Asymmetric aldol reactions using (S,S)-(+)-pseudoephedrine-based amides: Stereoselective synthesis of α-methyl-β-hydroxy acids, esters, ketones, and 1,3-syn and 1,3-anti diols

Article abstract of DOI:10.1021/jo000035h

A very efficient method for performing stereoselective aldol reactions is reported. The reaction of (S,S)-(+)-pseudoephedrine-derived propionamide enolates with several aldehydes yielded exclusively one of the four possible diastereomers in good yields, although transmetalation of the firstly generated lithium enolate with a zirconium(II) salt, prior to the addition of the aldehyde, is necessary in order to achieve high syn selectivity. The so-formed syn-α-methyl-β-hydroxy amides were transformed into other valuable chiral nonracemic synthons such as α-methyl-β-hydroxyacids, esters, and ketones. Finally, a stereocontrolled reduction procedure starting from the so-obtained α-methyl-β-hydroxy ketones has been developed allowing the synthesis of either 1,3-syn- or 1,3-anti-α-methyl-1,3-diols in almost enantiopure form by choosing the appropriate reaction conditions.

Full text of DOI:10.1021/jo000035h

3754
J . Org. Chem. 2000, 65, 3754-3760
Asym m etr ic Ald ol Rea ction s Usin g
(S,S)-(+)-P seu d oep h ed r in e-Ba sed Am id es: Ster eoselective
Syn th esis of r-Meth yl-â-h yd r oxy Acid s, Ester s, Keton es, a n d
1,3-Syn a n d 1,3-An ti Diols
J ose L. Vicario, Dolores Bad´ıa,* Esther Dom´ınguez, Mo´nica Rodr´ıguez, and Luisa Carrillo
Departamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad del Pa´ıs Vasco, P.O. Box 644,
48080 Bilbao, Spain
Received J anuary 11, 2000
A very efficient method for performing stereoselective aldol reactions is reported. The reaction of
(S,S)-(+)-pseudoephedrine-derived propionamide enolates with several aldehydes yielded exclusively
one of the four possible diastereomers in good yields, although transmetalation of the firstly
generated lithium enolate with a zirconium(II) salt, prior to the addition of the aldehyde, is necessary
in order to achieve high syn selectivity. The so-formed syn-R-methyl-â-hydroxy amides were
transformed into other valuable chiral nonracemic synthons such as R-methyl-â-hydroxyacids, esters,
and ketones. Finally, a stereocontrolled reduction procedure starting from the so-obtained R-methyl-
â-hydroxy ketones has been developed allowing the synthesis of either 1,3-syn- or 1,3-anti-R-methyl-
1,3-diols in almost enantiopure form by choosing the appropriate reaction conditions.
In tr od u ction
conditions, the stereochemistry of the first chiral center
would be controlled by the approach of the aldehyde from
one of the two diastereotopic faces of the enolate (the so-
called enantiofacial differentiation1e or diastereofacial
selectivity1a) and therefore by the chiral information
The aldol reaction is regarded as one of the most
powerful tools in organic synthesis for the formation of
carbon-carbon bonds. Consequently, over the past 20
years, an extensive number of methodologies for per-
forming enantioselective aldol reactions of chiral enolates
with achiral aldehydes have been reported in the litera-
ture.1 The different strategies employed in order to
achieve the desired high stereocontrol can be classified
according to the position in which the chiral information
is incorporated: (1) the use of carbonyl compounds
carrying chiral auxiliaries that can be easily removed
from the final product,2 (2) the use of metal enolates,
typically B, Ti, Sn, or Li, with the presence of a chiral
ligand bound covalently or not to the metal center,3 and
(3) performing the reaction in a catalytic fashion in the
presence of a chiral catalyst.4 Among the first ones, a vast
array of compounds have been used as chiral inductors,
such as Evans-type oxazolidinones,1b,c,5 Meyers oxazoli-
dines,3a bornane derivatives,6 thiazolidinones, thiazoli-
dinethiones or oxazolidinethiones,7 imidazolidinones,8
Oppolzer’s sultams,9 amino alcohols,10 aziridines,11 chiral
sulfoxides,12 ferrocenyliron complexes,13 diols,14 diamines,15
benzoxazinones,16 hydrazones,17 atropisomeric amines,18
menthone derivatives,19 and so on.
(3) For boron enolates, see: (a) Meyers, A. I.; Yamamoto, Y.
Tetrahedron 1984, 40, 2309-2315. (b) Reetz, M. T.; Kunisch, F.;
Heitman, P. Tetrahedron Lett. 1986, 27, 4721-4724. (c) Masamune,
S.; Sato, T.; Kim, B.-M.; Wollmann, T. A. J . Am. Chem. Soc. 1986,
108, 8279-8281. (d) Reetz, M. T.; Rivaedeneira, E.; Niemeyer, C.
Tetrahedron Lett. 1990, 27, 3863-3866. (e) Corey, E. J .; Kim, S. S. J .
Am. Chem. Soc. 1990, 112, 4976-4977. (f) Gennari, C.; Hewkin, C. T.;
Molinari, F.; Bernardi, A.; Comotti, A.; Goodman, J . M.; Paterson, I.
J . Org. Chem. 1992, 57, 5173-5177. (g) Gennari, C.; Moresca, D.; Vieth,
S.; Vulpetti, A. Angew. Chem., Int. Ed. Engl. 1993, 32, 1618-1621.
(h) Abu Hena, M.; Terauchi, S.; Kim, C.-S.; Horiike, M.; Kiyooka, S.-I.
Tetrahedron: Asymmetry 1998, 9, 1883-1890. For titanium enolates,
see: (i) Duthaler, R. O.; Hafner, A. Chem. Rev. 1992, 92, 807-832.
For tin enolates, see: (j) Kobayashi, S.; Uchiro, H.; Fujishita, Y.; Shiina,
I.; Mukaiyama, T. J . Am. Chem. Soc. 1991, 113, 4247-4252. For
lithium enolates, see: (k) Laube, T.; Dunitz, J . D.; Seebach, D. Helv.
Chim. Acta 1985, 68, 1373-1377. (l) Ando, A.; Shioiri, T. J . Chem.
Soc., Chem. Commun. 1987, 1620-1623. (m) Muraoka, M.; Kawasaki,
H.; Koga, K. Tetrahedron Lett. 1988, 29, 337-338. (n) Ando, A.; Shioiri,
T. Tetrahedron 1989, 45, 4969-4988. (o) J uaristi, E.; Beck, A. K.;
Hansen, J .; Matt, T.; Mukhopadhyay, T.; Simson, M.; Seebach, D.
Synthesis 1993, 1271-1290. (p) Landais, Y.; Ogay, P. Tetrahedron:
Asymmetry 1994, 5, 541-544. (q) Uragami, M.; Tomioka, K.; Koga, K.
Tetrahedron: Asymmetry 1995, 6, 701-704.
(4) For recent reviews on catalytic asymmetric aldol reactions, see:
(a) Gro¨ger, H.; Vogl, E. M.; Shibasaki, M. Chem. Eur. J . 1998, 4, 1137-
1141. (b) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357-389.
(5) (a) Evans, D. A. In Asymmetric Synthesis; Morrison, J . D., Ed.;
Academic Press: New York, 1984; Vol. 3, Part B, p 1. And also: (b)
Blaser, D.; Ko, S. Y.; Seebach, D. J . Org. Chem. 1991, 56, 6230-6233.
(c) Ghosh, A. K.; Cho, H.; Onishi, M. Tetrahedron: Asymmetry 1997,
8, 821-824.
If we assume that an enolate with one substituent at
the R-possition and with a determined geometry (E or
Z) undergoes an aldol reaction with an aldehyde, four
possible diastereoisomers can be formed. Under kinetic
(6) (a) Helmchen, G.; Leikauf, U.; Knopfel, I. T. Angew. Chem., Int.
Ed. Engl. 1985, 24, 874-880. (b) Oppolzer, W. Tetrahedron 1987, 43,
1969-2004. (c) Bonner, M. P.; Thornton, E. R. J . Am. Chem. Soc. 1991,
113, 1299-1308. (d) Yan, T. H.; Chu, V. V.; Lin, T. C.; Tseng, W. H.;
Cheng, T. W. Tetrahedron Lett. 1991, 32, 5563-5566. (e) Boeckman,
R. K.; J ohnson, A. T.; Musselman, R. A. Tetrahedron Lett. 1994, 35,
8521-8524. (f) Palomo, C.; Gonza´lez, A.; Garc´ıa, J . M.; Landa, C.;
Oiarbide, M.; Rodr´ıguez, S.; Linden, A. Angew. Chem., Int. Ed. Engl.
1998, 37, 180-184. (g) Palomo, C.; Oiarbide, M.; Aizpurua, J . M.;
Gonza´lez, A.; Garc´ıa, J . M.; Landa, C.; Odriozola, I.; Linden, A. J . Org.
Chem. 1999, 64, 8193-8200 and references therein. See also refs 7c-
f, 8b, and 9.
(1) For some reviews, see: (a) Heathcock, C. H. In Asymmetric
Synthesis; Morrison, J . D., Ed.; Academic Press: New York, 1984; Vol.
3, Part B, Chapter 2. (b) Kim, B. M.; Williams, S. F.; Masamune, S. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 2 (Heathcock, C. H., Ed.), Chapter
1, p 239. (c) Evans, D. A.; Nelson, J . V.; Taber, T. R. Top. Stereochem.
1982, 13, 1-28. (d) Paterson, I. Contemp. Org. Synth. 1994, 1, 317-
338. (e) Braun, M. Angew. Chem., Int. Ed. Engl. 1987, 26, 24-37. (e)
Heathcock, C. H. Science 1981, 214, 395-401.
(2) Seyden-Penne, J . Chiral Auxiliaries and Ligands in Asymmetric
Synthesis; J ohn Wiley and Sons: New York, 1995; Chapter 6, p 306.
10.1021/jo000035h CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/20/2000

Reactions Using (S,S)-(+)-Pseudoephedrine dAmides
J . Org. Chem., Vol. 65, No. 12, 2000 3755
Sch em e 1
F igu r e 1.
attached to the enolate. The stereochemistry of the
second chiral center would be controlled by the approach
of the aldehyde from one of its two enantiotopic faces
(named as simple diastereoselection1a) and therefore by
the steric requirements derived from a cyclic transition
state such as a Zimmermann-Traxler-like or related
mechanism.20 The main target when planning an aldol
reaction is to achieve complete stereocontrol in both of
the aforementioned aspects, thus allowing the prepara-
tion of a single isomer from the four possible ones (Figure
1).
In this context, in connection with our studies in the
field of the asymmetric synthesis of natural products,21
and continuing with our preliminary study on the ste-
reocontrolled aldol reaction,22 we wanted to develop an
easy and cheap methodology to access to 1,3-dioxygenated
chiral nonracemic building blocks. Taking into account
the fact that (S,S)-(+)-pseudoephedrine, which is a com-
mercially available reagent in both enantiomeric forms,
has been recently used as a chiral auxiliary in asym-
metric alkylation reactions with excellent results,23 we
decided to develop an extensive protocol for performing
stereoselective aldol reactions employing this particular
amino alcohol as the chirality source. Moreover, the
obtained chiral nonracemic aldol products could be used
as suitable starting materials for their conversion into
useful chiral building blocks such as â-hydroxy acids,
esters, and ketones and into 1,3-syn and 1,3-anti diols.
Resu lts a n d Discu ssion
(7) Nagao, Y.; Hagiwara, Y.; Kumagai, T.; Ochiai, M.; Inoue, T.;
Hashimoto, K.; Fujita, E. J . Org. Chem. 1986, 51, 2391-2393. (b)
Hsiao, C. L.; Liu, L.; Miller, M. J . J . Org. Chem. 1987, 52, 2201-2206.
(c) Yan, T.-H.; Lee, H.-C.; Tan, C.-W. Tetrahedron Lett. 1993, 34, 3559-
3562. (d) Yan, T.-H.; Tan, C.-W.; Lee, H.-C.; Lo, H.-C.; Huang, T.-Y. J .
Am. Chem. Soc. 1993, 115, 2613-2621. (e) Yan, T.-H.; Hung, A.-W.;
Lee, H.-C.; Chang, C.-S. J . Org. Chem. 1994, 59, 8187-8191. (f) Yan,
T.-H.; Hung, A.-W.; Lee, H.-C.; Chang, C.-S.; Liu, W.-H. J . Org. Chem.
1995, 60, 3301-3306.
(8) (a) Davies, S. G.; Edwards, A. J .; Evans, G. B.; Mortlock, A. A.
Tetrahedron 1994, 50, 6621-6642. (b) Palomo, C.; Oiarbide, M.;
Gonza´lez, A.; Garc´ıa, J . M.; Berre´e, F.; Linden, A. Tetrahedron Lett.
1996, 37, 6931-6934.
(9) (a) Oppolzer, W.; Blagg, J .; Rodr´ıguez, I.; Walther, E. J . Am.
Chem. Soc. 1990, 112, 2767-2772. (b) Oppolzer, W.; Lienard, P.
Tetrahedron Lett. 1993, 34, 4321-4324.
(10) For a review, see: (a) Ager, D. J .; Prakash, I.; Schaad, D. R.
Chem. Rev. 1996, 96, 835-875. See also: (b) Katsuki, T.; Yamaguchi,
M. Tetrahedron Lett. 1985, 26, 5807-5810. (c) Gennari, C.; Colombo,
L.; Bertolini, G.; Schimperna, G. J . Org. Chem. 1987, 52, 2754-2760.
(d) Myers, A. G.; Widdowson, K. L. J . Am. Chem. Soc. 1990, 110, 9672-
9674. (e) Xiang, Y.; Olivier, E.; Ouimet, N. Tetrahedron Lett. 1992,
33, 457-460. (f) Abiko, A.; Liu, J .-F.; Masamune, S. J . Am. Chem. Soc.
1997, 119, 2586-2587.
(11) Tanner, D.; Bigerson, C.; Gogoll, A. Tetrahedron 1994, 50,
9797-9824.
(12) (a) Soladie´, G. In Asymmetric Synthesis; Morrison, J . D., Ed.;
Academic Press: New York, 1984; Vol. 2, p 157. (b) Wills, M.; Butlin,
R. J .; Linney, I. D. Tetrahedron Lett. 1992, 33, 5427-5430. (c) Walker,
A. J . Tetrahedron: Asymmetry 1992, 3, 961-998.
In a first test reaction, the amide 1 prepared by a
reported procedure23a was deprotonated with 2 equiv of
LDA at -78 °C and treated with benzaldehyde at 0 °C
yielding a 1:1 mixture of 2a and 3a (Scheme 1), which
could be easily separated by flash column chromatogra-
phy. The presence of the corresponding diastereomers
ent-2a or ent-3a could not be detected. Lowering the
temperature to -78 °C increased the 2a /3a ratio to 60:
40 and to 65:35 at -105 °C. The absolute configuration
of the two newly generated chiral centers of both products
was established by hydrolysis and esterification to the
corresponding methyl esters, whose coupling constants
between H1 and H2 and [R]20D values were compared with
those reported in the literature (see Experimental Sec-
tion). In order to unambiguously assure that the products
ent-2a and ent-3a were not present, the reaction mixture
was subjected to HPLC analysis under previously opti-
mized conditions with a mixture of the four products
obtained by other procedures.24 Although the syn/anti
ratio (simple diastereoselection) was not good, the excel-
lent results concerning to the face selection of the reaction
indicated the utility of the chiral auxiliary (S,S)-(+)-
pseudoephedrine in this reaction. It should also be
pointed out that the reaction was clean and fast and did
not require the aid of LiCl salts to accelerate it, as was
previously reported in other reactions of pseudoephedrine
amide lithium enolates.25
(13) (a) Liebeskind, L. S.; Welker, M. E. Tetrahedron Lett. 1984,
25, 4341-4344. (b) Ojima, I.; Kwon, H. B. J . Am. Chem. Soc. 1988,
110, 5617-5621. (c) Cooke, J . W. B.; Daveis, S. G.; Naylor, A.
Tetrahedron 1993, 49, 7955-7966.
(14) Braun, M.; Sacha, H. Angew. Chem., Int. Ed. Engl. 1991, 30,
1218-1320.
(15) Ahn, K. H.; Yoo, D. J .; Kim, J . S. Tetrahedron Lett. 1992, 33,
6661-6664.
(16) Miyake, T.; Seki, M.; Nakamura, Y.; Ohmizu, H. Tetrahedron
Lett. 1996, 37, 3129-3132.
(22) Vicario, J . L.; Bad´ıa, D.; Dom´ınguez, E.; Carrillo, L. Tetrahedron
Lett. 1998, 39, 9267-9270.
(17) Enders, D.; Dyker, H.; Raabe, G. Angew. Chem., Int. Ed. Engl.
1993, 32, 421-423.
(23) For the use of (S,S)-(+)-pseudoephedrine as chiral auxiliary,
see: (a) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky,
D. J .; Gleason, J . L. J . Am. Chem. Soc. 1997, 119, 6496-6511. (b)
Myers, A. G.; McKinstry, L. J . Org. Chem. 1996, 61, 2428-2440. (c)
Myers, A. G.; Gleason, J . L.; Yoon, T.; Kung, D. W. J . Am. Chem. Soc.
1997, 119, 656-673.
(18) Hughes, A. D.; Price, D. A.; Shishkin, O.; Simpkins, N. S.
Tetrahedron Lett. 1996, 37, 7607-7610.
(19) Abiko, A.; Liu, J .-F.; Masamune, S. J . Org. Chem. 1996, 61,
2590-2591.
(20) Zimmerman, H. E.; Traxler, M. D. J . Am. Chem. Soc. 1957,
79, 1920-1923.
(24) The isomers ent-2a and ent-3a were obtained as pure com-
pounds by epimerizing the R-carbon of 3a and 2a , respectively, with
LDA in refluxing THF followed by column chomatography separation
of the two formed diastereoisomers (3a and ent-2a in the reaction of
3a and 2a and ent-3a in the reaction of 2a ).
(21) See, for example: (a) Carrillo, L.; Bad´ıa, D.; Dom´ınguez, E.;
Vicario, J . L.; Tellitu, I. J . Org. Chem. 1997, 62, 6716-6721. (b) Vicario,
J . L.; Bad´ıa, D.; Dom´ınguez, E.; Carrillo, L. J . Org. Chem. 1999, 64,
4610-4616.

3756 J . Org. Chem., Vol. 65, No. 12, 2000
Vicario et al.
Ta ble 1. Tr a n sm eta la tion Assa ys in Or d er To Im p r ove
th e Syn /An ti Ra tio of th e Ald ol Rea ction
Sch em e 2
entry
metal salt
Ti(OiPr)4
equiv Ta (°C) yield (%) syn/antib
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1
1
2
1
2
1
2
2
2
2
2
1
2
2
2
2
1
0
-105
-105
-105
-105
0
65
71
68
73
77
75
70
38c
0
81
78
80
79
75
79
90
87
66/34
71/29
77/23
64/36
75/25
53/47
57/43
61/39
Ti(OiPr)4
Ti(OiPr)4
TiCl(OiPr)3
TiCl(OiPr)3
SnCl4
SnCl4
0
rt
0
0
Ta ble 2. Yield s a n d Ster eoselectivities Obta in ed in th e
Asym m etr ic Ald ol Rea ction of Am id e 1 w ith Sever a l
Rep r esen ta tive Ald eh yd es
CF3SO3B(nBu)2
CF3SO3B(nBu)2
ZnCl2
60/40
78/22
61/39
71/29
80/20
89/11
94/6
entry
product
R
syn/antia
2/ent-2a
yieldb (%)
ZnCl2
MgCl2
MgCl2
ZrCp2Cl2
ZrCp2Cl2
ZrCp2Cl2
ZrCp2Cl2
-78
-105
-105
0
-78
-105
-105
1
2
3
4
5
2a
2b
2c
2d
2e
Ph
Me
Et
94/6
90/10
96/4
>99/<1
>99/<1
>99/<1
>99/<1
>99/<1
>99/<1
>99/<1
90
88
90
94
94
iPr
tBu
83/17
a
Determined by HPLC (Chiralcel OD column, UV detector,
hexanes/iPrOH 70:30, flow rate 1.00 mL/min). b Yield of 2a -e after
flash column chromatography purification.
a
Temperature at which the PhCHO addition step was per-
b
formed. Determined by HPLC (Chiralcel OD column, UV detec-
tor, hexanes/iPrOH 70:30, flow rate 1.00 mL/min). c Complete
conversion was not achieved.
As it is known that the use of enolates of metals other
than lithium with stronger chelation abilities improve
the simple diastereoselection in aldol reactions,26 several
other metals in different proportions and temperatures
were tested. In all cases, the lithium enolate was sub-
jected to a transmetalation process, which was performed
by adding the corresponding metal salt at -78 °C
followed by stirring for 1h at this temperature (Table 1).
In all trials, the use of 2 equiv of ZrCpCl2 followed by
addition of the aldehyde at -105 °C resulted in the best
2a /3a ratio. This tendency for a high syn selection for
zirconium enolates in aldol reaction has been previously
reported.10b,26a,h As expected, the temperature of the
addition step had a strong influence on the syn/anti
selectivity. It should also be pointed out that the im-
provement observed with two equivalents of the metal
salts instead of one turned out to be relevant to the
mechanistic pathway of the reaction.
F igu r e 2.
anti selectivity improved when the bulkiness of the R
chain in the aldehyde is increased.
Once the methodology was optimized, it was extended
to a full range of representative aldehydes, all of which
reacted as expected to yield the aldols 2a -e (Scheme 2,
Table 2) in excellent yields and with high distereoface
and syn selection, as HPLC analysis of the crude mix-
tures indicated. It could also be observed that the syn/
These results are in accordance with a previously
proposed mechanism21b,23a in which the adduct of the
pseudoephedrine amide aldol reaction arises from attack
of the preformed Z enolate of the less hindered si face of
an intermediate in an opened staggered conformation,
which remains rigid with the help of bridging solvent or
iPrNH (from LDA) molecules (Figure 2). In this case, the
fact that 2 equiv of metal salt was needed in order to
improve the syn/anti diastereoselection overrides the
possibility of an intermediate incorporating only one
metal that could bind both alkoxide units via an O-M-O
bond and supports the existence of the mentioned open
intermediate. However, the possible formation of an
internal chelate between the metal on the alkoxide
oxygen of the chiral auxiliary and the amide nitrogen has
been pointed out.27
(25) For the effect of LiCl in the reaction of pseudoephedrine amide
enolates, see: Ru¨ck, K. Angew. Chem., Int. Ed. Engl. 1995, 34, 433-
435. See also: Henderson, K. W.; Dorigo, A. E.; Liu, Q.-Y.; Williard,
P. G.; Schleyer, P. v. R.; Bernstein, P. R. J . Am. Chem. Soc. 1996, 118,
1339-1347 and references therein.
(26) For some representative examples of aldol reactions with a
previous transmetalation step, see: (a) Evans, D. A.; McGee, L. R.
Tetrahedron Lett. 1980, 21, 3975-3978. (b) Imamoto, T.; Kusumoto,
T.; Yokoyama, M. Tetrahedron Lett. 1983, 24, 5233-5236. (c) Naka-
mura, E.; Kuwajima, I. Tetrahedron Lett. 1983, 24, 3343-3346. (d)
Heathcock, C. H.; Arseniyadis, S. Tetrahedron Lett. 1985, 26, 6009-
6012. (e) Shibasaki, M.; Ishida, Y.; Okabe, N. Tetrahedron Lett. 1985,
26, 2217-2220. (f) Nerz-Stormes, M.; Thornton, E. R. Tetrahedron Lett.
1986, 27, 897-900. (g) Siegel, C.; Thornton, E. R. Tetrahedron Lett.
1986, 27, 457-460. (h) Murphy, P. J .; Procter, G.; Russell, A. T.
Tetrahedron Lett. 1987, 28, 2037-2040. (i) Nerz-Stormes, M.; Thorn-
ton, E. R. J . Org. Chem. 1991, 56, 2489-2498. (j) Swiss, K. A.; Choi,
W.-B.; Liotta, D. C.; Abdel-Magid, A. F.; Maryanoff, C. A. J . Org. Chem.
1991, 56, 5978-5980. (k) van Draanen, N. A.; Arseniyadis, S.;
Crimmins, M. T.; Heathcock, C. H. J . Org. Chem. 1991, 56, 2499-
2506. (l) Hayashi, T. Tetrahedron Lett. 1991, 32, 5369-5372. (m) Duffy,
J . L.; Yoon, T. P.; Evans, D. A. Tetrahedron Lett. 1995, 36, 9245-9248.
See also refs 6c, 9a, 10b, 13, 14, and 16.
Concerning simple diastereoselection, the use of eno-
lates of transition metals allows the metal to employ its
empty orbitals, exerting a strong influence on the angles
between RCHO‚‚‚M‚‚‚Oenolate, as postulated in the Zim-
(27) Micouin, L.; J ullian, V.; Quirion, J .-C.; Husson, H.-P. Tetrahe-
dron: Asymmetry 1996, 7, 2839-2846.

Reactions Using (S,S)-(+)-Pseudoephedrine dAmides
J . Org. Chem., Vol. 65, No. 12, 2000 3757
Sch em e 3
Sch em e 4
Sch em e 5
Ta ble 3. Yield s a n d Ster eoselectivities Obta in ed in th e
Asym m etr ic Syn th esis of th e r-Meth yl-â-h yd r oxy Acid s
a n d Ester s 4a -e a n d 5a -e
entry product
R
yielda (%) product yieldb (%) eec (%)
1
2
3
4
5
4a
4b
4c
4d
4e
Ph
Me
Et
90
93
85
98
96
5a
5b
5c
5d
5e
91
92
88
86
90
>99
>99
>99
>99
>99
iPr
tBu
At this point, and as an example of useful products that
can be obtained by this methodology, we were able to
synthesize (2S,3R)-1-ethylpropyl-3-hydroxy-2-methylpen-
tanoate 5f, the enantiomer of the natural product (+)-
sitophilate, which is the aggregation pheromone of the
male granary weevil Sitophilus granarius.29,30 The syn-
thesis was posssible by performing the esterification
reaction of the acid 4c using 3-pentanol instead of
methanol. The product was obtained in excellent yield
(89%) and almost optically pure (ee >99%) according to
chiral HPLC analysis.
a
Yield of pure product after acid-base standard workup. b Yield
of pure product after flash column chromatography purification.
c Determined by chiral HPLC (Chiracel OD, UV detector, hexanes/
isopropyl alcohol 93:7 as eluent. Flow rate 0.75 mL/min.).
merman-Traxler transition state. This would result in
a pseudo-chair28 conformation for the transition state in
which the bulky R substituent on the aldehyde would lie
in an equatorial position in order to avoid steric repul-
sions with the chiral auxiliary and therefore afford the
diastereoisomer of relative syn configuration (see Figure
2).
(2) Syn th esis of r-Meth yl-â-h yd r oxy Keton es. It
is known that reaction of organolithium reagents with
tertiary amides yields the corresponding ketones in a
single step.31 In this case the key step is the formation
of a stable tetrahedral intermediate after the addition
of the organolithium reagent across the CdO double bond
which, upon aqueous workup, affords the desired ketones.
The stability of this intermediate avoids further attack
by other molecules of organometallic reagent, which
would result in the formation of a tertiary alcohol
byproduct. In the particular case of the aldols 2a -e,
several other side reactions could occur as a consequence
of the presence of a strongly basic medium. Thus,
enolization would lead to epimerization at the R-carbon
and thus to a mixture of syn- and anti-R-methyl-â-
hydroxy ketones or amides, and â-elimination of the OH
functionality would yield R,â unsaturated ketones or
amides. However, by employing the conditions optimized
by Myers et al. in the reaction of pseudoephedrine amides
with organolithium reagents,23a and including an extra
equivalent of organolithium reagent in order to depro-
tonate the extra hydroxy group present in the substrate,
none of these side reactions were found to occcur and the
desired ketones 6a -i were obtained in excellent yields
and as single diastereomers as the analysis of the 1H
NMR spectra of the crude reaction products indicated
(Scheme 4). Also, in order to assure that no racemization
had occurred during the process, the crude ketones were
subjected to HPLC analysis on chiral column showing
that all were nearly optically pure (ee >99%). It should
Tr a n sfor m a tion of th e Ald ol P r od u cts in to Oth er
Va lu a ble Syn th on s. The R-methyl-â-hydroxy amides
obtained from the aldol reaction were subjected to several
derivatization processes in order to survey their possibili-
ties in synthetic organic chemistry. In this way, R-methyl-
â-hydroxy acids, esters, and ketones were obtained in
nearly optically pure form. Also a protocol for reducing
the latter to yield selectively chiral nonracemic 1,3-syn
or 1,3-anti diols was investigated.
(a ) Hyd r olysis a n d Ester ifica tion . The amides
2a -e were subjected to acid hydrolysis by refluxing them
in a 1:1 mixture of 4 M H2SO4/dioxane, yielding the
corresponding R-methyl-â-hydroxy acids in excellent
yields (Scheme 3, Table 3). In none of the cases dehydra-
tion products from the possible action of sulfuric acid on
the hydroxy functionality were observed. The acids were
obtained as pure oils after standard acid-base workup,
and upon treatment with refluxing methanol under acid
catalysis, they yielded R-methyl-â-hydroxy esters in
excellent yields after flash column chromatography pu-
rification. All the esters 5a -e showed >99% ee as HPLC
analysis in a chiral stationary phase indicated, showing
that both processes procceded without racemization in
any of the chiral centers of the starting molecule. Another
remarkably feature on the synthetic scheme is the fact
that the chiral auxiliary, (S,S)-(+)-pseudoephedrine,
could be recovered from the extracts of the basic aqueous
layer after workup of the hydrolysis mixture followed by
crystallization in hexane/EtOAc 1:1 in ca. 80% yield and
without racemization as the measurement of its [R]20
value indicated.
D
(29) (a) Phillips, J . K.; Miller, S. P. F.; Andersen, J . F.; Fales, H.
M.; Burkholder, W. E. Tetrahedron Lett. 1987, 28, 6145-6146. (b)
Philips, J . K.; Chong, J . M.; Andersen, J . F.; Burkholder, W. E.
Entomol. Exp. Appl. 1989, 51, 149-155.
(30) Razkin, J .; Gonza´lez, A.; Gil, P. Tetrahedron: Asymmetry 1996,
7, 3479-3484.
(31) For a review, see: O’Neill, B. T. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991;
Vol. 1, p 397.
(28) For computer modeling calculations supporting this pseudo-
chair intermediate, see: (a) Goodman, J . M.; Kahn, S. D.; Paterson, I.
J . Org. Chem. 1990, 55, 3295-3303. (b) Leung-Toung, R.; Tidwell, T.
T. J . Am. Chem. Soc. 1990, 112, 1042-1048. (c) Li, Y.; Paddon-Row:
N.; Houk, K. N. J . Org. Chem. 1990, 55, 481-493. (d) Bernardi, A.;
Gennari, C.; Goodman, J . M.; Paterson, I. Tetrahedron: Asymmetry
1995, 6, 1613-1636.

3758 J . Org. Chem., Vol. 65, No. 12, 2000
Vicario et al.
Ta ble 4. Yield s a n d Ster eoselectivities Obta in ed in th e
Asym m etr ic Syn th esis of th e r-Meth yl-â-h yd r oxy Keton es
6a -i
conditions, the reduction can proceed with or without
chelation control,36 which would result in the selective
formation of 1,3-syn or 1,3-anti diols, although the
influence of the additional chiral center at the R-position
in the starting ketone has to be taken into account in
the stereochemical outcome of the reduction reaction.37
entry
product
R
R′
yielda (%)
eec (%)
1
2
3
4
5
6
7
8
9
6a
6b
6c
6d
6e
6f
6g
6h
6i
Ph
Ph
Ph
Me
Et
Ph
Me
nBu
Ph
Ph
Me
Et
81
79
72
79
79
88
75
69
89
>99
>99
>99
>99
>99
>99
>99
>99
>99
With these premises in mind, we chose the ketone (+)-
(2R,3R)-3-hydroxy-2-methyl-1,3-diphenyl-1-propanone 6a
as a model compound to assay several reducing agents.
We found that the use of an electrophilic hydride like
BH3(Me2S) in THF led to the final product preferentially
with a 1,3-syn relative stereochemistry and the use of
nucleophilic hydride sources such as metal borohydrides
led to the preferential obtention of products with a 1,3-
anti relationship. In the first case temperature control
had a striking effect in the stereoselection of the process;
thus, by refluxing the reaction mixture, fast conversion
was observed to the final products but with low stereo-
selection (55/45). However, at room temperature, full
stereochemical control of the reaction was achieved (only
the 1,3-syn isomer could be detected), although longer
reaction times were needed for achieving full conversion
(12 h). In the case of the metal borohydride mediated
reduction, the use of NaBH4 in MeOH proceeded with
low stereocontrol but by employing LiBH4 in the same
reaction the 1,3-anti isomer was cleanly obtained. The
1,3-syn/1,3-anti product distribution and the absolute
configuration of the newly created chiral center were
Et
Et
iPr
tBu
Ph
Ph
a
Yield of pure product after flash column chromatography
b
purification. Determined by chiral HPLC (Chiracel OD, UV
detector, hexanes/isopropyl alcohol 96:4 as eluent. Flow rate 0.75
mL/min).
Ta ble 5. Yield s a n d Ster eoselectivities Obta in ed in th e
Asym m etr ic Syn th esis of th e 1,3-Syn a n d 1,3-An ti Diols
7a -h a n d 8a -h
yielda eec
yielda eec
entry
R
R′ product
(%)
(%) product
(%)
(%)
1
2
3
4
5
6
8
9
Ph Ph
Ph Me
Ph nBu
Me Ph
7a
7b
7c
7d
7e
7f
78
72
75
79
89
85
93
90
8a
8b
8c
8d
8e
8f
95
77
84
89
80
81
83
90
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
Et
Et
Ph
Me
iPr Ph
tBu Ph
7g
7h
8g
8h
1
a
assigned by H NMR spectroscopy by comparison of the
Yield of pure product after flash column chromatography
b
coupling constants (J 1,2 ) 2.8 Hz for the syn isomer and
J 1,2 ) 6.8 Hz and J 2,3 ) 2.4 Hz for the anti isomers, see
Experimental Section) and also from the fact that in this
particular case the 1,3-syn diol is a meso compound in
which both carbon atoms C1 and C3 are equivalents.
purification. Determined by chiral HPLC (Chiracel OD, UV
detector, hexanes/isopropyl alcohol 93:7 as eluent. Flow rate 0.90
mL/min).
also be pointed out that even in the presence of the
strongly basic n-BuLi reagent no enolization was ob-
served and the desired ketone was obtained as a single
isomer.
It should also be noted that the (4R,5S)-(-)-5-hydroxy-
4-methyl-3-heptanone 6g is the enantiomer of the natural
product (+)-sitophilure, which is also a pheromone com-
mon to the rice weevil Sitophilus oryzae and the maize
weevil Sitophilus zeamais (Table 4).32
(3) Syn th esis of 1,3-Syn a n d 1,3-An ti Diols. The 1,3-
diol framework is often found in compounds with inter-
esting pharmacological properties. In particular, the
propionate-based aldol products are important building
blocks in the synthesis of natural products bearing 1,3-
polyol moieties such as macrolide or ionophore antibiot-
ics.33 Among the different strategies for the access to this
kind of compound,34 the direct hydride reduction of
â-hydroxy ketones is one of the most employed ones. In
particular, when the chiral center that contains the
hydroxy function has a fixed stereochemistry it can exert
a very effective 1,3-chiral induction during the formation
of the new stereogenic center in the reduction of the
carbonyl group.35 Besides, by careful choice of reaction
(35) For 1,3-syn reduction of â-hydroxy ketones, see: (a) Narasaka,
K.; Pai, F.-C. Tetrahedron 1984, 40, 2233-2238. (b) Sletzinger, M.;
Verhoeven, T. R.; Volante, R. P.; McNamara, J . M.; Corley, E. G.; Lin,
J . M. H. Tetrahedron Lett. 1985, 26, 2951-2954. (c) Chen, K.-M.;
Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro, M. J . Tetrahedron
Lett. 1985, 28, 155-158. (d) Kiyooka, S.; Kuroda, H.; Shimasaki, Y.
Tetrahedron Lett. 1986, 27, 3009-3012. (e) Bonadies, F.; Di Fabio, R.;
Gubbioti, A.; Mecozzi, S.; Bonini, C. Tetrahedron Lett. 1987, 28, 703-
706. (f) Hanamoto, T.; Hiyama, T. Tetrahedron Lett. 1988, 29, 6467-
6470. (g) Mori, Y.; Kuhara, M.; Takeuchi, A.; Suzuki, M. Tetrahedron
Lett. 1988, 29, 5419-5422. (h) Evans, D. A.; Hoveyda, A. H. J . Org.
Chem. 1990, 55, 5190-5192. (i) Mohr, P. Tetrahedron Lett. 1991, 32,
2219-2222. (j) Vedejs, E.; Duncan, S. M.; Haight, A. R. J . Org. Chem.
1993, 58, 3046-3050. (k) Kaneko, Y.; Matsuo, T.; Kiyooka, S. Tetra-
hedron Lett. 1994, 35, 4107-4110. (l) Yamashita, H.; Narasaka, K.
Chem. Lett. 1996, 539-543. (m) Ravikumar, K. S.; Sinha, S.; Chan-
drasekaran, S. J . Org. Chem. 1999, 64, 5841-5844. For 1,3-anti
reduction, see: (n) Saksena, A. K.; Mangiaracina, P. Tetrahedron Lett.
1983, 24, 273-276. (o) Masamune, S.; Choy, W.; Peterson, J . S.; Sita,
L. R. Angew. Chem., Int. Ed. Engl. 1985, 24, 1-12. (p) Evans, D. A.;
Chapman, K. T.; Carreira, E. M. J . Am. Chem. Soc. 1988, 110, 3560-
3578. (q) Anwar, S.; Davis, A. P. Tetrahedron 1988, 44, 3761-3770.
(r) Evans, D. A.; Hoveyda, A. H. J . Am. Chem. Soc. 1990, 112, 6447-
6449. (s) Umekawa, Y.; Sakaguchi, S.; Nishiyama, Y.; Ishii, Y. J . Org.
Chem. 1997, 62, 3409-3412. (t) Narayana, C.; Reddy, M. R.; Hair, M.;
Kabalka, G. W. Tetrahedron Lett. 1997, 38, 7705-7708.
(36) (a) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1984, 23, 556-
569. (b) Hoveyda, A.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93,
1307-1370.
(37) For some examples of reduction of R-alkyl substituted â-hydroxy
ketones, see: (a) Oishi, T.; Nakata, T. Acc. Chem. Res. 1984, 17, 338-
345. (b) Suzuki, K.; Shimazaki, M.; Tsuchihashi, G.-I. Tetrahedron Lett.
1986, 27, 6233-6237. (c) Bloch, R.; Gilbert, L.; Girard, C. Tetrahedron
Lett. 1988, 29, 1021-1024. (d) Evans, D. A.; Clark, J . S.; Metternich,
R.; Novack, V. J .; Sheppard, G. S. J . Am. Chem. Soc. 1990, 112, 866-
868. (e) Bonini, C.; Racioppi, R.; Righi, G.; Rossi, L. Tetrahedron:
Asymmetry 1994, 5, 173-176. (f) Sarko, C. R.; Collibee, S. E.; Knorr,
A. L.; DiMare, M. J . Org. Chem. 1996, 61, 868-873. (g) Mahrwald,
R.; Costisella, B. Synthesis 1996, 1087-1089. (h) Bartoli, G.; Bellucci,
M. C.; Bosco, M.; Dalpozzo, R.; Mercantoni, E.; Sambri, L. Tetrahedron
Lett. 1999, 40, 2845-2848.
(32) (a) Schmuff, N. R.; Phillips, J . K.; Burkholder, W. E.; Fales, H.
M.; Chen, C.-W.; Roller, P. P.; Ma, M. Tetrahedron Lett. 1984, 25,
1533-1534. (b) Walgenbach, C. A.; Phillips, J . K.; Burkholder, W. E.;
King, G. G. S.; Slessor, K. N.; Mori, K. J . Chem. Ecol. 1987, 13, 2159-
2166.
(33) (a) Omura, S.; Tanaka, H. In Macrolide Antibiotics: Chemistry,
Biology, Practice; Omura, S., Ed.; Academic Press: New York, 1984; p
351.
(34) For a review on the synthesis of 1,3-polyol chains, see: (a)
Rychnovsky, S. D. Chem. Rev. 1995, 95, 2021-2040. (b) Oishi, T.;
Nakata, T. Synthesis 1990, 635-645.

Reactions Using (S,S)-(+)-Pseudoephedrine dAmides
J . Org. Chem., Vol. 65, No. 12, 2000 3759
Exp er im en ta l Section 40
Gen er a l P r oced u r e for th e Ald ol Rea ction of (S,S)--
(+)-P seu d oep h ed r in e P r op ion a m id e. Syn t h esis of
(2R,3R,1′S,2′S)-(+)-N-(2′-Hyd r oxy-1′-m eth yl-2′-p h en yleth -
yl)-3-h yd r oxy-N,2-d im eth yl-3-p h en ylp r op a n a m id e (2a ).
A solution of the propionamide 1 (1.00 g, 4.52 mmol) in dry
THF (15 mL) was slowly added to a cooled (-78 °C) solution
of LDA (9.04 mmol) in dry THF (20 mL). The mixture was
stirred at this temperature for 1 h and allowed to reach to
room temperature. The mixture was cooled again to -78 °C,
at which temperature a THF (20 mL) solution of bis(cyclopen-
tadienyl)zirconium dichloride (2.64 g, 9.04 mmol) was added
at once and the resulting solution was stirred for 1 h at this
temperature. The mixture was cooled to -105 °C, at which
temperature a solution of benzaldehyde (0.51 mL, 4.52 mmol)
in dry THF (10 mL) was dropwise added within 20 min. The
mixture was stirred at -105 °C for 2 h and quenched with a
saturated NH4Cl solution (50 mL). The mixture was extracted
with CH2Cl2, the combined organic fractions were collected,
dried over Na2SO4, and filtered, and the solvent was removed
in vacuo to yield a yellowish oil that was flash column
chromatographed (hexanes/ethyl acetate 2:8) affording amide
F igu r e 3.
These optimized conditions were further extended to the
ketones 6a -i yielding the diols 7a -i and 8a -i in good
yields. Also this time, in order to assure that no racem-
ization occurred during reduction of the ketones, the
enantiomeric excesses of the final products were deter-
mined by chiral HPLC.
The stereochemical outcome of the reduction could be
explained in terms of the Felkin model.38 For LiBH4,
reduction in a very polar solvent like MeOH an open
transition state can be proposed, followed by hydride
attack from the less hindered face of the carbonyl group,
as shown in Figure 3. In the BH3‚(Me2S) reduction in
THF, a closed Cram-Kopecki39 transition state could be
proposed in which the boron atom would remain in-
tramolecularly coordinated to both oxygen atoms in the
substrate resulting in the formation of the 1,3-syn isomer
(Figure 3). This assumption was corroborated by reacting
the ketone 6a with LiBH4 in THF in the presence of 1 eq
of a Lewis acid like n-Bu3B, yielding preferently the
product with 1,3-syn relative stereochemistry (80:20).
2a : yield 90%; mp 132-134 °C (Et2O); [R]20 ) +87.6 (c )
D
0.2, CH2Cl2); 1H NMR (CDCl3) (3:2 rotamer ratio; *denotes
minor rotamer peaks) δ 0.87-1.27 (m, 6H), 2.74 (s, 3H), 2.91*
(s, 3H), 2.96 (m, 1H), 3.94 (m, 1H), 4.03* (m, 1H), 4.11 (bs,
2H), 4.46 (m, 1H), 4.90 (d, 1H, J ) 3.3 Hz), 7.21-7.39 (m, 10H);
13C NMR (CDCl3) (3:2 rotamer ratio; *denotes minor rotamer
peaks) δ 9.6*, 10.0, 13.9, 15.5*, 27.3, 31.5*, 41.0*, 42.6, 57.7,
72.7, 73.4*, 75.1, 75.6*, 125.9*, 126.2, 126.5, 126.6*, 127.0,
127.5*, 127.8, 127.9*, 128.0, 128.1*, 128.4, 128.5*, 141.6, 141.7,
178.3*, 178.8; IR (KBr) ν 3377, 1607 cm-1; MS (EI) m/z (rel
int) 327 (M+, 1), 58 (100). Anal. Calcd for C20H25NO3: C, 73.37;
H, 7.70; N, 4.28. Found: C, 73.28; H, 7.61; N, 4.20.
Gen er a l P r oced u r e for th e Hyd r olysis of th e Am id es
2a -e. Syn th esis of (2R,3R)-(+)-3-Hyd r oxy-2-m eth yl-3-
p h en ylp r op a n oic Acid (4a ). A solution of the amide 2a (0.50
g, 1.53 mmol) in dioxane (10 mL) was slowly added over a
cooled (0 °C) 4 M H2SO4 solution (10 mL). When the addition
was complete, the mixture was refluxed for 2 h. The reaction
was quenched with water, carefully basified to pH ) 12, and
washed with EtOAc. The aqueous layer was carefully driven
to pH ) 3 and extracted with CH2Cl2. After drying (Na2SO4),
filtering, and removing the solvent from the basic organic
extracts, it was possible to recover, after crystallization (hex-
anes/EtOAc), pure (+)-(S,S)-pseudoephedrine in 80% yield. The
collected organic acidic fractions were dried over Na2SO4 and
filtered, and the solvent was removed in vacuo yielding the
Con clu sion s
A highly stereoselective protocol for performing aldol
additions using (S,S)-(+)-pseudoephedrine as the chiral-
ity inductor has been developed through transmetalation
of the starting lithium enolate with a zirconium salt prior
to addition of the aldehyde. Also, the fact that 2 equiv of
a metal salt were needed to achieve this high diastereo-
control provided further insight into the reaction mech-
anism. The aldol products were successfully converted
into synthetically useful chiral nonracemic synthons such
as R-methyl-â-hydroxy acids, esters, and ketones in ee’s
higher than 99%. Also, a procedure to selectively syn-
thesize both 1,3-syn or 1,3-anti diols from the obtained
R-methyl-â-hydroxy ketones has been optimized, with
excellent diastereo- and enantioselectivities. In this
context, the insect pheromones ent-sitophilure and ent-
sitophilate were synthesized almost optically pure as a
direct application. The main advantages of the methodol-
ogy developed by us reside in the fact that the chirality
source is cheap and commercially available in both
enantiomeric forms. Clean and easy reactions convert the
aldol products into other useful chiral synthons and no
racemization during these conversions are observed.
These reasons, together with the high stereoselectivities
and yields, make this methodology an attractive tool for
the synthetic organic chemist.
wanted acid as a yellowish oil: yield 90%; [R]20 ) +29.3 (c )
D
0.2, CH2Cl2) (lit.26k +28.5, c ) 1.27, CH2Cl2); 1H NMR (CDCl3)
δ 1.13 (d, 3H, J ) 7.1 Hz), 2.83 (m, 1H), 5.18 (d, 1H, J ) 3.5
Hz), 5.18-5.58 (bs, 2H), 7.26-7.40 (m, 5H); 13C NMR (CDCl3)
δ 10.2, 46.2, 73.3, 125.9, 127.6, 128.3, 141.0, 180.2; IR (CHCl3)
ν 3401, 1707 cm-1; MS (EI) m/z (rel int) 180 (M+, 2), 107 (100).
Anal. Calcd for C10H12O3: C, 66.65; H, 6.71. Found: C, 66.58;
H, 6.62.
Gen er a l P r oced u r e for th e Ester ifica tion of th e Acid s
4a -e. Syn th esis of (2R,3R)-(+)-Meth yl-3-h yd r oxy-2-m eth -
yl-3-p h en ylp r op a n oa te (5a ). A solution of the acid 4a (0.29
g, 1.39 mmol) in MeOH (15 mL) was added concd HCl (5 mL)
and the mixture was refluxed for 4 h. The reaction was
quenched with water and extracted with CH2Cl2. After the
solution was dried (Na2SO4) and filtered and the solvent
removed from the collected organic fractions, the ester 5a was
isolated after purification by flash column chromatography
(hexanes/EtOAc 1:1): yield 91%; [R]20D ) +23.3 (c ) 0.2, CH2-
Cl2) (lit.10c +23.1, c ) 0.2, CH2Cl2); 1H NMR (CDCl3) δ 1.05 (d,
3H, J ) 7.1 Hz), 2.72 (m, 1H), 3.61 (s, 3H), 4.77 (bs, 1H), 5.03
(d, 1H, J ) 3.8 Hz), 7.18-7.27 (m, 5H); 13C NMR (CDCl3) δ
10.6, 46.3, 51.9, 73.5, 125.9, 127.5, 128.2, 141.3, 176.4; IR
(CHCl3) ν 3462, 1722 cm-1; MS (EI) m/z (rel int) 194 (M+, 3),
(38) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
18, 2199-2204.
(39) Cram, D. J .; Kopecki, K. R. J . Am. Chem. Soc. 1959, 81, 2748-
2755.
(40) For general experimental procedures, see ref 21b.

3760 J . Org. Chem., Vol. 65, No. 12, 2000
Vicario et al.
88 (100). Anal. Calcd for C11H14O3: C, 68.02; H, 7.27. Found:
C, 68.10; H, 7.21.
4.1, 46.4, 77.6, 125.3, 126.9, 127.9, 142.9; IR (CHCl3) ν 3366
cm-1; MS (EI) m/z (rel int) 242 (M+, 1), 118 (100). Anal. Calcd
for C16H18O2: C, 79.31; H, 7.49. Found: C, 79.28; H, 7.53.
Gen er a l P r oced u r e for th e Syn th esis of th e Keton es
6a -i. Syn th esis of (2R,3R)-(+)-3-Hyd r oxy-2-m eth yl-1,3-
d ip h en yl-1-p r op a n on e (6a ). Over a cooled (-78 °C) solution
of the starting amide 2a (0.92 g, 2.83 mmol) in dry THF was
dropwise added a solution of PhLi (9.91 mmol). After the
addition was complete, the mixture was allowed to warm to 0
°C, and after 25 min diisopropylamine (0.40 mL, 2.83 mmol)
was added. The reaction was stirred for a further 15 min and
quenched with a 10% solution of acetic acid in Et2O (5 mL).
Water (15 mL) was added, and the mixture was extracted with
CH2Cl2. After drying (Na2SO4), filtering, and removing the
solvent from the collected organic fractions, the ketone 6a was
isolated after purification by flash column chromatography
(hexanes/EtOAc 7:3): yield 81%; [R]20D ) +71.8 (c ) 0.2, CH2-
Cl2); 1H NMR (CDCl3) δ 1.20 (d, 3H, J ) 7.2 Hz), 3.72 (m, 1H),
5.23 (d, 1H, J ) 3.3 Hz), 7.19-7.59 (m, 10H); 13C NMR
(CDCl3): δ 11.2, 47.0, 73.0, 125.9, 127.2, 127.2, 128.1, 128.3,
128.6, 133.4, 141.7, 205; MS (EI) m/z (rel int) 240 (M+, 1), 146
(100). Anal. Calcd for C16H16O2: C, 79.97; H, 6.71. Found: C,
79.90; H, 6.68.
Gen er a l P r oced u r e for th e Syn th esis of 1,3-An ti Diols
8a -h . Syn th esis of (1R,3R)-(+)-2-Meth yl-1,3-d ip h en yl-1,3-
p r op a n ed iol 8a . Over a cooled (0 °C) solution of the ketone
6a (17 mg, 0.07 mmol) in dry methanol (10 mL) was dropwise
added a solution of LiBH4 (7 mg, 0.15 mmol) in dry MeOH (5
mL) at 0 °C, and then the resulting solution was allowed to
reach to room temperature. The reaction was stirred at this
temperature for 7 h, after which it was quenched with
saturated Na2CO3 (10 mL). The mixture was extracted with
CH2Cl2, the collected organic fractions were dried over Na2-
SO4 and filtered, and the solvent was removed in vacuo
affording pure diol 8a after flash column chromatography
(hexanes/EtOAc 7:3): yield 95%; [R]20 ) +2.4 (c ) 0.1, CH2-
D
Cl2); 1H NMR (CDCl3) δ 0.75 (d, 3H, J ) 7.1 Hz), 2.19 (m, 1H),
3.13 (s, 1H), 3.19 (d, 1H, J ) 3.2 Hz), 4.71 (d, 1H, J ) 6.7 Hz),
5.03 (s, 1H), 7.24-7.38 (m, 10H); 13C NMR (CDCl3) δ 4.4, 46.6,
76.5, 125.3, 127.8, 127.9, 143.1; IR (CHCl3) ν 3540 cm-1; MS
(EI) m/z (rel int) 242 (M+, 1), 118 (100). Anal. Calcd for
C
16H18O2: C, 79.31; H, 7.49. Found: C, 79.33; H, 7.50.
Gen er a l P r oced u r e for th e Syn th esis of 1,3-Syn Diols
7a -h . Syn th esis of (1R,3S)-2-m eth yl-1,3-d ip h en yl-1,3-
p r op a n ed iol 7a . Over a cooled (0 °C) solution of the ketone
6a (37 mg, 0.15 mmol) in dry THF (10 mL) was dropwise added
a 1M solution of BH3‚(Me2S) (0.33 mL, 0.33 mmol) in CH2Cl2
at 0 °C and then the resulting solution was allowed to reach
to room temperature. The reaction was stirred at this tem-
perature for 12 h after which it was quenched with saturated
Na2CO3 (10 mL). The mixture was extracted with CH2Cl2, and
the collected organic fractions were dried over Na2SO4, filtered
and the solvent removed in vacuo affording pure diol 7a after
flash column chromatography (hexanes/EtOAc 7:3): yield 78%;
1H NMR (CDCl3) δ 0.68 (d, 3H, J ) 7.0 Hz), 1.98 (m, 1H), 3.07
(s, 2H), 5.11 (s, 2H), 7.20-7.32 (m, 10H); 13C NMR (CDCl3) δ
Ack n ow led gm en t . Financial support from the
Basque Government (a fellowship to J .L.V.) and from
the University of the Basque Country (Project UPV37/
98) and the Spanish DGES (Project PB98-0600) is
gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Characterization of
products 2b-e, 4b-e, 5b-f, 6b-i, 7b-h , and 8b-h . This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O000035H