Br?nsted acid catalyzed asymmetric reduction of 2- and 2,9-substituted 1,10-phenanthrolines

Article abstract of DOI:10.1055/s-2008-1032103

Several 2- and 2,9-substituted 1,10-phenanthrolines are reduced asymmetrically for the first time using a Hantzsch dihydropyridine in the presence of BINOL-derived phosphoric acid catalysts. The best results are obtained with phenanthrolines bearing unbranched or nitrogen-containing alkyl groups in the 2- or 2,9-positions, which afford chiral octahydrophenanthrolines in a range of yields (40-88%) and good to excellent levels of enantiomeric purity (78-99% ee). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032103

720
LETTER
Brønsted Acid Catalyzed Asymmetric Reduction of 2- and 2,9-Substituted
1,10-Phenanthrolines
Brønsted
Acid
C
a
o
talyzed Asy
s
mmetric
R
t
educti
a
n
M
throlines etallinos,* Fred B. Barrett, Shufen Xu
Department of Chemistry, Brock University, 500 Glenridge Ave., St. Catharines, ON L2S 3A1, Canada
Fax +1(905)6829020; E-mail: cmetallinos@brocku.ca
Received 6 December 2007
EtO2C
CO2Et
Abstract: Several 2- and 2,9-substituted 1,10-phenanthrolines are
reduced asymmetrically for the first time using a Hantzsch dihydro-
N
pyridine in the presence of BINOL-derived phosphoric acid cata-
lysts. The best results are obtained with phenanthrolines bearing
unbranched or nitrogen-containing alkyl groups in the 2- or 2,9-po-
sitions, which afford chiral octahydrophenanthrolines in a range of
yields (40-88%) and good to excellent levels of enantiomeric puri-
ty (78-99% ee).
H
3
Ar
N
R
N
H
R
1
O
O
O
P
2 84–99% ee
OH
Key words: reduction, phenanthroline, Brønsted acid, enantiose-
lective, organocatalysis
Ar
4a Ar = 2-naphthyl
4b Ar = 9-phenanthryl
Pioneering work by Akiyama1, Terada,2 and others3,4 has
demonstrated the power of BINOL derivatives of phos-
phoric acid in Brønsted acid catalyzed asymmetric syn-
thesis. Among the growing applications of this
methodology is a report by Rueping5 that 2-substituted
quinolines can be reduced to tetrahydroquinolines (1 → 2,
Scheme 1) in high enantiomeric purity with Hantzsch di-
hydropyridine 3 in the presence of catalysts 4a or 4b.6 Al-
though several other excellent methods have been
developed for the asymmetric reduction of quinolines7
and pyridines,8 they involve less convenient high-pressure
conditions (e.g. 1 → 5, Scheme 1), or they are not amena-
ble to the reduction of substituted 1,10-phenanthrolines
that are of interest to our group.9,10
[Ir(COD)Cl]2, (S)-SEGPHOS
ClCO2Bn, Li2CO3, THF
H2 (41 bar), r.t.
N
R
CO2Bn
5 88–90% ee
Scheme 1 Brønsted acid and iridium-catalyzed asymmetric reduc-
tion of quinolines.
3 (6 equiv),
4a or 4b (2 mol%),
N
Me
N
Me
PhH, 60 °C
In this communication we report our findings regarding
the ability of Rueping’s conditions to effect the asymmet-
ric reduction of 2- and 2,9-substituted phenanthrolines,
which have not been previously investigated as substrates
in this process. To begin our study, catalysts 4a, 4b11 and
variously 2- and 2,9-substituted 1,10-phenanthrolines10,12
were prepared according to established procedures. Sub-
jection of 2-methyl-1,10-phenanthroline (6a, Scheme 2)
to asymmetric reduction under Rueping’s conditions5 [4a
or 4b (2 mol%), 3 (6 equiv), 60 °C, PhH) gave octahydro-
phenanthroline 7a in 54% yield, regardless which catalyst
was used. The enantiomeric purity of 7a was determined
by chiral HPLC analysis of the corresponding urea adduct
8a to be 78% and 83% ee for catalysts 4a and 4b, respec-
tively.13 This result was encouraging considering that pre-
vious achiral reduction of 6a (NaBH3CN, AcOH-MeOH)
afforded 7a in similar yield (57%),10 and that the substrate
posed a greater challenge to the catalysts over similar
H
N
NH
6a
7a 54%
triphosgene (1.1 equiv)
Me
N
O
Et3N (3 equiv), THF
(85%)
N
78% ee with 4a
83% ee with 4b
8a
Scheme 2 Brønsted acid catalyzed asymmetric reduction of 2-
methyl-1,10-phenanthroline.
quinolines owing to the generation of a basic tetrahydro-
phenanthroline intermediate.10
The absolute stereochemistry of product 7a was deter-
mined by comparing the optical rotations of the urea de-
rivatives 8a with the known rotation of the S-enantiomer
of 8a {[a]D20 +21.0 at 68% ee}.14 In both cases, the mea-
sured optical rotations were negative {[a]D -23.6 and
[a]D -26.9 for the products of catalysts 4a and 4b, re-
SYNLETT 2008, No. 5, pp 0720–0724
x
x.
x
x.
2
0
0
8
20
Advanced online publication: 26.02.2008
DOI: 10.1055/s-2008-1032103; Art ID: S09607ST
© Georg Thieme Verlag Stuttgart · New York
20

LETTER
Brønsted Acid Catalyzed Asymmetric Reduction of 1,10-Phenanthrolines
721
Table 1 Brønsted Acid Catalyzed Asymmetric Reduction of 2- and 2,9-Substituted 1,10-Phenanthrolines
3 (6 equiv),
4a or 4b (2 mol%),
N
R1
N
R1
PhH, 60 °C
H
N
NH
7a–h
6a–h
R2
R2
Entry
Substrate
R1
R2
Catalyst
4a
Yield of 7 (%)a
ee of 7 (%)b
1
2
6a
6a
6b
6b
6c
6c
6d
6d
6e
6f
Me
H
H
H
H
H
H
H
H
H
Me
54
78
83
56
78
32
40
82
95
84
99
99
25g
Me
4b
54
3
n-Bu
n-Bu
i-Pr
4a
52
4
4b
54
5
4a
40
6
i-Pr
4b
28
7
Ph
4ac
4bc
4b
21
8
Ph
11
9
CH2NHAc
Me
40d
10
11
12
4be
4be
4be
72 (3:2 ent/meso)
88f (3:2 ent/meso)
81g
6g
6h
n-Bu
Ph
n-Bu
Ph
a Unoptimized yields of column-purified material.
b Measured by HPLC analysis of the corresponding ureas (8a-g) on Chiralcel OD-H or Chiralpak AS-H columns.
c Catalyst loading was 10 mol%; 9-phenyl-1,2,3,4-tetrahydro-1,10-phenanthroline (9d) was also isolated (22% and 30% for catalysts 4a and
4b, respectively).
d 9-(N-Acetyl)methyl-1,2,3,4-tetrahydro-1,10-phenanthroline (9e) was also isolated (40%).
e Catalyst loading was 5 mol%.
f 2,9-Dibutyl-1,2,3,4-tetrahydro-1,10-phenanthroline (9g) was also isolated (8%).
g Only 2,9-diphenyl-1,2,3,4-tetrahydro-1,10-phenanthroline (9h) was isolated; ee measured for the unprotected amine.
N
Ph
N
CH2NHAc
N
n-Bu
N
Ph
H
H
NH
NH
N
N
9d
9e
9g
9h
n-Bu
Ph
spectively) indicating that the R-enantiomer of 7a was phenanthroline (6c). In this case, the corresponding oc-
formed preferentially during reduction. Notably, the rela- tahydrophenanthroline 7c was obtained in 40% yield and
tive stereochemistry of (R)-7a is identical to that reported 32% ee using catalyst 4a (entry 5), versus 28% yield and
by Rueping and coworkers for 2-substituted 40% ee with catalyst 4b (entry 6). Enantioselectivity was
tetrahydroquinolines5 (2, Scheme 1). Based on these re- much higher for reduction of 2-phenyl-1,10-phenanthro-
sults, it is expected that other octahydrophenanthrolines line (6d) which furnished 7d in 82% ee and 95% ee with
prepared by this route will have the same relative stere- 4a and 4b, respectively (entries 7 and 8), albeit at the ex-
ochemistry as (R)-7a.
pense of low yields (21% and 11%). It is worth noting that
significant quantities of 9-phenyl-1,2,3,4-tetrahydro-
1,10-phenanthroline (9d) were isolated in each of these
experiments (22% and 30%, respectively) indicating a
limitation of catalysts 4a and 4b in facilitating reduction
of the prochiral phenyl-substituted ring of 9d. Increasing
the catalyst loading (20 mol% of 4b) and temperature
(100 °C, PhMe) did not improve the yield of 7d. Given
that only small amounts of tetrahydrophenanthrolines
(<5%) were isolated after reduction of 6a-c, it is difficult
to identify a general trend of structure versus yield and
The results from reduction of phenanthrolines 6a-h with
catalysts 4a or 4b are summarized in Table 1. Reduction
of 2-n-butyl-1,10-phenanthroline (6b) provided octahy-
drophenanthroline 7b in similar yield as 7a, but in compa-
rable enantiomeric purity only when the 9-phenanthryl
catalyst 4b (78% ee, entry 4) was employed. The less ster-
ically encumbered 2-naphthyl catalyst 4a gave 7b in low-
er 56% ee (entry 3). A pronounced drop in both yield and
enantioselectivity was observed with 2-isopropyl-1,10-
Synlett 2008, No. 5, 720–724 © Thieme Stuttgart · New York

722
C. Metallinos et al.
LETTER
enantioselectivity for substrates 6a-d. While it is clear A preliminary experiment has shown that 10 catalyzes the
that the bulkier starting materials 6c,d gave substantially reduction of 2-phenylquinoline5 12 [10 (5 mol%), 3 (2.4
reduced yields of octahydrophenanthrolines, only the equiv), PhH, 60 °C, 24 h] to the tetrahydroquinoline 13 in
alkylated compounds 6a-c showed a discernible trend of good yield (71%), but low enantioselectivity (9% ee). Al-
decreasing ee versus increasing steric bulk.
though the selectivity is low, this result obviates the need
for the installation of electron-withdrawing groups to en-
sure activity of phosphorodiamidic acid catalysts with a
phenylenediamine core, and may simplify the preparation
of bulkier chiral catalysts in this series.
To gain more insight into the effect that substituents have
on asymmetric reduction of phenanthrolines, four addi-
tional substrates were evaluated. The first of these, 2-(N-
acetyl)methyl-1,10-phenanthroline (6e) was prepared by
acetylation of 2-aminomethyl-1,10-phenanthroline.15 To
a first approximation, it was expected that 6e would be re-
duced with comparable enantioselectivity as 6a or 6b if
steric effects were primarily responsible for the trend ob-
served in reduction of 6a-c. Indeed, 4b-catalyzed reduc-
tion of 6e provided 7e in 40% yield and 84% ee (entry 9),
in addition to the tetrahydro byproduct 9e (40% yield).
Thus, 6e fits into the general trend observed for the 2-
alkyl derivatives 6a-c.
10 (5 mol%),
3 (2.4 equiv),
PhH, 60 °C, 24 h
N
Ph
N
Ph
(71%)
H
12
13 9% ee
In contrast, 4b-catalyzed reduction of the 2,9-diphenyl-
1,10-phenanthroline (6h, entry 12) provided only the tet-
rahydro reduction product 9h in 81% yield, mirroring the
sluggish reactivity observed for 6d. Unlike 7d, which was
formed in high 95% ee, 9h was produced in surprisingly
low 25% ee. These results imply that steric bulk may ex-
plain the recalcitrance to reduction of the second prochiral
pyridyl rings of 9d and 9h, but a secondary interaction
such as p-stacking may be responsible for the high enan-
tiomeric purity observed for 7d. A similar interaction may
be absent during reduction of 6h as a result of excessive
steric demand of the substrate.
N
N
N
O
N
Ts
Ts
P
P
n-Bu
n-Bu
O
OH
OH
10
11
Scheme 3 Reduction of 2-phenylquinoline catalyzed by phosphoro-
diamidic acid 10.
To summarize, we have reported the first asymmetric re-
duction of 2- and 2,9-substituted 1,10-phenanthrolines by
adapting Rueping’s conditions for the reduction of quino-
lines. The method is useful for reducing phenanthrolines
bearing unbranched or nitrogen-containing alkyl groups
in the 2- or 2,9-positions (6a,b,e-g), providing chiral oc-
tahydrophenanthrolines in a range of yields (40-88%)
and good to excellent levels of enantiomeric purity (78-
84% ee for 7a,b,e; 99% ee for 7f,g). The method does not
extend easily to substrates with larger substituents (i-Pr,
Ph), which are plagued by low enantioselectivity (6c), low
yields (6d), or both (6h). Nevertheless, it has been demon-
strated that catalysts 4a and 4b are capable of catalyzing
the sequential asymmetric reduction of two pyridyl rings
within the same molecule. For this reason, it may be worth
investigating the scope of this procedure in additional
prochiral bispyridyl systems.
Significantly better results were obtained with 2,9-di-
alkyl-1,10-phenanthrolines. Asymmetric reduction of 6f
(R1 = R2 = Me, entry 10) with 4b gave octahydrophenan-
throline 7f in 72% yield as a 3:2 mixture of ent and meso
stereoisomers. Chiral HPLC analysis of the corresponding
urea adducts returned a value of 99% ee for ent-7f. Simi-
larly, reduction of 2,9-di-n-butyl-1,10-phenanthroline
(6g, entry 11) gave 7g, again as a 3:2 mixture of ent and
meso isomers.16 The isomeric diamines were easily sepa-
rated by column chromatography as urea adducts, and
chiral HPLC analysis returned a value of 99% ee for (-)-
(R,R)-8g.16 The higher enantioselectivities observed with
7f,g over 7a,b may be a consequence of the formation of
meso stereoisomers that consume the minor enantiomer
during reduction of the second pyridyl ring.
Acknowledgment
The ease of chromatographic separation of (R,R)-8g from
meso-8g allowed us to explore the utility of ent-7g as a
catalyst precursor. Hydrolysis of (R,R)-8g to (R,R)-7g fol-
lowed by cyclization with phosphorus oxychloride and
aqueous workup provided the enantiomerically pure C2-
symmetric phosphorodiamidic acid 10 (Scheme 3). Previ-
We thank NSERC Canada for support of our research program. F.
B. B. thanks Brock University’s Career Services for an Experience
Works Award, which made his contribution possible. Special
thanks go to Mr. Tim Jones and Mr. Razvan Simionescu for assi-
stance with MS and NMR determinations, respectively.
ous studies by Terada17 have shown that the achiral bis-N- References and Notes
tosylated phosphorodiamidic acid 11 was capable of cata-
(1) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem.
lyzing the direct Mannich reaction N-acyl imines with
1,3-dicarbonyl compounds. Catalyst 10 thus serves to test
the importance of an electron-withdrawing group in en-
hancing the acidity, and hence activity, of such catalysts.
Int. Ed. 2004, 43, 1566.
(2) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126,
5356.
Synlett 2008, No. 5, 720–724 © Thieme Stuttgart · New York

LETTER
Brønsted Acid Catalyzed Asymmetric Reduction of 1,10-Phenanthrolines
723
(3) (a) Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc.
2006, 128, 1086. (b) Yamanaka, M.; Itoh, J.; Fuchibe, K.;
Akiyama, T. J. Am. Chem. Soc. 2006, 128, 6756.
(c) Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem.
Soc. 2004, 126, 11804. (d) Storer, R. I.; Carrera, D. E.; Ni,
Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 84.
(e) Wanner, M. J.; van der Haas, R. N. S.; de Cuba, K. R.;
van Maarseveen, J. H.; Hiemstra, H. Angew. Chem. Int. Ed.
2007, 46, 7485.
(4) Reviews: (a) Connon, S. J. Angew. Chem. Int. Ed. 2006, 45,
3909. (b) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv. Synth.
Catal. 2006, 348, 999. (c) Taylor, M. S.; Jacobsen, E. N.
Angew. Chem. Int. Ed. 2006, 45, 1520.
(m, 3 H), 1.50–1.40 (m, 1 H), 1.20 (d, 3 H, J = 6.3 Hz). 13
NMR (75.5 MHz, acetone-d6): d = 132.7, 132.1, 119.0,
C
118.5, 118.2, 117.9, 47.5, 42.2, 30.4, 27.0, 26.7, 22.4, 22.0.
A solution of 7a (24 mg, 0.12 mmol), triphosgene (39 mg,
0.13 mmol), and Et3N (33 mL, 0.24 mmol) in dry THF (2
mL) was stirred at r.t. for 16 h. Then, H2O (4 mL) was added
and the THF was removed under reduced pressure. The
remaining aqueous mixture was extracted with CH2Cl2 (3 ×
4 mL), washed with H2O (5 mL) and brine (5 mL), dried over
anhyd Na2SO4, filtered, and concentrated in vacuo. Column
chromatography (silica gel, 3:1 CH2Cl2-Et2O, Rf = 0.35)
gave (-)-(R)-8a (23 mg, 85%).
Compound (-)-(R)-8a: colorless solid; [a]D20 -26.9 (c 1.08,
CHCl3); lit.14 [a]D20 +21.0 (c 4.37, CHCl3) at 68% ee. CSP
HPLC analysis [Chiralpak AS-H; eluent: hexanes–i-PrOH
(80:20), 1.0 mL/min] determined 90.5:9.5 er, 81% ee
[tR(minor) = 10.63 min, tR(major) = 11.73 min]. 1H NMR
(300 MHz, CDCl3): d = 6.76 (s, 2 H), 4.45–4.37 (m, 1 H),
3.89–3.78 (m, 2 H), 2.92–2.72 (m, 4 H), 2.12 (quin, 2 H,
J = 5.7 Hz), 2.07–1.98 (m, 2 H), 1.40 (d, 3 H, J = 6.3 Hz).
13C NMR (75.5 MHz, CDCl3): d = 152.7, 125.2, 124.7, 118.3
(2 C), 116.8, 116.7, 45.3, 38.9, 29.3, 23.4, 22.8, 20.2, 19.2.
(14) Metallinos, C.; Dudding, T.; Zaifman, J.; Chaytor, J. L.;
Taylor, N. J. J. Org. Chem. 2007, 72, 957.
(5) Rueping, M.; Antonchick, A. P.; Theissmann, T. Angew.
Chem. Int. Ed. 2006, 45, 3683.
(6) For other applications of this methodology, see:
(a) Rueping, M.; Antonchick, A. P. Angew. Chem. Int. Ed.
2007, 46, 4562. (b) Rueping, M.; Antonchick, A. P.;
Theissmann, T. Angew. Chem. Int. Ed. 2006, 45, 6751.
(c) Rueping, M.; Sugiono, E.; Schoepke, F. R. Synlett 2007,
1441. (d) Rueping, M.; Antonchick, A. P. Angew. Chem. Int.
Ed. 2007, 46, 2097.
(7) Lu, S.-M.; Wang, Y.-Q.; Han, X.-W.; Zhou, Y.-G. Angew.
Chem. Int. Ed. 2006, 45, 2263.
(8) (a) Glorius, F.; Spielkamp, N.; Holle, S.; Goddard, R.;
Lehmann, C. W. Angew. Chem. Int. Ed. 2004, 43, 2850.
(b) Legault, C. Y.; Charette, A. B. J. Am. Chem. Soc. 2005,
127, 8966.
(15) 2-Aminomethyl-1,10-phenanthroline was prepared
according to a literature procedure: Engbersen, J. F. J.;
Koudijs, A.; Joosten, M. H. A.; van der Plas, H. C.
J. Heterocycl. Chem. 1986, 23, 989.
(9) Metallinos, C.; Barrett, F. B.; Chaytor, J. L.; Heska, M. E. A.
Org. Lett. 2004, 6, 3641.
(16) Reduction of 6g with Catalyst 4b and Enantiomeric
Assay
(10) Metallinos, C.; Barrett, F. B.; Wang, Y.; Xu, S.; Taylor, N.
J. Tetrahedron 2006, 62, 11145.
A flame-dried screw-cap vial with a stir bar was charged
with 6g (58 mg, 0.20 mmol), dihydropyridine 3 (304 mg,
1.20 mmol, 6 equiv), catalyst 4b (7 mg, 0.01 mmol, 5 mol%)
and dry benzene (4 mL). The vial was flushed with argon,
capped, and the mixture was heated with stirring at 60 °C for
24 h. The reaction mixture was transferred to a round-
bottomed flask and the solvent was removed under reduced
pressure. Column chromatography [silica gel, hexanes-
EtOAc (97:3)] gave, sequentially, 2,9-dibutyl-1,2,3,4-
tetrahydro-1,10-phenanthroline (9g, 5 mg, 8%, Rf = 0.39)
and octahydrophenanthroline 7g (53 mg, 88%, Rf = 0.19) as
a 3:2 mixture of ent and meso isomers.
(11) For preparation of 2,2¢-dimethoxy-1,1¢-binaphthyl, see:
(a) Lingenfelter, D. S.; Helgeson, R. C.; Cram, D. J. J. Org.
Chem. 1981, 46, 393. For preparation of 3,3¢-diaryl BINOL,
see: (b) Simonsen, K. B.; Gothelf, K. V.; Jørgensen, K. A. J.
Org. Chem. 1998, 63, 7536. (c) Wipf, P.; Jung, J.-K. J. Org.
Chem. 2000, 65, 6319. For preparation of 3,3¢-diaryl-1,1¢-
binaphthyl-2,2¢-diyl hydrogen phosphates, see: (d) Jacques,
J.; Fouquey, C. Org. Synth. 1989, 67, 1.
(12) (a) Dietrich-Buchecker, C. O.; Marnot, P. A.; Sauvage, J.-P.
Tetrahedron Lett. 1982, 23, 5291. (b) Dietrich-Buchecker,
C.; Colasson, B.; Fujita, M.; Hori, A.; Geum, N.; Sakamoto,
S.; Yamaguchi, K.; Sauvage, J.-P. J. Am. Chem. Soc. 2003,
125, 5717.
Compound 9g: pale yellow oil. 1H NMR (300 MHz, acetone-
d6): d = 7.98 (d, 1 H, J = 8.4 Hz), 7.26 (d, 1 H, J = 8.4 Hz),
7.06 (d, 1 H, J = 8.1 Hz), 6.93 (d, 1 H, J = 8.1 Hz), 6.10 (b,
1 H), 3.49–3.39 (m, 1 H), 2.93–2.82 (m, 5 H), 1.82–1.75 (m,
2 H), 1.68–1.43 (m, 9 H), 0.95 (t, 6 H, J = 7.5 Hz).
Compound ent/meso-7g:10 pale yellow oil. 1H NMR (300
MHz, acetone-d6): d = 6.26 (s, 1 H), 6.25 (s, 1 H), 3.59 (b, 1
H), 3.50 (b, 1 H), 3.20–3.05 (m, 2 H), 2.71–2.60 (m, 4 H),
1.93–1.88 (m, 2 H), 1.56–1.32 (m, 14 H), 0.92 (t, 6 H, J = 6.9
Hz). 13C NMR (75.5 MHz, acetone-d6): d = 133.2, 133.1,
119.9, 119.8 118.9, 118.7, 52.8, 52.7, 37.1, 37.0, 28.9, 28.8,
28.6, 27.2, 23.5, 14.3.
(13) Reduction of 6a with Catalyst 4b and Enantiomeric
Assay
A flame-dried screw-cap vial with a stir bar was charged
with 6a (50 mg, 0.26 mmol), dihydropyridine 3 (390 mg,
1.54 mmol, 6 equiv), catalyst 4b (3.6 mg, 0.005 mmol, 2
mol%) and dry benzene (5 mL). The vial was flushed with
argon, capped, and the mixture was heated with stirring at
60 °C for 24 h. The reaction mixture was transferred to a
round-bottomed flask and the solvent was removed under
reduced pressure. Absolute EtOH (5 mL) and KOH (2
pellets, ca. 200 mg) were added, and the mixture was heated
to reflux for 45 min. Then, H2O (5 mL) was added and EtOH
was removed under reduced pressure. The remaining
aqueous mixture was extracted with CH2Cl2 (3 × 5 mL) and
the combined organic extract was dried over anhyd Na2SO4,
filtered, and concentrated in vacuo. Column chromatog-
raphy (silica gel, 83:15:2 hexanes-EtOAc-Et3N; Rf = 0.28)
gave (+)-(R)-7a (29 mg, 54%).
A solution of ent/meso-7g (51 mg, 0.17 mmol), triphosgene
(55 mg, 0.19 mmol), and Et3N (47 mL, 0.34 mmoL) in dry
THF (4 mL) was stirred at r.t. for 16 h. Then, H2O (4 mL)
was added and the THF was removed under reduced
pressure. The remaining aqueous mixture was extracted with
CH2Cl2 (3 × 4 mL), washed with H2O (5 mL) and brine (5
mL), dried over anhyd Na2SO4, filtered, and concentrated in
vacuo. Column chromatography [silica gel, hexane-EtOAc
(90:10)] gave, sequentially, (-)-(R,R)-8g (30 mg, 55%, Rf =
0.16), and meso-8g (20 mg, 36%, Rf = 0.08).
Compound (+)-(R)-7a: viscous colorless oil; [a]D20 +53.5 (c
1.27, acetone); lit.14 [a]D20 -41.4 (c 1.70, acetone) at 68% ee.
1H NMR (300 MHz, acetone-d6): d = 6.23 (ABq, 2 H), 3.62
(b, 2 H), 3.30-3.22 (m, 3 H), 2.79–2.54 (m, 4 H), 1.89–1.74
Compound (-)-(R,R)-8g: clear colorless oil; [a]D20 -102 (c
1.50, CHCl3). CSP HPLC analysis [Chiralcel OD-H; eluent:
hexanes-i-PrOH (98:2), 0.5 mL/min] determined 99.5:0.5
Synlett 2008, No. 5, 720–724 © Thieme Stuttgart · New York

724
C. Metallinos et al.
LETTER
13C NMR (75.5 MHz, CDCl3): d = 152.8, 124.8, 118.0,
116.5, 49.5, 33.0, 28.1, 26.2, 22.6, 20.0, 14.0. MS (EI): m/z
(%) = 326 (71) [M+], 269 (100). HRMS (EI): m/z calcd for
C21H30N2O: 326.2358; found: 326.2356.
er, 99% ee [tR(minor) = 11.09 min, tR(major) = 11.81 min].
IR (KBr, neat): 2954, 2931, 2858, 1703 cm–1. 1H NMR (300
MHz, CDCl3): d = 6.72 (s, 2 H), 4.31–4.28 (m, 2 H), 2.83–
2.75 (m, 4 H), 2.19–2.13 (m, 2 H), 2.00–1.95 (m, 2 H), 1.83–
1.78 (m, 4 H), 1.53–1.32 (m, 10 H), 0.91 (t, 6 H, J = 6.9 Hz).
(17) Terada, M.; Sorimachi, K.; Uraguchi, D. Synlett 2006, 133.
Synlett 2008, No. 5, 720–724 © Thieme Stuttgart · New York

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