Chiral polycyclic ketones via desymmetrization of dihaloolefins

Article abstract of DOI:10.1021/jo070222g

(Chemical Equation Presented) 3-Chloronorbornenone (R)-1a (98% ee) was obtained from trichloronorbornene 5 in two steps by the in situ generation of dichloronorbornadiene 2a with t-BuOK and desymmetrization with (-)-ephedrine, followed by hydrolysis with

Full text of DOI:10.1021/jo070222g

SCHEME 1. Retrosynthetic Approach
Chiral Polycyclic Ketones via Desymmetrization
of Dihaloolefins
Giuseppe Borsato,*,§ Anthony Linden,† Ottorino De Lucchi,‡
Vittorio Lucchini,§ David Wolstenholme,| and
Alfonso Zambon§
Dipartimento di Scienze Ambientali and Dipartimento di
Chimica, UniVersita` Ca’ Foscari di Venezia, Dorsoduro 2137,
I-30123 Venezia, Italy, Institute of Organic Chemistry,
UniVersity of Zurich, Winterthurerstrasse 190, CH-8057,
Zurich, Switzerland, and Department of Chemistry, Dalhousie
UniVersity, Halifax, N.S., Canada B3H 4J3
Customarily, the construction of the norbornenone unit is
achieved by a Diels-Alder reaction between a cyclic diene and
an electron-poor dienophile,6 followed by basic hydrolysis.7 In
recent years, several different approaches have been developed
in order to obtain enantiopure norbornenones by enantioselective
cycloadditions catalyzed by chiral Lewis acids,8 enzymatic
resolution of 2-norborneol,9 or chromatographic separation of
the diastereoisomeric precursors.10 Our research group has
pursued the synthesis of enantiopure 3-phenylsulfonylnor-
bornenones through the desymmetrization of bis(phenylsulfo-
nyl)norbonadienes by C2 chiral diolates.11
gborsato@uniVe.it
ReceiVed February 12, 2007
We present in this paper an evolution of the original protocol,
which uses the dichloroolefin 2a, instead of the sulfonyl olefin
2b, to produce the ketone 1a12 (a synthetic equivalent of 1b) in
the key desymmetrization step (Scheme 1). As 2a was used as
a precursor of 2b in the first report,13 the new synthetic route
presents, according to the atom-economy rule,14 the advantage
of significantly reducing the molecular weights of the reagents
(i.e., the number of atoms) and the number of steps. As the
norbornenone core is usually required in the early stages of
natural product syntheses, the requisites of rapidity and inex-
pensiveness in the production of this building block may be
appreciated. The bicyclic structure 2a is readily available via a
Diels-Alder reaction of the inexpensive reagents trichloroet-
hylene and cyclopentadiene,15 followed by elimination with
base.
3-Chloronorbornenone (R)-1a (98% ee) was obtained from
trichloronorbornene 5 in two steps by the in situ generation
of dichloronorbornadiene 2a with t-BuOK and desymmetri-
zation with (-)-ephedrine, followed by hydrolysis with
PPTS. The generality of this desymmetrization with (-)-
ephedrine was tested with dibromonorbornadiene 2c and
other substituted dichloronorbornadienes.
(6) Bartlett, P. D.; Tate, B. E. J. Am. Chem. Soc. 1956, 78, 2473.
(7) Freeman, P. K.; Balls, D. M.; Brown, D. J. J. Org. Chem. 1968, 33,
2211.
(8) (a) Corey, E. J.; Loh, T. J. Am. Chem. Soc. 1991, 113, 8966. (b)
Corey, E. J.; Loh, T.; Roper, T. D.; Azimiora, M. D.; Noe, M. C. J. Am.
Chem. Soc. 1992, 114, 8290.
(9) Kageyama, B.; Nakae, M.; Sonoyama, T.; Kawata, K. U.S. Patent
US5459067, 1995, to Shionogi & Co.
(10) Plettner, E.; Mohle, A.; Mwangi, M. T.; Griscti, J.; Patrick, B. O.;
Nair, R.; Batchelora, R. J; Einstein, F. Tetrahedron: Asymmetry 2005, 16,
2754.
(11) (a) Cossu, S.; De Lucchi, O.; Pasetto, P. Angew. Chem., Int. Ed.
Engl. 1997, 36, 1504. (b) Cossu, S.; De Lucchi, O.; Peluso, P.; Volpicelli,
R. Tetrahedron Lett. 1999, 40, 8705. (c) Che´ry, F.; Rollin, P.; De Lucchi,
O.; Cossu, S. Tetrahedron Lett. 2000, 41, 2357. (d) Cossu, S.; De Lucchi,
O.; Peluso, P.; Volpicelli, R. Tetrahedron Lett. 2000, 41, 7263. (e) Ballini,
R.; Bosica, G.; Cossu, S.; De Lucchi, O.; Peluso, P. Tetrahedron 2001, 57,
4461. (f) Cossu, S.; Peluso, P. Indian J. Org. Chem. 2005, 1, 1. (g) Cossu,
S.; Peluso, P. Tetrahedron Lett. 2006, 47, 4015.
(12) (a) Miller, J. B. J. Org. Chem. 1961, 26, 4905. (b) Meinwald, J.;
Meinwald, Y. C.; Baker, T. N. J. Am. Chem. Soc. 1964, 86, 4074. (c) Ponder,
B. W.; Walker, D. R. J. Org. Chem. 1967, 32, 4136. (d) Bachelor, F. W.;
Cheriyan, U. O. Tetrahedron Lett. 1973, 35, 3291. (e) Guerrero, A. F.;
Kim, H.; Schlecht, M. F. Tetrahedron Lett. 1988, 29, 6707.
(13) Peluso, P.; Greco, C.; De Lucchi, O.; Cossu, S. Eur. J. Org. Chem.
2002, 23, 4024.
Bicyclic ketones play a key role as building blocks in several
total syntheses of natural products, thanks to their ability to
simultaneously generate multiple stereocenters after the ap-
propriate chemical transformations. For example, they are
intermediates in the synthesis of prostaglandins,1 of the antitu-
mor echinosporin,2 and of the dolabellane diterpenoids: claenone,3a
stolonidiol,3b palominol,3c and dolabellatrienone.3c Furthermore,
these structures represent the core of complex molecules, such
as (-)-sordarin4 and nonsteroidal estrogens.5
§ Dipartimento di Scienze Ambientali, Universita` Ca’ Foscari di Venezia.
‡ Dipartimento di Chimica, Universita` Ca’ Foscari di Venezia.
† University of Zurich.
|| Dalhousie University.
(1) (a) Corey, E. J.; Weinshenker, N. M.; Schaff, T. A.; Huber, W. J.
Am. Chem. Soc. 1969, 91, 5675. (b) Corey, E. J.; Weinshenker, N. M.;
Schaff, T. A.; Huber, W.; Koelliker, N. M. J. Am. Chem. Soc. 1970, 92,
397.
(2) Kinsella, M. A.; Kalish, V. J.; Weinreb, S. M. J. Org. Chem. 1990,
55, 105.
(3) (a) Miyaoka, H.; Isaji, Y.; Kajiwara, Y.; Kunimune, I.; Yamada, Y.
Tetrahedron Lett. 1998, 39, 6503. (b) Miyaoka, H.; Baba, T.; Mitome, H.;
Yamada, Y. Tetrahedron Lett. 2001, 42, 9233. (c) Miyaoka, H.; Isaji, Y.;
Mitome, H.; Yamada, Y. Tetrahedron 2003, 59, 61.
(4) Chiba, S.; Kitamura, M.; Narasaka, K. J. Am. Chem. Soc. 2006, 128,
6931.
(14) Trost, B M. Acc. Chem. Res. 2002, 35, 695.
(15) Reagents 5 and 10 were synthesized with modifications of the
original procedures (see Supporting Information). (a) Schmerling, L. U.S.
Patent US2914571, 1959, to Universal Oil Prod. Co. (b) Nagendrappa, G.;
Griesbaum, K. J. Agric. Food Chem. 1978, 26, 581. (c) Herberich, G. E.;
Spaniol, T. P.; Steffan, U. Chem. Ber. 1994, 127, 1401.
(5) Muthyala, R. S.; Sheng, S.; Carlson, K. E.; Katzenellenbogen, B. S.;
Katzenellenbogen, J. A. J. Med. Chem. 2003, 46, 1589.
10.1021/jo070222g CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/03/2007
4272
J. Org. Chem. 2007, 72, 4272-4275

SCHEME 2. Synthesis of Acetals 6
SCHEME 3. Synthesisa of Oxazolidines 12, 12′, 13, and
Ketone (R)-1a12
TABLE 1. Reaction Conditions of 5 with Alcoholates and Diols 4
a Reagents and conditions: (i) 1.5 equiv of 7, t-BuOK, NMP, 16 h, 80
°C; (ii) PPTS (pyridinium p-toluenesulfonate), H2O-THF, 2 days, rt.
base
alcohol or 4:5 product time
temp conva dea
diol 4
ratio
6
(°C)
3 days 80
3 days 80
(%) (%)
TABLE 2. Yields and Diastereoselectivity of the Reaction of
Dihaloalkenes with Aminoalcohols
1
2
3
4
5
6
t-BuONa
t-BuOLi
t-BuOK
t-BuOK
t-BuOK
t-BuOK
4a
4a
4a
4b
4c
4d
3.5:1
3.5:1
3.5:1
2:1
1:1
1:1
6a
6a
6a
6b
6c
6d
20
24 h
48 h
48 h
12 h
80
80
80
60f80
70
<5
<5
70
61
66
2
a Calculated on the basis of NMR spectra.
Our studies come as an extension of the substitution reaction
we applied to the synthesis of perfunctionalized benzocyclot-
rimers,16 by replacing the thiol nucleophiles with the alcoholates
and diols 4. The synthetic protocol is represented in Scheme 2,
and the results are summarized in Table 1.There are only a few
examples of nucleophilic substitution by alcoholates on halo-
genated alkenes.17
substrate
aminoalcohol
product
yield (%)
de (%)
1
2
3
4
5
6
2a
2a
2a
10
11
2c
7
8
9
7
7
7
12
1a
1a
90
80
82
94a
33b
60b
16
17
70
90
93a
94a
The acetalic products 6 are obtained in one pot from 5,15 after
elimination with 1 equiv of base. To assess the best reaction
conditions, 5 was initially reacted with ethylene glycol 4a using
different tert-butanolate salts, as suggested in the literature.18
When the reaction was carried out with t-BuONa (Table 1,
entry 1), the formation of 2a was observed after 24 h at 80 °C
and the acetal 6a after 3 days in low conversion. When the
base t-BuOLi was employed (entry 2), the selective elimination
of the exo-proton of 5 was observed, while 6a was not detected,
even at higher temperature and with longer reaction times. These
data suggest that the use of t-BuOK as base for 24 h (entry 3)
is best for this reaction.
The role of steric hindrance in the chiral process was
evaluated by reacting 5 with the alcohol 4b and the diols 4c
and 4d (entries 4-6). The larger auxiliaries 4b and 4c induce
enantioselectivity, although at low conversion, while 4d is more
reactive but gives two diastereoisomers in a 1:1 ratio. The neutral
workup procedure12 used for all these experiments led to the
isolation of a single epimer with the exo orientation of the H3
proton (from the detection of NOESY dipolar interactions with
the methano bridge).
a Calculated on the basis of H NMR spectra. b Taken as the ee of (S)-
1a over (R)-1a (from chiral GC analysis).
1
approach of the alcoholate to the vinyl bond, in which the bulky
group plays a key role; on the other hand, its steric hindrance
might prevent the second ring closure. Opposite considerations
may be done for entry 6: the methyl groups of 4d are not bulky
enough to induce diastereoselectivity on the first addition step
but are sufficiently small to allow the ring-forming acetalization.
The aforementioned remarks led us to take into account the
use of nonsymmetric chiral auxiliaries in order to induce the
required high stereoselectivity during the first addition step,
while at the same time allowing the successive ring-closing
acetalization. The easily available aminoalcohols 7-919 provide
a series of appropriate, inexpensive chiral auxiliaries. The
reaction, exemplified in Scheme 3 for 2a, is general for
substrates 10, 11, and 2c, as shown in Table 2. In principle, the
addition of (-)-ephedrine20 may occur at the pro-R or pro-S
faces of the dichlorovinyl double bond and from the endo or
exo directions. Actually, the 1H NMR spectrum of the reaction
crude shows only three doublets at about δ 5.1 and in the
intensity ratios 85:12:3, attributed to H5′ of the oxazolidine ring,
that exactly match, in terms of intensity, three doublets at about
δ 4.4, attributed to H3 of the norbornene unit.
These results led to the following considerations. According
to the AdN-E mechanism generally assumed for this reaction,11
the diastereoselectivity of 4c (entry 5) may be due to the initial
(16) Borsato, G.; Brussolo, S.; Crisma, M.; De Lucchi, O.; Lucchini,
V.; Zambon, A. Synlett 2005, 7, 1125.
(17) Adams, C. H. M.; Mackenzie, K.; Young, P. R. J. Chem. Soc., Perkin
Trans. 2 1972, 1856.
(18) (a) Moyano, A.; Charbonier, F.; Greene, A. E. J. Org. Chem. 1987,
52, 2919. (b) Himbert, G.; Lo¨ffler, A. Synthesis 1992, 495. (c) Smith, B.
A.; Callinan, A. J.; Swenton, J. S. Tetrahedron Lett. 1994, 35, 2283.
(19) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. ReV. 1996, 96, 835.
(20) (a) Clayden, J.; Wah, L.; Helliwell, M. Tetrahedron: Asymmetry
2001, 12, 695. (b) Clayden, J.; Wah, L. Tetrahedron Lett. 2001, 42, 3163.
(c) Clayden, J.; Wah, L.; Helliwell, M. Tetrahedron 2004, 60, 4399. (d)
Clayden, J.; Lund, A.; Vallverdu´, L.; Helliwell, M. Nature 2004, 431, 966.
J. Org. Chem, Vol. 72, No. 11, 2007 4273

and 2c23 (entries 4-6). Olefin 10 was unreactive, probably
because of stronger steric hindrance. On the other hand, (-)-
ephedrine proved to be adequately efficient with substrates 11
and 2c. The major diastereoisomers 16 (subjected to an X-ray
crystal structure analysis; see Supporting Information) and 17
were purified by crystallization.
SCHEME 4. Isomerization of 12 into 13
The NOESY analysis of a sample (obtained as described
below), where the major and the intermediate isomers are in an
approximate 1:1 ratio, is consistent with the determined structure
of 12 (see below) and also allows the assignment of the
configuration of 13 (with inverted orientation of the oxazolidine
ring) to the intermediate substance. The mother liquor, collected
from the crystallization process, is sufficiently enriched in the
minor isomer for a NOESY analysis, allowing the assignment
of the configuration of 12′. The details of the NOESY analyses
are reported in the Supporting Information. Thus, the diastere-
oisomeric excess (de) for the desymmetrization process is 94%
on the pro-R face.
The synthesis, presented in this paper, of bicyclic ketones
with excellent ee offers several advantages: among them, the
use of inexpensive reagents, the short synthetic sequence, the
high crystallinity of the products, and the mild conditions,
described in the literature,24 required for the removal of the
auxiliary and the halogen atom.
The potential extension of this protocol has been tested with
haloolefins 11 and 2c, which are representative of a wide variety
of substrates containing the dihalovinyl moiety.25 The protocol
can be exploited for other chemical transformations of dichlo-
roolefins, recently reported.26
The major product can be easily separated by crystallization
from pentane and is characterized as 12 by an X-ray crystal
structure analysis (see Supporting Information).
As for the mechanism, these findings agree with an AdN-E
approach of the oxygen base of (-)-ephedrine 7 exclusively to
the dichlorovinyl exo face of 2a, with a strong preference for
the pro-R approach over the pro-S one, and formation of the
diastereoisomeric vinyl ethers 14 and 14′.
There follows the AdN closure of nitrogen, which is easier
from the exo direction (although Ph and Me are pushed toward
the chlorine atom) than from the endo orientation: thus the
major 14 vinyl ether gives the 12 and the 13 isomers in an 88:
12 ratio, while from the minor ether 14′ we can detect only the
formation of 12′.
The position of the Ph group in 14, which is oriented away
from the chlorine atom, explains the preference for the isomers
12 and 13 in the desymmetrization process.
After the ring closure, chlorine is pushed by protonation into
the endo direction and the steric interaction in 12 between
chlorine and Ph becomes more important. As a matter of fact,
in an acidic contest (the case was monitored by NMR in CDCl3
for 14 days), the new equilibrium of 59:41 between 12 and 13
is reached. The oxacationic intermediate 15 is proposed (Scheme
4), where the chlorine atom maintains the endo orientation, and
neither epimerization nor deuteration (these occurrences are not
actually observed) are permitted.
Experimental Section
General Procedure for the Reaction of Dihaloolefins with
Amino Alcoholates, Alcohols, and Diols: 1.5 equiv of aminoal-
coholates, or alcoholates or diolates 4, prepared in situ by reaction
with base (3 equiv), in dry NMP (10 mL), was added to a solution
of 1.0 equiv of dihaloolefins 10, 11, or 2c in dry NMP (5 mL). 2a
was previously prepared in situ by reacting 5 with 1.0 equiv of
base. After 16 h at 80 °C under an Ar atmosphere, the cooled
reaction mixture was treated with H2O (20 mL) and extracted with
n-pentane (3 × 20 mL); the combined organic layers were dried
over MgSO4, and the solvent was eliminated. Products 6 were
purified no further. Products 12, 16, and 17 were isolated by
crystallization from n-pentane. Products 13 and 12′ could not be
purified further and were analyzed in a mixture by 1H NMR, COSY,
1
and NOESY experiments. 6a: oil; H NMR (CDCl3, 400 MHz) δ
6.13 (2H, AB system), 4.14 (1H, d, J ) 3.7 Hz), 4.02-3.97 (3H,
m), 3.94-3.89 (1H, m), 3.06 (1H, m), 2.76 (1H, m), 1.83 (1H,
dm, J ) 9.6 Hz), 1.81 (1H, dm, J ) 9.6 Hz); 13C NMR (CDCl3,
100 MHz) δ 136.1, 134.9, 114.6, 66.9, 65.7, 64.6, 50.5, 47.6, 45.2.
6d: oil; 1H NMR (CDCl3, 400 MHz) δ 6.30 (2H, AB system), 4.10
(1H, d, J ) 3.4 Hz), 3.73-3.53 (2H, m), 3.06 (1H, m), 2.72 (1H,
m), 3.00 (1H, m), 1.84 (1H, dm, J ) 9.5 Hz), 1.74 (1H, dt, J )
1
9.5, 1.9 Hz), 1.24 (6H, m). 6d′: oil; H NMR (CDCl3, 400 MHz)
δ 6.31 (2H, AB system), 4.18 (1H, d, J ) 3.4 Hz), 3.67 (2H, m),
3.03 (1H, m), 2.79 (1H, m), 1.80 (2H, AB system), 1.26 (6H, m);
(23) Tranmer, G. K.; Yip, C.; Handerson, S.; Jordan, R. W.; Tam, W.
Can. J. Chem. 2000, 78, 527.
(24) (a) Ballestri, M.; Chatgilialoglu, C.; Guerra, M.; Guerrini, A.;
Lucarini, M.; Seconi, G. J. Chem. Soc., Perkin Trans. 2 1993, 3, 421. (b)
Chatgilialoglu, C.; Guerra, M.; Guerrini, A.; Seconi, G.; Clark, K. B. J.
Org. Chem. 1992, 57, 2427. (c) Chatgilialoglu, C.; Guerrini, A.; Lucarini,
M. J. Org. Chem. 1992, 57, 3405.
(25) (a) Komatsu, K.; Aonuma, S.; Jinbu, Y.; Tsuji, R.; Hirosawa, C.;
Takeuchi, K. J. Org. Chem. 1991, 56, 195. (b) Altundas, A.; Dastan, A.;
McKee, M. M.; Balci, M. Tetrahedron 2000, 33, 6115. (c) Adam, W.;
Cakmak, O.; Saha-Moeller, C. R.; Tutar, A. Synlett 2002, 1, 49. (d) Lemal,
D. M. J. Am. Chem. Soc. 1966, 88, 582. (e) Alden, C. K. J. Chem. Soc. C
1968, 1228. (f) Wilt, V. J. Org. Chem. 1970, 35, 2410. (g) Neudorff, W.
D.; Schulte, N.; Lentz, D.; Schlueter, A. D. Org. Lett. 2001, 3, 3115. (h)
Tanyeli, C.; Karadag, T.; Akhmedov, I. M. Tetrahedron: Asymmetry 2004,
15, 307. (i) Tuerkmen, Y. E.; Akhmedov, I. M.; Tanyeli, C. Tetrahedron:
Asymmetry 2005, 16, 2315. (j) Zonta, C.; Fabris, F.; De Lucchi, O. Org.
Lett. 2005, 6, 1003.
The desymmetrization process of 2a was also tested with the
aminoalcohols L-prolinol 8 and (2S)-3-exo-aminoisoborneol 921
(entries 2 and 3 in Table 2). The degree of conversion can be
1
established from observation of the vinylic region of the H
NMR spectra, while the single adducts (ethers or oxazolidine)
could neither be separated nor characterized. The de for the
desymmetrization process is then taken as the ee measured by
chiral GC analysis (see Supporting Information) for the (S)-1a
and (R)-1a chloroketones, obtained from the crude mixture by
the action of PPTS in THF-H2O (Table 2).
These results highlight the efficiency of (-)-ephedrine 7 as
a chiral auxiliary. It was then tested with haloolefins 10,15 11,22
(21) White, J. D.; Duncan, J. W.; Sundermann, K. F. Organic Syntheses;
Wiley & Sons: New York, 2004; Collect. Vol. 10, p 305.
(22) Reagent 11 was synthesized with modification of the original
procedures (see Supporting Information). (a) Pomerantz, M.; Witherup, T.
H.; Schumann, W. C. J. Org. Chem. 1971, 36, 2080. (b) Buttus, N. H.;
Cornforth, J.; Hitchcock, P. B.; Kumar, A.; Stuart, A. S. J. Chem. Soc.,
Perkin Trans. 1 1987, 851.
(26) (a) Khan, F. A.; Prabhudas, B. A. Tetrahedron Lett. 1999, 40, 9289.
(b) Khan, F. A.; Prabhudas, B.; Dash, J.; Sahu, N. J. Am. Chem. Soc. 2000,
122, 9558. (c) Khan, F. A.; Dash, J. J. Am. Chem. Soc. 2002, 124, 2424.
(d) Khan, F. A.; Dash, J.; Sahu, N.; Gupta, S. Org. Lett. 2002, 4, 1015. (e)
Khan, F. A.; Dash, J.; Prabhudas, B. Chem. Eur. J 2004, 10, 2507. (f)
Khan, F. A.; Dash, J.; Bhimsen, R. Tetrahedron Lett. 2004, 45, 9285. (g)
Khan, F. A.; Bhimsen, R. Tetrahedron Lett. 2006, 47, 9285.
4274 J. Org. Chem., Vol. 72, No. 11, 2007

IR (neat) νmax (cm-1) 3452, 2979, 2878, 1726, 1455, 1280, 1190,
1080, 727, 697, 581. 12: solid; mp 116.2 °C; [R]D ) -43 (c )
0.53, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.42 (2H, d, J ) 7.0
Hz), 7.27 (2H, t, J ) 7.3 Hz), 7.21 (1H, t, J ) 7.2 Hz), 6.38 (2H,
AB system), 5.06 (1H, d, J ) 7.9 Hz), 4.45 (1H, d, J ) 3.4 Hz),
3.23 (1H, dq, J ) 6.5, 1.3 Hz), 3.12 (1H, m), 3.09 (1H, m), 2.47
(3H, s), 1.79 (1H, dm, J ) 9.8 Hz), 1.79 (1H, dt, J ) 9.8, 1.9 Hz),
0.71 (3H, d, J ) 6.5 Hz); 13C NMR (CDCl3, 100 MHz) δ 139.2,
137.8, 135.8, 127.8, 127.7, 127.4, 102.9, 80.8, 65.3, 61.6, 48.0,
44.9, 43.9, 34.7, 15.4; IR (KBr) νmax (cm-1) 3435, 2971, 2805,
1651, 1574, 1494, 1457, 1334, 1100, 766, 755, 585, 470. Anal.
Calcd for C17H20ClNO: C, 70.46; H, 6.96; N, 4.83. Found: C,
J ) 7.0 Hz), 6.37 (2H, AB system), 5.06 (1H, d, J ) 8.1 Hz), 4.51
(1H, d, J ) 3.3 Hz), 3.22 (1H, dq, J ) 6.5, 1.5 Hz), 3.17 (1H, m),
3.08 (1H, m), 2.46 (3H, s), 1.85 (2H, m), 0.70 (3H, d, J ) 6.5 Hz);
13C NMR (CDCl3, 100 MHz) δ 139.1, 137.9, 136.7, 128.1, 127.6,
127.4, 101.2, 80.9, 61.4, 57.0, 48.3, 45.1, 43.8, 34.6, 15.6; IR (KBr)
ν
max (cm-1) 3400, 3069, 2973, 2871, 1685, 1493, 1455, 1333, 1197,
757, 613, 583, 470. Anal. Calcd for C17H20BrNO: C, 61.09; H,
6.03; N, 4.19. Found: C, 61.20; H, 6.28; N, 4.49.
Synthesis of Ketone (R)-1a: A solution of 12 (220 mg, 0.76
mmol) and PPTS (190 mg, 0.76 mmol) in THF (5 mL) and H2O
(5 mL) was stirred at rt for 2 days and then diluted with 20 mL of
water and extracted with pentane (3 × 20 mL). The combined
organic layers were dried over MgSO4. The crude reaction product
was purified by Kugelrohr giving (R)-1a (90 mg, 83%, ee ) 98%,
GC) as oil. Spectral data were identical to those reported in
literature: IR (neat) νmax (cm-1) 1758 stretching CdO (lit.12c 1750);
1
70.37; H, 6.78; N 4.49. 13: H NMR (CDCl3, 400 MHz) δ 7.31
(2H, d, J ) 4.4 Hz), 7.28-7.19 (3H, m), 6.38 (2H, AB system),
5.02 (1H, d, J ) 7.6 Hz), 4.38 (1H, d, J ) 3.8 Hz), 3.86 (1H, q,
J ) 7.0 Hz), 3.14 (1H, m), 3.07 (1H, m), 2.44 (3H, s), 2.16 (1H,
dm, J ) 8.8 Hz), 1.85 (1H, dt, J ) 9.0, 1.9 Hz), 0.82 (3H, d, J )
1
[R]D ) +518 (c ) 0.26, CHCl3); H NMR (CDCl3, 400 MHz) δ
1
6.9 Hz). 12′: H NMR (CDCl3, 400 MHz) δ 7.29 (2H, d, J ) 5.2
6.57 (1H, m), 6.22 (2H, m), 4.10 (1H, d, J ) 3.5 Hz), 3.33 (1H,
m), 3.22 (1H, m), 2.38 (1H, dm, J ) 10.2 Hz), 2.07 (1H, dm, J )
10.2 Hz); 13C NMR (CDCl3, 100 MHz) δ 206.8, 140.7, 131.3, 56.9,
54.6, 46.2, 45.8; MS (EI, 70 eV) m/z 142 (M+, 40), 113 (6), 79
(100), 66 (75), 51 (45) 39 (55).
Hz), 7.27-7.19 (3H, m), 6.5 and 6.36 (2H, AB system), 5.13 (1H,
d, J ) 7.5 Hz), 4.35 (1H, d, J ) 3.6 Hz), 3.40 (1H, q, J ) 7.1 Hz),
3.09 (1H, m), 3.07 (1H, m), 2.42 (3H, s), 1.85-1.74 (2H, m),
0.73 (3H, d, J ) 6.6 Hz). 16: solid; mp 155.2 °C; [R]D ) +51 (c
1
) 0.6, CHCl3); H NMR (CDCl3, 400 MHz) δ 7.26 (2H, d, J )
8.3 Hz), 7.25-7.19 (3H, m), 6.76 (1H, d, J ) 9.0 Hz), 6.73 (1H,
d, J ) 9.0 Hz), 5.52 (1H, d, J ) 8.1 Hz), 4.60 (1H, s), 4.08 (1H,
dq, J ) 6.4, 1.6 Hz), 3.82 (3H, s), 3.82 (3H, s), 2.88 (1H, d, J )
9.8 Hz), 2.87 (3H, s), 2.85 (1H, d, J ) 9.8 Hz), 0.58 (3H, d, J )
6.4 Hz); 13C NMR (CDCl3, 100 MHz) δ 150.7, 150.6, 138.9, 131.2,
128.7, 127.7, 127.4, 127.3, 113.8, 113.4, 100.6, 82.0, 74.7, 70.9,
68.6, 60.4, 59.8, 56.9, 56.6, 31.9, 15.7; IR (KBr) νmax (cm-1) 3421,
3008, 2974, 2831, 1606, 1475, 1460, 1256, 1206, 1027, 1016, 754,
701, 565, 477. Anal. Calcd for C23H24Cl3NO3: C, 58.93; H, 5.16;
N, 2.99. Found: C, 58.71; H, 4.84; N, 3.12. 17: solid; mp 136.6
Acknowledgment. Alessandra Ciappa, Sara Bovo, Pi-
etrogiulio Frascella, and Sonia Ceoldo are gratefully acknowl-
edged for the GC measurements, the NMR analyses, and
elemental analysis. This work was co-funded by MIUR (Rome)
within the national PRIN framework.
Supporting Information Available: Crystallographic data,
NMR data, and experimental section. This material is available free
of charge via the Internet at http://pubs.acs.org.
1
°C; [R]D ) -55 (c ) 0.56, CHCl3); H NMR (CDCl3, 400 MHz)
δ 7.44 (2H, d, J ) 7.0 Hz), 7.26 (2H, t, J ) 6.8 Hz), 7.22 (1H, t,
JO070222G
J. Org. Chem, Vol. 72, No. 11, 2007 4275