Highly π-facial stereoselective aldol reaction of (S)-proline-derived amide enolate with benzaldehydes

Article abstract of DOI:10.1002/ejoc.200390097

The asymmetric aldol reaction of the (S)-proline-derived bicyclic amide enolate 1 with benzaldehydes selectively affords the two diastereomeric aldol adducts (3S,3′R,8S)-3a and (3S,3′S,8S)-3a, of four possible diastereomers, in good yield. The high control of π-facial stereoselectivity at the endocyclic C-3 stereocenter is due to perfect shielding by the pseudo-axial phenyl ring at the C-1 position. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200390097

FULL PAPER
Highly π-Facial Stereoselective Aldol Reaction of (S)-Proline-Derived Amide
Enolate with Benzaldehydes
Waldemar Adam[a] and Aimin Zhang*[a]
Keywords: Aldol reactions / Stereoselectivity / Reaction mechanism / X-ray diffraction
The asymmetric aldol reaction of the (S)-proline-derived bi-
docyclic C-3 stereocenter is due to perfect shielding by the
cyclic amide enolate 1 with benzaldehydes selectively af- pseudo-axial phenyl ring at the C-1 position.
fords the two diastereomeric aldol adducts (3S,3ЈR,8S)-3a
and (3S,3ЈS,8S)-3a, of four possible diastereomers, in good
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
yield. The high control of π-facial stereoselectivity at the en- Germany, 2003)
Introduction
The aldol reaction is an efficient method for the genera-
tion of two adjacent stereogenic centers in a single
carbonϪcarbon bond-forming process.[1] In view of the
Scheme 1. Ar ϭ 4-MeOC6H4-
value of stereoselective aldol reactions in organic synthesis,
intensive efforts[2,3] have been expended to develop them. A
persistent challenge has been to achieve asymmetric pro-
cesses, for which chiral auxiliaries[4,5] as well as optically
active Lewis acids[6] have been employed.
A relevant recent application of the chiral-auxiliary con-
cept has been described by Andrus,[7Ϫ9] namely the asym-
metric aldol reaction of benzaldehyde with the boron enol-
ate of bis(4-methoxyphenyl)dioxanone (Scheme 1). The ste-
reocontrol at the exocyclic stereogenic site (the C-3Ј posi-
tion in the aldol) is high, due to the chelating effect of the
boron functionality, resulting in only one isomer being
found. In contrast, the π-facial stereoselectivity at the endo-
cyclic chirality center (the C-3 stereogenic center in the al-
dol) is only moderate [(3S)/(3R) ϭ 86:14]. Evidently, for this
aldol process, the two aryl groups are not sufficiently effect-
ive in preferentially shielding one face of the double bond
in the boron enolate.[10,11] Presumably, the π-facial stereo-
selectivity of the aldol reaction with a cyclic enolate may be
improved if the six-membered ring of the enolate is made
conformationally more rigid and substituents with effective
steric interactions are introduced. For this purpose we have
chosen the bicyclic amide 1, which is derived from (S)-pro-
line and which, on deprotonation, would generate an (E)-
configured cyclic enolate whose two π faces should be
sterically differentiated in an electrophilic attack by benzal-
dehyde (Scheme 2).[12]
Scheme 2
Inspection of molecular models reveals that the proline
structural unit imparts greater conformational rigidity to
the six-membered-ring enolate, while the two phenyl groups
provide massive steric interactions with the attacking alde-
hyde. High π-facial stereoselectivity at the C-3 stereogenic
center is thus anticipated. We report herein a highly π-facial
stereoselective aldol reaction of the (S)-proline-derived
amide enolate with benzaldehydes, in which the
(3S,3ЈR,8S)-3a and (3S,3ЈS,8S)-3a diastereomers are pro-
duced exclusively.
[a]
Results and Discussion
Institut für Organische Chemie, Universität Würzburg,
Am Hubland, 97074 Würzburg, Germany
Fax: (internat.) ϩ 49-(0)931/888-4756
As shown in Scheme 3, (S)-α,α-diphenylprolinol was
readily synthesized from commercially available (S)-proline
E-mail: adam@chemie.uni-wuerzburg.de
Internet: http://www.organik.chemie.uni-wuerzburg.de
Eur. J. Org. Chem. 2003, 587Ϫ591  2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0203Ϫ0587 $ 20.00ϩ.50/0
587

W. Adam, A. Zhang
FULL PAPER
according to a literature procedure.[13] The total yield of
(S)-α,α-diphenylprolinol over the two steps was 54%. N-
Acylation of (S)-α,α-diphenylprolinol by treatment with
bromoacetyl bromide, triethylamine and DMAP in THF at
Ϫ78 °C, followed by cyclization with NaH/DMF, provided
the cyclic amide 1 in 70% yield.[14] The structure of amide
1 was confirmed by HMQC and HMBC spectroscopy.
Table 1. π-Facial stereoselective aldol reaction of (S)-proline-de-
rived bicyclic amide enolate 1 with benzaldehydes
Scheme 3. a) C2H5COCl, K2CO3, CH3OH, 0 °C, 93%; b) i.
PhMgBr, THF; ii. KOH, methanol, reflux, 57%; c) i. BrCOCH2Br,
Et3N, DMAP, THF; ii. NAH, DMF, 70%; d) LDA, THF, Ϫ78 °C,
ArCHO (2)
[a]
[b]
Yield of pure material isolated by chromatography.
Relative
amounts were calculated from the isolated individual diastereo-
mers, except for the last two Entries, which were determined by 1H
NMR spectroscopy (error ca. 5% of the stated values).
The aldol reaction was first conducted with benzaldehyde
(2a) by treatment of amide 1 with 1.1 equiv. of LDA (li-
thium diisopropylamide) in THF at Ϫ78 °C for 1 h. Of the
four possible diastereomers, only the (3S,3ЈR,8S)-3a (50%)
and (3S,3ЈS,8S)-3a[15] (40%) diastereomers were obtained
(Scheme 3). The scope of the aldol reaction was assessed by
employing several substituted benzaldehydes. The results
are summarized in Table 1. As for the parent benzaldehyde
(2a), the (3S,3ЈR,8S) and (3S,3ЈS,8S) diastereomers of the
aldol 3 were obtained for all derivatives. The similar NMR
spectroscopic data of these compounds confirmed that their
configurations were the same. The yields range between 53
and 90% and the diastereoselectivity is moderate (dr up to
76:24). Both diastereomers could be readily obtained in
pure form by silica-gel chromatography.
the C-3 position in the two isomers are the same, while
those at the C-3Ј center are different. Indeed, an X-ray ana-
lysis of the aldol adduct (3S,3ЈR,8S)-3e confirmed this ste-
reochemical assignment (Figure 1). Since the configuration
in (S)-proline is known, the configurations of the other two
stereocenters in the aldol adduct (3S,3ЈR,8S)-3e may be as-
signed as (3S) and (3ЈR), as shown in Figure 1. From the
combined data of the X-ray structure for (3S,3ЈR,8S)-3e
and the 2D-NOE effects of (3S,3ЈR,8S)-3a and (3S,3ЈS,8S)-
3a, the complete absolute configurations of the two diaster-
eomers for all aldol adducts in Table 1 may be assigned as
(3S,3ЈR,8S) and (3S,3ЈS,8S); the other two possible diaster-
eomers (3R,3ЈR,8S) and (3R,3ЈS,8S) are not observed.
The structural assignment of the aldol adducts are exem-
plified for the (3S,3ЈR,8S)-3a and (3S,3ЈS,8S)-3a. Their rel-
ative configurations were assessed from the 1H and 13C
NMR spectra, together with 2D-NOE spectroscopy. In the
NOE spectrum of adduct (3S,3ЈR,8S)-3a, the strong effect
between the 8-H and 3-H protons shows clearly that these
are on the same side and the configuration at the ste-
reogenic center C-3 is therefore (S) (Figure 1). The same
interaction is observed in the NOESY study of (3S,3ЈS,8S)-
3a, which indicates that its C-3 chirality center also has the
(S) configuration. Similar NOE effects are observed be-
tween the 3-H and 3Ј-H protons in both aldol adducts
(3S,3ЈR,8S)-3a and (3S,3ЈS,8S)-3a, which show that the en-
vironment of the 3Ј-H proton in the two diastereomers is
similar. However, TLC and NMR spectra disclose that they
are different aldol adducts. Examination of the molecular
models of the adducts (3S,3ЈR,8S)-3a and (3S,3ЈS,8S)-3a
Figure 1. 2D-NOE spectroscopy of (3S,3ЈR,8S)-3a and (3S,3ЈS,8S)-
3a and the X-ray structure of (3S,3ЈR,8S)-3e
The formation of only the two diastereomeric adducts
reveals that the carbonϪcarbon bond between the C-3 and (3S,3ЈR,8S)-3a and (3S,3ЈS,8S)-3a, which have the same (S)
C-3Ј atoms in the two diastereomers may rotate without any configuration at the new endocyclic C-3 stereogenic center
hindrance. Thus, the similar NOE effects of (3S,3ЈR,8S)-3a of the enolate ring, shows a high π-facial stereoselectivity.
and (3S,3ЈS,8S)-3a show that the absolute configurations at Evidently, the attack of the benzaldehyde electrophile is ex-
588
Eur. J. Org. Chem. 2003, 587Ϫ591

Highly π-Facial Stereoselective Aldol Reaction of (S)-Proline-Derived Amide Enolate
FULL PAPER
clusively from above (C-3 Si face), as displayed in the mech-
Conclusion
anism of Scheme 4 for the asymmetric aldol reaction.[16,17]
The reason for this becomes evident on inspection of mo-
lecular models of the enolate, which show that the (S)-con-
figured proline ring lies nearly perpendicular to the enolate
double bond. Steric effects thus oblige one of the phenyl
groups at the C-1 position of the enolate to assume the
pseudo-axial site (almost antiparallel to the proline five-
membered ring), while the other phenyl group is situated
pseudo-equatorially (essentially in-plane with the enolate
double bond). That one of the two phenyl rings lies below
the enolate double bond is confirmed by the NOE effects in
both diastereomers (Figure 1), in which strong interactions
occur between the 3-H and 8-H atoms and one of the hy-
drogen atoms in the benzene ring at the C-1 position. Con-
sequently, the C-3 Re side of the enolate double bond is
shielded by the pseudo-axial phenyl ring and the benzal-
dehyde attacks preferentially from the C-3 Si side (from
above, pathways A and B). In both pathways A and B, the
absolute configuration at the C-3 stereocenter should be
(3S), as assigned by X-ray and NOESY analysis. The high
degree of steric control is remarkable, as attack from the C-
3 Re side (from below, pathways C and D) is not observed.
The aldol reaction of the amide enolate 1 with benzal-
dehydes proceeds with high π-facial control of stereoselect-
ivity (C-3 Si attack) at the endocyclic C-3 stereocenter. This
is because of perfect shielding by the pseudo-axial phenyl
ring at the C-1 position. Evidently, the diastereoselectivity
at the endocyclic C-3Ј site is low because the steric interac-
tions with the pseudo-equatorial phenyl ring at the C-1 po-
sition are ineffective.
Experimental Section
General Aspects: 1H and 13C NMR spectra were recorded in CDCl3
with a Bruker AC 200 (1H: 200 MHz; 13C: 50 MHz) or a Bruker
Avance 400 (1H: 400 MHz; 13C: 100 MHz) spectrometer with
CDCl3 as reference standard. The NMR shifts have been assigned
according to the numbering of compound 1 in Scheme 2. For the
IR spectra, a PerkinϪElmer 1420 ratio-recording infrared spectro-
photometer was used. TLC analysis was conducted on precoated
silica-gel foils 60 F254 (20 ϫ 20 cm) from Merck (Darmstadt, Ger-
many). The spots were visualised either by UV (254 nm) irradiation
or by spraying with a 5% solution of polymolybdic acid in ethanol.
Silica gel (32Ϫ62 mm) from Woelm (Erlangen, Germany) was used
for column chromatography. The solvents were dried by standard
methods and purified by distillation before use. Melting points (un-
corrected) were determined with a Büchi B-545. Elemental analyses
were carried out by the Microanalytical Division of the Institute
of Inorganic Chemistry, University of Würzburg. All commercial
reagents were used without further purification.
Pyrrolooxazinone 1:
A
mixture of (S)-α,α-diphenylprolinol[13]
(253 mg, 1.0 mmol), triethylamine (0.14 mL, 2.0 mmol) and
DMAP (30.0 mg) in dry THF (25 mL) was treated with bromoace-
tyl bromide (0.087 mL, 1.0 mmol) in THF (5 mL) over 5 min at
room temperature (ca. 20 °C). The reaction mixture was stirred
overnight, then the solvent was removed (40 °C, 20 Torr) in vacuo.
The resulting oil was taken up in ethyl acetate (50 mL) and
washed with 1  NaOH. The combined organic layers were dried
with anhydrous Na2SO4 and concentrated (40 °C, 20 Torr). The
residue was dissolved in DMF (20 ml), then NaH (50 mg) was ad-
ded. After stirring at room temperature for 24 h, water (5 mL) was
added to the suspension and the mixture was extracted with ethyl
acetate (3 ϫ 20 mL). The combined extracts were dried (Na2SO4),
filtered and concentrated (40 °C, 20 Torr). The crude product was
purified by silica gel chromatography (petroleum ether/ethyl acet-
ate, 2:1) to afford 1 (206 mg, 70%) as colorless plates, m.p. 55Ϫ56
Scheme 4. Mechanism of the aldol reaction of (S)-proline-derived
bicyclic amide enolate 1 with benzaldehyde
°C. [α]2D0 ϭ 91.1 (c ϭ 2.1, CHCl3). IR (KBr): ν˜ ϭ 3500, 1690 cmϪ1
.
1H NMR (400 MHz, CDCl3): δ ϭ 1.7Ϫ1.9 (m, 2 H, 6-H, 7-H), 2.1
(m, 1 H, 6-H), 2.3 (m, 1 H, 7-H), 3.6 (d, J ϭ 16.68 Hz, 1 H, 3-H),
3.7 (m, 1 H, 5-H), 3.8 (m, 1 H, 5-H), 4.05 (m, 1 H, 8-H), 4.21 (d,
J ϭ 16.56 Hz, 1 H, 3-H), 7.17Ϫ7.19 (m, 2 H), 7.26Ϫ7.29 (m, 8 H)
ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 21.8 (t, C-6), 28.5 (t, C-
7), 45.2 (t, C-5), 63.8 (t, C-2), 65.2 (d, C-8), 80.7 (s, C-1), 126.7,
127.5, 127.8, 127.9, 128.1, 128.9, 138.7, 143.6, 166.6 (s, C-4) ppm.
HRMS (EI): calcd. for C19H19NO2 [Mϩ] 293.1416; found 293.1411.
In contrast, the diastereoselectivity at the endocyclic C-
3Ј stereogenic center (the original carbonyl atom of the
benzaldehyde electrophile) is low (52:48) to moderate
(76:24), as shown for the various benzaldehyde derivatives
in Table 1. The transition structures in Scheme 2 reveal that
there are no severe steric interactions (with the pseudo-
equatorial phenyl group, for example) in the two possible
approaches of the benzaldehyde along the pathways A and
B; thus, the two diastereomers (3S,3ЈR,8S)-3a and
(3S,3ЈS,8S)-3a are formed in nearly equal amounts.
General Procedure for the Aldol Reaction of Amide 1 and Benzal-
dehyde: A well-stirred solution of amide 1 (211 mg, 0.72 mmol) in
THF (5 mL) at Ϫ78 °C (dry ice/acetone) was treated dropwise with
a solution of LDA (0.43 mL, 2  in THF, 0.86 mmol) over 3 min.
After stirring for 30 min at this temperature, benzaldehyde
Eur. J. Org. Chem. 2003, 587Ϫ591
589

W. Adam, A. Zhang
FULL PAPER
(86.0 mg, 0.81 mmol) in THF (5 mL) was added over 5 min. The
resulting mixture was stirred at Ϫ78 °C for 2 h, then warmed to
room temperature. A saturated aqueous solution of NH4Cl (5 ml)
was added and the organic layer was extracted with ethyl acetate
(3 ϫ 30 mL). The combined organic layers were dried (Na2SO4)
and filtered. The solvent was evaporated (40 °C, 20 Torr) and the
residue was purified by silica gel chromatography (petroleum ether/
ethyl acetate, 2:1 as eluent) to provide the desired aldol adduct.
2 H, 7-H, 6-H), 1.60 (m, 1 H, 6-H), 1.74 (m, 1 H, 7-H), 3.31 (m, 1
H, 5-H), 3.56 (m, 1 H, 5-H), 4.01 (d, J ϭ 3.4 Hz, 1 H, 3-H), 4.11
(t, J ϭ 7.04 Hz, 1 H, 8-H), 5.31 (d, J ϭ 3.28 Hz, 1 H, 3Ј-H),
6.95Ϫ7.5 (m, 14 H, Ph-H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ
23 (t, C-6), 30.1 (t, C-7), 44.8 (t, C-5), 62.4 (d, C-8), 72.5 (d, C-3Ј),
75.2 (d, C-3), 81.9 (s, C-1), 125, 125.1, 127.3, 127.8, 128.0, 128.3,
128.5, 142.6, 143, 144.7 (s, CF3), 170.4 (s, C-4) ppm. HRMS (CI):
calcd. for C27H25F3NO4 [Mϩ] 468.1787; found 468.1783.
Pyrrolooxazinone 3a. Minor Isomer (3S,3ЈS,8S)-3a: Colorless
Pyrrolooxazinone 3d. Minor Isomer (3S,3ЈS,8S)-3d: Colorless pow-
1
needles, m.p. 176Ϫ178 °C. [α]2D0 ϭ Ϫ345.9 (c ϭ 1.05, CHCl3). IR der, m.p. 158Ϫ159 °C. [α]2D0 ϭ Ϫ219 (c ϭ 1.2, CHCl3). H NMR
(KBr): ν˜ ϭ 3450, 1670 cmϪ1
.
1H NMR (400 MHz, CDCl3): δ ϭ
(400 MHz, CDCl3): δ ϭ 1.5 (m, 2 H, 7-H, 6-H), 1.75 (m, 1 H, 6-
1.25Ϫ1.33 (m, 2 H, 7-H, 6-H), 1.53 (m, 1 H, 6-H), 1.81 (m, 1 H, H), 2.0 (m, 1 H, 7-H), 3.6 (m, 2 H, 5-H), 3.74 (d, J ϭ 8.7 Hz, 1 H,
7-H), 3.32 (m, 1 H, 5-H), 3.43 (m, 1 H, 5-H), 3.59 (d, J ϭ 8.5 Hz, 3-H), 4.20 (d, J ϭ 7.2 Hz, 1 H, 8-H), 5.05 (d, J ϭ 8.84 Hz, 1 H,
1 H, 3-H), 3.98 (t, J ϭ 7.08 Hz, 1 H, 8-H), 4.87 (d, J ϭ 8.7 Hz, 1 3Ј-H), 5.15 (br., 1 H, OH), 6.85Ϫ7.43 (m, 14 H, Ph-H) ppm. 13C
H, 3Ј-H), 6.63Ϫ7.19 (m, 15 H, Ph-H) ppm. 13C NMR (100 MHz, NMR (100 MHz, CDCl3): δ ϭ 23.3 (t, C-6), 30.8 (t, C-7), 44.8 (t,
CDCl3): δ ϭ 23.4 (t, C-6), 30.8 (t, C-7), 44.8 (t, C-5), 62.9 (d, C-
8), 74.2 (d, C-3Ј), 74.8 (d, C-3), 82.6 (s, C-1), 127.4, 127.6, 128,
C-5), 62.9 (d, C-8), 73.5 (d, C-3Ј), 74.7 (d, C-3), 82.7 (s, C-1), 127.2,
127.3, 127.4, 127.6, 127.9, 128.1, 128.3, 128.4, 128.5, 128.6, 128.9,
128.3, 128.4, 128.6, 140.7, 142.6, 142.9, 172.5 (s, C-4) ppm. Major 129, 129.4, 134, 139.3, 142.6, 142.8, 172.2 (s, C-4) ppm. Major Iso-
Isomer (3S,3ЈR,8S)-3a: Colorless plates, m.p. 165Ϫ166 °C. [α]2D0 mer (3S,3ЈR,8S)-3d: Colorless plates, m.p. 124Ϫ125 °C. [α]D 20ϭ
Ϫ276.7 (c ϭ 1, CHCl3). IR (KBr): ν˜ ϭ 3495, 1665 cmϪ1. 1H NMR Ϫ267 (c ϭ 0.55, CHCl3). IR (KBr): ν˜ ϭ 3450, 1670 cmϪ1. 1H NMR
(400 MHz, CDCl3): δ ϭ 1.20 (m, 2 H, 7-H, 6-H), 1.56 (m, 2 H, 7- (400 MHz, CDCl3): δ ϭ 1.29 (m, 2 H, 7-H, 6-H), 1.70 (m, 2 H, 7-
ϭ
H, 6-H), 3.25 (m, 1 H, 5-H), 3.60 (m, 1 H, 5-H), 3.97 (d, J ϭ H, 6-H), 3.34 (m, 1 H, 5-H), 3.64 (m, 1 H, 5-H), 4.05 (d, J ϭ
3.54 Hz, 1 H, 3-H), 4.05 (t, J ϭ 6.19 Hz, 1 H, 8-H), 4.18 (br., 1 H, 7.04 Hz, 1 H, 3-H), 4.17 (m, 1 H, 8-H), 4.35 (b, 1 H, OH), 5.28 (d,
OH), 5.21 (s, 1 H, 3Ј-H), 6.95Ϫ7.4 (m, 15 H, Ph-H) ppm. 13C NMR
J ϭ 6.4 Hz, 1 H, 3Ј-H), 7.07Ϫ7.48 (m, 14 H, Ph-H) ppm. 13C NMR
(100 MHz, CDCl3): δ ϭ 22.5 (t, C-6), 29.5 (t, C-7), 44.6 (t, C-5), (100 MHz, CDCl3): δ ϭ 22.4 (t, C-6), 29.9 (t, C-7), 44.8 (t, C-5),
62.2 (d, C-8), 73 (d, C-3Ј), 75.3 (d, C-3), 81.4 (s, C-1), 127.5, 127.8,
127.9, 128.5, 128.6, 129.1, 141.1, 143.1, 143.8, 171.2 (s, C-4) ppm.
C26H25NO3 (399.5): calcd. C 78.17, H 6.31, N 3.51; found C 77.81,
H 6.64, N 3.45.
62.3 (d, C-8), 72.5 (d, C-3Ј), 74.5 (d, C-3), 81.6 (s, C-1), 126.8,
127.2, 127.6, 127.9, 128.2, 128.3, 128.4, 128.5, 128.7, 128.8, 128.9,
129, 129.1, 129.7, 133.5, 139.3, 142.6, 143.2, 171.5 (s, C-3) ppm.
HRMS (CI): calcd. for C26H25ClNO3 [Mϩ] 434.1523; found
434.1520.
Pyrrolooxazinone 3b. Minor Isomer (3S,3ЈS,8S)-3b: Colorless
needles, m.p. 179Ϫ180 °C. [α]2D0 ϭ Ϫ243 (c ϭ 1, CHCl3). IR (KBr):
Pyrrolooxazinone 3e. Minor Isomer (3S,3ЈS,8S)-3e: Colorless
ν˜ ϭ 3450, 1675 cmϪ1.1H NMR (400 MHz, CDCl3): δ ϭ 1.41 (m, needles, m.p. 148Ϫ149 °C. [α]2D0 ϭ Ϫ290.3 (c ϭ 1.5, CHCl3). IR
2 H, 7-H, 6-H), 1.66 (m, 1 H, 6-H), 1.92 (m, 1 H, 7-H), 2.29 (s, 3 (KBr): ν˜ ϭ 3610, 1670 cmϪ1 1H NMR (400 MHz, CDCl3): δ ϭ
.
H, CH3), 3.43 (m, 1 H, 5-H), 3.58 (m, 1 H, 5-H), 3.72 (d, J ϭ 1.4Ϫ1.6 (m, 2 H, 7-H, 6-H), 1.7 (m, 1 H, 6-H), 1.98 (m, 1 H, 7-
8.7 Hz, 1 H, 3-H), 4.11 (t, J ϭ 7.08 Hz, 1 H, 8-H), 4.97 (d, J ϭ H), 3.4Ϫ3.72 (m, 2 H, 5-H), 3.66 (s, 3 H, OMe), 4.09 (d, J ϭ
8.72 Hz, 1 H, 3Ј-H), 6.78Ϫ7.28 (m, 14 H, Ph-H) ppm. 13C NMR 7.18 Hz, 1 H, 3-H), 4.23 (m, 1 H, 8-H), 5.58 (d, J ϭ 7.94 Hz, 1 H,
(100 MHz, CDCl3): δ ϭ 21.6 (q, CH3), 23.4 (t, C-6), 30.8 (t, C-7),
3Ј-H), 6.7Ϫ7.4 (m, 14 H, Ph-H) ppm. 13C NMR (100 MHz,
44.8 (t, C-5), 63 (d, C-8), 74 (d, C-3Ј), 74.8 (d, C-3), 82.6 (s, C-1), CDCl3): δ ϭ 14.6 (q, -OMe), 23.3 (t, C-6), 44.7 (t, C-7), 55.4 (t, C-
127.5, 127.6, 127.9, 128.2, 128.6, 129, 137.8, 142.7, 142.9, 172.6 (s, 5), 63.1 (d, C-8), 67.3 (d, C-3Ј), 74.2 (d, C-3), 82.2 (s, C-1), 111,
C-4) ppm. Major Isomer (3S,3ЈR,8S)-3b: Colorless powder, m.p.
120.9, 127.3, 127.4, 127.5, 127.8, 128, 128.1, 128.1, 128.2, 128.3,
128.5, 128.6, 128.8, 128.9, 129, 129.1, 143, 143.1, 143.3, 156, 157.9,
172.6 (s, C-4) ppm. C27H28NO4 (430.2): calcd. C 75.50, H 6.34, N
162Ϫ163 °C. [α]2D0 ϭ Ϫ112 (c ϭ 1.8, CHCl3). IR (KBr): ν˜ ϭ 3450,
1
1675 cmϪ1. H NMR (400 MHz, CDCl3): δ ϭ 1.25 (m, 2 H, 7-H,
6-H), 1.62 (m, 2 H, 7-H, 6-H), 2.28 (s, 3 H, -CH3), 3.28 (m, 1 H, 3.26; found C 75.96, H 6.62, N 3.25. Major Isomer (3S,3ЈR,8S)-3e:
5-H), 3.63 (m, 1 H, 5-H), 3.99 (d, J ϭ 3.68 Hz, 1 H, 3-H), 4.09 (t,
Colorless cubes, m.p. 120Ϫ121 °C. [α]2D0 ϭ Ϫ452.8 (c ϭ 1, CHCl3).
J ϭ 6.2 Hz, 1 H, 8-H), 5.21 (d, J ϭ 3.44 Hz, 1 H, 3Ј-H), 7.02Ϫ7.3 IR (KBr): ν˜ ϭ 3600, 1675 cmϪ1. 1H NMR (400 MHz, CDCl3): δ ϭ
(m, 14 H, Ph-H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 21.5 (q, 1.35Ϫ1.6 (m, 2 H, 7-H, 6-H), 1.7 (m, 1 H, 6-H), 1.95 (m, 1 H, 7-
CH3), 22.8 (t, C-6), 29.8 (t, C-7), 44.8 (t, C-5), 62.3 (d, C-8), 72.9 H), 3.58 (m, 3 H, OCH3), 3.7Ϫ3.4 (m, 2 H, 5-H), 4.14 (m, 1 H, 8-
(d, C-3Ј), 75.4 (d, C-3), 81.4 (s, C-1), 127.2, 127.4, 127.7, 128.3,
H), 4.22 (d, J ϭ 2.29 Hz, 1 H, 3-H), 5.80 (d, J ϭ 2.0 Hz, 1 H, 3Ј-
128.7, 128.8, 137.2, 137.7, 142.7, 143.4, 170.7 (s, C-4) ppm. HRMS H), 6.80Ϫ7.3 (m, 14 H, Ph-H) ppm. 13C NMR (100 MHz, CDCl3):
(CI): calcd. for C27H28NO3 [Mϩ] 414.2069; found 414.2061.
δ ϭ 14.6 (q, -OMe), 23.4 (t, C-6), 44.7 (t, C-7), 55.3 (t, C-5), 63.1
(d, C-8), 67.3 (d, C-3Ј), 74 (d, C-3), 82 (s, C-1), 110.2, 120.9, 127.3,
127.4, 127.5, 127.8, 127.9, 128.1, 128.2, 128.3, 128.5, 128.6, 128.7,
128.8, 129.1, 143.3, 143.4, 155.9, 171.3 (s, C-4) ppm. HRMS (CI):
calcd. for C27H28NO4 [Mϩ] 430.2018; found 430.2019.
Pyrrolooxazinone 3c. Minor Isomer (3S,3ЈS,8S)-3c: Colorless cubes,
m.p. 172Ϫ173 °C. [α]2D0 ϭ Ϫ191 (c ϭ 1.25, CHCl3). 1H NMR
(400 MHz, CDCl3): δ ϭ 1.45 (m, 2 H, 7-H, 6-H), 1.67 (m, 1 H, 6-
H), 1.99 (m, 1 H, 7-H), 3.46 (m, 1 H, 5-H), 3.55 (m, 1 H, 5-H),
3.69 (d, J ϭ 8.84 Hz, 1 H, 3-H), 4.13 (t, J ϭ 7.2 Hz, 1 H, 8-H),
5.08 (d, J ϭ 8.72 Hz, 1 H, 3Ј-H), 6.7Ϫ7.55 (m, 14 H, Ph-H) ppm.
Pyrrolooxazinone 3f. (3S,3ЈR,8S)-3f: Colorless plates, m.p.
129Ϫ130 °C. [α]2D0 ϭ Ϫ286 (c ϭ 1.5, CHCl3). IR (KBr): ν˜ ϭ 3470,
13C NMR (100 MHz, CDCl3): δ ϭ 23.4 (t, C-6), 30.9 (t, C-7), 44.8 1670 cmϪ1. H NMR (400 MHz, CDCl3): δ ϭ 1.42 (m, 2 H, 7-H,
1
(t, C-5), 62.9 (d, C-8), 73.6 (d, C-3Ј), 74.7 (d, C-3), 82.9 (s, C-1), 6-H), 1.64 (m, 1 H, 6-H), 1.84 (m, 1 H, 7-H), 3.38 (m, 1 H, 5-H),
125.1, 125.2, 127.2, 127.6, 128.2, 128.4, 128.6, 142.5, 142.7, 144.7 (s,
3.48 (s, 3 H, OCH3), 3.60 (m, 1 H, 5-H), 3.70 (m, 1 H, 3-H), 3.73
(s, 3 H, OCH3), 4.10 (m, 1 H, 8-H), 5.63 (d, J ϭ 2.28 Hz, 1 H, 3Ј-
H), 6.29Ϫ6.48 (m, 3 H, Ph-H), 6.9Ϫ7.5 (m, 10 H, Ph-H) ppm. 13C
CF3), 172.1 (s, C-4) ppm. Major Isomer (3S,3ЈR,8S)-3c: Colorless
prisms, m.p. 136Ϫ137 °C. [α]2D0 ϭ Ϫ130 (c ϭ 1, CHCl3). IR (KBr):
1
ν˜ ϭ 3495, 1670 cmϪ1. H NMR (400 MHz, CDCl3): δ ϭ 1.27 (m, NMR (100 MHz, CDCl3): δ ϭ 23.3 (t, C-6), 30.6 (t, C-7), 44.7 (t,
590
Eur. J. Org. Chem. 2003, 587Ϫ591

Highly π-Facial Stereoselective Aldol Reaction of (S)-Proline-Derived Amide Enolate
FULL PAPER
C-5), 55.4 (q, OMe), 55.8 (q, OMe), 62.9 (d, C-8), 67.1 (d, C-3Ј), authors thank Prof. Guoqiang Lin (Shanghai Institute of Organic
74.1 (d, C-3), 81.9 (s, C-6), 98.4, 104.4, 121.4, 127.5, 127.6, 127.7, Chemistry, Chinese Academy of Sciences) for determining the X-
128, 128.1, 128.2, 128.5, 128.5, 128.6, 143.3, 143.5, 157, 160.4, ray structure of the (3S,3ЈR,8S)-3e aldol adduct. A. Z. is grateful
171.3 (s, C-4) ppm. C28H29NO5 (459.5): calcd. C 73.18, H 6.38, N
3.05; found C 73.12, H 6.45, N 3.20.
to the Alexander-von-Humbolt Foundation for a postdoctoral
fellowship (2001Ϫ2002).
Pyrrolooxazinone 3g. (3S,3ЈR,8S)-3g: Colorless needles, m.p.
229Ϫ230 °C. [α]2D0 ϭ Ϫ300 (c ϭ 1.8, CHCl3). IR (KBr): ν˜ ϭ 3450,
[1]
1
D. A. Evans, J. Bartroli, T. L. Shih, J. Am. Chem. Soc. 1981,
1670 cmϪ1. H NMR (400 MHz, CDCl3): δ ϭ 1.45 (m, 2 H, 7-H,
103, 2127Ϫ2129.
6-H), 1.66 (m, 1 H, 6-H), 1.85 (m, 1 H, 7-H), 3.3Ϫ3.6 (m, 2 H, 5-
H), 3.49 (s, 3 H, OCH3), 3.60 (s, 3 H, OCH3), 3.8 (m, 1 H, 3-H),
3.82 (s, 3 H, OCH3), 4.10 (m, 1 H, 8-H), 5.66 (d, J ϭ 2.28 Hz, 1
H, 3Ј-H), 6.36Ϫ6.44 (m, 2 H, Ph-H), 6.89Ϫ7.4 (m, 10 H, Ph-H)
ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 23.3 (t, C-6), 30.7 (t, C-
7), 44.8 (t, C-5), 56.3 (q, OMe), 56.6 (q, OMe), 57 (q, OMe), 62.9
(d, C-8), 67.0 (d, C-3Ј), 74.3 (d, C-3), 81.9 (s, C-1), 97.4, 112.7,
120.6, 127.4, 127.5, 127.6, 127.7, 127.8, 128, 128.1, 128.2, 128.4,
128.5, 128.6, 129.4, 143.2, 143.5, 150.3, 160.4, 171.1 (s, C-4) ppm.
C29H31NO6 (489.6): calcd. C 71.15, H 6.38, N 2.86; found C 70.72,
H 6.43, N 2.77.
[2]
B. List, R. A. Lerner, C. F. Barbas, III, J. Am. Chem. Soc.
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[3]
[4]
[5]
[6]
[7]
[8]
Crystallographic Data of Pyrrolooxazinone (3S,3ЈR,8S)-3e:
¯
C27H27NO4 (429.5), colorless, triclinic; space group P1: a ϭ
[9]
953.01(10), b ϭ 954.07(10), c ϭ 1352.34(14) pm; α ϭ 89.970(2),
β ϭ 103.718(2), γ ϭ 111.876(2)°; V ϭ 1.1032(2) nm3, Z ϭ 2;
Dcalcd. ϭ 1.293 g cmϪ3. The data were collected from shock-cooled
crystals with a Bruker SMART-APEX diffractometer with a D8
[10]
[11]
goniometer (graphite-monochromated Mo-Kα radiation,
λ ϭ
˚
0.71073 A), equipped with a low-temperature device in ω-scan
mode at 193(2) K. A total of 15943 reflections were collected to a
maximum 2θ of 56.38°, of which 5082 were unique [R(int) ϭ
0.0224]. CCDC-194677 [(3S,3ЈR,8S)-3e] contains the supplement-
ary crystallographic data for this paper. These data can be obtained
free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or
from the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK; Fax: (internat.) ϩ 44-1223/336-
033; E-mail: deposit@ccdc.cam.ac.uk].
[12]
[13]
[14]
[15]
[16]
[17]
Acknowledgments
Generous financial support by the Deutsche Forschungsgemeinsch-
aft and the Fonds der Chemischen Industrie is appreciated. The
Received August 9, 2002
[O02464]
Eur. J. Org. Chem. 2003, 587Ϫ591
591