Furan approach to vitamin D analogues. Synthesis of the A-ring of calcitriol and 1α-hydroxy-3-deoxyvitamin D3

Article abstract of DOI:10.1021/jo101155c

The A-rings of calcitriol (1α,25-dihydroxyvitamin D₃) and 1α-hydroxy-3-deoxyvitamin D₃ were synthesized using the furan approach. The critical steps in the synthesis of the A-ring of calcitriol involved an asymmetric carbonyl-ene reaction of 3-methylene-2,3-dihydrofuran with 3-(tert-butyldimethylsiloxy)propanal, a diastereoselective Friedel-Crafts hydroxyalkylation, an oxidation of the 2,3-disubstituted furan to give a γ-hydroxybutenolide, and a Peterson olefination. The A-ring (Z)-dienol of calcitriol was synthesized in 12 steps from 3-(tert-butyldimethylsiloxy)propanal in 17% yield.

Full text of DOI:10.1021/jo101155c

pubs.acs.org/joc
Furan Approach to Vitamin D Analogues. Synthesis of the A-Ring of
Calcitriol and 1r-Hydroxy-3-deoxyvitamin D3
€
William H. Miles,* Katelyn B. Connell, Gozde Ulas, Hannah H. Tuson,
Elizabeth A. Dethoff, Varun Mehta, and April J. Thrall
Department of Chemistry, Lafayette College, Easton, Pennsylvania 18042
milesw@lafayette.edu
Received June 21, 2010
The A-rings of calcitriol (1R,25-dihydroxyvitamin D3) and 1R-hydroxy-3-deoxyvitamin D3 were synthe-
sized using the furan approach. The critical steps in the synthesis of the A-ring of calcitriol involved an
asymmetric carbonyl-ene reaction of 3-methylene-2,3-dihydrofuran with 3-(tert-butyldimethylsiloxy)-
propanal, a diastereoselective Friedel-Crafts hydroxyalkylation, an oxidation of the 2,3-disubstituted
furan to give a γ-hydroxybutenolide, and a Peterson olefination. The A-ring (Z)-dienol of calcitriol was
synthesized in 12 steps from 3-(tert-butyldimethylsiloxy)propanal in 17% yield.
Introduction
A-ring have been developed over the years, including the
synthetic manipulation of (S)-carvone4 and (5S)-tert-butyldi-
methylsiloxy-2-cyclohexenone,5 the Diels-Alder reaction of
electron-rich pyrones with dienophiles,6 and the intramolecular
Heck reaction.7
We recently demonstrated that the furan approach to the
synthesis of the A-ring of 1R-hydroxy-3-deoxyvitamin D3
(1c) was a viable strategy.8 Our synthesis of 4c was a significant
step in defining the conditions for the conversion of 2,3-
disubstituted furans 5 into the required (Z)-dienols 4, but the
synthesis of (Z)-dienols 4a and 4b also required the successful
introduction of the C-3 sterogenic center. This paper gives a
full account of our synthesis of 4c as well as our successful
synthesis of 4a and attempted synthesis of 4b.
Calcitriol (1a), the active metabolite of vitamin D3 (1b),
has a broad range of biological activity (Figure 1).1 In
addition to its well-known role in maintaining calcium and
phosphorus homeostasis, 1a has also been shown to promote
cell differentiation and inhibit tumor cell proliferation.
Although the clinical efficacy of 1a has been demonstrated
in the treatment of hyperproliferation diseases such as psoriasis,
therapeutic levels of 1a often lead to hypercalcemia. In order to
retain the desired biological activity but attenuate the effects of
hypercalcemia, thousands of analogues of 1a have been pre-
pared and undergone biological testing.2 The continued interest
in synthesizing new analogues has spurred the development of
new methodologies for the synthesis of vitamin D3 analogues.
One of the most popular synthetic strategies for the synthesis
of vitamin D3 analogues is based on the work of Lythgoe.3 The
general strategy involves the coupling of A-ring phosphine
oxides (2) with C,D-ring ketones (3) (Scheme 1). This highly
convergent synthetic strategy was used by the Hoffmann-La
Roach chemists to synthesize 1a for the first time, a benchmark
in vitamin D3 chemistry.4a Many different approaches to the
Results and Discussion
Synthesis of 3-Substituted Furans. We envisioned that the
synthesis of the prerequisite 2,3-disubstituted furans 5 would
(4) (a) Baggiolini, E. G.; Iacobelli, J. A.; Hennessy, B. M.; Batcho, A. D.;
ꢀ
Sereno, J. F.; Uskokovic, M. R. J. Org. Chem. 1986, 51, 3098–3108.
(b) Daniewski, A. R.; Garofalo, L. M.; Hutchings, S. D.; Kabat, M. M.;
Liu, W.; Okabe, M; Radinov, R.; Yiannikouros, G. P. J. Org. Chem. 2002,
67, 1580–1587.
(1) Vitamin D, 2nd ed.; Feldman, D., Pike, J. W., Glorieux, F. H., Eds.;
Academic Press: San Diego, 2005. Campbell, M. J.; Adorini, L. Expert Opin.
Ther. Targets 2006, 177, 8504–8511.
(5) (a) Hareau, G. P. J.; Koiwa, M.; Sato, F. Tetrahedron Lett. 2000, 41,
2385–2388. (b) Koiwa, M.; Hareau, G. P. J.; Sato, F. Tetrahedron Lett. 2000,
41, 2389–2390.
(2) Zhu, G.; Okamura, W. H. Chem. Rev. 1995, 95, 1877–1952. Dai, H.;
Posner, G. H. Synthesis 1994, 1383–1398.
(3) Lythgoe, B.; Moran, T. A.; Nambudiry, M. E. N.; Tideswell, J.;
Wright, P. W. J. Chem. Soc., Perkin Trans. 1 1978, 590–595.
(6) Posner, G. H.; Kinter, C. M. J. Org. Chem. 1990, 55, 3967–3969.
(7) Hiyamizu, H.; Ooi, H.; Inomoto, Y.; Esumi, T.; Iwabuchi, Y.;
Hatakeyama, S. Org. Lett. 2001, 3, 473–475.
(8) Miles, W. H.; Connell, K. B. Tetrahedron Lett. 2003, 44, 1161–1163.
6820 J. Org. Chem. 2010, 75, 6820–6829
Published on Web 09/16/2010
DOI: 10.1021/jo101155c
r
2010 American Chemical Society

Miles et al.
JOCArticle
SCHEME 2. Thermal Ene Reactions of 6
FIGURE 1. Structure of calcitriol, vitamin D3, and 3-deoxy-1-
hydroxyvitamin D3.
illustrative of the utility of alicyclic isomer 6 in the synthesis
of 3-substututed furans (Scheme 2).
In addition to the thermal ene reaction of 6 with alkenes
and electron-poor carbonyl compounds, such as butyl glyox-
ylate, 6 undergoes Lewis acid-catalyzed carbonyl-ene reac-
tions with simple aldehydes.9b,c The Lewis acids required for
catalysis of the carbonyl-ene reaction of 6 with aliphatic and
aromatic aldehydes are relatively weak: Yb(fod)3, Eu(fod)3,
Al(CH3)3 and Ti(O-i-Pr)4 are all effective.9b The most serious
limitation we have encountered is the low reactivity of
R-substituted aldehydes, which invariably leads to the iso-
merization/decomposition of 6 and low yields of alcohol
product. We also have demonstrated that the asymmetric
carbonyl-ene reaction of 6 with benzaldehyde using Ti(O-i-
Pr)4/(S)-BINOL gives nonracemic 2-(3-furyl)-1-phenyl-1-
ethanol (90% yield and 95% ee),9c a reaction modeled after
Mikami’s asymmetric carbonyl-ene reaction of electron-
poor glyoxylates with alkenes13a and Keck’s asymmetric
allylation of aldehydes.13b We envisioned the asymmetric
carbonyl-ene reaction of 6 with a suitably substituted ali-
phatic aldehyde as the key reaction in establishing the C-3
stereogenic center (vitamin D3 numbering).
We choose 3-(tert-butyldimethylsiloxy)propanal (9) as the
aldehyde partner in the asymmetric carbonyl-ene reaction
with 6. The Ti(O-i-Pr)4/(R)-BINOL-catalyzed reaction of
6 with 9 (prepared by the TEMPO oxidation of 3-(tert-
butyldimethylsiloxy)propan-1-ol) gave alcohol 10 in 78%
yield and >95% ee (Scheme 3). As we found with the
carbonyl-ene reaction of 6 with benzaldehyde,9c the level of
hydration of the molecular sieves (achieved by storing the
molecular sieves at 110 °C) was critical for good enantio-
selectivity.14 Protection of alcohol 10 as a TBS ether to give
11 was accomplished by the use of TBSOTf with 2,6-lutidene
as the base (96% yield). The selective deprotection of the
primary silyl ether of 11 to give alcohol 12 required a careful
balance of conversion and yield, since the further cleavage of
the secondary silyl ether of 12 to give the corresponding diol
was a serious side reaction. The deprotection of 11 with a mixture
of THF/H2O/AcOH (50:15:35) gave recovered 11 (19% yield)
and 12 (65% yield; 81% yield based on recovered 11). We also
SCHEME 1. Retrosynthetic Analysis
be available by the cyclization of suitably substituted 3-sub-
stituted furans. The readily available starting materials for
the synthesis of 3-substituted furans include 3-furoic acid,
3-furaldehyde, 3-furylmethanol, 3-furylmethylbromide, and
3-methylene-2,3-dihydrofuran (6). Our numerous investiga-
tions of 3-methylene-2,3-dihydrofuran (6), the abnormal
reduction product of 3-furaldehyde, have demonstrated that
it is a convenient starting material for a variety of 3-sub-
stituted furans.9 The thermal ene reaction of 6 with simple
monosubstituted alkenes proceeds at a nearly unprecedented
rate (refluxing CH2Cl2 for 1 day), presumably reflecting the
aromatic nature of the transition state in a concerted
reaction.9a For comparison, the ene reaction of β-pinene, a
reactive ene, with maleic anhydride, an excellent enophile,
required heating for 8 h at 140 °C.10 The synthesis of
aldehyde 7 (82% yield), previously prepared in five steps
from 3-furanmethanol,11 and ester 8 (72% yield), which was
previously prepared in three steps from 3-furoic acid,12 is
(9) (a) Miles, W. H.; Berreth, C. L.; Smiley, P. M. Tetrahedron Lett. 1993,
34, 5221–5222. (b) Miles, W. H.; Berreth, C. B.; Anderton, C. A. Tetrahedron
Lett. 1996, 37, 7893–7896. (c) Miles, W. H.; Fialcowitz, E. J.; Halstead, E. S.
Tetrahedron 2001, 57, 9925–9929.
(10) Arnold, R. T.; Showell, J. S. J. Am. Chem. Soc. 1957, 79, 419–422.
For reviews of the ene and carbonyl-ene reactions, see: (a) Clarke, M. L.;
France, M. B. Tetrahedron 2008, 64, 9003–9031. Dias, L. C. Curr. Org. Chem.
2000, 4, 305–342. Mikami, K.; Shimizu, M. Chem. Rev. 1992, 92, 1021–1050.
(11) New, D. G.; Tesfai, Z.; Moeller, K. D. J. Org. Chem. 1996, 61, 1578–
1598.
(13) (a) Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc. 1990, 112,
3949–3954. (b) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc.
1993, 115, 8467–8468. For a review of the use of BINOL in asymmetric
reactions, see: Brunel, J. M. Chem. Rev. 2005, 105, 857–897.
(14) For studies related to the role played by the hydration of the
molecular sieves in Ti-catalyzed reactions, see: Terada, M.; Matsumoto,
Y.; Nakamura, K. J. Chem. Soc., Chem. Commun. 1997, 281–282. Kurosu,
M.; Lorca, M. Synlett 2005, 1109–1112. Posner, G. H.; Dai, H.; Bull, D. S.;
Lee, J.; Eydoux, F.; Ishihara, Y.; Welsh, W.; Pryor, N.; Petr, S., Jr. J. Org.
Chem. 1996, 61, 671–676.
(12) Walsh, E. J., Jr.; Stone, G. B. Tetrahedron Lett. 1986, 27, 1127–1130.
J. Org. Chem. Vol. 75, No. 20, 2010 6821

Miles et al.
JOCArticle
SCHEME 3. Synthesis of Furanyl Alcohol 12
SCHEME 4. Synthesis of Furan 5c
investigated several other protecting groups (Ac, TES, and
Bn instead of TBS) for the primary alcohol center in the
three-step synthetic sequence of 12, but one or more steps
were problematic. The Ti(O-i-Pr)4/(R)-BINOL-catalyzed
reaction of 6 with 3-(triethylsiloxy)propanal and 3-benzyloxy-
propanal gave good yields and enantioselectivity of the
corresponding alcohol, but 3-acetoxypropanal gave only
moderate yields. Protection of the secondary alcohol of (2R)-
4-(triethylsilyoxy)-1-(3-furyl)butan-2-ol as a TBS ether was
complicated by the migration of the TES group from the
primary position to the secondary position. The major
problem with using a benzyl protecting group occurred in
the last step of the three-step sequence; the reduction of the
furan ring competed with the reductive deprotection of the
primary benzyl ether corresponding to 11.
Synthesis of 2,3-Disubstituted Furans 5. The cyclization of
3-substituted furans is an excellent method for the synthesis
of 2,3-disubstituted furans,15 although there are serious
limitations as to what kind of reaction conditions can be
employed due to the sensitivity of the furan moiety to acidic
conditions. Further, the Friedel-Crafts cyclization reactions
of aromatic aldehydes to R-hydroxy or R-alkoxy aromatic
compounds are often complicated by the further Friedel-
Crafts reactions of the initial product due to the facile
formation of a carbocation.16 The reactivity of R-hydroxy
aromatic compounds under Friedel-Crafts conditions can
be turned into an advantage; the condensation of electron-
rich aromatic compounds with aldehydes and ketones pro-
vides ready access to diaryl- and triarylmethanes, important
classes of organic compounds.16c-e
oxidation of furans, but nonracemic 5c was necessary for
testing the durability of the C-1 (vitamin D3 numbering
system) stereogenic center in the subsequent synthetic
steps.
One approach we explored for the synthesis of 5c was the
enantioselective intramolecular Friedel-Crafts hydroxyalk-
ylation of aldehyde 7 (Scheme 4). Although there are many
reports of diastereoselective intermolecular and intramolecu-
lar Friedel-Crafts hydroxyalkylations19 and, more recently,
enantioselective intermolecular Friedel-Crafts hydroxyal-
kylations,20 we are unaware of any enantioselective intra-
molecular Friedel-Crafts hydroxyalkylation reactions. We
obtained nonracemic alcohol 13 in moderate yield and
enantioselectivity using Ti(O-i-Pr)4/(R-BINOL) (entries 1-3;
Table 1). There was an incremental increase in enantioselec-
tivity in using the Ti(O-i-Pr)4/(R)-6,60-Br2-BINOL catalyst
system (entries 4-7), with a 10 mol % loading of Ti(O-i-Pr)4 in
a 1:2 ratio of Ti(O-i-Pr)4/ligand in ether (entry 7) giving 13 in
49% yield and 61% ee. Alcohol 13 was obtained in good yields
using (R)-BINAP with either AgOTf (entry 8) or Cu(OTf)2
(entry 9) as the catalyst, but the product was racemic. We also
tried several metal/BOX (BOX = bisoxazoline) catalyst sys-
tems (entry 10-12); as expected, the product was racemic,
since these catalyst systems appear to require a bidentate
electrophile.20a-c
Although 5c, the furan necessary for the synthesis of (Z)-
dienol 4c, has been previously prepared in racemic form,17 an
enantioselective synthesis was not known until our initial
communication appeared.8 We explored several methods for
the synthesis of 5c and rac-5c in hopes of defining suitable
conditions for the cyclization reaction. We first developed an
alternative synthesis of rac-5c based on the Friedel-Crafts
silyloxyalkylation of aldehyde 7, a reaction that has very
little precedent (Scheme 4).18 The addition of TBSOTf to
aldehyde 7 and 2,6-lutidine gave rac-5c in 71% yield. This
racemic material was critical for the initial exploration of the
(19) (a) van Lingen, H. L.; Zhuang, W.; Hansen, T; Rutjes, F. P. J. T.;
Jørgensen, K. A. Org. Biomol. Chem. 2003, 1, 1953–1958. (b) Casiraghi, G.;
Bigi, F.; Casnati, G.; Sartorti, G.; Soncini, P.; Fava, G. G.; Belicchi, M. F.
J. Org. Chem. 1988, 53, 1779–1785. (c) Casiraghi, G.; Cornia, M.; Rassu, G.
J. Org. Chem. 1988, 53, 4919–4922. (d) Bigi, F; Casnati, G.; Sartorti, G.;
Araldi, G.; Bocelli, G. Tetrahedron Lett. 1989, 30, 1121–1124. (e) Wipf, P.;
Hopkins, C. R. J. Org. Chem. 2001, 66, 3133–3139. (f) Giles, R. G. F.; Joll,
C. A.; Sargent, M. V.; Tilbrook, D. M. G. J. Chem. Soc., Perkin Trans. 1
1999, 3029–3038. (g) Giles, R. G. F.; Joll, C. J. Chem. Soc., Perkin Trans. 1
1999, 3039–3043. (h) Chandrasekhar, S.; Reddy, M. V. Tetrahedron 2000, 56,
1111–1114.
(20) Poulsen, T. B.; Jørgensen, K. A. Chem. Rev. 2008, 108, 2903–2915.
Zhao, J.; Liu, L.; Gu, C.; Wang, D.; Chen, Y. Tetrahedron Lett. 2008, 49,
1476–1479. Majer, J.; Kwiatkowski, P.; Jurczak, J. Org. Lett. 2008, 10, 2955–
2958. Kwiatkowski, P.; Majer, J.; Chaladaj, W.; Jurczak, J. Org. Lett. 2006,
8, 5045–5048. Zhao, J.; Liu, L.; Sui, Y.; Liu, L.; Wang, D.; Chen, Y. Org.
Lett. 2006, 8, 6127–6130. Wilson, M. P. A..; Draper, N. D.; Wilson, P. D.
Org. Lett. 2005, 7, 901–904. Gathergood, N.; Zhuang, W.; Jørgensen, K. A.
J. Am. Chem. Soc. 2000, 122, 12517–12522. Zhuang, W.; Gathergood, N.;
Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2001, 66, 1009–1013. Yuan, Y.;
Wang, X.; Li, X.; Ding, K. J. Org. Chem. 2004, 69, 146–149. Ishii, A.;
Soloshonok, V. A.; Mikami, K. J. Org. Chem. 2000, 65, 1597–1599.
(15) Tanis, S. P.; Herrinton, P. M. J. Org. Chem. 1983, 48, 4572–4580.
Tanis, S. P.; Herrinton, P. M. J. Org. Chem. 1985, 50, 3988–3996. Tanis, S. P.;
Chuang, Y.; Head, D. B. J. Org. Chem. 1988, 53, 4929–4938.
(16) (a) Roberts, R. M.; El-Khawaga, A. M.; Sweeney, K. M.; El-Zohry,
M. F. Org. Chem. 1987, 52, 1591–1599. (b) Gutnov, A. V.; Abaev, V. T.;
Butin, A. V.; Dmitriev, A. S. J. Org. Chem. 2001, 66, 8685–8686. (c) Riad, A.;
Mouloungui, Z.; Delmas, M.; Gaset, A. Synth. Commun. 1989, 19, 3169–
3173. (d) Li, T.; Cheng, S.; Lee, J.; Jang, L. J. Mol. Catal. A: Chem. 2003, 198,
139–149. (e) Nair, V.; Abhilash, K. G.; Vidya, N. Org. Lett. 2005, 7, 5857–
5859.
(17) Seki, M.; Sakamoto, T.; Suemune, H.; Kanematsu, K. J. Chem. Soc.,
Perkin Trans. 1 1997, 1707–1714.
(18) Shanmugham, M. S.; White, J. D. J. Chem. Soc., Chem. Commun.
2004, 44–45.
6822 J. Org. Chem. Vol. 75, No. 20, 2010

Miles et al.
JOCArticle
TABLE 1. Intramolecular Friedel-Crafts Hydroxyalkylation of 17
entry
catalyst
M/ligand; mol % M
solvent
T (°C)
time (h)
% yield; % ee
1
2
3
4
5
6
7
8
9
Ti(O-i-Pr)4/(R)-BINOL
Ti(O-i-Pr)4/(R)-BINOL
Ti(O-i-Pr)4/(R)-BINOL
Ti(O-i-Pr)4/(R)-6,60-Br2-BINOL
Ti(O-i-Pr)4/(S)-6,60-Br2-BINOL
Ti(O-i-Pr)4/(R)-6,60-Br2-BINOL
Ti(O-i-Pr)4/(R)-6,60-Br2-BINOL
AgOTf/(R)-BINAP
Cu(OTf)2/(R)-BINAP
Cu(OTf)2/t-BuBOX
Sc(OTf)3/pyBOX
Cu(OTf)2/pyBOX
1:2; 5
Et2O
Et2O
CH2Cl2
CH2Cl2
toluene
Et2O
Et2O
THF
THF
Et2O
0 f 22
0 f 22
0
0 f 22
0 f 22
22
0 f 22
22
22
22
22
1
20
0.5
1
1
22
1
1
0.75
1
1
1
50; 40
69; 53
87; 40
60; 39
53; 48
55; 48
49; 61
85; 0
56; 0
85; 0
0; 0
26; 0
1:2; 10
1:2; 20
1:2; 5
1:2; 10
1:2; 5
1:2; 10
1:1; 10
1:1; 10
1:1; 3
1:1; 10
1:1; 2
10
11
12
CH2Cl2
CH2Cl2
22
Since we obtained alcohol 13 in only moderate enantios-
electivity with the preceding asymmetric hydroxyalkylation
reaction, we used an alternative method for the preparation
of nonracemic 13. One of the most attractive methods for the
synthesis of nonracemic benzylic alcohols is by the asym-
metric reduction of aromatic ketones.21 Of all the methods
currently available, Noyori’s ruthenium(II) asymmetric
transfer hydrogenation21a was the most appealing because of
its simplicity and remarkably high enantioselectivity. The
requisite ketone 14 has been previously prepared in one step
by the condensation of 1,2-cyclohexadione and chloroacet-
aldehyde,17 but in our hands the reaction proceeded in
relatively low yields to give ketone 14 of questionable purity
(Scheme 4). High-purity 14 was obtained in three steps from
ester 8 with some minor modifications of Walsh’s synthesis12
of 14 and remained the preferred method for the preparation
despite the greater number of steps. Subjecting 14 to the
standard Noyori reduction conditions gave alcohol 13 in
91% yield and 96% ee. The assignment of the stereochem-
istry of the stereogenic center as S was accomplished by the
synthesis of the methoxytrifluoromethylphenyl (MPTA)
SCHEME 5. Synthesis of Furans 5a and 5b
1
ester of 13 and analysis by H NMR.22 The enantiofacial
selectivity found in the reduction of ketone 13 is consistent
with previous studies employing this catalyst system.21a
Alcohol 13 was converted into the corresponding TBS
ether 5c in 81% yield using standard conditions (the con-
version of rac-13 into rac-14 was reported to proceed in
96% yield17).
triflate of 4-(3-furyl)butan-1-ol did not give cyclized product
under these reaction conditions.24
In order to incorporate the desired C-1 (vitamin D3
numbering system) oxygenated stereogenic center in furan
5a, we envisioned two possible solutions: selective reduction
of the appropriate ketone (available from the Friedel-Crafts
acylation reaction) or selective cyclization of aldehyde 16,
relying on the possible directing effects of the existing C-3
stereogenic center and/or relying on asymmetric catalysis.
The Swern oxidation of 12 gave unstable aldehyde 16 in
nearly quantitative yield (Scheme 5). Since the silyloxyalk-
ylation reaction of 16 to give 5a offered the most direct
solution to the problem, we investigated many different
conditions for this reaction. Although we obtained accepta-
ble yields (65-70%) of 5a under the conditions we developed
for the cyclization of 7 to rac-5c, the diastereoselective ratio
was only 3:1 (5a:cis-5a). As an alternative route to 5a, we
investigated the hydroxyalkylation of 16 under a variety of
We envisioned the synthesis of furans 5a and 5b from a
common intermediate, alcohol 12. For the synthesis of furan
5b, the cyclization of the primary alcohol posed serious
problems under standard conditions due to the sensitivity
of the furan to standard cyclization conditions and the
potential for carbocation rearrangements. A report by Trost
and Toste23 suggested a solution to this problem, in which
they found that the conversion of a very electron-rich aro-
matic alcohol into the corresponding triflate rapidly gave
cyclized product under slightly basic conditions. We used
conditions similar to those reported and initially obtained
triflate 15, which cyclized at room temperature to furan 5b in
84% yield (Scheme 5). This cyclization reaction may be
limited to very electron-rich aromatic compounds with a
favorable conformational bias, since the cyclization of the
(24) The Au(III)-catalyzed Friedel-Crafts reactions of triflates or mesy-
lates with electron-rich aromatic compounds may offer a more general
solution to Friedel-Crafts cyclization reactions. See: Shi, Z; He, C. J. Am.
Chem. Soc. 2004, 126, 13596–13597. In our hands, however, the cyclization
of the triflate or mesylate of 4-(3-furyl)butan-1-ol under these conditions did
not give the desired bicyclic furan.
(21) (a) Fujii, A.; Hashiguchi, S.; Uematsu, N; Ikariya, T.; Noyori, R.
J. Am. Chem. Soc. 1996, 118, 2521–2522. (b) Brown, H. C.; Park, W. S.; Cho,
B. T.; Ramachandran, P. V. J. Org. Chem. 1987, 52, 5406–5412.
(22) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512–519.
(23) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1998, 120, 9074–9075.
J. Org. Chem. Vol. 75, No. 20, 2010 6823

Miles et al.
JOCArticle
TABLE 2. Intramolecular Friedel-Crafts Hydroxyalkylation of 16a
entry
catalyst
Ti(O-i-Pr)4/BINOL; mol % Ti(O-i-Pr)4
solvent
T (°C)
time (h)
% yield (ratio of 17/cis-17)
1
2b
3
4
5
6
7
8
9
10
Ti(O-i-Pr)4/(R)-BINOL
Ti(O-i-Pr)4/(R)-BINOL
Ti(O-i-Pr)4/(S)-BINOL
Ti(O-i-Pr)4/rac-BINOL
Ti(O-i-Pr)4/(R)-BINOL
Ti(O-i-Pr)4/(S)-BINOL
Ti(O-i-Pr)4/(R)-BINOL
Ti(O-i-Pr)4/(R)-BINOL
Ti(O-i-Pr)4/(R)-BINOL
Ti(O-i-Pr)4/(R)-BINOL
1:2; 10
1:2; 10
1:2; 10
1:2; 10
1:2; 10
1:2; 10
1:2; 10
1:1; 10
1:2; 20
1:2; 20
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
22
22
22
22
22
22
22
22
3
3
0.75
1
1
20
4
22
1.3
3.5
77 (16:1)
52 (26:1)
73 (8:1)
67 (14:1)
62 (5:1)
61 (5:1)
Et2O
CH3C6H5
CH2Cl2
CH2Cl2
Et2O
41 (6:1)
73 (28:1)
66 (38:1)
67 (4.5:1)
0f22
0f22
aMolecular sieves were dried at 160-180 °C under vacuum (0.05 mm) except for entry 2. bMolecular sieves were dried in an oven at 110 °C at
atmospheric pressure.
conditions (Table 2). Many catalysts we investigated (e.g.,
ZnCl2, SnCl4, Cu(OTf)2, Sc(OTf)3, Yb(OTf)3, AgOTf/(R)-
BINAP, Ti(O-i-Pr)4/(R)-6,60-Br2-BINOL; not included in
Table 2) gave poor yields of 5a, but we were successful in
using the Ti(O-i-Pr)4/BINOL catalyst system. One impor-
tant variable that distinguished this reaction from our pre-
FIGURE 2. Transition state for Friedel-Crafts cyclization of 16
and conformation of alcohol 17.
vious work with this catalyst system in the asymmetric
carbonyl-ene reaction was the need to scrupulously dry the
molecular sieves for maximum chemical yields. The ideal
level of hydration for the molecular sieves for the asymmetric
hydroxyalkylation reaction of 16 was achieved by heating
them to 160-180 °C under vacuum (0.05 mm) for 16 h
(entries 1 and 2), in contrast to the asymmetric carbonyl-ene
reaction of 6 with aldehydes, in which the optimal level of
hydration for the molecular sieves was achieved by storing
the molecular sieves in an oven at 110 °C. The preferred
solvent was CH2Cl2 (entries 1-4, 8, and 9), with Et2O giving
good yields but lower diastereoselectivity (entries 5, 6, and
10) and toluene (entry 7) giving poor yields and moderate
selectivity. Surprisingly, the diastereoselectivity was only
weakly dependent on the chirality of the BINOL ligand,
since we observed only incremental diminishment of diaster-
eoselectivity using either (S)-BINOL (entry 3) or rac-BINOL
(entry 4). The ratio of Ti(O-i-Pr)4/(R)-BINOL does not appear
to be a major factor in the diastereoselectivity, although the
reaction proceeds much faster with a 1:2 ratio of Ti(O-i-
Pr)4/(R)-BINOL (entries 1 and 8). On a preparative scale,
alcohol 17 (isolated as a 14:1 mixture of 17:cis-17) was
synthesized in 68% yield. There was some epimerization
and/or decomposition of alcohol 17 during the workup
procedure, especially on the preparative scale, as evidenced
by the higher diastereoselectivity observed in the rapid
workup of small aliquots of larger scale reactions. Alcohol
17 was then converted into 5a in 84% yield under standard
reaction conditions, with the unwanted cis-5a cleanly sepa-
rated from 5a by flash chromatography.
for the two possible alcohol products 17 and cis-17 was based
on the coupling constants of the benzylic protons (Figure 2).
The preferred conformation for 17 appears to be one in
which the C-7 alcohol occupies a pseudoaxial position, while
the C-5 OTBS group is pseudoequatorial.25
Synthesis of Z-Dienol 4c. The usefulness of furans in the
synthesis of oxygenated natural products has been exten-
sively demonstrated in many elegant applications.26 The
literature suggested that the oxidation of a bicyclic 2,3-
disubstituted furan with peracids would give unsaturated
1,4-dicarbonyl compounds.27 For example, the perbenzoic
acid oxidation of 4,5,6,7-tetrahydrobenzo[2,1-b]furan gave
the unsaturated ketoaldehyde.27 Our initial studies were
consistent with the literature; when we oxidized furan 5c
with MCPBA, we obtained 18 (approximately 50% yield)
along with several other products. In an attempt to improve
the yield, the reaction mixture was buffered with NaOAc or
NaHCO3 (Scheme 6). There was a dramatic change in the
product profile, in which one of the minor products (19c)
became the sole product. A 2 equiv amount of m-CPBA were
necessary for complete conversion of furan 5c; if only one
equiv of buffered m-CPBA was used, we observed 50% con-
version of 5c to 19c and no evidence for any other product.
The oxidation of furans to γ-hydroxybutenolides is usually
achieved by singlet oxygen addition to silylfurans, although
there is some precedent for peracid oxidation of 3-substituted28a,b
and 2,3-disubstituted furans28c,d to γ-hydroxybutenolides. Since
the separation of 19c from 3-chlorobenzoic acid was problematic,
Our working model for the observed diastereoselectivity in
the intramolecular cyclization of 16 is given in Figure 2. We
assume the OTBS group occupies a pseudoequatorial posi-
tion in a chairlike transition state. The orientation of the
aldehyde must then be such that the hydrogen is pseudoe-
quatorial and the aldehyde is stacking with the furan ring.
The diminished diastereoselectivity observed in some cases
(e.g., 16 f 5a) may be due to competing steric factors that
disfavor the transition state given in Figure 2. There are very
few examples of intramolecular Friedel-Crafts hydroxyalk-
ylation reactions in the literature with this level of stereochem-
ical control.19e The definitive assignment of the stereochemistry
(25) Although the intramolecular Friedel-Crafts reaction of 16 is
mechanistically distinct from the intramolecular carbonyl-ene reaction of
substrates used in the synthesis of the A-ring of calcitriol, there are some
interesting similarities in the transition state. See: Kabat, M. M.; Lange, M.;
ꢀ
Wovkulich, P. M.; Uskokovic, M. R. Tetrahedron Lett. 1992, 33, 7701–7704.
Mikami, K.; Osawa, A.; Isaka, A.; Sawa, E.; Shimizu, M.; Terada, M.;
Kubodera, N.; Nakagawa, K.; Tsugawa, N.; Okano, T. Tetrahedron Lett.
1998, 39, 3359–3362.
(26) Devarie-Baez, N. O.; Kim, W.; Smith, A. B., III; Xian, M. Org. Lett.
2009, 11, 1861–1864. Merino, P.; Tejero, T.; Delso, J. I.; Matute, R. Curr.
Org. Chem. 2007, 11, 1076–1091. Lipshutz, B. H. Chem. Rev. 1986, 86, 795–
819. Martin, S. F.; Lee, W.; Pacofsky, G. J.; Gist, R. P.; Mulhern, T. A.
J. Am. Chem. Soc. 1994, 116, 4674–4674. Martin, S. F.; Zinke, P. W. J. Org.
Chem. 1991, 56, 6600–6606.
(27) Manfredi, K. P.; Jennings, P. W. J. Org. Chem. 1989, 54, 5186–5188.
6824 J. Org. Chem. Vol. 75, No. 20, 2010

Miles et al.
JOCArticle
SCHEME 6. Synthesis of 4c
SCHEME 7. Synthesis of 4b
the optimal procedure employed peracetic acid with NaOAc
acting as a buffer (87% yield). We observed one major
diastereomer for 19c, in which we have assigned the stereo-
chemistry based on the equatorial disposition of the OTBS
group at C-1 (deduced from the coupling constants) and the
geometric constraints of the bicyclic γ-hydroxybutenolide, in
which the OH group occupies a pseudoaxial position.
With γ-hydroxybutenolide 19c in hand, a method was
needed to convert the ketone (of the open-chain form) into a
terminal alkene. Many of the standard synthetic methods,
such as the Wittig reaction or Tebbe procedure, failed to give
synthetically useful yields of methylenation product. Con-
verting γ-hydroxybutenolide 19c into the corresponding
ethyl ester and subjecting it to methylenation conditions
(Wittig or Tebbe) also failed. We then turned to the Peterson
olefination reaction,29 employing the modifications devel-
oped by Johnson.30 The reaction of excess LiCH2Si(CH3)3/
CeCl3 (at least 2 equiv is necessary since 1 equiv is consumed
in an acid-base reaction with 19c) with 19c gave 20c after
hydrolysis, which lactonized upon acidic workup to give
lactone 21c in 76% yield (Scheme 6). The reaction was very
diastereoselective, with only one diastereomer observed in
the crude product. The assignment of the stereochemistry of
21c was based on NOESY experiments and the coupling
constants. Although excess DIBAL readily reduces lactones
to diols in many cases, we were unable to obtain synthetically
useful yields of 22c by the reaction of excess DIBAL with 21c.
The reduction of 21c with LiAlH4 gave significant cleavage
of the TBS ether, a side reaction noted in the literature for R-
silyloxycarbonyl compounds.31 The reduction of lactone 21c
to diol 22c was optimized in a two-step procedure: DIBAL
reduced lactone 21c to the lactol, which then was reduced to
diol 22c with NaBH4 (89% yield). The elimination of tri-
methylsilanol from 22c to give the desired (Z)-dienol 4c32
(68% yield) was best done with aqueous HF in CH3CN.
Attempted Synthesis of Z-Dienol 4b. The conversion of
furan 5b into (Z)-dienol 4b proceeded in a fashion similar to
the aforementioned synthesis of 5c. The peracetic acid oxi-
dation of 5b gave γ-hydroxybutenolide 19b as a 2:1 mixture
of diastereomers in 86% yield (Scheme 7). The reaction of
excess LiCH2Si(CH3)3/CeCl3 and 19b gave 21b in 98% yield,
again as a 2:1 mixture of diastereomers. The lack of diaster-
eoselectivity is not surprising given the 1,4-relationship of the
chiral center to the reacting ketone. Unlike the reduction of
(28) (a) Ferland, J. M.; Lefebvre, Y.; Deghenghi, R. Tetrahedron Lett.
1966, 3617–3620. (b) Wiesner, K.; Tsai, T. Y. R.; Jin, H. Helv. Chim. Acta
(31) deVries, E. F. J.; Brussee, J.; van der Gen, A. J. Org. Chem. 1994, 59,
7133–7137.
ꢀ
1985, 68, 300–314. (c) Gonzalez, A. G.; Darias, J.; Martın Tetrahedron Lett.
(32) For previous syntheses of 4c and rac-4c, see: Uskokovic, M. R.;
Baggiolini, E.; Shiuey, S.; Iacobelli, J.; Hennessy, B. In Vitamin D: Gene
Regulation, Structure Function Analysis and Clinical Application; Norman,
A. W., Bouillon, R., Thomasset, M., Eds.; Walter de Gruyter and Co.: Berlin,
1973, 3625–3626. (d) Takikawa, H.; Ueda, K.; Sasaki, M. Tetrahedron Lett.
2004, 45, 5569–5571.
(29) Ager, D. J. Org. React. 1990, 38, 1–224. van Staden, L. F.;
Gravestock, D.; Ager, D. J. Chem. Soc. Rev. 2002, 31, 195–200.
(30) Johnson, C. R.; Tait, B. D. J. Org. Chem. 1987, 52, 281–283.
~
1991; p 139. Mascarenas, J. L.; Garcıa, A. M.; Castedo, L.; Mourino, A.
Tetrahedron Lett. 1992, 33, 4365–4368.
~
J. Org. Chem. Vol. 75, No. 20, 2010 6825

Miles et al.
JOCArticle
SCHEME 8. Synthesis of 4a
protocol was worth pursuing in the context of synthesizing
(Z)-dienol 4a. The reaction of LiCH2Si(CH3)3/CeCl3 and
γ-hydroxybutenolide 19a gave lactone 21a (90% yield) as a
single diastereomer. Lactonization of the intermediate car-
boxylic acid/alcohol was slower than the lactonization of 21c
and incomplete with the standard workup procedure, so a
catalytic amount of TsOH was added, which gently lacto-
nized the intermediate, before doing the column. The stere-
ochemistry shown for 21a was consistent with the coupling
constants and NOE measurements, which established the cis
relationship between the (trimethylsilyl)methyl group and
the C-7 hydrogen on the ring. The reduction of lactone 21a to
22a (90% crude yield) was accomplished in a manner similar
to the two-step procedure for the reduction of 21c, although
the reduction of the intermediate lactol was slower and required
a greater amount of NaBH4. As in the case of diol 22b, crude
diol 22a was used without purification and subjected to
conditions that minimized the cleavage of the TBS ether.
The conversion of 21a to (Z)-dienol 4a was accomplished in
67% overall yield in three steps.
21c and the subsequent elimination to give 4c, the reduction
of 21b was complicated by the instability of the resulting diol
22b under the many different reaction conditions. Since there
was no neighboring TBS ether group, the reduction of 21b
could be carried out with LiAlH4, but diol product (22b)
could not be purified without significant loss of material.
Since purification of the reduction product was not possible,
crude 22b was used directly in subsequent elimination reac-
tion (aqueous HF in CH3CN), but subjecting 22b to the
conditions we used for 22c led to a significant amount of
cleavage of the TBS ether, as evidenced by the lack of a TBS
group in the crude product. By reducing the quantity of HF,
running under more dilute conditions, and carefully mon-
itoring the reaction by TLC, we were able to keep the cleav-
age of the TBS ether to a minimum, although there were
other undefined side reactions leading to diminished yield.
Our optimal conditions gave (Z)-dienol 4b33 from 21b in two
steps in 5% yield. Even this unacceptable procedure was
capricious, as we were unable to replicate the yields in later
studies. Since we were unable to isolate pure side compounds
and identify them, we do not have an explanation for the
difference between 22b and 22c but note that in the prepara-
tion of 2-hydroxysilanes side reactions can lead to complex
mixtures under certain conditions.30 As in the case of
γ-hydroxybutenolide 19c, we found alternative olefination
procedures (Tebbe reagent, Lombardo’s reagent, etc.) with
either 19b or its corresponding methyl ester gave complex
mixtures and very low yields of the desired product.
Synthesis of Z-Dienol 4a. In contrast to the difficulties we
encountered in the synthesis of 4b, the synthesis of 4a pro-
ceeded in a manner similar to our approach for the synthesis
of 4c. The peracetic acid oxidation of furan 5a, however, was
significantly slower than the peracetic acid oxidation of
either 5b or 5c. Fortunately, the m-CPBA oxidation was
fast, and γ-hydroxybutenolide 19a (81% yield) was easily
separated from 3-chlorobenzoic acid, the side product of the
oxidation reaction (Scheme 8). γ-Hydroxybutenolide 19a
has been previously prepared by an alternate route using
(S)-5-(tert-butyldimethylsiloxy)-2-cyclohexenone as the starting
material.5b In this paper, 19a was converted into (Z)-dienol
4a in three steps, with the critical methylenation reaction
achieved by the use of the Tebbe reagent with the corre-
sponding ethyl ester of 19a, but the reported yield (48%) was
modest. Since we had not been successful in using the Tebbe
reagent, which is expensive and difficult to handle, with 19b,
19c or their corresponding esters, we felt that the Peterson
Conclusion
We have demonstrated the viability of the furan approach
to the (Z)-dienol moiety of the A-ring of vitamin D3 analo-
gues. The A-ring (Z)-dienol of calcitriol (4a), an important
intermediate in the synthesis of calcitriol and numerous
analogues, was synthesized in 12 steps from 3-(tert-butyldi-
methylsiloxy)propanal in 17% overall yield. The key step in
the conversion of 5a into 4a, the methylenation of the pre-
requisite γ-hydroxybutenolide by the Peterson olefination,
will not always be the answer (cf. 5b to 4b), although in our
hands, the Peterson olefination is an excellent alternative to
the reaction of the ester of the γ-hydroxybutenolide with the
Tebbe reagent.5b We are continuing to explore different meth-
ylenation methodologies in the hopes of developing a more
general protocol for the methylenation of γ-hydroxybuteno-
lides and new alkenylation methodologies for the synthesis
of C-19 analogues of vitamin D3.34 Further, the synthesis of
2,3-annulated furans with different substitution patterns
may allow for the synthesis of A-ring derivatives, which con-
tinue to be of interest in the vitamin D field.35 The reactions
of γ-hydroxybutenolides are a rich but underdeveloped field;
the diastereoselective addition of the LiCH2Si(CH3)3/CeCl3
to 5a and 5c is a glimpse into possible stereoselective syn-
thetic approaches to lactones.36
The genesis of this project was our interest in using the
highly reactive alicyclic isomer 6 as an ene partner in the ene
reaction. Although alicyclic isomer 6 is representative of only
a small class of compounds, the potential of alicyclic isomers
of aromatic compounds for synthesis has been realized in
several studies.9a-c,37 The asymmetric carbonyl-ene reaction
(34) Wojtkielewicz, A.; Morzycki, J. M. Org. Lett. 2006, 8, 839–842.
Ahmed, M.; Atkinson, C. E.; Barrett, A. G. M.; Malagu, K.; Procopiou,
P. A. Org. Lett. 2003, 5, 669–672.
€
(35) Antony, P.; Sigueiro, R.; Huet, T.; Sato, Y.; Ramalanjaona, N.;
~
Rodrigues, L. C.; Mourino, A.; Moras, D.; Rochel, N. J. Med. Chem. 2010,
53, 1159–1171. Jeon, H. B.; Posner, G. H. Tetrahedron 2009, 50, 1235–1240.
(36) For other studies involving diastereoselective addition of nucleo-
philes to γ-hydroxybutenolides, see: Miles, W. H.; Duca, D. G.; Freedman,
J. T.; Goodzeit, E. O.; Hamman, K. B.; Selfridge, B.; Pahla De Sousa, C. A.
ꢀ
Heterocycl. Commun. 2007, 13, 195–198. Teijeira, M.; Suarez, P. L.; Gomez,
G.; Teran, C.; Fall, Y. Tetrahedron Lett. 2005, 46, 5889–5892. Tsai, T. Y. R.;
ꢀ
ꢀ
(33) Blakemore, P. R.; Kocienski, P. J.; Marzcak, S.; Wicha, J. Synthesis
1999, 1209–1215.
Wiesner, K. Heterocycles 1984, 22, 1683–1686. See also: Nagao, Y.; Dai, W.;
Ochiai, M.; Shiro, M. J. Org. Chem. 1989, 54, 5211–5217.
6826 J. Org. Chem. Vol. 75, No. 20, 2010

Miles et al.
JOCArticle
of 6 with electron-rich aldehydes nicely compliments the
extensive literature for the asymmetric carbonyl-ene reaction
of electron-rich enes with electron-poor enophiles, such as
ethyl glyoxylate.13a In addition, the intramolecular Friedel-
Crafts alkylation (12 f 5b), silyloxyalkylation (7 f rac-5c
and 16 f 5a), and hydroxyalkylation (16 f 17) of 3-sub-
stituted furans offers new approaches to 2,3-disubstitued
furans. The ability to efficiently and stereoselectively synthe-
size 2,3-disubstituted furans will not only provide new inter-
mediates for the synthesis of analogues of vitamin D3 but
also potential starting materials for the synthesis of diverse
natural products.
6.28 (br s, 1H), 3.97 (app pentet, J = 5.8 Hz, 1H), 3.65 (m, 2H),
2.59 (dd, J = 6.2, 14.3 Hz, 1H), 2.54 (dd, J = 5.5, 14.3 Hz, 1H),
1.62 (m, 2H), 0.87 (s, 18H), 0.03 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H),
-0.03 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 142.5, 140.2,
121.4, 112.1, 69.4, 59.9, 39.7, 33.1, 26.05, 26.01, 18.4, 18.2, -4.5,
-4.7, -5.3 (2C). Anal. Calcd for C20H40O3Si2: C, 62.44; H,
10.48. Found: C, 62.39; H, 10.54.
(3R)-3-(tert-Butyldimethylsiloxy)-4-(3-furyl)butan-1-ol (12).
Furan 11 (17.99 g, 46.8 mmol) was added to THF/H2O/AcOH
(300 mL, 50:15:35) and stirred for 16 h at ambient temperature.
Na2CO3 (120 g) in water (400 mL) was added carefully to
quench the reaction. The reaction mixture was transferred to a
separatory funnel with EtOAc (250 mL), and the organic phase
was separated. The aqueous phase was extracted with EtOAc
(2 ꢀ 250 mL), the combined organic phases were washed with
brine (100 mL) and dried over Na2SO4, and the volatiles were
removed on the rotary evaporator. The crude product was
purified by flash chromatography (150 g of silica gel; hexanes
f15% ethyl acetate in hexanes) to give starting material 11 (3.48
g, 19% yield) and 12 (8.27 g, 65% yield; 81% yield based on
Experimental Section
(2R)-4-(tert-Butyldimethylsiloxy)-1-(3-furyl)butan-2-ol (10). (R)-
1,10-Bi-2-naphthol (4.56 g, 15.9 mmol) and Ti(OCH(CH3)2)4
(2.35 mL, 2.26 g, 7.96 mmol) were added to 4 A molecular
sieves (5.0 g) in dry ether (100 mL). The reaction mixture was
heated to reflux for 1 h, the heating mantel was replaced with a
cold (20 °C) water bath, and 3-(tert-butyldimethylsiloxy)-
propanal (9) (16.6 g, 88.1 mmol) was added. 3-Methylene-2,3-
dihydrofuran (6)9c (14.4 g of a 3.5:1 mixture of 6:3-methylfuran,
approximately 136 mmol) then was added immediately over
8 min, with a mild exothermic reaction evident. After the mix-
ture was stirred for an additional 15 min, saturated NaHCO3
(12 mL) was added, and the reaction mixture was stirred for 1 h.
The reaction mixture was filtered through a Celite bed, washed
with 10% NaOH/brine (150 mL), and filtered through silica gel,
washing with additional ether. The volatiles were removed on a
rotary evaporator, and the crude product was purified by
vacuum distillation (0.5 mm, 110-122 °C) to give 10 (18.68 g,
78% yield, >95% ee) as an oil: [R]22D þ12.3 (c 2.0, CH2Cl2); IR
(neat) 3446 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.35 (br s, 1H),
7.28 (br s, 1H), 6.31 (br s, 1H), 3.98 (m, 1H), 3.88 (m, 1H), 3.79
(m, 1H), 3.37 (d, J = 2.2 Hz, 1H), 2.62 (dd, J = 6.8, 14.5 Hz,
1H), 2.55 (dd, J = 5.9, 14.3 Hz, 1H), 1.66 (m, 2H), 0.89 (s, 9H),
0.06 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 143.0, 140.1, 121.5,
111.6, 72.0, 62.7, 37.8, 31.1, 26.0, 18.3, -5.40, -5.43. Anal.
Calcd for C14H26O3Si: C, 62.18; H, 9.69. Found: C, 62.40; H,
9.96. The enantiomeric excess was determined by the use of the
chiral shift reagent europium tris[3-heptafluoropropylhydro-
xymethylene)-(þ)-camphorate]. The C-2 furanyl proton reso-
nates at δ 8.34 for (S)-10 and δ 8.25 for 10 as a broad singlet
(0.1 M of 10 with 30 mol % Eu(hfc)3 in CDCl3).
(3R)-Bis-1,3-(tert-butyldimethylsiloxy)-4-(3-furyl)butane (11).
To a solution of alcohol 10 (18.33 g, 67.8 mmol) and 2,6-lutidine
(12.0 mL, 11.0 g, 103 mmol) in methylene chloride (350 mL) was
added TBSOTf (18.0 mL, 20.7 g, 78.4 mmol) over 8 min at 0 °C.
After the reaction mixture was stirred for 25 min at 0 °C,
methanol (1.0 mL) was added to quench the reaction. After
being stirred for an additional 5 min, the reaction mixture was
transferred to a separatory funnel with CH2Cl2 (200 mL). The
organic phase was washed with 0.25 M HCl (200 mL) and brine
(200 mL) and dried over Na2SO4, and the volatiles were re-
moved on the rotary evaporator. The crude product was dis-
solved in 10% EtOAc in hexanes (300 mL) and filtered through a
plug of silica gel. After removal of the volatiles on the rotary
evaporator, the crude product was distilled under vacuum
(0.3 mm, 125-135 °C) to give 11 (25.09 g, 96% yield) as an
oil: [R]22D -15.9 (c 2.0, CH2Cl2); IR (neat) 1502 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.33 (t, J = 1.6 Hz, 1H), 7.22 (br s, 1H),
recovered starting material) as a clear oil: [R]22 -19.5 (c 0.9,
D
1
CH2Cl2); IR (neat) 3366 cm-1; H NMR (400 MHz, CDCl3)
δ 7.34 (br s, 1H), 7.23 (br s, 1H), 6.26 (br s, 1H), 4.06 (ddd, J =
4.1, 6.5, 12.7 Hz, 1H), 3.81 (m, 1H), 3.70 (app pentet, J = 5.4 Hz,
1H), 2.63 (m, 1H), 2.32 (br s, 1H), 1.78 (m, 1H), 1.62 (m, 1H),
0.89 (s, 9H), 0.08 (s, 3H), 0.02 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 142.8, 140.2, 121.0, 111.7, 71.8, 60.2, 37.7, 32.7, 26.0,
25.8, 18.1, -4.5, -4.8. Anal. Calcd for C14H26O3Si: C, 62.18; H,
9.69. Found: C, 62.10; H, 9.83.
(5S)-5-(tert-Butyldimethylsiloxy)-4,5,6,7-tetrahydrobenzo-
[2,1-b]furan (5b). To a solution of alcohol 12 (5.11 g, 18.9 mmol)
and 2,6-lutidine (5.50 mL, 5.06 g, 47.2 mmol) in CH2Cl2 (300
mL) was added triflic anhydride (3.40 mL, 5.70 g, 20.2 mmol)
dropwise while the reaction mixture was cooled in a cold water
bath. The reaction mixture was stirred for 20 h at 22 °C. The
reaction mixture was transferred to a separatory funnel, washed
with 0.25 M HCl (100 mL), water (100 mL), 5% Na2CO3 (100
mL), and brine (100 mL), and dried over Na2SO4. After removal
of the volatiles on the rotary evaporator, the crude product was
purified by flash chromatography (100 g of silica gel; hexanes) to
give 5b (4.36 g) as a yellow oil. Further purification by bulb-to-
bulb distillation (125-135 °C, 0.5 mm) gave 5b (4.00 g, 84%
yield) as a colorless oil: [R]22D -34.6 (c 1.0, CH2Cl2); IR (neat)
1504 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.23 (br s, 1H), 6.15
(d, J = 1.8 Hz, 1H), 4.05 (m, 1H), 2.56-2.76 (m, 3H), 2.41 (m,
1H), 1.81-1.99 (m 2H), 0.89 (s, 9H), 0.082 (s, 3H), 0.076 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 149.7, 141.0, 114.9, 110.7, 68.6,
32.1, 32.0, 26.0, 25.8, 21.3, 18.3, -4.5, -4.6. Anal. Calcd for
C14H24O2Si: C, 66.61; H, 9.58. Found: C, 66.42; H, 9.61.
(3R)-3-(tert-Butyldimethylsiloxy)-4-(3-furyl)butanal (16). DMSO
(6.8 mL, 7.5 g, 96 mmol) in CH2Cl2 (12 mL) was added to oxalyl
chloride (4.2 mL, 6.1 g, 48 mmol) in CH2Cl2 (100 mL) over 5 min at
-65 °C. After the mixture was stirred at -65 °C for 8 min, alcohol
12 (8.240 g, 30.5 mmol) in CH2Cl2 (20 mL) was added to the
reaction mixture over 10 min. After the mixture was stirred for an
additional 10 min, NEt3 (16.5 mL, 12.0 g, 120 mmol) was added over
1 min. After the reaction mixture was allowed to warm to ambient
temperature, it was transferred to a separatory funnel with water
(200 mL) and additional CH2Cl2 (100 mL). The organic phase was
separated and the aqueous phase extracted with CH2Cl2 (100 mL).
The combined organic phases were washed with brine (100 mL) and
dried over Na2SO4, and the volatiles were removed on the rotary
evaporator. The crude product was redissolved in petroleum ether
(250 mL), washed with water, and dried over Na2SO4, and the
volatiles were removed on the rotary evaporator to give the crude 16
(8.122 g, 99% yield) as an oil that was used without further
purification: IR (CH2Cl2) 2726, 1726 cm-1; 1H NMR (400 MHz,
CDCl3) δ 9.75 (t, J = 2.2 Hz, 1H), 7.35 (t, J = 1.6 Hz, 1H), 7.24
(37) For recent examples, see: Camp, J. E.; Craig, D. Tetrahedron Lett.
2009, 50, 3503–3508. Miles, W. H.; Dethoff, E. A.; Tuson, H. H.; Ulas, G.
J. Org. Chem. 2005, 70, 2862–2865. Tidwell, J. H.; Senn, D. R.; Buchwald,
S. L. J. Am. Chem. Soc. 1991, 113, 4685–4686.
J. Org. Chem. Vol. 75, No. 20, 2010 6827

Miles et al.
JOCArticle
(brs,1H),6.28(brs,1H),4.34(apppentet,J= 5.9 Hz, 1H), 2.65 (m,
2H), 2.51 (m, 2H), 0.87 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 201.9, 143.0, 140.5, 120.4, 111.8, 68.3, 50.3,
33.3, 25.9, 18.1, -4.5, -4.8. Aldehyde 16 is thermally unstable and
unstable on silica gel; we used it immediately or stored it in the
freezer.
1H), 4.81 (m, 1H), 4.34 (m, 1H), 2.73 (dd, J = 5.1, 15.4 Hz, 1H),
2.33 (dd, J = 9.2, 15.4 Hz, 1H), 2.10 (m, 1H), 1.92 (m, 1H), 0.91
(s, 9H), 0.90 (s, 9H), 0.14 (s, 3H), 0.09 (br s, 6H), 0.07 (s, 3H); 13
C
NMR (100 MHz, CDCl3) δ 150.7, 142.5, 117.9, 110.4, 65.8, 62.8,
43.0, 32.4, 26.1, 26.0, 18.42, 18.39, -4.58, -4.60, -4.65, -4.8.
Anal. Calcd for C20H38O3Si2: C, 62.77; H, 10.01. Found: C,
62.82; H, 10.15.
(5R,7S)-5-(tert-Butyldimethylsiloxy)-4,5,6,7-tetrahydro-1-
benzofuran-7-ol (17). Small-Scale Procedure (Entry 1, Table 2).
Molecular sieves (3 A, 0.25 g) were dried under vacuum (0.05 mm)
at 180 °C for 16 h. After they were cooled to room temperature,
CH2Cl2 (3 mL), (R)-BINOL (0.098 g, 0.34 mmol), and Ti(O-i-
Pr)4 (0.050 mL, 0.048 g, 0.169 mmol) were added, and the
mixture was refluxed for 1 h. Aldehyde 16 (0.45 g, 1.68 mmol)
was added in one portion at 22 °C, and the reaction mixture was
stirred for 1 h. Saturated Na2CO3 (1 mL) was added, and the
reaction mixture was stirred for 1 h at ambient temperature. The
reaction mixture was filtered, transferred to a separatory funnel
with CH2Cl2 (100 mL), washed with 0.25 M NaOH (2 ꢀ 30 mL)
and brine (200 mL), and dried over Na2SO4, and the volatiles
were removed on the rotary evaporator. The crude product was
purified by flash chromatography (30 g of silica gel; 5f10%
ethyl acetate in hexanes) to give 17 (0.348 g, 77% yield; 17:cis-17,
16:1) as a clear oil.
(5R,7S)-5,7-Bis(tert-butyldimethylsiloxy)-4,5,6,7-tetrahydro-
1-benzofuran (5a) from 16. Aldehyde 16 (0.220 g, 0.820 mmol)
was dissolved in methylene chloride (3 mL), the solution was
cooled to 0 °C, and 2,6-lutidine (0.25 mL, 0.32 g. 2.1 mmol) was
added. TBSOTf (0.25 mL, 0.29 g, 1.1 mmol) was added drop-
wise. After being stirred for 5 min at 0 °C, the reaction was
allowed to warm to room temperature and quenched with water
(2 mL). The reaction mixture was transferred to a separatory
funnel with water (30 mL) and methylene chloride (30 mL). The
organic phase was separated, washed with 0.5 M HCl (50 mL)
and brine (50 mL), and dried over MgSO4, and the volatiles were
removed on the rotary evaporator. The crude product was
purified by flash chromatography (20 g of silica gel; hexanes)
to give a 3:1 mixture of 5a and cis-5a (0.22 g, 70% yield) as an oil.
(5R,7S)-Bis(tert-butyldimethylsiloxy)-7a-hydroxy-5,6,7,7a-
tetrahydro-1-benzofuran-2(4H)-one (19a)5b. Sodium acetate (1.89 g,
23.0 mmol) and m-CPBA (4.32 g, 77%; 19.3 mmol) were added to
furan 5a (3.041 g, 7.95 mmol) in CH2Cl2 (100 mL) at 22 °C. After
the initial exothermic reaction, the reaction mixture was stirred for
an additional 1.25 h at ambient temperature. The reaction mixture
was washed with water (100 mL), the aqueous phase was extracted
with additional CH2Cl2 (100 mL), and the combined milky organic
phases were filtered through a plug of silica gel, washing the silica
gel with CH2Cl2 (50 mL). After the volatiles were removed on the
rotary evaporator, the crude product was redissolved in hexanes
and ether (100 mL; 3:1), washed with 10% NaHCO3 (2 ꢀ 20 mL),
water (50 mL), 1 M HCl (25 mL), and brine (2 ꢀ 50 mL), and dried
over Na2SO4, and the solvent was removed on the rotary evapora-
tor. The crude product was purified by flash chromatography
(100 g of silica gel; hexanes f 15% ethyl acetate in hexanes) to
(5R,7S)-5-(tert-Butyldimethylsiloxy)-4,5,6,7-tetrahydro-1-ben-
zofuran-7-ol (17). Preparative Procedure. Molecular sieves (3 A,
2.5 g) were dried under vacuum (0.05 mm) at 170 °C for 16 h.
After they were cooled to room temperature, CH2Cl2 (50 mL),
Ti(O(CH(CH3)2)4 (1.00 mL, 0.963 g, 3.39 mmol), and (R)-
BINOL (2.00 g, 6.98 mmol) were added, and the mixture was
refluxed for 1 h. Aldehyde 16 (7.90 g, 29.4 mmol) was added in
one portion, and the reaction mixture was stirred at 0 °C for
0.5 h and then for 4 h at 22 °C. Saturated Na2CO3 (20 mL) was
added, and the reaction mixture was stirred for 1 h at ambient
temperature. The reaction mixture was transferred to a separa-
tory funnel with water (200 mL) and CH2Cl2 (300 mL) and
separated, and the aqueous phase was extracted with additional
CH2Cl2 (2 ꢀ 200 mL). The combined organic extracts were
washed with 0.25 M NaOH (100 mL) and brine (200 mL) and
dried over Na2SO4, and the volatiles were removed on the rotary
evaporator. The crude product was dissolved in EtOAc (100 mL)
and filtered through a plug of silica gel, washing with additional
EtOAc. After removal of the solvent on the rotary evaporator,
the crude product was purified by flash chromatography (100 g
of silica gel; 10% ethyl acetate in hexanes) to give 17 (5.40 g, 68%
yield; 17:cis-17, 14:1) as a clear oil: [R]22D -41.5 (c 1.1, CH2Cl2);
IR (CH2Cl2) 3352 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.32 (d,
J = 1.8 Hz, 1H), 6.18 (d, J = 1.8 Hz, 1H), 4.88 (br t, J = 3.5 Hz,
1H), 4.30 (m, 1H), 2.75 (dd, J = 4.9, 15.6 Hz, 1H), 2.37 (dd, J =
8.6, 15.6 Hz, 1H), 1.9-2.1 (m, 3H), 0.90 (s, 9H), 0.102 (s, 3H),
0.097 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 150.1, 143.1,
118.5, 110.5, 65.6, 62.4, 41.8, 32.3, 26.0, 18.3, -4.5, -4.6. Anal.
Calcd for C141H24O3Si: C, 62.64; H, 9.01. Found: C, 62.88; H,
9.02. Partial H NMR (400 MHz, CDCl3) of cis-17: δ 7.35 (d,
J = 1.5 Hz), 6.21 (d, J = 1.5 Hz), 4.69 (m), 4.43 (m), 0.86 (s).
(5R,7S)-5,7-Bis(tert-butyldimethylsiloxy)-4,5,6,7-tetrahydro-
1-benzofuran (5a). To a solution of alcohol 17 (5.22 g, 19.4
mmol; 17:cis-17, 14:1) in DMF (20 mL) were added imidazole
(2.00 g, 29.4 mmol) and tert-butyldimethylsilyl chloride (3.92 g,
26.0 mmol). After being stirred for 1.5 h at 22 °C, the reaction
mixture was poured into water (150 mL) and extracted with
ether (3 ꢀ 150 mL). The combined organic extracts were washed
with 0.1 M HCl (100 mL) and brine (200 mL) and dried over
Na2SO4, and the volatiles were removed on the rotary evapora-
tor. The crude product (composed of 5a and cis-5a) was purified
by flash chromatography (100 g of silica gel; hexanes f 2%
ethyl acetate in hexanes) to give 5a (6.24 g, 84% yield) as a
give 19a (2.646 g, 81% yield) as a white solid: mp 99-105 °C; [R]22
D
1
-73.6 (c 1.0, CH2Cl2); IR (CH2Cl2) 3498, 1763, 1665 cm-1; H
NMR (400 MHz, CDCl3) δ 5.84 (d, J = 2.2 Hz, 1H), 4.49 (s, 1H),
4.26 (m, 1H), 4.07 (dd, J = 5.1, 11.0 Hz, 1H), 2.66 (dt, J = 2.6, 13.6
Hz, 1H), 2.53 (dt, J = 2.6, 13.6 Hz, 1H), 1.89 (m, 1H), 1.69 (ddd,
J = 2.3, 11.1, 13.5 Hz, 1H), 0.91 (s, 9H), 0.82 (s, 9H), 0.16 (s, 3H),
0.11 (s, 3H), 0.04 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 170.4,
163.7, 119.3, 104.0, 72.5, 66.5, 39.3, 34.4, 25.6, 25.5, 18.2, 18.0, -4.6,
-4.8, -4.93, -4.95.
(5R,7S,7aR)-5,7-Bis(tert-butyldimethylsiloxy)-7a-[(trimethyl-
silyl)methyl]-5,6,7,7a-tetrahydro-1-benzofuran-2(4H)-one (21a).
CeCl3 7H2O (1.98 g, 5.31 mmol) was dried under vacuum (0.1
3
mm) at 140 °C for 2 h. THF (15 mL) was added, and the slurry
was stirred for 1 h at room temperature. After the mixture was
cooled to -78 °C, LiCH2Si(CH3)3 (5.3 mL, 4.5 mmol, 0.85 M in
pentane) was added dropwise over 5 min, and the reaction
mixture was stirred at -78 °C for 0.5 h. γ-Hydroxybutenolide
19a (0.518 g, 1.25 mmol) was added in one portion, and the
reaction mixture was stirred at -78 °C for 0.5 h and then at
-42 °C for 3 h. TMEDA (0.57 mL, 3.8 mmol) was added, and
the reaction mixture was stirred for 0.25 h. The reaction mixture
was poured into saturated ammonium chloride (20 mL) and 2.5 M
HCl (10 mL), and the mixture was extracted with CH2Cl2 (3 ꢀ
50 mL). The combined organic extracts were washed with brine
(100 mL), dried over sodium sulfate, and decanted into a clean
Erlenmeyer flask. The solution of the crude product (1H NMR
indicated variable ratios of the lactone 21a, and the correspond-
ing open-chain carboxylic acid/alcohol) was treated with TsOH
(0.060 g) in CH2Cl2 (20 mL) for 30 min. The mixture was
transferred to a separatory funnel, washed with 5% Na2CO3
(100 mL) and brine (100 mL), and dried over sodium sulfate, and
colorless oil: [R]22 -40.9 (c 1.1, CH2Cl2); IR (CH2Cl2) 1500
D
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.29 (br s, 1H), 6.15 (br s,
6828 J. Org. Chem. Vol. 75, No. 20, 2010

Miles et al.
JOCArticle
the solvent was removed on the rotary evaporator. The crude
product was purified by flash chromatography (50 g of silica gel;
5% ethyl acetate in hexanes) to give the lactone 21a (0.549 g,
90% yield) as a solid: mp 126.0-128.0 °C; [R]22D þ52.2 (c 1.1,
(d, J = 15.4 Hz, 1H), 0.90 (s, 9H), 0.88 (s, 9H), 0.11 (s, 3H), 0.10
(s, 3H), 0.07 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 143.7, 126.5, 78.8, 78.1, 67.8, 59.3, 45.8, 39.7,
26.9, 26.0, 25.9, 18.3, 18.1, 0.5, -4.1, -4.5, -4.6, -4.9.
1
CH2Cl2); IR (CH2Cl2) 1750, 1652 cm-1; H NMR (400 MHz,
Crude diol 22a was dissolved in CH3CN (15 mL), and HF in
CH3CN (0.35 M; 1.0 mL, 0.35 mmol; stock solution prepared by
the addition 48% HF to CH3CN) was added in one portion.
Additional HF in CH3CN (0.35 M; 2 ꢀ 0.5 mL, 0.35 mmol) was
added after 10 and 20 min. After the mixture was stirred at room
temperature (while carefully monitoring the reaction mixture by
TLC) for a total of 30 min, hexane (50 mL) was added followed
by water (6 mL). After being stirred for 1 min, the hexane layer
was decanted, and the aqueous CH3CN phase was extracted
with further hexane (2 ꢀ 50 mL). The combined hexane extracts
were dried with Na2SO4, and the volatiles were removed on the
rotary evaporator. The crude product was purified by flash
chromatography (50 g of silica gel; 5% ethyl acetate in hexanes)
to give 4a (0.301 g, 67% yield from 21a) as a white solid: mp
CDCl3) δ 5.73 (d, J = 1.8 Hz, 1H), 4.00-4.10 (m, 2H), 2.90
(ddd, J = 2.0, 5.3, 12.8 Hz, 1H), 2.33 (ddd, J = 2.0, 10.4, 12.6
Hz, 1H), 1.93 (m, 1H), 1.82 (ddd, J = 1.9, 10.7, 14.0 Hz, 1H),
1.22 (d, J = 15.0 Hz, 1H), 1.16 (d, J = 15.0 Hz, 1H), 0.88 (s, 9H),
0.81 (s, 9H), 0.06 (s, 3H), 0.05 (br s, 6H), 0.04 (br s, 12H); 13
C
NMR (100 MHz, CDCl3) δ 173.1, 169.9, 115.7, 89.2, 73.5, 68.3,
39.5, 36.8, 25.9, 25.8, 23.7, 18.2, 18.0, -0.0, -4.7 (2C), -5.0,
-5.2. Anal. Calcd for C24H48O4Si3: C, 59.45; H, 9.98. Found: C,
59.29; H, 10.31.
(2Z)-2-[(3S,5R)-3,5-Bis(tert-butyldimethylsiloxy)-2-methyle-
necyclohexylidene]ethanol (4a). Lactone 21a (0.575 g, 1.19 mmol)
was dissolved in toluene (10 mL) and cooled to -78 °C, and DIBAL
(2.9 mL, 1.2 M in toluene, 3.5 mmol) was added dropwise. The
reaction mixture was stirred for 1 h at -78 °C and then allowed to
slowly warm to -30 °C. Methanol (0.25 mL) and then 30%
sodium potassium tartrate (20 mL) were added to quench the
reaction mixture. The reaction mixture was transferred to an
Erlenmeyer flask and stirred vigorously with ether (40 mL) for
1 h. The organic phase was separated, and the aqueous phase was
extracted with ether (2 ꢀ 40 mL). The combined extracts were
washed with brine (100 mL), dried over sodium sulfate, and
concentrated on the rotary evaporator. The crude lactol was
dissolved in ethanol (5 mL), and NaBH4 (0.40 g, 10 mmol) was
added. After the reaction mixture was stirred at 22 °C for 18 h,
water (15 mL) and ether (15 mL) were added, and the reaction
mixture was stirred for 30 min. The reaction mixture was
transferred to a separatory funnel, the phases were separated,
and the aqueous phase was extracted with ether (3 ꢀ 50 mL). The
combined organic extracts were washed with brine (50 mL), dried
over Na2SO4, and concentrated on the rotary evaporator to give
crude diol 22a (0.574 g), which was used in the next reaction
without further purification due to loss of yield on silica gel. Diol
22a was an oil that slowly solidified: mp 58-60 °C; [R]22D þ9.1
68-70 °C (lit.4a mp 69-71 °C). [R]25D þ7.8 (c 0.40, EtOH) [lit.4a
1
[R]25 þ7.9 (c 0.4, EtOH)]; IR (CH2Cl2) 3609, 1638 cm-1; H
D
NMR (400 MHz, CDCl3) δ 5.53 (t, J = 7.0 Hz, 1H), 5.15 (m,
1H), 4.76 (m, 1H), 4.39 (m, 1H), 4.15-4.21 (m, 3H), 2.40 (br dd,
J = 3.7, 13.2 Hz, 1H), 2.18 (dd, J = 6.8, 13.0 Hz, 1H),1.78-1.85
(m, 2H), 1.30 (br s, 1H), 0.87 (s, 9H), 0.86 (s, 9H), 0.06 (s, 3H),
0.052 (s, 3H), 0.050 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
147.8, 139.6, 126.8, 110.8, 71.5, 67.5, 59.8, 45.4, 44.7, 25.93,
25.91, 18.3, 18.2, -4.6, -4.72, -4.74, -4.9.
Acknowledgment. We thank the Petroleum Research
Foundation, administered by the American Chemical So-
ciety, and Lafayette College’s Academic Research Commit-
tee for financial support. We also thank Dr. Michael Garst of
Allergan, Inc., for helpful discussions. We gratefully acknow-
ledge a grant from the Kresge Foundation for the purchase a
400 MHz NMR spectrometer.
1
(c 1.1, CH2Cl2); IR (CH2Cl2) 3443, 1646 cm-1; H NMR (400
Supporting Information Available: Experimental details and
characterization data for 4b,c, 5b,c, rac-5c, 7-14, 16, 17, 19b,c,
21b,c, and 22c; copies of 1H and 13C NMR spectra for 4, 5, 7-14,
16, 17, 19, 21, and 22. This material is available free of charge via
the Internet at http://pubs.acs.org.
MHz, CDCl3) δ 5.51 (t, J = 6.2 Hz, 1H), 4.21-4.35 (m, 2H), 3.92
(m, 1 H), 3.67 (br t, J = 3.0 Hz, 1H), 3.32 (br s, 1H), 2.58 (dd,
J = 3.7, 8.1 Hz, 1H), 2.20-2.25 (m, 2H), 1.91 (m, 1H), 1.81
(ddd, J = 2.2, 11.0, 13.9 Hz, 1H), 1.23 (d, J = 15.0 Hz, 1H), 1.17
J. Org. Chem. Vol. 75, No. 20, 2010 6829