Michael reactions of titanium enolates of glycolic acid derivatives with the Weinreb and morpholine amides of acrylic acid

Article abstract of DOI:10.1021/jo702240n

(Chemical Equation Presented) The conjugate additions of titanium enolates of glycolate-derived chiral oxazolidin-2-ones to various Michael acceptors have been evaluated as an entry to enantiopure 1,2,5-trioxygenated and related synthons. α,β-unsaturated

Full text of DOI:10.1021/jo702240n

SCHEME 1. Representative Series of C1-C5 Fragments
Available from 3 and Michael Acceptors
Michael Reactions of Titanium Enolates of
Glycolic Acid Derivatives with the Weinreb and
Morpholine Amides of Acrylic Acid
Anna Olivella, Carles Rodr´ıguez-Escrich, Fe`lix Urp´ı,* and
Jaume Vilarrasa*
Departament de Qu´ımica Orga`nica, Facultat de Qu´ımica,
UniVersitat de Barcelona, 08028 Barcelona, Catalonia, Spain
jVilarrasa@ub.edu
ReceiVed October 23, 2007
1) with high diastereoselection; methacrylate derivatives turned
out to be more reluctant as Michael acceptors.1a,3c
In this context, we examined the reaction of 34 with a set of
acceptors for which there were no precedents. We report here
the particular but representative case of 3 where Aux* is the
1,3-oxazolidin-2-one coming from D-Phe and R/OR is OTBS.5
The main results can be summarized as follows.
When N-methoxy-N-methylpropenamide (the Weinreb amide
of acrylic acid), prepared by treating free N,O-dimethylhy-
droxylamine with acryloyl chloride according to a reported
procedure,6 was added to titanium enolates3a,7 of 3, R/OR )
OTBS, the yields of adduct 4a were very poor with TiCl4 as
the Lewis acid (Table 1, entry 1) but improved up to 40-50%
with a 75:25 TiCl4-Ti(OiPr)4 mixture and increased up to 50-
65% with 2 equiv of this mixture (Table 1).
The conjugate additions of titanium enolates of glycolate-
derived chiral oxazolidin-2-ones to various Michael acceptors
have been evaluated as an entry to enantiopure 1,2,5-
trioxygenated and related synthons. R,â-unsaturated Weinreb
and morpholine amides do react under suitable conditions
and their adducts can be converted to diverse C1-C5 chiral
fragments.
Our ongoing studies toward the total syntheses of cytotoxic
macrolides have required enantiopure C1-C5 building blocks
of type 1 (and/or their C4-Me derivatives).1 From synthons such
as 1, a diversity of fragments of structure 2 may be readily
accessible. We have obtained some of these fragments from
L-glutamic acid or its enantiomer, through its hydroxy analogues
(butyrolactone derivatives).1b A more general approach involves
a Michael reaction between compounds of type 3 and EWG-
conjugated olefins. Alkaline enolates of type 3 decompose before
reacting with H2CdCH-EWG,2,3 but Evans et al. found3a that
Ti enolates of propanoyl oxazolidin-2-ones 3 (Aux* ) L-Phe-
derived auxiliary, R/OR ) Me) reacted with alkyl acrylates and
acrylonitrile to give the corresponding adducts of type 4 (Scheme
When N-propenoylmorpholine, prepared from acryloyl chlo-
ride, morpholine, and diisopropylethylamine in CH2Cl2 in
quantitative yield, was added to Ti enolates of 3 (R/OR )
OTBS), the yields of the Michael adduct were 60-70%. When
2 equiv of TiCl3OiPr were used (exactly 1.05 equiv in the
enolization step and 1.10 equiv for the pre-complexation of the
propenoylmorpholine), the yield went up to 86% (see Table 1,
entry 2).
Although the electron-withdrawing character of CONR2 and
CON(OMe)Me groups was expected to be lower than that of
CN and COOR groups, the fact was that the corresponding
Michael adducts could be obtained in acceptable or good yields.
1
In all cases, a single diastereomer was observed by H NMR,
in the crude product and after column chromatography; the
(1) (a) Mas, G.; Gonza´lez, L.; Vilarrasa, J. Tetrahedron Lett. 2003, 44,
8805 (amphidinolide K). (b) Andreou, T.; Costa, A. M.; Esteban, L.;
Gonza´lez, L.; Mas, G.; Vilarrasa, J. Org. Lett. 2005, 7, 4083 (amphidinolide
K). (c) Rodr´ıguez-Escrich, C.; Olivella, A.; Urp´ı, F.; Vilarrasa, J. Org. Lett.
2007, 9, 989 (amphidinolide X/Y).
(2) Li and Na enolates of type 3, when the temperature is raised up to
-30 °C to increase the reaction rates, begin to decompose.
(3) (a) Evans, D. A.; Bilodeau, M. T.; Somers, T. C.; Clardy, J.;
Cherry, D.; Kato, Y. J. Org. Chem. 1991, 56, 5750. (b) Evans, D. A.;
Gage, J. R.; Leighton, J. L.; Kim, A. S. J. Org. Chem. 1992, 57, 1961
(application to the total synthesis of calyculin). (c) Mas, G. Ph.D. Thesis,
Universitat de Barcelona, 2000. (d) For the reaction of enolates of
trisubstituted oxazolidinones with nitroalkenes, see: Brenner, M.; Seebach,
D. HelV. Chim. Acta 1999, 82, 2365. (e) For Michael additions of
Li enolates to more reactive CF3-substituted acrylates, see: Shinohara, N.;
Haga, J.; Yamazaki, T.; Kitazume, T.; Nakamura, S. J. Org. Chem. 1995,
60, 4363.
(4) In preliminary experiments, we had examined the reactions of
Aux*COEt (3, Aux* ) Evans L-Phe-derived auxiliary, R/OR ) Me) with
Michael acceptors such as CH2dCH-CON(OMe)Me and morpholine amide
CH2dCH-CON(C4H8O). The results were parallel to those reported here.
(5) The TBS protecting group was chosen in view of its stability under
the reaction conditions and the availability of specific cleavage methods.
The OBn derivative decomposes before reacting, under similar conditions.
The synthetic utility of the enolates of glycolate-derived oxazolidinones in
other reactions, such as aldol reactions and alkylations, has been estab-
lished: (a) Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc. 1988,
110, 2506. (b) Crimmins, M. T.; Emmitte, K. A.; Katz, J. D. Org. Lett.
2000, 2, 2165.
(6) Corminboeuf, O.; Renaud, P. Org. Lett. 2002, 4, 1735.
(7) Evans, D. A.; Urp´ı, F.; Somers, T. C.; Clark, J. S.; Bilodeau, M. T.
J. Am. Chem. Soc. 1990, 112, 8215.
10.1021/jo702240n CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/17/2008
1578
J. Org. Chem. 2008, 73, 1578-1581

TABLE 1. Michael Additions of Ti Enolates of 3a
SCHEME 2. Chemoselective Transformations
yield (%) with
TiCl4
yield (%) with
entry
EWG
TiCl3OiPr
adduct
1
2
3
4
5
CON(OMe)Me
CON(C4H8O)c
COSC12H25
COOMe
10
61
41
20
65b
86b
53
80
80
4a
4b
4c
4d
4e
COOtBu
a See the Experimental Section for details. b An extra amount of the Lewis
acid (1.10 equiv) was added to the Michael acceptor solution before adding
it via canula to the Ti enolate solution; when the extra amount of Lewis
acid was 1.50 equiv, a slurry of difficult addition or transfer was formed
(in practice, the isolated yields of the adducts diminished). c Morpholine
amide.
al.10 to 4a and 4b (cleavage of Aux*-CO bonds with RSH
under basic conditions, followed by the catalytic reduction of
thioesters with Et3SiH), the formyl group-containing compounds
6a and 6b were obtained, which were reduced in situ to (and
stored as) 5a and 5b, respectively.
On the other hand, reduction of the hydroxamate group of
4a with DIBALH (1.5 equiv) in THF or Et2O at -78 °C gave
7 in 95% yield,11 without touching at all the acyl-oxazolidinone
moiety.12 This could be expected, but no examples have been
reported so far.11b
Even more interesting, as there are no reports in the chemical
literature about the chemoselective reduction of morpholine
amides13 in the presence of acyl-oxazolidinones or other acylated
chiral auxiliaries, was the reduction of the morpholine amide
group of 4b with DIBALH (1.5 equiv, between -100 and
-78 °C, in Et2O or THF for a few minutes), which also gave
rise to an oxo group at C5 (7) in 80% yield.14
HPLC analysis of the isolated compounds indicated a purity of
98-99%. Thus, the dr (g98:2) turned out to be similar to those
found in related Michael additions.1c,3,4
Reactions of 3, R/OR ) OTBS, with an unsaturated thiol
ester and alkyl acrylates were also investigated (see Table 1,
entries 3-5). With the thiol ester shown in entry 3 the addition
did not reach completion even in the presence of an excess of
Lewis acids; thus, we ruled out this adduct for subsequent
manipulations. On the other hand, with methyl acrylate and tert-
butyl acrylate (entries 4 and 5) the reactions with TiCl3OiPr
were quite efficient with only 1.05 equiv of this Lewis acid
and did not improve with additional amounts. Again, only one
diastereoisomer was detected in every case by 1H NMR and by
HPLC.
Transformations of adducts 4d and 4e were also examined.
The conditions of Fukuyama et al.10 were useful to convert the
Aux*CO moiety into a CHO group, without affecting the
The configuration of 4d was established by its hydrolysis to
R-hydroxyglutaric acid, which after acidification and concentra-
tion gave the expected, known (+)-(S)-lactone-carboxylic acid.
The configurations of the other adducts were assigned by
analogy (NMR comparison with related Michael adducts of
well-established absolute configurations).1c,3a
(10) (a) Miyazaki, T.; Han-ya, Y.; Tokuyama, H.; Fukuyama, T. Synlett
2004, 477. (b) Fukuyama, T.; Tokuyama, H. Aldrichim. Acta 2004, 37, 87.
(11) The direct reduction of Weinreb amides to aldehydes is a standard.
Since the pioneering work of Nahm and Weinreb (Nahm, S.; Weinreb, S.
M. Tetrahedron Lett. 1981, 22, 3815), ca. 200 out of 500 papers have utilized
DIBALH as the reducing agent, according to a SciFinder-based search. (b)
Very often R*CO-Aux* are converted to R*CO-N(OMe)Me and then to
R*CHO, but no examples are found of competition between the two first
groups for nucleophiles.
(12) It is known that diisobutylaluminum hydride (DIBALH), in
CH2Cl2 at -78 °C, attacks both the endo and exo CO groups of acylated
oxazolidinones, whereas only the exocyclic CO reacts in the case of
their 5,5-dimethyl analogues (“Super Quats”): (a) Bull, S. D.; Davies, S.
G.; Nicholson, R. L.; Sanganee, H. J.; Smith, A. D. Tetrahedron: Asym-
metry 2000, 11, 3475. (b) Bull, S. D.; Davies, S. G.; Nicholson, R. L.;
Sanganese, H. J.; Smith, A. D. Org. Biomol. Chem. 2003, 1, 2886. To
favor the selective attack on the hydroxamate, we have utilized ethereal
solvents.
(13) For the use of morpholine amides as an alternative to Weinreb
amides, see: (a) Mart´ın, R.; Romea, P.; Tey, C.; Urp´ı, F.; Vilarrasa, J.
Synlett 1997, 1414. (b) Kurosu, M.; Kishi, Y. Tetrahedron Lett. 1998, 39,
4793. (c) Sengupta, S.; Mondal, S.; Das, D. Tetrahedron Lett. 1999, 40,
4107. (d) Douat, C.; Heitz, A.; Martinez, J.; Fehrentz, J.-A. Tetrahedron
Lett. 2000, 41, 37. (e) Jackson, M. M.; Leverett, C.; Toczko, J. F.; Roberts,
J. C. J. Org. Chem. 2002, 67, 5032. (f) Badioli, M.; Ballini, R.; Bartolacci,
M.; Bosica, G.; Torregiani, E.; Marcantoni, E. J. Org. Chem. 2002, 67,
8938. (g) Goodman, S. N.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2002,
41, 4703. (h) Clark, C. T.; Milgram, B. C.; Scheidt, K. A. Org. Lett. 2004,
6, 3977. (i) Tosaki, S.; Horiuchi, Y.; Nemoto, T.; Ohshima, T.; Shibasaki,
M. Chem. Eur. J. 2004, 10, 1527 and references cited therein. (j) Ruiz, J.;
Ardeo, A.; Ignacio, R.; Sotomayor, N.; Lete, E. Tetrahedron 2005, 61, 3311.
(k) Denmark, S. E.; Hemmstra, J. R. J. Am. Chem. Soc. 2006, 128, 1038.
(l) Concello´n, J. M.; Rodr´ıguez-Solla, H.; Me´jica, C.; Blanco, E. G. Org.
Lett. 2007, 9, 2981.
At this point, it was essential to distinguish one carboxyl
group derivative from the other one of 4a and 4b for further
chemical transformations of the C1-C5 fragment, according
to our initial plans. Thus, we examined if the attack on the
exocyclic CO group at C1 was feasible or not without touching
the CO at C5, and vice versa. Attacks on the endocyclic CO
group had to be avoided in all cases.
When 4a was treated with NaBH48 with a slight modification8b
of the standard procedure, or with LiBH4,9 complete reduction
to the expected hydroxy derivative (5a) took place (Scheme
2). Under identical conditions, 4b gave 5b in almost quantitative
yield. By application of the cleavage method of Fukuyama et
(8) (a) Prashad, M.; Har, D.; Kim, H.-Y.; Repic, O. Tetrahedron
Lett. 1998, 39, 7067. (b) NaBH4 was dissolved in phosphate-buffered
water (pH 8); the reaction time was shortened to 30 min. Migration of the
TBS group to the primary hydroxy group did not occur under these
conditions.
(9) (a) Penning, T. D.; Djuric, S. W.; Haack, R. A.; Kalish, V. J.;
Miyashiro, J. M.; Rowell, B. W.; Yu, S. S. Synth. Commun. 1990, 307. (b)
Evans, D. A.; Gage, J. R. J. Org. Chem. 1992, 57, 1958. (c) Also see ref
1b for complex substrates where undesired conjugate additions can take
place.
J. Org. Chem, Vol. 73, No. 4, 2008 1579

CHCl3); tR (HPLC) 8.0 min (4.6 mm × 250 cm silica gel column,
0.9 µL/min, 90:10 hexane-isopropanol); IR (film) 1779, 1713, 1664
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.4-7.2 (m, 5 H), 5.39 (dd,
J ) 7.2, 4.0 Hz, 1 H), 4.73 (ddt, J ) 10.2, 7.8, 3.6 Hz, 1 H), 4.25
(dd, J ) 9.0, 7.8 Hz, 1 H), 4.19 (dd, J ) 9.0, 3.6 Hz, 1 H), 3.69
(s, 3 H), 3.34 (dd, J ) 13.4, 3.6 Hz, 1 H), 3.17 (s, 3 H), 2.72 (dd,
J ) 13.4, 10.2 Hz, 1 H), 2.8-2.6 (m, 2 H), 2.2-2.1 (m, 1 H), 2.05
(dddd, J ) 13.6, 10.0, 7.2, 6.4 Hz, 1 H), 0.94 (s, 9 H), 0.10 (s, 3
H), 0.08 (s, 3 H); 13C NMR (100.6 MHz, CDCl3) δ 173.8 (C),
170.2 (C), 153.0 (C), 135.1 (C), 129.4 (CH), 129.0 (CH), 127.4
(CH), 70.6 (CH), 66.8 (CH2), 61.2 (CH3), 55.0 (CH), 37.9 (CH2),
31.6 (CH3), 29.9 (CH2), 27.7 (CH2), 25.7 (CH3), 18.3 (C), -4.8
(CH3), -5.3 (CH3); HRMS (+ESI) calcd for C23H37N2O6Si [M +
H]+ m/z 465.2415, found 465.2420.
ester groups. The reaction with NaBH4 under pH-buffered
conditions8b was also chemoselective, as only the Aux*
group was removed. By sharp contrast, the reduction of 4d
with LiBH4 led mainly to the diol (reduction of both the COOMe
and COAux* groups, even with equimolar amounts of LiBH4).
Moreover, treatment of 4d with DIBALH, under the smooth
conditions indicated above (addition of 1.5 equiv of DIBALH
in hexane at -100 °C to 4d in THF at -100 °C, stirring
for 15 min at -78 °C), afforded a 2:1 mixture of 4d and 7;
with 2.2 equiv of DIBALH for 2 h at -78 °C, a 60:40 mix-
ture of 7 and its alcohol (by reduction in situ of the formyl
group of 7) was obtained. Reduction of 4e with DIBALH (1.5
equiv for 6 h at -78 °C) gave a 1.3:1 mixture of 4e and 7;
with a larger excess of DIBALH (2.5 equiv, for 2 h at -78 °C)
the ratio among 4e, 7, and the alcohol derived from the formyl
group of 7 was 1:4:3. In other words, we were unable to find
as large a range of reaction conditions allowing us to discrimi-
nate between COOR and COAux* as we were with CONRR′
and COAux*.
In summary, previous functionalization of the propenoic
(acrylic) acid derivatives as hydroxamates or morpholine
amides does not preclude their highly diastereoselective reac-
tions with appropriate chiral Ti enolates. With the more stable
morpholine amide, the yields of the Michael adducts are
remarkable under the conditions reported here. These adducts
may then be cleaved smoothly by attack of appropriate
nucleophiles at either C1 or C5, with high chemoselectivity.
The reaction of the morpholine amides14b with DIBALH (in
the presence of N-acyl oxazolidinones), which are reported for
the first time to the best of our knowledge, are interesting
alternatives to the synthetic arsenal for the carboxyl-to-carbonyl
conversions. Various enantiopure fragments of type 1 and 2 are
accessible via this approach, bearing in mind that the formyl
groups of 6 and 7 are amenable to single and double C-C bond-
forming reactions.
1-[(S)-2-tert-Butyldimethylsilyloxy]-4-(4-morpholinylcarbon-
yl)butanoyl]-4-[(R)-phenylmethyl]-1,3-oxazolidin-2-one (4b): col-
orless oil; Rf 0.62 (CH2Cl2/MeOH 95:5); tR (HPLC) 10.6 min (90:
10 hexane-isopropanol, as above); [R]D -37.7 (c 0.96, CHCl3);
1
IR (film) 1777, 1712, 1646 cm-1; H NMR (400 MHz, CDCl3) δ
7.4-7.2 (m, 5 H), 5.37 (dd, J ) 6.8, 4.4 Hz, 1 H), 4.72 (ddt, J )
10.0, 8.0, 3.6 Hz, 1 H), 4.26 (t, J ) 9.0 Hz, 1 H), 4.20 (dd, J )
9.0, 3.6 Hz, 1 H), 3.7-3.5 (m, 8 H), 3.32 (dd, J ) 13.4, 3.6 Hz, 1
H), 2.73 (dd, J ) 13.4, 10.0 Hz, 1 H), 2.6-2.4 (m, 2 H), 2.2-2.0
(m, 2 H), 0.93 (s, 9 H), 0.10 (s, 3 H), 0.07 (s, 3 H); 13C NMR
(100.6 MHz, CDCl3) δ 173.6 (C), 170.8 (C), 153.1 (C), 135.0 (C),
129.4 (CH), 129.0 (CH), 127.4 (CH), 70.5 (CH), 66.9 (CH2), 66.8
(CH2), 66.6 (CH2), 55.0 (CH), 45.9 (CH2), 41.9 (CH2), 37.9 (CH2),
30.6 (CH2), 28.7 (CH2), 25.7 (CH3), 18.3 (C), -4.8 (CH3), -5.2
(CH3); HRMS (+ESI) calcd for C25H39N2O6Si [M + H]+ m/z
491.2572, found 491.2580.
Reduction Reactions. Reductions of 4a and 4b with NaBH4
(400 mol %, phosphate-buffered water at pH 8, THF, rt, ca. 95%
yields)8 and with LiBH4 (110 mol %, plus 110 mol % of MeOH,
THF, 0 °C, 92-95% yields)9 gave 5a and 5b, respectively; as soon
as TLC indicated the disappearance of the starting compounds (ca.
30 min), the reactions were diluted with cold water, partially
neutralized, and extracted with EtOAc. Alternatively, the two-step
cleavage of the chiral auxiliary of 4a and 4b with C12H25SH (3
equiv) and BuLi (0.3 equiv) in THF at 0 °C, followed by treatment
with Et3SiH and Pd/C in CH2Cl2 at rt,10 gave crude products
(identified and characterized by their CHO groups and by chro-
matography), which were immediately reduced in situ, with NaBH4
at rt, to store them as the hydroxy derivatives, 5a and 5b,
respectively. Reduction of Weinreb amide 4a (0.50 mmol in 5 mL
of THF) with DIBALH (750 µL of a 1.0 M hexane solution, 0.75
mmol, 1.5 equiv) at -78 °C for 15 min afforded the formyl
derivative 7 (193 mg, 95% yield) after purification by column
chromatography under N2.
Experimental Section
General Procedure (Michael Reaction). To 1.00 mmol of 3
(Aux*H ) (R)-4-benzyloxazolidin-2-one, R/OR ) OTBS) in 6 mL
of CH2Cl2 at 0 °C were added 1.05 mmol of a previously prepared
0.5 M solution of TiX4 in CH2Cl2 and then 1.05 mmol of iPr2NEt.
Stirring for 1 h, addition of 1.50 mmol of the Michael acceptor (in
3 mL of CH2Cl2 via canula), stirring for a further 16 h, partitioning
of the final mixture between aqueous NaHCO3 and EtOAc, and
purification by flash column chromatography gave the desired
adducts.
In the case of entries 1 and 2, when 1.05 mmol of TiCl3OiPr
[from a 75:25 TiCl4-Ti(OiPr)4 mixture in CH2Cl2] were employed
in the enolization step, the Michael acceptor was pre-complexed
with an additional 1.10 mmol of TiCl3OiPr.
1-[(S)-2-tert-Butyldimethylsilyloxy-5-oxopentanoyl]-4-[(R)-
phenylmethyl]-1,3-oxazolidin-2-one (7): colorless oil; Rf 0.37
(CH2Cl2); [R]D -74.7 (c 0.96, CHCl3); IR (film) 1779, 1716 cm-1
;
1H NMR (400 MHz, CDCl3) δ 9.80 (t, J ) 1.2 Hz, 1 H), 7.4-7.2
(m, 5 H), 5.34 (dd, J ) 7.4, 4.0 Hz, 1 H), 4.8-4.7 (m, 1 H), 4.28
(t, J ) 9.0 Hz, 1 H), 4.22 (dd, J ) 9.0, 3.6 Hz, 1 H), 3.30 (dd, J
) 13.4, 3.4 Hz, 1 H), 2.76 (dd, J ) 13.4, 9.6 Hz, 1 H), 2.7-2.6
(m, 2 H), 2.2-2.1 (m, 1 H), 2.06 (quint, J ) 7.4 Hz, 1 H), 0.93 (s,
9 H), 0.08 (s, 3 H), 0.06 (s, 3 H); 13C NMR (100.6 MHz, CDCl3)
δ 201.5 (CH), 173.5 (C), 153.1 (C), 134.8 (C), 129.4 (CH), 129.0
(CH), 127.5 (CH), 70.3 (CH), 66.9 (CH2), 55.0 (CH), 39.6 (CH2),
37.9 (CH2), 27.6 (CH2), 25.7 (CH3), 18.2 (C), -4.9 (CH3), -5.3
(CH3); HRMS (+ESI) calcd for C21H32NO5Si [M + H]+ m/z
406.2044, found 406.2053.
4-[(R)-Benzyl]-1-[(S)-2-tert-butyldimethylsilyloxy-4-(N-meth-
oxy-N-methylamino)carbonyl]butanoyl-1,3-oxazolidin-2-one, or
4-[(S)-tert-Butyldimethylsilyloxy]-5-[(R)-4-phenylmethyl-2-oxo-
1,3-oxazolidin-3-yl]-N-methoxy-N-methyl-5-oxopentanamide (4a):
colorless oil; Rf 0.52 (CH2Cl2/MeOH 98:2); [R]D -52.9 (c 0.98,
(14) (a) In our experiments with the morpholine amide (4b), which is
less reactive than the Weinreb amide (4a), we preferred stopping the
reactions at conversions of 80-90%, recovering the unreacted starting
material, rather than adding larger amounts of DIBALH or increasing the
reaction times, as byproducts coming from the attack on the other CO carbon
atoms could appear. (b) Morpholine amide Aux*COCH(Me)CH2CH2CON-
(C4H8O), that is 3 (R/OR ) Me), was also cleaved successfully, in the
same way. Independent studies regarding the reduction of morpholine amides
to aldehydes will be reported in due course.
Reduction of the Morpholine Amide with DIBALH. To a
solution of 4b (36 mg, 0.075 mmol) in anhydrous THF (280 µL)
at -100 °C was added a hexane solution of DIBALH (112 µL, 1.0
M, 1.5 equiv) previously cooled also at -100 °C. After stirring for
15 min at -78 °C, dilution with a few milliliters of THF at -78 °C
followed by a quick filtration through a pad of silica gel, with CH2-
1580 J. Org. Chem., Vol. 73, No. 4, 2008

Cl2 as the eluent, gave a crude product that contained (NMR) only
the desired compound, 7, and ca. 10% of the starting material (4b).
Purification by column chromatography (under N2) gave pure 7
(24 mg, 80%).
(Barcelona) contributed partially to this project by means of
grant 2001SGR065 (2002-2005, GRC S´ıntesi Estereoselectiva
d’Antibio`tics i Antiv´ırics).
Supporting Information Available: Experimental details for
Acknowledgment. Financial support from the Spanish
Ministerio de Educacio´n y Ciencia (Madrid), through grant
SAF2002-02728 that included a studentship to C.R.E. (May
2003-May 2007) and more recently through grant CTQ-2006-
15393 (to J.V.) is acknowledged. The Generalitat de Catalunya
1
4c, 4d, 4e, 5a, and 5b and copies of H and 13C NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO702240N
J. Org. Chem, Vol. 73, No. 4, 2008 1581