A short olefin metathesis-based route to enantiomerically pure arylated dihydropyrans and α,β-unsaturated δ-valero lactones

Article abstract of DOI:10.1021/jo0264729

The synthesis of arylated dihydropyrans and unsaturated lactones starting from enantiomerically pure α-hydroxy ketones (prepared by an enzyme-catalyzed benzoin condensation) is described. The key steps are a highly diastereoselective addition of vinyl metal compounds under chelate control and a ruthenium-catalyzed ring-closing olefin metathesis reaction. Elucidation of the relative configuration of the final products was achieved by NOE experiments.

Full text of DOI:10.1021/jo0264729

A Sh or t Olefin Meta th esis-Ba sed Rou te to En a n tiom er ica lly P u r e
Ar yla ted Dih yd r op yr a n s a n d r,â-Un sa tu r a ted δ-Va ler o La cton es
Holger Wildemann,† Pascal Du¨nkelmann,‡ Michael Mu¨ller,‡ and Bernd Schmidt*,†
FB Chemie der Universita¨t Dortmund, Organische Chemie, D-44221 Dortmund, Germany, and
Institut fu¨r Biotechnologie 2, Forschungszentrum J u¨lich GmbH, D-52425 J u¨lich, Germany
bschmidt@chemie.uni-dortmund.de
Received September 25, 2002
The synthesis of arylated dihydropyrans and unsaturated lactones starting from enantiomerically
pure R-hydroxy ketones (prepared by an enzyme-catalyzed benzoin condensation) is described. The
key steps are a highly diastereoselective addition of vinyl metal compounds under chelate control
and a ruthenium-catalyzed ring-closing olefin metathesis reaction. Elucidation of the relative
configuration of the final products was achieved by NOE experiments.
Arylated heterocycles have been a synthetic target in
several pharmaceutical research laboratories. Potential
applications range from 5-Lipoxygenase inhibitors1 to
NK-1 receptor antagonists2,3 and ligands for receptors of
neurotransmitters.4,5 Methods for the introduction of aryl
moieties to heterocycles include Heck reactions2 or Stille
couplings,3 asymmetric Michael reactions of aryl acetic
acids,6 and addition of aryl metal compounds to hetero-
cycloalkanones. Two examples of biologically active het-
erocycles synthesized by this method are depicted in
Figure 1: the piperidine 1 shows adrenoceptor agonist
activity,7 while the tetrahydropyran 2 inhibits leuko-
triene synthesis in vitro.1
The structural pattern present in 2 inspired a short
and highly diastereoselective synthesis of more densely
functionalized enantiomerically pure analogues. Our
synthetic concept is based on the ring-closing olefin
metathesis reaction8-11 and uses enantiomerically pure
R-hydroxy-aryl ketones 3 as starting materials. The
ketones 3 were obtained on a preparative scale in high
F IGURE 1. Examples for biologically active, arylated het-
erocycles.
chemical and optical yield by benzaldehyde lyase (BAL)-
catalyzed benzoin condensation-like reaction from aro-
matic aldehydes and acetaldehyde.12,13 Using this thia-
mine diphosphate (ThDP)-dependent enzyme in an
aqueous buffer solution a large number of highly enantio-
enriched (R)-benzoins and (R)-2-hydroxy-1-phenyl-1-pro-
panones substituted in ortho-, meta-, and para-positions
by diverse moieties are available in one reaction step.
Additionally, direct access to the corresponding (S)-
enantiomers is also given by using the same enzymes’
racemic resolution ability or by using other ThDP-
dependent enzymes.14,15
Following the sequence outlined in Scheme 1, dihy-
dropyrans 7a -e were obtained as single diastereomers
in enantiomerically pure form.
Starting from R-hydroxy ketones 3, allyloxy ketones 4
were obtained using silver oxide and allyl bromide.16 By
using this method, racemization at the R-carbon was
avoided and allyl ethers 4 were obtained in an enantio-
† FB Chemie der Universita¨t Dortmund.
‡ Institut fu¨r Biotechnologie 2.
(1) Crawley, G. C.; Dowell, R. I.; Edwards, P. N.; Foster, S. J .;
McMillan, R. M.; Walker, E. R. H.; Waterson, D. J . Med. Chem. 1992,
35, 2600-2609.
(2) Kulagowski, J . J .; Curtis, N. R.; Swain, C. J .; Williams, B. J .
Org. Lett. 2001, 3, 667-670.
(3) Wallace, D. J .; Goodman, J . M.; Kennedy, D. J .; Davies, A. J .;
Cowden, C. J .; Ashwood, M. S.; Cottrell, I. F.; Dolling, U.-H.; Reider,
P. J . Org. Lett. 2001, 3, 671-674.
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Ye, Y. P.; J ohnson, K. M.; Tella, S. R. J . Med. Chem. 2002, 45, 3161-
3170.
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D.; Huffman, M. A.; Murry, J .; McNamara, J .; Reider, P. J . Org. Lett.
2002, 4, 1963-1966.
(12) Demir, A. S.; Pohl, M.; J anzen, E.; Mu¨ller, M. J . Chem. Soc.,
Perkin Trans. 1 2001, 633-635.
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J anzen, E.; Kolter, D.; Feldmann, R.; Du¨nkelmann, P.; Mu¨ller, M. Adv.
Synth. Catal. 2002, 344, 96-103.
(7) Macchia, B.; Balsamo, A.; Epifani, E.; Lapucci, A.; Nencetti, S.;
Macchia, F.; Breschi, M. C.; Martinotti, E.; Ceserani, R. J . Med. Chem.
1986, 29, 740-747.
(14) Demir, A. S.; Du¨nnwald, T.; Iding, H.; Pohl, M.; Mu¨ller, M.
Tetrahedron: Asymmetry 1999, 10, 4769-4774.
(15) Iding, H.; Du¨nnwald, T.; Greiner, L.; Liese, A.; Mu¨ller, M.;
Siegert, P.; Gro¨tzinger, J .; Demir, A. S.; Pohl, M. Chem. Eur. J . 2000,
6, 1483-1495.
(16) Aurich, H. G.; Biesemeier, F.; Boutahar, M. Chem. Ber. 1991,
124, 2329-2334.
(8) Armstrong, S. K. J . Chem. Soc., Perkin Trans. 1 1998, 371-388.
(9) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450.
(10) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997,
36, 2036-2055.
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10.1021/jo0264729 CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/13/2002
J . Org. Chem. 2003, 68, 799-804
799

Wildemann et al.
a
SCHEME 1
F IGURE 2. First (A) and second (B) generation Grubbs’
catalyst.
become higher in energy compared to derivatives not
substituted in the ortho-position.
Modification of the sequence outlined above allows the
conversion of R-hydroxy ketones to R,â-unsaturated lac-
tones 10. Starting from 3c,f, vinylation to the corre-
sponding diol 8c,f is achieved by addition of excess
vinylmagnesium chloride. Again, HPLC on chirally modi-
fied stationary phases proved that no racemization occurs
on this step. For this purpose, racemic 8c was prepared
from the corresponding racemic benzoin and compared
with material obtained from enantiomerically pure (R)-
3c. In this case a small amount of the S-enantiomer was
observed (ee of (R)-8c: 98%). The diols 8c,f were con-
verted to the acrylates 9c,f by reaction with acryloyl
chloride. Competitive esterification of the tertiary alcohol
was not observed if a large excess of base and acryloyl
chloride was avoided and if the reaction was quenched
immediately after consumption of the starting material
(TLC control). Conversion of the sterically more hindered
substrate 8c to 9c requires longer reaction times and the
addition of a catalytic amount of DMAP. 8f is readily
converted to 9f without additives.
Ring-closing metathesis of dienes containing one elec-
tron-deficient double bond with the first generation
catalyst A is normally not a facile process due to the
inhibition of the catalytically active species by chelation.
This problem may be circumvented by addition of a Lewis
acid,18 or by using the second generation catalyst B.19 We
chose the latter option for converting dienes 9c,f to the
corresponding lactones 10c,f. In the presence of 4 mol %
of B complete conversion was achieved within 30 min at
70 °C. Over the past three years some examples of the
formation of R,â-unsaturated lactones by olefin metath-
esis of acrylates using complex B have been described in
the literature.20-23 Nevertheless, it is surprising that ring
closure of the sterically demanding and electron-deficient
dienes 9 is such a smooth process. The results are
summarized in Scheme 2 and Table 2.
a
Reagents and conditions: (i) Ag2O (1.5 equiv), H2CdCHCH2Br,
ether,20°C;(ii)H2CdCHMgCl,ether,-78°C;(iii)Cl2(Cy3P)2RudCHPh
(A) (3 mol %), CH2Cl2, 20 °C.
TABLE 1. Syn th esis of Ar yla ted Dih yd r op yr a n s
% yield
of 4
% yield % yield
compd
R1
R2
4:5
of 6 (dr)
of 7
(R)-3a Ph
(R)-3b Me
(S)-3b Me
(R)-3c 3-OMe-Ph 3-OMe-Ph
(R)-3d 2-Cl-Ph
(R)-3e 4-Br-Ph
Ph
Ph
Ph
90
47
47
99
75
73
10:1 99 (>19:1)
1:1 67 (>19:1)
1:1 62 (>19:1)
>19:1 79 (>19:1)
5:1 85 (>19:1)
5:1 90 (>19:1)
90
86
80
90
75
78
2-Cl-Ph
4-Br-Ph
merically pure form. If strong bases, such as NaH, are
used, an O-allylation-Wittig rearrangement takes place,
leading to aryl-allyl carbinols.17 In the case of (R)- and
(S)-3b, allyl benzoate was formed as an inseparable
byproduct. Obviously, oxidative cleavage of the acyloin
linkage occurs, leading to benzoic acid, which is then
allylated to give the corresponding allyl ester. In all other
cases, only minor amounts of allyl esters 5 result. The
amount of 5 increases with an increasing amount of silver
oxide, thus, a large excess of silver oxide should be
carefully avoided. By treatment of the R-allyloxy ketones
4 with vinylmagnesium chloride in THF/ether at low
temperature, the dienes 6 were obtained with very high
diastereoselectivity. In all cases investigated, only one
diastereomer could be detected in the proton NMR
spectrum of the crude reaction mixture, corresponding
to a diastereomeric ratio higher than 19:1. For 6a we
proved that the vinylation reaction occurs without any
racemization. Racemic 6a was prepared from commercial
benzoin and compared with material obtained via the
same sequence from (R)-3a using HPLC on chirally
modified stationary phases. The amount of the S-enan-
tiomer was below the detection limit corresponding to an
enanantiomeric excess of >99%. Ring-closing metathesis
of the dienes 6 to the dihydropyrans 7 proceeded smoothly
in the presence of 3 mol % of the first generation Grubbs’
catalyst (A in Figure 2). Only 6d required 10 mol % of
the ruthenium catalyst for complete conversion to the
dihydropyran 7d . The significantly reduced reactivity of
6d might be explained by steric interactions of the
substituent in the ortho-position of the aromatic ring with
the ligand sphere of the ruthenium complex. As a
consequence, conformations suitable for ring closure
The relative stereochemistry was investigated for the
cyclic products by NOE experiments. Gradient-selected
one-dimensional NOE experiments were conducted at
600 MHz for the dihydropyrans 7a ,b,e and the lactone
10f. For the dihydropyrans a NOE interaction of H2 with
one of the protons H6 is indicative of a pseudoaxial
(18) Fu¨rstner, A.; Langemann, K. Synthesis 1997, 792-803.
(19) Scholl, M.; Trnka, T. M.; Morgan, J . P.; Grubbs, R. H.
Tetrahedron Lett. 1999, 40, 2247-2250.
(20) Fu¨rstner, A.; Thiel, O. R.; Kindler, N.; Bartkowska, B. J . Org.
Chem. 2000, 65, 7990-7995.
(21) Held, C.; Fro¨hlich, R.; Metz, P. Angew. Chem., Int. Ed. 2001,
40, 1058-1060.
(22) Fu¨rstner, A.; Ackermann, L.; Gabor, B.; Goddard, R.; Lehmann,
C. W.; Mynott, R.; Stelzer, F.; Thiel, O. R. Chem. Eur. J . 2001, 7, 3236-
3253.
(17) Schmidt, B.; Wildemann, H. J . Chem. Soc., Perkin Trans. 1
2000, 2916-2925.
(23) Schmidt, B.; Pohler, M.; Costisella, B. Tetrahedron 2002, 58,
7951-7958.
800 J . Org. Chem., Vol. 68, No. 3, 2003

Enantiomerically Pure Arylated Dihydropyrans
SCHEME 2a
F IGURE 4. Rationalization of the stereochemical outcome in
vinylation reactions.
cyclic model”).24,25 The oxygen of the R-allyloxy substitu-
ent or the hydroxy group and the carbonyl oxygen form
a five-membered chelate complex, which is preferentially
attacked from the sterically less shielded side, as outlined
for the formation of 6a in Figure 4. The addition of
organomagnesium compounds to R-hydroxy ketones and
factors governing the stereoselectivity of the addition step
have already been thoroughly investigated.25,26
In conclusion, we have developed a highly diastereo-
selective route to enantiomerically pure dihydropyrans
and R,â-unsaturated lactones bearing one or two aromatic
substituents. The synthetic concept is based on the use
of R-hydroxy ketones which are conveniently obtained in
enantiomerically pure form, a highly diastereoselective
vinylation relying on efficient chelate control, and a ring-
closing olefin metathesis step.
a
Reagents and conditions: (i) H2CdCHMgCl, THF, -78 °C; (ii)
H2CdCHCOCl, NEt3, DCM (10 mol % of DMAP for 9c); (iii) B (4
mol %), toluene, 70 °C
TABLE 2. Syn th esis of Ar yla ted La cton es
% yield
of 8 (dr)
% yield % yield
3
R1
R2
of 9
of 10
(R)-3c 3-OCH3-Ph 3-OCH3-Ph 76 (17:1)
(R)-3f -CH3 3-Cl-Ph 81 (>19:1)
80
72
95
90
Exp er im en ta l Section
Gen er a l. All experiments were conducted in dry reaction
vessels in an atmosphere of dry argon. Solvents were purified
by standard procedures. 1H NMR spectra were recorded at 400
or 500 MHz in CDCl3 with CHCl3 (δ 7.24 ppm) as internal
standard. Coupling constants are given in hertz. 13C NMR
spectra were recorded at 100 or 125 MHz in CDCl3 with CDCl3
(δ 77.0 ppm) as internal standard. The number of coupled
protons was analyzed by DEPT or APT experiments and is
denoted in parentheses following the δC values. Signal assign-
ment for cyclic products follows a numbering scheme where
the oxygen atom is numbered as 1 and the R-carbon atom
bearing the substituent R1 (cf. Schemes 1 and 2) as C2.
Selective 1D-NOE experiments were conducted using shaped
pulses and pulsed field gradients at 600 MHz with a mixing
time of 800 ms. IR spectra were recorded as films on NaCl or
KBr plates or as KBr disks. The peak intensities are defined
as strong (s), medium (m), and weak (w). Mass spectra were
obtained at 70 eV. Optical purities were determined by HPLC
using a HP-LC-1050 system equipped with a Daicel Chiralcel
OD, a Daicel Chiralcel OD-H, or a Daicel Chiralpak AD
column. Starting materials 3 were employed with ee values
>99%, except for (S)-3b (ee 92%) and (R)-3d (ee 97%). The
ruthenium catalyst A27
F IGURE 3. Representative NOE interactions in 7e and 10f.
orientation of these protons. H2 shows an NOE to the
ortho-protons of the aromatic ring in the 3-position and
to the substituent in the 2-position. However, no NOE
interaction to the OH proton was observed. In contrast,
the OH proton shows NOEs to both aromatic substituents
and to the olefinic proton H4, but not to H2. From these
observations we conclude that the substituents at C2 and
C3 are trans-arranged. These NOE interactions are
summarized for the example 7e in Figure 3. For the
lactone series, NOEs were recorded for 10f. Indicative
NOE interactions are found between H2 and both ortho
protons of the aryl moiety. NOE interactions between the
methyl group in the 2-position and these ortho protons
are significantly weaker (Figure 3).
was purchased from Fluka, the second
generation catalyst B was prepared following a literature
procedure.28
Gen er a l P r oced u r e for th e P r ep a r a tion of Allyloxy
Keton es 4. To a solution of the corresponding R-hydroxy
ketone 3 (2.0 mmol) and allyl bromide (0.26 mL, 3.0 mmol) in
ether (30 mL) was added silver oxide (700 mg, 3.0 mmol). The
mixture was heated to reflux for 2 h, and stirring was
continued at ambient temperature in the dark for 2 days. All
solids were removed by filtration through a small pad of Celite,
(24) Cram, D. J .; Wilson, D. R. J . Am. Chem. Soc. 1963, 85, 1245-
1249.
(25) Chen, X.; Hortelano, E. R.; Eliel, E. L.; Frye, S. V. J . Am. Chem.
Soc. 1992, 114, 1778-1784.
(26) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1984, 23, 556-569.
(27) Schwab, P.; Grubbs, R. H.; Ziller, J . W. J . Am. Chem. Soc. 1996,
118, 100-110.
The relative RS-stereochemistry of the alcohols 6 and
8 and the high degree of diastereoselectivity originates
from a chelation effect first proposed by Cram (“Cram’s
(28) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953-956.
J . Org. Chem, Vol. 68, No. 3, 2003 801

Wildemann et al.
the solvent was removed in vacuo, and the residue was purified
by flash chromatography on silica using cyclohexane/MTBE
mixtures as eluent.
(3S,4R)- a n d (3R,4S)-4-Allyloxy-3-p h en ylp en t-1-en -3-ol
((3S,4R)-6b a n d (3R,4S-6b)). Starting from (R)-4b (290 mg,
1.5 mmol of a mixture with allyl benzoate), (3S,4R)-6b (220
mg, 67%) was obtained. Analogously, from (S)-4b (270 mg, 1.4
mmol), (3R,4S)-6b (190 mg, 62%) was obtained. In both cases
the products were contaminated with allylbenzoate from the
preceding step. MS (EI): m/z 191 (M+ - C2H3, 100), 105 (85).
1H NMR (400 MHz, CDCl3): δ 7.44-7.40 (2H), 7.33-7.28 (2H),
7.21 (m, 1H), 6.34 (dd, 1H, J ) 17.3, 10.5), 5.86 (dddd, 1H, J
) 17.3, 10.8, 5.8, 5.3), 5.35 (dd, 1H, J ) 17.3, 1.5), 5.25 (dddd,
1H, J ) 17.3, 1.5, 1.5, 1.5), 5.18 (dd, 1H, J ) 10.5, 1.5), 5.14
(dddd, 1H, J ) 10.8, 1.5, 1.5, 1.5), 4.09 (ddm, 1H, J ) 12.8,
5.3), 3.94 (ddm, 1H, J ) 12.8, 5.8), 3.77 (q, 1H, J ) 6.0), 2.73
(br s, 1H), 0.92 (d, 3H, J ) 6.0). 13C NMR (100 MHz, CDCl3):
δ 142.9 (1), 134.9 (1), 128.7 (0), 128.0 (1), 126.7 (1), 125.4 (1),
116.8 (2), 113.5 (2), 79.8 (1), 78.8 (0), 70.7 (2), 13.7 (3).
(R)-2-Allyloxy-1,2-d ip h en yleth a n on e (4a ). Starting from
(R)-benzoin (3a ) (700 mg, 3.3 mmol), 4a (750 mg, 90%) was
obtained. Anal. Calcd for C17H16O2: C, 80.93; H, 6.39. Found:
C, 80.75; H, 6.25. MS (EI): m/z 253 (M+ + 1, 10), 105 (100).
IR (film): 1694 (s) cm-1. 1H NMR (400 MHz, CDCl3): δ 7.94-
7.90 (2H), 7.44-7.38 (3H), 7.33-7.18 (5H), 5.88 (dddd, 1H, J
) 17.3, 10.3, 5.5, 5.5), 5.60 (s, 1H), 5.23 (dddd, 1H, J ) 17.3,
1.5, 1.5, 1.5), 5.15 (dddd, 1H, J ) 10.3, 1.5, 1.5, 1.5), 4.04 (dm,
2H, J ) 5.5). 13C NMR (100 MHz, CDCl3): δ 197.3 (0), 136.2
(0), 135.0 (0), 134.0 (1), 133.2 (1), 129.1 (1), 128.8 (1), 128.4
(1), 128.4 (1), 127.5 (1), 118.1 (2), 83.9 (1), 70.5 (2). [R]22D +36.4
(c 1.0, CH2Cl2).
(S)- a n d (R)-2-Allyloxy-1-p h en ylp r op a n -1-on e ((S)-4b
a n d (R)-4b). Starting from either enantiomer of 3b (490 mg,
3.3 mmol), the corresponding enantiomer of 4b (approximately
290 mg, 47%) and benzoic acid allyl ester were obtained as an
inseparable mixture, which was used for subsequent trans-
formations. The yield of 4b was estimated from the NMR
spectrum of the mixture. NMR spectroscopic data for 4b
(obtained from the mixture): 1H NMR (400 MHz, CDCl3): δ
8.00-7.94 (2H), 7.45 (m, 1H), 7.39-7.31 (2H), 5.81 (dddd, 1H,
J ) 17.3, 10.5, 5.8, 5.5), 5.17 (dddd, 1H, J ) 17.3, 1.5, 1.5,
1.5), 5.08 (dm, 1H, J ) 10.3), 4.67 (q, 1H, J ) 7.0), 4.00 (ddm,
1H, J ) 12.5, 5.5), 3.85 (ddm, 1H, J ) 12.5, 5.8), 1.41 (d, 3H,
J ) 7.0). 13C NMR (100 MHz, CDCl3): δ 200.5 (0), 134.1 (0),
133.2 (1), 128.6 (1), 128.5 (1), 128.5 (1), 117.5 (2), 77.9 (1), 70.5
(2), 18.7 (3).
(1R,2S)-1-Allyloxy-1,2-bis(3-m eth oxyp h en yl)bu t-3-en -
2-ol (6c). Starting from 4c (598 mg, 1.9 mmol), 6c (513 mg,
79%) was obtained.
(1R,2S)-1-Allyloxy-1,2-b is(2-ch lor op h en yl)b u t -3-en -2-
ol (6d ). Starting from 4d (135 mg, 0.4 mmol), 6d (130 mg,
85%) was obtained.
(1R,2S)-1-Allyloxy-1,2-b is(4-b r om op h en yl)b u t -3-en -2-
ol (6e). Starting from 4e (207 mg, 0.5 mmol), 6e (190 mg, 90%)
was obtained.
Gen er a l P r oced u r e for th e P r ep a r a tion of Dih yd r o-
p yr a n s 7. To a solution of the corresponding diene 6 (3.9
mmol) in DCM (50 mL) was added the catalyst A (97 mg, 3
mol %). The mixture was stirred until the starting material
was completely converted, as indicated by TLC. The solvent
was removed in vacuo, and the residue was purified by flash
chromatography on silica.
(R)-2-Allyloxy-1,2-bis(3-m eth oxyp h en yl)eth a n on e (4c).
Starting from 3c (565 mg, 2.1 mmol), 4c (640 mg, 99%) was
obtained.
(2R,3S)-2,3-Dip h en yl-3,6-d ih yd r o-2H-p yr a n -3-ol (7a ).
Starting from 6a (0.55 g, 1.9 mmol), 7a (0.44 g, 90%) was
obtained. Signal assignments in the H NMR spectrum are
supported by NOE experiments. Anal. Calcd for C17H16O2: C,
80.93; H, 6.39. Found: C, 80.75; H, 6.35. MS (EI): m/z 251
(M+ - 1, <5), 146 (100). IR (disk, KBr): 3510 (s), 1495 (m),
(R)-2-Allyloxy-1,2-bis(2-ch lor op h en yl)eth a n on e (4d ).
Starting from 3d (420 mg, 1.5 mmol), 4d (361 mg, 75%) was
obtained after purification by column chromatography on
silica.
(R)-2-Allyloxy-1,2-b is(4-br om op h en yl)et h a n on e (4e).
Starting from 3e (580 mg, 1.5 mmol), 4e (450 mg, 73%) was
obtained after purification by column chromatography on
silica.
1
1447 (m), 766 (s), 698 (s) cm-1. H NMR (400 MHz, CDCl3): δ
7.21-7.16 (3H, Ph), 7.13-7.04 (5H, Ph), 6.78-6.74 (2H, Ph),
6.09 (ddd, 1H, J ) 10.0, 3.5, 1.5, H5), 6.02 (ddd, 1H, J ) 10.0,
1.5, 1.5, H4), 4.57 (s, 1H, H2), 4.48 (ddd, 1H, J ) 17.1, 3.5,
1.5, H6), 4.38 (ddd, 1H, J ) 17.1, 1.5, 1.5, H6), 2.33 (br s, 1H,
-OH). 13C NMR (100 MHz, CDCl3): .δ 142.0 (0), 136.2 (0),
132.2 (1), 128.3 (1), 127.8 (1), 127.6 (1), 127.5 (1), 127.5 (1),
Gen er a l P r oced u r e for t h e P r ep a r a t ion of Vin yl
Ca r bin ols 6. A solution of the corresponding ketone 4 (4.0
mmol) in ether (100 mL) was cooled to -78 °C. A solution of
vinylmagnesium chloride in THF (1.7 M, 4.7 mL, 7.9 mmol)
was added, and the mixture was stirred until the starting
material was completely consumed, as indicated by TLC. The
mixture was poured onto aqueous NH4Cl solution, the organic
layer was separated, and the aqueous layer was extracted with
MTBE. The combined organic extracts were dried with MgSO4,
filtered, and evaporated. The residue was purified by flash
chromatography on silica.
24
127.2 (1), 126.1 (1), 85.3 (1), 71.9 (0), 66.8 (2). [R]D 17.1 (c )
0.69, CH2Cl2).
(2R,3S)- a n d (2S,3R)-2-Meth yl-3-p h en yl-3,6-d ih yd r o-
2H-p yr a n -3-ol ((2R,3S)-7b a n d (2S,3R)-7b). Starting from
(3S,4R)-6b (214 mg, 1.0 mmol), (2R,3S)-7b (160 mg, 86%) was
obtained. Analogously, from (3R,4S)-6b (140 mg, 0.6 mmol),
(2S,3R)-7b (97 mg, 80%) was obtained. Signal assignments in
the H NMR spectrum are based on NOE experiments. Color-
less crystals, mp 86 °C. Anal. Calcd for C12H14O2: C, 75.76;
H, 7.42. Found: C, 75.56; H, 7.45. MS (EI): m/z 189 (M+ - 1,
<5), 173 (100), 146 (80). IR (disk, KBr): 3463 (s), 1447 (m),
(1R,2S)-1-Allyloxy-1,2-d ip h en ylbu t-3-en -2-ol (6a ). Start-
ing from 4a (0.70 g, 2.8 mmol), 6a (0.77 g, 99%) was obtained.
The enantiomeric excess of 6a was determined by HPLC
analysis (Chiralpak AD, eluent: isohexane/2-propanol 95:5,
flow 0.9 mLmin-1, 20 °C) to be >99% after comparison with
racemic 6a under identical conditions. Anal. Calcd for
1
1117 (s), 994 (m), 700 (s) cm-1. H NMR (500 MHz, CDCl3): δ
7.40 (dd, 2H, J ) 8.5, 1.5, Ph), 7.32 (dd, 2H, J ) 8.5, 7.0, Ph),
7.23 (tt, 1H, J ) 7.0, 1.5, Ph), 6.01 (ddd, 1H, J ) 10.0, 2.5,
2.5, H4/H5), 5.93 (ddd, 1H, J ) 10.0, 1.5, 1.5, H4/H5), 4.32
(dm, 1H, J ) 17.1, H6), 4.26 (dm, 1H, J ) 17.1, H6), 3.68 (q,
1H, J ) 6.3, H2), 2.58 (br s, 1H, -OH), 1.04 (d, 3H, J ) 6.3,
-CH3). 13C NMR (125 MHz, CDCl3): δ 142.5 (0), 132.4 (1),
128.1 (1), 128.0 (1), 127.0 (1), 125.7 (1), 79.5 (1), 71.2 (0), 66.2
C
19H20O2: C, 81.40; H, 7.19. Found: C, 81.30; H, 7.15. MS
(EI): m/z 281 (M+ + 1, <5), 147 (70), 105 (100). IR (film): 3463
(br m), 1449 (m), 925 (m), 700 (s) cm-1 1H NMR (400 MHz,
.
CDCl3): δ 7.24-7.20 (2H), 7.17-7.07 (6H), 7.03-6.98 (2H),
6.50 (dd, 1H, J ) 17.5, 10.8), 5.73 (dddd, 1H, J ) 17.0, 10.8,
5.3, 5.0), 5.29 (dd, 1H, J ) 17.3, 1.3), 5.19 (dd, 1H, J ) 10.8,
1.3), 5.09 (ddm, 1H, J ) 17.0, 1.5), 5.05 (ddm, 1H, J ) 10.8,
1.5), 4.48 (s, 1H), 3.88 (dddd, 1H, J ) 13.0, 5.0, 1.5, 1.5), 3.65
(ddm, 1H, J ) 13.0, 5.3), 2.63 (br s, 1H). 13C NMR (100 MHz,
CDCl3): δ 142.7 (0), 141.5 (1), 136.6 (0), 134.3 (1), 128.7 (1),
127.8 (1), 127.5 (1), 127.5 (1), 126.8 (1), 126.2 (1), 117.0 (2),
27
(2), 13.8 (3). (2R,3S)-(7b): [R]D -79.5 (c 1.50, CH2Cl2).
27
(2S,3R)-(7b): [R]D +81.0 (c 1.02, CH2Cl2).
(2R,3S)-2,3-Bis(3-m eth oxyp h en yl)-3,6-d ih yd r o-2H-p y-
r a n -3-ol (7c). Starting from 6c (217 mg, 0.6 mmol), 7c (180
mg, 90%) was obtained.
(2R,3S)-2,3-Bis(2-ch lor op h en yl)-3,6-d ih yd r o-2H-p yr a n -
3-ol (7d ). Starting from 6d (102 mg, 0.3 mmol), 7d (70 mg,
114.4 (2), 86.8 (1), 78.5 (0), 70.0 (2). [R]25 -8.6 (c 1.00, CH2-
D
Cl2).
802 J . Org. Chem., Vol. 68, No. 3, 2003

Enantiomerically Pure Arylated Dihydropyrans
75%) was obtained. A higher amount of ruthenium catalyst
(25 mg, 10 mol %) was required in this case.
Acr ylic Acid (1R,2S)-2-(3-Ch lor op h en yl)-2-h yd r oxy-1-
m eth ylbu t-3-en yl Ester (9f). Starting from 8f (240 mg, 1,1
mmol), 9f (210 mg, 72%) was obtained. Anal. Calcd for
C14H15O3Cl: C, 63.04; H, 5.67. Found: C, 63.05; H, 5.45. MS
(EI, 70 eV): m/z 194 (5%, M+ - H2CdCHCO2H), 167 (40), 55
(100). IR (film) 3491 (s), 1713 (s), 1635 (m), 1617 (m), 808 (m),
(2R,3S)-2,3-Bis(4-br om op h en yl)-3,6-d ih yd r o-2H-p yr a n -
3-ol (7e). Starting from 6e (171 mg, 0.4 mmol), 7e (139 mg,
78%) was obtained.
Gen er a l P r oced u r e for th e P r ep a r a tion of Diols 8. To
a solution of the corresponding ketone 3 (2.3 mmol) in dry THF
(20 mL) was added a solution of vinylmagnesium chloride (1
M solution in THF, 5.0 mL, 5.0 mmol) at -78 °C. The mixture
was stirred at this temperature until the starting material was
fully consumed as indicated by TLC. Aqueous workup followed
by flash chromatography on silica yielded the corresponding
diol 8.
1
786 (m), 697 (m) cm-1. H NMR (500 MHz, CDCl3): δ 7.51 (s,
1H), 7.34 (d, 1H, J ) 7.7), 7.29 (d, 1H, J ) 7.7), 7.25 (dd, 1H,
J ) 7.7, 7.7), 6.41 (d, 1H, J ) 17.2), 6.22 (dd, 1H, J ) 17.0,
10.7), 6.11 (dd, 1H, J ) 17.2, 10.5), 5.86 (d, 1H, J ) 10.5),
5.41 (q, 1H, J ) 6.2), 5.36 (d, 1H, J ) 17.2), 5.21 (d, 1H, J )
10.7), 2.40 (s, 1H), 1.08 (d, 3H, J ) 6.2). 13C NMR (125 MHz,
CDCl3): δ 165.3 (0), 144.0 (0), 141.3 (1), 134.4 (0), 131.3 (2),
129.6 (1), 128.2 (1), 127.4 (1), 125.8 (1), 123.6 (1), 114.6 (2),
(1R,2S)-1,2-Bis(3-m eth oxyph en yl)-bu t-3-en e-1,2-diol (8c).
Starting from 3c (270 mg, 1.0 mmol), 8c (230 mg, 76%) was
obtained. The enantiomeric excess of 8c was determined by
HPLC analysis (Daicel Chiralcel OD, eluent: heptane/2-
propanol 90:10, flow 1.0 mL min-1, 20 °C) to be >99% after
comparison with racemic 8c under identical conditions. MS
(EI, 70 eV): m/z 283 (3%, M+ - OH), 165 (100). IR (film): 3474
(s), 1601 (s), 1585 (s), 1489 (s), 733 (s) cm-1. 1H NMR (400 MHz,
CDCl3): δ 7.17 (dd, 1H, J ) 8.0, 8.0), 7.08 (dd, 1H, J ) 8.0,
8.0), 6.88 (d, 1H, J ) 7.7), 6.81 (m, 1H, Ar), 6.75-6.71 (2H),
6.68 (d, 1H, J ) 7.5), 6.58 (m, 1H), 6.51 (dd, 1H, J ) 17.2,
10.7), 5.49 (dd, 1H, J ) 17.2, 1.0), 5.34 (dd, 1H, J ) 10.7, 1.0),
4.87 (d, 1H, J ) 3.0), 3.68 (s, 3H), 3.63 (s, 3H), 2.51 (s, 1H),
2.48 (d, 1H, J ) 3.0). 13C NMR (100 MHz, CDCl3): δ 159.3 (0),
158.9 (0), 143.7 (0), 140.7 (1), 139.8 (0), 128.8 (1), 128.5 (1),
120.1 (1), 118.5 (1), 115.4 (2), 113.9 (1), 113.0 (1), 112.8 (1),
21
78.1 (0), 74.9 (1), 14.0 (3). [R]D -24.5 (c 0.40, CH2Cl2).
Gen er a l P r oced u r e for th e Rin g Closin g Meta th esis
of Acr yla tes 9. To a solution of the corresponding acrylate 9
(0.6 mmol) in toluene (30 mL) was added ruthenium complex
B (19 mg, 4 mol %). The solution was heated to 70 °C until
the starting material was completely consumed (approximately
1 h). The solvent was evaporated and the residue was purified
by flash chromatography on silica to give the corresponding
lactone 10.
(5S,6R)-5-Hyd r oxy-5,6-bis(3-m eth oxyp h en yl)-5,6-d ih y-
d r op yr a n -2-on e (10c). Starting from 9c (130 mg, 0.4 mmol),
10c (115 mg, 95%) was obtained as colorless crystals, mp 120
°C. Signal assignments in the H NMR spectrum are based on
H,H-COSY, and signal assignments in the C NMR spectrum
are based on C-H-correlation spectroscopy. Anal. Calcd for
22
111.9 (1), 79.7 (1), 79.2 (0), 55.2 (3), 55.1 (3). [R]D +18.7 (c
C
19H18O5: C, 69.93; H, 5.56. Found: C, 69.85; H, 5.30. MS (EI,
1.30, CH2Cl2).
70 eV): m/z 326 (M+, 1%), 190 (100). IR (film): 3376 (s), 1721
(s), 1604 (s), 797 (s), 779 (s) cm-1. 1H NMR (600 MHz, CDCl3):
δ 7.23 (dd, 1H, J ) 8.0, 8.0, C3-Ar-H5′), 7.06 (dd, 1H, J ) 8.0,
8.0, C2-Ar-H5′), 6.98 (d, 1H, J ) 9.9, H4), 6.83 (dd, 1H, J )
8.4, 2.2, C3-Ar-H4′), 6.79 (dd, 1H, J ) 8.1, 2.2, C2-Ar-H4′),
6.74 (d, 1H, J ) 7.7, C3-Ar-H6′), 6.66 (s, 1H, C3-Ar-H2′), 6.52
(s, 1H, C2-Ar-H2′), 6.48 (d, 1H, J ) 7.7, C2-Ar-H6′), 6.28 (d,
1H, J ) 9.9, H5), 5.54 (s, 1H, H2), 3.67 (s, 3H, C3-Ar-OCH3),
3.59 (s, 3H, C2-Ar-OCH3), 2.94 (s, 1H, -OH). 13C NMR (150
MHz, CDCl3): δ 163.8 (0, C6), 159.6 (0, C3-Ar-C-OCH3), 158.9
(0, C2-Ar-C-OCH3), 149.4 (1, C4), 142.0 (0, C3-Ar-C1′), 134.0
(0, C2-Ar-C1′), 129.5 (1, C3-Ar-C5′), 128.6 (1, C2-Ar-C5′), 121.6
(1, C5), 120.3 (1, C2-Ar-C6′), 118.1 (1, C3-Ar-C6′), 115.0 (1,
C2-Ar-C4′), 113.9 (1, C3-Ar-C4′), 113.1, (1, C2-Ar-C2′), 111.8
(1, C3-Ar-C3′), 86.9 (1, C2), 70.9 (0, C3), 55.3 (3, C3-Ar-OCH3),
(2R,3S)-3-(3-Ch lor oph en yl)pen t-4-en e-2,3-diol (8f). Start-
ing from 3f (420 mg, 2.3 mmol), 8f (396 mg, 81%) was obtained.
Anal. Calcd for C11H13O2Cl: C, 62.12; H, 6.16. Found: C, 62.00;
H, 5.95. MS (EI, 70 eV): m/z 211 (5%, M+ - 1), 167 (71), 139
(100). IR (film): 3442 (s), 1596 (s), 1572 (s), 786 (s), 697 (s)
1
cm-1. H NMR (400 MHz, CDCl3): δ 7.41 (s, 1H), 7.30-7.18
(3H), 6.26 (dd, 1H, J ) 17.1, 10.5), 5.46 (dd, 1H, J ) 17.1,
1.0), 5.31 (dd, 1H, J ) 10.5, 1.0), 4.06 (q, 1H, J ) 6.3), 2.67 (s,
1H), 1.97 (s, 1H), 0.94 (d, 3H, J ) 6.3). 13C NMR (100 MHz,
CDCl3): δ 144.5 (0), 141.7 (1), 134.4 (0), 129.5 (1), 127.2 (1),
21
125.7 (1), 123.5 (1), 115.2 (2), 78.5 (0), 72.5 (1), 16.1 (3). [R]D
-36.0 (c 0.60, CH2Cl2).
Gen er a l P r oced u r e for th e P r ep a r a tion of Acr yla tes
9. To a solution of the corresponding diol 8 (1.1 mmol) in dry
DCM (15 mL) was added triethylamine (0.50 mL, 3.3 mmol).
The mixture was cooled to 0 °C, and freshly distilled acryloyl
chloride (0.13 mL, 1.6 mmol) was added, followed by DMAP
(11 mg, 0.1 mmol). After 30 min the starting material was
completely consumed and the mixture was extracted with
water. The organic layer was dried, filtered, and evaporated.
The residue was purified by flash chromatography on silica
to give the corresponding acrylate 9.
23
55.1 (3, C2-Ar-OCH3). [R]D -75.9 (c 0.22, CH2Cl2).
(5S,6R)-5-(3-Ch lor op h en yl)-5-h yd r oxy-6-m eth yl-5,6-d i-
h yd r op yr a n -2-on e (10f). Starting from 9f (150 mg, 0.6
mmol), 10f (121 mg, 90%) was obtained as a colorless solid,
mp 156 °C. Signal assignments in the H NMR spectrum are
based on H,H-COSY, and signal assignments in the C NMR
spectrum are based on C-H-correlation spectroscopy. Anal.
Calcd for C12H11O3Cl: C, 60.39; H, 4.65. Found: C, 60.30; H,
4.35. MS (EI, 70 eV): m/z 194 (M+ - H3CCHO, 95%), 131 (100).
IR (film): 3406 (s), 1719 (s), 1063 (s), 833 (m), 792 (m), 696
(m) cm-1. 1H NMR (600 MHz, CDCl3): δ 7.47 (s, 1H, Ar), 7.36-
7.25 (3H, Ar), 6.88 (d, 1H, J ) 9.5, H4), 6.20 (d, 1H, J ) 9.5,
H5), 4.62 (q, 1H, J ) 6.5, H2), 3.28 (s, 1H, OH), 1.25 (d, 3H, J
) 6.5, -CH3). 13C NMR (125 MHz, CDCl3): δ 163.9 (0, C6),
149.4 (1, C4), 142.6 (0, ipso-C, Ar), 134.7 (0, C-Cl, Ar), 129.9
(1, Ar), 128.4 (1, Ar), 126.0 (1, Ar), 123.8 (1, Ar), 121.8 (1, C5),
Acr ylic Acid (1R,2S)-2-Hydr oxy-1,2-bis(3-m eth oxyph en -
yl)bu t-3-en yl Ester (9c). Starting from 8c (130 mg, 0.4
mmol), 9c (113 mg, 80%) was obtained. Anal. Calcd for
C
21H22O5: C, 71.17; H, 6.26. Found: C, 71.20; H, 6.25. MS (EI,
70 eV): m/z 283 (M+ - H2CdCHCO2H, 5%), 210 (91), 181
(100). IR (film): 3489 (s), 2958 (s), 1724 (s), 1601 (s), 768 (s),
735 (s) cm-1. H NMR (500 MHz, CDCl3): δ 7.18 (dd, 1H, J )
1
8.0, 8.0), 7.09 (dd, 1H, J ) 8.0, 8.0), 6.94 (d, 1H, J ) 8.0), 6.88
(m, 1H), 6.76-6.69 (3H), 6.60 (s, 1H), 6.46 (dd, 1H, J ) 17.2,
11.0), 6.42 (d, 1H, J ) 17.5), 6.16 (dd, 1H, J ) 17.5, 10.5),
6.12 (s, 1H), 5.85 (d, 1H, J ) 10.5), 5.40 (d, 1H, J ) 17.2), 5.26
(d, 1H, J ) 11.0), 3.70 (s, 3H), 3.63 (s, 3H), 2.34 (s, 1H). 13C
NMR (125 MHz, CDCl3): δ 164.8 (0), 159.4 (0), 158.8 (0), 143.4
(0), 140.4 (1), 136.8 (0), 131.5 (2), 128.9 (1), 128.6 (1), 128.1
(1), 120.5 (1), 118.5 (1), 115.0 (2), 113.9 (1), 113.6 (1), 113.0
21
82.1 (1, C2), 69.9 (0, C3), 13.4 (3, -CH3). [R]D -73.5 (c 0.31,
CH2Cl2).
Ack n ow led gm en t. This work was generously sup-
ported by the Deutsche Forschungsgemeinschaft (P.D.,
M.M.: SFB 380) and the Fonds der Chemischen Indus-
21
(1), 111.8 (1), 80.0 (1), 78.5 (0), 55.2 (3), 55.0 (3). [R]D +12.0
(c 0.40, CH2Cl2).
J . Org. Chem, Vol. 68, No. 3, 2003 803

Wildemann et al.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra of 4c-e, 6d ,e, 7c-e, and 8c; analytical data for
compounds 4c-e, 6c-e, and 7c-e. This material is available
free of charge via the Internet at http://pubs.acs.org.
trie. Financial support by the Department of Chemistry,
Universita¨t Dortmund, is also gratefully acknowledged.
B.S. thanks Dr. B. Plietker for HPLC measurements
and Dr. B. Costisella for conducting nonroutine NMR
experiments.
J O0264729
804 J . Org. Chem., Vol. 68, No. 3, 2003