A versatile stereocontrolled approach to chiral tetrahydrofuran and tetrahydropyran derivatives by use of sequential asymmetric Horner-Wadsworth-Emmons and ring-closure reactions

Article abstract of DOI:10.1021/jo0259111

An approach to chiral tetrahydrofuran and tetrahydropyran derivatives based on the sequential use of an asymmetric Horner-Wadsworth-Emmons reaction and a cyclization step is presented. The approach is both stereochemically and structurally versatile since three different cyclization methods can be employed starting from the same HWE product: (i) palladium-catalyzed substitution, (ii) hetero-Michael addition, or (iii) epoxide opening. The asymmetric HWE reaction controls the absolute configuration of the ultimate product, whereas the relative configuration is controlled by the combined influence of the geometric selectivity in the HWE reaction and the stereochemistry of the respective cyclization method.

Full text of DOI:10.1021/jo0259111

A Ver sa tile Ster eocon tr olled Ap p r oa ch to Ch ir a l Tetr a h yd r ofu r a n
a n d Tetr a h yd r op yr a n Der iva tives by Use of Sequ en tia l
Asym m etr ic Hor n er -Wa d sw or th -Em m on s a n d Rin g-Closu r e
Rea ction s
Lauri Vares†,‡,§ and Tobias Rein*,†,|
Department of Organic Chemistry, Technical University of Denmark, DK-2800 Lyngby, Denmark, and
National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618 Tallinn, Estonia
tobias.rein@astrazeneca.com
Received May 7, 2002
An approach to chiral tetrahydrofuran and tetrahydropyran derivatives based on the sequential
use of an asymmetric Horner-Wadsworth-Emmons reaction and a cyclization step is presented.
The approach is both stereochemically and structurally versatile since three different cyclization
methods can be employed starting from the same HWE product: (i) palladium-catalyzed substitu-
tion, (ii) hetero-Michael addition, or (iii) epoxide opening. The asymmetric HWE reaction controls
the absolute configuration of the ultimate product, whereas the relative configuration is controlled
by the combined influence of the geometric selectivity in the HWE reaction and the stereochemistry
of the respective cyclization method.
In tr od u ction
selective at inhibiting A-548 (lung cancer) and PACA-2
(pancreatic cancer) cell lines compared to the known
antitumor agent adriamycin.6
Functionalized tetrahydrofuran (THF) and tetrahy-
dropyran (THP) derivatives are receiving attention be-
cause of their frequent occurrence as subunits in many
types of bioactive natural products, such as annonaceous
acetogenins,1 polyether antibiotics,2 and several groups
of macrolides.3 The range of biological activities exhibited
by these types of compounds is very wide, including
among others antibiotic,2 antimicrobal,1 cytotoxic,3,4 pes-
ticidal,1 antimalarial,1 and antiviral5 effects. For example,
studies of the annonaceaous acetogenins, a class of
natural products found in the tropical plant family
Annonaceae, have increased considerably in recent years.
Structurally, the annonaceaous acetogenins are deriva-
tives of long-chain fatty acids containing THF and/or THP
as well as butenolide moieties. Several of these com-
pounds are potent cytotoxic agents, acting by blocking
mitochondrial complex I (NADH-ubiquinone oxidoreduc-
tase) and by inhibiting plasma membrane NADH oxidase.
For example, mucocin (1) is up to 10 000 times more
The need for appropriately functionalized building
blocks, such as those shown in Chart 1, has motivated
the development of many different synthetic approaches.7
Among previously reported methods for preparing func-
tionalized THF and THP derivatives, some of the more
frequently used are acid-induced ring closure of an epoxy
alcohol,8 intramolecular hetero-Michael addition,9 metal-
catalyzed oxidative cyclization of a hydroxyalkene,10
reduction of bicyclic ketals,11 oxabicyclic systems,12 or
spiro compounds,13 intramolecular Williamson-type reac-
tions,14 and [3 + 2] annulation of allylsilanes and
aldehydes.15
* Send correspondence to this author at the AstraZeneca address.
† Technical University of Denmark.
(6) Shi, G.; Alfonso, D.; Fatope, M. O.; Zeng, L.; Gu, Z.-M.; Zhao,
G.-X.; He, K.; MacDougal, J . M.; McLaughlin, J . L. J . Am. Chem. Soc.
1995, 117, 10409.
‡ National Institute of Chemical Physics and Biophysics.
§ Present address: AstraZeneca R&D, Discovery Chemistry, S-151
85 So¨derta¨lje, Sweden.
(7) For reviews, see: (a) Boivin, T. L. B. Tetrahedron 1987, 43, 3309.
(b) Harmange, J .-C.; Figade`re, B. Tetrahedron: Asymmetry 1993, 4,
1711. (c) Elliott, M. C. J . Chem. Soc., Perkin Trans. 1 1998, 4175.
(8) For selected examples, see: (a) Bartlett, P. A.; Chapuis, C. J .
Org. Chem. 1986, 51, 2799. (b) Nicolaou, K. C.; Prasad, C. V. C.;
Somers, P. K.; Hwang, C.-K. J . Am. Chem. Soc. 1989, 111, 5335. (c)
Iqbal, J .; Pandey, A.; Chauhan, B. P. S. Tetrahedron 1991, 47, 4143.
(d) Fotsch, C. H.; Chamberlin, A. R. J . Org. Chem. 1991, 56, 4141. (e)
Maguire, R. J .; Thomas, E. J . J . Chem. Soc., Perkin Trans. 1 1995,
2487. (f) Li, K.; Vig, S.; Uckun, F. M. Tetrahedron Lett. 1998, 39, 2063.
(g) Ley, S. V.; Brown, D. S.; Clase, J . A.; Fairbanks, A. J .; Lennon, I.
C.; Osborn, H. M. I.; Stokes (ne´e Owen), E. S. E.; Wadsworth, D. J . J .
Chem. Soc., Perkin Trans. 1 1998, 2259.
| Present addresses: AstraZeneca R&D, Discovery Chemistry, S-151
85 So¨derta¨lje, Sweden, and Royal Institute of Technology, Department
of Chemistry, Organic Chemistry, S-100 44 Stockholm, Sweden.
(1) For a recent review, see: Alali, F. Q.; Liu, X.-X.; McLaughlin, J .
L. J . Nat. Prod. 1999, 62, 504.
(2) Wesley, J . W. Polyether Antibiotics: Naturally Occurring Acid
Ionophores; Marcel Dekker: New York, 1982; Vols. I and II.
(3) Norcross, R. D.; Paterson, I. Chem. Rev. 1995, 95, 2041.
(4) Corley, D. G.; Herb, R.; Moore, R. E.; Scheuer, P. J .; Paul, V. J .
J . Org. Chem. 1988, 53, 3644.
(5) Sakemi, S.; Higa, T.; J efford, C. W.; Bernardinelli, G. Tetrahe-
dron Lett. 1986, 27, 4287.
10.1021/jo0259111 CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/21/2002
7226
J . Org. Chem. 2002, 67, 7226-7237

Sequential Asymmetric HWE and Ring-Closure Reactions
CHART 1
SCHEME 1
In this paper, we describe a stereochemically versatile
approach to cis- and trans-substituted THF and THP
derivatives of the types illustrated above (Chart 1) that
is based on the sequential use of an asymmetric Horner-
Wadsworth-Emmons (HWE) reaction16 with a dialde-
hyde and a ring closure via either (i) an intramolecular
Pd(0)-catalyzed allylic substitution,17 (ii) a hetero-Michael
addition,9 or (iii) an intramolecular opening of a terminal
epoxide (Scheme 1).18 The fact that the use of different
cyclization methods leads to different THF or THP
derivatives from the same HWE product makes the
overall strategy versatile.
Resu lts a n d Discu ssion
Syn th etic Str a tegies. We have previously reported
that R-oxygen-substituted meso-dialdehydes of type 2 can
be efficiently desymmetrized by use of an asymmetric
HWE reaction, giving either the (E)- or the (Z)-alkene
as product with essentially full control of geometric
(9) For selected examples, see: (a) Banwell, M. G.; Bui, C. T.; Pham,
H. T. T.; Simpson, G. W. J . Chem. Soc., Perkin Trans. 1 1996, 967. (b)
Takagi, R.; Sasaoka, A.; Kojima, S.; Ohkata, K. Heterocycles 1997, 45,
2313. (c) Betancort, J . M.; Mart´ın, V. S.; Padro´n, J . M.; Palazo´n, J .
M.; Ram´ırez, M. A.; Soler, M. A. J . Org. Chem. 1997, 62, 4570, and
references therein. (d) Ram´ırez, M. A.; Padro´n, J . M.; Palazo´n, J . M.;
Mart´ın, V. S. J . Org. Chem. 1997, 62, 4584. (e) Paterson, I.; Arnott, E.
A. Tetrahedron Lett. 1998, 39, 7185.
(10) For examples using Pd(II), see: (a) Semmelhack, M. F.; Epa,
W. R.; Cheung, A. W.-H.; Gu, Y.; Kim, C.; Zhang, N.; Lew, W. J . Am.
Chem. Soc. 1994, 116, 7455, and references therein. For recent
examples using Re(VII), see: (b) Kennedy, R. M.; Tang, S. Tetrahedron
Lett. 1992, 33, 3729. (c) Towne, T. B.; McDonald, F. E. J . Am. Chem.
Soc. 1997, 119, 6022. (d) Sinha, S. C.; Sinha, A.; Sinha, S. C.; Keinan,
E. J . Am. Chem. Soc. 1997, 119, 12014. (e) Sinha, S. C.; Keinan, E.;
Sinha, S. C. J . Am. Chem. Soc. 1998, 120, 9076. (f) Morimoto, Y.; Iwai,
T.; Kinoshita, T. J . Am. Chem. Soc. 1999, 121, 6792 and references
therein.
(11) Kotsuki, H. Synlett 1992, 97 and references therein.
(12) Molander, G. A.; Swallow, S. J . Org. Chem. 1994, 59, 7148.
(13) (a) Oikawa, M.; Ueno, T.; Oikawa, H.; Ichihara, A. J . Org. Chem.
1995, 60, 5048. (b) Crimmins, M. T.; Rafferty, S. W. Tetrahedron Lett.
1996, 37, 5649.
(14) For recent examples, see: (a) Berninger, J .; Koert, U.; Eisen-
berg-Ho¨hl, C.; Knochel, P. Chem. Ber. 1995, 128, 1021 and references
therein. (b) Wang, Z.-M.; Shen, M. J . Org. Chem. 1998, 63, 1414.
(15) (a) Micalizio, G. C.; Roush, W. R. Org. Lett. 2000, 2, 461 and
references therein. (b) Panek, J . S.; Yang, M. J . Am. Chem. Soc. 1991,
113, 9868.
(16) (a) To¨mo¨sko¨zi, I.; J anszo´, G. Chem. Ind. (London) 1962, 2085.
For reviews, see: (b) Rein, T.; Reiser, O. Acta Chem. Scand. 1996, 50,
369. (c) Rein, T.; Pedersen, T. M. Synthesis 2002, 579. Asymmetric
HWE reactions with dicarbonyl substrates: (d) Trost, B. M.; Curran,
D. P. J . Am. Chem. Soc. 1980, 102, 5699. (e) Trost, B. M.; Curran, D.
P. Tetrahedron Lett. 1981, 22, 4929. (f) Kann, N.; Rein, T. J . Org. Chem.
1993, 58, 3802. (g) Tanaka, K.; Ohta, Y.; Fuji, K.; Taga, T. Tetrahedron
Lett. 1993, 34, 4071. (h) Mandai, T.; Kaihara, Y.; Tsuji, J . J . Org. Chem.
1994, 59, 5847. (i) Tanaka, K.; Watanabe, T.; Ohta, Y.; Fuji, K.
Tetrahedron Lett. 1997, 38, 8943. (j) Tullis, J . S.; Vares, L.; Kann, N.;
Norrby, P.-O.; Rein, T. J . Org. Chem. 1998, 63, 8284. (k) Rein, T.;
Vares, L.; Kawasaki, I.; Pedersen, T. M.; Norrby, P.-O.; Brandt, P.;
Tanner, D. Phosphorus, Sulfur Silicon 1999, 144-146, 169. (l) Tanaka,
K.; Watanabe, T.; Shimamoto, K.-Y.; Sahakitpichan, P.; Fuji, K.
Tetrahedron Lett. 1999, 40, 6599. (m) Vares, L.; Rein, T. Org. Lett.
2000, 2, 2611.
selectivity and with good to excellent levels of asymmetric
induction.16j The key intermediate 3, obtained after
reduction of the unreacted formyl group accompanied by
protective group migration to the formed primary hy-
droxyl, can directly afford a THF or THP derivative via
a Pd(0)-catalyzed allylic substitution or a hetero-Michael
addition, in both cases with the liberated secondary
hydroxyl acting as an internal nucleophile (Scheme 1).
Control of the alkene geometry in 3 translates into
control of the relative configuration of the ring-closed
product, a fact that makes this approach attractive
(Scheme 2). Generally, (E)-allylic substrates are known
to undergo Pd(0)-catalyzed allylic substitution with O-
nucleophiles with overall retention of configuration,17 and
4 would thus be converted to 6; (Z)-allylic compounds,
on the other hand, might undergo a π-σ-π rearrange-
ment of the intermediate palladium complex before the
nucleophilic attack takes place, resulting in overall
inversion of configuration to give 7 from 5.19 In hetero-
(19) (a) Hayashi, T.; Yamamoto, A.; Hagihara, T. J . Org. Chem.
1986, 51, 723. (b) Shimizu, I.; Oshima, M.; Nisar, M.; Tsuji, J . Chem.
Lett. 1986, 1775. (c) Sugiura, M.; Yagi, Y.; Wei, S.-Y.; Nakai, T.
Tetrahedron Lett. 1998, 39, 4351. (d) Noguchi, Y.; Yamada, T.; Uchiro,
H.; Kobayashi, S. Tetrahedron Lett. 2000, 41, 7493, and references
therein.
(17) Tsuji, J . Palladium Reagents and Catalysts: Innovations in
Organic Synthesis; J ohn Wiley & Sons: Chichester, 1995.
(18) Part of this work has been reported in earlier communications;
see ref 16k,m.
J . Org. Chem, Vol. 67, No. 21, 2002 7227

Vares and Rein
SCHEME 2
SCHEME 3a
a
Reaction conditions: (a) 11a : PivCl, 4-DMAP, pyridine, reflux,
3 h, 59%; 11b: TBDPSCl, imidazole, DMF, rt, 30 h, 85%; (b) 12a :
cat. RuCl3, NaIO4, MeCN/H2O, 0 °C, 5 min, 94%; 12b: cat. RuCl3,
NaIO4, MeCN/EtOAc/H2O, 0 °C, 60 s, 73%; (c) H5IO6, THF, rt, 70-
80 min, 99% (13a ), 96% (13b).
SCHEME 4
Michael additions, a (Z)-alkene substrate normally af-
fords a product having the substituents vicinal to the ring
oxygen in a cis relationship (e.g., 9), both under kinetic
and thermodynamic control.9 In contrast, an (E)-alkene
substrate can give predominantly trans product (e.g., 8)
under conditions of kinetic control, while thermodynamic
control tends to favor the cis product.9 In the case of the
route proceeding via opening of a terminal epoxide, a few
additional steps are needed to convert the intermediate
3 into an epoxide (Scheme 1), which subsequently is
opened via an SN2 reaction by the allylic alcohol to form
the corresponding oxacycle.
Ch oice a n d P r ep a r a tion of Su bstr a tes. We chose
the R-oxygen-substituted meso-dialdehydes 13 and 2716j
as key substrates in this study for two reasons: from
earlier work, we knew that dialdehydes of type 27 can
perform well in asymmetric HWE reactions,16j and the
expected HWE products are appropriately functionalized
to allow further transformation to five- or six-membered
oxacycles with the desired substitution patterns. The
choice of hydroxyl protecting groups has particular
importance by enabling the respective type of ring closure
to occur. Pivaloyl protective groups were chosen as one
alternative (in meso-dialdehydes 13a and 27a ) since
allylic carboxylates are known to be good precursors for
η3-allylpalladium complexes. Even though silyloxy groups
are not suitable for Pd(0)-catalyzed substitutions due to
their inability to function as leaving groups, their choice
was motivated because they could be efficiently employed
en route to hetero-Michael additions and epoxide opening
reactions and they are often superior to pivalates when
selective deprotection is needed. Furthermore, the ability
of silyl groups to migrate from one oxygen to another is
well-known.
conventional OsO4/NMMO oxidation system gave only ca.
75% (12a ) and 45% (12b) conversion, respectively, even
after several days at 50 °C. The desired dialdehydes were
obtained in essentially quantitative yield after oxidative
cleavage with periodic acid.
Asym m etr ic HWE Rea ction s. For the synthesis of
HWE products 15a ,b and 17a ,b (Scheme 4, Table 1), we
applied the best conditions found earlier16j for reactions
with dialdehydes 27. The (E)-alkenes were obtained with
good to excellent levels of asymmetric induction and in
moderate yields by using diisopropyl phosphonate 14a 16j
and the KHMDS/18-crown-6 base system (entries 1 and
The dialdehydes 13a and 13b were prepared in three
simple steps from the known cis-2-cyclohexene-1,4-diol
(10) that, in turn, is accessible from 1,3-cyclohexadiene20
(Scheme 3). The protected diols 11 were dihydroxylated
in high yield using RuCl3/NaIO4,21 whereas the more
(20) (a) Ba¨ckvall, J . E.; Bystro¨m, S. E.; Nordberg, R. E. J . Org. Chem.
1984, 49, 4619. (b) Ba¨ckvall, J .-E.; Granberg, K. L.; Hopkins, R. B.
Acta Chem. Scand. 1990, 44, 492.
(21) (a) Shing, T. K. M.; Tam, E. K. W.; Tai, W.-F.; Chung, I. H. F.;
J iang, Q. Chem. Eur. J . 1996, 2, 50. (b) Shing, T. K. M.; Tam, E. K. W.
Tetrahedron Lett. 1999, 40, 2179.
7228 J . Org. Chem., Vol. 67, No. 21, 2002

Sequential Asymmetric HWE and Ring-Closure Reactions
TABLE 1. Asym m etr ic HWE Rea ction s w ith Dia ld eh yd es 13a
entry
phosphonate
substrate
T (°C)
product
yieldb (%)
drc
yield of bisadd (%)
1
2
3
4
5
14a
14c
14a
14b
14cf
13a
13a
13b
13b
13b
-85
-85
-78
-78
-78
15a
17a
15b
15b
17b
55
71
59d
69
88
98:2
g98:2
95:5
80:20
g98:2
44
25
36
n.d.e
n.d.
a
General reaction conditions: 1.2-1.3 equiv of dialdehyde, 1.1-1.3 equiv of phosphonate, 1.0 equiv of KHMDS, 5 equiv of 18-crown-6,
ca. 0.02 M in THF, 3-12 h. Yield of isolated monoaddition product. c Ratio of 15a ,b/16a ,b or 17a ,b/18a ,b, respectively. The geometric
b
selectivity was >98:2 for all entries. Yield after reduction of the monoaddition product to the alcohol. e Not determined. f NaHMDS was
d
used as base, without a crown ether.
SCHEME 5a
For the Pd(0)-catalyzed allylic substitution, several
different ligands for palladium were tested. With dppe,
all starting material was recovered, and the use of
triphenylphosphine afforded predominantly an undesired
diene, presumably via a â-elimination pathway. Addition
of bases (pyridine, triethylamine, DBU) to increase the
nucleophilicity of the hydroxyl group gave, at best, only
ca. 10% of the desired product. However, use of phenan-
throline-type ligands afforded the desired ring-closed
products in moderate to high yields. Among the tested
ligands, 2,9-dimethyl-1,10-phenanthroline (neocuproine)
turned out to be the best for our system. When the (E)-
alkene 20a was treated with Pd(0) in the presence of
neocuproine, THF derivative 21 formed readily in 76%
yield with clean retention of configuration at the allylic
stereocenter.
The ring closure of (Z)-alkene 23a needed heating to
65 °C to proceed. The rate-determining step in this
reaction is presumably the initial formation of the
disfavored syn,anti-π-allylpalladium complex, which re-
arranges to the more stable syn,syn complex via a π-σ-π
rearrangement.19 The subsequent nucleophilic attack
then gives THF derivative 24 as the main product. The
product is obtained with overall inversion of configuration
at the allylic stereocenter, accompanied by (Z)- to (E)-
isomerization which is consistent with the suggested
π-σ-π rearrangement.
A minor product, assigned to have structure 25, was
also isolated from this reaction in ca. 10% yield, together
with some dba ligand. The (Z)-geometry of the alkene in
25 is proven by NMR. It is known that for monosubsti-
tuted η3-allylpalladium complexes containing neocu-
proine as ligand, the syn complex is destabilized relative
to the anti complex due to interference between the
methyl substituents on neocuproine and the syn substit-
uents of the η3-allyl unit.23 As a result, the anti complex
undergoes slower rearrangement when the ligand is
neocuproine, which favors retention of the (Z)-alkene
geometry in the product when a (Z)-alkene is used as
substrate. On the basis of this precedence, it is reasonable
to assume that in the reaction giving 25, the allylic
substitution has proceeded with overall retention at the
allylic stereocenter via direct ring closure of the syn,anti-
palladium complex to give the relative configuration of
the stereocenters in the THF ring as cis; however, an
unambiguous assignment has not been possible.
a
Reaction conditions: (a) NaBH4, MeOH/THF, 0 °C, 85%; (b)
DMAP, EtOH, 75 °C; 63% 20a , 27% recovered 19a (see ref 22); (c)
Pd2(dba)3‚CHCl3 (0.05 equiv), neocuproine (0.2 equiv), THF, 25 °C,
76%; (d) LiBH4, i-PrOH/THF, 0 °C; 49% 23a , 38% 22a (see ref
22); (e) Pd2(dba)3‚CHCl3 (0.15 equiv), neocuproine (0.4 equiv), THF,
65 °C; 78% 24, 10% 25.
3). When diethyl phosphonate 14b16j was used instead
of 14a , the diastereoselectivity dropped significantly
(entry 4). The (Z)-alkene products 17a and 17b, in turn,
were obtained in high yields with essentially complete
geometric and diastereoselectivities by using bis(trifluo-
roethyl) phosphonate 14c16j (entries 2 and 5). The piv-
aloyl-protected dialdehyde 13a performed best with our
“standard” KHMDS/18-crown-6 base system, whereas the
silyl-protected dialdehyde 13b gave better results when
NaHMDS was used as base, without a crown ether.
P d (0)-Ca ta lyzed In tr a m olecu la r Allylic Su bstitu -
tion s. The reduction of the remaining aldehyde func-
tionality in HWE products 15a and 17a , followed by
acyl group migration, afforded intermediates 20a and
23a , respectively (Scheme 5). Different reagent combina-
tions can be used for the reduction/PG-migration se-
quence. The use of NaBH4 followed by treatment with
imidazole, DMAP, or Et3N afforded roughly a 2:1 mixture
of the desired secondary alcohol 20a or 23a and the
isomeric primary alcohol 19a 22 or 22a ,22 respectively. The
use of LiBH4 as reducing agent, however, afforded
directly a ca. 2:1 mixture of secondary and primary
alcohols as products.
(22) The primary alcohols recovered after the acyl group migration
could be converted to mixtures of secondary/primary alcohols again,
thereby increasing the overall yield of the desired secondary alcohol.
(23) (a) Sjo¨gren, M. P. T.; Hansson, S.; Norrby, P.-O.; A° kermark,
B.; Cucciolito, M. E.; Vitagliano, A. Organometallics 1992, 11, 3954.
(b) Sjo¨gren, M. P. T.; Hansson, S.; A° kermark, B.; Vitagliano, A.
Organometallics 1994, 13, 1963.
J . Org. Chem, Vol. 67, No. 21, 2002 7229

Vares and Rein
SCHEME 6a
SCHEME 7a
a
Reaction conditions: (a) NaBH4, MeOH/THF, 0 °C, 88%; (b)
Pd2(dba)3‚CHCl3 (0.05 equiv), neocuproine (0.2 equiv), THF, 65 °C,
82%.
The protective group migration during the reduction
of the HWE product 17a was suppressed by using NaBH4
in MeOH/THF,24 and the primary alcohol 22a could be
isolated in high yield (Scheme 6). By subjecting 22a to
the ring-closing conditions, THP derivative 26 was
obtained in good yield as a single isomer. The alkene
geometry of 26 is proven by NMR to be (E). If it is
postulated that 26 is formed via a mechanism analogous
to the formation of 24 from 23a , the relative configuration
of the stereocenters in the THP ring of 26 can be
tentatively assigned as cis, but this has not been un-
equivocally proven.
In an analogous manner to the routes to THF deriva-
tives 21 and 24 (vide supra, Scheme 5), the products
obtained from asymmetric HWE reactions with dialde-
hyde 27a 16j could be converted into THP derivatives as
shown in Scheme 7.16m Base-induced migration of one
pivaloyl group transformed 28a and 31a to 29a and 32a ,
respectively.22 Subsequent palladium-catalyzed ring clo-
sure then afforded 3025 and 33 in diastereomerically pure
form.
Heter o-Mich a el Ad d ition s. We found that HWE
products 15b and 17a ,b could be readily converted into
trisubstituted THP’s via a hetero-Michael addition
(Scheme 8). The intermediates 20b and 23a ,b were
obtained from the HWE products by reduction of the
remaining formyl group accompanied by migration of one
silyl or pivaloyl protective group to the adjacent primary
hydroxyl. The bulky silyl groups were more prone to
migration than the pivalate esters, and the migration
occurred readily even when NaBH4 was used as reducing
agent, affording a ca. 5:1 mixture of the corresponding
secondary and primary alcohols.22,24 When the (E)-alkene
20b was treated with base (t-BuOK), 2,6-trans-THP 34
was obtained as product in excellent yield and selectivity
(34/35 ) 97:3). The (Z)-alkenes 23, in contrast, afforded
exclusively 2,6-cis-THPs 36 as products under analogous
reaction conditions.
a
Reaction conditions: (a) imidazole, EtOH, 75 °C; 59% 29a , 28%
recovered 28a (see footnote 22); (b) Pd2(dba)3‚CHCl3 (0.1 equiv),
neocuproine (0.4 equiv), THF, 25 °C, 80%; (c) DMAP, EtOH, 75
°C; 48% 32a , 42% recovered 31a (see ref 22); (d) Pd2(dba)3‚CHCl3
(0.15 equiv), neocuproine (0.4 equiv), THF, 50 °C, 59%.
on earlier studies by Banwell9a and Mart´ın,9b,c we believe
that the former factor is more important than the latter.
According to the mechanistic model proposed by Martin,9b
the transition states leading from the (E)- and (Z)-alkenes
to 2,6-trans- and 2,6-cis-THP derivatives, respectively,
are shown in Scheme 9. The 2,6-cis product should be
thermodynamically favored in both cases, implying that
at least the formation of the 2,6-trans-alkene 34 proceeds
via kinetic control. Upon longer reaction time and higher
temperature, the trans/cis ratio 34/35 dropped signifi-
cantly, supporting the suggested formation of 34 via
kinetic control.
Ep oxid e Op en in g. We also explored the possibilities
to convert the reduced HWE product 28b16j into a THP
derivative via intramolecular opening of a terminal
epoxide by an oxygen nucleophile (Scheme 10).16k Nor-
mally, the opening of epoxides via an SN2-type mecha-
nism occurs with complete inversion of stereochemistry.26
While in the case of the Pd(0)-catalyzed allylic substitu-
tion one may, by choosing a (Z)-alkene substrate, invert
the stereochemistry at the allylic stereocenter, the epox-
ide opening approach instead has the allylic hydroxyl
group acting as a nucleophile, and therefore the config-
uration is inverted at the C-8 stereocenter and retained
at the allylic position. The primary hydroxyl group in triol
37, which was obtained after cleavage of both silyl groups
in 28b, was regioselectively tosylated in 76% yield.
The difference in stereoselectivity could depend on
either the difference in alkene geometry or the difference
in relative stereochemistry between the auxiliary and the
other stereocenters (or a combination of the two). Based
(24) The use of either LiBH4 or NaBH4 in combination with i-PrOH/
THF resulted in much faster protective group migration during the
reduction compared to when MeOH/THF was used as solvent mixture.
(25) The ring-closed product 30 was obtained in diastereomerically
pure form, even though the starting material contained 5% of minor
diastereomer 45 (see the Experimental Section).
(26) For a review on epoxide openings, see: Smith, J . K. Synthesis
1984, 629.
7230 J . Org. Chem., Vol. 67, No. 21, 2002

Sequential Asymmetric HWE and Ring-Closure Reactions
SCHEME 8a
SCHEME 10a
a
Reaction conditions: (a) n-Bu4NF, THF, rt, 80%; (b) TsCl,
pyridine, 0 °C, 76%; (c) NaHMDS, THF, rt, 95%; (d) cat. CF3SO3H,
MeCN, 0 °C, 89%.
a
Reaction conditions: (a) NaBH4, i-PrOH/THF, 0 °C, overall
yield from 13b: 54% 20b, 5% 19b (see ref 22); (b) t-BuOK, THF,
0 °C, 96%; (c) R ) pivaloyl: see Scheme 5, step d; R ) TBDPS:
NaBH4, i-PrOH/THF, 0 °C; 59% 23b, 19% 22b (see ref 22); (d)
t-BuOK, Et2O, rt; 95% (36a ); 97% (36b).
CHART 2
SCHEME 9
the Mosher ester derivatives 41 and 42 (Chart 2),
respectively, according to the method developed by
Mosher and Dale, and extended by Kakisawa et al.27 The
absolute configurations of the silyl-protected HWE prod-
ucts 15b and 17b were assigned on the basis of analogies
with compounds 15a /17a and 28b/31b (Chart 2).16j
The assignments of relative configurations for the ring-
closed products 21, 24, 33, 36a , and 40 are based on NOE
experiments. The assignment for compound 30 is based
on 1H and 13C NMR analysis of derivative 43 (Scheme
11), which is meso (not pseudo-C2-symmetric) implying
Subsequent treatment with base afforded the terminal
epoxide 39 in 95% yield. Initial attempts to open the
epoxide by activating the nucleophile with base failed,
but the use of a catalytic amount of triflic acid to activate
the epoxide afforded the desired 2,6-trans-THP derivative
40 as a single isomer in good yield.
Deter m in a tion of Absolu te a n d Rela tive Con figu -
r a tion s. The absolute configurations of the pivaloyl-
protected HWE products 15a and 17a were assigned on
(27) (a) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512.
(b) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J . Am. Chem.
Soc. 1991, 113, 4092, and references therein. For details regarding
the NMR analyses of the Mosher esters 41 and 42, see the Supporting
Information.
1
the basis of H NMR analyses of both diastereomers of
J . Org. Chem, Vol. 67, No. 21, 2002 7231

Vares and Rein
86:14 mixture of cis and trans isomers) and 4-(dimethylamino)-
pyridine (1.08 g, 8.85 mmol) in 30 mL of dry pyridine was
added pivaloyl chloride (5.5 mL, 44.3 mmol). The reaction
mixture was refluxed for 3 h, diluted with 1 M HCl, and
extracted with EtOAc. Drying, concentration, and purification
by flash chromatography (2-6% EtOAc in hexanes) afforded
1.48 g (59%) of cis-ester 11a and 1.01 g (40%) of a ca. 1.4:1
mixture of cis and trans isomers. 11a : Rf ) 0.45 (hexanes/
EtOAc 9/1); 1H NMR (250 MHz) δ 5.84 (app d, J ) 1.4 Hz,
SCHEME 11
2H), 5.20-5.13 (m, 2H), 1.94-1.68 (m, 4H), 1.18 (s, 18 H); 13
C
NMR (62.9 MHz) δ 178.0, 130.2, 67.0, 38.6, 27.0, 24.8; IR 2972,
1728, 1480, 1279, 1156, 1035, 1019 cm-1; HRMS-FAB (m/z)
[M]+ calcd for C16H26O4 282.1831, found 282.1821.
m eso-(3R,6S)-3,6-Bis(ter t-bu tyld ip h en ylsilyloxy)cyclo-
h ex-1-en e (11b). To a solution of crude diol 1020 (2.2 g, 19.3
mmol, 86:14 mixture of cis and trans isomers) and imidazole
(6.56 g, 96.5 mmol) in 190 mL of dry DMF was added TBDPSCl
(13.3 g, 48.4 mmol). After the mixture was stirred for 30 h at
rt, EtOAc was added, and the organic layer was washed with
water, dried, filtered, and concentrated. Purification by flash
chromatography (0-10% EtOAc in hexanes) afforded 9.7 g
(85%) of bis-silyl ether 11b (86:14 mixture of cis and trans
isomers). This mixture could be used without further separa-
tion in the subsequent step.29 11b: Rf ) 0.3 (1.6% EtOAc in
hexanes); 1H NMR (250 MHz) δ 7.82-7.67 (m, 8H), 7.52-7.31
(m, 12H), 5.65 (br s, 2H), 4.14 (br t, J ) 4.8 Hz, 2H), 2.0-1.84
(m, 2H), 1.62-1.45 (m, 2H), 1.15 (s, 18H); 13C NMR (62.9 MHz)
δ 135.7, 134.3, 131.8, 129.4, 127.4, 66.6, 28.2, 26.8, 19.1; IR
2958, 2931, 2857, 1428, 1111, 1082, 701, 506 cm-1. Anal. Calcd
for C38H46O2Si2: C, 77.23; H, 7.85. Found: C, 76.98; H, 7.73.
that the stereochemistry of 30 is the one shown. The
relative configurations of the hetero-Michael products 34
and 36b are assigned on the basis of 13C NMR analysis.28
Con clu sion s
m eso-(1R,2S,3S,6R)-3,6-Bis(2,2-d im eth ylp r op ion yloxy)-
cycloh exa n e-1,2-d iol (12a ). Meth od a .21b A solution of
alkene 11a (447 mg, 1.58 mmol) in CH3CN (26 mL) was cooled
to 0 °C. A solution of RuCl3 hydrate (38 mg, ca. 0.17 mmol)
and NaIO4 (818 mg, 3.75 mmol) in 5 mL of H2O was then
added. The reaction mixture was stirred vigorously for 5 min
and then quenched with 20% aq Na2S2O3 (5 mL). The aqueous
phase was separated and extracted with EtOAc. Drying,
filtration, and concentration followed by flash chromatography
(25% EtOAc in hexanes) afforded 473 mg (94%) of diol 12a as
a colorless oil that slowly solidified. 12a : Rf ) 0.2 (hexanes/
In this paper, we have demonstrated that the use of
an asymmetric HWE reaction with a meso-dialdehyde
followed by a ring-closure reaction is an efficient and
versatile strategy for the synthesis of several types of
substituted THF and THP derivatives possessing differ-
ent relative configurations. In the asymmetric HWE
reactions, either (E)- or (Z)-monoaddition products could
be obtained with essentially complete geometric control
by slight structural variation in the phosphoryl group of
the chiral phosphonate reagent; furthermore, both (E)-
and (Z)-products were obtained in good to excellent
diastereoselectivities and good yields. Three different
methods were employed for converting the products from
the asymmetric HWE reactions into THF or THP deriva-
tives: (i) intramolecular Pd(0)-catalyzed allylic substitu-
tion, (ii) hetero-Michael addition, or (iii) intramolecular
opening of a terminal epoxide. These methods give
products with different and complementary substitution
patterns as well as relative configurations.
1
EtOAc 3/1); H NMR (250 MHz) δ 5.00 (br s, 2H), 3.84 (app
dd, J ) 8.2, 2.4 Hz, 2H), 3.20 (br s, 2H), 1.97-1.82 (m, 2H),
1.73-1.56 (m, 2H), 1.20 (s, 18H); 13C NMR (62.9 MHz) δ 178.5,
72.0, 71.5, 38.8, 27.1, 23.7; IR 3481, 2974, 1732, 1481, 1283,
1156, 734 cm-1. Anal. Calcd for C16H28O6: C, 60.74; H, 8.85.
Found: C, 61.07; H, 8.87. Meth od b. To a solution of alkene
11a (397 mg, 1.41 mmol) and N-methylmorpholine N-oxide
(165 mg, 1.41 mmol) in a mixture of THF, t-BuOH, and H2O
(16, 8, and 4 mL, respectively) was added 540 µL of a 2.5 wt
% solution of OsO4 in t-BuOH (0.042 mmol). The reaction
mixture was stirred for 60 h at 55 °C and then quenched by
the addition of Na2S2O3 (5 mL, 20% aq solution). Dilution with
brine followed by extraction (EtOAc), drying, and concentration
afforded 425 mg of crude product. Purification by flash
chromatography (4-40% EtOAc in hexanes) afforded 65 mg
(16%) of unreacted alkene 11a and 340 mg (76%) of diol 12a
as a colorless oil that slowly solidified.
meso-(1R,2S,3S,6R)-3,6-Bis(ter t-bu tyldiph en ylsilyloxy)-
cycloh exa n e-1,2-d iol (12b). Meth od a .21a A solution of
alkene 11b (cis/trans 86:14; 50 mg, 0.085 mmol) in a mixture
of EtOAc (3 mL) and CH3CN (3 mL) was cooled to 0 °C. A
solution of RuCl3 hydrate (2 mg, ca. 0.009 mmol) and NaIO4
(50 mg, 0.23 mmol) in 1 mL of H2O was then added to the
alkene solution. The two-phase mixture was vigorously stirred
for 60 s and then quenched with 20% aq Na2S2O3 (ca. 5 mL).
The aqueous phase was separated and extracted (EtOAc).
Drying of the combined organic extracts, concentration, and
flash chromatography (10% EtOAc in hexanes) afforded 39 mg
Exp er im en ta l Section
Gen er a l Meth od s. Reagent and solvent purification, work-
up procedures, and analyses were in general performed as
described previously.16j If not otherwise indicated, isolated
compounds were colorless oils.
m eso-(3R,6S)-3,6-Bis(2,2-d im eth ylp r op ion yloxy)cyclo-
h ex-1-en e (11a ). To a solution of diol 1020 (1.01 g, 8.85 mmol,
(28) In a separate experiment, performed at higher temperature and
for a longer reaction time, a ca. 70:30 mixture of 34 and 35 was
obtained as product from 20b. In compound 34, the carbons at C-2
and C-6 give 13C NMR peaks at 73.8 and 68.5 ppm, respectively,
whereas the corresponding carbons in the minor product 35 give peaks
at 79.2 and 72.2 ppm, respectively. In 2,6-trans-THP derivatives the
carbons at C-2 and C-6 are, on average, shifted upfield by ca. 7 ppm
compared to the same carbons in the corresponding 2,6-cis-THP
derivative; see: (a) Pihlaja, K.; Kleinpeter, E. Carbon-13 NMR Chemi-
cal Shifts in Structural and Stereochemical Analysis; VCH Publish-
ers: New York, 1994; pp 108-114. (b) Eliel, E. L.; Manoharan, M.;
Pietrusiewicz, K. M.; Hargrave, K. D. Org. Magn. Reson. 1983, 21, 94.
(29) The cis and trans isomers could be separated by careful flash
chromatography (2-8% EtOAc in hexanes).
7232 J . Org. Chem., Vol. 67, No. 21, 2002

Sequential Asymmetric HWE and Ring-Closure Reactions
1
(73%) of diol 12b. Only one stereoisomer was detected by H
8.89. 16a : 1NMR (250 MHz, selected data assigned from a 98:2
mixture of diastereomers 15a /16a ) δ 6.16 (dd, J ) 16.0, 4.3
Hz, 1H).
1
and 13C NMR. 12b: Rf ) 0.15 (hexanes/EtOAc 9/1); H NMR
(250 MHz) δ 7.73-7.61 (m, 8H), 7.47-7.32 (m, 12H), 4.00-
3.85 (m, 4H), 2.29 (br s, 2H), 1.66-1.32 (m, 4H), 1.09 (s, 18H);
13C NMR (62.9 MHz) δ 135.74, 135.65, 134.0, 133.8, 129.8,
129.7, 127.7, 127.6, 73.7, 71.9, 27.0, 26.7, 19.3; IR 3579, 2931,
2857, 1428, 1105, 701, 501 cm-1; HRMS-FAB (m/z) [M + H]+
calcd for C38H48O4Si2 625.3169, found 625.3169. Meth od b.
To a solution of alkene 11b (cis/trans 86:14; 2.32 g, 3.92 mmol)
and N-methylmorpholine N-oxide (508 mg, 4.34 mmol) in 14
mL of THF were added t-BuOH (7 mL) and H2O (3.5 mL),
followed by a solution of OsO4 in t-BuOH (2.5 wt %, 1.52 mL,
0.118 mmol). The reaction mixture was stirred for 60 h at 45
°C and then quenched with 5 mL of 20% aq Na2S2O3. Dilution
with brine followed by extraction (EtOAc), drying, concentra-
tion, and flash chromatography (10% EtOAc in hexanes)
afforded 1.12 g (46%) of diol 12b as a single stereoisomer.
(E)-(4R,7S)-4,7-Bis(ter t-b u t yld ip h en ylsilyloxy)-8-oxo-
octa-2-en oic Acid (1R,2S,5R)-5-Meth yl-2-(1-m eth yl-1-ph en -
yleth yl)cycloh exyl Ester (15b). Prepared from 13b and 14a .
An approximately 2:1 mixture of mono- and bis-HWE conden-
sation products was obtained. The bis-HWE byproduct was
readily separated after reduction of 15b to alcohol 19b (vide
infra). 15b: 1NMR [250 MHz, assigned from a mixture of
diastereomers 15b/16b (95:5) and bis-HWE product] δ 9.44
(d, J ) 1.5 Hz, 1H), 7.65-6.98 (m, 25 H), 6.63 (dd, J ) 15.6,
5.3 Hz, 1H), 5.56 (dd, J ) 15.6, 1.5 Hz, 1H), 4.85 (ddd [app
td], J ) 10.7, 4.4, 1H), 4.33-4.24 (m, 1H), 4.24-4.12 (m, 1H),
3.98-3.91 (m, 1H), 1.29 (s, 3H), 1.25 (s, 3H), 1.09 (s, 9 H), 1.06
(s, 9H), 0.89 (d, J ) 6.4 Hz, 3H). 16b: 1NMR [250 MHz,
selected data assigned from a mixture of diastereomers 15b/
16b (95:5) and bis-HWE product] δ 9.43 (d, J ) 1.5 Hz, 1H).
(Z)-(4S,7R)-4,7-Bis(2,2-dim eth ylpr opion yloxy)-8-oxoocta-
2-en oic Acid (1R,2S,5R)-5-Meth yl-2-(1-m eth yl-1-p h en yl-
eth yl)cycloh exyl Ester (17a ). Prepared from 13a and 14c
in 71% yield. (Z)/(E) g 98:2, dr 17a /18a g 98:2. 17a : Rf )
m eso-(2R,5S)-2,5-Bis(2,2-d im et h ylp r op ion yloxy)h ex-
a n ed ia l (13a ). To a solution of diol 12a (127 mg, 0.402 mmol)
in THF (8 mL) was added a solution of H5IO6 (91.6 mg, 0.402
mmol) in THF (8 mL) at 0 °C. After 80 min at rt, 5 mL of
phosphate buffer (pH 7) and 10 mL of brine was added. The
solution was extracted (EtOAc), dried, and concentrated. The
residue was dissolved in CHCl3 (2 mL) and filtered through a
plug of cotton, giving 126 mg (99%) of 13a as a white solid.
Due to its limited stability, the dialdehyde was generally used
in HWE reactions without further purification. 13a : 1H NMR
(200 MHz) δ 9.47 (d, J ) 0.7 Hz, 2H), 5.03-4.87 (m, 2H), 2.04-
1.74 (m, 4H), 1.26 (s, 18H); 13C NMR (50.3 MHz) δ 197.8, 177.9,
77.1, 38.8, 27.0, 24.2; IR 3466, 2974, 1732, 1481, 1282, 1151
1
0.56 (hexanes/EtOAc 3/1); H NMR (250 MHz, selected data)
δ 9.50 (d, J ) 0.6 Hz, 1H), 7.27-7.17 (m, 4H), 7.14-7.04 (m,
1H), 6.07 (app br q, J ) 6 Hz, 1H), 5.81 (dd, J ) 11.5, 7.6 Hz,
1H), 5.02 (dd, J ) 11.5, 1.4 Hz, 1H), 5.03-4.95 (m, 1H), 4.79
(ddd [app td], J ) 10.7, 4.4 Hz, 1H), 1.28 (s, 9H), 1.17 (s, 9H),
0.86 (d, J ) 6.5, 3H); 13C NMR (62.9 MHz) δ 197.9, 178.0,
177.5, 164.4, 151.6, 146.4, 127.8, 125.2, 124.9, 121.2, 77.5, 74.2,
70.9, 50.3, 41.6, 39.5, 38.7, 38.6, 34.4, 31.2, 29.4, 27.9, 27.1,
27.0, 26.4, 24.6, 24.5, 21.7; IR 2962, 2928, 1714, 1480, 1202,
1152 cm-1; [R]546 +4.0 (c 8.3, CHCl3). Anal. Calcd for
cm-1
.
m eso-(2R,5S)-2,5-Bis(ter t-b u t yld ip h en ylsilyloxy)h ex-
a n ed ia l (13b). To a solution of diol 12b (210 mg, 0.335 mmol)
in THF (7 mL) was added a solution of H5IO6 (84 mg, 0.368
mmol) in THF (4 mL) at 0 °C. After 70 min at rt, 10 mL of
brine was added. The solution was extracted with EtOAc,
dried, and concentrated to give 201 mg (96%) of 13b as a white
solid. The dialdehyde was used in HWE reactions without
further purification. 13b: 1H NMR (200 MHz) δ 9.49 (br d, J
) 1.2 Hz, 2H), 7.25-7.68 (m, 20H), 4.04-3.94 (m, 2H), 1.82-
1.69 (m, 2H) 1.64-1.52 (m, 2H), 1.09 (s, 18H); 13C NMR (50.3
MHz) δ 203.2, 135.7, 132.8, 130.0, 127.8, 77.5, 27.4, 26.9, 19.3;
IR 2931, 2859, 1737, 1428, 1112, 702, 505 cm-1. Anal. Calcd
for C38H46O4Si2: C, 73.27; H, 7.44. Found: C, 73.00; H, 7.43.
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 (14a -c, 1.1
equiv) and 18-crown-6 (if applicable, 5 equiv) in dry 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 tolune) or NaHMDS
(0.6 M in toluene). After 30 min, the resulting slurry was
transferred via cannula to a precooled solution of the dialde-
hyde (13a ,b) in a small volume of dry THF. The reaction
mixture was stirred at the indicated temperature for 3-12 h
(monitoring by TLC) and then quenched with phosphate buffer
(pH 7). After dilution with brine, extractive workup (EtOAc),
drying, concentration, and flash chromatography (EtOAc in
hexanes) afforded the products.
(E)-(4R,7S)-4,7-Bis(2,2-dim eth ylpr opion yloxy)-8-oxoocta-
2-en oic Acid (1R,2S,5R)-5-Meth yl-2-(1-m eth yl-1-p h en yl-
eth yl)cycloh exyl Ester (15a ). Prepared from 13a and 14a
in 55% yield. (E)/(Z) g 98:2, diastereomeric ratio 15a /16a )
98:2. 15a : Rf ) 0.56 (hexanes/EtOAc 3/1); 1H NMR (250 MHz,
selected data) δ 9.47 (d, J ) 0.6 Hz, 1H), 7.28-7.16 (m, 4H),
7.13-7.03 (m, 1H), 6.45 (dd, J ) 15.7, 5.1 Hz), 5.38 (dd, J )
15.7, 1.6 Hz, 1H), 5.34-5.26 (m, 1H), 4.98-4.90 (m, 1H), 4.85
(ddd [app td], J ) 10.7, 4.3 Hz, 1H), 1.27 (s, 9H), 1.21 (s, 9H),
0.86 (d, J ) 6.5, 3H); 13C NMR (62.9 MHz, some signals in the
aliphatic region overlap) δ 197.8, 177.9, 177.1, 164.9, 151.4,
143.6, 127.8, 125.3, 124.9, 122.4, 77.2, 74.6, 70.9, 50.3, 41.6,
39.6, 38.9, 38.8, 34.5, 31.2, 29.0, 27.7, 27.1, 26.5, 25.1, 24.1,
21.7; IR 2960, 2928, 1732, 1480, 1280, 1152, 733 cm-1. Anal.
Calcd for C34H50O7: C, 71.55; H, 8.83. Found: C, 71.50; H,
C
34H50O7: C, 71.55; H, 8.83. Found: C, 71.55; H, 8.79.
(Z)-(4S,7R)-4,7-Bis(ter t-bu tyldiph en ylsilyloxy)-8-oxooc-
ta -2-en oic Acid (1R,2S,5R)-5-Meth yl-2-(1-m eth yl-1-p h en -
yleth yl)cycloh exyl Ester (17b). Prepared from 13b and 14c
in 88% yield. (Z)/(E) g 98:2; diastereomeric ratio 17b/18b g
98:2. 17b: Rf ) 0.55 (hexanes/EtOAc 85/15); 1H NMR (250
MHz, selected data) δ 9.50 (d, J ) 1.54 Hz, 1H), 7.68-7.04
(m, 25H), 5.94 (dd, J ) 11.6, 8.0 Hz, 1H), 5.39-5.28 (m, 1H),
4.81 (dd, J ) 11.6, 1.3 Hz, 1H), 4.63 (ddd [app td], J ) 10.7,
4.3 Hz, 1H), 4.09-4.0 (m, 1H), 1.21 (s, 3H), 1.16 (s, 3H), 1.13
(s, 9H), 1.03 (s, 9H), 0.89 (d, J ) 6.4 Hz, 3H); 13C NMR (125
MHz, some singals overlap) δ 203.3, 164.4, 151.5, 151.4, 135.8,
135.7, 134.0, 133.8, 133.1, 133.0, 129.9, 129.6, 129.5, 127.9,
127.8, 127.7, 127.5, 127.4, 125.3, 125.0, 118.5, 78.0, 73.8, 69.4,
50.4, 41.6, 39.6, 34.5, 32.1, 31.2, 28.0, 27.2, 27.0, 26.6, 25.5,
21.8, 19.4, 19.2; IR 2958, 2858, 1713, 1428, 1198, 1112, 700
cm-1; [R]546 +14.8 (c 2.83, CHCl3).
Gen er a l P r oced u r e for Red u ction of th e HWE P r od -
u cts. To a solution of aldehyde in a 1:1 mixture of MeOH/
THF or i-PrOH/THF (0.015 M with respect to the aldehyde)
was added NaBH4 or LiBH4 (3-5 equiv) at 0 °C. After being
stirred at 0 °C until the reaction was finished (monitoring by
TLC), the reaction mixture was diluted with brine, extracted
(EtOAc), dried, filtered, concentrated, and purified by flash
chromatography (EtOAc in hexanes) to afford the product.
Gen er a l P r oced u r e for P r otective Gr ou p Migr a tion .
To a solution of the primary alcohol in EtOH (ca. 0.03 M with
respect to alcohol) was added an amine (4-DMAP, Et3N, or
imidazole). After the mixture was refluxed for ca. 15 h, the
ethanol was evaporated, and the mixture of secondary and
primary alcohols was separated by flash chromatography.22
(E)-(4R,7S)-4,7-Bis(2,2-dim eth ylpr opion yloxy)-8-h ydr ox-
yoct a -2-en oic Acid (1R,2S,5R)-5-Met h yl-2-(1-m et h yl-1-
p h en yleth yl)cycloh exyl Ester (19a ). Prepared from 15a in
85% yield. 19a :30 Rf ) 0.28 (hexanes/EtOAc 3/1); 1H NMR (250
MHz, selected data) δ 7.27-7.17 (m, 4H), 7.14-7.04 (m, 1H),
6.49 (dd, J ) 15.7, 5.1 Hz, 1H), 5.39 (dd, J ) 15.7, 1.6 Hz,
1H), 5.34-5.25 (m, 1H), 4.91-4.80 (m, 1H), 4.85 (ddd [app td],
(30) A single diastereomer could be detected by 1H NMR.
J . Org. Chem, Vol. 67, No. 21, 2002 7233

Vares and Rein
1
J ) 10.6, 4.3 Hz, 1H), 3.69 (dd, J ) 11.9, 4.0 Hz, 1H), 3.61
(dd, J ) 11.9, 5.8 Hz, 1H), 1.21 (s, 18H), 0.86 (d, J ) 6.5, 3H);
13C NMR (62.9 MHz, some signals in the aliphatic region
overlap) δ 178.6, 177.2, 165.1, 151.3, 144.1, 127.9, 125.4, 125.0,
122.1, 74.65, 74.56, 71.3, 64.7, 50.4, 41.6, 39.7, 38.9, 34.5, 31.2,
29.5, 27.4, 27.1, 26.6, 25.9, 25.5, 21.7; IR 3504, 2958, 2928,
5.3 mg (76%) of 21. 21:30 Rf ) 0.48 (hexanes/EtOAc 3/1); H
NMR (250 MHz, selected data) δ 7.29-7.20 (m, 4H), 7.17-
7.07 (m, 1H), 6.59 (dd, J ) 15.6, 4.8 Hz, 1H), 5.52 (dd, J )
15.6, 1.6 Hz, 1H), 4.84 (ddd [app td], J ) 10.7, 4.3 Hz, 1H),
4.44 (app br qd, J ) 4.9, 1.6 Hz, 1H), 4.26-4.16 (m, 1H), 4.14
(dd, J ) 11.5, 4.0 Hz, 1H), 4.06 (dd, J ) 11.4, 5.2 Hz, 1H),
1.30 (s, 9H), 0.86 (d, J ) 6.5 Hz, 3H); 13C NMR (62.9 MHz,
some signals in the aliphatic region overlap) δ 178.5, 165.7,
151.5, 147.3, 127.9, 125.4, 125.0, 120.9, 78.2, 77.2, 74.4, 66.0,
50.5, 41.7, 39.7, 38.8, 34.6, 31.3, 27.6, 27.2, 26.6, 25.7, 21.8;
IR 2955, 1714, 1278, 1162 cm-1; [R]546 -8.4 (c 0.5, CHCl3);
HRMS-EI (m/z) [M]+ calcd for C29H42O5 470.3032, found
470.3050.
1731, 1480, 1281, 1157, 1032 cm-1
.
(E)-(4R,7S)-4,8-Bis(2,2-d im et h ylp r op ion yloxy)-7-h y-
d r oxyocta -2-en oic Acid (1R,2S,5R)-5-Meth yl-2-(1-m eth yl-
1-p h en yleth yl)cycloh exyl Ester 20a . Prepared from 19a ;
52% of secondary alcohol 20a and 38% of a 1:2.5 mixture of
secondary and primary alcohols (20a and 19a , respectively)
was obtained.22 20a :30 Rf ) 0.33 (hexanes/EtOAc 3/1); 1H NMR
(250 MHz, selected data) δ 7.28-7.18 (m, 4H), 7.15-7.06 (m,
1H), 6.52 (dd, J ) 15.7, 5.1 Hz, 1H), 5.41 (dd, J ) 15.7, 1.6
Hz, 1H), 5.37-5.28 (m, 1H), 4.86 (ddd [app td], J ) 10.7, 4.4
Hz, 1H), 4.12 (dd, J ) 11.3, 3.4 Hz, 1H), 3.97 (dd, J ) 11.3,
6.8 Hz, 1H), 3.90-3.78 (m, 1H), 1.22 (s, 9H), 1.21 (s, 9H), 0.86
(d, J ) 6.5 Hz, 3H); 13C NMR (62.9 MHz) δ 178.7, 177.4, 165.1,
151.4, 144.4, 127.9, 125.4, 125.4, 122.1, 74.7, 71.7, 69.8, 68.4,
50.4, 41.7, 39.7, 38.9, 34.5, 31.3, 29.9, 29.7, 28.6, 27.4, 27.19,
27.15, 26.6, 25.5, 21.8; IR 3522, 2958, 2926, 1732, 1282, 1155
cm-1; [R]546 +9.8 (c 1.5, CHCl3).
(Z)-(4S,7R)-4,8-Bis(2,2-d im et h ylp r op ion yloxy)-7-h y-
d r oxyocta -2-en oic Acid (1R,2S,5R)-5-Meth yl-2-(1-m eth yl-
1-p h en yleth yl)cycloh exyl Ester (23a ) a n d (Z)-(4S,7R)-4,7-
Bis(2,2-d im et h ylp r op ion yloxy)-8-h yd r oxyoct a -2-en oic
Acid (1R,2S,5R)-5-Meth yl-2-(1-m eth yl-1-p h en yleth yl)cy-
cloh exyl Ester (22a ). The reduction of 17a with LiBH4,
according to the general procedure, afforded 49% of secondary
alcohol 23a and 38% of primary alcohol 22a ,22 which were
readily separated by flash chromatography (12% EtOAc in
hexanes). 23a :30 Rf ) 0.4 (hexanes/EtOAc 3/1); H NMR (250
1
(E)-(4R,7S)-4,8-Bis(ter t-b u t yld ip h en ylsilyloxy)-7-h y-
d r oxyocta -2-en oic Acid (1R,2S,5R)-5-Meth yl-2-(1-m eth yl-
1-p h en yleth yl)cycloh exyl Ester (20b) a n d (E)-(4R,7S)-4,7-
Bis(ter t-b u t yld ip h en ylsilyloxy)-8-h yd r oxyoct a -2-en oic
Acid (1R,2S,5R)-5-Meth yl-2-(1-m eth yl-1-p h en yleth yl)cy-
cloh exyl Ester (19b). The reduction of the crude 15b
(mixture with the corresponding bis-HWE product, vide supra)
with NaBH4 according to the general procedure afforded three
fractions: (a) (E,E)-bis-HWE product (39%); (b) 20b (diaster-
eomeric ratio 20b/4431 ) 95:5, 52%); and (c) a 78:22 mixture
of 19b and 20b (dr 95:5) (7%).22 20b: 1H NMR [250 MHz,
selected data assigned from a mixture (95:5) of diastereomers
20b and 44] δ 7.70-7.57 (m, 8H) and 7.50-7.05 (m, 17H), 6.68
(dd, J ) 15.6, 5.2 Hz, 1H), 5.62 (dd, J ) 15.6, 1.5 Hz, 1H),
4.86 (ddd [app td], J ) 10.6, 4.3 Hz, 1H), 4.35-4.25 (m, 1H),
3.53 (dd, J ) 10.7, 3.2 Hz, 1H) and 3.38 (dd, J ) 9.8, 8.0 Hz,
1H), 1.31 (s, 3H), 1.26 (s, 3H), 1.08 (s, 18H), 0.89 (d, J ) 6.4
Hz, 3H); 13C NMR (62.9 MHz) δ 165.6, 150.9, 149.3, 135.8,
135.5, 129.8, 129.7, 127.9, 127.8, 127.6, 127.5, 125.5, 125.2,
121.1, 74.6, 72.1, 71.8, 67.9, 50.6, 41.8, 40.1, 34.5, 32.5, 31.3,
28.1, 27.3, 27.0, 26.8, 25.3, 21.8, 19.3, 19.1; IR 2957, 2930, 2858,
1712, 1428,1112, 735, 701, 505 cm-1; [R]546 +18.5 (c 1.24,
CHCl3). Anal. Calcd for C56H72O5Si2: C, 76.32; H, 8.23.
Found: C, 76.32; H, 8.45. 44: 1NMR [250 MHz, selected data
assigned from a mixture (95:5) of diastereomers 20b and 44]
δ 6.32 (dd, J ) 15.6, 5.2 Hz, 1H), 5.46 (dd, J ) 15.6, 1.5 Hz,
1H). 19b: 1NMR (250 MHz, selected data) δ 6.61 (dd, J ) 15.6,
5.3 Hz, 1H), 5.53 (dd, J ) 15.6, 1.4 Hz, 1H).
MHz, selected data) δ 7.28-7.18 (m, 4H), 7.16-7.06 (m, 1H),
6.15-6.03 (m, 1H), 5.83 (dd, J ) 11.5, 7.7 Hz, 1H), 5.05 (dd, J
) 11.5, 1.3 Hz, 1H), 4.79 (ddd [app td], J ) 10.7, 4.3 Hz, 1H),
4.15 (dd, J ) 11.2, 3.3 Hz, 1H), 4.01 (dd, J ) 11.2, 6.6 Hz,
1H), 3.97-3.86 (m, 1H), 1.23 (s, 9H), 1.17 (s, 9H), 0.86 (d, J )
6.5 Hz, 3H); 13C NMR (62.9 MHz) δ 178.7, 177.7, 164.5, 151.6,
146.9, 127.9, 125.4, 124.9, 121.0, 74.4, 71.4, 70.0, 68.4, 50.4,
47.9, 41.6, 39.6, 38.9, 34.5, 31.3, 30.0, 29.0, 27.8, 27.2, 27.1,
26.5, 25.0, 21.1; IR 3528, 2960, 1732, 1715, 1283, 1202, 1155,
702 cm-1; [R]546 -1.9 (c 1.6, CHCl3). 22a :30 Rf ) 0.27 (hexanes/
EtOAc 3/1); 1H NMR (250 MHz, selected data) δ 7.25-7.17
(m, 4H), 7.14-7.05 (m, 1H), 6.10-6.00 (m, 1H), 5.81 (dd, J )
11.5, 7.6 Hz, 1H), 5.01 (dd, J ) 11.5, 1.3 Hz, 1H), 4.97-4.87
(m, 1H), 4.79 (ddd [app td], J ) 10.7, 4.3 Hz, 1H), 3.71 (br dd,
J ) 11.9, 3.2 Hz, 1H), 3.64 (br dd, J ) 11.9, 6.5 Hz, 1H), 1.23
(s, 9H), 1.17 (s, 9H), 0.85 (d, J ) 6.5 Hz, 3H); 13C NMR (62.9
MHz) δ 178.9, 177.7, 164.4, 151.6, 146.9, 127.8, 125.3, 124.9,
120.9, 74.8, 74.2, 71.2, 64.8, 50.4, 41.6, 39.6, 38.9, 38.6, 34.4,
31.2, 29.7, 27.8, 27.1, 27.0, 26.45, 26.36, 24.8, 21.7; IR 3524,
2971, 1728, 1283, 1201, 1156 cm-1
.
(Z)-(4S,7R)-4,8-Bis(ter t-b u t yld ip h en ylsilyloxy)-7-h y-
d r oxyocta -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) a n d (Z)-(4S,7R)-4,7-
Bis(ter t-b u t yld ip h en ylsilyloxy)-8-h yd r oxyoct a -2-en oic
Acid (1R,2S,5R)-5-Meth yl-2-(1-m eth yl-1-p h en yleth yl)cy-
cloh exyl Ester (22b). The reduction of 17b with NaBH4,
according to the general procedure, afforded 59% of alcohol
23b and 19% of alcohol 22b.22 23b:30 1H NMR (250 MHz,
selected data) δ 7.70-7.53 (m, 8H), 7.47-7.04 (m, 17H), 5.97
(dd, J ) 11.7, 8.0 Hz, 1H), 5.41-5.29 (m, 1H), 4.80 (dd, J )
11.7, 1.2 Hz, 1H), 4.58 (ddd [app td], J ) 10.7, 4.3 Hz, 1H),
3.73-3.64 (m, 1H), 3.61 (dd, J ) 9.8, 3.5 Hz, 1H), 3.45 (dd, J
) 9.8, 7.3 Hz, 1H), 1.15 (s, 3H), 1.13 (s, 3H), 1.07 (s, 9H), 1.03
(s, 9H), 0.88 (d, J ) 6.6 Hz, 3H); 13C NMR (62.9 MHz, some
signals overlap) δ 164.4, 151.7, 151.4, 135.8, 135.5, 134.1,
133.9, 133.2, 129.8, 129.6, 129.5, 127.8, 127.76, 127.5, 127.4,
125.3, 125.0, 118.3, 74.0, 72.1, 69.6, 68.0, 50.4, 41.6, 39.6, 34.5,
33.5, 31.2, 27.9, 27.2, 27.0, 26.9, 26.6, 25.5, 21.8, 19.2; IR 2956,
2930, 2858, 1713, 1428, 1198, 1112, 700 cm-1; [R]546 +26.3 (c
1.9, CHCl3). Anal. Calcd for C56H72O5Si2: C, 76.32; H, 8.23.
Found: C, 76.09; H, 8.26. 22b:30 1H NMR (250 MHz, selected
data) δ 7.72-7.03 (m, 25H), 5.84 (dd, J ) 11.7, 8.0 Hz, 1H),
5.33-5.22 (m, 1H), 4.76 (dd, J ) 11.7, 1.3 Hz, 1H), 4.60 (ddd
[app td], J ) 10.7, 4.3 Hz, 1H), 3.84-3.72 (m, 1H), 3.44 (br s,
1H), 3.43 (d, J ) 2.2 Hz, 1H), 1.20 (s, 3H), 1.15 (s, 3H), 1.07
(s, 9H), 0.99 (s, 9H), 0.87 (d, J ) 6.4 Hz, 3H); 13C NMR (125
MHz) δ 164.4, 151.8, 151.4, 135.9, 135.8, 135.7, 135.65, 135.5,
134.8, 134.0, 133.9, 133.6, 129.7, 129.54, 129.47, 127.9, 127.74,
127.66, 127.5, 127.4, 125.4, 125.0, 118.2, 74.2, 73.8, 69.6, 65.8,
(E)-3-[(2R,5S)-5-(2,2-Dim eth ylp r op ion yloxym eth yl)tet-
r a h yd r ofu r a n -2-yl]a cr ylic Acid (1R,2S,5R)-5-Meth yl-2-(1-
m eth yl-1-p h en yleth yl)cycloh exyl Ester (21). Neocuproine
hemihydrate (1.3 mg, 0.006 mmol) and Pd2(dba)3‚CHCl3 (1.5
mg, 0.0015 mmol) were dissolved in 1 mL of THF, and the
solution was added via syringe to a solution of alkene 20a (8.5
mg, 0.015 mmol) in 2 mL of THF. After the mixture was stirred
for 45 min at rt, 1 mL of 2% aq HCl was added. Filtration
through a plug of MgSO4, concentration, and flash chro-
matograpy of the residue (7.5% EtOAc in hexanes) afforded
(31) Compound 44 originates from 16b, the minor diastereomer
formed in the reaction between 13b and 14a .
7234 J . Org. Chem., Vol. 67, No. 21, 2002

Sequential Asymmetric HWE and Ring-Closure Reactions
50.4, 41.7, 39.7, 34.5, 32.8, 31.2, 28.5, 27.2, 27.1, 27.0, 26.6,
25.6, 21.8, 19.4, 19.2; IR 2955, 2945, 2855, 1715, 1195, 1115,
(m, 1H), 6.52 (dd, J ) 15.8, 5.2 Hz, 1H), 5.58-5.47 (m, 1H),
5.42 (dd, J ) 15.6, 1.5 Hz, 1H), 4.85 (ddd [app td], J ) 10.7,
4.3 Hz, 1H), 4.57 (d, J ) 10.7 Hz, 1H), 4.45 (d, J ) 10.7 Hz,
1H), 4.17-3.93 (m, 3H), 3.83-3.68 (m, 1H), 1.23 (s, 9H), 1.22
(s, 9H), 0.86 (d, J ) 6.4 Hz, 3H); 13C NMR (62.9 MHz, some
signals in the aliphatic region overlap) δ 178.5, 177.1, 165.1,
151.4, 144.8, 137.5, 128.6, 128.2, 128.0, 127.9, 125.4, 125.0,
121.8, 74.6, 73.2, 72.5, 69.1, 68.4, 66.9, 50.4, 41.6, 39.7, 39.4,
38.8, 37.0, 34.5, 31.2, 27.2, 26.6, 25.6, 21.8; IR 3508, 2960, 2930,
1731, 1281, 1153, 700 cm-1; [R]546 +9.2 (c 3.7, CHCl3).
702 cm-1
.
(E)-3-[(2R,5R)-5-(2,2-Dim et h ylp r op ion yloxym et h yl)-
tetr a h yd r ofu r a n -2-yl]a cr ylic Acid (1R,2S,5R)-5-Meth yl-
2-(1-m eth yl-1-p h en yleth yl)cycloh exyl Ester (24). Neocu-
proine hemihydrate (3.4 mg, 0.0155 mmol) and Pd2(dba)3‚
CHCl3 (4 mg, 0.0039 mmol) were dissolved in 1 mL of THF
and the solution added via syringe to a solution of alkene 23a
(22.1 mg, 0.0387 mmol) in 2 mL of THF. After the mixture
was heated to 65 °C for 1.5 h, an additional portion of 2 mg
(0.002 mmol) of Pd2(dba)3‚CHCl3 was added. After another 1.5
h at 65 °C, the THF was evaporated, and the crude product
was purified by flash chromatography (5% EtOAc in hexanes)
to give 14.3 mg (78%) of 24. In addition, ca. 10% of a compound
tentatively assigned as the ring-closed (Z)-product 25 was
isolated in a separate fraction, together with some dba ligand.
24:30 Rf ) 0.53 (hexanes/EtOAc 3/1); 1H NMR (250 MHz,
selected data) δ 7.30-7.20 (m, 4H), 7.17-7.05 (m, 1H), 6.52
(dd, J ) 15.6, 4.9 Hz, 1H), 5.49 (dd, J ) 17.6, 1.6 Hz, 1H),
4.85 (ddd [app td], J ) 10.7, 4.3 Hz, 1H), 4.52 (app br qd, J )
6.7, 1.6 Hz, 1H), 4.26 (br quintet, J ) 5.8 Hz, 1H), 4.12 (dd, J
) 11.5, 4.2 Hz, 1H), 4.05 (dd, J ) 11.5, 5.4 Hz, 1H), 1.22 (s,
9H), 0.86 (d, J ) 6.5 Hz, 1H); 13C NMR (62.9 MHz, some
signals in aliphatic region overlap) δ 178.4, 165.6, 151.5, 147.2,
127.9, 125.4, 125.0, 120.8, 78.0, 76.8, 74.5, 50.5, 41.6, 39.7, 38.8,
34.5, 31.5, 31.3, 29.7, 27.9, 27.3, 27.2, 26.6, 25.6; IR 2958, 2924,
1732, 1283, 1156, 700 cm-1; [R]546 +17.4 (c 0.7, CHCl3). Anal.
Calcd for C29H42O5: C, 74.01; H, 8.99. Found: C, 73.76; H,
9.19. 25:30 Rf ) 0.56 (hexanes/EtOAc 3/1); 1H NMR (500 MHz,
selected data) δ 7.27-7.22 (m, 4H), 7.14-7.10 (m, 1H), 6.13
(dd, J ) 11.5 Hz, 7 Hz, 1H), 5.23 (app br q, J ) 7 Hz, 1H),
5.07 (dd, J ) 11.5 Hz, 1.5 Hz, 1H), 4.77 (app td, J ) 11, 4.5
Hz, 1H), 4.21-4.15 (m, 1H), 4.12 (dd, J ) 11.5, 4 Hz, 1H), 4.07
(dd, J ) 11.5, 5.5 Hz, 1H), 2.38-2.30 (m, 1H), 1.30 (s, 3H),
1.22 (s, 9H), 0.86 (d, J ) 6.5 Hz, 3H); 13C NMR (125 MHz) δ
178.4, 170.0, 151.4, 150.3, 127.9, 125.4, 125.0, 119.9, 77.2, 76.8,
72.3, 66.2, 50.1, 41.7, 39.7, 38.8, 34.5,31.8, 31.3, 28.2, 27.6, 27.2,
(E)-3-[(2R,4R,6S)-4-Ben zyloxy-6-(2,2-dim eth ylpr opion yl-
oxym eth yl)tetr ah ydr opyr an -2-yl]acr ylic Acid (1R,2S,5R)-
5-Met h yl-2-(1-m et h yl-1-p h en ylet h yl)cycloh exyl E st er
(30). Neocuproine hemihydrate (0.9 mg, 0.0042 mmol) and
Pd2(dba)3‚CHCl3 (1.1 mg, 0.001 mmol) were dissolved in 1 mL
of dry THF, and the solution was added via syringe to a
solution of alkene 29a (7.2 mg, 0.0104 mmol; dr 29a /45 ) 95:
5) in 1.5 mL of THF. After the mixture was stirred for 50 min
at room temperature, the THF was evaporated and the residue
was purified by flash chromatograpy (7.5% EtOAc in hexanes)
to give 4.9 mg (80%) of 30 as a colorless oil that slowly
1
solidified. 30:30 Rf ) 0.52 (hexanes/EtOAc 3/1); H NMR (250
MHz, selected data) δ 7.38-7.21 (m, 9H), 7.16-7.06 (m, 1H),
6.52 (dd, J ) 15.7, 4.1 Hz, 1H), 5.54 (dd, J ) 15.7, 1.8 Hz,
1H), 4.85 (ddd [app td], J ) 10.7, 4.3 Hz, 1H), 4.60 (app s,
2H), 4.16 (dd, J ) 11.5, 5.8 Hz, 1H), 4.10 (dd, J ) 11.5, 4.5
Hz, 1H), 3.88 (dddd, J ) 11.8, 4.0, 2.0, 2.0 Hz, 1H), 3.69-3.55
(m, 2H), 1.21 (s, 9H), 0.85 (d, J ) 6.5 Hz, 3H); 13C NMR (62.9
MHz) δ 178.4, 165.6, 151.4, 145.7, 138.2, 128.5, 127.9, 127.7,
127.5, 125.4, 125.0, 120.9, 74.5, 74.0, 73.6, 69.8, 66.4, 50.5, 41.6,
39.7, 38.8, 37.0, 34.5, 34.2, 31.2, 27.7, 27.1, 26.6, 25.8, 25.1,
21.8; IR 2951, 2922, 1726, 1710, 1283, 1176, 700 cm-1; [R]546
+5.5 (c 0.6, CHCl3). Anal. Calcd for C37H49O6: C, 75.35; H,
8.37. Found: C, 75.02; H, 8.75.
26.6, 25.3, 21.8; IR 2955, 2925, 1730, 1710, 1170, 1090 cm-1
.
(E)-3-[(2R,5R)-5-(2,2-Dim et h ylp r op ion yloxy)t et r a h y-
d r op yr a n -2-yl]a cr ylic Acid (1R,2S,5R)-5-Met h yl-2-(1-
m eth yl-1-p h en yleth yl)cycloh exyl Ester (26). To a solution
of primary alcohol 22a (35.5 mg, 0.062 mmol) in 3 mL of THF
were added Pd2(dba)3‚CHCl3 (6 mg, 0.0058 mmol) and neocu-
proine hemihydrate (5 mg, 0.023). The reaction mixture was
refluxed for 2 h, cooled to rt, and concentrated. Purification
by flash chromatography (8% EtOAc in hexanes) afforded 24
mg (82%) of 26 as a white crystalline compound. 26:30 Rf )
0.53 (hexanes/EtOAc 3/1); 1H (500 MHz, selected data) δ 7.29-
7.22 (m, 4H), 7.12-7.08 (m, 1H), 6.55 (dd, J ) 15.8, 4.4 Hz,
1H), 5.52 (dd, J ) 15.8, 1.6 Hz, 1H), 4.86 (td, J ) 10.7, 4.3 Hz,
1H), 4.77 (br s, 1H), 4.01 (br dt, J ) 12.7, 1.85 Hz, 1H), 3.89
(br d quintet, J ) 10.7, 2 Hz, 1H), 3.61 (dd, J ) 12.7, 1.3 Hz,
1H), 1.31 (s, 3H), 1.24 (s, 9H), 1.22 (s, 3H), 0.86 (d, J ) 6.6
Hz, 3H); 13C NMR (125 MHz) δ 178.0, 165.7, 151.4, 146.5,
127.9, 125.4, 124.9, 121.0, 75.5, 74.4, 69.2, 66.4, 50.5, 41.7, 39.8,
38.9, 34.5, 31.3, 27.19, 27.16, 27.13, 26.7, 26.1, 25.8, 21.8; IR
2945, 1720, 1440, 1285, 1185, 700 cm-1; [R]546 +24.0 (c 1.67,
CHCl3). Anal. Calcd for C29H42O5: C, 74.01; H, 8.99. Found:
C, 73.93; H, 8.90.
(Z)-(4S,6S,8R)-6-Ben zyloxy-4,9-bis(2,2-d im eth ylp r op io-
n yloxy)-8-h yd r oxyn 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 (32a ). Pre-
pared from 31a 16j according to the general procedure; 48% of
secondary alcohol 32a and 42% of starting material 31a 22 (Rf
) 0.27, hexanes/EtOAc 3/1) were obtained. 32a :30 Rf ) 0.47
(hexanes/EtOAc 3/1); 1H NMR (500 MHz, selected data) δ
7.48-7.19 (m, 9H), 7.15-7.07 (m, 1H), 6.26-6.16 (m, 1H), 5.85
(dd, J ) 11.6, 7.6 Hz, 1H), 5.04 (dd, J ) 11.6, 1.5 Hz, 1H),
4.81 (td, J ) 10.7, 4.3 Hz, 1H), 4.62 (d, J ) 11.7 Hz, 1H), 4.56
(d, J ) 11.7, 1H), 4.14-4.00 (m, 3H), 3.87-3.80 (m, 1H), 0.86
(d, J ) 6.4 Hz, 3H); 13C (125 MHz, some signals overlap) δ
178.7, 177.5, 164.6, 151.7, 146.4, 133.3, 128.4, 128.3, 127.93,
127.89, 127.7, 125.4, 125.0, 121.2, 74.7, 74.5, 73.3, 71.6, 69.1,
65.7, 50.4, 41.5, 39.6, 38.7, 38.6, 37.9, 34.6, 31.4, 27.8, 27.2,
27.0, 26.6 24.9, 21.8; IR 3506, 2965, 1725, 1280, 1160, 700
cm-1
.
(E)-3-[(2R,4S,6R)-4-Ben zyloxy-6-(2,2-dim eth ylpr opion yl-
oxym eth yl)tetr ah ydr opyr an -2-yl]acr ylic Acid (1R,2S,5R)-
5-Meth yl-2-(1-m eth yl-1-ph en yleth yl)cycloh exyl Ester (33).
To a solution of 32a (50 mg, 0.072 mmol) in 5 mL of THF were
added neocuproine hemihydrate (6 mg, 0.028 mmol) and Pd2-
(dba)3‚CHCl3 (7.5 mg, 0.007 mmol) at 50 °C. After the mixture
was stirred for 30 min at 50 °C, an additional portion of 4 mg
of Pd2(dba)3‚CHCl3 was added. After being stirred for another
30 min at 50 °C, the reaction mixture was concentrated and
purified by flash chromatography (10% EtOAc in hexanes) to
give 25 mg (59%) of 33. 33:30 Rf ) 0.61 (hexanes/EtOAc 3/1);
1H NMR (250 MHz, selected data) δ 7.41-7.06 (m, 10H), 6.54
(dd, J ) 16.0, 3.4 Hz, 1H), 5.51 (dd, J ) 16.0, 2.3 Hz, 1H),
(E)-(4R,6R,8S)-6-Ben zyloxy-4,9-bis(2,2-d im eth ylp r op io-
n yloxy)-8-h yd r oxyn 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 (29a ). Pre-
pared from 28a 16j according to the general procedure; 59% of
secondary alcohol 29a (diastereomeric ratio 29a /4532 ) 95:5)
and 28% of starting material 28a 22 (Rf ) 0.21, hexanes/EtOAc
1
3/1) were obtained. 29a : Rf ) 0.35 (hexanes/EtOAc 3/1); H
NMR [250 MHz, selected data assigned from a mixture (95:5)
of diastereomers 29a and 45] δ 7.40-7.18 (m, 9H), 7.13-7.03
(32) Compound 45 originates from the minor (E)-diastereomer
formed in the asymmetric HWE reaction with 27a .
J . Org. Chem, Vol. 67, No. 21, 2002 7235

Vares and Rein
4.87 (ddd [app td], J ) 10.7, 4.4 Hz, 1H), 4.66 (app td, J ) 7.9,
2.3 Hz, 1H), 4.57 (d, J ) 11.2 Hz, 1H), 4.53 (d, J ) 11.8 Hz,
1H), 4.23 (dd, J ) 11.6, 7.1 Hz, 1H), 4.09 (dd, J ) 11.6, 3.7
Hz, 1H), 3.82 (app ddd, J ) 13.4, 6.8, 3.3 Hz, 1H), 3.82 (app
ddd, J ) 13.9, 9.2, 4.2 Hz, 1H), 1.23 (s, 9H), 0.87 (d, J ) 6.5
Hz, 3H); 13C NMR (50.3 MHz, some signals in the aliphatic
region overlap) δ 178.3, 165.2, 151.3, 146.7, 138.3, 128.5, 127.9,
127.7, 127.5, 125.5, 125.0, 122.7, 74.6, 70.9, 70.4, 70.1, 69.1,
66.1, 50.6, 41.8, 39.8, 38.8, 34.7, 34.6, 33.4, 31.3, 27.2, 26.7,
(1R,2S,5R)-5-Meth yl-2-(1-m eth yl-1-p h en yleth yl)cycloh ex-
yl Ester (36b). To a solution of 23b (212 mg, 0.24 mmol) in
10 mL of dry ether was added t-BuOK (40 mg, 0.356 mmol).
The reaction mixture was stirred for 30 min at rt and then
quenched with 2 mL of phosphate buffer (pH 7). Extractive
workup, followed by flash chromatography (3% EtOAc in
hexanes), afforded 206 mg (97%) of 36b. 36b:30 Rf ) 0.48
1
(hexanes/EtOAc 85/15); H NMR (500 MHz, selected data) δ
7.71-7.68 (m, 4H), 7.60-7.57 (m, 4H), 7.48-7.20 (m, 17H),
7.13-7.10 (m, 1H), 4.83 (ddd [app td], J ) 10.7, 4.4 Hz, 1H),
3.70 (ddd [app td], J ) 10.1, 2 Hz, 1H), 3.61 (dd, J ) 10, 4.5
Hz, 1H), 3.46-3.39 (m, 1H), 3.36-3.27 (m, 2H), 2.68 (dd, J )
15, 2 Hz, 1H), 1.28 (s, 3H), 1.18 (s, 3H), 1.05 (s, 9H), 0.97 (s,
9H), 0.67 (d, J ) 6.5 Hz, 3H); 13C NMR (50.3 MHz, some
signals overlap) δ 171.4, 151.2, 135.9, 135.8, 135.51, 135.45,
134.2, 133.5, 129.8, 129.7, 129.5, 127.8, 127.7, 127.6, 125.5,
125.1, 79.3, 77.6, 77.1, 74.5, 72.1, 66.3, 50.3, 41.7, 39.9, 38.7,
34.5, 32.7, 31.2, 28.0, 27.0, 26.8, 26.1, 21.6, 19.3, 19.2; IR 2956,
2931, 2857, 1725, 1427, 1111, 700 cm-1; [R]546 +19.3 (c 1.1,
CHCl3). Anal. Calcd for C56H72O5Si2: C, 76.32; H, 8.23.
Found: C, 76.27; H, 8.49.
(E)-(4R,6R,8S)-6-Ben zyloxy-4,8,9-tr ih yd r oxyn on -2-en o-
ic Acid (1R,2S,5R)-5-Meth yl-2-(1-m eth yl-1-p h en yleth yl)-
cycloh exyl Ester (37). To a solution of bis-silyl ether 28b16j
(diastereomeric ratio g 98:2; 131.7 mg, 0.13 mmol) in 7 mL of
dry THF was added 525 µL (0.53 mmol) of Bu4NF solution (1
M in THF). After being stirred for 2 h at room temperature,
the reaction mixture was diluted with 10 mL of aq saturated
NH4Cl, extracted with CH2Cl2 (3 × 20 mL), dried, filtered
through a plug of cotton, and concentrated. Purification by
flash chromatography (3% MeOH in CH2Cl2) yielded 55 mg
(80%) of triol 37. 37:30 Rf ) 0.31 (CH2Cl2/MeOH 19/1); 1H NMR
(200 MHz, selected data) δ 7.42-7.18 (m, 9H), 7.16-7.04 (m,
1H), 6.58 (dd, J ) 15.6, 4.4 Hz, 1H), 5.53 (dd, J ) 15.6, 1.7
Hz, 1H), 4.85 (ddd [app td], J ) 10.7, 4.3 Hz, 1H), 4.63 (d, J )
11.2 Hz, 1H), 4.56 (d, J ) 11.2 Hz, 1H), 4.48-4.35 (m, 1H),
4.08-3.88 (m, 2H), 3.64 (dd, J ) 11.1, 3.1 Hz, 1H), 3.44 (dd, J
) 11.1, 6.7 Hz, 1H), 1.30 (s, 3H), 1.21 (s, 3H), 0.86 (d, J ) 6.4
Hz, 3H); 13C NMR (50.3 MHz) δ 165.7, 151.5, 149.2, 137.6,
128.6, 128.2, 128.1, 127.9, 125.4, 124.9, 120.6, 74.5, 74.2, 71.9,
69.0, 68.1, 66.9, 50.4, 41.7, 39.8, 39.7, 36.5, 34.5, 31.2, 27.2,
26.6, 25.7, 21.8, 20.1; IR 3384, 2952, 1709, 1274, 1092, 700
cm-1; HRMS-FAB (m/z) [M+] calcd for C32H44O6 524.3138,
found 524.3156.
25.9, 21.8; IR 2955, 2927, 1713, 1283, 1162, 1094, 700 cm-1
;
[R]546 -35.7 (c 0.8, CHCl3). HRMS-FAB (m/z) [M + H]+ calcd
for C37H48O6 589.3529, found 589.3526.
[(2R,3R,6S)-3-ter t-Bu tyld ip h en ylsilyloxy-6-(ter t-bu tyl-
diph en ylsilyloxym eth yl)tetr ah ydr opyr an -2-yl]acetic Acid
(1R,2S,5R)-5-Meth yl-2-(1-m eth yl-1-p h en yleth yl)cycloh ex-
yl Ester (34). To a solution of alkene 20b (24 mg, 0.027 mmol;
dr 20b/44 ) 95:5) in 3 mL of THF was added t-BuOK (5 mg,
0.04 mmol) at 0 °C. The reaction mixture was stirred for 30
min at 0 °C and then quenched with 1 mL of phosphate buffer
(pH 7). Extractive workup followed by flash chromatography
(3% EtOAc in hexanes) afforded 23 mg (96%) of 34. According
to NMR analysis, the product contained ca. 3% of a minor
isomer, tentatively assigned as the 2,6-cis-THP derivative
35.28,33 34: Rf ) 0.48 (hexanes/EtOAc 9/1); 1H (500 MHz,
selected data) δ 7.72-7.53 (m, 8H), 7.47-7.27 (m, 16H), 7.20-
7.15 (m, 1H), 4.77 (ddd [app td], J ) 10.7, 4.3 Hz, 1H), 4.22-
4.15 (m, 1H), 3.81 (ddd, J ) 10, 4.5, 4.5 Hz, 1H), 3.55 (dd, J )
9.5, 4.2 Hz, 1H), 3.46-3.40 (m, 1H), 3.29 (dd, J ) 9.3, 7.5 Hz,
1H), 2.27 (dd, J ) 14.5, 3 Hz, 1H), 2.16 (dd, J ) 14.5, 11.5 Hz,
1H), 1.98 (br t, J ) 9.7 Hz, 1H), 1.33 (s, 3H), 1.22 (s, 3H), 1.07
(s, 9H), 1.02 (s, 9H), 0.70 (d, J ) 6.5 Hz, 3H); 13C NMR (125
MHz) δ 171.7, 151.9, 135.74, 135.68, 135.6, 135.5, 129.8, 129.7,
129.6, 127.9, 127.7, 127.62, 127.57, 125.5, 124.9, 74.3, 73.8,
69.2, 68.5, 66.5, 50.4, 41.7, 39.7, 34.5, 31.2, 31.1, 28.2, 27.1,
26.96, 26.88, 26.8, 24.8, 26.5, 21.6, 19.3, 19.2; IR 2930, 2857,
1728, 1428, 1112, 700, 504 cm-1; [R]546 +24.7 (c 1.4, CHCl3).
Anal. Calcd for C56H72O5Si2: C, 76.32; H, 8.23. Found: C,
76.08; H, 8.31. 35: 1H (500 MHz, selected data assigned from
a ca. 70:30 mixture of 34 and 35) δ 3.65 (dd, J ) 10, 4.5 Hz,
1H), 2.70 (dd, J ) 14.5, 2.6 Hz, 1H); 13C (125 MHz, selected
data assigned from a ca. 70:30 mixture of 34 and 35) δ 171.2,
151.2, 77.2, 74.7, 72.2, 66.4, 50.6, 41.6, 39.9, 34.6.
[(2R ,3S ,6R )-3-(2,2-Dim e t h ylp r op ion yloxy)-6-(2,2-d i-
m et h ylp r op ion yloxym et h yl)t et r a h yd r op yr a n -2-yl]a ce-
tic Acid (1R,2S,5R)-5-Meth yl-2-(1-m eth yl-1-p h en yleth yl)-
cycloh exyl Ester (36a ). To a solution of alkene 23a (52 mg,
0.091 mmol) in 2 mL of dry ether was added t-BuOK (10 mg).
The reaction mixture was stirred for 10 min at rt and then
quenched with 0.5 mL of phosphate buffer (pH 7). Extractive
workup (EtOAc/brine), drying, and evaporation of solvents
afforded 54 mg (ca. 95% pure based on 1H NMR, crude yield
99%) of tetrahydropyran 36a . An analytically pure sample was
obtained in 95% yield after purification by flash chromatog-
raphy (5% EtOAc in hexanes). 36a :30 Rf ) 0.72 (hexanes/EtOAc
(E)-(4R,6R,8S)-6-Ben zyloxy-4,8-d ih yd r oxy-9-(tolu en e-
4-su lfon yloxy)n 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 (38). To a solution
of triol 37 (51 mg, 0.097 mmol) in 200 µL of pyridine was added
via syringe TsCl (27 mg, 0.141 mmol) dissolved in 200 µL of
pyridine. After 2 h at 0 °C, an additional 18.5 mg of TsCl in
100 µL of pyridine was added. After being stirred for an
additional 2 h at 0 °C, the reaction mixture was diluted with
brine, extracted with CH2Cl2 (1 × 10 mL) and ether (2 × 10
mL), dried, filtered through a plug of cotton, and concentrated
to give 99 mg of pale yellow oil. Flash chromatography (0.5%
MeOH in CH2Cl2) yielded 50.1 mg (76%) of 38. 38:30 Rf ) 0.18
1
3/1); H NMR (250 MHz, selected data) δ 7.30-7.19 (m, 4H),
7.14-7.06 (m, 1H), 4.82 (ddd [app td], J ) 10.7, 4.3 Hz, 1H),
4.36 (ddd [app br td], J ) 9.8, 4.6 Hz, 1H), 4.00 (dd, J ) 11.4,
5.0 Hz, 1H), 3.93 (dd, J ) 11.4, 5.8 Hz, 1H), 3.74 (ddd [app
dt], J ) 9.9, 2.6 Hz, 1H), 3.62-3.51 (m, 1H), 1.20 (s, 9H), 1.18
(s, 9 H), 0.86 (d, J ) 6.4 Hz, 3H); 13C NMR (62.9 MHz, some
signals overlap) δ 178.2, 177.5, 170.4, 151.3, 127.8, 125.4,
125.1, 76.1, 75.1, 74.6, 70.8, 66.0, 50.2, 41.8, 39.7, 38.7, 37.6,
34.5, 31.3, 29.7, 28.5, 27.2, 27.1, 26.6, 25.7, 21.8; IR 2956, 2926,
2870, 1731, 1284, 1153 cm-1; [R]546 +30.4 (c 3.7, CHCl3);
HRMS-FAB (m/z) [M + H]+ calcd for C34H52O7 573.3791, found
573.3794.
1
(2% MeOH in CH2Cl2); H NMR (250 MHz, selected data) δ
7.83-7.75 (m, 2H), 7.41-7.19 (m, 11H), 7.14-7.03 (m, 1H),
6.54 (dd, J ) 15.6, 4.5 Hz, 1H), 5.51 (dd, J ) 15.6, 1.7 Hz,
1H), 4.85 (ddd [app td], J ) 10.7, 4.3 Hz, 1H), 4.56 (s, 2 H),
4.38 (app qd, J ) 4.1, 1.6 Hz, 1H), 4.13-4.01 (m, 2H), 4.01
(dd, J ) 10.0, 3.7 Hz, 1H), 3.91 (dd, J ) 10.0, 6.4 Hz, 1H),
2.44 (s, 3H), 1.30 (s, 3H), 1.21 (s, 3H), 0.86 (d, J ) 6.5 Hz,
3H); 13C NMR (50.3 MHz, some signals in the aromatic region
overlap) δ 165.6, 151.6, 148.9, 145.1, 137.5, 132.6, 129.9, 128.6,
128.2, 127.9, 125.4, 124.9, 120.7, 74.5, 73.8, 72.2, 68.0, 66.5,
50.5, 41.7, 39.74, 39.70, 36.6, 34.5, 31.3, 27.4, 26.6, 25.6, 21.8,
21.6; IR 3474, 2951, 2924, 1708, 1176, 700 cm-1; HRMS-FAB
(m/z) [M + H]+ calcd for C39H50O8S 679.3305, found 679.3275.
[(2R,3S,6R)-3-ter t-Bu tyld ip h en ylsilyloxy-6-ter t-bu tyl-
diph en ylsilyloxym eth yltetr ah ydr opyr an -2-yl]acetic Acid
(33) We cannot exclude the possibility that the product contains
trace amounts of the 2,6-trans-THP product resulting from ring closure
of compound 44; we have only been able to detect product isomers 34
and 35, however.
(E)-(4R,6R,8S)-6-Ben zyloxy-4-h yd r oxy-8,9-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 (39). To a solution of tosylate 38 (63 mg,
7236 J . Org. Chem., Vol. 67, No. 21, 2002

Sequential Asymmetric HWE and Ring-Closure Reactions
0.092 mmol) in 6 mL of dry THF under Ar was added dropwise
NaHMDS solution (0.585 M in toluene, 190 µL, 0.111 mmol).
After the mixture was stirred for 10 min at room temperature,
0.5 mL of water was added. Filtration through a layer of
MgSO4 and silica gel followed by evaporation gave 44 mg (95%)
of 39. No further purification was needed. 39:30 Rf ) 0.28
(hexanes/EtOAc 7/3); 1H NMR (250 MHz, selected data) δ
7.42-7.20 (m, 9H), 7.16-7.06 (m, 1H), 6.61 (dd, J ) 15.6, 4.3
Hz, 1H), 5.56 (dd, J ) 15.6, 1.8 Hz, 1H), 4.86 (ddd [app td], J
) 10.7, 4.3 Hz, 1H), 4.66 (d, J ) 11.2 Hz, 1H), 4.53 (d, J )
11.2 Hz, 1H), 4.53-4.41 (m, 1H), 3.94 (app ddd, J ) 13.2, 6.4,
4.0 Hz, 1H), 3.07-2.98 (m, 1H), 2.82 (dd, J ) 4.9, 4.1 Hz, 1H),
2.74 (br d, J ) 3.2 Hz, 1H), 2.52 (dd, J ) 5, 2.7 Hz, 1H), 1.31
(s, 3H), 1.23 (s, 3 H), 0.87 (d, J ) 6.4 Hz, 3H); 13C NMR (62.9
MHz, some signals in the aromatic region overlap) δ 165.4,
151.3, 149.0, 137.5, 128.4, 127.8, 127.7, 125.3, 124.7, 120.5,
74.6, 74.2, 71.7, 67.9, 50.3, 49.1, 47.1, 41.5, 39.8, 39.6, 37.0,
34.4, 31.1, 26.9, 26.5, 25.7, 21.6; IR 3468, 2953, 2923, 1710,
1273, 1092, 700 cm-1; HRMS-FAB (m/z) [M + H]+ calcd for
J ) 11.5, 7.5 Hz, 1H), 3.56 (dd, J ) 11.5, 3.9 Hz, 1H), 1.29 (s,
3H), 1.20 (s, 3H), 0.86 (d, J ) 6.4 Hz, 3H); 13C NMR (50.3 MHz,
some signals in the aromatic region overlap) δ 165.5, 151.6,
147.1, 138.3, 128.4, 127.9, 127.6, 127.4, 125.5, 124.9, 120.9,
74.4, 70.6, 70.1, 69.7, 69.4, 64.1, 50.5, 41.7, 39.7, 34.6, 31.4,
31.3, 29.7, 27.3, 26.6, 25.6, 21.8; IR 3453, 2954, 2924, 1710,
1271, 1175, 1094, 700 cm-1; HRMS-FAB (m/z) [M + H]+ calcd
for C32H42O5 507.3110, found 507.3112.
Ack n ow led gm en t. We thank the Danish Technical
Science Research Council (STVF), the Danish Natural
Science Research Council (SNF), the Swedish Natural
Science Research Council (NFR), the Swedish Institute,
the Sale´n Foundation (Sweden), the Nordic Baltic
Scholarship Scheme (Denmark), the Axel and Margaret
J ohnson Foundation (Sweden), and the Estonian Sci-
ence Foundation (Grant No. 4230) for financial support.
We are grateful to Professor Christian Pedersen and Dr.
Torben M. Pedersen, Technical University of Denmark,
and Professor To˜nis Pehk, National Institute of Chemi-
cal Physics and Biophysics, Tallinn, for skilful as-
sistance with NMR experiments. We also gratefully
acknowledge Mrs. Nonka Sevova, University of Notre
Dame, for assistance with HRMS analyses and M.Sc.
J ohn J . Kane, University of Notre Dame, for critically
reading the manuscript.
C
32H42O5 507.3110, found 507.3102.
(E)-3-[(2R,4R,6R)-4-Ben zyloxy-6-h ydr oxym eth yltetr ah y-
d r op yr a n -2-yl]a cr ylic Acid (1R,2S,5R)-5-Met h yl-2-(1-
m eth yl-1-p h en yleth yl)cycloh exyl Ester (40). To a solution
of epoxide 39 (7.4 mg, 0.0146 mmol) in 3 mL of acetonitrile
was added a catalytic amount of triflic acid (0.5% solution in
CH2Cl2, 40 µL) under argon at 0 °C. The reaction mixture was
stirred for 20 min at 0 °C and then quenched by addition of
50 µL of Et3N. The reaction mixture was warmed to rt, diluted
with water (8 mL), and extracted with EtOAc (3 × 10 mL);
the combined extracts were dried, filtered through a plug of
cotton, and concentrated. Purification by flash chromatograpy
(20% EtOAc in hexanes) afforded 6.6 mg (89%) of tetrahydro-
Su p p or tin g In for m a tion Ava ila ble: NMR data for com-
pounds 41 and 42, details concerning the preparation of
compound 43 (including analytical data), general NMR data
for the 8-phenylmenthyl unit, NOE spectra for compounds 21,
24, 33, 36a , and 40, and copies of 1H NMR spectra for
compounds 11a , 12b, 13a , 17b, 19a , 20a , 21, 22a ,b, 23a , 25,
29a , 32a , 33, 35, 36a , and 37-40. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
pyran 40. 40:30 Rf ) 0.18 (hexanes/EtOAc 7/3); H NMR (250
MHz, selected data) δ 7.39-7.19 (m, 9H), 7.16-7.06 (m, 1H),
6.83 (dd, J ) 15.8, 4.7 Hz, 1H), 5.43 (dd, J ) 15.8, 1.9 Hz,
1H), 4.85 (ddd [app td], J ) 10.7, 4.3 Hz, 1H), 4.55 (d, J )
11.8 Hz, 1H), 4.47 (d, J ) 11.8 Hz, 1H), 4.40 (br qd, J ) 5.0,
1.7 Hz, 1H), 4.21-4.09 (m, 1H), 3.87-3.76 (m, 1H), 3.64 (dd,
J O0259111
J . Org. Chem, Vol. 67, No. 21, 2002 7237