Studies on the diastereoselective reductive alkylation of (R)-phenylglycinol derived phthalimide: Observation of stereoelectronic effects

Article abstract of DOI:10.1016/j.tet.2004.10.109

Full details of a flexible approach to N-protected (R)-3-alkyl-isoindolin- 1-ones 13 via diastereoselective reductive-alkylation are described, with emphasis on the stereochemical outcome of the key diastereoselective reactions. Additional experiments allowed finding remarkable stereoelectronic effects on the reductive ring-opening reactions.

Full text of DOI:10.1016/j.tet.2004.10.109

Tetrahedron 61 (2005) 1335–1344
Studies on the diastereoselective reductive alkylation of
(R)-phenylglycinol derived phthalimide: observation of
stereoelectronic effects
Ming-De Chen, Ming-Zhu He, Xiang Zhou, Li-Qiang Huang, Yuan-Ping Ruan and
*
Pei-Qiang Huang
The Key Laboratory for Chemical Biology of Fujian Province, Department of Chemistry, College of Chemistry and Chemical Engineering,
Xiamen University, Xiamen, Fujian 361005, People’s Republic of China
Received 30 July 2004; revised 26 October 2004; accepted 28 October 2004
Available online 15 December 2004
Abstract—Full details of a flexible approach to N-protected (R)-3-alkyl-isoindolin-1-ones 13 via diastereoselective reductive-alkylation are
described, with emphasis on the stereochemical outcome of the key diastereoselective reactions. Additional experiments allowed finding
remarkable stereoelectronic effects on the reductive ring-opening reactions.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
3-Substituted isoindolin-1-one (2,3-dihydro-1H-isoindolin-
1-one) is a key structural feature found in many pharma-
ceutically interesting molecules and natural products. For
example, PD-172938 (S-2) was shown to have affinity for
the dopamine D4 receptor;1 pazinaclone 3 is an anxiolytic
drug candidate;2 (S)-pagoclone 4 is a licensed compound
under development for the treatment of general anxiety
disorder and panic disorder3 and chlorthalidone 5 is a
diuretic and antihypertensive drug.4 while lennoxamine,5
nuevamine, and chilenine are alkaloids isolated from
various barberry species. Moreover, (R) and (S)-3-methyl-
1H-isodindolin-1-ones have been shown to be valuable
chiral auxiliaries.6 Consequently, the chemistry of 3-alkyl-
isoindolin-1-ones has attracted much attention, and a
number of synthetic methods have been developed.1,3,5–13
Among them, the most flexible and straightforward ones are
those where the alkyl groups at the C-3 position are
introduced directly. This has been achieved either by the
reaction of 3-metalated isoindolin-1-ones with electrophiles
(Scheme 1, path a);9 by the reaction of an N-acyliminium
equivalent with nucleophiles (path b);10 by the reaction of
methyl o-lithiobenzoate to imines (path c);11 or by
organometallic reagents addition to phthalimide followed
Keywords: Isoindolin-1-one; Phenylglycinol; Reductive alkylation; Dia-
stereoselective reaction; Stereoelectronic effects.
* Corresponding author. Tel.: C86 592 218 0433; fax: C86 592 218 8054;
e-mail: pqhuang@xmu.edu.cn
Scheme 1.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.109

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M.-D. Chen et al. / Tetrahedron 61 (2005) 1335–1344
by reductive deoxygenation (path d).12,13However, few
flexible methods are available for the asymmetric synthesis
of simple 3-alkyl-isoindolin-1-ones in high enantiomeric
excess.6,8,9c,10,12d Accordingly, development of flexible
method for the asymmetric synthesis of 3-alkyl-isoindolin-
1-ones is highly desirable. In a previous communication,13a
we reported a flexible approach to N-protected optically
active 3-alkyl-isoindolin-1-ones. Herein, we provide a
complete account of our work in this area as well as the
studies undertaken to gain an insight into the stereochemical
outcome of the key reactions.
Figure 1. (3R,10R)-13g.
2. Results and discussion
16 or 17 as the key intermediates was considered. This
required the transformation of aza-carbinols 12 to tricyclic
lactams. The literature precedents show that such a
conversion is, in some cases,18 difficult to accomplish.
Indeed, when we stirred a methanolic solution of 12a under
acidic conditions, no cyclized product was isolated, we
obtained instead compound 15 (stereochemistry no deter-
mined) as the sole diastereomer in 84% yield. Gratefully, it
was found that the desired transformation could be achieved
simply by stirring, at room temperature, the aza-carbinol
12a in dichloromethane in the presence of a catalytic
amount of p-toluenesulfonic acid (Scheme 4). Thus,
tricyclic lactam 16a was formed in excellent diastereos-
electivity (Table 1, entry 1).
In recent years, we have been engaged in the development
of a synthetic methodology based on the highly regio- and
diastereo-selective reductive alkylation of (S)-malimide
(Scheme 2, 7/8).14 As an extension of this work, we
began, in 1998, to explore the similar reductive alkylation
for a flexible approach to optically active 3-alkyl-isoindolin-
1-ones (6/9).15,16 Central to our approach was the
asymmetric induction. For this purpose, (R)-phenylglyci-
nol17 was selected as the chiral auxiliary, which was
expected to display an exo-cyclic 1,3-asymmetric induction.
Noteworthy is that the acid catalyzed cyclisation of the
diastereomeric mixture of aza-carbinol 12a at either room
temperature or refluxing conditions led to the same major
diastereoisomer 16a (RZMe), which was also the same as
that obtained by an alternative method.8 This allowed us to
assume that the isolated tricyclic lactam 16a was the
thermodynamically more stable diastereoisomer. The
observed stereochemical preference during the formation
of 16 can be understood by comparing the structure of 16
with that of 17. In 16, the phenyl group is situated in the
convex face of the tricyclic system, while that of 17 is in the
concave face of the tricyclic system, which suffers from
severe steric interaction. The formation of other homolo-
gous (16c, 16g and 16f) proceeded similarly in excellent
diastereoselectivity (Table 1, entries 2, 4, 5). Mention
should also be made that in the case of 16e/17e, the
diastereoselectivity was only 81:19 (vide infra).
Scheme 2.
Thus, the requisite (R)-phthalimide derivative 11 was
prepared by heating a mixture of phthalic anhydride and
(R)-phenylglycinol under solvent free conditions.18 Treat-
ment of the phthalimide derivative (R)-11 with an excess of
methyl magnesium iodide yielded diastereomeric N,O-
acetal 12a (RZMe), which was subjected to boron
trifluoride etherate mediated triethylsilane reduction14,19 to
afford 13a as the major diastereomer. The diastereomeric
ratio of 13a/14a was 87:13 according to the chromato-
graphic separation. Extension of this procedure to other
Grignard reagents (RMgX, b: RZEt, c: n-Bu, d: i-Bu, e: n-
C7H15, f: Bn, g: Ph) led to the corresponding products 13b–
13g and 14b–14g in diastereoselectivities ranged from
71:29 to 91:9. The stereochemistries of the major diaster-
eomers 13 were determined by single-crystal X-ray crystal-
lographic analysis of compounds (3R,10R)-13c13a and
(3R,10R)-13g (Fig. 1). The stereochemistries of the major
diastereomers 13a, 13b and 13d–13f were ascertained by
comparing the spectroscopic data with those of 13c and 13g,
and were shown in the general structure 13.
The reductive ring opening of 16a under the standard
conditions (TiCl4, Et3SiH, CH2Cl2, K78 8C)8,19e,19f
afforded, as anticipated, 13a and 14a in excellent diaster-
eoselectivity (13a:14aZ95:5, Table 1, entry 1). Similarly,
the reductive ring opening of compounds 16c, 16e and 16g
afforded, respectively 13c, 13e and 13g in diastereoselec-
tivities ranged from 91:9 to 97:3. Thus, the two variations
depicted, respectively in Schemes 3 and 4 are complemen-
tary in view of chemical yield and stereoselectivity.
Since compound 18 is a commercially available cheap
product, we also explored the possibility to use it as a
starting material for the preparation of 19, which was
considered as a precursor of 16f. Thus, heating a neat
mixture of 18 and (R)-phenylglycinol led to the desired 19a
and its geometric isomer 19b in 92:8 ratio and in a combined
To improve the diastereoselectivity of the reductive alkyl-
ation, a modified approach using tricyclic lactams7j,8,19e,19f,20

M.-D. Chen et al. / Tetrahedron 61 (2005) 1335–1344
1337
Table 1. Preparation of 3-substituted isoindolin-1-ones 13 via reductive ring-opening of the tricyclic lactams 16
Entry
Starting compound (R)
Cyclic ethers (yield, %)a
Diastereo-selectivityb
Products (yield, %)a
Diastereo-selectivityb
1
2
3
4
5
12a (Me)
12c (n-Bu)
12e (n-C7H15
12g (Ph)
19 (Bn)
16aC17a (92)
16cC17c (94)
16eC17e (83)
16gC17g (86)
16f (40)d
96:4
95:5
81:19
R99:1
ca.100:0
13aC14a (90)
13cC14c (78)
13eC14e (72)c
13gC14g (88)
13fC14f (97)
95:5
97:3
91:9
96:4
92:8
)
a Isolated yield.
b Ratio determined by chromatographic separation.
c The reaction used a diastereomeric mixture of 16e and 17e (81:19) as the starting material.
d 37% of the starting material 19 was recovered (vide infra).
Scheme 3. Reagents and conditions: (i) neat, 160–170 8C, 96%; (ii) RMgX (a, RZMe, 87%; b, RZEt, 96%; c, RZn-Bu, 87%; d, RZi-Bu, 91%; e, RZn-
C7H15, 88%; f, RZBn, 96%; g, RZPh, 90%), THF, K15 8C; (iii) Et3SiH, F3B$OEt2, CH2Cl2, K78 8C (diastereoselectivity, 13:14/combined yields: a, 87:13/
92%; b, 85:15/95%; c, 84:16/98%; d, 91:9/85%; e, 77:23/61%; f, 81:19/97%; g, 71:29/90%).
Scheme 5.
Scheme 4.
yield of 87% (Scheme 5). In contrast to the N-unsubstituted
analogues,22a,22b the NOESY experiments showed that the
major geometric isomer 19a exists in (E)-form.22c,22d
Stirring a solution of the inseparable mixture of 19a and
19b in the presence of a catalytic amount of TsOH afforded
16f as the only observable diastereomer in 40% yield. In
Scheme 6.
addition, 37% of the starting material 19 was recovered.
system,19e,19f which was adopted recently by Allin et al. (B
Attempting to form 13f directly by catalytic hydrogenation of
19 under acidic conditions yielded 13f and 16f in 44:56 ratio,
and C)8 and Decroix et al.22c,22d to explain the observed
high diastereoselectivity during the formation of the
diastereomers 13a, 13g8 and related compounds.22c,22d
Namely, the predominant formation of the chelation
stabilized N-acyliminium21 conformer C ensures the facile
approach of the hydride from the less hindered b-face,
leading to 13 as the predominant diastereomer (Fig. 2). In
the case of BF3$OEt2 mediated reductive deoxygenation of
N,O-acetals 12, being unable to form a chelating
and in a disappointing combined yield of 36% (Scheme 6).
Next, we addressed the problem of the stereochemical
outcome of the key reactions. The high diastereoselectivity
for the TiCl4 mediated reductive ring-opening of the
tricyclic lactams 16/17 can be rationalized on the basis of
both allylic 1,3-interaction23 and Felkin–Anh model,24
originally proposed by Meyers and co-workers for a related

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M.-D. Chen et al. / Tetrahedron 61 (2005) 1335–1344
14e were obtained. In this case, we observed instead partial
epimerization of 16e to 17e, which gave a mixture of 16e
and 17e in ca. 1:1 ratio. These results suggested that the
yields of 13e/14e depended only on the content of the
diastereomer 16e in the starting diastereomeric mixture
(16e/17e), namely, only the diastereomer 16e was con-
vertible to 13e/14e.
These surprising phenomena can be explained in terms of
stereoelectronic effect25 in the N-acyliminium formation
step. For the diastereomer 16, the stereoelectronically-
favored pathway involves the chelation between an
oxygen lone lobe with Lewis acid from the convex face
of the ring system (Fig. 3, F). For diastereomer 17, the
stereoelectronic effect requires the chelation of the Lewis
acid with the lone pair lobe located in the concave of the
ring system (G), which is unfavored due to severe steric
interaction.
Figure 2.
intermediate like C, D and E will co-exist in the medium,
with the later being predominant. Thus the approach of
hydride from the b-face of E and from the a-face of D will
lead, respectively, to 13 or 14.
Noteworthy is that the reductive deoxygenation of O-
protected carbinol 21 led to 22 in 3:2 diastereomeric ratio
(Scheme 7).
Figure 3.
The fact that 17e can be epimerized to 16e (Table 2, entry
4), while the later could not be converted to the reductive
ring-opening product, might implicate that the epimeriza-
tion occurred during work-up procedure (Brønsted acidic
conditions), where proton being a small ‘acid’ is capable of
forming the N-acyliminium intermediate via G.
Scheme 7.
To gain an insight into the lower chemical yield observed
during the formation of 13e/14e from 16e/17e (Table 1,
entry 3), the following experiments were performed.
Starting with a 81:19 diastereomeric mixture of 16e/17e,
the reductive ring opening (TiCl4, Et3SiH) gave 13e and 14e
in 91:9 ratio and in a combined yield of 72% (Table 1, entry
3 and Table 2, entry 1). Higher diastereomeric ratio (86:14)
of the starting material (16e/17e) gave similar diastereo-
selectivity, but in higher yield (Table 2, entry 2). Pure
diastereomer 16e provided the deoxygenative products 13e
and 14e in 95:5 diastereoselectivity and in 91% yield (Table
2, entry 3). Unexpectedly, when starting with pure
diastereomer 17e, no desired deoxygenative products 13e/
3. Conclusion
In summary, we have developed a versatile and flexible
approach to N-protected (R)-3-alkyl-isoindolin-1-ones 13
via highly diastereoselective reductive-alkylation procedure
(11/13) and a complementary cyclisation-reductive ring-
opening protocol (12/16/13). This approach is versatile
in scope, since various C-3 substituents can be introduced
easily by Grignard reaction. Detailed studies on the
diastereoselective reactions allowed us to reveal that the
steric and stereoelectronic effects operated in the selective
reactions.
Table 2. Influence of diastereomeric ratio of tricyclic lactams 16e/17e on the yields and diastereomeric ratio of products 13e/14e
Entry
Starting cyclic ether (diastereomeric ratio)
Products 13e/14e (Yield, %)a/diastereomeric ratiob (13e:14e)
1
2
3
4
16e/17e (81:19)
16e/17e (86:14)
(G)-16e (100:0)
(G)-17e (0:100)
72/91:9
77/92:8
91/95:5
c
—
a Isolated yield.
b Ratio determined by chromatographic separation.
c No desired product was obtained, some epimerized product was isolated in 47% combined yield (56% conversion), the diastereomeric ratio of the final
products (G)-16e:(G)-17e was about 1:1.

M.-D. Chen et al. / Tetrahedron 61 (2005) 1335–1344
1339
4. Experimental
(1.71 mmol) were added. After stirred at K78 8C for 6 h, the
mixture was allowed to warm up. The reaction was
quenched by a saturated aqueous sodium bicarbonate and
extracted with dichloromethane (3!20 mL). The combined
extracts were dried (MgSO4) and concentrated in vacuum.
The crude was chromatographied on a column of silica gel
eluting with ethyl acetate–petroleum ether (bp0 60–90 8C)
(60:40) to give separable diastereomers (3R,1 R)-13 and
(3S,10R)-14
4.1. General
All melting points were determined on a Yanaco MP-500
micro melting point apparatus and were uncorrected.
Infrared spectra were measured with a Nicolet Avatar 360
1
FT-IR spectrometer using film KBr pellet techniques. H
NMR spectra were recorded in CDCl3 on a Varian unity C
500 spectrometer with tetramethylsilane as an internal
standard. Chemical shifts are expressed in d (ppm) units
downfield from TMS. Mass spectra were recorded on a
Finnigan MAT-GCQ (direct injection, EI). Optical rotations
were measured with Perkin–Elmer 341 automatic polari-
meter. Flash column chromatography was carried out with
silica gel (200–300 mesh). THF was distilled over sodium.
Dichloromethane was distilled over P2O5.
4.2.1. (3R) and (3S)-3-Methyl-2-[(1R)-2-hydroxy-1-
phenylethyl]-2,3-dihydro-1H-isoindol-1-one (3R,10R-
13a) and (3S,10R-14a). Diastereomeric ratio: 87:13,
combined yield: 92%. Less polar diastereomer (3R,10R)-
13a: white viscous oil. Rf: 0.41 (AcOEt/P.E.Z1:2).
[a]2D0ZC88.6 (c 2.3, CH2Cl2); [a]2D0ZC87.9 (c 1.0,
CHCl3); [Lit.8 [a]D20ZC21.3 (c 2.34, CH2Cl2). Lit.9c
[a]2D0ZC84 (c 0.9, CH2Cl2)]. IR (film) nmax: 3390, 3083,
3053, 3027, 2971, 2930, 2868, 1664, 1470, 1406, 1355,
CCDC-253349 contains the supplementary crystallographic
data for this paper (compound 13g). These data can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the Cambridge Crystallographic
Data Center, 12 Union Road, Cambridge CB2 1EZ,UK; fax:
C44 1223 336 033; or e-mail: deposit@ccdc.cam.ac.uk).
1
1214, 1066 cmK1. H NMR (500 MHz, CDCl3) d: 1.46 (d,
JZ6.8 Hz, 3H, CH3), 4.12 (dd, JZ3.4, 12.4 Hz, 1H,
CH2OH), 4.35 (q, JZ6.8 Hz, 1H, CH3CH), 4.49 (dd, JZ
8.0, 12.4 Hz, 1H, CH2OH), 4.78 (dd, JZ3.4, 8.0 Hz, 1H,
PhCHN), 7.27–7.88 (m, 9H, Ar) ppm. MS (ESI, m/z): 268
(MCHC, 25), 148 (100). HRFABMS calcd for
[C17H17O2NCH]C: 268.1338. Found: 268.1331.
4.1.1. 2-[(1R)-2-Hydroxy-1-phenylethyl]-isoindolin-1,3-
dione (11). A mixture of phthalic anhydride (437 mg,
2.95 mmol) and (R)-(K)-phenylglycinol (386 mg,
2.81 mmol) was heated to 160–170 8C and stirred for 7 h.
The reaction mixture was cooled, and then CH2Cl2 was
added to dissolve the product. The solution was dried over
anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The crude was purified by flash column chromato-
graphy on silica gel to give 11 (740 mg, yield 98%) as pale
yellow oil, which crystallized upon standing at low
temperature. Rf: 0.55 (AcOEt/P.E.Z1:2). Mp 59–60 8C.
[a]2D0ZC42.4 (c 1.3, CHCl3). IR (KBr, Pellet) nmax: 3462,
1772, 1708, 1467, 1390, 1367, 1334, 1189, 1067 cmK1. 1H
NMR (500 MHz, CDCl3) d: 2.69 (brs, 1H, OH), 4.22 (dd,
JZ5.2, 11.6 Hz, 1H, CH2OH), 4.65 (dd, JZ9.0, 11.6 Hz,
1H, CH2OH), 5.47 (dd, JZ5.2, 9.0 Hz, 1H, PhCHN), 7.23–
7.88 (m, 9H, Ar) ppm. HRFABMS calcd for [C16H13O3NC
H]C: 268.0974. Found: 268.0969.
More polar diastereomer (3S,10R)-14a: white solid. Rf: 0.30
(AcOEt/P.E.Z1:2). mp 109–111 8C. [a]2D0ZC41.8 (c 0.6,
CHCl3). IR (KBr, Pellet) nmax: 3280, 2971, 2926, 2858,
1665, 1619, 1455, 1429, 1361, 1173, 1102, 1072, 1030 cmK1
.
1H NMR (500 MHz, CDCl3) d: 1.32 (d, JZ6.7 Hz, 3H,
CH3), 4.24 (dd, JZ3.8, 11.7 Hz, 1H, CH2OH), 4.43 (dd, JZ
7.6, 11.7 Hz, 1H, CH2OH), 4.54 (q, JZ6.7 Hz, 1H,
CH3CH), 5.13 (dd, JZ3.8, 7.6 Hz, 1H, PhCHN), 7.27–
7.88 (m, 9H, Ar) ppm. MS (ESI, m/z): 268 (MCHC, 27),
148 (100). HRFABMS calcd for [C17H17O2NCH]C:
268.1338. Found: 268.1327.
4.2.2. (3R) and (3S)-3-Ethyl-2-[(1R)-2-hydroxy-1-phenyl-
ethyl]-2,3-dihydro-1H-isoindol-1-one (3R,10R-13b) and
(3S,10R-14b). Diastereomeric ratio: 85:15, combined yield:
95%. Less polar diastereomer (3R,10R)-13b: white viscous
oil. Rf: 0.50 (AcOEt/P.E.Z1:1.5). [a]2D0ZC98.0 (c 1.0,
CHCl3). IR (film) nmax: 3366, 3083, 3058, 3027, 2967, 2934,
2878, 1664, 1616, 1491, 1469, 1454, 1421, 1361, 1332,
4.2. General procedure for the reductive alkylation of
(R)-phthalimide derivative (11)
1
1301, 1066, 1030 cmK1. H NMR (500 MHz, CDCl3) d:
A solution of phthalimide 11 (0.72 mmol) in anhydrous
THF (5 mL) was cooled to K15 8C under argon atmos-
phere, a Grignard reagent (3.61 mmol) in diethyl ether was
added dropwise. After stirred at K15 8C for 1.5 h, the
reaction was quenched with a saturated aqueous solution of
ammonium chloride and extracted with dichloromethane
(3!15 mL). The combined extracts were dried (MgSO4)
and concentrated in vacuum. Column chromatography
separation (eluent: ethyl acetate–petroleum ether, 60:40)
yielded a mixture of two diastereomers (3R/S,10R)-12,
which without further separation, was used in the next step.
0.56 (t, JZ7.5 Hz, 3H, CH3), 1.92–2.00 (m, 1H, CH2),
2.02–2.11 (m, 1H, CH2), 4.11 (dd, JZ3.4, 12.5 Hz, 1H,
CH2OH), 4.41 (dd, JZ2.5, 5.0 Hz, 1H, CHCH2), 4.50 (dd,
JZ8.0, 12.5 Hz, 1H, CH2OH), 4.63 (dd, JZ3.4, 8.0 Hz, 1H,
PhCHN), 7.22–7.39 (m, 6H, Ar), 7.46–7.60 (m, 2H, Ar),
7.90 (d, JZ7.5 Hz, 1H, Ar) ppm. MS (ESI, m/z): 282 (MC
HC, 18), 585 [(2MCNa)C, 100]. HRFABMS calcd for
[C18H19O2NCH]C: 282.1494. Found: 282.1487.
More polar diastereomer (3S,10R)-14b: white solid. Rf: 0.39
(AcOEt/P.E.Z1:1.5). mp 133–134 8C. [a]2D0ZC66.9 (c
1.0, CHCl3). IR (KBr, Pellet) nmax: 3255, 3073, 3048, 2966,
A mixture of diastereomers (3R/S,10R)-12 (0.53 mmol) was
dissolved in dry dichloromethane (10 mL) under argon
atmosphere. The solution was cooled to K78 8C, to which
triethylsilane (5.33 mmol) and boron trifluoride etherate
2926, 2868, 1662, 1614, 1470, 1440, 1378, 1055, 1030 cmK1
.
1H NMR (500 MHz, CDCl3) d: 0.39 (t, JZ7.3 Hz, 3H,
CH3), 1.76–1.86 (m, 1H, CH2), 1.88–1.96 (m, 1H, CH2),
4.22 (dd, JZ4.0, 11.6 Hz, 1H, CH2OH), 4.45 (dd, JZ8.0,

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M.-D. Chen et al. / Tetrahedron 61 (2005) 1335–1344
11.6 Hz, 1H, CH2OH), 4.57 (dd, JZ4.3, 4.8 Hz, 1H,
CHCH2), 4.98 (dd, JZ4.0, 8.0 Hz, PhCHN), 7.28–7.40
(m, 4H, Ar), 7.43–7.60 (m, 4H, Ar), 7.89 (d, JZ7.5 Hz, 1H,
Ar) ppm. MS (ESI, m/z): 282 (MCHC, 15), 585 [(2MC
Na)C, 100]. HRFABMS calcd for [C18H19O2NCH]C:
282.1494. Found: 282.1486.
CH3), 0.71 (d, JZ6.3 Hz, 3H, CH3), 1.40–1.50 (m, 1H,
CH2CH), 1.60–1.80 (m, 2H, CH2CH), 4.20 (dd, JZ4.0,
11.7 Hz, 1H, CH2OH), 4.47 (dd, JZ8.0, 11.7 Hz, 1H,
CH2OH), 4.53 (dd, JZ3.8, 8.5 Hz, 1H, CHCH2), 4.95 (dd,
JZ4.0, 8.0 Hz, 1H, PhCHN), 7.21–7.57 (m, 8H, Ar), 7.86
(d, JZ7.6 Hz, 1H, Ar) ppm. MS (ESI, m/z): 310 (MCHC,
4), 641 [(2MCNa)C, 100]. HRFABMS calcd for
[C20H23O2NCH]C: 310.1807. Found: 310.1796.
4.2.3. (3R) and (3S)-3-n-Butyl-2-[(1R)-2-hydroxy-1-phe-
nylethyl]-2,3-dihydro-1H-isoindol-1-one (3R,10R-13c)
and (3S,10R-14c). Diastereomeric ratio: 86:14, combined
yield: 98%. Less polar diastereomer (3R,10R)-13c: white
solid. Rf: 0.52 (AcOEt/P.E.Z1:1). mp 130–132 8C.
[a]2D0ZC61.8 (c 1.0, CHCl3). IR (KBr, Pellet) nmax: 3361,
4.2.5. (3R) and (3S)-3-n-Heptyl-2-[(1R)-2-hydroxy-1-
phenylethyl]-2,3-dihydro-1H-isoindol-1-one (3R,10R-
13e) and (3S,10R-14e). Diastereomeric ratio: 77:203, com-
bined yield: 61%. Less polar diastereomer (3R,1 R)-13e:
colorless viscous oil. Rf: 0.46 (AcOEt/P.E.Z1:1). [a]2D0Z
C41.1 (c 0.7, CHCl3). IR (film) nmax: 3337, 3083, 3058,
3027, 2955, 2927, 2856, 1668, 1614, 1468, 1455, 1414,
1362 cmK1. 1H NMR (500 MHz, CDCl3) d: 0.60–0.78 (m,
1H, C6H12), 0.84 (t, JZ7.0 Hz, 3H, CH3), 1.09–1.32 (m,
9H, C6H12), 1.83–2.02 (m, 2H, C6H12), 4.11 (dd, JZ3.5,
12.5 Hz, 1H, CH2OH), 4.38 (dd, JZ3.0, 5.0 Hz, 1H,
CHCH2), 4.47 (dd, JZ8.0, 12.5 Hz, 1H, CH2OH), 4.65
(dd, JZ3.5, 8.0 Hz, PhCHN), 7.23–7.27 (m, 1H, Ar), 7.28–
7.36 (m, 4H, Ar), 7.49 (t, JZ7.5 Hz, 1H, Ar), 7.53–7.58 (m,
1H, Ar), 7.52–7.59 (m, 1H, Ar), 7.88 (d, JZ7.5 Hz, 1H, Ar)
ppm. MS (ESI, m/z): 352 (MCHC, 30), 725 [(2MCNa)C,
100]. HRFABMS calcd for [C23H29O2NCH]C: 352.2277.
Found: 352.2268.
1
1716, 1652, 1614, 1470, 1408 cmK1. H NMR (500 MHz,
CDCl3) d: 0.64–0.74 (m, 1H, CH2CH2CH2), 0.80 (t, JZ
7.3 Hz, 3H, CH3), 1.06–1.16 (m, 1H, CH2CH2CH2), 1.16–
1.28 (m, 2H, CH2CH2CH3), 1.86–2.01 (m, 2H, CH2CH2-
CH2), 4.11 (dd, JZ3.2, 12.4 Hz, 1H, CH2OH), 4.39 (dd, JZ
2.9, 5.2 Hz, 1H, CHCH2), 4.48 (dd, JZ8.0, 12.4 Hz, 1H,
CH2OH), 4.66 (dd, JZ3.2, 8.0 Hz, 1H, PhCHN), 7.24–7.40
(m, 6H, Ar), 7.50 (t, JZ7.5 Hz, 1H, Ar), 7.56 (dt, JZ1.1,
7.5 Hz, 1H, Ar), 7.88 (d, JZ7.5 Hz, 1H, Ar) ppm. MS (ESI,
m/z): 310 (MCHC, 100). Anal. Calcd for C20H23NO2: C
77.64, H 7.49, N 4.53. Found: C 77.34, H 7.47, N 4.53.
More polar diastereomer (3S,10R)-14c: white solid. Rf: 0.41
(AcOEt:P.E.Z1:1). mp 139–140 8C. [a]2D0ZC84.1 (c 0.5,
CHCl3). IR (KBr, Pellet) nmax: 3373, 1653, 1619, 1465,
1
1455, 1429 cmK1. H NMR (500 MHz, CDCl3) d: 0.54 (t,
More polar diastereomer (3S,10R)-14e: white solid. Rf: 0.36
(AcOEt/P.E.Z1:1). mp 91–92 8C. [a]2D0ZC93.0 (c 1.0,
CHCl3). IR (KBr, Pellet) nmax: 3357, 3083, 3063, 3030,
2985, 2954, 2925, 2869, 2854, 1665, 1618, 1470, 1454,
JZ7.1 Hz, 3H, CH3), 0.56–0.66 (m, 1H, CH2CH2CH2),
0.70–0.80 (m, 2H, CH2CH2CH2), 0.86–0.98 (m, 1H,
CH2CH2CH2), 1.64–1.78 (m, 1H, CHCH2CH2), 1.82–1.94
(m, 1H, CHCH2CH2), 4.19 (dd, JZ4.0, 11.6 Hz, 1H,
CH2OH), 4.46 (dd, JZ7.8, 11.6 Hz, 1H, CH2OH), 4.59 (t,
JZ4.0 Hz, 1H, CHCH2), 4.90 (dd, JZ4.0, 7.8 Hz, 1H,
PhCHN), 7.28–7.38 (m, 4 H, Ar), 7.45 (t, JZ7.5 Hz, 3H,
Ar), 7.53 (t, JZ7.5 Hz, 1H, Ar), 7.85 (d, JZ7.5 Hz, 1H, Ar)
ppm. MS (ESI, m/z): 310 (MCHC, 100). Anal. Calcd for
C20H23NO2: C 77.64, H 7.49, N 4.53. Found: C 77.40, H
7.56, N 4.80.
1
1432, 1360, 1219 cmK1. H NMR (500 MHz, CDCl3) d:
0.51–0.64 (m, 1H, C7H15), 0.66–0.77 (m, 2H, C7H15), 0.80
(t, JZ7.0 Hz, 3H, CH3), 0.86–0.96 (m, 3H, C7H15), 0.96–
1.07 (m, 2H, C7H15), 1.09–1.20 (m, 2H, C7H 15), 1.64–1.78
(m, 1H, C7H15), 1.80–1.92 (m, 1H, C7H15), 4.19 (dd, JZ4.1,
11.7 Hz, 1H, CH2OH), 4.45 (dd, JZ7.8, 11.7 Hz, 1H,
CH2OH), 4.60 (t, JZ4.3 Hz, CHCH2), 4.88 (dd, JZ4.1,
7.8 Hz, 1H, PhCHN), 7.27–7.38 (m, 4H, Ar), 7.44–7.48 (m,
3H, Ar), 7.53 (t, JZ7.5 Hz, 1H, Ar), 7.85 (d, JZ7.5 Hz, 1H,
Ar) ppm. MS (ESI, m/z): 352 (MCHC, 16), 725 [(2MC
Na)C, 100]. HRFABMS calcd for [C23H29O2NCH]C:
352.2277. Found: 352.2272.
4.2.4. (3R) and (3S)-3-iso-Butyl-2-[(1R)-2-hydroxy-1-
phenylethyl]-2,3-dihydro-1H-isoindol-1-one (3R,10R-
13d) and (3S,10R-14d). Diastereomeric ratio: 91:9, com-
bined yield: 85%. Less polar diastereomer (3R,10R)-13d:
white solid. Rf: 0.48 (AcOEt/P.E.Z1:1). mp 54–56 8C.
[a]2D0ZC44.7 (c 0.9, CHCl3). IR (KBr, Pellet) nmax: 3352,
3053, 2950, 2930, 2868, 1662, 1469, 1434, 1387, 1230,
4.2.6. (3R) and (3S)-3-Benzyl-2-[(1R)-2-hydroxy-1-
phenylethyl]-2,3-dihydro-1H-isoindol-1-one (3R,10R-
13f) and (3S,10R-14f). Diastereomeric ratio: 81:19, com-
bined yield: 97%. Less polar diastereomer (3R,10R)-13f:
white solid. Rf: 0.36 (AcOEt/P.E.Z1:2). mp 165–167 8C
(lit.9c mp 167 8C). [a]D20ZC54 (c 1.1, CHCl3) [Lit.9c
[a]2D0ZC66 (c 0.5, CH2Cl2)]. IR (KBr, Pellet) nmax: 3435,
3083, 3063, 3027, 2950, 2922, 2851, 1666, 1618, 1496,
1470, 1450, 1424, 1219 cmK1. 1H NMR (500 MHz, CDCl3)
d: 2.88 (dd, JZ7.9, 13.9 Hz, 1H, PhCH2CH), 3.38 (dd, JZ
4.4, 13.9 Hz, 1H, PhCH2CH), 4.10 (dd, JZ3.3, 12.6 Hz, 1H,
CH2OH), 4.46 (dd, JZ8.0, 12.6 Hz, 1H, CH2OH), 4.55 (dd,
JZ4.4, 7.9 Hz, CHBn), 4.87 (dd, JZ3.3, 8.0 Hz, 1H,
PhCHN), 6.82–6.90 (m, 1H, Ar), 6.90–7.00 (m, 2H, Ar),
7.14–7.45 (m, 10H, Ar), 7.81 (d, JZ7.6 Hz, 1H, Ar) ppm.
MS (ESI, m/z): 344 (MCHC, 30), 709 [(2MCNa)C, 100].
Anal Calcd for C23H21O2N: C 80.44, H 6.16, N 4.08. Found:
C 80.16, H 6.22, N 4.12.
1
1153 cmK1. H NMR (500 MHz, CDCl3) d: 0.69 (d, JZ
6.3 Hz, 3H, CH3), 0.92 (d, JZ6.3 Hz, 3H, CH3), 1.62–1.78
(m, 2H, CH2CH), 1.80–1.92 (m, 1H, CH2CH), 4.13 (dd, JZ
2.9, 11.7 Hz, 1H, CH2OH), 4.33 (dd, JZ3.1, 7.0 Hz, 1H,
CHCH2), 4.48 (dd, JZ7.8, 11.7 Hz, 1H, CH2OH), 4.72 (dd,
JZ2.9, 7.8 Hz, 1H, PhCHN), 7.22–7.60 (m, 8H, Ar), 7.88
(m, 1H, Ar) ppm. MS (ESI, m/z): 310 (MCHC, 4), 641
[(2MCNa)C, 100]. HRFABMS calcd for [C20H23O2NC
H]C: 310.1807. Found: 310.1804.
More polar diastereomer (3S,10R)-14d: white solid. Rf: 0.31
(AcOEt/P.E.Z1:1). mp 154–155 8C. [a]2D0ZC93.9 (c 0.9,
CHCl3). IR (KBr, Pellet) nmax: 3356, 3088, 3027, 2979,
2949, 2925, 2868, 2848, 1662, 1613, 1470, 1465, 1436 cmK1
.
1H NMR (500 MHz, CDCl3) d: 0.70 (d, JZ6.3 Hz, 3H,

M.-D. Chen et al. / Tetrahedron 61 (2005) 1335–1344
1341
More polar diastereomer (3S,10R)-14f: white solid. Rf: 0.21
(AcOEt/P.E.Z1:2). mp 134–135 8C. [a]2D0ZC111.5 (c 1.1,
CHCl3). IR (KBr, Pellet) nmax: 3435, 3083, 3063, 2958,
2922, 2851, 1668, 1616, 1496, 1460, 1429, 1255 cmK1. 1H
NMR (500 MHz, CDCl3) d: 2.43 (dd, JZ10.4, 13.5 Hz, 1H,
PhCH2CH), 3.44 (dd, JZ4.5, 13.5 Hz, 1H, PhCH2CH), 4.31
(dd, JZ4.2, 11.6 Hz, 1H, CH2OH), 4.58 (dd, JZ7.9,
11.6 Hz, 1H, CH2OH), 4.76 (dd, JZ4.5, 10.4 Hz, CHBn),
5.18 (dd, JZ4.2, 7.9 Hz, 1H, PhCHN), 6.49 (d, JZ7.6 Hz,
1H, Ar), 6.93–7.03 (m, 2H, Ar), 7.24–7.59 (m, 10H, Ar),
7.89 (d, JZ7.6 Hz, 1H, Ar) ppm. MS (ESI, m/z): 344 (MC
HC, 14), 709 [(2MCNa)C, 93], 1052 [(3MCNa)C, 100].
HRFABMS calcd for [C23H21O2NCH]C: 344.1641.
Found: 344.1640.
HRFABMS calcd for [C18H19O3NCNa]C: 320.1259.
Found: 320.1265.
4.3. Representative procedure for the preparation of
(3R,9bS)-9b-alkyl-3-phenyl-2,3,5,9b-tetrahydro[1,3]
oxazolo[2,3-a]-isoindol-5-one (16)
A solution of 12a (80 mg, 0.28 mmol) and p-toluenesulfonic
acid monohydrate (8 mg, 0.05 mmol) in dichloromethane
(15 mL) was stirred at room temperature for 22 h. To the
mixture was added K2CO3. The resulting mixture was
extracted with dichloromethane (3!15 mL). The combined
extracts were washed with brine and dried over anhydrous
Na2SO4 then concentrated in vacuum. The crude was
purified by flash column chromatography on silica gel to
give 16a (69 mg) and 17a (3 mg) (diastereomeric ratioZ
96:4) in a combined yield of 92%.
4.2.7. (3R) and (3S)-3-Phenyl-2-[(1R)-2-hydroxy-1-
phenylethyl]-2,3-dihydro-1H-isoindol-1-one (3R,10R-
13g) and (3S,10R-14g). Diastereomeric ratio: 71:29,
combined yield: 90%. Less polar diastereomer (3R,10R)-
13g: white soild. Rf: 0.52 (AcOEt/P.E.Z1:1). mp 134–
135 8C (Lit.8 mp 115–116 8C). [a]D20ZK75 (c 2.6, CH2Cl2);
[a]D20ZK69 (c 1.0, CHCl3) [Lit.8 [a]2D0ZC84.8 (c 3.28,
CH2Cl2) for antipode]. IR (KBr, Pellet) nmax: 3459, 3088,
3063, 3027, 2935, 2873, 1711, 1666, 1614, 1465, 1395,
1358, 1245 cmK1. 1H NMR (500 MHz, CDCl3) d: 4.06 (dd,
JZ8.0, 15.0 Hz, 1H, CH2OH), 4.30–4.38 (m, 2H, CH2OH
CPhCHN), 5.21 (s, 1H, PhCH), 7.00–7.58 (m, 13H, Ar),
7.92–8.00 (m, 1H, Ar) ppm. MS (ESI, m/z): 330 (MCHC,
10), 681 [(2MCNa)C, 100]. Anal Calcd for C22H19O2N: C
80.22, H 5.81, N 4.25. Found: C 80.04, H 5.93, N 4.23.
4.3.1. (3R,9bS)-9b-Methyl-3-phenyl-2,3,5,9b-tetrahydro
[1,3]oxazolo[2,3-a]-isoindol-5-one (3R,9bS-16a). Dia-
stereomeric ratio: 96:4, combined yield: 92%. Faster eluting
(major) diastereomer 16a: white crystal. Rf: 0.66 (AcOEt-
P.E.Z1:2). mp 128–130 8C. [Lit.8 119–122 8C]. [a]D20Z
K112.1 (c 0.9, CHCl3) {Lit.8 [a]DZK123.7 (c 3.07,
CH2Cl2)}. IR (KBr, Pellet) nmax: 2983, 2884, 1710, 1612,
1494, 1465, 1350, 1319, 1224, 1165, 1119 cmK1. 1H NMR
(500 MHz, CDCl3) d: 1.75 (s, 3H, CH3), 4.38 (dd, JZ7.3,
8.6 Hz, 1H, CH2O), 4.83 (dd, JZ7.6, 8.6 Hz, 1H, CH2O),
5.32 (dd, JZ7.3, 7.6 Hz, 1H, CHCH2), 7.28–7.42 (m, 5H,
Ar), 7.54–7.67 (m, 4H, Ar) ppm. MS (ESI, m/z): 266 (MC
HC, 100). HRFABMS calcd for [C17H15NO2CH]C:
266.1181. Found: 266.1177.
More polar diastereomer (3S,10R)-14g: white solid. Rf: 0.38
(AcOEt/P.E.Z1:1). mp 172–173 8C. [a]2D0ZC48.6 (c 0.9,
CHCl3). IR (KBr, Pellet) nmax: 3412, 3088, 3058, 3032,
2926, 2879, 2848, 1666, 1612, 1495, 1468, 1429, 1356,
4.3.2. (3R,9bS)-9b-n-Butyl-3-phenyl-2,3,5,9b-tetrahydro
[1,3]oxazolo[2,3-a]-isoindol-5-one (3R,9bS-16c). Dia-
stereomeric ratio: 95:5, combined yield: 94%. Faster eluting
(major) diastereomer 16c: white viscous oil. Rf: 0.75
(AcOEt/P.E.Z1:3). [a]2D0ZK111.6 (c 0.9, CHCl3). IR
(film) nmax: 3060, 3030, 2956, 2872, 1718, 1465, 1357,
1
1222 cmK1. H NMR (500 MHz, CDCl3) d: 3.87 (dd, JZ
5.6, 11.2 Hz, 1H, CH2OH), 3.95 (dd, JZ8.6, 11.2 Hz, 1H,
CH2OH), 5.21 (s, 1H, PhCH), 5.40 (dd, JZ5.6, 8.6 Hz,
PhCHN), 7.05–7.50 (m, 13H, Ar), 7.92–7.98 (m, 1H, Ar)
ppm. MS (ESI, m/z): 330 (MCHC, 13), 681 [(2MCNa)C,
59], 1010 [(3MCNa)C, 100]. Anal. Calcd for C22H19O2N:
C 80.22, H 5.81, N 4.25. Found: C 80.34, H 6.02, N 4.30.
1
1320, 1300, 1156 cmK1. H NMR (500 MHz, CDCl3) d:
0.84 (t, JZ7.3 Hz, 3H, CH3), 0.91–1.20 (m, 4H, CH2-
CH2CH2CH3), 1.94–2.08 (m, 2H, CH2CH2CH2CH3), 4.41
(dd, JZ7.1, 8.6 Hz, 1H, CH2O), 4.82 (dd, JZ7.4, 8.6 Hz,
1H, CH2O), 5.33 (dd, JZ7.1, 7.4 Hz, 1H, CHCH2), 7.20–
7.40 (m, 5H, Ar), 7.50–7.90 (m, 4H, Ar) ppm. HRFABMS
calcd for [C20H21O2NCH]C: 308.1651. Found: 308.1649.
4.2.8. (3R) or (3S)-3-Methoxy-3-methyl-2-[(1R)-2-
hydroxy-1-phenylethyl]-2,3-dihydro-1H-isoindol-1-one
(3R or 3S,10R-15). To a methanolic solution of 12a (45 mg,
0.16 mmol) (5 mL) was added 1 M HCl solution until pH 1.
The resulting solution was stirred at room temperature for
4 h. The mixture was neutralized with a saturated solution of
K2CO3. The resulting mixture was extracted with dichloro-
methane. The combined extracts were washed with brine
and dried over anhydrous Na2SO4 then concentrated in
vacuum. The crude was purified by flash column chromato-
graphy on silica gel to give diastereomerically pure 15
(38 mg, yield 84%) as white crystal. mp 95–97 8C.
4.3.3. (3R,9bS)-9b-n-Heptyl-3-phenyl-2,3,5,9b-tetra-
hydro[1,3]oxazolo[2,3-a]-isoindol-5-one (3R,9bS-16e).
Diastereomeric ratio: 81:19, combined yield: 92%. Faster
eluting (major) diastereomer 16e: white viscous oil. Rf: 0.72
(AcOEt/P.E.Z1:2). [a]2D0ZK109.4 (c 1.1, CHCl3). IR
(film) nmax: 3057, 2925, 2854, 1651, 1540, 1458, 1360,
1
1268, 1122, 1025 cmK1. H NMR (500 MHz, CDCl3) d:
0.82 (t, JZ7.2 Hz, 3H, CH3), 1.11–1.34 (m, 10H, CH2
(C5H10)CH3), 1.90–2.11 (m, 2H, CH2(C5H10)CH3), 4.41
(dd, JZ7.1, 8.6 Hz, 1H, CH2O), 4.81 (dd, JZ8.0, 8.6 Hz,
1H, CH2O), 5.27 (dd, JZ7.1, 8.0 Hz, 1H, CHCH2), 7.28–
7.42 (m, 5H, Ar), 7.45–7.67 (m, 3H, Ar), 7.85 (m, 1H, Ar)
ppm. HRFABMS calcd for [C23H27NO2CH]C: 350.2120.
Found: 350.2110.
[a]2D0ZC61.5 (c 0.89, CH2Cl2). IR (KBr, Pellet) nmax
3357, 3063, 2981, 2930, 2904, 2858, 2822, 1669, 1603,
1496, 1468, 1421, 1363, 1158, 1136, 1081, 1062, 1021 cmK1
:
.
1H NMR (500 MHz, CDCl3) d: 1.75 (s, 3H, CCH3), 3.47 (s,
3H, OCH3), 4.37 (dd, JZ7.2, 8.6 Hz, 1H, CH2OH), 4.84
(dd, JZ8.0, 8.6 Hz, 1H, CH2OH), 5.32 (dd, JZ7.2, 8.0 Hz,
1H, PhCHN), 7.19–7.43 (m, 5H, Ar), 7.46–7.67 (m, 3H, Ar),
7.82 (m, 1H, Ar) ppm. MS (ESI, m/z): 298 (MCHC, 100).
Slower eluting (minor) diastereomer 17e: white viscous oil.

1342
M.-D. Chen et al. / Tetrahedron 61 (2005) 1335–1344
Rf 0.44 (AcOEt/P.E.Z1:2). [a]2D0ZC62.2 (c 0.8, CHCl3).
IR (film) nmax: 3062, 3031, 2953, 2927, 2856, 1708, 1467,
1387, 1371, 1332, 1074 cmK1. 1H NMR (500 MHz, CDCl3)
d: 0.84 (t, JZ7.2 Hz, 3H, CH3), 1.18–1.38 (m, 10H,
CH2(C5H10)CH3), 1.90–2.12 (m, 2H, CH2(C5H10)CH3),
4.41 (dd, JZ7.1, 8.5 Hz, 1H, CH2O), 4.81 (dd, JZ7.8,
8.5 Hz, 1H, CH2O), 5.34 (dd, JZ7.1, 7.8 Hz, 1H, CHCH2),
7.28–7.42 (m, 5H, Ar), 7.45–7.67 (m, 3H, Ar), 7.85 (m, 1H,
Ar) ppm. HRFABMS calcd for [C23H27NO2CH]C:
350.2115. Found: 350.2115.
2,3-dihydro-1H-isoindol-1-one (13g and 14g). Diastereo-
meric ratioZ96:4 (combined yield: 88%).
4.4.6. (E) and (Z)-Benzylidene-2-[(1R)-2-hydroxy-1-
phenylethyl]-2,3-dihydro-1H-isoindol-1-one (19). A mix-
ture of 2-benzylidenephthalide 18 (437 mg, 2.95 mmol) and
(R)-(K)-phenylglycinol (151 mg, 1.10 mmol) was heated to
160–170 8C and stirred for 23 h. The reaction mixture was
cooled, to which CH2Cl2 was added. The solution was dried
over anhydrous Na2SO4, filtered and concentrated under
reduced pressure. The crude was purified by flash column
chromatography on silica gel to give a geometric mixture of
19 (326 mg, 19a:19bZ92:8, combined yield 87%) as a
white solid. Rf: 0.43 (AcOEt/P.E.Z1:7). mp 182–184 8C.
[a]2D0ZC96.8 (c 1.1, CH2Cl2). IR (KBr, Pellet) nmax: 3433,
3058, 3027, 2930, 2879, 1679, 1640, 1491, 1470, 1445,
1401, 1312, 1265, 1178 cmK1. 1H NMR (500 MHz, CDCl3)
data of E-19 d: 4.33 (dd, JZ3.6, 12.3 Hz, 1H, CH2OH), 4.62
(dd, JZ7.8, 12.3 Hz, 1H, CH2OH), 5.35 (dd, JZ3.6,
7.8 Hz, 1H, PhCHN), 6.50 (s, 1H, PhCH]C), 7.10–7.50
(m, 13H, Ar), 7.90–7.96 (m, 1H, Ar) ppm. MS (ESI, m/z):
342 (MCHC, 4), 705 [(2MCNa)C, 100]. HRFABMS calcd
for [C23H19O2NCH] C: 342.1485. Found: 342.1494.
4.3.4. (3R,9bS)-3,9b-Diphenyl-2,3,5,9b-tetrahydro[1,3]
oxazolo[2,3-a]-isoindol-5-one (3R,9bS-16g). Only one
diastereomer 16g was isolated, yield 86%. White solid. Rf:
0.67 (AcOEt/P.E.Z1:1). mp 100–102 8C {Lit.8 (3S,9bR)-
16g: 104–106 8C}. [a]2D0ZK240.5 (c 1.8, CH2Cl2) {Lit.8
[a]DZC282.0 (c 1.9, CH2Cl2)}. IR (KBr, Pellet) nmax
:
3062, 3021, 2924, 2878, 1720, 1608, 1465, 1447, 1337,
1308, 1237 cmK1. 1H NMR (500 MHz, CDCl3) d: 4.20 (dd,
JZ8.3, 8.8 Hz, 1H, CH2O), 4.92 (dd, JZ8.4, 8.8 Hz, 1H,
CH2O), 5.28 (dd, JZ8.3, 8.4 Hz, 1H, CHCH2), 7.15–7.42
(m, 9H, Ar), 7.50–7.70 (m, 4H, Ar), 7.82–7.88 (m, 1H, Ar)
ppm. HRFABMS Calcd for [C22H22O2NCH]C: 328.1338.
Found: 328.1328.
4.4.7. (3R,9bS)-9b-Benzyl-3-phenyl-2,3,5,9b-tetrahydro
[1,3]oxazolo[2,3-a]-isoindol-5-one (3R,9bS-16f). A solu-
tion of 19 (238 mg, 0.70 mmol) and p-toluenesulfonic acid
monohydrate (23 mg, 0.12 mmol) in dichloromethane
(5 mL) was stirred at rt for 22 h. To the mixture was
added NaHCO3. After filtration and concentration, the crude
was purified by flash column chromatography on silica gel
eluting with ethyl acetate–petroleum ether to give 16f
(98 mg, yield: 40%). Rf: 0.52 (AcOEt/P.E.Z1:3). [a]2D0Z
K130.9 (c 0.9, CH2Cl2). IR (KBr, Pellet) nmax: 3078, 3063,
3022, 2996, 2945, 2925, 2879, 2848, 1726, 1614, 1598,
1496, 1465, 1450, 1359, 1301, 1224, 1137 cmK1. 1H NMR
(500 MHz, CDCl3) d: 3.03 (d, JZ14.1 Hz, 1H, PhCH2),
3.51 (d, JZ14.1 Hz, 1H, PhCH2), 4.67 (dd, JZ6.9, 8.8 Hz,
1H, CH2OH), 4.92 (dd, JZ8.2, 8.8 Hz, 1H, CH2OH), 5.37
(dd, JZ6.9, 8.2 Hz, 1H, PhCHN), 6.96–7.52 (m, 13H, Ar),
7.76 (m, 1H, Ar) ppm. MS (ESI, m/z): 705 [(2MCNa)C,
100]. HRFABMS calcd for [C23H19O2NCH]C: 342.1485.
Found: 342.1491.
4.4. Representative procedure for the reductive ring-
opening of (3R,9bS)-9b-alkyl-3-phenyl-2,3,5,9b-
tetrahydro[1,3]oxazolo[2,3-a]-isoindol-5-one (16)
To a cooled (K78 8C) solution of less polar diastereomer 16
(716 mg, 2.7 mmol) in dry dichloromethane (15 mL) was
added dropwise titanium tetrachloride (0.44 mL,
4.05 mmol) followed by triethylsilane (0.64 mL,
4.05 mmol) under nitrogen atmosphere. After stirred at
K78 8C for 1 h, the mixture was allowed to react at room
temperature and stirred until the completion of the reaction.
The reaction was quenched by saturated aqueous sodium
bicarbonate at 0 8C and extracted with dichloromethane
(3!15 mL). The combined extracts were washed with brine
and dried over anhydrous Na2SO4 then concentrated in
vacuum. The crude was purified by flash column chromato-
graphy on silica gel eluting with ethyl acetate–petroleum
ether (1:2) to give (3R,10R)-13a and its diastereomer 14a in
95:5 ratio (combined yield: 90%, 649 mg).
4.4.8. 2-[(1R)-2-Benzyloxy-1-phenylethy]-isoindolin-1,3-
dione (20). To a solution of 11 (112 mg, 0.42 mmol) in
diethyl ether was added Ag2O (286 mg, 1.23 mmol) and a
solution of benzyl bromide (0.3 mL, 2.52 mmol) in diethyl
ether. The suspension was stirred at room temperature for 16
days in dark. After filtration through Celite and concen-
tration in vacuo, the crude was flash chromatographed to
afford 20 (90 mg, 60%) as a white viscous oil. [a]2D0ZC2.7
(c 0.93, CHCl3). IR (film) nmax: 3058, 3027, 2925, 2858,
1772, 1712, 1496, 1470, 1455, 1387, 1368, 1132, 1107,
4.4.1. (3R)-3-Methyl-2-[(1R)-2-hydroxy-1-phenylethyl]-
2,3-dihydro-1H-isoindol-1-one (13a and 14a). Diastereo-
meric ratioZ95:5 (combined yield: 90%).
4.4.2. (3R)-3-n-Butyl-2-[(1R)-2-hydroxy-1-phenylethyl]-
2,3-dihydro-1H-isoindol-1-one (13c and 14c). Diastereo-
meric ratioZ97:3 (combined yield: 78%).
1
1020 cmK1. H NMR (500 MHz, CDCl3) d: 4.03 (dd, JZ
4.4.3. (3R)-3-n-Heptyl-2-[(1R)-2-hydroxy-1-phenyl-
ethyl]-2,3-dihydro-1H-isoindol-1-one (13e and 14e).
Diastereomeric ratioZ91:9 (combined yield: 72%).
5.5, 9.9 Hz, 1H, PhCHN), 4.58 (s, 2H, PhCH2O), 4.63 (dd,
JZ9.9, 10.2 Hz, 1H, CH2OBn), 5.62 (dd, JZ5.5, 10.2 Hz,
1H, CH2OBn), 7.22–7.88 (m, 14H, Ar) ppm. MS (ESI, m/z):
358 (MCHC, 16), 376 (MCNaC, 100). HRFABMS calcd
for [C23H19O3NCH]C: 358.1434. Found: 358.1439.
4.4.4. (3R)-3-Benzyl-2-[(1R)-2-hydroxy-1-phenylethyl]-
2,3-dihydro-1H-isoindol-1-one (13f and 14f). Diastereo-
meric ratioZ92:8 (combined yield: 97%).
4.4.9. (3R/S,10R)-3-Methyl-2-[2-benzyloxy-1-phenyl-
ethyl]-2,3-dihydro-1H-isoindolin-1-one (3R/S,10R-22). To
4.4.5. (3R)-3-Phenyl-2-[(1R)-2-hydroxy-1-phenylethyl]-

M.-D. Chen et al. / Tetrahedron 61 (2005) 1335–1344
1343
2. Wada, T.; Fukuda, N. Psychopharmacology 1991, 103,
314–322.
a cooled (K10 8C) solution of 20 (189 mg, 0.53 mmol) in
anhydrous tetrahydrofuran (4 mL) was added dropwise a
solution of MeMgI (2.0 mmol/mL, 5.3 mL, 2.64 mmol) in
diethyl ether under nitrogen atmosphere. After stirred at the
same temperature for 4 h, the reaction was quenched with
saturated aqueous solution of ammonium chloride (6 mL) and
extracted with dichloromethane (3!30 mL). The combined
extracts were dried with anhydrous Na2SO4 and concentrated
in vacuum. Filtration with a short pad of column eluting with
ethyl acetate–petroleum ether (1:1) yielded a mixture of two
diastereomers (3R,10R)-21a and (3R,10S)-21b (203 mg, yield:
100%).
3. Stuk, T. L.; Assink, B. K.; Bates, R. C. Jr.; Erdman, D. T.;
Fedij, V.; Jennings, S. M.; Lassig, J. A.; Smith, R. J.; Smith,
T. L. Org. Proc. Res. Dev. 2003, 7, 851–855.
4. (a) Labios, M.; Romero, M.; Gabriel, F.; Fuster, E.; Tatay, E.;
Valles, R. Rev. Clin. Esp. 1990, 187, 158–161. (b) Batista,
Mc.; Costa, Ch.; Dalbosco, Is. Hypertension 1997, 29,
184–184.
5. (a) Fuchs, J. R.; Funk, R. L. Org. Lett. 2001, 3, 3923–3925.
(b) Yoda, H.; Nakahama, A.; Koketsu, T.; Takabe, K.
Tetrahedron Lett. 2002, 43, 4667–4669. (c) Koseki, Y.;
Katsura, S.; Kusano, S.; Sakata, H.; Sato, H.; Monzene, Y.;
Nagasaka, T. Heterocycles 2003, 59, 527–540.
To a cooled (K78 8C) solution of diastereomer mixture
21a,b (117 mg, 0.31 mmol) in dry dichloromethane
(10 mL) was added dropwise triethylsilane (0.49 mL,
3.13 mmol) and boron trifluoride etherate (0.12 mL,
0.94 mmol) under nitrogen atmosphere. After stirred at
K78 8C for 6 h, the mixture was allowed to react at room
temperature and stirred overnight. The reaction was
quenched by saturated aqueous sodium bicarbonate and
extracted with dichloromethane. The combined extracts
were washed with brine and dried over anhydrous Na2SO4,
then concentrated under vacuum. The crude was purified by
flash column chromatography on silica gel eluting with
ethyl 0 acetate–petroleum ether (1:2) to give unseparable
(3R,1 R)-22 and (3S,10R)-22 (111 mg, yield 99%) as a white
viscous oil, which is a 3:2 diastereomeric mixture as
indicated by 1H NMR analysis. Rf: 0.52 (AcOEt/P.E.Z
1:1.5). IR (film) nmax: 3462, 3350, 3061, 3030, 2973, 2928,
2867, 1683, 1616, 1496, 1360, 1218, 1101 cmK1. 1H NMR
(500 MHz, CDCl3), major diastereomer d: 1.38 (d, JZ
6.8 Hz, 3H, CH3), 4.12 (dd, JZ6.8, 10.0 Hz, 1H, NCHCH2),
4.42 (dd, JZ8.0, 10.0 Hz, 1H, NCHCH2), 4.48 (q, JZ
6.8 Hz, 1H, CHCH3), 4.62 (s, 2H, OCH2Ph), 5.33 (dd, JZ
6.8, 8.0 Hz, 1H, NPhCH), 7.20–7.80 (m, 14H, Ar) ppm.
Minor diastereomer d: 1.26 (d, JZ6.6 Hz, 3H, CH3), 4.23
(dd, JZ5.7, 10.2 Hz, 1H, NCHCH2), 4.48 (dd, JZ8.0,
10.2 Hz, 1H, NCHCH2), 4.61 (s, 2H, OCH2Ph), 4.64 (q, JZ
6.6 Hz, 1H, CHCH3), 5.42 (dd, JZ5.7, 8.0 Hz, 1H,
NPhCH), 7.20–7.80 (m, 14H, Ar) ppm. MS (ESI, m/z):
250 (79), 358 (MCHC, 85), 148 (100). HRFABMS calcd
for [C24H23O2NCH]C: 358.1807. Found: 358.1804.
6. (a) Oppolzer, W.; Wills, M.; Kelly, M. J.; Signer, M.; Blagg, J.
Tetrahedron Lett. 1990, 31, 5015–5018. (b) Murphy, J. P.;
Nieuwenhuyzen, M.; Reynolds, K.; Sarma, P. K. S.; Steven-
son, P. J. Tetrahedron Lett. 1995, 36, 9533–9536. (c)
McAlonan, H.; Murphy, J. P.; Nieuwenhuyzen, M.; Reynolds,
K.; Sarma, P. K. S.; Stevenson, P. J.; Thompson, N. J. Chem.
Soc., Perkin Trans. 1 2002, 69–79.
7. (a) Hunter, R.; Richards, P. Org. Biol. Chem. 2003, 1,
2348–2356. (b) Kundu, N. G.; Khan, M. W. Tetrahedron 2000,
56, 4777–4792. (c) Epsztajn, J.; Jozwiak, A.; Koluda, P.;
Sadokierska, I.; Wilkowska, I. D. Tetrahedron 2000, 56,
4837–4844. (d) Hoarau, C.; Couture, A.; Deniau, E.; Grand-
claudon, P. Synthesis 2000, 655–660. (e) Deniau, E.; Enders,
D. Tetrahedron Lett. 2000, 41, 2347–2350. (f) Yoda, H.;
Matsuda, K.; Nomura, H.; Takabe, K. Tetrahedron Lett. 2000,
41, 1775–1779. (g) Koseki, Y.; Kusano, S.; Sakata, H.;
Nagasaka, T. Tetrahedron Lett. 1999, 40, 2169–2172. (h)
Luzzio, F. A.; Zacherl, D. P. Tetrahedron Lett. 1998, 39,
2285–2288. (i) Gai, X.; Grigg, R.; Khamnaen, T.; Rajvir-
oongit, S.; Sridharan, V.; Zhang, L.; Collard, S.; Keep, A.
Tetrahedron Lett. 2003, 44, 7441–7443. (j) Bahajaj, A. A.;
Hoore, M. H.; Vernon, J. M. Tetrahedron 2004, 60, 1235–1246
and references cited therein.
8. Allin, S. M.; Northfield, C. J.; Page, M. I.; Slawin, A. M. Z.
J. Chem. Soc., Perkin Trans. 1 2000, 1715–1721 and
references cited therein.
9. (a) Couture, A.; Deniau, E.; Jonescu, D.; Grandclaudon, P.
Tetrahedron Lett. 1998, 39, 2319–2320. (b) Deniau, E.;
´
Enders, D. Tetrahedron 2001, 57, 2581–2588. (c) Perard-
´
Viret, J.; Prange, T.; Tomas, A.; Royer, J. Tetrahedron 2002,
58, 5103–5108.
10. Ukaji, Y.; Tsukamoto, K.; Nasada, Y.; Shimizu, M.; Fujisawa,
T. Chem. Lett. 1993, 221–224.
Acknowledgements
11. Campbell, J. B.; Dedinas, R. F.; Trumbower-Walsh, S. A.
J. Org. Chem. 1996, 61, 6205–6211.
The authors are grateful to the National Science Fund for
Distinguished Young Investigators, the NNSF of China
(20272048. 203900505) and the Ministry of Education (Key
Project 104201) for financial support. We also thank the
State Key Laboratory for Physical Chemistry of Solid
Surface for providing the X-Ray diffraction facilities and for
Mr. Z. B. Wei for data collection.
12. (a) Deniau, E.; Enders, D. Tetrahedron Lett. 2000, 41,
2347–2350. (b) Enders, D.; Braig, V.; Raabe, G. Can.
J. Chem. 2001, 79, 1528–1535. (c) Wang, E. C.; Chen,
H. F.; Feng, P. K.; Lin, Y. L.; Hsu, M. K. Tetrahedron Lett.
2002, 43, 9163–9165. (d) Deniau, E.; Enders, D.; Couture, A.;
Grandclaudon, P. Tetrahedron: Asymmetry 2003, 14,
2253–2258.
13. (a) Chen, M. D.; He, M. Z.; Huang, L. Q.; Ruan, Y. P.; Huang,
P.-Q. Chin. J. Chem. 2002, 20, 1149–1153. (b) Chen, M.-D.;
Zhou, X.; He, M.-Z.; Ruan, Y.-P.; Huang, P.-Q. Tetrahedron
2004, 60, 1651–1657. (c) Ruan, Y. P.; Chen, M. D.; He, M. Z.;
Zhou, X.; Huang, P.-Q. Synth. Commun. 2004, 34, 853–861.
14. (a) Huang, P.-Q.; Wang, S. L.; Ye, J. L.; Ruan, Y. P.; Huang,
Y. Q.; Zheng, H.; Gao, J. Tetrahedron 1998, 54, 12547–12560.
References and notes
1. Belliotti, T. R.; Brink, W. A.; Kesten, S. R. Bioorg. Med.
Chem. Lett. 1998, 8, 1499–1502.

1344
M.-D. Chen et al. / Tetrahedron 61 (2005) 1335–1344
(b) Huang, P.-Q.; Chen, Q. F.; Chen, C. L.; Zhang, H.-K.
235–242. (d) Rolf, D.; Gray, G. R. J. Am. Chem. Soc. 1982,
104, 3539–3541. (e) Burgess, L. E.; Meyers, A. I. J. Am. Chem.
Soc. 1991, 113, 9858–9859. (f) Burgess, L. E.; Meyers, A. I.
J. Org. Chem. 1992, 57, 1656–1662. (g) Yoda, H.; Kitayama,
H.; Yamada, W.; Katagiri, T.; Takabe, K. Tetrahedron:
Asymmetry 1993, 4, 1451–1454.
Tetrahedron: Asymmetry 1999, 10, 3827–3832. (c) He, B.-Y.;
Wu, T. J.; Yu, X.-Y.; Huang, P.-Q. Tetrahedron: Asymmetry
2003, 14, 2101–2108 and references therein.
15. This work was taken in part from the Master Thesis of Li-
Qiang Huang, Xiamen University, China, 2000 and that of
Ming-Zhu He, Xiamen University, China, 2003.
20. (a) Meyers, A. I.; Lefker, B. A.; Sowin, T. J.; Westrum, L. J.
J. Org. Chem. 1989, 54, 4243–4246. (b) Vega-Perez, J. M.;
Vega, M.; Blanco, E.; Iglesias-Guerra, F. Tetrahedron:
Asymmetry 2001, 12, 135–147.
16. Huang, L.-Q.; Chen, M.-D.; Huang, P.-Q. In The 8th National
Symposium on Organic Synthesis, November, Xiamen, 1999.
Abstract book (J. Xiamen Univ., Nat. Sci. Ed. supplementary
issue) p 94 (in Chinese).
21. For recent reviews on the N-acyliminium chemistry, see: (a)
Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56,
3817–3856. (b) Maryanoff, B. E.; Zhang, H. C.; Cohen, J. H.;
Turchi, I. J.; Maryanoff, C. A. Chem. Rev. 2004, 104,
1431–1628.
17. For reviews on the use of (R)-phenylglycinol as a chiral
auxiliary, see: (a) Husson, H. P.; Royer J. Chem. Soc. Rev.
1999, 28, 383–394. (b) Groaning, M. D.; Meyers, A. I.
Tetrahedron 2000, 56, 9843–9873.
18. (a) Kumar, G. B.; Shah, A. C.; Pilati, T. Tetrahedron Lett.
1997, 38, 3297–3300. (b) Mishra, S. K.; Vani, T. R.; Rao, R. B.
Indian J. Chem. 1993, 32B, 641–644. (c) Sikoraiova, J.;
Marchalin, S.; Daich, A.; Decroix, B. Tetrahedron Lett. 2002,
43, 4747–4751. (d) Sikoraiova, J.; Chihab-Eddine, A.;
Marchalin, S.; Daich, A. J. Heterocyclic Chem. 2002, 39,
383–390. (e) Nair, D. S.; Pauranik, V.; Shah, A. C. J. Chem.
Res. (S) 2003, 772–774.
22. (a) Kato, Y.; Takemoto, M.; Achiwa, K. Chem. Pharm. Bull.
1993, 41, 2003–2006. (b) Kato, Y.; Takemoto, M.; Achiwa, K.
Chem. Pharm. Bull. 1993, 47, 529–535. (c) Chihab-Eddine,
A.; Daich, A.; Jilale, A.; Decroix, B. Heterocycles 2002, 58,
449–456. (d) Chihab-Eddine, A.; Daich, A.; Jilale, A.;
Decroix, B. Heterocycles 1999, 51, 2907–2914.
23. Hoffmann, R. W. Chem. Rev. 1989, 89, 1841–1860 and
references cited therein.
24. Ahn, N. T. Top. Curr. Chem. 1980, 88, 145.
19. (a) Kursanov, D. N.; Parnes, Z. N.; Loim, N. M. Synthesis
1974, 633–651. (b) Nagai, Y. Org. Prep. Proc. Int. 1980, 12,
13–48. (c) Hart, D. J.; Yang, T.-K. J. Org. Chem. 1985, 50,
25. Deslongchamps, P. Stereoelectronic Effects in Organic
Chemistry; Pergamon: New York, 1983.