
9
t-Bu SiO P(OEt)2
anti-2
10
Scheme 2 Proposed mechanism of the stereoselective elimination
of anti-2 using TBS-BEZA–cat. PyH+·OTf–
Acknowledgment
This research was partially supported by a Grant-in-Aid for Scien-
tific Research on Priority Areas (A) ‘17035087’ from the Ministry
of Education, Culture, Sports, Science and Technology (MEXT).
Synlett 2006, No. 1, 129–132 © Thieme Stuttgart · New York