Highly diastereofacial anti-aldol reaction: Practical synthesis of optically active anti-2-alkyl-3-hydroxycarboxylic acid ester units

Article abstract of DOI:10.1021/jo001293h

A variety of esters derived from commercially available norephedrine were used in diastereoselective anti-aldol reactions. The aldol reaction of designed 2-(N-2-methylbenzyl-N-2,4,6-trimethylbenzyl)-amino-1-phenylpropanol esters 4a-d with aldehydes furnished anti-2-alkyl-3-hydroxycarboxylic acid esters in excellent diastereomeric ratios (>98:2) when LDA-Cp₂ZrCl₂ (0.3 equiv) was used for enolization, followed by transmetalation into the zirconium enolate for aldolization. The novel auxiliary 3 for the anti-aldol reaction does not exhibit the ordinary basicity of tertiary amines; 3 can be extracted from acidic media with organic solvents. Its use is, therefore, very advantageous not only for extraction of the aldol products from the acidic water solutions; but also for recovering the chiral auxiliary 3 after the reductive cleavage. Treatment of aldol or 3-protected aldol products with DIBAL-H or LiAIH₄ affords the versatile synthons, 2-alkyl-propane-1,3-diols or those 3-protected diols in >98% ee's together with 3 in nearly quantitative recovery.

Full text of DOI:10.1021/jo001293h

J . Org. Chem. 2001, 66, 1205-1209
1205
High ly Dia ster eofa cia l An ti-Ald ol Rea ction : P r a ctica l Syn th esis of
Op tica lly Active a n ti-2-Alk yl-3-Hyd r oxyca r boxylic Acid Ester
Un its†
Michio Kurosu* and Miguel Lorca
Department of Chemistry, The Florida State University, Tallahassee, Florida 32306
kurosu@chem.fsu.edu
Received August 28, 2000
A variety of esters derived from commercially available norephedrine were used in diastereoselective
anti-aldol reactions. The aldol reaction of designed 2-(N-2-methylbenzyl-N-2,4,6-trimethylbenzyl)-
amino-1-phenylpropanol esters 4a -d with aldehydes furnished anti-2-alkyl-3-hydroxycarboxylic
acid esters in excellent diastereomeric ratios (>98:2) when LDA-Cp2ZrCl2 (0.3 equiv) was used
for enolization, followed by transmetalation into the zirconium enolate for aldolization. The novel
auxiliary 3 for the anti-aldol reaction does not exhibit the ordinary basicity of tertiary amines; 3
can be extracted from acidic media with organic solvents. Its use is, therefore, very advantageous
not only for extraction of the aldol products from the acidic water solutions, but also for recovering
the chiral auxiliary 3 after the reductive cleavage. Treatment of aldol or 3-protected aldol products
with DIBAL-H or LiAlH4 affords the versatile synthons, 2-alkyl-propane-1,3-diols or those
3-protected diols in >98% ee’s together with 3 in nearly quantitative recovery.
In tr od u ction
some of these methods have been applied in relatively
large-scale synthesis.4 However, anti selective aldol reac-
tions that are able to create a variety of 2-alkyl-3-
hydroxycarbonyl units are one of the remaining chal-
lenges. Efforts in this area have been made for over the
past decade.5 In many instances known technologies
provide anti-aldols with good to excellent enantio- or
diastereoselectivities but appear to be impractical, be-
cause (1) most of the reagents are not commercially
available, (2) separation of diastereomers after the reac-
tion is difficult, and (3) complete recovery of chiral
catalysts including intact ligands or auxiliaries after
hydrolysis or reduction is desirable. We have centered
our attention on developing efficient methods for C-C
bond formation by employing readily available substrates
from commercial sources. We now wish to report a
practical synthesis6 of optically active anti-2-alkyl-3-
hydroxycarboxylic acid esters using the (-)-N,N-dibenz-
ylnorephedrine derivatives 3 (Scheme 1) and conven-
tional reagents such as LDA-Cp2ZrCl2 in greater than
98% enatiomeric excess and high chemical yields.
Optically active 2-alkyl-3-hydroxycarbonyl units which
exist as four possible stereoisomers play a very significant
role in syntheses of most natural products of polyketide
origin. The aldol reaction provides a rapid means for
setting up several stereogenic centers in a single step.1
The efficient construction of syn-aldol units2 can be
achieved by stereocontrolled aldol condensations in out-
standing diastereomeric and enantiomeric purity,3 and
† Dedicated to Professors Isao Kitagawa and Martin A. Schwartz
on the occasion of their 70th and 60th birthdays, respectively.
(1) For selected examples of aldol reactions in natural product
synthesis, see (a) Evans, D. A. Aldrichimica Acta 1982, 15, 47. (b)
Masamune, S.; Imperiali, B.; Garvey, D. S. J . Am. Chem. Soc. 1982,
104, 5528. (c) Masamune, S.; Choy, W. Aldrichimica Acta 1982, 15,
47. (d) Evans, D. A.; Trotter, B. W.; Coleman, P. J .; Coˆte´, B.; Dias, L.
C.; Rajapakse, H. A.; Tyler, A. N. Tetrahedron 1999, 55, 8671.
(2) In the present paper, the main chain is drawn in zigzag fashion,
and two substituents on the same side are designated syn, and those
which are not are anti, see ref 3a
(3) (a) Masamune, S.; Ali, Sk. A.; Snitman, D. L.; Garvey, D. S.
Angew. Chem., Int. Ed. Engl. 1980, 19, 557. (b) Evans, D. A.; Bartroli,
J .; Shih, T. L. J . Am. Chem Soc. 1981, 103, 217. (b) Evans, D. A.;
Nelson, J . V.; Taber, T. R. Top. Stereochem. 1982, 13, 1. (c) Mukaiyama,
T. Org. React. 1982, 28, 203. (d) Masamune, S.; Choy, W. Aldrichimica
Acta 1982, 15, 47. (e) Heathcock, C. H. In Asymmetric Synthesis;
Morison, J . D, Ed.; Academic Press: New York, 1984; Vol. 3, Part B,
Chapter 2, pp 111-212. (f) Katsuki, T.; Yamaguchi, M. Tetrahedron
Lett. 1985, 47, 5807. (g) Oppolzer, W. Pure Appl. Chem. 1988, 60, 39.
(h) Gage, J . R.; Evans, D. A. Org. Synth. 1989, 68, 77. (i) Siegel, C.;
Thornton, E. R. J . Am. Chem. Soc. 1989, 111, 5722. (j) Mukaiyama,
T.; Kobayashi, S.; Uchiro, H.; Shiina, I. Chem. Lett. 1990, 129. (k)
Kobayashi, S.; Fujita, Y.; Mukaiyama, T. Chem. Lett. 1990, 1455. (l)
Furuta, K.; Maruyama, T.; Yamamoto, H. J . Am. Chem. Soc. 1991,
113, 1041. (m) Heathcock, C. H. In Comprehensive Organic Synthesis;
Trost, B. M, Ed.; Pergamon Press: Oxford, 1993; Vol. 2, Chapter 1.6,
pp 181-238. (n) Franklin, A. S.; Paterson, I. Contemp. Org. Synth.
1994, 1, 317. (o) Mikami, K.; Matsukawa, S. J . Am. Chem. Soc. 1994,
116, 4077. (p) Uotsu, K.; Sasai, H.; Shibasaki, M. Tetrahedron:
Asymmetry 1995, 6, 71. (q) Mukaiyama, T.; Kobayashi, S. Org. React.
1995, 46, 1. (r) Evans. D. A.; Kozlowski, M. C.; Murry, J . A.; Burgey,
C. S.; Campos, K. R.; Connell, B. T.; Staples, R. J . J . Am. Chem. Soc.
1999, 121, 669. (s) Evans, D. A.; Burgey, C. S.; Kozlwski, M. C.; Tregay,
S. W. J . Am. Chem. Soc. 1999, 121, 686. (t) Taylor, S. J .; Duffey, M.
O.; Morken, J . P. J . Am. Chem. Soc. 2000, 122, 4528.
(4) For example, the oxazolidinone auxiliaries of Evans have defined
the standard in the synthesis of optically active syn-2-methyl-3-hydroxy
carbonyl units.
(5) (a) Gennari, C.; Bernardi, A.; Colombo, L.; Carlo. S. J . Am. Chem.
Soc. 1985, 107, 5812. (b) Corey, E. J .; Kim, S. S. J . Am. Chem. Soc.
1990, 112, 4976. (c) Braun, M.; Sacha, H. Angew. Chem., Int. Ed. Engl.
1991, 30, 1318. (d) Sacha, H.; Waldmu¨ller, D.; Braun, M. Chem. Ber.
1994, 127, 1959. (e) Abiko, A.; Liu, J . F.; Masamune, S. J . Org. Chem.
1996, 61, 2590. (f) Ghosh, A. K.; Onishi, M. J . Am. Chem. Soc. 1996,
118, 2527. (g) Abiko, A.; Liu, J . F.; Masamune, S. J . Am. Chem. Soc.
1997, 119, 2586. (h) Corey, E. J .; Li, W.; Reichard, G. A. J . Am. Chem.
Soc. 1998, 120, 2330. (i) Ishitani, H.; Yamashita, Y.; Shimizu, H.;
Kobayashi, S. J . Am. Chem. Soc. 2000, 122, 5403. For anti-aldol
reactions with ketone enolates, see (j) Masamune, S.; Sato, T.; Kim,
B. M.; Wollmann, T. A. J . Am. Chem. Soc. 1986, 108, 8279. (k) Van
Draanen, N. A.; Arseniyadis, S.; Crimmins, M. T.; Heathcock. C. H. J .
Org. Chem. 1991, 56, 2499. (l) Cowden, C. J .; Paterson, I. Org. React.
1997, 51, 1. (m) Denmark, S. E.; Stavenger, R. A.; Ken-Tsung, W.;
Xiping, S. J . Am. Chem. Soc. 1999, 121, 4982.
10.1021/jo001293h CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/25/2001

1206 J . Org. Chem., Vol. 66, No. 4, 2001
Kurosu and Lorca
Sch em e 1a
have observed that in the enolization of chiral propi-
onates the E/Z selectivity is strictly controlled by the
structure of the chiral moieties and that it is difficult to
design chiral esters that produce E-lithium enolates
exclusively.12 N-Methylephedrine or N,N-disubstituted
norephedrine esters have been introduced as a stereo-
chemical template to direct aldol reactions, the conditions
involving either a TiCl4-mediated Mukaiyama reaction13
or diastereoselective dicyclohexylboron enolate forma-
tion.14 Their reactions possess several disadvantages
because they require the preparation of commercially
unavailable reagents and because they involve difficult
separations of diastereomers from the reaction mixture.
We envisioned using norephedrine,15 which is readily
available in bulk and is inexpensive, for diastereoselec-
tive and diastereofacial selective anti-aldol reactions via
a conventional metalloenolate.
a
Reagents and yields: (a) (i) mesitaldehyde MgSO4, toluene,
80 °C; (ii) NaCNBH3, AcOH, MeOH, rt (65%); (b) 2-methylbenzyl
bromide, Cs2CO3, toluene, 90 °C (95%); (c) propionyl chloride,
DMAP, CH2Cl2 (98%) or carboxylic acid, EDCI‚HCl, DMAP, CH2-
Cl2 (95%).
Resu lts a n d Discu ssion
Two general approaches to the preparation of optically
active anti-2-methyl-3-hydroxycarbonyl units, asymmet-
ric aldol processes and asymmetric crotylation,7 have
been utilized in natural product synthesis.8 It is worth
noting that the asymmetric aldol process possesses a
strategic advantage over crotylation because of its flex-
ibility for synthesizing a variety of 2-alkyl-substituted
3-hydroxy derivatives. The stereochemical outcome for
anti-aldol reactions through metallo enolates is governed
by two critical issues: (1) selective generation of E(O,R)-
enolate,9 and (2) creation of a relatively tight six-
membered chelated chairlike transition state.10 The
stereochemistry of the aldol reaction with ester deriva-
tives is limited in many cases by the difficulty of forming
E and Z enolates selectively. Deprotonation of simple
esters with lithium amides at low temperature generally
affords the E-enolate in major amount.11 However, we
In preliminary studies, the transmetalations of lithium
enolates derived from N,N-dibenzylnorephedrine propi-
onates into Cp2TiCl, (iPrO)2TiCl, and Cp2ZrCl enolates16
enhanced the diastereofacial selectivity in the aldol
reaction. Interestingly, the Cp2TiCl or (iPrO)2TiCl eno-
lates furnished anti-aldol products whose stereochemis-
tries possess opposite absolute configurations to those
induced by the Cp2ZrCl enolates. Since aldolization of
Cp2ZrCl enolate with aldehydes furnished superior dia-
sterofacial selectivity and Cp2ZrCl2 is more accessible in
bulk, we selected Cp2ZrCl2 as the metal salt for trans-
metalation of enolate.
We then looked for suitable substituents on the nitro-
gen of (-)-norephedrine to induce exclusive diastereo-
facial selectivity for anti-aldols and initially selected
benzylic groups to decrease the polarity of norephedrine.
Of the various substituents screened, 2-(N-2-methy-
benzyl-N-2,4,6-trimethylbenzyl)amino-1-phenylpropyl pro-
pionate (4a ) proved to be the most effective (entry 7 in
Table 1).
Both enantiomers of esters 4 were synthesized from
(+)- or (-)-norephedrine by the following sequence: (1)
oxazolidine formation with mesitaldehyde in the presence
of MgSO4, followed by selective cleavage of the C-O bond
via NaCNBH3 in the presence of AcOH, (2) selective
N-benzylation with 2-methylbenzyl bromide and Cs2CO3
as a base, and (3) esterification with acyl chlorides in the
presence of (dimethylamino)pyridine (DMAP) or with the
corresponding acids via 1-[3-(dimethylamino)propyl]-3-
ethylcarbodiimide hydrochloride (EDCI‚HCl) and DMAP.
Through NOESY experiments17 and molecular model-
ing18 (Figure 1), we can attribute the origin of the
(6) Many of the articles on reagent-controlled asymmetric aldol
reactions, most of which are enantioselective Mukaiyama aldol reac-
tions, described that the chiral enolate technologies were not ideal from
a practical point of view because they required stoichiometric amount
of covalently bound auxiliaries. However, a number of total syntheses
of natural products have relied on the chiral auxiliary methodologies
or stoichiometric amounts of readily available chiral reagents in order
to synthesize starting materials. Low catalyst loading (<2 mol %) and
elimination of preconversion of ketones or esters to silyl enol ethers
should be required in
a practical catalytic enantioselectve aldol
reaction. An outstanding development of catalytic asymmetric syn-
thesis of â-hydroxy ketones was reported; see Yoshikawa, N.; Yamada,
Y. M. A.; Das, J .; Sasai, H.; Shibasaki, M. J . Am. Chem. Soc. 1999,
121, 4168.
(7) Many other crotylation methods to generate anti adducts exist.
Brown’s method is the most widely used and general method. (a)
Brown, H. C.; Bhat, K. S. J . Am. Chem. Soc. 1986, 108, 5919. (b) Brown,
H. C.; Ramdad, R. S.; Bhat, K. S. J . Org. Chem. 1989, 54, 1570. For
selected application of Brown’s crotylboration protocol, see: (c) Hay-
ward, M. M.; Roth, R. M.; Duffy, K. J .; Dalko, P. I.; Steves, K. L.; Guo,
J .; Kishi, Y. Angew Chem., Int. Ed. 1998, 37, 187. (b) Kobayashi, Y.;
Lee, J .; Tezuka, K.; Kishi, Y. Org. Lett. 1999, 1, 2177.
(8) Other nonaldol processes to synthesize anti-2-methyl-3-alkoxy
carbonyls, see (a) Kishi, Y.; Nagaoka, H. Tetrahedron 1981, 37, 3873.
(b) J ung, M. E.; Lee, W. S.; Sun, D. Org. Lett. 1999, 1, 307.
(9) For attempts to generate anti-aldols from Z-O-silylketene acetal,
see (a) Heathcock, C. H.; Walker, M. A. J . Org. Chem. 1991, 56, 5747.
(b) Oppolzer, W.; Starkemann, C.; Rodriguez, I.; Bernardinelli, G.
Tetrahedron Lett. 1991, 32, 61. Anti selective aldolizations observed
with O-silylenolates in the presence of Lewis acid have been ascribed
to open transition states. Recently, Denmark and co-workers reported
a chiral phosphoramide-catalyzed anti-aldol reaction with Z-trichlo-
rosilyl enol ether; see ref 5m.
(10) No rationale has been made thus far for Lewis acid promoted
anti-aldol reactions of enolsilanes with aldehydes. For an article
regarding this issue, see (a) Chan, T. H.; Aida, T.; Lau, P. W. K.; Gorys,
V.; Harpp, D. N. Tetrahedron Lett. 1979, 42, 4029. (b) Heathcock, C.
H.; Hug, K. T.; Flippin, L. A. Tetrahedron Lett. 1984, 25, 5973. Catalytic
enantioselective anti-aldol reactions of enolsilanes with glyoxylate and
pyruvate esters via chiral Lewis acids was recorded, see Evans, D. A.;
MacMillan, D. W. C.; Campos, K. R. J . Am. Chem. Soc. 1997, 119,
10859.
(11) (a) Ireland, R. E.; Muller, R. H.; Willard, A. K. J . Am. Chem.
Soc. 1976, 98, 2868. (b) Oare, A. D.; Heachcock, C. H. J . Org. Chem.
1990, 55, 157. (c) Ireland, R. E.; Wipf, P.; Armstrong, J . D. J . Org.
Chem. 1991, 56, 650.
(12) Pirrung, M. C.; Heathcock, C. H. J . Org. Chem. 1980, 45, 1727.
(13) (a) Gennari, C.; Colombo, L.; Bertolini, G.; Schimperna, G. J .
Org. Chem. 1987, 52, 2754. (b) Review: Mahrward, R. Chem. Rev.
1999, 99, 1095 and references therein.
(14) Abiko, A.; Liu, J . F.; Masamune, S. J . Am. Chem. Soc. 1997,
119, 2586.
(15) Chiral N,N-dialkylnorephedrines as catalysts of enantionse-
lective addition of dialkyllzincs to aldehydes have been reported, see:
Soai, K.; Yokoyama, S.; Hayasaka, T. J . Org. Chem. 1991, 56, 4264.
(16) (a) Evans, D. A.; McGee, L. R. J . Am. Chem. Soc. 1981, 103,
2876. (b) Katsuki, T.; Yamaguchi, M. Tetrahedron Lett. 1985, 47, 5807.
(17) Because none of esters prepared were crystalline, nuclear
Overhauser enhancement spectroscopy (NOESY) studies proved in-
dispensable in determining the conformation of 4a .
(18) A SPARTAN conformational search by semiempirical calcula-
tion using the AM1 basis set indicated that lowest energy conformation
of 4a was well in agreement with the data obtained from NOESY.

Highly Diastereofacial Anti-Aldol Reaction
J . Org. Chem., Vol. 66, No. 4, 2001 1207
Ta ble 1. Effects of th e N,N-Diben zyl Gr ou p on
Dia ster eofa cia l Selectivity in th e Ald ol Rea ction a
entry
R1
R2
i/iib
1
2
benzyl
benzyl
benzyl
benzyl
3,5-dimethylbenzyl
2-bromobenzyl
benzyl
SO2Tol
SO2Mes
2,6-diisopropylbenzyl
2,4,6-trimethylbenzyl
2,4,6-trimethylbenzyl
2,4,6-trimethylbenzyl
50/50
55/45
60/40
75/25
75/25
82/25
>98/2
3
4c
5
6
7
2-methylbenzyl
a
All reaction were carried out in a 0.1 mmol scale at -78 °C.
bDiastereofacial selectivity of the products was established by 1H
NMR. Masamune ester.
c
F igu r e 2. Anti/syn selectivity for aldol reaction of 4a and 4c
with benzaldehyde. The reations were carried out at 0.1 M
concentration with varying amount of Cp2ZrCl2.
addition of inorganic salts. Addition of varying amounts
of LiCl or LiOTf to LDA22 did not change the E/Z
selectivity in the formation of 4a enolate but hampered
the transmetalation from lithium to zirconium enolate.
However, a substantial increase in anti/syn selectivity
(up to 15:1 for 4c) was observed when Cp2ZrCl2 was
added to LDA with maximum anti/syn selectivity being
attained by addition of 0.3 equiv of Cp2ZrCl2.23 Higher
concentrations of Cp2ZrCl2 reduced the selectivities; 1
equiv of Cp2ZrCl2 completely quenched the reaction and
ester 4a was recovered after the reaction (Figure 2).24
We also explored temperature and concentration varia-
tion to optimize selectivity. Enolization did not proceed
at lower than -78 °C, and the generated enolate was not
stable at higher than -50 °C under the LDA-Cp2ZrCl2
(0.3 equiv) conditions. Maximum selectivity was not
decreased by varying the reaction concentration; over the
range of concentrations that we have investigated (0.05-
0.3 M) both diastereo- and diastereofacial selectivity
remain unchanged. To the best of our knowledge this is
the first example of amplification of E-enolization of
chiral esters by addition of Cp2ZrCl2 to LDA.25
F igu r e 1. The lowest energy conformation of 4a with selected
NOESY correlations.
excellent diastereofacial selectivity to the following fac-
tors. The bulky mesityl group on nitrogen is on the
sterically less demanding site (opposite to the ester
moiety). Because of a significant steric interaction be-
tween the mesityl group and methyl of o-methylbenzyl
group the methyl group of o-methylbenzyl locates toward
the propionyl ester moiety. Zirconium enolate formation
from the corresponding lithium enolate is known,19 and
Cp ligands of zirconium metal enhance the steric conges-
tion of re-face of enolate. Therefore, the aldolizations with
zirconium enolate of 4a furnish (2S,3R)-2-methyl-3-
hydroxy esters. The reactions occur on the si-face pre-
sumably via a chairlike transition state. Thus, enolization
of 4a with LDA (2 equiv) in THF,20 followed by trans-
metalation into the zirconium enolate at -78 °C with Cp2-
ZrCl2 (2.5 equiv), and aldolization with benzaldehyde (1.1
equiv) furnishes anti-aldol product in greater than 98%
de and in excellent yield. However, the anti/syn diaste-
reoselectivity was disappointingly low (3.5:1).
Having accomplished a diastereofacialselective anti-
aldol reaction, we next surveyed additives in order to
increase the anti/syn ratio. Lithium salts are known to
be effective in enhancing E/Z selectivity in ketone eno-
lization.21 Although the mechanism is not clear, their use
is the most effective method to date for preparing ketone
enolates with E geometry. We surmised that selective
ester enolate formation might also be facilitated by
As shown in Table 2, a variety of optically active anti-
2-alkyl-3-hydroxy ester derivatives could be synthesized
(21) (a) Narasaka, K.; Ukaji, Y.; Watanabe, K. Chem. Lett. 1986,
1755. (b) Hall, P. L.; Gilchrist, J . H.; Collum, D. B. J . Am. Chem. Soc.
1991, 113, 9571. (c) Hall, P. L.; Gilchrist, J . H.; Harrison, A. T.; Fuller,
D. J .; Collum, D. B. J . Am. Chem. Soc. 1991, 113, 9575. (d) J uaristi,
E.; Beck, A. K.; Hansen, J .; Matt, T.; Muckhopadhyay, T.; Simson, M.;
Seebach, D. Synthesis 1993, 1271.
(22) For studies on the structure of LDA and mechanistic studies
on enolization with LDA, see: (a) Sun, X.; Collum, D. B. J . Am. Chem.
Soc. 2000, 122, 2452. (b) Sun, X.; Collum, D. B. J . Am. Chem. Soc.
2000, 122, 2459 and references therein.
(23) Similar to the trend observed for ketone enolization with LDA/
LiCl (0.3-0.4 equiv), a maximum selectivity was given when LDA/
Cp2ZrCl2 (0.3 equiv) was used.
(24) The origins of enhancement of E-enolate ratio are far from clear
and a subject of current study. For a discussion of the influence of
lithium halides upon the structure and reactivity of lithium enolates,
see: Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27, 1624.
(25) The change of amide from LDA to lithium isopropylcyclohexyl-
amide (LICA), and lithium 2,2,6,6-tetramethylpiperidide (LTMP) did
not alter the diastereoselectivity. Lithium di-tert-butylamide did not
deprotonate to form lithium enolate at -78 °C. Lithium diethylamide
reacted with Cp2ZrCl2 to form a dark-red colored THF solution at -78
°C, putatively represented as “Cp2Zr(Cl)NEt2”, which was an inert
species for enolization of 4a .
(19) Evans, D. A.; McGee, L. R. J . Am. Chem. Soc. 1981, 103, 2876.
(20) Except for THF, Cp2ZrCl2 is difficult to solubilize in commonly
employed organic solvents for aldol reactions.

1208 J . Org. Chem., Vol. 66, No. 4, 2001
Kurosu and Lorca
Ta ble 2. Dia ster eoselective Ald ol Rea ction s
syntheses of propargyl alcohols from alkynals by this
method afforded a 1:1 mixture of anti/syn diastereomers
with low diastereofacial selectivity.
Con clu sion s
We disclose a practical synthesis of optically active
2-alkyl-3-hydroxycarboxylic acid esters using a readily
synthesized norephedrine derivative 4a as a stereocon-
troller and LDA-Cp2ZrCl2 as a selective E-enolization
method. The anti-aldol reaction described herein has
several advantages: (1) the high degree of diastereofacial
selectivity, (2) the use of easily handled chemicals which
are commercially available, (3) wide scope for both
aldehydes and the length of carbon chain of ester
moieties, and (4) easy purification of aldol products and
quantitative recovery of auxiliary. The present method
should provide a valuable asset to the synthesis of
natural products.
yield
(%)
anti/
synb
ds for
antic
ester
R′ (aldehyde)
product
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
4c
4c
4d
4d
Ph
5a
5b
5c
5d
5e
5f
5b
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
98
90:10 >90:2
90:10 >98:2
90:10 >98:2
90:10 >98:2
90:10 >98:2
Ph(CH2)2
94a
90a
90a
92a
95a
95a
95
Et
CH3(CH2)4
BnOCH2
i-Pr
c-Hex
(E)-MeCHdCH
(E)-MeCHdCH(Me)
PhCHdCH
TMSCtC
93:7
>98:2
90:10 >98:2
90:10 >98:2
90:10 >98:2
90:10 >98:2
59:41
56:44
94:6
93:7
94:6
94:6
Exp er im en ta l Section
92a
96
All reactions were conducted under an argon or nitrogen
atmosphere. Reaction vessels were flame-dried or oven-dried
and allowed to cool under an inert atmosphere. Reagents and
solvents are commercial grade and were used as with the
following exceptions. THF was distilled from potassium ben-
zophenone ketyl. Dichloromethane was purified through Al2O3
column (MBRAUN System), and diisopropylamine was dis-
tilled from CaH2. 1H NMR and 13C NMR spectra were recorded
on 300 MHz and 500 MHz spectrometer in CDCl3. Electrospray
mass spectra (ESI) were obtained with lithium trifluoro-
methanesulfonate using CH3CN as a solvent. Poly(ethylene
glycol) was added as an internal reference.
90a
95
-
-
CH3(CH2)4CtC
Ph
95
>98:2
>98:2
>98:2
>98:2
i-Pr
Ph
i-Pr
Ph
93a
93a
95a
96
90:10 >98:2
89:11 >98:2
Et
95a
The reaction was not completed. bAnti/syn ratio was deter-
mined by isolated product yield and 3H NMR. cDiastereomeric ratio
was established by 1H NMR.
a
N-(2,4,6-Tr im eth ylben zyl)n or ep h ed r in e 2. To a stirred
solution of (1R,2S)-(-)-norephedrine (1) (20 g, 0.132 mol) in
toluene (100 mL) were added mesitaldehyde (21.6 g, 0.145 mol,
1.1 equiv) and MgSO4 (25 g). The reaction mixture was heated
at 80 °C; after 6 h the reaction was cooled to room temperature
and filtered, and the solvent was concentrated in vacuo. The
crude material was dissolved in MeOH (150 mL), and AcOH
(30 mL) was added. At 0 °C, to the reaction mixture was added
NaCNBH3 (17.0 g, 0.257, 1.9 equiv), and it was stirred at room
temperature for 3 h, after which it was quenched with 0.1 N
NaOH. The reaction mixture was extracted with AcOEt (three
times). The combined extracts were washed with brine, dried
over Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by silica gel chromatography (CH2Cl2 to 1:1,
hexanes:EtOAc) to afford 2 (24.3 g, 0.0859 mol, 65%): 1H NMR
(300 MHz, CDCl3) 7.23-7.15 ppm (5H, m), 6.79 (2H, s), 4.75
(1H, d, J ) 4.2 Hz), 3.76 (2H, s), 2.97 (1H, s), 2.28 (6H, s),
2.18 (3H, s), 0.78 (3H, d, J ) 7.2 Hz). 13C NMR: 141.2, 136.9,
136.4, 133.2, 129.2, 128.1, 127.1, 126.1, 72.9, 59.2, 45.2, 20.8,
19.3, 14.6. IR (neat) 3557.0 cm-1, 3434.9, 2964.5, 2856.0,
1668.9, 1613.2, 1580.6, 1377.2, 763.3, 743.2. HRMS (ESI):
in good anti/syn selectivities of 90-95:10-5 and in
excellent diastereomeric ratios of >98:2 for anti by a
combination of diastereoselective E-enolization using
LDA-Cp2ZrCl2 and diastereofacial selective aldolization
induced by the Cp2ZrCl enolate.26 Importantly, the
mixture of anti/syn diastereomers could be separated by
silica gel chromatography. The isolated anti-aldol prod-
ucts were converted to 2-alkyl-3-silyloxypropane-1,3-
diols, advanced intermediates for natural products syn-
theses, in two steps: (1) silylation with TESCl and
imidazole in CH2Cl2 at 0 °C or TBSOTf and 2,6-lutidine
in CH2Cl2 at 0 °C, 2) DIBAL-H reduction in CH2Cl2 at
-78 °C.27 The direct reduction of the anti-aldol products
with DIBAL-H afforded 2-alkyl-propane-1,3-diols with
greater than 98% ee’s,28 the auxiliary 3 being recovered
in nearly quantitative yield. The (2S,3R) absolute chem-
istries for representative 2-methylpropane-1,3-diols, de-
rived from 5a , 5b, 5c, 5f, 5g, 5j, were confirmed by
comparison of optical rotations.29 The multigram scale
synthesis of (2S,3R)-2-alkyl-3-hydroxy esters could be
achieved by this method. It should be noted, however,
that a limitation exists in the use of aldehyde; the
C
19H25NO (M + H+) calcd. 284.200891, found 284.20126. [R]D
+49.2° (c 0.2, CHCl3, at 25 °C).
N-(2-Meth ylben zyl)-N-(2,4,6-tr im eth ylben zyl)n or ep h e-
d r in e 3. To a stirred solution of 2 (20.0 g, 70.7 mmol) in
toluene (100 mL)-CH3CN (30 mL) was added 2-methylbenzyl
bromide (1.49 g, 77.8 mmol, 1.1 equiv). The reaction mixture
was heated at 90 °C. After 1 h, the reaction was cooled to room
temperature and filtered, and the combined solvent was
concentrated in vacuo. The residue was purified by silica gel
chromatography (8:1, hexanes:EtOAc) to afford 3 (28.8 g, 73.9
mmol, 95%): 1H NMR (300 MHz, CDCl3) 7.01-7.22 ppm (9H,
m), 6.78 (2H, s), 4.83 (1H, m), 3.69 (3H, t, J ) 6.9 Hz), 3.52
(26) Diastereoselectivity of syn products was ca. 1.5: 1. This poor
selectivity for syn diastereomers would be attributed to a boatlike
transition structure that can accommodate two possible orientations
of aldehydes.
(27) A general transformation of (2S,3R)-2-alkyl-3-hydroxylcarboxy-
lic acid esters into the advanced intermediates for the synthesis of
propionate origin natural products is described in Supporting Informa-
tion. For a general strategy for propionate-derived natural products,
see: Evans, D. A.; Kim, A. S.; Metternich, R.; Novack, V. J . J . Am.
Chem. Soc. 1998, 120, 5921.
(29) (a) Suzuki, K.; Katayma, E.; Tsuchihashi, G. Tetrahedron Lett.
1984, 25, 2479. (b) Mori. K.; Sano, S.; Yokoyama, Y.; Bando, M.; Kido,
M. J . Org. Chem. 1941, 6, 1135. (c) Domon, L.; Vogeleisen, F.; Uguen,
D. Tetrahedron Lett. 1996, 37, 2773. (d) Meyer, H. H. Liebigs. Ann.
Chem. 1984, 791.
(28) The ee values were determined by esterification of the diols
with Mosher’s reagent and subsequent 1H NMR and 19F NMR
spectroscopies.

Highly Diastereofacial Anti-Aldol Reaction
J . Org. Chem., Vol. 66, No. 4, 2001 1209
(1H, d, J ) 12.9 Hz), 3.08 (1H, q, J ) 6.9 Hz), 2.75 (3H, m),
2.17 (9H, s), 2.12 (1H, m), 1.23 (3H, d, J ) 6.6 Hz). 13C NMR
(75 MHz, CDCl3) 143.6, 138.4, 137.6, 137.3, 136.2, 132.1, 130.6,
130.2, 129.1, 128.1, 127.1, 126.8, 126.5, 125.4, 75.9, 58.2, 51.4,
48.1, 20.7, 20.0, 19.1, 8.1. IR (neat) 2920.4 cm-1, 1737.9, 1177.2,
761.9, 744.1, 698.8. HRMS (ESI): C27H33NO (M + H+) calcd.
387.25621, found 387.25652. [R]D +28.9° (c 0.2, CHCl3 at 25
°C).
2.10 (9H, s), 1.23 (3H, d, J ) 6.6 Hz), 0.96 (3H, d, J ) 6.6 Hz).
13C NMR (75 MHz, CDCl3) 174.5, 139.9, 138.5, 138.4, 137.3,
137.1, 136.3, 135.1, 131.6, 131.3, 130.7, 130.2, 129.8, 129.4,
129.0, 128.3, 128.1, 127.3, 127.0, 126.9, 126.8, 126.6, 125.3,
74.5, 55.6, 51.0, 47.2, 32.1, 28.2, 22.6, 20.8, 19.2, 15.5, 9.6, 9.4.
IR (neat) 3500.1 cm-1, 3031.1, 2971.4, 2854.9, 1731.5, 1613.5,
1585.2, 1378.3, 764.8, 742.7, 700.1. HRMS (ESI): C37H43NO3
(M + H+) calcd. 550.33157, found 550.32909. [R]D -12.6° (c
0.1, CHCl3 at 25 °C).
2-(N-2-Meth ylben zyl-N-2,4,6-tr im eth ylben zyl)a m in o-1-
p h en ylp r op ylp r op ion a te (4a ). To a stirred solution of 3
(1.00 g, 2.57 mmol) in CH2Cl2 (10 mL) at 0 °C were added
DMAP (628 mg, 5.14 mmol, 2 equiv) and propionyl chloride
(219 µL, 5.14 mmol, 2 equiv). The reaction mixture was
warmed to room temperature; after 5 h, the reaction was
quenched with NaHCO3. The mixture was extracted with
AcOEt (three times). The combined extracts were washed with
brine and dried over Na2SO4 and concentrated in vacuo. The
residue was purified by silica gel chromatography (15:1,
hexanes:EtOAc) to afford 4a (1.06 g, 2.39 mmol, 93%): 1H
NMR (300 MHz, CDCl3) 7.04-7.22 ppm (7H, m), 6.91 (2H, dd,
J ) 7.5, 2.1 Hz), 6.76 (2H, s), 6.06 (1H, d, J ) 6 Hz), 3.72 (2H,
d, J ) 12.6 Hz), 3.56 (2H, dd, J ) 12.9, 7.2 Hz), 3.19 (1H, q, J
) 6.6 Hz), 2.34 (2H, q, J ) 8.1 Hz), 2.25 (3H, s), 2.09-2.10
(9H, s), 1.23 (3H, d, J ) 6.6 Hz), 0.96 (3H, d, J ) 6.6 Hz). 13C
NMR (75 MHz, CDCl3) 173.4, 139.8, 138.4, 137.3, 137.0, 136.2,
131.0, 130.6, 130.1, 128.9, 127.9, 127.3 126.9, 126.8, 125.3,
56.5, 51.2, 47.4, 31.5, 28.0, 22.6, 20.8, 20.1, 19.2, 14.1, 9.1. IR
(neat) 2920.4 cm-1, 1737.9, 1177.2, 761.9, 744.1, 698.8. HRMS
(ESI): C30H37NO2 (M + H+) calcd. 443.28243, found 443.28195.
[R]D -13.6° (c 0.2, CHCl3 at 25 °C).
Gen er a l P r oced u r e for th e Ald ol Rea ction . To a stirred
solution of diisopropylamine (190 µL, 2 equiv) in THF (3.5 mL)
at 0 °C was added n-BuLi (1.5 M, 903 µL, 2 equiv). The LDA
solution was cooled to -78 °C, and a THF solution of Cp2ZrCl2
(59.3 mg, 0.203 mmol, 0.3 equiv) was added. After 15 min, 4a
(300 mg, 0.677 mmol) in THF (1 mL) was added. The reaction
mixture was stirred for 90 min, and Cp2ZrCl2 (495 mg, 1.69
mmol, 2.5 equiv) was added. After an additional 10 min at
-78 °C, to the reaction was added PhCHO (79.1 mg, 0.745
mmol, 1.1 equiv) in THF (1.5 mL). The reaction mixture was
stirred at -78 °C for 30 min and quenched with 1 N HCl. The
mixture was extracted with ether (three times). The combined
extracts were washed with brine, dried over Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by silica
gel chromatography (12:1:1, hexanes:EtOAc:CH2Cl2, 10:1, hex-
anes:EtOAc) to afford 5a (330 mg, 0.603 mmol, 89%), together
with a mixture of syn products (36.4 mg, 0.0663 mmol, 9.8%):
1H NMR (300 MHz, CDCl3): 7.02-7.28 ppm (12H, m), 6.92
(2H, d, J ) 6.9 Hz), 6.76 (2H, s), 6.05 (1H, d, J ) 6.6 Hz), 4.74
(1H, dd, J ) 8.7, 4.8 Hz), 3.70 (2H, dd, J ) 13.5, 3.9 Hz), 3.55
(2H, dd, J ) 12.0, 3.9 Hz), 3.22 (1H, q, J ) 6.6 Hz), 3.00 (1H,
d, J ) 4.2 Hz), 2.82 (1H, q, J ) 7.5 Hz), 2.25 (3H, m), 2.09-
Exp er im en ta l P r oced u r es for th e La r ge-Sca le Ald ol
Rea ction . To a stirred solution of diisopropylamine (2.80 mL,
2 equiv) in THF (50 mL) at 0 °C was added n-BuLi (1.5 M,
13.3 mL, 2 equiv). The LDA solution was cooled to -78 °C and
a THF solution of Cp2ZrCl2 (879 mg, 3.00 mmol, 0.3 equiv)
was added. After 15 min, 4d (5.00 g, 10.0 mmol) in THF (10
mL) was added. The reaction mixture was stirred for 90 min,
and Cp2ZrCl2 (7.30 g, 25.0 mmol, 2.5 equiv) in THF (9 mL)
was added. After additional 10 min at -78 °C, to the reaction
was added propionaldehyde (794 mg, 11.0 mmol, 1.1 equiv) in
THF (5 mL). The reaction mixture was stirred at -78 °C for
30 min and quenched with 1 N HCl. The mixture was extracted
with ether (three times). The combined extracts were washed
with brine, dried over Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by silica gel chromatography
(12:1:1, hexanes:EtOAc:CH2Cl2, 10:1, hexanes:EtOAc) to afford
5r (4.79 g, 8.60 mmol, 86%) and unreacted 4d (250 mg, 0.05
mmol): 1H NMR (300 MHz, CDCl3) 7.01-7.22 ppm (7H, m),
6.88 (2H, d, J ) 6.6 Hz), 6.71 (2H, s), 5.98 (1H, d, J ) 9.6 Hz),
3.67 (2H, dd, J ) 13.5, 9.3 Hz), 3.47 (2H, dd, J ) 13.8, 4.2
Hz), 3.34 (1H, q, J ) 6.9 Hz), 2.49 (1H, m), 2.23 (3H, s), 2.04
(3H, s), 1.98 (6H, s), 1.68 (2H, td, J ) 17.0, 4.0 Hz), 1.40 (3H,
m), 1.32 (3H, d, J ) 6.9 Hz) 1.05-1.23 (2H, m), 0.91 (3H, t, J
) 9.6 Hz), 0.81 (2H, m), 0.62-0.65 (6H, m). 13C NMR (75 MHz,
CDCl3) 175.1, 139.1, 138.5, 137.3, 136.6, 136.1, 131.3, 130.9,
130.0, 128.8, 127.9, 127.7, 127.6, 126.8, 125.2, 74.4, 55.1, 50.8,
48.5, 47.3, 37.1, 32.0, 30.0, 28.5, 20.3, 20.0, 19.2, 18.3, 14.1,
11.0, 10.7, 10.0, 9.8. IR (neat) 3514.0 cm-1, 2926.1, 1727.3,
1613.4, 1581.0, 1378.4, 763.2, 743.1, 699.3. HRMS (ESI):
C
37H51NO3 (M + H+) calcd 558.394171, found 558.39451. [R]D
-8.7° (c 0.1, CHCl3 at 25 °C).
Ack n ow led gm en t. This work was supported by a
grant from The Florida State University. Dr. Alan
Marshall is gratefully acknowledged for the high-
resolution mass spectra measurements.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails including characterization for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O001293H