Reagent control of geometric selectivity and enantiotopic group preference in asymmetric Horner-Wadsworth-Emmons reactions with meso- dialdehydes

Article abstract of DOI:10.1021/jo981102z

Results from asymmetric Horner-Wadsworth-Emmons reactions between chiral phosphonate reagents 3a-d, which contain (1R,2S,5R)-8-phenylmenthol as a chiral auxiliary, and mesodialdehydes 6 and 14 are presented. It was found that both the geometric selectivities and the levels of asymmetric induction depended on the structure of the phosphonate (i.e., the alkyl group R¹ in the phosphoryl unit) and to a certain extent also on the reaction conditions. Furthermore, the nature of the protecting group used on the α-oxygen substituent in dialdehydes 14 influenced the outcome somewhat. By an appropriate choice of reagent and conditions, either (E)- or (Z)-monoaddition products could be obtained geometrically pure and with good to excellent diastereoselectivities, in synthetically useful yields. Analyses of the absolute configurations of the products showed that the (E)-selective reagents (3a-c) and the (Z)-selective phosphonate 3d reacted at opposite enantiotopic carbonyl groups in the substrates. A mechanistic model which accounts for the products formed is presented.

Full text of DOI:10.1021/jo981102z

8284
J . Org. Chem. 1998, 63, 8284-8294
Rea gen t Con tr ol of Geom etr ic Selectivity a n d En a n tiotop ic Gr ou p
P r efer en ce in Asym m etr ic Hor n er -Wa d sw or th -Em m on s
Rea ction s w ith m eso-Dia ld eh yd es†
J oshua S. Tullis,‡,§,| Lauri Vares,‡,§ Nina Kann,§, Per-Ola Norrby,X and Tobias Rein*,‡,§
Department of Organic Chemistry, Technical University of Denmark, DK-2800 Lyngby, Denmark,
Department of Organic Chemistry, Royal Institute of Technology, S-100 44 Stockholm, Sweden,
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, and
Department of Medicinal Chemistry, Royal Danish School of Pharmacy, Universitetsparken 2,
DK-2100 Copenhagen, Denmark
Received J une 9, 1998
Results from asymmetric Horner-Wadsworth-Emmons reactions between chiral phosphonate
reagents 3a -d , which contain (1R,2S,5R)-8-phenylmenthol as a chiral auxiliary, and meso-
dialdehydes 6 and 14 are presented. It was found that both the geometric selectivities and the
levels of asymmetric induction depended on the structure of the phosphonate (i.e., the alkyl group
R1 in the phosphoryl unit) and to a certain extent also on the reaction conditions. Furthermore,
the nature of the protecting group used on the R-oxygen substituent in dialdehydes 14 influenced
the outcome somewhat. By an appropriate choice of reagent and conditions, either (E)- or (Z)-
monoaddition products could be obtained geometrically pure and with good to excellent diastereo-
selectivities, in synthetically useful yields. Analyses of the absolute configurations of the products
showed that the (E)-selective reagents (3a -c) and the (Z)-selective phosphonate 3d reacted at
opposite enantiotopic carbonyl groups in the substrates. A mechanistic model which accounts for
the products formed is presented.
In tr od u ction
Wittig-type reactions studied so far, however, monocar-
bonyl compounds have been utilized as substrates; only
in a few cases4f,n,q,bb have prochiral diketones been
employed, and prior to our first report4m the possibility
Selective reaction of only one of two enantiotopic
groups in a bifunctional substrate is a powerful strategy1
for asymmetric synthesis, as witnessed by the increasing
attention such processes have received in recent years;
a variety of examples, using both enzymatic2 and non-
enzymatic3 reactions, has been reported. Based on this
concept, reaction types in which no additional sp3 ste-
reocenter is created at any of the bond-forming sites can
also be used for asymmetric synthesis, since asymmetric
induction is achieved by “desymmetrization” of the
substrate. One such class of reactions is asymmetric
Wittig-type reactions, an area which in recent years has
been studied by a number of research groups,4 with
several examples of highly selective transformations
being reported. In the vast majority of asymmetric
(4) For a review, see: (a) Rein, T.; Reiser, O. Acta Chem. Scand.
1996, 50, 369-379. See also: (b) Li, A.-H.; Dai, W.-M.; Aggarwal, V.
K. Chem. Rev. 1997, 97, 2341-2372. (c) Bennani, Y. L.; Hanessian, S.
Chem. Rev. 1997, 97, 3161-3195. (d) Nicolaou, K. C.; Ha¨rter, M. W.;
Gunzner, J . L.; Nadin, A. Liebigs Ann./ Recueil 1997, 1283-1302. For
selected examples, see: (e) To¨mo¨sko¨zi, I.; J anszo´, G. Chem. Ind.
(London) 1962, 2085-2086. (f) Trost, B. M.; Curran, D. P. Tetrahedron
Lett. 1981, 22, 4929-4932. (g) Hanessian, S.; Delorme, D.; Beaudoin,
S.; Leblanc, Y. J . Am. Chem. Soc. 1984, 106, 5754-5756. (h) Gais, H.-
J .; Schmiedl, G.; Ball, W. A.; Bund, J .; Hellmann, G.; Erdelmeier, I.
Tetrahedron Lett. 1988, 29, 1773-1774. (i) Rehwinkel, H.; Skupsch,
J .; Vorbru¨ggen, H. Tetrahedron Lett. 1988, 29, 1775-1776. (j) Han-
essian, S.; Beaudoin, S. Tetrahedron Lett. 1992, 33, 7655-7658. (k)
Denmark, S. E.; Chen, C.-T. J . Am. Chem. Soc. 1992, 114, 10674-
10676. (l) Narasaka, K.; Hidai, E.; Hayashi, Y.; Gras, J .-L. J . Chem.
Soc., Chem. Commun. 1993, 102-104. (m) Kann, N.; Rein, T. J . Org.
Chem. 1993, 58, 3802-3804. (n) Tanaka, K.; Ohta, Y.; Fuji, K.; Taga,
T. Tetrahedron Lett. 1993, 34, 4071-4074. (o) Rein, T.; Kann, N.;
Kreuder, R.; Gangloff, B.; Reiser, O. Angew. Chem. 1994, 106, 597-
599; Angew. Chem., Int., Ed. Engl. 1994, 33, 556-558. (p) Furuta, T.;
Iwamura, M. J . Chem. Soc., Chem. Commun. 1994, 2167-2168. (q)
Mandai, T.; Kaihara, Y.; Tsuji, J . J . Org. Chem. 1994, 59, 5847-5849.
(r) Denmark, S.; Rivera, I. J . Org. Chem. 1994, 59, 6887-6889. (s)
Rein, T.; Kreuder, R.; von Zezschwitz, P.; Wulff, C.; Reiser, O. Angew.
Chem. 1995, 107, 1099-1102; Angew. Chem., Int. Ed. Engl. 1995, 34,
1023-1025. (t) Rein, T.; Anvelt, J .; Soone, A.; Kreuder, R.; Wulff, C.;
Reiser, O. Tetrahedron Lett. 1995, 36, 2303-2306. (u) Abiko, A.;
Masamune, S. Tetrahedron Lett. 1996, 37, 1077-1080. (v) Tanaka, K.;
Otsubo, K.; Fuji, K. Tetrahedron Lett. 1996, 37, 3735-3738. (x)
Kumamoto, T.; Koga, K. Chem. Pharm. Bull. 1997, 45, 753-755. (y)
Gais, H.-J .; Schmiedl, G.; Ossenkamp, R. K. L. Liebigs Ann./ Recueil
1997, 2419-2431. (z) Dai, W.-M.; Wu, J .; Huang, X. Tetrahedron:
Asymmetry 1997, 8, 1979-1982. (aa) Mendlik, M. T.; Cottard, M.; Rein,
T.; Helquist, P. Tetrahedron Lett. 1997, 38, 6375-6378. (bb) Tanaka,
K.; Watanabe, T.; Ohta, Y.; Fuji, K. Tetrahedron Lett. 1997, 38, 8943-
8946. (cc) Kreuder, R.; Rein, T.; Reiser, O. Tetrahedron Lett. 1997, 38,
9035-9038. (dd) Mizuno, M.; Fujii, K.; Tomioka, K. Angew. Chem.
1998, 110, 525-527; Angew. Chem., Int. Ed. 1998, 37, 515-517. (ee)
Arai, S.; Hamaguchi, S.; Shioiri, T. Tetrahedron Lett. 1998, 39, 2997-
3000.
* To whom correspondence should be addressed. E-mail address:
oktr@pop.dtu.dk.
† This paper is gratefully dedicated to our colleague and friend
Professor Paul Helquist, University of Notre Dame.
‡ Technical University of Denmark.
§ Royal Institute of Technology.
| University of Notre Dame.
Present address: Department of Organic Chemistry, Chalmers
University of Technology, S-412 96 Go¨teborg, Sweden.
X Royal Danish School of Pharmacy.
(1) For reviews on the use of bifunctional substrates in two-
directional synthesis, see: (a) Poss, C. S.; Schreiber, S. L. Acc. Chem.
Res. 1994, 27, 9-17, and references therein. (b) Magnuson, S. R.
Tetrahedron 1995, 51, 2167-2213. (c) Maier, M. In Organic Synthesis
Highlights II; Waldmann, H., Ed.; VCH: Weinheim, 1995; pp 203-
222.
(2) For an excellent recent review, see: Schoffers, E.; Golebiowski,
A.; J ohnson, C. R. Tetrahedron 1996, 52, 3769-3826.
(3) (a) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem. 1971, 83,
492-493. (b) Hajos, Z. G.; Parrish, D. R. J . Org. Chem. 1974, 39, 1615-
1621. For reviews, see: (c) Ward, R. S. Chem. Soc. Rev. 1990, 19, 1-19.
(d) Gais, H.-J . In Houben-Weyl, Stereoselective Synthesis; Helmchen,
G., Hoffman, R. W., Mulzer, J ., Schaumann, E., Eds.; Thieme:
Stuttgart, 1996; Vol. 1, pp 589-643.
10.1021/jo981102z CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/27/1998

Asymmetric Horner-Wadsworth-Emmons Reactions
J . Org. Chem., Vol. 63, No. 23, 1998 8285
of using dialdehyde substrates5 had not been investi-
gated. From the viewpoint of synthetic efficiency, this
alternative is appealing since the reaction product di-
rectly can take part in an additional chain-extending
reaction involving the unreacted aldehyde, as exemplified
in Scheme 1. Thus, relatively complex chiral structures
should be quickly accessible from nonchiral precursors.
In this paper, we report results from an extension of
our earlier6 studies of asymmetric Horner-Wadsworth-
Emmons (HWE) reactions7 with dialdehydes and dem-
onstrate that complementary product selectivities are
possible by an appropriate choice of reagent: by slight
structural variation in the chiral phosphonate, either (E)-
or (Z)-alkenes can be obtained as products, with both high
geometric selectivity and good to excellent levels of asym-
metric induction. Furthermore, the (E)- and (Z)-selective
reagents are complementary also in the sense that they
react with opposite enantiotopic group preference.
Sch em e 1
Resu lts
Ch oice a n d P r ep a r a tion of Ch ir a l P h osp h on a te
Rea gen ts. For our initial studies, we chose to examine
reactions between suitable model dialdehyde sub-
strates and the chiral phosphonates 3a -d , derived from
(1R,2S,5R)-8-phenylmenthol (eq 1). Reagent 3a has
earlier been shown to give useful levels of diastereose-
geometry in the product. This expectation was realized
in practice.
A procedure for preparation of the chiral phosphonates
3a and 3c by transesterification of the achiral precursors
1a and 1c with 8-phenylmenthol (2) has previously been
reported by Takano and co-workers.8 In the same man-
ner, we prepared4o reagents 3b and 3d in good yields from
the corresponding known phosphonates 1b and 1d .9
Ch oice a n d P r ep a r a tion of Mod el Su bstr a tes. As
our model dialdehyde substrates, we chose compounds
610 and 14. The motivation for this choice was 2-fold:
(i) reactions with these substrates would give information
on the influence of different types of R-substituents (CH3
or RO) in the dialdehyde on the reaction selectivity; (ii)
the expected chiral monoaddition products are potentially
useful synthetic intermediates, as they correspond to
partial structures of a number of natural products of
biomedical interest. Thus, the products expected from
dialdehyde 6 match subunits of several strongly cytotoxic
macrolides,11 whereas products derived from dialdehydes
of type 14 can be envisioned as building blocks for
polyene/polyol macrolide antibiotics.12
lectivity in reactions with a prochiral monoketone4h,y and
with some structurally related chiral ketones.4h,i Fur-
thermore, we felt that incorporation of a chiral auxiliary
in the anion-stabilizing functionality rather than in the
phosphorus-based functional group could give larger
synthetic versatility, since choice of different alkyl groups
R1 in the reagent then might enable control of the alkene
(7) (a) Horner, L.; Hoffman, H.; Wippel, H. G. Chem. Ber. 1958, 91,
61-63. (b) Horner, L.; Hoffman, H.; Wippel, H. G.; Klahre, G. Chem.
Ber. 1959, 92, 2499-2505. (c) Wadsworth, W. S.; Emmons, W. D. J .
Am. Chem. Soc. 1961, 83, 1733-1738. For reviews discussing general
aspects of the HWE reaction, see: (d) Boutagy, J .; Thomas, R. Chem.
Rev. 1974, 74, 87-99. (e) Wadsworth, W. S., J r. Org. React. 1977, 25,
73-253. (f) Walker, B. J . In Organophosphorus Reagents in Organic
Synthesis; Cadogan, J . I. G., Ed.; Academic Press: New York, 1979;
pp 155-205. (g) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89,
863-927. (h) Kelly, S. E. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 1, pp 730-
817. See also ref 4d.
(8) Hatakeyama, S.; Satoh, K.; Sakurai, K.; Takano, S. Tetrahedron
Lett. 1987, 28, 2713-2716. In our hands, stoichiometric amounts of
DMAP were in some cases required for the reactions to give good yields.
(9) Compound 1b is commercially available. Phosphonate 1d was
prepared according to the procedure of Still: Still, W. C.; Gennari, C.
Tetrahedron Lett. 1983, 24, 4405-4408.
(10) After our initial report on asymmetric HWE reactions with 6,
this dialdehyde has also been used as substrate in group-selective
asymmetric aldol reactions; see refs 5g and 5h.
(5) For examples of the use of meso-dialdehydes as substrates for
other types of asymmetric transformations, see: (a) Yamazaki, Y.;
Hosono, K. Tetrahedron Lett. 1988, 29, 5769-5770. (b) Roush, W. R.;
Park, J . C. Tetrahedron Lett. 1990, 31, 4707-4710. (c) Wang, Z.;
Descheˆnes, D. J . Am. Chem. Soc. 1992, 114, 1090-1091. (d) Ward, D.
E.; Liu, Y.; Rhee, C. K. Synlett 1993, 561-563. (e) Ward, D. E.; Liu, Y.
D.; Rhee, C. K. Can. J . Chem. 1994, 72, 1429-1446. (f) Roush, W. R.;
Wada, C. K. J . Am. Chem. Soc. 1994, 116, 2151-2152. (g) Oppolzer,
W.; De Brabander, J .; Walther, E.; Bernardinelli, G. Tetrahedron Lett.
1995, 36, 4413-4416. (h) De Brabander, J .; Oppolzer, W. Tetrahedron
1997, 53, 9169-9202. (i) Oppolzer, W.; Walther, E.; Balado, C. P.; De
Brabander, J . Tetrahedron Lett. 1997, 38, 809-812.
(6) Part of this work has been described in an earlier communication;
see ref 4m.
(11) Norcross, R. D.; Paterson, I. Chem. Rev. 1995, 95, 2041-2114.
(12) Rychnovsky, S. D. Chem. Rev. 1995, 95, 2021-2040.

8286 J . Org. Chem., Vol. 63, No. 23, 1998
Tullis et al.
Sch em e 2
Sch em e 4
Sch em e 3
palladium-catalyzed cis-diacetoxylation18 of diene 9 to
give diacetate 10.19 To gain some insight into the
influence of different oxygen-protecting groups R in 14
on the outcome of the asymmetric HWE reactions, the
tert-butyldiphenylsilyl-protected substrate 14a , and the
pivaloyl-protected 14b were then prepared from 10 by
straightforward transformations.20
Diols 13a and 13b were both formed as diastereomeric
mixtures, but upon treatment with periodic acid, both
diastereomers of each compound were cleanly converted
to the desired dialdehyde. Dialdehyde 14a is quite robust
and stable enough to be purified by chromatography
without detectable epimerization. Compound 14b, how-
ever, is more sensitive, and is best prepared fresh
immediately prior to use.
Asym m etr ic HWE Rea ction s. To investigate the
influence of reactant stoichiometry and reaction temper-
ature, we first studied reactions between dimethylphos-
phonate 3a and dialdehydes 6 and 14a (Scheme 4, Table
1). Conditions which were expected to favor kinetic
control in the initial addition step, by increasing the
relative rate of the subsequent elimination, were chosen
[potassium hexamethyldisilazide (KHMDS) as base in
combination with 18-crown-6, low temperature].21 In
these initial experiments, the crude reaction product was
reduced with NaBH4 to facilitate separation of the
products from both bis-addition products and remaining
unreacted dialdehyde.
Diol 5, the immediate precursor of dialdehyde 6, was
obtained by double hydroboration of diene 4,13 as de-
scribed by Harada and co-workers.14 Compound 6 could
be prepared in pure form by Swern oxidation15 of 5 if
water was carefully excluded during the workup (Scheme
2). In the presence of water, the cyclic hydrate 7 was
isolated as the major product,16 and it proved difficult to
regenerate 6 once the hydrate had been formed. Dial-
dehyde 6 is stable in solution for some time, if stored
protected from water; we recommend, however, that it
is freshly prepared for use.
The other model substrates, dialdehydes 14, were
synthesized in five steps from 6-(benzyloxy)-1,3-cyclo-
heptadiene (9) which, in turn, is accessible from 1,3,5-
cycloheptatriene17 (Scheme 3). The relative stereochem-
istry of the three stereocenters in 14 was controlled by a
Somewhat to our surprise, essentially only (E)-products
were obtained from both substrates, although nonasym-
metric HWE reactions with dimethyl phosphonates often
give (Z)-products under similar reaction conditions.
These initial experiments demonstrated that (E)-alkenes
1522 and 1722 could be obtained in reasonable yields and
(13) For experimental details regarding the preparation of 4 and 5,
see Supporting Information.
(14) (a) Harada, T.; Matsuda, Y.; Uchimura, J .; Oku, A. J . Chem.
Soc., Chem. Commun. 1990, 21-22. (b) Harada, T.; Inoue, A.; Wada,
I.; Uchimura, J .; Tanaka, S.; Oku, A. J . Am. Chem. Soc. 1993, 115,
7665-7674. For an enzyme-catalyzed desymmetrization of 5 by group-
selective esterification, see: Chenevert, R.; Courchesne, G. Tetrahe-
dron: Asymmetry 1995, 6, 2093-2096.
(15) Mancuso, A.; Huang, S.-L.; Swern, D. J . Org. Chem. 1978, 43,
2480-2482.
(16) Harada, T.; Kagamihara, Y.; Tanaka, S.; Sakamoto, K.; Oku,
A. J . Org. Chem. 1992, 57, 1637-1639.
(17) Schink, H. E.; Petterson, H.; Ba¨ckvall, J .-E. J . Org. Chem. 1991,
56, 2769-2774.
(18) Ba¨ckvall, J .-E.; Bystro¨m, S. E.; Nordberg, R. E. J . Org. Chem.
1984, 49, 4619-4631.

Asymmetric Horner-Wadsworth-Emmons Reactions
J . Org. Chem., Vol. 63, No. 23, 1998 8287
Ta ble 1. Rea ction s of P h osp h on a te 3a w ith Dia ld eh yd es
6 a n d 14a a
Sch em e 5
substrate temp
yieldb diaster yield of bis-
(%)
entry
(equiv)
(°C) product
ratioc addition (%)
1
2
3
4
5
6
7
8
6 (2.0)
6 (2.1)
6 (1.2)
6 (1.3)
14a (2.0)
14a (2.0) -100
14a (1.2)
-78
-100
-78
15
15
15
15
17
17
17
17
88
87
36
77
68
50
60d
49
87:13
90:10
97:3
5
-
48
6
-
-
e
-100
-78
91:9
87:13
89:11
88:12
91:9
-78
14a (1.2) -100
-
a
General reaction conditions: 1.1 equiv of phosphonate, 1.0
equiv of KHMDS, 5 equiv of 18-crown-6, ca. 0.02 M in THF, 2.5-
b
15 h. Isolated yield of product judged as g95% pure by NMR and
TLC, unless otherwise noted. c Ratio in isolated product; ratios in
crude products were within (2% of these values. Entries 1-4:
ratio 15:16; entries 5-8: ratio 17:18. Geometric ratios were g98:
d
2. Another product, tentatively assigned as being the product of
silyl group migration from the secondary to the primary hydroxyl,
was isolated in 18% yield. e Although small amounts of bis-addition
product were detected in the crude product, none were isolated
after chromatography.
diastereoselectivities even when close to equimolar
amounts of substrate and reagent were used (compare
entries 2 and 4, 5 and 7). In addition, the reaction
temperature turned out to be an important parameter,
as expected. With the more reactive substrate 6, reaction
at -78 °C gave considerable amounts of bis-addition
product (entry 3); this was largely suppressed by per-
forming the reaction at -100 °C (entry 4). On the other
hand, the slightly lower yields obtained from dialdehyde
14a at the lower reaction temperature presumably
resulted from incomplete conversion due to this substrate
being more sterically hindered (compare entries 6 and 8
with 5 and 7).
We then embarked on a more extensive study of
reactions involving dialdehydes 6, 14a , and 14b. De-
pending on the synthetic objective, it is desirable that
either (E)- or (Z)-alkenes can be prepared with high
selectivity in the asymmetric HWE reactions. For this
reason, we investigated the utility of reagents 3a -d
containing different alkyl groups R1 in the phosphoryl
unit. It is known from standard nonasymmetric HWE
reactions7,21 that the alkene geometry of the product often
can be controlled by an appropriate choice of R1 and
reaction conditions. The results obtained in reactions
with 6 (Scheme 5, Table 2) demonstrated that selective
preparation of either (E)- or (Z)-products was indeed
possible.
Ta ble 2. Rea ction s of P h osp h on a tes 3a -d w ith
Dia ld eh yd e 6a
temp
yieldb diaster yield of bis-
entry phosphonate (°C) product
(%)
ratioc
addition (%)
1
2
3
4
5
6
7
3a
3b
3c
3d
3d
3d
3d
-100
-90
19
19
19
21
21
21
21
53
95:5d
e
38f
12f
-
25f ca. 95:5d
-90
2f ca. 97:3d
-100
-90
74
83
76
38i
g98:2g
g98:2
g98:2
g98:2
-
-78
e
0h
36i
a
General reaction conditions: 1.1 equiv of dialdehyde, 1.1 equiv
of phosphonate, 1.0 equiv of KHMDS, 5 equiv of 18-crown-6, ca.
b
0.02 M in THF, 6-22 h. Isolated yield of product judged as g95%
pure by NMR and TLC, unless otherwise noted. c Ratio in isolated
product; ratios in crude products were within (2% of these values.
Entries 1-3: ratio 19:20; entries 4-7: ratio 21:22. Geometric
d
ratios were g98:2, unless stated otherwise. Small amounts of
another isomer, assigned as an epimer, were also present in the
isolated product: entry 1, 3%; entry 2, 9%; entry 3, 4% (see
Supporting Information). e Not determined. f (E)-Mono- and (E,E)-
bis-addition products were obtained in the same fraction after
g
chromatography. The isolated product also contained 6% of
another isomer, assigned as an epimer; this was not present in
the crude, but was formed during chromatography (see Supporting
h
Information). Reaction time 2 h. i After chromatography, the (Z)-
Phosphonates 3a -c all gave essentially exclusive
formation of (E)-products. However, the structure of
monoaddition product 21 (38% yield) and the (E,Z)-bis-addition
product 28 (25% yield; see Chart 1) were obtained in the same
fraction. In separate fractions, the (Z,Z)- and (E,E)-bis-addition
products were isolated, in 9% and 2% yield, respectively.
(19) Diacetate 10 was assigned as meso-(3R,5s,7S)-5-(benzyloxy)-
3,7-diacetoxycyclohept-1-ene on the basis of 1H NMR data, by com-
parison with the known18 compound meso-(3R,5s,7S)-5-methoxy-3,7-
diacetoxycyclohept-1-ene. As evidenced by NMR on the crude product,
the Pd-catalyzed diacetoxylation was not completely stereoselective.
However, the other product isomers could be cleanly removed by use
of the MPLC system described by Baeckstro¨m: Baeckstro¨m, P.; Stridh,
K.; Li, L.; Norin, T. Acta Chem. Scand., Ser. B 1987, 41, 442-447.
(20) Dihydroxylation of diacetate 10 gave a complex mixture of
regioisomeric products, presumably due to facile acyl group migration
in the initially formed diol. In contrast, dihydroxylation of bis-pivalate
12b proceeded more cleanly. Upon chromatographic purification, acyl
migration sometimes occurred also with diols 13b; however, if the crude
diastereomeric mixture of diols 13b was directly cleaved with H5IO6,
excellent yields of isomerically pure dialdehyde 14b were reproducibly
obtained. Oxidative cleavage of the alkenes 12 by ozonolysis was also
attempted, but in our hands the two-step osmylation/periodic acid
protocol gave much cleaner products.
R1 did influence the yield of monoaddition product
strongly: the dimethylphosphonate 3a was clearly su-
perior to the diethyl and diisopropyl analogues. Use of
3a in combination with KHMDS/18-crown-6 gave the (E)-
monoaddition product 1922,23 in 53% yield with a diaste-
reomer ratio of 95:5 (entry 1).
The (Z)-selective reagent 3d proved to be even more
efficient than the (E)-selective reagents 3a -c in its
reactions with 6. Together with KHMDS/18-crown-6 as
(22) For details regarding how structure assignments for the HWE
product isomers have been made, and how isomer ratios have been
determined, see Supporting Information.
(21) Thompson, S. K.; Heathcock, C. H. J . Org. Chem. 1990, 55,
3386-3388, and references therein.

8288 J . Org. Chem., Vol. 63, No. 23, 1998
Tullis et al.
Sch em e 6
under optimized chromatography conditions, diastereo-
merically pure 23a was obtained in a synthetically useful
yield, even though the diastereoselectivity in the crude
product was slightly lower than for 23b.
The bis(trifluoroethyl)phosphonate 3d provided access
to the (Z)-products 25a 22,23 and 25b22,23 with excellent
levels of asymmetric induction and in good yields. The
reactions with aldehyde 14a proved to be special cases:
both KHMDS and NaHMDS alone gave better results
than our “standard” base system KHMDS/18-crown-6
(entries 4-6). The reaction between 3d and 14b, how-
ever, gave best selectivities under the standard conditions
(entry 10).
Deter m in a tion of Absolu te Con figu r a tion s. The
assignments of absolute configurations for compounds 15
and 19 are based on 1H NMR analyses of both diaster-
eomers of the Mosher ester derivative 27 (Chart 1),
according to the method introduced by Mosher and Dale
and extended by Kakisawa and co-workers.24 Compound
21 is assigned the indicated absolute configuration based
on a correlation with 19: both 19 and 21 were converted
to the same mono-(Z)/mono-(E)-diastereomer 28 by reac-
tion with 3d and 3a , respectively. On the basis of NMR
analysis, the products from these two reactions were
identical, which, in turn, implies that the monoaddition
products 19 and 21 must have been formed by reaction
at enantiotopic carbonyl groups in 6. In contrast, if the
(E)- and (Z)-monoaddition products were formed via
reaction at the same carbonyl group, further reaction of
the (Z)-product with 3a would have given the diastere-
omeric mono-(Z)/mono-(E)-isomer 29 as product.
The assignments of absolute configurations for the
products from dialdehydes 14 have been made on the
basis of similar investigations. The (E)-product 23a was
converted to both diastereomers of the Mosher ester
derivative 30, and NMR analysis24 of these compounds
gave the assigned absolute configuration. The pivaloyl-
protected (E)-product 23b was correlated with 23a by
conversion of both compounds to derivative 31; based on
NMR analysis, the same diastereomer of 31 was produced
in both cases. The (Z)-products 25a and 25b were
correlated with 23a and 23b, respectively, by conversion
to the mono-(Z)/mono-(E)-bisaddition products: 23a and
25a both formed 32a , and 23b and 25b both gave 32b.
base, reagent 3d gave the (Z)-product 2122,23 in high yield,
with excellent geometric selectivity and as a single
detectable diastereomer (entry 5). The temperature
dependence of this reaction was investigated to some
extent: reactions at -78 °C and lower afforded good
yields of monoaddition product, but a reaction performed
at 0 °C gave a much reduced yield due to formation of
substantial amounts of bisaddition products.
The reactions with the R-oxygenated substrates 14a
and 14b (Scheme 6, Table 3) followed similar general
trends as the reactions with 6, although there are some
differences worth noting.
Reagents 3a -c all gave high (E)-selectivities in reac-
tions with both 14a and 14b. The diastereoselectivities
observed for the (E)-product 23a 22,23 were similar for all
three reagents (entries 1-3); although the amount of
unreacted dialdehyde was not determined, the slightly
lower yield observed in the reaction with the diisopropyl
phosphonate 3c may well be due to incomplete conver-
sion. On the other hand, in reactions with the more
reactive, pivaloyl-protected substrate 14b, the dimethyl
phosphonate 3a performed poorly (entry 7), whereas both
3b and 3c gave 23b22,23 in much better yields and
diastereoselectivities (entries 8 and 9). Thanks to the
fact that the diastereomers of 23a could be separated
Discu ssion
Our results show that the structure of the group R1 in
the chiral phosphonates 3 controls not only the (E)/(Z)-
selectivity of the asymmetric HWE reactions but also
which enantiotopic carbonyl group in the dialdehyde
substrate reacts faster,25 both of which factors contribute
to giving these reactions increased synthetic versatility.
The bis(trifluoroethyl) reagent 3d was found to give
(Z)-products with excellent diastereoselectivities in good
yields from all three substrates studied. The results
obtained with 14a show that the specific choice of
reaction conditions is important: although the use of
KHMDS/18-crown-6 as base often is the most efficient
(23) In general, the (E)- and (Z)-monoaddition products could be
separated by flash chromatography. It also proved possible to separate
the (E)-diastereomers 23a and 24a (Scheme 6, vide infra) by chroma-
tography, if Amicon silica (see Experimental Section) was used;
however, we have not yet found conditions which enable complete
separation of other diastereomeric products (i.e., 19/20, 23b/24b, 25a /
26a ). Some of the HWE products showed tendencies to undergo slight
epimerization during chromatography, but this could be suppressed
by use of appropriate conditions: compounds 19 and 21 could be
chromatographed on Merck silica (see Experimental Section) if the
silica was deactivated by elution with EtOAc or EtOAc/MeOH prior
to chromatography; compounds 23b and 25b could be chromatographed
on Amicon silica without detectable epimerization, whereas use of the
Merck silica caused some epimerization. The silyl-protected products
23a and 25a did not undergo observable epimerization on either type
of silica.
(24) (a) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512-
519. (b) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J . Am.
Chem. Soc. 1991, 113, 4092-4096, and references therein. For further
details regarding the preparation and NMR analyses of compounds
27 and 30, see Supporting Information.
(25) We have found the same general trend to be valid also in
kinetic/dynamic resolutions of racemic monoaldehydes by reaction with
phosphonates 3a -d ; see refs 4o, 4s, and 4t.

Asymmetric Horner-Wadsworth-Emmons Reactions
J . Org. Chem., Vol. 63, No. 23, 1998 8289
Ta ble 3. Rea ction s of P h osp h on a tes 3a -d w ith Dia ld eh yd es 14a a n d 14ba
yield of bis-
addition (%)
entry
phosphonate
substrate
temp. (°C)
product
yieldb (%)
diast. ratioc
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3d g
3d i
3a
3b
3c
14a
14a
14a
14a
14a
14a
14b
14b
14b
14b
-78
-78
-78
-78
-78
-78
-90
-90
-90
-90
23a
23a
23a
25a
25a
25a
23b
23b
23b
25b
65d
60d
46d
61f
76
60
10
62
65
g98:2 (87:13)
g98:2 (88:12)
g98:2 (91:9)
86:14
98:2
96:4
82:18
95:5
94:6
g98:2
e
e
e
24f
h
h
65j
35j
26j
29j
10
3d
62
a
General reaction conditions: 1.1-1.3 equiv of dialdehyde, 1.05-1.2 equiv of phosphonate, 1.0 equiv of KHMDS, 5 equiv of 18-crown-
6, ca. 0.02 M in THF, 6-17 h. Isolated yield of product judged as g95% pure by NMR and TLC, unless otherwise noted. c Ratio in
isolated product. If different, the ratio in the crude product is given in parentheses. Entries 1-3: ratio 23a :24a ; entries 4-6: ratio
25a :26a ; entries 7-9: ratio 23b:24b; entry 10: ratio 25b:26b. Geometric ratios were g98:2, unless stated otherwise. dThe isolated product
also contained small amounts of unreacted dialdehyde: entry 1, 6%; entry 2, 6%; entry 3, 3%. e After chromatography, (E,E)-bis-addition
product and the minor (E)-monoaddition diastereomer 24a were obtained as a mixture; the yield of bis-addition product was not determined.
f Some (Z,E)-bis-addition product 32a (7% yield; see Chart 2) was obtained in the same fraction as the monoaddition product. The (Z,Z)-
b
g
h
i
bis-addition product was isolated separately (17% yield). Only KHMDS (no 18-crown-6) used as base. Not determined. NaHMDS
used as base. Mixture of bis-addition products.
j
Ch a r t 1
Sch em e 7
Ch a r t 2
astereoseletivities g 95:5 and in synthetically useful
yields. An additional factor to take into account is the
choice of protecting group in R-oxygenated substrates:
although substrates 14a and 14b gave the same overall
trends in their reactions, the structure of the protecting
group clearly influenced both the yields and selectivities
of the reactions.26
As demonstrated by the results obtained in reactions
with 6 (Table 1), the diastereoselectivity observed for the
monoaddition product depends on the reaction stoichi-
ometry. This outcome is to be expected, since increased
conversion to the bisaddition product (e.g., 33, Scheme
7) should increase the ratio between the diastereomeric
monoaddition products (the ratio 19:20 in the example
shown), due to the minor monoaddition diastereomer
reacting faster in the second step.27,28
with other substrates, the particular reaction between
3d and 14a gave best results if the crown ether was
omitted. The (E)-selective reagents 3a -c, on the other
hand, generally performed best in combination with
KHMDS/18-crown-6. Depending on the substrate, either
3a or 3b proved to be the most efficient reagent, the
diisopropyl phosphonate 3c seemingly being too sterically
hindered to be generally useful. By choosing the ap-
propriate reagent, (E)-products were obtained with di-
(26) A topic worthy of future investigation is whether the use of
another protecting group would enable a change in the mechanism by
which the R-stereocenter in the substrate influences the reaction
stereochemistry (see mechanistic discussion below, and also ref 4cc);
such a change could, in turn, enable complementary preparation of
other product diastereomers.

8290 J . Org. Chem., Vol. 63, No. 23, 1998
Tullis et al.
Sch em e 8
Mech a n ism . Recent results from computational stud-
ies, using both high level ab initio calculations29 and
molecular mechanics methods,30 fully support our previ-
ously reported working model4a,cc for rationalizing the
stereochemical outcome of these asymmetric HWE reac-
tions. This analysis is based on the postulate that
phosphonates 3 form (E)-enolates31 34 under the reaction
conditions used, an assumption which is reasonable
based on previous studies.32,33 Since two new stereo-
centers are formed at the bond-forming sites (C2 and C3)
in the intermediates, and the substrate contains two
enantiotopic carbonyl groups, eight different diastereo-
meric forms of the intermediate oxyanion 35 are theoreti-
cally possible. Our computational studies indicate that
for reactions involving phosphonates 3a -c, which nor-
mally are (E)-selective, the transition states for oxyanion
formation (TS1) and for ring closure to the oxaphosphe-
tane 36 (TS2) are close in energy, making it necessary
to include appropriate models of both transition states
Sch em e 9
when analyzing reaction stereoselectivities. In reactions
with trifluoroethyl phosphonate 3d , on the other hand,
the initial addition step will be irreversible, and it will
be sufficient to model diastereomeric forms of TS1.
The particular diastereomeric intermediates which
according to our modeling studies are the precursors of
the main product isomers are illustrated in Schemes 8
and 9. The formation of these intermediates is rational-
ized as follows. The chiral auxiliary efficiently blocks the
Re-face of the phosphonate enolate 34. Diastereomers
of TS1 leading to oxyanions with (2R)-configuration are
therefore prohibitively high in energy, leading to a very
high preference for oxyanions with (2S)-configuration.
The configuration at the former aldehyde carbonyl
carbon, C3, is mainly controlled by the stereochemistry
at C4, the former aldehyde R-carbon. The effect can be
interpreted as a formal Felkin-Anh-Eisenstein34,35 (FAE)
or anti-FAE effect in TS1, depending on the substituents
at C4, but is in fact even more pronounced in the tighter
TS2. The overall effect is that oxyanion diastereomers
with an unfavorable relative configuration at C3/C4 will
revert to starting material instead of proceeding to
product.
This analysis also explains the, at first perhaps puz-
zling, observation that the major (E)- and (Z)-products
have opposite absolute configuration at the allylic ste-
reocenter. Since the favored absolute configuration at
C2 always is the same, but the configuration at C3 is
controlled by the one at C4, it automatically follows that
reactions at opposite enantiotopic aldehyde groups must
lead to intermediates with opposite relative configuration
at C2/C3 and therefore to products with opposite alkene
geometry.36
(27) Schreiber, S. S.; Schreiber, T. S.; Smith, D. B. J . Am. Chem.
Soc. 1987, 109, 1525-1529, and references therein.
(28) This expectation rests on the assumption that the unreacted
aldehyde carbonyl groups in the monoaddition diastereomers show
relative reactivities similar to the corresponding enantiotopic carbonyl
groups in the dialdehyde substrate.
(29) Brandt, P.; Norrby, P.-O.; Martin, I.; Rein, T. J . Org. Chem.
1998, 63, 1280-1289.
(30) (a) Norrby, P.-O. In Transition State Modelling for Catalysis;
Truhlar, D., Morokuma, K., Eds.; ACS Symposium Series, in press.
(b) Norrby, P.-O.; Brandt, P.; Rein, T., manuscript in preparation. At
present, modeling tools are available for reactions involving phospho-
nates containing simple alkyl groups (e.g., 3a -c). Work toward the
design of parameter sets which will allow modeling of trifluoroethyl
reagents is in progress.
(34) (a) Che´rest, M.; Felkin, H. Tetrahedron Lett. 1968, 2205-2208.
(b) Anh, N. T.; Eisenstein, O.; Lefour, J .-M.; Traˆn Huu Daˆu, M. E. J .
Am. Chem. Soc. 1973, 95, 6146-6147. (c) Anh, N. T.; Eisenstein, O.
Nouv. J . Chem. 1977, 1, 61-70. (d) Anh, N. T. Top. Curr. Chem. 1980,
88, 145-162. (e) Lodge, E. P.; Heathcock, C. H. J . Am. Chem. Soc.
1987, 109, 2819-2820. (f) Lodge, E. P.; Heathcock, C. H. J . Am. Chem.
Soc. 1987, 109, 3353-3361. For excellent discussions of different
models for diastereoselection in nucleophilic additions to carbonyl
compounds, see: (g) Roush, W. R. J . Org. Chem. 1991, 56, 4151-4157.
(h) Evans, D. A.; Dart, M. J .; Duffy, J . L.; Yang, M. G. J . Am. Chem.
Soc. 1996, 118, 4322-4343. (i) Gung, B. W. Tetrahedron 1996, 52,
5263-5301.
(31) Note that the designation of the geometry of enolate 34 as (E)
or (Z) depends on whether a counterion is considered as being bonded
to the anionic oxygen or not, and if so, on the CIP priority of that
counterion relative to carbon.
(32) Gais and co-workers have reported4y that the lithium enolate
formed from 3a has (E)-geometry. We are presently studying the
stuctures of enolates derived from reagents 3b-d , as well as the
dependence of the enolate ratios on the reaction conditions; these
studies will be reported upon separately.
(35) Evans has introduced34h a stereochemical model which rational-
izes the merged influence of R- and â-substituents in aldol-type
additions to substituted aldehydes, including R-methyl-â-alkoxy-alde-
hydes. However, from substrates containing R- and â-substituents in
an anti relationship (as in dialdehyde 6), the Evans model also predicts
formation of FAE-type products.
(33) (a) Bottin-Strzalko, T.; Corset, J .; Froment, F.; Pouet, M.-J .;
Seyden-Penne, J .; Simmonin, M.-P. J . Org. Chem. 1980, 45, 1270-
1276. (b) Seyden-Penne, J . Bull. Soc. Chim. France 1988 (II), 238-
242, and references therein.

Asymmetric Horner-Wadsworth-Emmons Reactions
J . Org. Chem., Vol. 63, No. 23, 1998 8291
prepared just before use. Cooling below -78 °C was effected
by use of either EtOH/liquid N2 or an immersion cooler. TLC
analyses were performed on Merck aluminum-backed F254
silica gel plates, using UV light and phosphomolybdic acid for
visualization. Drying of organic phases obtained from extrac-
tive workup was generally done with MgSO4. Flash chroma-
tography was performed as described by Still and co-workers38
and medium-pressure liquid chromatography (MPLC) as
described by Baeckstro¨m and co-workers,19 in both cases using
either Merck silica gel 60 (230-400 mesh) or Amicon Matrex
60 Å silica gel (35-70 µm). NMR spectra were recorded in
CDCl3 unless otherwise indicated, using CHCl3 (δ 7.24 ppm)
It should also be noted that the favored relative
configuration at C3/C4 cannot easily be predicted from
empirical rules. However, our recently developed mo-
lecular mechanics method30 has been able to rationalize
the product pattern.
Con clu sion s
In this paper, we have demonstrated that when meso-
dialdehydes 6 and 14 are used as substrates in asym-
metric HWE reactions, either (E)- or (Z)-monoaddition
products can be obtained with high geometric selectivity
by slight structural variation in the phosphoryl group of
the chiral reagent. By an appropriate choice of chiral
reagent and reaction conditions, both (E)- and (Z)-
products are obtained with good to excellent diastereo-
selectivities and in synthetically useful yields; these
results show that both R-methyl and R-oxygen substitu-
tion in the substrate enable high selectivities to be
obtained. The reactions with dialdehydes 14 also show
that the choice of oxygen protecting groups in the
substrate can be used for fine-tuning the outcome.
Furthermore, (E)- and (Z)-products are formed with
opposite enantiotopic group preference. Thus, when
applying these reactions in synthesis, both enantiomeric
series of a projected synthetic intermediate can be
accessed using the same enantiomer of the chiral auxil-
iary, as long as the alkene geometry of the product is of
no consequence for the particular application at hand.
The stereochemical outcome of these reactions is in all
cases consistent with a mechanistic model in which the
product stereochemistry is determined by the combined
influence of the chiral auxiliary, the alkyl group in the
phosphonate unit, and the R-stereocenters in the dial-
dehyde substrate. In particular, this model explains why
reactions at opposite enantiotopic carbonyl groups in the
substrate give products having opposite alkene geometry.
Our continuing studies in this area are aimed at
further improvement and generalization of this method-
ology through (1) the design of even more efficient chiral
reagents, (2) investigations of mechanistic details, and
(3) studies of reactions with new substrates. The prod-
ucts obtained from the asymmetric HWE reactions have
projected utility in synthetic approaches to various
natural products, and several such synthetic applications
are under active investigation.
1
and CDCl3 (δ 77.0 ppm) as internal references for H and 13C,
respectively. (1R,2S,5R)-8-Phenylmenthol was prepared ac-
cording to a literature procedure.39 Tropone40 and 1,3-cyclo-
heptadien-6-ol41 are intermediates in the synthetic route to
diene 9 and were prepared according to literature procedures.
Stereochemical descriptors for the meso compounds reported
here have been assigned in accordance with a recent treatise.42
(Dieth oxyp h osp h or yl)a cetic Acid (1R,2S,5R)-5-Meth yl-
2-(1-m eth yl-1-p h en yleth yl)cycloh exyl Ester (3b). Pre-
pared from triethyl phosphonoacetate (1b) and (1R,2S,5R)-8-
phenylmenthol (2) in 81% yield, in analogy with the published
procedure8 for preparation of 3a . 1H NMR (400 MHz, selected
data) δ 7.24-7.16 (m, 4 H), 7.08-7.03 (m, 1 H), 4.77 (ddd [app
td], J ) 10.8, 4.4 Hz, 1 H), 4.08-3.91 (m, 4 H), 2.31 (dd, J )
21.3, 14.4 Hz, 1 H), 2.02 (dd, J ) 21.3, 14.4 Hz, 1 H), 0.81 (d,
J ) 6.5 Hz, 3 H); 13C NMR (100 MHz) δ 165.1 (d, J ) 5.8 Hz),
151.8, 127.9 (2 C), 125.4 (2 C), 125.1, 75.1, 62.4 (d, J ) 5.7 Hz,
2 C), 50.3, 41.3, 39.5, 34.5, 33.9 (d, J ) 133 Hz), 31.3, 29.2,
26.3, 23.2, 21.8, 16.3 (d, J ) 6.1 Hz, 2 C). Anal. Calcd for
C
22H35O5P: C, 64.37; H, 8.59. Found: C, 63.97; H, 8.51.
[Bis(2,2,2-t r iflu or oet h oxy)p h osp h or yl]a cet ic Acid
(1R,2S,5R)-5-Meth yl-2-(1-m eth yl-1-p h en yleth yl)cycloh ex-
yl est er (3d ). Prepared from methyl bis(trifluoroethyl)
phosphonoacetate (1d ) and (1R,2S,5R)-8-phenylmenthol in
89% yield, according to the same procedure as was used for
3b. 1H NMR (400 MHz, selected data) δ 7.30-7.23 (m, 4 H),
7.17-7.07 (m, 1 H), 4.82 (ddd [app td], J ) 10.7, 4.4 Hz, 1 H),
4.48-4.20 (m, 4 H), 2.27 (dd, J ) 20.7, 15.9 Hz, 1 H), 2.25 (dd,
J ) 20.4, 15.9 Hz, 1 H), 1.27 (s, 3 H), 1.17 (s, 3 H), 0.86 (d, J
) 6.4 Hz, 3 H); 13C NMR (100 MHz) δ 164.0 (d, J ) 5.8 Hz),
151.9, 128.1 (2 C), 125.3 (2 C), 125.1, 122.4 (app quartet of m,
one J ) ca 277 Hz, 2 C), 75.9, 62.4 (app quartet of m, one J )
ca. 40 Hz, 2 C), 50.1, 41.2, 39.3, 34.4, 33.4 (d, J ) 144 Hz),
31.2, 30.0, 26.1, 22.2, 21.7. Anal. Calcd for C22H29O5FP: C,
50.97; H, 5.64. Found: C, 50.81; H, 5.66.
m eso-(2R,3r ,4S)-3-((ter t-(Bu t yld im et h ylsilyl)oxy)-2,4-
d im eth ylp en ta n ed ia l (6). To a solution of oxalyl chloride
(136 µL, 1.55 mmol) in CH2Cl2 (8 mL) at -78 °C under argon
was added dropwise a solution of DMSO (147 µL, 2.07 mmol)
in CH2Cl2 (1 mL). After 30 min, a solution of 514 (136 mg,
0.518 mmol) in CH2Cl2 (1 mL) was added dropwise followed,
after 30 min, by triethylamine (722 µL, 5.18 mmol). The
reaction mixture was stirred at -78 °C for 1 h and then
warmed slowly to 0 °C during 1 h. After 30 min of stirring at
0 °C, the solution was diluted with dry toluene (25 mL), filtered
through a dried glass frit, and concentrated. The residue was
dissolved in dry hexane (25 mL), filtered again, and concen-
trated yielding 131 mg (quantitative crude yield) of 6 as a pale
yellow oil which due to its limited stability was used without
further purification in the HWE reactions: 1H NMR (250 MHz)
δ 9.73 (d, J ) 2.1 Hz, 2H), 4.28 (t, J ) 5.1 Hz, 1H), 2.59 (qdd,
J ) 7.1, 5.1, 2.0 Hz, 2H), 1.08 (d, J ) 7.1 Hz, 6H), 0.84 (s, 9H),
0.06 (s, 6H); 13C NMR (62.5 MHz) δ 203.4, 74.2, 50.8, 25.7,
18.0, 10.5, -4.5.
Exp er im en ta l Section
Gen er a l. All reactions were performed in oven-dried or
flame-dried glassware. Commercial reagents were used as
received, unless otherwise indicated. Solvents were generally
distilled before use. Potassium hexamethyldisilazide [KN-
(SiMe3)2, KHMDS] was purchased as a stock solution (0.5 M
in toluene) and titrated according to the method of Ireland
and Meissner.37 18-Crown-6 was recrystallized from anhy-
drous acetonitrile and dried under vacuum. Toluene, CH2Cl2,
hexane, Et3N, and pyridine were distilled from CaH2. THF
was distilled from sodium/benzophenone ketyl. Pd(OAc)2 was
recrystallized from acetic acid, and benzoquinone was recrys-
tallized from ethanol. Dialdehydes 6 and 14b were freshly
(38) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2925.
(36) We have observed the same general trend in all asymmetric
HWE reactions studied by us to date. A similar argumentation is used
by Fuji and co-workers when analyzing the results of asymmetric HWE
reactions between a chiral phosphonate and a group of meso-diketones;
see ref 4bb.
(37) Ireland, R. E.; Meissner, R. S. J . Org. Chem. 1991, 56, 4566-
4568.
(39) Ort, O. Org. Synth. 1987, 65, 203-214.
(40) Dahnke, K. R.; Paquette, L. A. Org. Synth. 1992, 71, 181-188.
(41) Schuster, D. I.; Palmer, J . M.; Dickerman, S. C. J . Org. Chem.
1966, 31, 4281-4282.
(42) Helmchen, G. In Houben-Weyl, Stereoselective Synthesis; Helm-
chen, G., Hoffman, R. W., Mulzer, J ., Schaumann, E., Eds.; Thieme:
Stuttgart, 1996; Vol. 1, pp 1-74.

8292 J . Org. Chem., Vol. 63, No. 23, 1998
Tullis et al.
m eso-(3R,5s,7S)-5-(Ben zyloxy)-3,7-d ia cetoxycycloh ep t-
1-en e (10). Diene 917 (1.00 g, 5.0 mmol) was added neat to a
solution of palladium(II) acetate (56 mg, 0.25 mmol), lithium
acetate dihydrate (2.55 g, 25 mmol), and benzoquinone (108
mg, 1.0 mmol) in glacial acetic acid (10 mL). After addition
of MnO2 (869 mg, 10 mmol), the resulting slurry was stirred
at room temperature. The reaction was followed by TLC until
all starting material had been consumed (2-3 days) and then
worked up by addition of water and hexane/EtOAc 1/1. The
resulting emulsion was filtered through Celite, the phases
were separated, and the aqueous phase was extracted with
three portions of hexane/EtOAc 1/1. The combined organic
phases were washed with water, 2 M NaOH, and water again
and then dried and concentrated to give 1.42 g of a yellowish-
brown oil. Purification was effected by MPLC (0-100% EtOAc
in hexanes), yielding 811 mg (51%) of 10 as a colorless oil: 1H
NMR (250 MHz) δ 7.42-7.23 (5H), 5.76 (dd, J ) 10.8, 2.3 Hz,
2H), 5.7 (s, 2 H), 4.65 (s, 2H), 3.92 (tt, J ) 5.6, 2.7 Hz, 1H),
2.22 (ddd, J ) 13.4, 5.6, 2.3 Hz, 2H), 1.86 (ddd, J ) 1.4, 10.8,
2.7 Hz, 2H), 2.05 (s, 6H); 13C NMR (62.5 MHz) δ 169.9, 138.3,
132.5, 128.2, 127.5, 127.3, 71.7, 70.0, 68.8, 36.6, 21.1. Anal.
Calcd for C18H22O5: C, 67.91; H, 6.97. Found: C, 67.83; H,
6.85.
m eso-(1R,4S,6s)-6-(Ben zyloxy)cycloh ep t -2-en e-1,4-d i-
ol (11). To a solution of diacetate 10 (111 mg, 0.35 mmol) in
MeOH (1.5 mL) at 0 °C was added dropwise an aqueous
solution of KOH (98 mg, 1.75 mmol, in 1.5 mL of water). The
resulting pale yellow solution was stirred at 0 °C until no
starting material was detected by TLC (ca. 30 min). The
reaction mixture was neutralized with 2 M H2SO4 and diluted
with water. Extractive workup (CH2Cl2), drying, and concen-
tration gave 82 mg of a white solid. Purification by flash
chromatography (hexanes/EtOAc 1/1) gave 76 mg (93%) of
white crystalline 11: 1H NMR (400 MHz, DMSO) δ 7.37-7.23
(m, 5H), 5.55 (s, 2H), 4.79 (d, J ) 4.7, 2H), 4.53 (s, 2H), 4.50-
4.41 (m, 2H), 3.83-3.75 (m, 1H), 2.02 (ddd, J ) 13.3, 5.2, 2.4
Hz, 2H), 1.55 (ddd, J ) 13.4, 11.1, 2.5 Hz, 2H); 13C NMR (100
MHz, DMSO) δ 139.0, 136.1, 128.3, 127.4, 127.3, 73.2, 69.1,
64.1, 40.0. Anal. Calcd for C14H18O3: C, 71.77; H, 7.74.
Found: C, 71.88; H, 7.61.
m eso-(3R,5s,7S)-5-(Ben zyloxy)-3,7-b is-((ter t-b u t yld i-
p h en ylsilyl)oxy)cycloh ep t-1-en e (12a ). To a solution of diol
11 (0.816 g, 3.35 mmol) and imidazole (1.14 g, 16.75 mmol) in
dry DMF (30 mL) under argon was added tert-butyldiphenyl-
silyl chloride (2.1 mL, 8.05 mmol). The reaction mixture was
stirred for 24 h at room temperature and then diluted with
brine and extracted with ethyl acetate. Drying (Na2SO4) and
concentration of the combined organic extracts followed by
flash chromatography (hexanes/EtOAc 99/1) afforded 2.432 g
(99%) of 12a as a colorless oil: 1H NMR (400 MHz) δ 7.72-
7.64 (m, 8H), 7.44-7.23 (m, 15H), 7.00-6.93 (m, 2H), 5.78 (s,
2H), 4.75 (d, J ) 9.9 Hz, 2H), 3.89 (s, 2H), 3.67-3.60 (m, 1H),
2.02 (ddd [app br dd], J ) 12, 4 Hz, 2H), 1.78 (ddd [app br t],
J ) 12 Hz, 2H), 1.09 (s, 18H); 13C NMR (100 MHz) δ 138.9,
135.8, 134.3, 134.0, 129.5, 128.0, 127.9, 127.5, 127.0, 72.6, 67.5,
69.0, 40.1, 27.0, 26.49, 19.2. Anal. Calcd for C46H54O3Si2: C,
77.70; H, 7.65. Found: C, 77.48; H, 7.62.
m eso-(1R,2S,3R,5s,7S)-5-(Ben zyloxy)-3,7-b is((ter t-b u -
tyld ip h en ylsilyl)oxy)cycloh ep ta n e-1,2-d iol a n d m eso-
(1R ,2S ,3S ,5s,7R )-5-(B e n zy lo x y)-3,7-b is-(t er t -b u t y ld i-
p h en ylsilyl)oxy)cycloh ep ta n e-1,2-d iol (13a ; m ixtu r e of
th e tw o m eso d iols). To a solution of silyl ether 12a (321
mg, 0.45 mmol) and N-methylmorpholine N-oxide (53 mg, 0.45
mmol) in 5 mL of THF were added tert-butyl alcohol (2.5 mL)
and H2O (1.2 mL), followed by 115 µL of a 2.5 weight-%
solution of OsO4 in tert-butyl alcohol (0.009 mmol). The pale
yellow solution was stirred for 30 h at room temperature and
then quenched with 5 mL of 10% Na2S2O4. Dilution with brine
followed by extraction (EtOAc), drying, and concentration
followed by flash chromatography (hexanes/EtOAc 88/12)
afforded 325 mg of a mixture of diastereomeric diols 13a (97%)
as a colorless oil. The diastereomeric mixture was normally
used as such for preparation of the dialdehyde 14a ; isomeri-
cally pure samples of the separate diastereomeric diols could
be obtained by chromatography, however. Faster eluting
isomer (Rf ) 0.42, hexanes/EtOAc 8/2): 1H NMR (250 MHz) δ
7.75-7.60 (m, 8H), 7.46-7.20 (m, 15H), 6.97-6.90 (m, 2H),
4.06 (br d, J ) 10.2 Hz, 2H), 3.91 (s, 2H), 3.65 (br s, 2H), 3.53-
3.43 (m, 1H), 3.10 (br d, J ) 4.9 Hz, 2H), 2.15 (ddd, J ) 14.4,
10.1, 4.1 Hz, 2H), 1.68 (ddd, J ) 14.4, 5.8, 2.8 Hz, 2H), 1.06
(s, 18H); 13C NMR (62.5 MHz) δ 138.6, 135.9, 133.6, 133.3,
129.8, 128.1, 127.7, 127.2, 74.7, 71.4, 70.6, 69.6, 34.8, 27.0, 19.2.
Anal. Calcd for C46H56O5Si2: C, 74.15; H, 7.58. Found: C,
74.37; H, 7.78. Slower eluting isomer (Rf ) 0.28, hexanes/
EtOAc 8/2): 1H NMR (250 MHz) δ 7.75-7.65 (m, 8H), 7.50-
7.20 (m, 15H), 7.08-7.00 (m, 2H), 4.21 (br td, J ) 7, 3 Hz,
2H), 4.01 (br dd, J ) 5.9, 2.2 Hz, 2H), 3.96 (s, 2H), 3.70-3.58
(m, 1H), 2.94 (d, J ) 2.4 Hz, 2H), 1.97 (ddd, J ) 14.7, 6.4, 3.2
Hz, 2H), 1.88 (ddd, J ) 14.7, 7.6, 4.8 Hz, 2H), 1.11 (s, 18H);
13C NMR (62.5 MHz) δ 138.3, 135.9, 133.9, 133.3, 129.9, 128.2,
127.9, 127.8, 127.4, 74.7, 71.0, 70.2, 69.7, 36.2, 27.1, 19.4.
Anal. Calcd for C46H56O5Si2: C, 74.15; H, 7.58. Found: C,
74.50; H, 7.82.
m eso-(2R ,4s,6S )-4-(Be n zyloxy)-2,6-b is(t er t -b u t yld i-
p h en ylsilyl)oxy)h ep ta n ed ia l (14a ). To a solution of diols
13a (412 mg, 0.552 mmol) in THF (10 mL) was added a
solution of H5IO6 (125 mg, 0.552 mmol) in THF (10 mL). The
reaction mixture became cloudy after a few minutes. After
2.5 h at room temperature, 20 mL of pH 7 phosphate buffer
was added, and the solution was extracted with ethyl acetate.
Drying and concentration followed by flash chromatography
(hexanes/EtOAc 9/1) yielded 365 mg (89%) of 14a as a pale
beige oil: 1H NMR (400 MHz) δ 9.50 (d, J ) 1.7 Hz, 2H), 7.68-
7.58 (m, 8H), 7.46-7.22 (m, 15H), 7.11-7.05 (m, 2H), 4.15 (ddd
[app td], J ) 6.0, 1.5 Hz, 2H), 4.06 (s, 2H), 3.75-3.67 (m, 1H),
2.02 (ddd [app td], J ) 14.6, 6.2 Hz, 2H), 1.78 (ddd, J ) 14.6,
6.0, 4.9 Hz, 2H), 1.11 (s, 18H); 13C NMR (100 MHz, some
signals in the aromatic region overlap) δ 202.2, 137.8, 135.8,
135.8, 132.9, 132.8, 130.1, 128.2, 127.8, 127.7, 127.4, 76.0, 72.1,
70.1, 38.3, 26.9, 19.3. Anal. Calcd for C46H54O5Si2: C, 74.35;
H, 7.32. Found: C, 74.12; H, 7.16.
m eso-(3R,5s,7S)-5-(Ben zyloxy)-3,7-b is((2,2-d im et h yl-
p r op ion yl)oxy)cycloh ep t-1-en e (12b). To a solution of diol
11 (442 mg, 1.39 mmol) and DMAP (170 mg, 1.39 mmol) in
dry pyridine (25 mL) under argon was added pivaloyl chloride
(520 µL, 4.22 mmol). The reaction mixture was stirred for 16
h at reflux. After cooling and concentration, the residue was
purified by flash chromatography (hexanes/EtOAc 95/5) to
afford 555 mg (99%) of 12b as white solid: 1H NMR (400 MHz)
δ 7.39-7.21 (m, 8H), 5.71 (br dd, J ) 11, 3 Hz, 2H), 5.66 (s,
2H), 4.63 (s, 2H), 3.9 (tt [app septet], J ) 5.8, 2.9 Hz, 1H),
2.18 (ddd, J ) 13.4, 5.8, 2.7 Hz, 2H), 1.89 (ddd, J ) 13.4, 10.7,
2.7 Hz, 2H), 1.18 (s, 18H); 13C NMR (100 MHz) δ 177.2, 138.3,
132.5, 128.2, 127.5, 127.3, 71.6, 70.0, 68.5, 38.4, 36.7, 27.0.
Anal. Calcd for C24H34O5: C, 71.61; H, 8.51. Found: C, 71.61;
H, 8.49.
m eso-(1R ,2S ,3R ,5s,7S )-5-(Be n zyloxy)-3,7-b is((2,2-d i-
m eth ylp r op ion yl)oxy)cycloh ep ta n e-1,2-d iol a n d m eso-
(1R,2S,3S,5s,7R)-5-(Ben zyloxy)-3,7-bis(2,2-d im et h ylp r o-
p ion yl)oxy)cycloh ep ta n e-1,2-d iol (13b; m ixtu r e of th e
tw o m eso d iols). To a solution of bis-pivaloyl ester 12b (557
mg, 1.38 mmol) and N-methylmorpholine N-oxide (162 mg,
1.38 mmol) in 16 mL of THF were added tert-butyl alcohol (8
mL) and H2O (4 mL), followed by 325 µL of a 2.5 wt % solution
of OsO4 in tert-butyl alcohol (0.026 mmol). The reaction
mixture was stirred for 4 h at room temperature and then
quenched with 7 mL of 10% Na2S2O4. Dilution with brine
followed by extraction (EtOAc), drying, and concentration
afforded an essentially quantitative yield of a crude mixture
of diols 13b as a colorless oil. This diastereomeric mixture
could be used in the preparation of dialdehyde 14b without
further purification. Alternatively, isomerically pure samples
of the separate diol diastereomers could be obtained by flash
chromatography38 (hexanes/EtOAc 7/3). Faster eluting isomer
(Rf ) 0.36, hexanes/EtOAc 7/3): 1H NMR (400 MHz) δ 7.33-
7.22 (m, 5H), 5.19 (dm, J ) 10.1 Hz, 2H), 4.49 (s, 2H), 4.03 (br
s, 2H), 3.82 (tt, J ) 6.5, 4.4 Hz, 1H), 2.81 (br s, 2H), 2.37 (ddd,
J ) 14.3, 10.1, 4.6 Hz, 2H), 1.94 (ddd, J ) 14.3, 6.4, 3.1 Hz,
2H), 1.18 (s, 18H); 13C NMR (100 MHz) δ 177.9, 138.2, 128.3,
127.5, 73.2, 71.0, 70.5, 70.3, 38.8, 31.9, 27.0. Slower eluting

Asymmetric Horner-Wadsworth-Emmons Reactions
J . Org. Chem., Vol. 63, No. 23, 1998 8293
isomer (Rf ) 0.22, hexanes/EtOAc 7/3): 1H NMR (400 MHz) δ
7.31-7.24 (m, 5H), 5.15 (ddd [app td], J ) 6.4, 4.4 Hz, 2H),
4.54 (s, 2H), 3.91 (d, J ) 6.4 Hz, 2H), 3.71 (tt, J ) 7.8, 2.9 Hz,
1H), 3.44 (br s, 2H), 2.30 (ddd, J ) 15.0, 7.6, 4.3 Hz, 2H), 1.95
(ddd, J ) 15.0, 6.1, 3.05 Hz, 2H), 1.17 (s, 18H); 13C NMR (100
MHz) δ 178.1, 137.6, 128.4, 127.8, 127.7, 73.5, 71.8, 70.4, 70.2,
38.7, 35.1, 27.0. Anal. Calcd for C24H36O7: C, 66.03; H, 8.31.
Found: C, 66.02; H, 8.37.
m eso-(2R,4s,6S)-4-(Ben zyloxy)-2,6-bis(2,2-d im eth ylp r o-
p ion yl)oxy)h ep ta n ed ia l (14b). To a solution of diols 13b
(147 mg, 0.339 mmol) in THF (4 mL) was added a solution of
H5IO6 (77.2 mg, 0.339 mmol) in THF (4 mL) at 0 °C. The ice
bath was removed after 15 min; the reaction mixture then
became cloudy in 10 min. After 1.5 h at room temperature, 3
mL of pH 7 phosphate buffer and 10 mL of brine were added.
The solution was extracted with EtOAc, dried, and concen-
trated, and the residue was dissolved in CHCl3 (2 mL) and
filtered through a plug of cotton, affording 147 mg (99%) of a
colorless oil after concentration. Dialdehyde 14b was used in
HWE reactions without further purification: 1H NMR (400
MHz) δ 9.48 (s, 2H), 7.37-7.27 (m, 5H), 5.13 (dd, J ) 9.8, 3.7
Hz, 2H), 4.38 (s, 2H), 3.69 (tt [app sept], J ) 7.9, 4.0, 1H),
2.18 (ddd, J ) 15.0, 7.9, 3.4 Hz, 2H), 1.95 (ddd, J ) 15.0, 9.5,
4.0 Hz, 2H), 1.22 (s, 18H); 13C NMR (100 MHz) δ 197.5, 177.8,
137.1, 128.6, 128.1, 75.3, 72.2, 71.5, 38.7, 34.0, 27.0.
Gen er a l P r oced u r e for th e Asym m etr ic HWE Rea c-
tion s. To a solution of the chiral phosphonate (3a -d ; 1.05-
1.2 equiv) and 18-crown-6 (if applicable; 5 equiv) in THF (ca
0.02 M with respect to the phosphonate) at -78 °C under argon
was added 1.0 equiv of KHMDS (0.5 M in toluene). After 30
min the resulting grayish slurry was transferred via cannula
to a precooled solution of the dialdehyde43 (6, 14a or 14b; Table
1: 1.2-2.1 equiv, Tables 2 and 3: 1.1-1.3 equiv). The reaction
mixture was stirred for the indicated time at the appropriate
reaction temperature (monitoring by TLC) and then quenched
with acetic acid (1 M in MeOH or THF). After 5 min, pH 7
phosphate buffer was added, and the reaction was slowly
warmed to room temperature. After dilution with water,
extractive workup (ethyl acetate), drying, and concentration
gave the crude condensation products. Purification by flash
chromatography or MPLC19 using EtOAc in hexanes as eluent
afforded the products as colorless oils.23
(E )-(4R ,6R ,8S )-6-(Be n zyloxy)-4,8-b is((t er t -b u t yld i-
p h en ylsilyl)oxy)-9-h yd r oxyn on -2-en oic Acid (1R,2S,5R)-
5-Meth yl-2-(1-m eth yl-1-ph en yleth yl)cycloh exyl ester (17).
Prepared from 3a and 14a in 60% overall yield; (E):(Z) ) 98:
2, diastereomeric ratio 17:18 ) 89:11.23 17: 1H NMR (400
MHz, selected data) δ 6.62 (dd, J ) 15.6, 5.9 Hz, 1H), 5.45
(dd, J ) 15.6, 1.1 Hz, 1H), 4.83 (ddd [app td], J ) 10.7, 4.3
Hz, 1H), 4.21 (app br q, J ) 5.8 Hz, 1H), 4.07 (d, J ) 11.1 Hz,
1H), 4.01 (d, J ) 11.1 Hz, 1H), 3.77-3.70 (m, 1H), 3.46 (ddd,
J ) 11.6, 5.7, 3.5 Hz, 1H), 3.31 (ddd, J ) 11.6, 7.23, 4.3 Hz,
1H), 3.24 (dddd [app quintet], J ) ca 6 Hz, 1H), 1.27 (s, 3H),
1.24 (s, 3H), 1.05 (s, 9H), 1.02 (s, 9H), 0.87 (d, J ) 6.4 Hz,
3H); 13C NMR (100 MHz, some signals in the aromatic region
overlap) δ 165.5, 150.8, 149.3, 138.2, 135.9, 135.7, 133.8, 133.6,
133.5, 133.2, 129.9, 129.8, 128.2, 127.9, 127.82, 127.76, 127.65,
127.57, 127.5, 127.4, 125.6, 125.2, 120.8, 74.5, 72.6, 71.6, 69.99,
69.95, 66.2, 50.7, 42.8, 41.8, 40.1, 38.7, 34.5, 31.3, 28.5, 27.04,
26.98, 25.0, 21.8, 19.3. Anal. Calcd for C64H80O6Si2: C, 76.76;
H, 8.05. Found: C, 76.54; H, 7.96. 18: 1H NMR (400 MHz,
selected data assigned from a mixture (89:11) of diastereomers
17 and 18) δ 6.41 (dd, J ) 15.6, 6.1 Hz, 1H), 5.34 (dd, J )
15.6, 1.1 Hz, 1H).
(E)-(4S,5S,6S)-5-(ter t-(Bu t yld im et h ylsilyl)oxy)-4,6-d i-
m eth yl-7-oxo-h ep t-2-en oic Acid (1R,2S,5R)-5-Meth yl-2-(1-
m eth yl-1-p h en yleth yl)cycloh exyl Ester (19). Prepared
from 3a and 6 in 53% yield; (E):(Z) ) 98:2, diastereomeric ratio
19:20 ) 95:5.23,44 19: 1H NMR (250 MHz, selected data) δ
9.73 (d, J ) 2.5 Hz, 1H), 7.27-7.19 (m, 4H), 7.14-7.05 (m,
1H), 6.68 (dd, J ) 15.8, 7.7 Hz, 1H), 5.20 (dd, J ) 15.8, 1.3
Hz, 1H), 4. 82 (ddd [app td]), J ) 10.7, 4.3 Hz, 1H), 3.81 (dd
[app t], J ) 4.6 Hz, 1H), 2.52-2.39 (m, 2H), 2.01 (ddd, J )
12.1, 10.6, 3.4 Hz, 1H), 1.28 (s, 3H), 1.19 (s, 3H), 1.05 (d, J )
7.1 Hz, 3H), 0.97 (d, J ) 6.9 Hz, 3H), 0.87 (s, 9H), 0.84 (d, J
) 6.5 Hz, 3H), 0.05 (s, 3H), 0.04 (s, 3H); 13C NMR (62.5 MHz)
δ 204.3, 165.6, 151.7, 149.2, 127.9, 125.4, 124.9, 122.2, 77.2,
74.4, 50.5, 50.2, 41.7, 41.6, 39.7, 34.6, 31.3, 27.5, 26.6, 25.9,
25.4, 21.8, 18.1, 15.5, 11.7, -4.2, -4.4. Anal. Calcd for
C
31H50O4Si: C, 72.32; H, 9.79. Found: C, 72.06; H, 9.74. 20:
1H NMR (250 MHz, selected data assigned from a mixture (95:
5) of diastereomers 19 and 20) δ 6.66 (dd, J ) 16, 7 Hz, 1H),
5.17 (dd, J ) 16, 1.5 Hz, 1H).
(Z)-(4R ,5R ,6R )-5-(t er t -(Bu t yld im e t h ylsilyl)oxy)-4,6-
d im eth yl-7-oxo-h ep t-2-en oic Acid (1R,2S,5R)-5-Meth yl-
2-(1-m eth yl-1-p h en yleth yl)cycloh exyl Ester (21). Pre-
pared from 3d and 6 in 83% yield; (Z):(E) ) 98:2, diastereo-
meric purity ) 98:2. 21: 1H NMR (400 MHz, selected data) δ
9.74 (d, J ) 2.7 Hz, 1H), 7.25-7.20 (m, 4 H), 7.13-7.09 (m,
1H), 6.11 (dd, J ) 11.6, 10.0 Hz, 1H), 5.18 (dd, J ) 11.5, 0.6
Hz, 1H), 4.79 (ddd [app td], J ) 10.7, 4.3 Hz, 1H), 3.81 (dd, J
) 5.8, 3.2 Hz, 1H), 3.82 (m, 1H), 2.47 (qdd, J ) 7.0, 5.8, 2.7
Hz, 1H), 1.98 (ddd, J ) 12.3, 10.6, 3.2 Hz, 1H), 1.28 (s, 3H),
1.21 (s, 3H), 1.08 (d, J ) 7.1 Hz, 3H), 1.00 (d, J ) 6.9 Hz, 3H),
0.89 (s, 9 H), 0.84 (d, J ) 6.5 Hz, 3H), 0.09 (s, 3H), 0.05 (s,
3H); 13C NMR (100 MHz) δ 204.4, 165.1, 151.5, 149.9, 127.8,
125.4, 125.0, 120.4, 77.2, 73.9, 51.5, 50.5, 41.8, 39.7, 36.6, 34.6,
31.3, 26.9, 26.7, 25.8, 25.4, 21.6, 18.2, 17.6, 11.3, -4.1, -4.4.
Anal. Calcd for C31H50O4Si: C, 72.32; H, 9.79. Found: C,
72.14; H, 9.63.
(E )-(4R ,6R ,8S )-6-(Be n zyloxy)-4,8-b is((t er t -b u t yld i-
p h en ylsilyl)oxy)-9-oxon on -2-en oic Acid (1R,2S,5R)-5-
Meth yl-2-(1-m eth yl-1-ph en yleth yl)cycloh exyl Ester (23a).
Prepared from 3a and 14a in 65% yield;45 (E):(Z) ) 98:2,
diastereomeric ratio 23a :24a ) 98:2 (in the crude product, this
diastereomer ratio was 89:11, but the diastereomers could be
separated by chromatography23). 23a : 1H NMR (400 MHz,
selected data) δ 9.45 (d, J ) 1.7 Hz, 1H), 7.65-7.53 (m, 8 H),
Gen er a l P r oced u r e for Red u ction of th e HWE P r od -
u cts. The crude condensation product was dissolved in MeOH
or i-PrOH (THF was sometimes added to increase solubility)
at 0 °C, and NaBH4 (5-10 equiv) was added. After stirring
at 0 °C until the reaction was finished (monitoring by TLC),
the reaction mixture was diluted with water and extracted
with CH2CH2. Drying, concentration, and purification by flash
chromatography (EtOAc in hexanes) gave the alcohols as
colorless oils.
(E)-(4S,5S,6R)-5-(ter t-(Bu t yld im et h ylsilyl)oxy)-7-h y-
d r oxy-4,6-d im eth ylh ep t-2-en oic Acid (1R,2S,5R)-5-Meth -
yl-2-(1-m eth yl-1-p h en yleth yl)cycloh exyl Ester (15). Pre-
pared from 3a and 6 in 77% overall yield; (E):(Z) ) 98:2,
diastereomeric ratio 15:16 ) 91:9.23 15: 1H NMR (250 MHz,
selected data) δ 7.27-7.19 (m, 4H), 7.13-7.06 (m, 1H), 6.72
(dd, J ) 15.8, 7.7 Hz, 1H), 5.21 (dd, J ) 15.7, 1.3 Hz, 1H),
4.84 (ddd [app td], J ) 10.7, 4.3 Hz, 1H), 3.61-3.53 (br m,
2H), 3.57 (dd [app t], J ) 5.1 Hz, 1H), 2.56-2.43 (m, 1H), 2.31
(br s, 1H), 2.00 (ddd, J ) 12.1, 10.7, 3.3 Hz, 1H), 1.84-1.73
(m, 1H), 1.28 (s, 3H), 1.19 (s, 3H), 1.00 (d, J ) 6.9 Hz, 3H),
0.90 (d, J ) 6.8 Hz, 3H), 0.89 (s, 9H), 0.84 (d, J ) 6.5 Hz, 3H),
0.09 (s, 3H), 0.06 (s, 3H); 13C NMR (100 MHz) δ 165.7, 151.6,
150.4, 127.9, 125.4, 124.9, 121.5, 79.8, 74.3, 65.7, 50.6, 41.72,
39.8, 38.0, 34.6, 31.3, 27.2, 26.7, 26.0, 25.7, 21.8, 18.2, 15.6,
15.6, -4.09, -4.12. Anal. Calcd for C31H52O4Si: C, 72.04; H,
10.14. Found: C, 71.81; H, 10.13. 16: 1H NMR (250 MHz,
selected data assigned from a mixture (91:9) of diastereomers
15 and 16) δ 6.70 (dd, J ) 15.8, 7.4 Hz, 1H), 5.18 (dd, J )
15.8, 1.4 Hz, 1H).
(44) The sample also contained 3% of an isomer tentatively assigned
as being epimeric at the carbon R to the aldehyde carbonyl; see
Supporting Information for details.
(45) The sample obtained after flash chromatography also contained
6% of unreacted dialdehyde 14a ; this could be removed, with good
material recovery, by a second chromatography. Alternatively, it was
easily removed by chromatography after NaBH4 reduction of the HWE
product.
(43) The opposite mode of addition (i.e., adding a precooled solution
of the aldehyde to the phosphonate enolate) gave identical results, if
the transfer was performed rapidly.

8294 J . Org. Chem., Vol. 63, No. 23, 1998
Tullis et al.
7.43-7.18 (m, 19H), 7.07-7.01 (m, 3H), 6.68 (dd, J ) 15.6,
6.1 Hz, 1H), 5.44 (dd, J ) 15.6, 1.2 Hz, 1H), 4.82 (ddd [app
td], J ) 10.6, 4.3 Hz, 1H), 4.28 (app br q, J ) 6.2 Hz, 1H),
4.08 (ddd [app td], J ) 6.0, 1.8 Hz, 1H), 4.03 (d, J ) 11.1 Hz,
1H), 3.99 (d, J ) 11.0 Hz, 1H), 3.54 (dddd [app br quintet], J
) ca 5 Hz, 1H), 1.26 (s, 3H), 1.23 (s, 3H), 1.08 (s, 9H), 1.04 (s,
9H), 0.86 (d, J ) 6.5 Hz, 3H); 13C NMR (100 MHz, some signals
overlap) δ 202.1, 165.5, 150.9, 149.1, 138.2, 135.97, 135.95,
135.92, 135.8, 133.6, 133.3, 133.0, 132.9, 130.2, 129.9, 128.3,
128.0, 127.9, 127.8, 127.7, 127.6, 127.4, 125.6, 125.5, 125.3,
121.1, 76.0, 74.6, 72.1, 70.3, 70.1, 50.7, 43.0, 41.8, 40.2, 38.2,
34.6, 31.4, 28.4, 27.1, 25.2, 21.9, 19.4. Anal. Calcd for
(dddd [app septet], J ) 4 Hz, 1H), 1.26 (s, 3 H), 1.21 (s, 3H),
1.23 (s, 9H), 1.19 (s, 9H), 0.84 (d, J ) 6.5 Hz, 3H); 13C NMR
(50 MHz, some peaks in the aliphatic region overlap) δ 197.3,
177.8, 177.0, 165.0, 151.3, 144.4, 137.3, 128.6, 128.2, 128.1,
127.9, 125.4, 125.1, 122.1, 75.3, 74.7, 72.6, 71.8, 69.1, 50.4, 41.6,
39.9, 38.8, 34.5, 34.1, 31.2, 27.1, 26.6, 25.9, 21.7. 24b: 1H NMR
(400 MHz, selected data assigned from a mixture (95:5) of
diastereomers 23b and 24b) δ 6.13 (dd, J ) 15.8, 4.5 Hz, 1H),
5.28 (dd, J ) 15.8, 1.7 Hz, 1H).
(Z)-(4S,6S,8R)-6-(Ben zyloxy)-4,8-bis((2,2-d im eth ylp r o-
p ion yl)oxy)-9-oxon on -2-en oic Acid (1R,2S,5R)-5-Meth yl-
2-(1-m eth yl-1-p h en yleth yl)cycloh exyl Ester (25b).46 Pre-
pared from 3d and 14b in 62% yield; (Z):(E) ) 98:2,
diastereomeric ratio 25b:26b ) 98:2. 25b: 1H NMR (250 MHz,
selected data) δ 9.48 (s, 1H), 7.38-7.16 (m, 9H), 7.13-7.04
(m, 1H), 6.24 (dddd, J ) 9.3, 7.5, 3.3, 1.3 Hz, 1H), 5.79 (dd, J
) 11.6, 7.4 Hz, 1H), 5.20 (dd, J ) 10.2, 3.4 Hz, 1H), 5.04 (dd,
J ) 11.6, 1.4 Hz, 1H), 4.82 (ddd [app td], J ) 10.7, 4.3 Hz,
1H), 4.60 (d, J ) 11.1 Hz, 1H), 4.40 (d J ) 11.1 Hz, 1H), 3.75-
3.65 (m, 1H), 1.21 (s, 9H), 1.14 (s, 9H), 0.86 (d, J ) 6.5 Hz,
3H); 13C NMR (125 MHz, some peaks in the aliphatic region
overlap) δ 197.6, 177.7, 177.4, 164.4, 151.5, 146.7, 137.9, 128.4,
128.1, 127.9, 127.7, 125.4, 125.0, 120.9, 75.5, 74.4, 72.3, 71.7,
69.8, 50.5, 41.7, 39.7, 38.8, 34.6, 31.3, 27.7, 27.1, 26.6, 25.2,
21.8. A sample enriched in diastereomer 26b was obtained
C
64H78O6Si2: C, 76.91; H, 7.87. Found: C, 76.63; H, 7.77. A
sample enriched in diastereomer 24a was obtained from a
different experiment. 24a : 1H NMR (400 MHz, selected data
assigned from a mixture (87:13) of diastereomers 23a and 24a )
δ 9.42 (d, J ) 1.8 Hz, 1H), 6.41 (dd, J ) 15.6, 6.1 Hz, 1H),
5.38 (dd, J ) 15.6, 1.4 Hz, 1H).
(Z)-(4S ,6S ,8R )-6-(B e n zy lo x y )-4,8-b is ((t er t -b u t y ld i-
p h en ylsilyl)oxy)-9-oxon on -2-en oic Acid (1R,2S,5R)-5-
Meth yl-2-(1-m eth yl-1-ph en yleth yl)cycloh exyl Ester (25a).
Prepared from 3d and 14a , using only KHMDS as base (i.e.,
no 18-crown-6), in 76% yield; (Z):(E) ) 98:2, diastereomeric
ratio 25a :26a ) 98:2. 25a : 1H NMR (400 MHz, selected data)
δ 9.41 (d, J ) 2.5 Hz, 1H), 7.66-7.51 (m, 8H), 7.44-7.01 (m,
22H), 5.95 (dd, J ) 11.6, 8.1 Hz, 1H), 5.44 (ddd [app br
quartet], J ) ca 6 Hz, 1H), 4.75 (dd, J ) 11.6, 1.1 Hz, 1H),
4.56 (ddd [app td], J ) 10.6, 4.2 Hz, 1H), 4.26 (d, J ) 11.2 Hz,
1H), 4.23 (ddd [app td], J ) 6.4, 2.5 Hz, 1H), 4.11 (d, J ) 11.0
Hz, 1H), 3.75-3.66 (m, 1H), 1.12 (s, 3H), 1.10 (s, 12H), 1.00
(s, 9H), 0.89 (d, J ) 6.4 Hz, 3H); 13C NMR (100 MHz, some
signals overlapping) δ 201.8, 164.3, 151.5, 151.1, 138.5, 135.8,
134.0, 133.7, 133.3, 133.2, 129.93, 129.87, 129.7, 129.6, 128.1,
127.8, 127.7, 127.6, 127.4, 127.2, 125.4, 124.9, 118.5, 76.5, 73.9,
72.1, 69.6, 67.8, 50.4, 42.1, 41.7, 39.8, 39.6, 34.5, 31.3, 27.3,
27.0, 26.6, 25.4, 21.9, 19.4, 19.2. Anal. Calcd for C64H78O6-
Si2: C, 76.91; H, 7.87. Found: C, 77.17; H, 7.58. A sample
enriched in diastereomer 26a was obtained from a different
experiment. 26a : 1H NMR (400 MHz, selected data assigned
from a mixture (86:14) of diastereomers 25a and 26a ) δ 9.38
(d, J ) 2.3 Hz, 1H), 6.00 (dd, J ) 11.6, 7.9 Hz, 1H), 4.93 (dd,
J ) 11.7, 1.3 Hz, 1H).
(E)-(4R,6R,8S)-6-(Ben zyloxy)-4,8-bis((2,2-d im eth ylp r o-
p ion yl)oxy)-9-oxon on -2-en oic Acid (1R,2S,5R)-5-Meth yl-
2-(1-m eth yl-1-p h en yleth yl)cycloh exyl Ester (23b).46 Pre-
pared from 3b and 14b in 62% yield; (E):(Z) ) 98:2,
diastereomeric ratio 23b:24b ) 95:5.23 23b: 1H NMR (400
MHz, selected data) δ 9.47 (s, 1H), 7.38-7.17 (m, 9H), 7.11-
7.02 (m, 1H), 6.49 (dd, J ) 15.8, 5.3 Hz, 1H), 5.50 (dddd, J )
9.3, 5.0, 3.5, 1.3 Hz, 1H), 5.41 (dd, J ) 15.8, 1.5 Hz, 1H), 5.17
(dd, J ) 9.7, 3.5, 1H), 4.83 (ddd [app td], J ) 10.7, 4.3 Hz,
1H), 4.41 (d, J ) 10.6 Hz, 1H), 4.35 (d, J ) 10.5 Hz, 1H), 3.59
from
a
different experiment. 26b: 1H NMR (250 MHz,
selected data) δ 9.46 (s, 1 H), 5.82 (dd, J ) 11.5, 7.5 Hz, 1H.
Ack n ow led gm en t. We gratefully acknowledge fi-
nancial support from the Danish Technical Science
Research Council (STVF), the Swedish Natural Science
Research Council (NFR), the Carl Trygger Foundation
(Sweden), the Pharmacia Research Foundation (Swe-
den), the Foundation Bengt Lundqvists Minne (Swe-
den), the Helge Ax:son J ohnson Foundation (Sweden),
the Technical University of Denmark, and the Royal
Institute of Technology. J .S.T. is grateful to Pfizer
Central Research (USA) for an Undergraduate Research
Fellowship and to the National Science Foundation
(USA) for a Graduate Fellowship. NMR instrumentation
at the Royal Institute of Technology was funded by the
Wallenberg Foundation. Professor Toshiro Harada,
Kyoto Institute of Technology, is acknowledged for
providing additional experimental information concern-
ing the preparation of diol 5. We also thank Ms Gurli
Hammarberg for assistance with spectroscopic analyses.
Su p p or tin g In for m a tion Ava ila ble: Additional experi-
mental and characterization data (31 pages). This material
is contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
(46) Due to their limited stability, aldehydes 23b and 25b did not
give satisfactory elemental analyses. The corresponding alcohols,
obtained after NaBH4 reduction, were fully characterized, however;
see Supporting Information for details.
J O981102Z