Role of pseudoephedrine as chiral auxiliary in the "acetate-Type" aldol reaction with chiral aldehydes; Asymmetric synthesis of highly functionalized chiral building blocks

Article abstract of DOI:10.1021/jo101878j

We have studied in depth the aldol reaction between acetamide enolates and chiral α-heterosubstituted aldehydes using pseudoephedrine as chiral auxiliary under double stereodifferentiation conditions, showing that high diastereoselectivities can only be achieved under the matched combination of reagents and provided that the α-heteroatom-containing substituent of the chiral aldehyde is conveniently protected. Moreover, the obtained highly functionalized aldols have been employed as very useful starting materials for the stereocontrolled preparation of other interesting compounds and chiral building blocks such as pyrrolidines, indolizidines, and densely functionalized β-hydroxy and β-amino ketones using simple and high-yielding methodologies.

Full text of DOI:10.1021/jo101878j

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Role of Pseudoephedrine as Chiral Auxiliary in the “Acetate-Type”
Aldol Reaction with Chiral Aldehydes; Asymmetric Synthesis of Highly
Functionalized Chiral Building Blocks
Marta Ocejo, Luisa Carrillo,* Jose L. Vicario, Dolores Badıa,* and Efraim Reyes
´ ´
Departamento de Quımica Organica II, Facultad de Ciencia y Tecnologıa, Universidad del Paıs Vasco/Euskal
Herriko Unibertsitatea, P.O. Box 644, E-48080 Bilbao, Spain
ꢀ
´
marisa.carrillo@ehu.es; dolores.badia@ehu.es
Received September 28, 2010
We have studied in depth the aldol reaction between acetamide enolates and chiral R-heterosub-
stituted aldehydes using pseudoephedrine as chiral auxiliary under double stereodifferentiation
conditions, showing that high diastereoselectivities can only be achieved under the matched
combination of reagents and provided that the R-heteroatom-containing substituent of the chiral
aldehyde is conveniently protected. Moreover, the obtained highly functionalized aldols have been
employed as very useful starting materials for the stereocontrolled preparation of other interesting
compounds and chiral building blocks such as pyrrolidines, indolizidines, and densely functionalized
β-hydroxy and β-amino ketones using simple and high-yielding methodologies.
Introduction
mely powerful C-C bond-forming reaction but also as a
direct and very effective procedure for the generation of 1,3-
dioxygenated structures in a stereocontrolled manner.1 As a
matter of fact, the literature shows a considerable number of
reports dealing with the total synthesis of natural pro-
ducts or therapeutics that have been accomplished using
this reaction as key step.2 Consequently, a plethora of
different strategies and methods have been developed by
many research groups worldwide in order to carry out this
important reaction in a stereocontrolled fashion.1 In this
context, one of the most widely used methodological ap-
proaches for carrying out asymmetric aldol reactions relies
on the use of chiral auxiliaries, and therefore many different
chiral reagents have been developed to be used in this
reaction, including the so-called “privileged auxiliaries”,
which have demonstrated an outstanding performance in
many total syntheses.3 Our group has also contributed to this
field, and a few years ago we developed a protocol for perform-
ing highly stereocontrolled aldol reactions using the amino
The asymmetric aldol reaction is one of the fundamental
transformations in organic chemistry not only as an extre-
(1) For some reviews on the asymmetric aldol reaction, see: (a) Mlynarski,
J.; Paradowska, J. Chem. Soc. Rev. 2008, 37, 1502. (b) Evans, D. A.; Helmchen,
G.; Rueping, M.; Wolfgang, J. In Asymmetric Synthesis; Christmann, M.,
Braese, S., Eds.; Wiley-VCH: Weinheim, 2007; p 3. (c) Carreira, E. M.; Fettes,
A.; Marti, C. Org. React. 2006, 67, 1. (d) Vicario, J. L.; Badia, D.; Carrillo, L.;
Reyes, E.; Etxebarria, J. Curr. Org. Chem. 2005, 9, 219. (e) Palomo, C.;
Oiarbide, M.; Garcia, J. M. Chem. Soc. Rev. 2004, 33, 65. (f) Modern Aldol
Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim, 2004. (g) Palomo, C.;
Oiarbide, M.; Garcia, J. M. Chem.;Eur. J. 2002, 8, 37. (h) Alcaide, B.;
Almendros, P. Eur. J. Org. Chem. 2002, 1595. (i) Machajewski, T. D.; Wong,
C.-H. Angew. Chem., Int. Ed. 2000, 39, 1352. (j) Arya, P.; Qin, H. Tetrahedron
2000, 56, 917. (k) Mahrwald, R. Chem. Rev. 1999, 99, 1095. (l) Carreira,
E. M. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Heidelberg, 1999; Vol. 3, p 997. (m) Nelson,
S. G. Tetrahedron: Asymmetry 1998, 9, 357. (n) Groger, H.; Vogl, E. M.;
Shibasaki, M. Chem.;Eur. J. 1998, 4, 1137. (o) Braun, M. In Houben-Weyl,
Methods of Organic Chemistry. Stereoselective Synthesis; Helmchen, G.,
Hoffmann, R., Mulzer, J., Schaumann, E., Eds.; Thieme: Stuttgart, 1996;
Vol. E21/3, p 1603. (p) Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1. (q)
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Winterfeldt, E.,
Eds.; Pergamon Press: Oxford, 1993; Vol. 2. (r) Heathcock, C. H. Aldrichimica
Acta 1990, 23, 99. (s) Heathcock, C. H. In Asymmetric Synthesis; Morrison,
J. D., Ed.; Academic Press: Orlando, 1984; Vol. 3, p 111. (t) Evans, D. A.;
Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982, 13, 1. (u) Mukaiyama, T.
Org. React. 1982, 28, 203.
(2) See, for example: Schetter, B.; Mahrwald, R. Angew. Chem., Int. Ed.
2006, 45, 7506.
(3) For selected recent reviews, see: (a) Gnas, Y.; Glorius, F. Synthesis
2006, 1899. (b) Pellissier, H. Tetrahedron 2006, 62, 1619. See also ref 1.
460 J. Org. Chem. 2011, 76, 460–470
Published on Web 12/28/2010
DOI: 10.1021/jo101878j
r
2010 American Chemical Society

Ocejo et al.
JOCArticle
alcohol (S,S)-(þ)-pseudoephedrine as chiral auxiliary.4 The
main advantages of the use of this auxiliary rely upon the fact
that it is a cheap reagent commercially available in both
enantiomeric forms and also that it is very easy to attach to
the starting carbonyl compound and to remove from the
final aldol adduct and can also be recovered in a very efficient
way after its removal, which allows recycling for further
uses.5 In addition, the pseudoephedrine amide moiety has
shown an outstanding synthetic versatility in the sense that
the aldol adducts could be easily transformed into many
other interesting chiral building blocks.
However, while many fundamental studies have been
performed for carrying out diastereoselective aldol reactions
with chiral reagents in which there is a single chirality source
devoted to the stereochemical control incorporated either at
the nucleophile (a chiral enolate or related derivative) or at
the electrophile (a chiral aldehyde or ketone), the same
reaction in which both reagents are chiral (double stereo-
differentiation conditions)6 incorporates true elements of
complexity that makes it very often a difficult problem to
be solved, especially when large structural fragments have to
be coupled together in the synthesis of a complex compound,
as is the case, for example, in the synthesis of polyketides.2 In
addition, there is also still a long-standing problem asso-
ciated with the asymmetric aldol reaction in general and the
chiral auxiliary-mediated methodologies in particular re-
lated to the fact that although most of the auxiliaries devel-
oped behave well with reactions in which the enolate reagent
bears an R-substituent (typically a methyl group, the so-
called “propionate-type” aldol reactions), most of them
perform poorly when the enolate lacks of this substituent
(the “acetate-type” aldol reaction).7 This situation, which is
apparently simpler in the sense that only one stereogenic
center is formed and therefore the syn/anti isomerism (simple
selectivity) problem is no longer present, turns out to be an
unexpectedly problematic reaction that deserves special
attention. Related to this topic, some research groups world-
wide have worked on the design of new chiral auxiliaries that
specifically apply to the acetate aldol reaction.8 We have also
carried out investigations directed to survey the applicability
of pseudoephedrine as chiral auxiliary in asymmetric acet-
ate-type aldol reactions but with little success, observing that
the aldol reaction between either aromatic or aliphatic
aldehydes and metal enolates derived from (S,S)-(þ)-pseu-
doephedrine acetamide always takes place with very low
diastereoselectivities under all conditions tried.9 Alterna-
tively, we explored the use of this chiral auxiliary in the
acetate-type aldol reaction using a chiral R-aminoalde-
hyde (R)-2a (Garner’s aldehyde),10 in a process proceeding
under double stereodifferentiation conditions, observing
that, in this case, the chiral auxiliary was an effective
stereocontrolling element that allowed the preparation
of the corresponding aldol in higher diastereoselectivity
than that observed in the simple reaction between an
achiral acetamide enolate and the same chiral aldehyde
(Scheme 1).
With all of these precedents in mind, we decided to further
investigate the scope and limitations of this methodology
with regard to the use of other different chiral R-heterosub-
stituted aldehydes.11 In this article, we wish to report in
detail our findings when working on the expansion of our
original procedure, together with an exploration of the
synthetic applicability of the obtained aldol adducts direc-
ted toward the stereoselective preparation of interesting
(4) (a) Vicario, J. L.; Badia, D.; Dominguez, E.; Rodriguez, M.; Carrillo,
L. J. Org. Chem. 2000, 65, 3754. (b) Vicario, J. L.; Badia, D.; Dominguez, E.;
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J. Org. Chem. Vol. 76, No. 2, 2011 461

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SCHEME 1
SCHEME 2
TABLE 1. Diastereoselective Aldol Reaction between Pseudoephedrine
Acetamides and R-Heterosubstituted Chiral Aldehydes (R)-2b and (R)-2ca
entry aldehyde amide 1 product conditionsa yield (%)b drc
1
2
3
4
5
6
7
8
(R)-2b (R,R)-1a
(R)-2b (S,S)-1a
(R)-2b 1c
3b
4b
5b
3c
4c
5c
3c
5c
3c
3b
5b
A
A
A
A
A
A
B
81
72
58
89
53
91
90
68
67
81
58
94:6
highly functionalized chiral building blocks and hetero-
cyclic compounds. These later transformations have focused
on exploiting the particular reactivity pattern displayed by the
pseudoephedrine amide moiety.
84:16
86:14
73:27
50:50
64:36
85:15
75:25
80:20
99:1
(R)-2c
(R)-2c
(R)-2c
(R)-2c
(R)-2c
(R)-2c
(R,R)-1a
(S,S)-1a
1c
(R,R)-1a
1c
(R,R)-1a
Results and Discussion
B
In our aforementioned preliminary report10 we had set up
the best conditions for carrying out the aldol reaction
between pseudoephedrine acetamide enolates and (R)-4-
formyl-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl
ester (R)-2a (also known as Garner’s aldehyde,12 see
Scheme 1) and had also identified matched and mismatched
combinations of reagents, concluding that (R,R)-pseudoe-
phedrine acetamide (R,R)-1a and (R)-2a furnished the cor-
responding aldol with excellent diastereoselectivity and
therefore that both reagents configured the matched couple
(Scheme 1). With these conditions in hand we proceeded next
to carry out the aldol reaction between pseudoephedrine
acetamides (R,R)-1a and (S,S)-1a and other different cyclic
chiral R-heterosubstituted aldehydes (R)-2b and (R)-2c,13
which are structurally related to Garner’s aldehyde (R)-2a
9
10
11
C
C
C
(R)-2b (R,R)-1a
(R)-2b 1c
89:11
aConditions. Method A: (i) LDA, THF, -78 °C; (ii) 2b-c, THF,
-105 °C. Method B: (i) LDA, LiCl (4 equiv), THF, -78 °C; (ii) 2b-c,
THF, -100 °C. Method C: (i) LDA, THF, -78 °C; (ii) Cp2ZrCl2, THF,
-78 °C; (iii) 2b-c, THF, -100 °C. bYield of combined diastereoisomeric
aldol products after flash column chromatography. cDetermined by
HPLC analysis of crude reaction mixture (see Supporting Information).
(Scheme 2). The obtained results have been summarized in
Table 1.
As it can be seen in this table, whereas the aldol reaction
between (R,R)-1a and (R)-2a proceeded with excellent diaster-
eoselectivity under our optimized conditions (see Scheme 1),
when these conditions were applied to chiral aldehyde (R)-2b
derived from glyceraldehyde,14 we observed the formation of
both diastereoisomers in a 94:6 ratio (entry 1). We also
checked that in this case (R,R)-1a and (R)-2b still formed
the matched combination of reagents by carrying out the aldol
reaction with (S,S)-1a, obtaining as expected a lower degree of
diastereoselection (entry 2). The matched/mismatched experi-
ment was also completed with the corresponding reaction
using the enolate derived from achiral N,N-dimethylaceta-
mide 1c, yielding the corresponding aldol in a 86:14 ratio
(entry 3).15 The same protocol was followed with N-Boc-(R)-
prolinal (R)-2c, observing a very similar behavior, with (R,R)-
1a and (R)-2c arising as the matched combination of reagents
(12) For a review on the use of aldehyde (R)-2a in organic synthesis, see:
(a) Liang, X.; Andersch, J.; Bols, M. J. Chem. Soc., Perkin Trans. 1 2001,
2136. For some examples of acetate aldol reactions with this chiral aldehyde,
see: (b) Enders, D.; Gasperi, T. Chem. Commun. 2007, 88. (c) Dondoni, A.;
Merino, P. J. Org. Chem. 1991, 56, 5294. (d) Garner, P.; Ramakanth, S. J.
Org. Chem. 1986, 51, 2609. (e) Kahne, D.; Yang, D.; Lee, M. D. Tetrahedron
Lett. 1990, 31, 21. For some examples of acetate aldol additions to other
chiral R-amino aldehydes, see: (f) Dias, L. C.; Fattori, J.; Perez, C. C.; de
Oliveira, V. M.; Aguilar, A. M. Tetrahedron 2008, 64, 5891. (g) Takizawa, T.;
Watanabe, K.; Narita, K.; Oguchi, T.; Abe, H.; Katoh, T. Chem. Commun.
2008, 14, 1677. (h) Gademann, K.; Bethuel, Y.; Locher, H. H.; Hubschwerlen,
C. J. Org. Chem. 2007, 72, 8361. (i) Dell’Agli, M.; Parapini, S.; Galli, G.;
Vaiana, N.; Taramelli, D.; Sparatore, A.; Liu, P.; Dunn, B. M.; Bosisio, E.;
Romeo, S. J. Med. Chem. 2006, 49, 7440. (j) Specker, E.; Boettcher, J.; Heine,
A.; Sotriffer, C. A.; Lilie, H.; Schoop, A.; Mueller, G.; Griebenow, N.; Klebe,
G. J. Med. Chem. 2005, 48, 6607. (k) Lou, S.; Westbrook, J. A.; Schaus, S. E.
J. Am. Chem. Soc. 2004, 126, 11440. (l) Pan, Q.; Zou, B.; Wang, Y.;Ma, D. Org.
Lett. 2004, 6, 1009. (m) Palomo, C.; Oiarbide, M.; Garcia, J. M.; Gonzalez, A.;
(14) For a review on the use of aldehyde (R)-2b in organic synthesis, see:
(a) Jurczak, J.; Pikul, S.; Bauer, T. Tetrahedron 1986, 42, 447. For some
examples of acetate aldol reactions with this chiral aldehyde, see: (b) Estevez,
R. E.; Paradas, M.; Millan, A.; Jimenez, T.; Robles, R.; Cuerva, J. M.; Oltra,
J. E. J. Org. Chem. 2008, 73, 1616. (c) Zhang, Y.; Sammakia, T. J. Org. Chem.
2006, 71, 6262. (d) Bodwell, G. J.; Davies, S. G.; Mortlock, A. A. Tetrahedron
1991, 47, 10077. (e) Pakulski, Z.; Zamojski, A. Tetrahedron 1995, 51, 871.
(15) It has been previously reported that the addition of the lithium
enolate of methyl acetate to aldehyde (R)-2b in THF at -70°C furnished a
85:15 mixture of diastereoisomers: Heathcock, C. H.; Young, S. D.; Hagen,
J. P.; Pirrung, M. C.; White, C. T.; VanDerveer, D. J. Org. Chem. 1980, 45,
3846.
~
Pazos, R.; Odriozola, J. M.; Banuelos, P.; Tello, M.; Linden, A. J. Org. Chem.
2004, 69, 4126 and references therein. (n) Andres, J. M.; Pedrosa, R.; Perez, A.;
Perez-Encabo, A. Tetrahedron 2001, 57, 8521. (o) Kiyooka, S.-i.; Goh, K.;
Nakamura, Y.; Takesue, H.; Hena, M. A. Tetrahedron Lett. 2000, 41,
6599.
(13) Aldehydes (R)-2a, (R)-2b, and (R)-2e are commercially available
compounds. The other R-amino aldehydes 2 were prepared from the
corresponding N-protected β-amino alcohols according to a procedure
developed by us: Ocejo, M.; Vicario, J. L.; Badia, D.; Carrillo, L.; Reyes,
E. Synlett 2005, 2110.
462 J. Org. Chem. Vol. 76, No. 2, 2011

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SCHEME 3
TABLE 2. Diastereoselective Aldol Reaction between Pseudoephedrine
Acetamide (R,R)-1a and R-Aminoaldehydes 2d-g
entry
aldehyde
compound
conditionsa
yield (%)b
drc
1
2
3
4
(R)-2d
(R)-2d
(R)-2d
(R)-2d
(R)-2e
(S)-2f
(R)-2g
(R)-2g
(R)-2g
3d
3d
3d
3d
B
75
70
80
65
50
45
90
72
60
69:31
52:48
64:36
59:41
50:50
56:44
98:2
Bd
A
C
B
5
3e
6d
7
ent-3f
3g
3g
B
B
B
A
8e
9
80:20
98:2
3g
aConditions. Method A: (i) LDA, THF, -78 °C; (ii) 2d-g, THF,
-100 °C. Method B: (i) LDA, LiCl (4 equiv), THF, -78 °C; (ii) 2d-g,
THF, -100 °C. Method C: (i) LDA, THF, -78 °C; (ii) Cp2ZrCl2, THF,
-78 °C; (iii) 2d-g, THF, -100 °C. bYield of combineddiastereoisomeric
aldol products after flash column chromatography. cDetermined by
HPLC analysis of crude reaction mixture (see Supporting Information).
d(S,S)-1a was employed as the enolate source. e1c was employed as the
enolate source.
that furnished the highest diastereoselectivity (entry 4),
whereas the reaction with (S,S)-1a (entry 5) and with achiral
1c (entry 6) proceeded with lower stereocontrol.16,17 We next
decided to survey some other modified conditions in order to
improve the diastereoselectivity of the reaction, starting with
the incorporation of LiCl asanadditivetothe reaction scheme
(reactionconditionsB), which insome caseshas beenreported
to have a beneficial effect on the diastereoselectivity of
processes in which pseudoephedrine amide enolates are
involved.18 In our case, the diastereoselectivity of the aldol
reaction using N-Boc-(R)-prolinal (R)-2c in the presence of 4
equiv of LiCl led to a better 85:15 dr (entry 7) under the
matched conditions. The beneficial effect associated to the
presence of the chiral auxiliary was confirmed by comparing
this result with the lower diastereoselectivity obtained using
the enolate derived form achiral 1c under the same reaction
conditions (entry 8 vs 7). We also surveyed changing the
nature of the enolate counterion by carrying out a transme-
talation reaction with Cp2ZrCl2 prior to the aldol addition
step (reaction conditions C), which we had already observed
had a positive effect in the diastereoselectivity of the closely
related “propionate-type” aldol reaction using pseudoephe-
drine as chiral auxiliary.19 However, in this case we could not
demonstrate any important improvement, observing that the
final aldol product had been formed as a 80:20 mixture of
diastereoisomers (entry 9). On the other hand, when these
conditions were applied to the reaction with glyceraldehyde
derivative (R)-2b, the reaction proceeded with complete dia-
stereocontrol, furnishing the corresponding aldol as a single
diastereoisomer (entry 10). Once again, the positive contribu-
tion of the chiral auxiliary was confirmed by carrying out the
reaction using 1c as the enolate source under these conditions
(entry 11 vs 10). It has also to be pointed out that the absolute
configuration of the newly generated stereocentre in the major
diastereoisomer was the same in all of the reactions, which
indicates that in all cases the influence exerted by the chiral
aldehyde in the stereochemical outcome of the reaction was
more important than the contribution made by the chiral
auxiliary.
We next evaluated the use of other different open-chain
R-amino aldehydes 2d-g13 employing the matched combina-
tion of reagents (Scheme 3), with the results shown in Table 2.
First, we checked that with reaction conditions B (R,R)-1a
and (R)-N-Boc-phenylalaninal (R)-2d formed the matched
combination of reagents by carrying out the aldol reaction
with (S,S)-1a, obtaining as expected a lower diastereoselec-
tivity in the later case compared with the former (entries 1
vs 2). Nevertheless, when either the standard conditions
(Method A) or the modified ones (Methods B and C) were
applied to (R)-2d, we observed in all cases that the reaction
proceeded with very poor levels of diastereoselection (entries
1, 3, and 4). We also tested R-aminoaldehydes (R)-2e20 and
(S)-2f,21 but also in these cases the reaction furnished mix-
tures of the two isomeric aldols in similar ratios as those
observed with (R)-2d (entries 5 and 6 vs 1), which indicated
that neither the nature of the alkyl side chain of the
R-aminoaldehyde reagent nor the carbamate protecting group
had an striking influence in the diastereoselectivity of the
process. We therefore hypothesized that the lower diaster-
eoselectivity observed in these reactions compared to that
observed for 2d-f could be possibly attributable to the
presence of an acidic N-H group in the aldehyde, and in
fact, when we carried out the reaction using N-methyl
substituted derivative (R)-2g in the reaction with (R,R)-1a
in the presence of LiCl as an additive (Method B), a fully
diastereoselective reaction occurred, isolating the corre-
sponding aldol 3g in excellent yield and as a highly dia-
stereopure material (entry 7). The positive influence of the
presence of the chiral auxiliary in the diastereoselectivity of
the reaction was also confirmed with the corresponding
experiment using the lithium enolate derived from achiral
1c under the same reaction conditions, obtaining in this case
a 80:20 mixture of diastereoisomers (entry 8). In this case,
(16) It has been previously reported that the addition of the lithium
enolate of ethyl acetate to aldehyde (R)-2c in THF at -78°C furnished a 4:1
mixture of diastereoisomers: Hanson, G. J.; Baran, J. S.; Lindberg, T.
Tetrahedron Lett. 1986, 27, 3577. On the other hand, the addition of the
corresponding zinc enolate to the same aldehyde furnished a 2:1 mixture of
diastereoisomers (see ref 12n). In all cases, the anti isomer was preferentially
formed.
(17) The addition of the lithium enolate of heptan-2-one to N-Cbz-(R)-
prolinal in THF at -78°C has been reported to proceed with excellent
diastereoselectivity, forming the corresponding anti aldol: Snider, B. B.;
Gao, X. Org. Lett. 2005, 7, 4419.
(18) For the influence of LiCl in the reactivity of pseudoephedrine
€
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 and references
therein. See also refs 5a, 5k, and 5l.
enolates, see: (a) Ruck, K. Angew. Chem., Int. Ed. Engl. 1995, 34, 433. (b)
(20) Aldehyde (R)-2g was prepared from D-mannitol according to a
literature procedure: Leyes, A. E.; Poulter, C. D. Org. Lett. 1999, 1, 1067.
(21) (S)-2f had to be used because the corresponding β-amino alcohol
needed for its preparation was commercially available only as the (S)
enantiomer. Consequently, the aldol reaction under matched conditions
was carried out using (S,S)-1a as nucleophile.
(19) Vicario, J. L.; Badıa, D.; Domınguez, E.; Rodrıguez, M.; Carrillo, L.
J. Org. Chem. 2000, 65, 3754.
J. Org. Chem. Vol. 76, No. 2, 2011 463

Ocejo et al.
JOCArticle
FIGURE 1. Proposed model for the diastereoselective aldol reac-
tion of (R,R)-1a and chiral aldehyde (R)-2g.
when the reaction was carried out under standard conditions
(Method A, without the presence of LiCl), only the yield of
the reaction became affected, obtaining the same high dia-
stereoselectivity in the reaction between (R,R)-1a and (R)-2g
as that obtained in the presence of LiCl (entry 9 vs 7).
These results can be rationalized by making use of the
polar Felkin-Ahn model22 and also assuming a Zimmer-
mann-Traxler-like six-membered transition state23 with no
chelation issues involved, as is normally accepted for the
aldol reactions of metal enolates with R-heterosubstituted
aldehydes. In our case, we have observed that the chirality at
the aldehyde plays the main role in regard to stereochemical
control, producing the 3,4-anti configured products in all
cases regardless of the configuration of the chiral auxiliary.
This indicates that pseudoephedrine is playing a secondary
role with regard to stereocontrol, although its incorporation
enables small but relevant increases on diastereoselectivity
when compared with the parent reaction when an achiral
enolate was employed (see for example entries 7 vs 8 and
10 vs 11 in Table 1 and entries 7 vs 8 in Table 2). As is shown
in Figure 1 using the reaction between (R,R)-1a and R-
aminoaldehyde (R)-2g as a model, a Felkin-Ahn model
accounts for the formation of the final adducts by assuming
that chiral aldehydes 2 would interact with the enolate
derived from (R,R)-1a through a reactive conformation in
which the CdO and C-N (or C-O) bonds should remain in
an antiperiplanar position because of repulsion between the
electronegative O- and N-atoms. As a result, the aldehyde si
face is sterically more accessible for the attack of the enolate
nucleophile. As is shown in Figure 1, a chairlike transition
state is proposed, although the possibility of the reaction to
proceed through a boat-like transition state should not be
discarded, as it is also proposed in the literature for many
cases of acetate-type aldol reactions.24 However, the funda-
mental role played by the chirality of the aldehyde in this
reaction makes this feature a minor fact to be considered
here. Other possible explanations for this selectivity invol-
ving alternative models reported in the literature, such as a
Cornforth-type transition state or syn-pentane interactions
operating in the transition state, have not been considered
FIGURE 2. Proposed model for the diastereoselective aldol reac-
tion of (R,R)-1a and (R)-2d-f.
for this case because of the absence of any substituent at the
R-carbon of the enolate reagent.22 Regarding the stereo-
chemical influence of the chiral auxiliary, this proposal takes
also into account the previously proposed models5b,k for
other reactions between (S,S)-(þ)-pseudoephedrine amide
enolates and different electrophiles in which the final pro-
duct arises from the attack to the less hindered face of an
intermediate in an opened staggered conformation, which
remains rigid with the help of bridging solvent or iPr2NH
(from LDA) molecules.25 For this reason, we can assume
that in this case one of the diastereotopic faces of the enolate
reagent is effectively blocked, although this is not a relevant
question operating in this case because of the nature of the
enolate reagent which, due to the lack of the R-substituent
does not lead to the formation of an stereocenter at this
position and therefore the facial discrimination of the dia-
stereotopic faces of the enolate does not have any conse-
quences on the stereochemical outcome of this reaction.
Nevertheless, the presence of the chiral auxiliary can also
be consider to contribute to the stabilization of the chairlike
transition state vs the competitive formation of other possi-
ble boat-type structures with similar energies for the two
transition states leading to each of the two possible
diastereoisomers.26 The exact role played by LiCl in this
reaction when used as additive which slightly increases the
diastereoselectivity of the reaction still remains unknown to
us, although a plausible proposal might involve its participa-
tion as bridging species similar to those mentioned before
which communicates both lithium atoms of the pseudoephe-
drine acetamide lithium enolate therefore contributing to a
more rigid transition state, although it might be simply
operating by modifying the aggregation state of the enolate
species as it has been pointed out earlier.18
A possible explanation for the poor stereoselectivity ob-
tained when N-H containing chiral R-aminoaldehydes 2d-f
were employed in this reaction can be found on the hypothe-
tical formation of an intramolecular hydrogen bond that
would stabilize an alternative conformation for the chiral
electrophile, which would turn the re face more accessible
(22) (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2199. (b) Anh, N. T.; Eisenstein, O. Nouv. J. Chim. 1977, 1, 61. (c) Anh, N. T.
Top. Curr. Chem. 1980, 88, 145. (d) Lodge, E. P.; Heathcock, C. H. J. Am.
Chem. Soc. 1987, 109, 3353. See also: (e) Mengel, A.; Reiser, O. Chem. Rev.
1999, 99, 1191.
(23) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920.
(24) See for example: (a) Crimmins, M. T.; Shamszad, M. Org. Lett. 2007,
9, 149. (b) Saito, S.; Hatanaka, K.; Kano, T.; Yamamoto, H. Angew. Chem.,
Int. Ed. 1998, 37, 3378. (c) Pridgen, L. N.; Abdel-Magid, A. F.; Lantos, I.;
Shilcrat, S.; Eggleston, D. S. J. Org. Chem. 1993, 58, 5107 and references
therein. See also: (d) Goodman, J. M.; Kahn, S. D.; Paterson, I. J. Org.
Chem. 1990, 55, 3295. See also ref 7.
(26) For several discussions, see: (a) Diaz-Oltra, S.; Carda, M.; Murga, J.;
Falomir, E.; Marco, J. A. Chem.;Eur. J. 2008, 14, 9240. (b) Diaz-Oltra, S.;
Murga, J.; Falomir, E.; Carda, M.; Peris, G.; Marco, J. A. J. Org. Chem.
2005, 70, 8130. (c) Evans, D. A.; Siska, S. J.; Cee, V. J. Angew. Chem., Int. Ed.
2003, 42, 1761.
(25) Vicario, J. L.; Badia, D.; Dominguez, E.; Carrillo, L. J. Org. Chem.
1999, 64, 4610.
464 J. Org. Chem. Vol. 76, No. 2, 2011

Ocejo et al.
JOCArticle
for the nucleophilic attack, therefore accounting for the
formation of the anti-Felkin 3,4-syn diastereoisomer (Figure
2). We assume that, under the reaction conditions, both
possible transition states could eventually compete and
therefore mixtures of the two possible diastereoisomers can
be formed in variable amounts. The formation of such an
intramolecular hydrogen bond in asymmetric aldol reactions
with chiral R-aminoaldehydes has also been proposed in
previous reports in order to explain anti-Felkin selectivity in
aldol reactions involving R-substituted enolates.27 It should
also be pointed out that all of the reactions carried out with
these NH-containing R-amino aldehydes proceeded with
complete conversion of the starting material, which also
indicates that the addition of the enolate to the aldehyde
has to occur faster than the possible competitive quenching
of the enolate reagent by the acidic NH hydrogen, which
would lead to the recovery of starting unreacted acetamide
(R,R)-1a. This behavior is also in agreement with other
literature examples.12m,n,28
SCHEME 5
After studying the aldol reaction and once the required
conditions for obtaining the corresponding aldols were fully
understood, we next faced the task of exploring the reactivity
of these highly functionalized compounds with a focus on the
preparation of polyfunctionalized chiral building blocks. In
this context, effective protocols have to be developed for the
removal of the chiral auxiliary in a clean way, using simple
and high-yielding procedures and, if possible, allowing the
recycling of the auxiliary. It is in this particular situation
where pseudoephedrine amides have found a wide field of
application because of the particular reactivity displayed by
this moiety. For this purpose, we limited our study to the
reactivity of aldols 3a-c and 3g, which were obtained as
highly stereoenriched compounds.
We started with the removal of the chiral auxiliary by
hydrolysis, which would allow the preparation of γ-amino-
β-hydroxy carboxylic acid derivatives. When we carried
the hydrolysis under acidic conditions, which has been the
methodology of choice in many other examples,5 we ob-
tained only complicated mixtures of unidentified products.
Alternatively, base-promoted hydrolysis proceeded smoothly,
providing cleanly the corresponding carboxylic acids, and
these were subsequently subjected to esterification with tri-
methylsilyldiazomethane29 for better purification (Scheme 4).
Remarkably, the chiral auxiliary (R,R)-(-)-pseudoephedrine
could be easily recovered after the hydrolysis step by standard
acid-base workup, which allowed its recycling for further uses.
At this point, we also faced the determination of the
configuration of the new stereogenic center generated in
the diastereoselective aldol reaction. For this purpose, we
decided to prepare conformationally locked cyclic deriva-
tives of the esters 6, which would be appropriate molecules
for the determination of the relative configuration by NOE
experiments, given the known configuration of the stereocen-
ter that was introduced at the starting aldehyde. We had
already described in our preceding communication, the de-
termination of the absolute configuration of aldol 3a (see
Scheme5),10 which could not be carried out directly from ester
6a and was needed for a four-step sequence starting from 3a.
The case of esters 6b, 6c, and 6g turned to be much easier; for
example, for 6c and 6g we were able to prepare pyrrolizidine
derivative 8 and γ-lactam 9, respectively, by TFA-mediated
deprotection followed by base-promoted intramolecular
amide formation. Cyclic lactone 10 was also prepared in a
very simple way from ester 6b by first carrying out the acid
hydrolysis of the acetonide moiety, which proceeded conco-
mitantly with a lactonization process, and next peracetylation
was carried out for better characterization purposes. Analyses
of NOE experiments carried out on these cyclic derivatives
confirmed the anti relationship between both contiguous
stereogenic centers and therefore allowed us to establish a
(3S) absolute configuration for the stereocenter created in the
aldolreactions. It has to be emphasized thatthis configuration
of the major aldols 3 was the same in all cases, confirming that
the stereochemical outcome of the diastereoselective aldol
reaction of chiral R-heterosubstituted aldehydes with pseu-
doephedrine acetamides did not change when R-amino alde-
hydes (R)-2c and (R)-2g or R-alkoxyaldehyde (R)-2b were
employed as electrophiles.
SCHEME 4
We also evaluated the possibility of removing the
chiral auxiliary by reduction, in order to obtain highly
(27) Vicario, J. L.; Badia, D.; Dominguez, E.; Carrillo, L. J. Org. Chem.
1999, 64, 4610.
(28) (a) Jung, C.-K.; Kirsche, M. J. J. Am. Chem. Soc. 2006, 128, 17051.
See also: (b) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Pedrini, P. J. Org.
Chem. 1990, 55, 1439. (c) Dondoni, A.; Perrone, D.; Merino, P. J. Org. Chem.
1995, 60, 8074.
(29) (a) Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull. 1981,
29, 1475. (b) Hodnett, N. S. Synlett 2003, 2095.
J. Org. Chem. Vol. 76, No. 2, 2011 465

Ocejo et al.
JOCArticle
SCHEME 6
SCHEME 7
TABLE 3. Selective 1,2-Addition of Organolithium Reagents to Aldols
3a and 3b
entry
substrate
X
R
product
yield (%)a
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
NBoc
NBoc
NBoc
NBoc
NBoc
NBoc
O
O
O
O
O
Me
Et
i-Pr
n-Bu
t-Bu
Ph
Me
Et
i-Pr
n-Bu
t-Bu
Ph
14a
14b
14c
14d
14e
14f
15a
15b
15c
15d
15e
15f
94
88
87
89
71
68
93
75
77
85
71
72
functionalized primary alcohols. We tried the use of lithium
amidotrihydroborate (LAB), which is known as a very
effective reagent for the conversion of pseudoephedrine
amides into the corresponding alcohols, 30 and in our case,
we observed that aldol 3c underwent fast and clean reduc-
tion, under the typical conditions, furnishing diol 11 good
yield (Scheme 6). This compound was subsequently em-
ployed as starting material for an alternative synthesis of
pyrrolizidines, which is the main structural basis of many
important natural products and therapeutics,31 following a
set of transformations as shown in Scheme 6. First, 11 was
reacted with excess MsCl, yielding cleanly dimesylated com-
pound 12, and next, removal of the N-Boc protecting group
occurred with a subsequent intramolecular cyclization that
happened during the workup procedure, which involved basic
conditions. In this way, pyrrolizidine 13 was isolated in ex-
cellent yield and as a single diastereoisomer, indicating that all
of the reactions proceeded with no epimerization in any of the
stereogenic centers present at the corresponding precursors.
Finally, we also decided to evaluate the removal of the
chiral auxiliary by exploiting the known ability of the
pseudoephedrine amide moiety to undergo fast and clean
1,2-addition of organolithium reagents, affording the corre-
sponding ketones after aqueous workup (Scheme 7). This
moiety has shown a behavior comparable in this context to
that of Weinreb amides.32 We had already demonstrated in
our preceding paper that aldol 3a was an excellent substrate
for this transformation, and a wide range of γ-amino-β,δ-
dihydroxyketones were prepared using different organo-
lithium reagents10 (Table 3, entries 1-6). We therefore
proceeded to check whether aldol 3b, which does not contain
any amino moiety on its structure, was also a suitable
substrate for this transformation, and indeed, the reaction
of 3b with organolithium reagents proved to be equally
efficient, yielding a set of different ketones in excellent yields
and as single diastereoisomers (entries 7-12 in Table 3). As
can be observed in Table 3, a wide range of organolithium
9
10
11
12
O
aYield of pure product after flash column chromatography purification.
reagents are acceptable regardless of their structure, and
therefore primary, secondary, and even tertiary alkyllithium
reagents, as well as phenyllithium, underwent clean 1,2-
addition, with no evidence of competitive aldolization at
the two highly acidic R-protons of the substrate under these
extremely basic conditions. It has also to be pointed out that
also in this case, the chiral auxiliary (R,R)-(-)-pseudoephe-
drine could be easily recovered after standard acid-base
work up and could be recycled for further uses.
Conclusions
In conclusion, we have shown that acetate-type aldol
reactions using chiral R-heterosubstituted aldehydes as elec-
trophiles can be carried out with high yields and stereose-
lectivities using pseudoephedrine as chiral auxiliary provided
that the correct matched combination of reagents is em-
ployed and also that the chiral aldehyde electrophile does
not contain any acidic H-atom at the R-heteroatom contain-
ing substituent. Although the diastereoselectivity of the
reaction is dominated by the chiral electrophile, the matched
combination is crucial to ensure a useful and high stereo-
selectivity. From a mechanistic point of view, the obtained
results can be explained by making use of the polar Felkin-
Ahn model with no contribution of any chelating element
in the transition state, and the poorer level of stereo-
selection observed when R-aminoaldehydes containing an
acidic NH group were employed should be attributed to the
presence of a competitive reaction pathway involving a chela-
tion-controlled transition state. On the other hand, it has also
been shown that the highly stereoenriched aldol adducts
obtained could be easily transformed into a variety of different
valuable chiral building blocks by exploiting the rich reactivity
profile of the pseudoephedrine amide moiety.
(30) (a) Myers, A. G.; Yang, B. H.; Kopecky, D. J. Tetrahedron Lett.
1996, 37, 3623. (b) Myers, A. G.; Yang, B. H.; Chen, H.; Kopecky, D. J.
Synlett 1997, 457. See also: (c) Whitlock, G. A.; Carreira, E. M. Helv. Chim.
Acta 2000, 83, 2007 and ref 5.
(31) (a) Pyne, S. G.; Davis, A. S.; Gates, N. J.; Hartley, J. P.; Lindsay,
K. B.; Machan, T.; Tang, M. Synlett 2004, 2670. (b) Liddell, J. R. Nat. Prod.
Rep. 2002, 19, 773.
(32) For a detailed study see ref 5b. For other related examples, see: (a)
Zhou, X.-T.; Lu, L.; Furkert, D. P.; Wells, C. E.; Carter, R. G. Angew.
Chem., Int. Ed. 2006, 45, 7622. (b) Robertson, J.; Dallimore, J. W. P.; Meo, P.
Org. Lett. 2004, 6, 3857. (c) White, J. D.; Xu, Q.; Lee, C.-S.; Valeriote, F. A.
Org. Biomol. Chem. 2004, 2, 2092. (d) Vicario, J. L.; Badıa, D.; Carrillo, L.
Tetrahedron: Asymmetry 2003, 14, 489. (e) Vicario, J. L.; Badıa, D.; Carrillo,
L. Tetrahedron: Asymmetry 2002, 13, 745. (f) Smith, A. B., III.; Adams,
C. M.; Kozmin, S. A.; Paone, D. V. J. Am. Chem. Soc. 2001, 123, 5925.
Experimental Section
General Procedures for the Diastereoselective Aldol Reaction
of Pseudoephedrine Acetamide and Chiral r-Heterosubstituted
Aldehydes. Method A. A solution of the acetamide (R,R)-1a or
466 J. Org. Chem. Vol. 76, No. 2, 2011

Ocejo et al.
JOCArticle
(S,S)-1a (1.0 mmol) in dry THF (10 mL) was slowly added to a
cooled (-78 °C) solution of LDA (2.0 mmol) in dry THF
(20 mL). The mixture was stirred at this temperature for 1 h
and allowed to reach room temperature. After stirring for
30 min, the mixture was cooled again to -100 °C at which
temperature a solution of the starting chiral aldehyde 2
(1.5 mmol) in dry THF (5 mL) was dropwise added within
20 min. The mixture was stirred at -100 °C for 7 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, which was flash
column chromatographed affording the corresponding aldols 3.
Method B. A solution of the acetamide (R,R)-1a (1.0 mmol) or
(S,S)-1a (1.0 mmol) in dry THF (10 mL) was slowly added to a
cooled (-78 °C) solution of LDA (2.0 mmol) in dry THF
(20 mL) and LiCl (5.0 mmol). The mixture was stirred at this
temperature for 1 h and allowed to reach room temperature.
After stirring for 30 min, the mixture was cooled again to -100 °C
at which temperature a solution of the starting chiral aldehyde 2
(1.5 mmol) in dry THF (5 mL) was dropwise added within 20
min. The mixture was stirred at -100 °C for 7 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, which was flash
column chromatographed affording the corresponding aldols 3.
Method C. A solution of the acetamide (R,R)-1a (1.0 mmol)
or (S,S)-1a (1.0 mmol) in dry THF (10 mL) was slowly added to
a cooled (-78 °C) solution of LDA (2.0 mmol) in dry THF
(20 mL). The mixture was stirred at this temperature for 1 h and
allowed to reach room temperature. After stirring for 30 min,
the mixture was cooled again to -78 °C, and next a solution of
Cp2ZrCl2 (2.0 mmol) in dry THF (5 mL) was added at once.
After stirring for 1 h at this temperature, the reaction was cooled
to -100 °C at which temperature a solution of chiral aldehyde 2
(1.5 mmol) in dry THF (3 mL) was dropwise added within
20 min. The mixture was stirred at -100 °C for 7 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, which was flash
column chromatographed affording the corresponding aldols 3.
(-)-(100R,200R,3S,40R)-3-(20,20-Dimethyl[1,3]dioxolan-40-yl)-
3-hydroxy-N-(100-hydroxy-100-phenylpropan-200-yl)-N-methyl-
propanamide (3b). Amide 3b was prepared according to proce-
dure C (see Table 1, entry 10) starting from amide (R,R)-1a
(2.00 g, 9.66 mmol) and using LDA (21.25 mmol), Cp2ZrCl2
(5.65 g, 19.32 mmol), and aldehyde (R)-2b (1.88 g, 14.49 mmol).
Yield: 81% (2.64 g, 7.82 mmol). HPLC analysis of the crude
reaction mixture (Chiralcel OD column, hexanes/2-propanol
97:3, flow rate 0.85 mL/min) indicated a 99:1 diastereomeric
ratio. tR for the minor (100R,200R,3R,40R) isomer: 52.0 min. tR
for the major (100R,200R,3S,40R) isomer: 61.3 min. [R]20D -84.4
(-)-(10S,100R,2R,200R)-N-tert-Butoxycarbonyl-2-{10-hydro-
xy-20-[N-(200-hydroxy-100-methylethyl-200-phenyl)-N-methyl-
carbamoyl]ethyl}pyrrolidine (3c). Amide 3c was prepared ac-
cording to procedure B (see Table 1, entry 7) starting from amide
(R,R)-1a (0.35 g, 1.67 mmol) and using LDA (3.34 mmol),
aldehyde (R)-2c (0.50 g, 2.51 mmol), and LiCl (0.36 g,
8.36 mmol) and isolated as a yellowish oil after flash column
chromatography purification (hexanes/AcOEt 2:8). Yield: 90%
(0.61 g, 1.51 mmol). HPLC analysis of the crude reaction
mixture (Chiralcel OJH column, hexanes/2-propanol 97:3, flow
rate 1.00 mL/min) indicated a 85:15 diastereomeric ratio. tR for
the minor (10R,100R,2R,200R) isomer: 15.29 min. tR for the major
(10S,100R,2R,200R) isomer: 26.04 min. [R]20 -30.7 (c 1.0 in
D
1
CH2Cl2). H NMR (300 MHz, CDCl3) (δ, ppm) (4:1 rotamer
ratio; *indicates minor rotamer resonances): 0.86 (d, 3H, J =
6.8 Hz), 1.45 (s, 9H), 1.75-1.93 (m, 3H), 2.14-2.27 (m, 1H),
2.46 (dd, 1H, J = 16.0, 3.8 Hz), 2.68 (dd, 1H, J = 16.0, 3.4 Hz),
2.89 (s, 3H), 2.93* (s, 3H), 3.23-3.41 (m, 2H), 3.54-3.66
(m, 1H), 4.08-4.18 (m, 1H), 4.45-4.65 (m, 2H), 4.84-4.97
(m, 1H), 5.50 (d, 1H, J = 9.0 Hz), 7.25-7.43 (m, 5H). 13C NMR
(75.5 MHz, CDCl3) (δ, ppm) (*indicates minor rotamer res-
onances): 14.5 15.2*, 23.3, 26.9*, 27.2, 28.4, 28.5*, 29.5, 35.0,
47.4, 54.9, 58.0*, 60.4, 61.4*, 70.4, 75.5, 75.7*, 79.4, 79.7*,
126.8*, 127.2, 127.8, 128.3, 128.6*, 141.2*, 141.3, 155.8,
173.8*, 174.8. IR (CHCl3): 3396 (OH), 1687, 1618 (CdO). MS
(CI) m/z (relative intensity): 407 (MþþH, 5), 389 (5), 333 (5), 308
(19), 307 (100), 305 (3), 243 (14), 236 (16), 166 (12), 148 (7), 142
(3). HRMS (m/z): [M þ H]þ calcd for[C22H35N2O5]þ 407.2540.
Found: 407.2535.
(-)-(10R,20R,3S,4R)-4-tert-Butoxycarbonylmethylamino-
3-hydroxy-N-methyl-N-(20-hydroxy-10-methylethyl-20-phenyl)-5-
phenylpentanamide (3g). Amide 3g was prepared according to
procedure B (see Table 2, entry 7) starting from amide (R,R)-1a
(0.26 g, 1.26 mmol)and using LDA (2.52 mmol), aldehyde (R)-
2g (0.50 g, 1.90 mmol), and LiCl (0.27 g, 6.33 mmol) and isolated
as a yellowish oil after flash column chromatography purifica-
tion (hexanes/AcOEt 2:8). Yield: 90% (0.53 g, 1.13 mmol).
[R]20D -38.3 (c 1.0 in CH2Cl2). Determination of the diastereos-
electivity of the reaction was carried out by HPLC analysis of
the corresponding methyl ester 6g obtained by hydrolysis/
esterification of the crude reaction mixture following the general
procedure (see Supporting Information for details). This anal-
ysis showed that aldol 3g had been obtained as a 98:2 mixture of
1
diastereoisomers. H NMR (300 MHz, CDCl3) (δ, ppm) (1:1
rotamer ratio; *indicates rotamer resonances): 0.90 (d, 3H, J =
6.9 Hz), 0.96* (d, 3H, J = 6.8 Hz), 1.03* (d, 3H, J = 6.7 Hz),
1.19* (s, 9H), 1.29 (s, 9H), 1.33* (s, 9H), 2.32-2.96 (m, 3H), 2.55
(s, 3H), 2.80* (s, 3H), 2.84 (s, 3H), 2.93* (s, 3H), 3.24-3.42
(m, 1H), 3.80-4.74 (m, 4H), 4.76-4.94 (m, 1H), 5.43 (d, 1H,
J = 5.6 Hz), 7.16-7.42 (m, 10H). 13C NMR (75.5 MHz, CDCl3)
(δ, ppm) (*indicates minor rotamer resonances): 14.3*, 14.6,
15.2,* 15.3*, 26.7*, 28.1*, 28.2, 28.3*, 30.3, 31.6, 33.6*, 34.0,
35.6, 37.0*, 55.6, 57.9, 68.9*, 70.2, 75.4, 76.0*, 79.3*, 79.8, 125.9,
126.0, 126.5, 126.6, 126.7, 127.0, 127.8, 128.1, 128.2, 128.3,
128.4, 128.7, 128.8, 129.0, 138.6, 139.1*, 141.3, 141.4, 141.8,
155.6*, 156.2*, 156.3, 173.6*, 173.7*, 174.0, 174.4*. IR (CHCl3):
3406 (OH), 1687, 1617 (CdO). MS (CI) m/z (relative intensity):
471 (MþþH, 18), 453 (8), 415 (15), 399 (14), 379 (16), 372 (26),
371 (100), 307 (9), 236 (27), 208 (8), 164 (8), 148 (12). HRMS(m/z):
[M þ H]þ calcd for[C27H39N2O5]þ 471.2853, found 471.2872.
General Procedure for the Hydrolysis/Esterification of Aldols
3. To a solution of the amide 3a-c or 3g (1.00 mmol) in dioxane
(3 mL), MeOH, (3 mL) and H2O (6 mL) was added NaOH
(5 mmol). The mixture was then refluxed for 2 h and allowed to
reach room temperature. More water (10 mL) was added, and
the mixture was washed with Et2O (3 ꢀ 15 mL). After drying
(Na2SO4), filtering, and removing the solvents, the chiral aux-
iliary (R,R)-(-)-pseudoephedrine was recovered in 71% yield as
1
(c 0.7 in CHCl3). H NMR (300 MHz, CDCl3) (δ, ppm) (3:1
rotamer ratio; *indicates minor rotamer resonances): 0.99
(d, 3H, J = 6.7 Hz); 1.31 (s, 3H); 1.37 (s, 3H); 2.44 (dd, 1H,
J = 16.2, 7.1 Hz); 2.64 (d, 1H, J = 16.2 Hz); 2.84 (s, 3H); 2.89*
(s, 3H); 3.89-4.07 (m, 5H); 4.51 (m, 2H); 4.64-4.70 (m, 1H);
7.29 (m, 5H). 13C NMR (75.5 MHz, CDCl3) (δ, ppm)
(*indicates minor rotamer resonances): 14.3; 15.2*; 25.2;
26.7; 31.2; 35.7*; 37.1; 56.1*; 58.1; 67.5; 70.1; 75.3; 75.8;
109.3; 126.6; 126.7*; 127.8*; 128.4; 128.6; 141.3*; 141.7;
173.5*; 173.9. IR (film): 3412 (OH); 1613 (CdO). MS (EI)
m/z (relative intensity): 301 (Mþ - 2H2O, 11), 202 (14), 147
(19), 118 (20), 100 (16); 91 (21), 71 (20), 58 (100). Anal. Calcd
for C18H27NO5: C, 64.07; H, 8.07; N, 4.15. Found: C, 64.12; H,
8.15; N, 4.08.
J. Org. Chem. Vol. 76, No. 2, 2011 467

Ocejo et al.
JOCArticle
a white solid after crystallization in hexane/AcOEt. The basic
aqueous layer was then carefully basified with 1 M HCl until
pH = 3, and the mixture was extracted with CH2Cl2 (3 ꢀ
15 mL). The combined organic fractions were collected, dried
over Na2SO4, and filtered, and the solvent was removed in vacuo
to yield the corresponding carboxylic acid, which was directly
subjected to esterification. This was carried out by the addition
of TMSCHN2 (4.00 mmol) over a cooled (0 °C) solution of the
crude acid in dry THF (10 mL). After stirring for 2 h, MeOH
(1 mL) was added at once, and the mixture was stirred for
further 45 min, after which it was quenched with water (15 mL).
The mixture was extracted with CH2Cl2 (3 ꢀ 15 mL), the
combined organic fractions were collected, dried over Na2SO4,
and filtered, and the solvent was removed in vacuo to yield ester
6a-c, 6g as colorless oils after flash column chromatography
purification.
(-)-(3S,40R)-3-(20,20-Dimethyl[1,3]dioxolan-40-yl)-3-hydroxy-
propanoic Acid Methyl Ester (6b). Ester 6b was prepared accord-
ing to the general procedure starting from aldol 3b (0.46 g, 1.36
mmol), NaOH (0.14 g, 3.6 mmol), and TMSCHN2 (3.04 mL of a
2 M solution in Et2O, 6.08 mmol) and isolated as a colorless oil
after flash column chromatography purification (hexanes/
AcOEt 1:1). NMR analysis of crude reaction mixture indicated
that ester 6b had been obtained as a >95:5 dr. Yield: 63% (0.17
g, 0.86 mmol). [R]20D -11.8 (c 0.4 in CHCl3). (lit.33 -10.6, c 1.0
in CHCl3). 1H NMR (300 MHz, CDCl3) (δ, ppm): 1.30 (s, 3H);
1.36 (s, 3H); 2.43 (dd, 1H, J = 16.7, 8.5 Hz); 2.68 (dd, 1H, J =
16.7, 2.4 Hz); 3.28 (bs, 1H); 3.67 (s, 3H); 3.95 (m, 2H); 4.03 (m,
1H). 13C NMR (75.5 MHz, CDCl3, 25 °C, δ, ppm): 25.0; 26.5;
37.5; 51.8; 66.5; 69.1; 77.5; 109.4; 173.0. IR (film): 3472 (OH);
1737 (CdO). MS (EI) m/z (relative intensity): 190 (6), 189 (66),
147 (7), 131 (3), 129 (38), 115 (21), 103 (15); 101 (100), 97 (52), 87
(7), 83 (9); 73 (34), 72 (18); 71(12); 61 (13); 59 (43); 55 (20).
(þ)-(3S,4R)-3-(N-tert-Butoxycarbonyl-pyrrolidin-20-yl)-3-hy-
droxy-2-methylpropanoic Acid Methyl Ester (6c). Ester 6c was
prepared according to the general procedure starting from
aldol 3c (0.15 g, 0.37 mmol), NaOH (0.07 g, 1.85 mmol), and
TMSCHN2 (0.74 mL of a 2 M solution in Et2O, 1.48 mmol)
and isolated as a yellowish oil after flash column chromato-
graphy purification (hexanes/AcOEt 6:4). Yield: 79% (0.08 g,
0.29 mmol). HPLC analysis (Chiralcel OJH column, hexanes/
2-propanol 97:3, flow rate 1.00 mL/min) indicated a 90:10
diastereomeric ratio. tR for the major (10S,2R) isomer: 10.09
min. tR for the minor (10R,2R) isomer: 10.94 min. [R]20D þ40.5 (c
1.67 in CHCl3). 1H NMR (300 MHz, CDCl3) (δ, ppm): 1.42 (s,
9H), 1.63-2.05 (m, 4H), 2.28-2.51 (m, 2H), 3.16-3.24 (m, 1H),
3.37-3.50 (m, 1H), 3.65 (s, 3H), 3.83-3.94 (m, 1H), 4.09-4.16
(m, 1H), 4.45 (bs, 1H). 13C NMR (75.5 MHz, CDCl3) (δ, ppm)
(*indicates minor rotamer resonances): 23.3*, 23.9, 26.4*, 27.5,
28.2*, 28.3, 37.7, 38.5*, 46.8*, 47.7, 51.6, 61.2*, 62.1, 69.0*, 70.2,
79.9, 80.3*, 154.7*, 156.2, 172.7. IR (CHCl3): 3448 (OH),
1740, 1693 (CdO). MS (CI) m/z (relative intensity): 274
(MþþH, 3), 228 (3), 218 (17), 200 (14), 174 (100), 170 (19),
156 (11), 142 (9), 124(6), 114 (27). HRMS (m/z): [M þ H]þ calcd
for[C13H24NO5]þ 274.11649, found 274.1662.
(c 0.18 in CHCl3). 1H NMR (300 MHz, CDCl3) (δ, ppm)
(*indicates minor rotamer resonances): 1.22* (s, 9H), 1.35 (s,
9H), 2.39-2.66 (m, 3H), 2.51 (s, 3H), 2.91-3.00 (m, 1H), 3.15
(dd, 1H, J = 14.1, 3.8 Hz), 3.28* (dd, 1H, J = 14.0, 2.3 Hz),
3.40-3.51* (m, 1H), 3.70* (s, 3H), 3.71 (s, 3H), 3.90-4.28 (m,
2H), 7.14-7.27 (m, 5H). 13C NMR (75.5 MHz, CDCl3) (δ, ppm)
(*indicates minor rotamer resonances): 28.1*, 28.2, 33.2, 34.3*,
37.9, 38.7*, 51.7*, 51.8, 60.9*, 62.9, 69.1*, 70.2, 79.7, 126.1*,
126.2, 128.2*, 128.3, 128.9, 138.8, 155.5*, 156.2, 173.1*, 173.4.
IR (CHCl3): 3433 (OH), 1664 (CdO). MS (CI) m/z (relative
intensity): 338 (Mþ þ H, 1), 280 (1), 264 (13), 246 (14), 238 (100),
234 (14), 206 (6), 178 (22), 146 (17), 134(11), 114 (5). HRMS
(m/z): [M þ H]þ calcd for[C18H28NO5]þ 338.1962, found
338.1983.
(þ)-(1S,8R)-1-Hydroxypyrrolizidin-3-one (8). To a solution
of the ester 6c (0.05 g, 0.18 mmol) in CH2Cl2 (5 mL) cooled to
0 °C was added TFA (0.28 mL, 3.66 mmol). The mixture was
stirred for 1 h, and then the solvent was removed in vacuo, after
which an aqueous solution of K2CO3 4.0 M (10 mL) was added.
The mixture was then refluxed for 30 min and allowed to reach
room temperature. Then was extracted with CH2Cl2 (3 ꢀ
15 mL). The combined organic fractions were collected, dried
over Na2SO4, and filtered, and the solvent was removed in vacuo
to yield lactam 8 as colorless oils.Yield: 70% (0.02 g, 0.13 mmol).
[R]20D þ93.1 (c 0.14 in CHCl3). (lit.16 -91.5, c 1.0 in CHCl3 for
the 1R,8S isomer). 1H NMR (300 MHz, CDCl3) (δ, ppm):
1.39-1.52 (m, 1H), 1.95-2.20 (m, 3H), 2.75 (d, 2H, J = 8.3
Hz), 3.00-3.08 (m, 1H), 3.52-3.61 (m, 1H), 3.72-3.79 (m, 1H),
4.21-4.28 (m, 1H). 13C NMR (75.5 MHz, CDCl3) (δ, ppm):
26.6, 29.8, 41.6, 44.4, 69.3, 73.2, 172.5. IR (CHCl3): 3386 (OH),
1664 (CdO). MS (CI) m/z (relative intensity): 142 (Mþ þ H,
100), 141 (23), 124 (23), 123 (4), 112 (10). HRMS (m/z): [M þ
H]þ calcd for[C7H12NO2]þ 142.0863, found 142.0866.
(-)-(4S,5R)-5-Benzyl-4-hydroxy-1-methylpyrrolidin-2-one (9).
To a solution of the ester 6g (0.08 g, 0.24 mmol) in CH2Cl2 (5 mL)
cooled to 0 °C was added TFA (0.36 mL, 4.75 mmol). The
mixture was stirred for 1 h, and then the solvent was removed
in vacuo, after which an aqueous solution of K2CO3 4.0 M
(10 mL) was added. The mixture was then refluxed for 30 min
and allowed to reach room temperature. Then it was extracted
with CH2Cl2 (3 ꢀ 15 mL). The combined organic fractions were
collected, dried over Na2SO4, and filtered, and the solvent was
removed in vacuo to yield lactam 9 as colorless oil.Yield:
92% (0.04 g, 0.24 mmol). [R]20D -64.0 (c 0.38 in CHCl3). (lit.34
[R]20D -64.4, c 0.4 in CHCl3). 1H NMR (300 MHz, CDCl3) (δ,
ppm): 2.02 (s, 1H), 2.10 (d, 1H, J = 17.6 Hz), 2.24 (dd, 1H, J =
17.6, 5.9 Hz), 2.69 (dd, 1H, J = 14.0, 7.4 Hz), 2.81 (s, 3H), 2.91
(dd, 1H, J = 14.0, 5.1 Hz), 3.64-3.68 (m, 1H), 4.06-4.14 (m,
1H), 7.11-7.32 (m, 5H). 13C NMR (75.5 MHz, CDCl3) (δ, ppm):
28.3, 36.8, 39.5, 68.4, 70.3, 126.9, 128.7, 129.1 136.3, 173.2. IR
(CHCl3): 3315 (OH), 1668 (CdO). MS (CI) m/z (relative
intensity): 205 (Mþ, 5), 168 (3), 116 (54), 114 (52), 96 (16), 70
(100), 57 (46). HRMS (m/z): [M]þ calcd for[C12H15NO2]þ
205.1103, found 205.1107.
(-)-(4S,5R)-4-Acetoxy-5-acetoxymethyl-4,5-dihydrofuran-
2(3H)-one (10). A solution of the ester 6b (180 mg, 0.88 mmol) in
TFA/H2O/THF (5 mL/1 mL/3 mL) was stirred at room tem-
perature during 4 h. Then, the solvent was removed in vacuo,
after which the mixture was dissolved in pyridine (2 mL)
and acetic anhydride (0.40 mL, 3.53 mmol) was added. The
mixture was stirred at rt for 24 h after which HCl 4 M (4 mL) was
added. Then the reaction crude was extracted with CH2Cl2 (3 ꢀ
15 mL). The combined organic fractions were collected, dried
over Na2SO4, and filtered, and the solvent was removed in
vacuo to yield after flash column chromatography purification
(þ)-(3S,4R)-4-(tert-Butoxycarbonyl(methyl)amino)-3-hydro-
xy-5-phenylpentanoic Acid Methyl Ester (6g). Ester 6g was
prepared according to the general procedure starting from aldol
3g (0.23 g, 0.49 mmol), NaOH (0.10 g, 2.44 mmol), and
TMSCHN2 (0.97 mL of a 2 M solution in Et2O, 1.96 mmol)
and isolated as a yellowish oil after flash column chromatogra-
phy purification (hexanes/AcOEt 6:4). Yield: 66% (0.08 g,
0.29 mmol). HPLC analysis (Chiralcel OJH column, hexanes/
2-propanol 96:4, flow rate 1.00 mL/min) indicated a 99:1
diastereomeric ratio. tR for the major (3S,4R) isomer: 13.76
min. tR for the minor (3R,4R) isomer: 17.37 min. [R]20D þ30.5
(34) Huang, P. Q.; Wang, S. L.; Ye, J. L.; Ruan, Y. P.; Huang, Y. Q.;
Zheng, H.; Gao, J. X. Tetrahedron 1998, 54, 12547.
(33) Pakulski, Z.; Zamojski, A. Tetrahedron 1995, 51, 871.
468 J. Org. Chem. Vol. 76, No. 2, 2011

Ocejo et al.
JOCArticle
(hexanes/AcOEt 1:1) lactone 10 as colorless oil. Yield: 87% (166
mg, 0.77 mmol). [R]20 -10.9 (c 0.6 in CH2Cl2). (lit.35 -11.5,
CH2Cl2 (3 ꢀ 15 mL). The combined organic fractions were
collected, dried over Na2SO4, and filtered, and the solvent was
removed in vacuo to yield pyrrolizidine 13 as colorless oil. Yield:
D
1
c 0.7 in CH2Cl2). H NMR (300 MHz, CDCl3) (δ, ppm): 2.05
1
(s, 3H); 2.07 (s, 3H); 2.57 (dd, 1H, J = 18.9, 2.0, Hz); 2.97 (dd,
1H, J = 18.7, 7.5 Hz); 4.23 (dd, 1H, J = 12.3, 3.6, Hz); 4.34 (dd,
1H, J = 12.3, 3.6 Hz); 4.64 (m, 1H); 5.22 (m, 1H). 13C NMR
(75.5 MHz, CDCl3) (δ, ppm) 20.5, 20.6, 34.7, 63.2, 71.0, 82.0,
170.0, 170.2, 173.7. IR (CHCl3): 3472 (OH), 1737 (CdO). MS
(EI) m/z (relative intensity): 217 (Mþ þ 1, 1), 145 (5), 143 (44),
128 (26), 126 (6), 114 (7), 103 (10), 96 (6), 86 (15), 84 (29), 83
(100), 73 (4), 71 (14), 68 (4), 55 (14).
LAB-Mediated Reduction of Aldol 3c. Synthesis of (þ)-
(10S,2R)-N-tert-Butoxycarbonyl-2-(10,30-dihydroxypropyl)-pyr-
rolidine (11). n-BuLi (4.27 mL of a 1.3 M solution in hexane,
5.55 mmol) was added over a solution of diisopropylamine
(0.76 mL, 5.38 mmol) in dry THF (10 mL) at -78 °C, and the
mixture was stirred for 15 min. The reaction was warmed to
89% (0.07 g, 0.34 mmol). [R]20 þ31.6 (c 1.0 in CH2Cl2). H
D
NMR (300 MHz, CDCl3) (δ, ppm): 1.39-1.52 (m, 1H),
1.70-1.81 (m, 2H), 1.99-2.20 (m, 3H), 2.44-2.53 (m, 1H),
2.69-2.76 (m, 1H), 3.01 (s, 3H), 3.01-3.08 (m, 1H), 3.15-3.23
(m, 1H), 3.54-3.60 (m, 1H), 4.82-4.84 (m, 1H). 13C NMR (75.5
MHz, CDCl3) (δ, ppm): 25.8, 30.2, 31.3, 38.6, 52.1, 55.2, 70.1,
86.0. IR (CHCl3): 1351 (SO2), 1173 (SO2). MS (CI) m/z (relative
intensity): 206 (Mþ þ H, 33), 204 (10), 126 (32), 110 (100), 108
(3). HRMS (m/z): [M þ H]þ calcd for[C8H16NO3S]þ 206.0845,
found 206.0846.
General Procedure for the Selective 1,2-Addition of Organo-
lithium Reagents to Aldols 3a and 3b. The organolithium
(3.5 mmol) was added over a solution of amide 3a or 3b
(1.00 mmol) in dry THF (20 mL) at -78 °C. The reaction
mixture was stirred 15 min at this temperature and then it was
warmed to 0 °C and stirred for further 45 min, after which a
saturated NH4Cl solution (20 mL) was added. The mixture
was extracted with CH2Cl2 (3 ꢀ 15 mL), the combined organic
fractions were collected, dried over Na2SO4, and filtered, and
the solvent removed in vacuo affording the wanted ketone
14a-f or 15a-f after flash column chromatography purifica-
tion (AcOEt/hexanes 1:1).
0 °C, and NH3 BH3 (0.17 g, 5.47 mmol) was added at once. The
3
mixture was stirred 15 min at 0 °C and another 15 min at room
temperature, after which a solution of 3c (0.37 g, 0.91 mmol) in
THF (5 mL) was added via canula at 0 °C, and the reaction was
stirred for 2 h. Then the reaction was quenched with HCl 1 N
(15 mL) and extracted with AcOEt (3 ꢀ 15 mL). The organic
fractions were collected, washed with satd NaHCO3, dried over
Na2SO4, and filtered, and the solvent removed in vacuo afford-
ing the wanted alcohol 11 after flash column chromatography
(-)-(4S,40R)-4-(20,20-Dimethyl[1,3]dioxolan-40-yl)-4-hydroxy-
butan-2-one (15a). The ketone 15a was prepared according to the
general procedure starting from amide 3b (120 mg, 0.36 mmol)
and MeLi (1.26 mL of a 1.0 M solution in Et2O, 1.26 mmol) as a
white solid. Yield: 87% (63 mg, 0.33 mmol). Mp 132-134 °C
purification (hexanes/AcOEt 1:9). Yield: 72% (0.16 g, 0.65
1
mmol). [R]20 þ48.3 (c 1.0 in CH2Cl2). H NMR (300 MHz,
D
CDCl3) (δ, ppm): 1.46 (s, 9H), 1.51-2.06 (m, 7H), 3.19-3.28
(m, 2H), 3.48-3.57 (m, 1H), 3.82-4.00 (m, 4H). 13C NMR
(75.5 MHz, CDCl3) (δ, ppm) (*indicates minor rotamer
resonances): 24.1, 28.1, 28.3*, 28.4, 32.9, 47.4*, 48.1, 61.4*,
61.8, 63.1, 74.5, 80.4, 80.7*, 156.8. IR (CHCl3): 3396, 2972 (OH),
1670 (CdO). MS (EI) m/z (relative intensity): 172 (Mþ - 73, 7),
170 (24), 114 (100), 108 (25), 98 (26), 96 (45), 70 (72), 57 (43).
HRMS (m/z): [M]þ calcd for[C12H23NO4]þ: 245.1627, found
245.1626.
(hexanes/AcOEt). [R]23 -30.6 (c 0.2 in CHCl3). (lit.36 -28.0,
D
1
c 1.2 in CHCl3). H NMR (300 MHz, CDCl3) (δ, ppm): 1.32
(s, 3H); 1.38 (s, 3H); 2.20 (s, 3H); 2.59 (dd, 1H, J = 17.8, 8.3 Hz);
2.80 (dd, 1H, J = 18.0, 2.0 Hz); 3.73 (m, 1H); 3.93 (m, 2H); 4.06
(m, 1H). 13C NMR (75.5 MHz, CDCl3) (δ, ppm): 25.1; 26.6;
30.7; 46.2; 66.8; 68.9; 76.5; 109.4; 209.7. IR (film): 3436 (OH);
1707 (CdO). MS (EI) m/z (relative intensity): 173 (Mþ - 15, 8),
113 (8), 101 (100); 95 (56), 87 (20), 83 (13), 73 (27), 61 (12), 59
(32), 55 (14).
(þ)-(10S,2R)-N-tert-Butoxycarbonyl-2-(10,30-bis(dimethane-
sulfonyloxy)propyl)pyrrolidine (12). To a solution of alcohol 10
(0.16 g, 0.65 mmol) in CH2Cl2 (20 mL) at 0 °C, was added
triethylamine (0.18 mL, 1.31 mmol) and methanesulfonyl chlor-
ide (0.10 mL, 1.31 mmol). The mixture was stirred for 1 h at
room temperature, after which the reaction was quenched with
2 M KOH (10 mL). The mixture was extracted with CH2Cl2 (3 ꢀ
15 mL) and the combined organic fractions were collected, dried
over Na2SO4, filtered, and the solvent was removed in vacuo to
yield 12 as a yellowish oil after flash column after flash column
(-)-(1S,40R)-4-(20,20-Dimethyl[1,3]dioxolan-40-yl)-1-hydroxy-
pentan-3-one (15b). The ketone 15b was prepared according to
the general procedure starting from amide 3b (126 mg, 0.37
mmol) and EtLi (2.88 mL of a 0.45 M solution in benzene/
cyclohexane, 1.29 mmol) as a yellowish oil. Yield: 75% (56 mg,
0.28 mmol). [R]23D -25.4 (c 0.3 in CHCl3). 1H NMR (300 MHz,
CDCl3) (δ, ppm): 1.05 (t, 3H, J = 7.5 Hz), 1.33 (s, 3H), 1.38
(s, 3H), 2.48 (q, 2H, J = 7.5 Hz), 2.58 (m, 1H), 2.77 (dd, 1H,
chromatography purification (hexanes:AcOEt 1:9). Yield: 74%
J = 17.0, 2.0 Hz), 3.27 (bs, 1H), 3.95 (m, 3H), 4.06 (m, 1H). 13
C
1
(0.19 g, 0.48 mmol). [R]20 þ45.1 (c 1.0 in CH2Cl2). H NMR
NMR (75.5 MHz, CDCl3) (δ, ppm): 7.5, 25.1, 26.6, 36.7, 44.8,
66.9, 69.1, 77.5, 107.6, 212.5. IR (film): 3443 (OH); 1703 (CdO).
MS (EI) m/z (relative intensity): 187 (Mþ - 15, 6), 127 (9), 109
(53); 101 (100); 97 (13), 83 (11), 73 (28), 59 (36), 57 (72); 55 (13).
Anal. Calcd forC10H18O4: C, 59.39; H, 8.97. Found: C, 59.28; H,
9.03.
(-)-(1S,40R)-4-(20,20-Dimethyl[1,3]dioxolan-40-yl)-1-hydroxy-
4-methylpentan-3-one (15c). The ketone 15c was prepared ac-
cording to the general procedure starting from amide 3b (123
mg, 0.36 mmol) and i-PrLi (2.00 mL of a 0.62 M solution in
D
(300 MHz, CDCl3) (δ, ppm) (*indicates rotamer resonances):
1.45*, 1.46 (s, 9H), 1.75-2.10 (m, 6H), 2.97 (s, 3H), 3.04 (s, 3H),
3.20-3.30 (m, 1H), 3.37-3.65 (m, 1H), 3.71-3.92 (m, 1H),
4.28-4.42 (m, 2H), 5.24-5.40 (m, 1H). 13C NMR (75.5 MHz,
CDCl3) (δ, ppm) (*indicates rotamer resonances): 23.8*, 24.0,
25.1, 25.7*, 28.3, 32.2, 37.3, 37.9, 38.3*, 47.1, 59.9, 65.9, 78.8,
79.4*, 80.1, 80.8*, 156.8. IR (CHCl3): 1686 (CdO), 1356 (SO2),
1174 (SO2). MS (EI) m/z (relative intensity): 401 (Mþ, 3), 335
(15), 242 (44), 238 (31), 148 (34), 147 (100), 118 (27), 117 (33), 115
(27), 91 (21), 73 (71). HRMS (m/z): [M]þ calcd for[C14H27-
NO8S2]þ 401.1178, found 401.1176.
pentane, 1.26 mmol) as a yellowish oil. Yield: 77% (60 mg, 0.28
1
mmol). [R]23 -40.3 (c 0.1 in CHCl3). H NMR (300 MHz,
D
(þ)-(1S,8R)-1-Methanesulfonyloxypyrrolizidine (13). To a so-
lution of 12 (0.15 g, 0.37 mmol) in CH2Cl2 (5 mL) cooled to 0 °C
was added TFA (0.57 mL, 7.48 mmol). The mixture was stirred
for 1 h, and then an aqueous solution of KOH 2.0 M (5 mL) was
added. The mixture was stirred for 2 h. Then was extracted with
CDCl3) (δ, ppm): 1.10 (d, 6H, J = 7.1 Hz), 1.33 (s, 3H), 1.39
(s, 3H); 2.58 (m, 2H), 2.85 (d, 1H, J = 17.4 Hz), 3.34 (bs, 1H,
OH), 3.94 (m, 3H); 4.05 (m, 1H). 13C NMR (75.5 MHz, CDCl3)
(δ, ppm): 17.9, 25.1, 26.6, 41.5, 42.9, 67.0, 69.3, 77.5, 109.4,
216.1. IR (film): 3448 (OH); 1707 (CdO). MS (EI) m/z (relative
(35) Kita, Y.; Tamura, O.; Itoh, F.; Yasuda, H.; Kishino, H.; Ke, Y. Y.;
Tamura, Y. J. Org. Chem. 1988, 53, 554.
(36) Cubero, I. I.; Lopez-Espinosa, M. T. P.; Gonzalez, D. G. Carbohydr.
Res. 1986, 154, 71.
J. Org. Chem. Vol. 76, No. 2, 2011 469

Ocejo et al.
JOCArticle
intensity): 201 (Mþ - 15, 4), 141 (4); 127 (11), 123 (35); 115 (37);
101 (100); 97 (25), 84 (9), 73 (28), 71 (58); 59 (37), 55 (9). Anal.
Calcd forC11H20O4: C, 61.09; H, 9.32. Found: C, 61.13; H, 9.38.
(-)-(1S,40R)-4-(20,20-Dimethyl[1,3]dioxolan-40-yl)-1-hydroxy-
heptan-3-one (15d). The ketone 15d was prepared according to
the general procedure starting from amide 3b (107 mg,
0.32 mmol) and n-BuLi (0.80 mL of a 1.45 M solution in hexane,
(-)-(3S,40R)-4-(20,20-Dimethyl[1,3]dioxolan-40-yl)-1-phenyl-
3-hydroxypropan-3-one (15f). The ketone 15f was prepared
according to the general procedure starting from amide 3b
(112 mg, 0.33 mmol) and PhLi (0.58 mL of a 2.00 M solution
in Et2O, 1.16 mmol) as a yellowish oil. Yield: 72% (60 mg,
0.23 mmol). [R]23D -48.9 (c 0.3 in CHCl3). 1H NMR (300 MHz,
CDCl3) (δ, ppm): 1.36 (s, 3H), 1.41 (s, 3H), 3.10 (dd, 1H, J =
17.8, 8.7 Hz), 3.51 (dd, 1H, J = 17.8, 2.3 Hz), 3.51 (bs, 1H, OH);
3.98-4.15 (m, 4H), 7.45 (t, 2H, J = 7.1 Hz), 7.55 (t, 1H, J = 1.7
Hz), 7.95 (d, 2H, J = 1.6 Hz). 13C NMR (75.5 MHz, CDCl3)
(δ, ppm): 25.1, 26.7, 41.6, 65.5, 67.1, 69.4, 109.5, 128.1, 128.6,
1.12 mmol) as a yellowish oil. Yield: 85% (65 mg, 0.27 mmol).
1
[R]23 -36.1 (c 0.3 in CHCl3). H NMR (300 MHz, CDCl3)
D
(δ, ppm): 0.88 (t, 3H, J = 7.1 Hz), 1.27 (m, 2H), 1.32 (s, 3H),
1.38 (s, 3H), 1.55 (m, 2H), 2.44 (t, 2H, J = 7.1 Hz), 2.51 (dd, 1H,
J =17.4, 9.5 Hz), 2.80 (d, 1H, J = 17.4 Hz), 3.30 (bs, 1H), 3.91
(m, 3H), 4.05 (m, 1H). 13C NMR (75.5 MHz, CDCl3) (δ, ppm):
13.8, 22.2, 25.1, 25.6, 26.6, 43.4, 45.2, 66.9, 69.1, 77.5, 109.4,
212.3. MS (EI) m/z (relative intensity): 215 (Mþ - 15, 3), 137
(38), 129 (24), 127 (9); 101 (100); 97 (10), 85 (44), 73 (24), 59 (27),
57 (29). Anal. Calcd forC12H22O4: C, 62.58; H, 9.63. Found: C,
61.49; H, 9.60.
128.9. 133.5, 200.7. MS (EI) m/z (relative intensity): 235 (Mþ
-
15, 4), 175 (5); 157 (31); 149 (32); 131 (5); 105 (100); 101 (87);
83 (8), 77 (51), 73 (28); 59 (27), 55 (10); 51 (15). Anal. Calcd
forC14H18O4: C, 67.18; H, 7.25. Found: C, 67.25; H, 7.31.
Acknowledgment. The authors thank the University of
ꢀ
the Basque Country (Subvencion General a Grupos de
Investigacion, GIU07/06 and fellowships to M.O. and E.R.),
(-)-(1S,40R)-4-(20,20-Dimethyl[1,3]dioxolan-40-yl)-1-hydroxy-
4,4-dimethylpentan-3-one (15e). The ketone 15e was prepared
according to the general procedure starting from amide 3b
(120 mg, 0.36 mmol) and t-BuLi (1.26 mL of a 1.45 M solu-
tion in hexane, 1.26 mmol) as a yellowish oil. Yield: 71% (58 mg,
0.25 mmol). [R]23D -45.2 (c 0.2 in CHCl3). 1H NMR (300 MHz,
CDCl3) (δ, ppm): 1.16 (s, 9H), 1.34 (s, 3H), 1.39 (s, 3H), 2.62
(dd, 1H, J = 18.2, 8.3 Hz), 2.95 (dd, 1H, J = 18.1, 2.0 Hz), 3.40
(bs, 1H), 3.95 (m, 3H), 4.08 (m, 1H). 13C NMR (75.5 MHz,
CDCl3) (δ, ppm): 25.2, 26.1, 26.7, 29.7, 39.5, 67.1, 69.5, 77.5,
107.6, 217.8. MS (EI) m/z (relative intensity): 215 (M þ - 15, 4),
137 (27); 129 (28), 127 (23); 115 (18); 101 (92); 97 (60), 85 (42), 73
(36), 69 (20); 61 (10); 59 (57), 57 (100); 55 (12). Anal. Calcd
forC12H22O4: C, 62.58; H, 9.63. Found: C, 62.53; H, 9.71.
ꢀ
ꢀ
the Spanish Ministerio de Ciencia e Innovacion (projects
CTQ2005-02131/BQU and CTQ2008-00136/BQU), and the
Basque Government (Grupos Consolidados del Sistema Uni-
versitario Vasco, IT328-10) for financial support. The authors
also acknowledge PETRONOR, S.A. (Muskiz, Bizkaia) for the
generous gift of solvents.
Supporting Information Available: Detailed descriptions of
determination of diastereomeric ratios and copies of HPLC
traces and NMR spectra of all new compounds. This material
is available free of charge via the Internet at http://pubs.
acs.org.
470 J. Org. Chem. Vol. 76, No. 2, 2011