Rhodium-catalyzed ring-opening reactions of N-Boc-azabenzonor-bornadiene with chiral amine nucleophiles derived from amino acids

Article abstract of DOI:10.1055/s-2008-1078596

The rhodium-catalyzed ring-opening of azabenzonor-bornadienes with chiral amino nucleophiles derived from amino acids such as (S)-proline and (R)-phenylglycine is reported. The desired products were obtained as a mixture of diastereomers, which could be easily separated in high yield. Enantiomerically pure ring-fused nitrogen heterocycles and 1,2-diamines were also obtained by further transformation of the ring-opened products. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078596

PAPER
2467
Rhodium-Catalyzed Ring-Opening Reactions of N-Boc-azabenzonor-
bornadiene with Chiral Amine Nucleophiles Derived from Amino Acids
R
hodium-Catalyze
o
d
Ring-Open
n
ing of
N
-B
o
g
c-azabenzon
-
Hiene wan Cho, Nai-Wen Tseng, Hisanori Senboku, Mark Lautens*
Davenport Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON, M5S 3H6, Canada
Fax +1(416)9468185; E-mail: mlautens@chem.utoronto.ca
Received 17 December 2007
the chemoselectivity between two nucleophilic centers
using substrates bearing amino and hydroxy functional
groups.
Abstract: The rhodium-catalyzed ring-opening of azabenzonor-
bornadienes with chiral amino nucleophiles derived from amino
acids such as (S)-proline and (R)-phenylglycine is reported. The de-
sired products were obtained as a mixture of diastereomers, which
could be easily separated in high yield. Enantiomerically pure ring-
fused nitrogen heterocycles and 1,2-diamines were also obtained by
further transformation of the ring-opened products.
Herein we report an expedient method to generate enan-
tiomerically pure 1,2-diamine scaffolds by the catalytic
ring-opening of N-Boc-azabenzonorbornadiene (1) using
chiral amino nucleophiles easily derived from amino
acids such as (S)-proline and (R)-phenylglycine in the
presence of a readily available achiral rhodium-phosphine
catalyst. We also demonstrate the preparation of optically
active ring-fused nitrogen heterocyclic compounds and
1,2-diaminotetrahydronaphthalene20 using this methodol-
ogy.
Key words: rhodium, ring-opening, diamines, heterocycles, diaste-
reoselective
Chiral vicinal 1,2-diamines and their derivatives have ex-
tensively been used as chiral auxiliaries and chiral ligands
for a variety of asymmetric reactions in the field of organ-
ic synthesis.1–5 In addition, 1,2-diamine scaffolds have
also been recognized as privileged structures in many bi-
ologically active compounds.6–12 For example, trans-1,2-
diaminotetrahydronaphthalenes such as DuP 747 and its
analogues have been identified as potent k-opioid receptor
agonists.9 Due to the versatile nature of the 1,2-diamine
scaffold, considerable attention has been paid to their
preparation and development of useful synthetic methods
giving high diastereoselectivity and enantioselectivity.13
Initial studies were conducted using proline derivatives in
order to probe the influence of the a-stereocenter, which
exists on its pyrrolidine ring in the catalytic asymmetric
ring-opening reaction. Initial conditions with catalytic
amounts of Et3NHI (20 mol%) were chosen based on our
previous reports15 of the catalytic ring opening of 1 with
amine nucleophiles. We found that the addition of the
salts could prevent catalyst poisoning, thereby leading to
dramatically lower catalyst loading for the efficient ring
opening of 1 and decrease equivalents of amine nucleo-
phile as well. It is noteworthy that proper selection of the
ammonium halide salt for a given reaction is crucial since
a dramatic halide effect on the reaction yield and enan-
tioselectivity was noted.14,15,17,21
Hydrogen iodide of (S)-proline methyl ester (2a)22 was
prepared and used as the amine nucleophile to optimize
the ring-opening reaction of 1. Preliminary screening us-
ing 2.0 equivalents of 2a and 3.0 equivalents of i-Pr2NEt
in the presence of 1.0 mol% of [Rh(cod)Cl]2 and 3.0
mol% of dppf gave the corresponding ring-opening prod-
ucts 3a and 3a¢ in 42% yield in 1:1.5 ratio (Table 1, entry
1). Increasing the catalytic loading from 1.0 mol% to 2.5
mol% (entry 2) as well as increasing the amount of nu-
cleophile and base improved the yield of the products 3a
and 3a¢ in 73% yield (entry 3).
We have previously reported the catalytic asymmetric
ring-opening reactions of azabenzonorbornadienes with
various aliphatic and aromatic amines to give optically ac-
tive 1,2-diamines with high yield and excellent enantio-
selectivity.14,15 We have subsequently applied this
methodology towards the total synthesis of an analgesic
compound14b and the preparation of new chiral ligands.15
In previous reports,14a,16,17a high levels of asymmetric in-
duction have been observed, however, the use of large
amounts of a tediously prepared chiral ligand14a,15,18 was
required.19 To date, a high yielding, diastereoselective
ring-opening of N-Boc-azabenzonorbornadiene (1) with
amine nucleophiles containing an a-functional group still
remains unexplored. We envisioned that by using our pre-
viously well-established procedures for ring-opening re-
actions, the use of chiral amine nucleophiles would
provide a rapid diastereoselective route to trans-1,2-di-
aminotetrahydronaphthalene derivatives. We also sought
to determine if the presence of functionality in the a-posi-
tion in the amino nucleophile would have any influence
on the diastereoselectivity. In addition, we investigated
Each of the diastereomers 3a and 3a¢ could easily be iso-
lated as the enantiomerically pure product (>99% ee) by
conventional column chromatography. The absolute con-
figuration of 3a was determined to be S,R,R by X-ray
crystal structure analysis of the cyclic derivative 4
(Figure 1),23 which could be obtained in good yield by a
TFA-mediated Boc-deprotection and subsequent intramo-
lecular cyclization (Scheme 1).
SYNTHESIS 2008, No. 15, pp 2467–2475
x
x.
x
x
.
2
0
0
8
Advanced online publication: 17.07.2008
DOI: 10.1055/s-2008-1078596; Art ID: Z29007SS
© Georg Thieme Verlag Stuttgart · New York

2468
Y.-H. Cho et al.
PAPER
Table 1 Catalytic Ring-Opening Reaction of N-Boc-azabenzonorbornadiene (1) with (S)-Proline Derivatives (2)a
Boc
X
N
X
N
[Rh(cod)Cl]2, dppf
HN
NH
+
Boc
Et3NHI, i-Pr2NEt
3
1,4-dioxane, 110 °C
1
+
X = CO2Me (2a)
CH2OMe (2b)
CH2OH (2c)
X
N
HN
Boc
3'
Entry
Nucleophile (equiv)
2a·HI (2.0)
2a·HI (2.0)
2a·HI (3.0)
2b (3.0)
i-Pr2NEt (equiv)
Time (h)
Product X
CO2Me
CO2Me
CO2Me
CH2OMe
CH2OH
CH2OH
drb 3:3¢
1.0:1.5
1.0:1.5
1.0:1.5
1.0:1.0
1.7:1.0
1.7:1.0
Yield (%)c
1d
2
3.0
3.0
5.0
5.0
6.0
10.0
72
72
72
36
72
72
42
54
73
88
54
70
3
4
5
2c (3.0)
6
2c (5.0)
a The reaction was carried out with 1 (0.25 mmol), nucleophile, Et3NHI (20 equiv to Rh), and i-Pr2NEt in dioxane (0.4 M) at 110 °C in the
presence of [Rh(cod)Cl]2 (2.5 mol%) and dppf (7.5 mol%).
b Diastereomeric ratio was measured by 1H NMR spectroscopy.
c Combined yield of 3 and 3¢.
d The reactions were performed with [Rh(cod)Cl]2 (1.0 mol%) and dppf (3.0 mol%).
methoxymethyl group (CH2OMe) showed an increase in
reactivity.
Compared to 2b, (S)-prolinol (2c) reacts more slowly. In
the presence of 2.5 mol% of [Rh(cod)Cl]2 and 7.5 mol%
of dppf, the reaction of 1 with 3.0 equivalents of 2c and
6.0 equivalents of i-Pr2NEt at 110 °C for 72 hours gave the
corresponding products 3c and 3c¢ in 54% yield (entry 5).
An increase in the yield (70%) was observed in the reac-
tion using 5.0 equivalents of 2c and 10.0 equivalents of i-
Pr2NEt (entry 6) and a slightly higher selectivity on the
formation of 3c (3c:3c¢ = 1.7:1.0) was obtained (entry 6).
The absolute configuration of ring-opened product 3c was
assigned to be S,R,R by correlation with the authentic
sample, (S,R,R)-3b (vide infra),25 after transformation of
the hydroxy group in 3c into methoxy group by treatment
with dimethyl sulfate (Scheme 2).
Figure 1 Crystal structure of cyclic 4
MeO2C
H
TFA, CH2Cl2
N
N
H
H
O
HN
OtBu
NH
then KOH (aq)
81% yield
O
(S,R,R)-3a
(S,R,R)-4
Scheme 1 Preparation of benzopyrroloquinoxalinone 4
Next, the ring-opening of 1 was carried out using (S)-2-
(methoxymethyl)pyrrolidine (2b) to give the enantiomer-
ically pure products 3b and 3b¢ in 88% yield as a 1:1 mix-
ture (entry 4). The enantiomeric purity of 3b and 3b¢ were
determined (>99% ee) by HPLC analysis,24 and the abso-
lute configuration of 3b was determined to be S,R,R by X-
ray analysis (Figure 2).25 Changing the functionality on
the pyrrolidine ring from an ester group (CO2Me) into
Figure 2 Crystal structure of 3b
Synthesis 2008, No. 15, 2467–2475 © Thieme Stuttgart · New York

PAPER
Rhodium-Catalyzed Ring-Opening of N-Boc-azabenzonorbornadiene
2469
yield (Scheme 3). Formation of the opposite diastereomer
(S,R,R)-3b was not observed in this reaction.
OH
N
OMe
N
(MeO)2SO2
The ring-opened products 3c and 3c¢ are also easily con-
verted into unique cyclic compounds 6 and 6¢ (Scheme 4).
The key compounds are cyclic (S,R,R)-5 and (S,S,S)-5¢,
obtained by the reaction of the hydroxy groups of 3c and
3c¢ with methanesulfonyl chloride followed by treatment
of the mesylate with NaH at 55 °C for 12 hours. Catalytic
hydrogenation of 5 and 5¢ in the presence of Degussa E1
Pd catalyst under hydrogen atmosphere gave the corre-
sponding cyclic products 6 and 6¢ in 61 and 65% yield, re-
spectively.
NaH, THF, r.t.
85% yield
HN
HN
Boc
Boc
(S,R,R)-3c
(S,R,R)-3b
Scheme 2 Preparation of (S,R,R)-3b from 3c
The difference in selectivity observed for (S)-prolinol (2c)
compared to 2a and 2b is likely due to a catalyst-nucleo-
phile interaction, which results in an increase of the selec-
tivity for 3c. Although, the specifics of this interaction
still remain to be studied, it has been reported that amine
nucleophile can affect the stereoselectivity of metal-cata-
lyzed reactions by binding to the metal center of the cata-
lyst.14a,17b Also, this strong interaction could explain the
sluggish result of the reaction using 2c. The ring-opening
of 1 with amines such as pyrrolidines known to bind
strongly to the metal catalyst typically showed slower re-
action rates than reactions using other nucleophiles.14a
Similarly, it is likely that (S)-proline methyl ester (2a) also
interacts with the catalyst, but in a different manner.
While the reaction using 2c has a preference for the for-
mation of the product 3c with S,R,R-configuration, the
ring-opening of 1 with 2a showed the selective formation
of the product 3a¢ with S,S,S-configuration (entries 1, 2,
and 3).
OH
N
OH
N
HN
HN
Boc
Boc
d, e
3c
3c'
a, b
H
H
N
H
N
H
H
H
N
N
Boc
Boc
f
5
5'
c
In contrast, the reaction using (S)-2-(methoxymethyl)pyr-
rolidine (2b) showed the best reactivity (entry 4), but had
no selectivity for either 3b or 3b¢ (3b:3b¢ = 1:1), suggest-
ing that the nature of the functionality on the a-position on
the pyrrolidine ring plays a significant role in the reaction
outcome.
H
H
N
H
N
H
H
H
N
N
Boc
Boc
6
6'
Scheme 4 Preparation of cyclic compounds 6 and 6¢. Reagents and
It is also found that carrying out the reaction using the conditions: a) MeSO2Cl, Et3N, 0 °C to r.t.; b) NaH, 55 °C, 82%; c) H2
enantiomerically pure ligand gave a single isomer. In the
(1 atm), 10% Pd/C, MeOH–EtOAc, 61%; d) MeSO2Cl, Et3N, 0 °C to
r.t.; e) NaH, 55 °C, 75%; f) H2 (1 atm), 10% Pd/C, MeOH–EtOAc,
presence of 2.5 mol% of [Rh(cod)Cl]2, 5.5 mol% of (S,S¢)-
65%.
(R,R¢)-C2-ferriphos,18 and 50 mol% of Et3NHCl, the ring-
opening of 1 with 5.0 equivalents of (S)-3b and 5.0 equiv-
In our previous work, we reported that the synthesis of the
enantiomerically pure free 1,2-diaminotetrahydronaph-
thalenes from the corresponding ring-opening products
alents of i-Pr2NEt proceeded in tetrahydropyran at 100 °C
for 96 hours to give only the product (S,S,S)-3b¢ in 93%
Boc
N
MeO
CH2OMe
NH
[Rh(cod)Cl]2 (2.5 mol%)
L* (5.5 mol%)
N
+
Et3NHCl (50 mol%)
i-Pr2NEt (5.0 equiv)
THP, 100 °C, 72 h
HN
Boc
1
2b (5.0 equiv)
(S,S,S)-3b' only (93% yield)
Me2N
Ph2P
L* =
Fe
Ph2P
Me2N
(S,S')-(R,R')-C2-Ferriphos
Scheme 3 Catalytic ring opening of 1 with (S)-2b in the presence of the rhodium catalyst coordinated with (S,S¢)-(R,R¢)-C2-ferriphos
Synthesis 2008, No. 15, 2467–2475 © Thieme Stuttgart · New York

2470
Y.-H. Cho et al.
PAPER
Boc
Ph
OH
N
[Rh(cod)Cl]2 (2.5 mol%)
dppf (7.5 mol%)
HO
N
Ph
+
HN
Et3NHI (50 mol%)
i-Pr2NEt (5.0 equiv)
dioxane, 110 °C, 72 h
95% yield (8 + 8')
HN
Ph
Ph
Boc
1
8
+
7
Ph
HO
N
HN
Ph
(1:1 diastereomeric mixture)
Boc
8'
Scheme 5 Catalytic ring opening of 1 with (R)-2-benzylamino-2-phenylethanol (7)
prepared by the asymmetric ring-opening of 1 using N,N- mol% of dppf, and 50 mol% of Et3NHI, the ring-opening
dibenzylamine as a nucleophile, by a sequential deprotec- of 1 using 3.0 equivalents of 7 and 5.0 equivalents of i-
tion.15 In a similar manner, we chose (R)-2-benzylamino- Pr2NEt gave the corresponding products 8 and 8¢ in 95%
2-phenylethanol26 (7) in order to prepare the enantiomeri- yield (8:8¢ = 1:1) (Scheme 5). It is very interesting that
cally pure 1,2-diaminonaphthalene following deprotec- the reaction using 7 does not show any diastereoselectivi-
tion. In the presence of 2.5 mol% of [Rh(cod)Cl]2, 7.5 ty while the reaction of 1 with 2c gave a modest dr (1.7:1).
The ring-opened product 8¢ was subsequently converted
Ph
O
a, b
into the versatile compound 10 (Scheme 6). Reduction of
the double bond and debenzylation of the benzylphenyl-
glycinol moiety27 were carried out by catalytic hydroge-
nation of 8¢ with HCO2NH4 in the presence of Pd/C.28
Acylation of the resulting debenzylated product with ben-
zoyl chloride gave 9 in 55% yield and the configuration of
9 was assigned to be 1S,2S by comparison of its specific
rotation, [a]D25 +53 (c 0.9, CHCl3), with the previously re-
HO
N
Ph
N
H
HN
HN
Ph
Boc
Boc
(R,S,S)-8'
(S,S)-9
[α]D25 +53 (c = 0.9, CHCl3)
25
ported value, [a]D +58 (c 1.0, CHCl3), for (1S,2S)-9.15
c, d
H3N
O2C
The enantiomeric purity of 9 was also determined (>99%
ee) by HPLC analysis.29 Finally, diamide 9 was deprotect-
ed by treatment of 50% aqueous HCl and was converted
into the 1,2-diaminonaphthalene tartrate 10 according to
the reported procedure.15
NH3
CO2
HO
OH
10
The catalytic ring-opening reactions of 1 using N-ben-
zylethanolamine (11) and N-benzylglycine ethyl ester
(12) were also examined. The results revealed that the
presence or absence of functionalities at the a-position in
Scheme 6 Preparation of diamine scaffold 10. Reagents and condi-
tions: a) 10% Pd/C, HCO2NH4, EtOAc, MeOH; b) benzoyl chloride,
pyridine, THF, 55% (2 steps); c) aq 50% HCl; d) L-tartaric acid,
EtOH–H2O, 72% (2 steps).
Boc
N
HO
HN
[Rh(cod)Cl]2 (0.5 mol%)
HO
dppf (1.5 mol%)
N
+
Et3NHI (10 mol%)
i-Pr2NEt (3.0 equiv)
dioxane, 110 °C, 24 h
HN
Ph
Boc
Ph
( )-13 (95% yield)
1
11 (3.0 equiv)
Boc
N
[Rh(cod)Cl]2 (1.0 mol%)
dppf (3.0 mol%)
EtO
HN
O
EtO2C
N
+
Et3NHI (20 mol%)
i-Pr2NEt (1.1 equiv)
dioxane, 110 °C, 24 h
HN
Ph
Boc
Ph
12 (1.1 equiv)
( )-14 (88% yield)
1
Scheme 7 Catalytic ring opening of 1 with N-benzylethanolamine (11) and N-benzylglycine ethyl ester (12)
Synthesis 2008, No. 15, 2467–2475 © Thieme Stuttgart · New York

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Rhodium-Catalyzed Ring-Opening of N-Boc-azabenzonorbornadiene
2471
1H NMR (300 MHz, CDCl3): d = 1.46 (s, 9 H), 1.74–2.05 (m, 4 H),
2.82–2.88 (m, 1 H), 3.05 (br s, 1 H), 3.51 (dd, J = 8.4, 4.8 Hz, 1 H),
3.65–3.70 (m, 1 H), 3.68 (s, 3 H), 4.90 (br s, 2 H), 5.96 (dd, J = 9.9,
3.6 Hz, 1 H), 6.59 (d, J = 9.9 Hz, 1 H), 7.06–7.09 (m, 1 H), 7.21–
7.24 (m, 2 H), 7.35–7.38 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 175.19, 155.92, 135.47, 132.29,
129.80, 127.92, 127.74, 127.10, 126.47, 79.22, 61.57, 59.63, 51.71,
51.39, 48.40, 29.72, 28.33.
amine nucleophiles has a strong influence to the reaction
rate (Scheme 7). The reactions using 11 and 12 proceeded
much faster than with 7, even with lower catalyst load-
ings. In the presence of 0.5 mol% of [Rh(cod)Cl]2, 1.5
mol% of dppf, and 10 mol% of Et3NHI, the ring-opening
of 1 with 3.0 equivalents of 11 and 3.0 equivalents of
i-Pr2NEt at 110 °C for 24 hours gave the corresponding
product 13 in 95% yield. Furthermore, in the presence of
1.0 mol% of [Rh(cod)Cl]2, 3.0 mol% of dppf, and 20
mol% of Et3NHI, the reaction of 1 with 12 at 110 °C for
24 hours gave the ring-opened product 14 in 88% yield.
HRMS (ESI): m/z calcd for C21H29N2O4 [M + H+]: 373.2121; found:
373.2117.
(1S,2S)-{2-[(S)-2¢-(Methoxycarbonyl)pyrrolidin-1¢-yl]-1,2-dihy-
dronaphthalen-1-yl}carbamic Acid tert-Butyl Ester (3a¢)
In summary, we have developed a rhodium-catalyzed
ring-opening of azabenzonorbornadiene 1 with chiral
amine nucleophiles derived from commercially available
amino acids such as (S)-proline and (R)-phenylglycine.
The reactions gave the desired products as a mixture of
separable diastereomers. The use of both Et3NHI and i-
Pr2NEt improved the reaction rate and yield in the present
reaction. In addition, studies on the scope of reaction re-
vealed that functionality at the a-position of the amine nu-
cleophile has a strong influence on the reaction rate and
the diastereoselectivity.
25
Rf = 0.45 (SiO2, hexanes–EtOAc, 7:3); [a]D +142.4 (c 1.00,
CHCl3).
IR (film): 3360, 1713, 1514, 1505, 1487, 1455, 1391, 1366, 1249,
1170, 1045, 1022, 863, 782 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.43 (s, 9 H), 1.61–1.83 (m, 3 H),
1.86–1.95 (m, 1 H), 2.06 (ddd, J = 17.1, 12.6, 8.4 Hz, 1 H), 2.48 (q,
J = 7.8 Hz, 1 H), 3.00–3.06 (m, 1 H), 3.63 (s, 3 H), 3.65–3.69 (m, 1
H), 3.77–3.61 (m, 1 H), 4.65 (br d, J = 7.8 Hz, 1 H), 4.90 (br d,
J = 7.8 Hz, 1 H), 5.98 (dd, J = 9.6, 5.1 Hz, 1 H), 6.62 (d, J = 9.6 Hz,
1 H), 7.08–7.11 (m, 1 H), 7.19–7.30 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 175.35, 154.86, 134.42, 132.20,
129.16, 128.53, 128.17, 126.74, 126.21, 79.49, 61.36, 59.02, 51.74,
49.45, 49.06, 29.98, 28.35, 23.63.
All moisture and air sensitive manipulations were carried out under
dry N2. NMR spectra were recorded on a Varian Mercury 300 MHz
or 400 MHz NMR spectrometer. Chemical shifts are reported in d
(ppm) relative to TMS. IR spectra were obtained using a Perkin-
Elmer Spectrum 1000 FT-IR spectrometer as neat films on NaCl
plates. High-resolution mass spectra were obtained from a Micro-
mass 70S-250 mass spectrometer (EI) or an ABI/Sciex Qstar mass
spectrometer (ESI). Optical rotations were measured on a Perkin-
Elmer Model 243 Polarimeter and melting points were taken on a
Fisher-Johns melting point apparatus. HPLC analysis was per-
formed on an Agilent 1100 Series HPLC with Chiralcel AD or AS
columns. Dioxane and THF were distilled from sodium benzophe-
none ketyl immediately prior to use. CH2Cl2 was distilled from
CaH2. Degussa E1 catalyst (Pd, 5% on activated carbon, uniform,
oxidic), [Rh(cod)Cl]2 and dppf were acquired from Strem Chemi-
cals Co. Ltd. Amine nucleophiles (S)-2b and (S)-2c were acquired
from Alfa Aesar®. (S)-Proline, 11, and 12 were acquired from Ald-
rich Chemical Co., Ltd. Azabenzonorbornadiene 115 and (R)-726
were prepared according to the reported procedures.
HRMS (ESI): m/z [M + H+] calcd for C21H29N2O4: 373.2121; found:
373.2114.
Ring Opening of 1 with (S)-2-(Methoxymethyl)pyrrolidine (2b)
in the Presence of Triethylamine Hydroiodide; (1R,2R)-{2-[(S)-
2¢-(Methoxymethyl)pyrrolidin-1¢-yl]-1,2-dihydronaphthalen-1-
yl}carbamic Acid tert-Butyl Ester (3b) and (1S,2S)-{2-[(S)-2¢-
(Methoxymethyl)pyrrolidin-1¢-yl]-1,2-dihydronaphthalen-1-
yl}carbamic Acid tert-Butyl Ester (3b¢); Typical Procedure
To a stirred solution of 1 (100 mg, 0.4 mmol), [Rh(cod)Cl]2 (5.1 mg,
10 mmol), dppf (17 mg, 31 mmol), and Et3NHI (47 mg, 0.2 mmol) in
anhyd 1,4-dioxane (1.0 mL) was added i-Pr2NEt (0.4 mL, 2.1
mmol) and (S)-2-(methoxymethyl)pyrrolidine (2b; 142 mg, 1.23
mmol) under N2. The mixture was allowed to stir at 110 ° C for 36
h. The resulting mixture was cooled to r.t. and quenched with aq 1
N NaOH. The mixture was extracted with CH2Cl2 (3 × 15 mL) and
the combined organic extracts were dried (MgSO4). After evapora-
tion under reduced pressure, the residue was purified by flash col-
umn chromatography (hexane–EtOAc, 70:30) to give 66 mg (45%)
of 3b and 63 mg of (43%) 3b¢.
Ring Opening of Azabenzonorbornadiene 1 with (S)-Proline
Methyl Ester Hydroiodide (2a)
To a stirred solution of 1 (100 mg, 0.4 mmol), [Rh(cod)Cl]2 (5.1 mg,
10 mmol), and dppf (17 mg, 31 mmol) in anhyd 1,4-dioxane (1.0 mL)
was added the hydrogen iodide salt of (S)-proline methyl ester (2a)
(317 mg, 1.23 mmol) and i-Pr2NEt (0.4 mL, 2.1 mmol) under N2.
The mixture was allowed to stir at 110 °C for 72 h. The resulting
mixture was cooled to r.t. and quenched with aq 1 N NaOH. The
mixture was extracted with CH2Cl2 (3 × 15 mL) and the combined
organic extracts were dried (MgSO4), and filtered. After evapora-
tion under reduced pressure, the residue was purified by flash col-
umn chromatography (hexane–EtOAc, 70:30) to give 46 mg (30%)
of 3a and 66 mg (43%) of 3a¢.
3b
More than 99% ee by HPLC analysis with a chiral column (Chiral-
cel AS, hexane–propan-2-ol, 99:1, 0.5 mL/min), tR (S,R,R)-(–)-,
14.5 min (major); (R,S,S)-(+)-, 17.6 min (minor); Rf = 0.41 (SiO2,
hexanes–EtOAc, 7:3); mp 90–92 °C; [a]D25 –287.8 (c 1.00, CHCl3).
IR (film): 3321, 2961, 1688, 1528, 1449, 1365, 1317, 1255, 1169,
1117, 1044, 1021, 780, 748 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.47 (s, 9 H), 1.51–1.57 (m, 1 H),
1.64–1.73 (m, 2 H), 1.76–1.88 (m, 1 H), 2.62 (q, J = 8.0 Hz, 1 H),
2.80 (br s, 1 H), 3.04–3.12 (m, 1 H), 3.22 (dd, J = 9.0, 6.0 Hz, 1 H),
3.29–3.35 (m, 4 H), 3.74–3.77 (m, 1 H), 4.80–4.95 (m, 1 H), 4.72
(br s, 1 H), 6.01 (dd, J = 9.9, 3.6 Hz, 1 H), 6.60 (d, J = 9.9 Hz, 1 H),
7.04–7.07 (m, 1 H), 7.18–7.22 (m, 2 H), 7.36–7.40 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 156.45, 136.18, 132.95, 129.78,
127.92, 127.81, 127.72, 126.99, 126.58, 78.12, 60.62, 59.44, 59.15,
53.62, 53.29, 48.40, 29.07, 28.65, 24.26.
(1R,2R)-{2-[(S)-2¢-(Methoxycarbonyl)pyrrolidin-1¢-yl]-1,2-di-
hydronaphthalen-1-yl}carbamic Acid tert-Butyl Ester (3a)
25
Rf = 0.55 (SiO2, hexanes–EtOAc, 7:3); [a]D –177.8 (c 1.00,
CHCl3).
IR (film): 3360, 1714, 1504, 1454, 1391, 1365, 1250, 1171, 1045,
1021, 861, 781 cm–1.
Synthesis 2008, No. 15, 2467–2475 © Thieme Stuttgart · New York

2472
Y.-H. Cho et al.
PAPER
Anal. Calcd for C21H30N2O3: C, 70.36; H, 8.44; N, 7.81. Found: C,
70.62; H, 8.78; N, 7.89.
(1R,2R)-{2-[N-(R)-2¢-Hydroxy-1¢-phenylethyl-N-benzyl]amino-
1,2-dihydronaphthalen-1-yl}carbamic Acid tert-Butyl Ester (8)
and (1S,2S)-{2-[N-(R)-2¢-Hydroxy-1¢-phenylethyl-N-ben-
zyl]amino-1,2-dihydronaphthalen-1-yl}carbamic Acid tert-
Butyl Ester (8¢) (Scheme 5)
Prepared by following the above typical procedure using (R)-2-ben-
zylamino-2-phenylethanol (7)26 as the nucleophile to give the cor-
responding products 8 and 8¢ in 95% yield (8:8¢ = 1:1).
3b¢
More than 99% ee by HPLC analysis with a chiral column (Chiral-
cel AD, hexane–propan-2-ol, 98:2, 1.0 mL/min), tR (R,R,R)-(–)-,
13.0 min (minor); (S,S,S)-(+)-, 19.7 min (major); Rf = 0.37 (SiO2,
hexanes–EtOAc, 7:3); [a]D25 +218.6 (c 1.00, CHCl3).
IR (film): 3332, 2972, 2927, 2823, 1709, 1489, 1454, 1390, 1365,
1249, 1170, 1112, 1045, 1023, 780, 748 cm–1.
8
25
Rf = 0.72 (SiO2, hexanes–EtOAc, 7:3); [a]D –267.6 (c 1.00,
CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.44 (s, 9 H), 1.53–1.70 (m, 3 H),
1.72–1.88 (m, 1 H), 2.23 (q, J = 8.7 Hz, 1 H), 2.74–2.82 (m, 1 H),
3.20–3.38 (m, 6 H), 3.69 (t, J = 3.8 Hz, 1 H), 4.66–4.78 (m, 1 H),
4.94 (br s, 1 H), 5.96 (dd, J = 9.9, 4.8 Hz, 1 H), 6.60 (d, J = 9.0 Hz,
1 H), 7.07–7.10 (m, 1 H), 7.19–7.24 (m, 2 H), 7.31–7.34 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 155.18, 135.47, 132.59, 128.73,
128.28, 128.13, 128.01, 126.79, 79.55, 76.44, 59.09, 59.04, 58.12,
49.57, 49.26, 28.83, 28.58, 23.57.
IR (film): 3319, 3026, 2975, 2927, 1691, 1494, 1452, 1391, 1366,
1250, 1170, 1044, 1027, 864, 782, 758, 701 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.57 (s, 9 H), 3.00 (d, J = 6.0 Hz,
1 H), 3.56–3.63 (m, 1 H), 3.64 (d, J = 13.8 Hz, 1 H), 3.89–4.00 (m,
3 H), 4.08 (t, J = 10.2 Hz, 1 H), 4.79 (d, J = 8.4 Hz, 1 H), 5.12 (dd,
J = 9.9, 3.0 Hz, 1 H), 5.22 (d, J = 9.0 Hz, 1 H), 6.28 (dd, J = 9.9, 1.8
Hz, 1 H), 6.97–6.99 (m, 1 H), 7.18–7.21 (m, 2 H), 7.22–7.37 (m, 9
H), 7.42 (d, J = 6.9 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 156.48, 139.81, 138.03, 135.27,
132.81, 129.42, 128.96, 128.80, 128.74, 128.67, 128.58, 128.45,
128.25, 128.09, 127.84, 127.40, 127.17, 126.76, 126.66, 80.16,
68.84, 62.76, 61.39, 57.41, 53.48, 51.88, 28.65.
Anal. Calcd for C21H30N2O3: C, 70.36; H, 8.44; N, 7.81. Found: C,
70.45; H, 8.48; N, 7.83.
(1R,2R)-{2-[(S)-2¢-(Hydroxymethyl)pyrrolidin-1¢-yl]-1,2-dihy-
dronaphthalen-1-yl}carbamic Acid tert-Butyl Ester (3c) and
(1S,2S)-{2-[(S)-2¢-(Hydroxymethyl)pyrrolidin-1¢-yl]-1,2-dihy-
dronaphthalen-1-yl}carbamic Acid tert-Butyl Ester (3c¢)
Prepared by following the above typical procedure using (S)-proli-
nol (2c) as the nucleophile to give the corresponding products 3c
and 3c¢ in 70% yield (3c:3c¢ = 1.7:1) (Table 1, entry 6).
HRMS (EI): m/z calcd for C30H34N2O3 [M+]: 470.2569; found:
470.2567.
8¢
25
Rf = 0.40 (SiO2, hexanes–EtOAc, 7:3); [a]D +94.6 (c 1.00,
3c
CHCl3).
25
Rf = 0.53 (SiO2, hexanes–EtOAc, 1:1); [a]D –139.2 (c 1.00,
CHCl3).
IR (film): 3415, 3027, 2975, 2927, 1710, 1494, 1452, 1390, 1365,
1250, 1169, 1046, 1027, 781, 751, 699 cm–1.
IR (film): 3334, 2971, 2869, 1699, 1505, 1451, 1391, 1366, 1250,
1169, 1145, 1023, 782, 747 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.45 (s, 9 H), 2.38 (br s, 1 H),
3.48–3.60 (m, 1 H), 3.64–3.74 (m, 1 H), 3.80–4.06 (m, 4 H), 4.43
(d, J = 9.0 Hz, 1 H), 4.85 (dd, J = 8.7, 4.5 Hz, 1 H), 5.81 (dd,
J = 9.6, 4.5 Hz, 1 H), 6.63 (dd, J = 9.6, 1.5 Hz, 1 H), 7.00 (d, J = 7.5
Hz, 3 H), 7.06 (d, J = 7.5 Hz, 1 H), 7.13 (dt, J = 7.5, 1.5 Hz, 1 H),
7.18–7.33 (m, 7 H), 7.40 (d, J = 6.9 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 155.09, 140.71, 139.26, 135.20,
132.07, 130.02, 129.18, 129.05, 128.92, 128.61, 128.53, 128.42,
128.14, 128.71, 127.40, 127.23, 126.92, 79.59, 64.23, 62.52, 59.79,
50.46, 49.69, 28.61.
1H NMR (300 MHz, CDCl3): d = 1.48 (s, 9 H), 1.67–1.89 (m, 4 H),
2.67 (q, J = 8.4 Hz, 1 H), 2.85–3.00 (m, 1 H), 3.05–3.11 (m, 1 H),
3.36 (dd, J = 11.0, 3.3 Hz, 1 H), 3.56–3.63 (m, 2 H), 4.58 (d, J = 9.0
Hz, 1 H), 5.02 (t, J = 9.0 Hz, 1 H), 5.97 (dd, J = 9.6, 3.0 Hz, 1 H),
6.63 (dd, J = 9.9, 1.8 Hz, 1 H), 7.07–7.10 (m, 1 H), 7.20–7.25 (m, 2
H), 7.37–7.40 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 156.16, 135.27, 132.96, 130.19,
128.04, 128.00, 126.67, 126.61, 126.56, 79.84, 62.84, 60.66, 59.95,
53.47, 48.29, 28.48, 28.39, 24.55.
HRMS (EI): m/z calcd for C30H34N2O3 [M+]: 470.2569; found:
470.2573.
HRMS (ESI): m/z calcd for C20H29N2O3 [M + H+]: 345.2172; found:
345.2174.
(4aR,10bR,12aS)-1,2,3,10b,11,12a-Hexahydro-4aH-ben-
zo[f]pyrrolo[1,2-a]quinoxalin-12-one (4)
3c¢
25
Rf = 0.30 (SiO2, hexanes–EtOAc, 1:1); [a]D +89.8 (c 1.00,
To a stirred solution of 3a (130 mg, 0.35 mmol) in anhyd CH2Cl2
(5.0 mL) was slowly added trifluoroacetic acid (0.5 mL, 6.98 mmol)
at 0 °C over 5 min. The mixture was allowed to stir at r.t. for 18 h
and the resulting mixture was carefully quenched with aq 4 N KOH
at 0 °C. The mixture was extracted with CH2Cl2 (3 × 15 mL) and the
separated organic layer was dried (MgSO4) and filtered. After con-
centration under reduced pressure, the residue was purified by flash
column chromatography (hexane–EtOAc, 50:50) to give 68 mg
(81%) of 4; mp 242–245 °C; [a]D25 –127.5 (c 1.01, CHCl3).
CHCl3).
IR (film): 3331, 2970, 1699, 1489, 1391, 1366, 1251, 1169, 1045,
781, 747 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.43 (s, 9 H), 1.48–1.73 (m, 4 H),
1.83–1.96 (m, 1 H), 2.30 (q, J = 8.4 Hz, 1 H), 2.74–2.81 (m, 1 H),
3.36–3.45 (m, 2 H), 3.62–3.66 (m, 2 H), 4.60 (d, J = 7.2 Hz, 1 H),
4.93 (d, J = 7.2 Hz, 1 H), 5.92 (dd, J = 9.6, 5.4 Hz, 1 H), 6.62 (d,
J = 9.9 Hz, 1 H), 7.10–7.13 (m, 1 H), 7.23–7.27 (m, 2 H), 7.29–7.33
(m, 1 H).
13C NMR (100 MHz, CDCl3): d = 155.22, 134.52, 132.51, 128.68,
128.63, 124.46, 127.19, 127.00, 79.85, 63.76, 59.61, 58.24, 49.38,
49.11, 28.96, 28.53, 24.20.
IR (film): 3208, 3058, 1660, 1459, 1416, 1311, 1229, 1187, 1136,
1004, 960, 780 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.84–2.00 (m, 2 H), 2.05–2.19 (m,
1 H), 2.27–2.38 (m, 1 H), 2.80–2.87 (m, 1 H), 2.99 (dd, J = 16.2, 7.7
Hz, 1 H), 3.63 (dd, J = 8.6, 6.0 Hz, 1 H), 3.80 (dt, J = 13.6, 2.3 Hz,
1 H), 4.84 (d, J = 13.6 Hz, 1 H), 6.11 (dd, J = 9.8, 1.5 Hz, 1 H), 6.56
HRMS (ESI): m/z calcd for C20H29N2O3 [M + H+]: 345.2172; found:
345.2169.
Synthesis 2008, No. 15, 2467–2475 © Thieme Stuttgart · New York

PAPER
Rhodium-Catalyzed Ring-Opening of N-Boc-azabenzonorbornadiene
2473
(dd, J = 9.8, 3.0 Hz, 1 H), 6.79 (br s, 1 H), 7.16–7.19 (m, 1 H), 7.24–
duced pressure and the residue was purified by flash column chro-
7.32 (m, 3 H).
matography on silica gel (hexane–EtOAc, 90:10) to give 49 mg
(61%) of (S,R,R)-6; Rf = 0.34 (SiO2, hexanes–EtOAc, 9:1);
mp 167–169 °C; [a]D25 –35.9 (c 1.01, CHCl3).
13C NMR (75 MHz, CDCl3): d = 174.39, 133.91, 132.27, 128.61,
127.95, 127.52, 126.82, 121.68, 63.17, 58.27, 51.48, 47.01, 27.35,
23.29.
HRMS (ESI): m/z calcd for C15H17N2O [M + H+]: 241.1335; found:
241.1342.
(S,R,R)-6
IR (film): 3289, 2934, 2790, 1671, 1539, 1437, 1362, 1330, 1252,
1180, 1072, 1016, 912, 841, 741 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.51 (s, 9 H), 1.65–1.83 (m, 3 H),
1.97–2.06 (m, 1 H), 2.10–2.20 (m, 1 H), 2.38 (t, J = 10.0 Hz, 1 H),
2.52–2.66 (m, 3 H), 2.75–2.94 (m, 2 H), 3.23–3.30 (m, 1 H), 3.89–
3.98 (m, 1 H), 4.55–4.65 (m, 1 H), 4.87 (t, J = 8.9 Hz, 1 H), 7.03–
7.07 (m, 1 H), 7.11–7.19 (m, 2 H), 7.36–7.40 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 156.5, 137.7, 136.3, 128.3, 128.1,
126.8, 126.1, 79.1, 66.7, 56.8, 56.4, 51.1, 50.4, 35.4, 29.1, 28.5,
25.6, 22.6.
(4aR,10bR,12aS)-2,3,4a,10b,12,12a-Hexahydro-1H-ben-
zo[f]pyrrolo[1,2-a]quinoxalin-11-carboxylic Acid tert-Butyl
Ester (5); Typical Procedure
To a solution of 3c (1.0 g, 2.90 mmol) and Et3N (1.2 mL, 8.71
mmol) in anhyd THF (30 mL) was added MeSO2Cl (0.3 mL, 3.48
mmol) dropwise at 0 °C over 5 min. The mixture was then stirred at
0 °C for 1 h under N2. NaH (60% oil dispersion) (174 mg, 4.35
mmol) was then added at 0 °C and the mixture heated to 55 °C for
5 h. The resulting mixture was quenched with H2O (20 mL) and ex-
tracted with Et2O (3 × 25 mL). The combined organic extracts were
dried (MgSO4) and filtered. After concentration under reduced pres-
sure, the residue was purified by flash column chromatography
(hexane–EtOAc, 90:10) to give 780 mg (82%) of 5; mp 176–178
°C; [a]D25 –254.0 (c 1.00, CHCl3).
+
HRMS (EI): m/z calcd for C20H28N2O2 [M ]: 328.2151; found:
328.2146.
(S,S,S)-6¢
The compound (S,S,S)-6¢ was prepared from 5¢ following the same
procedure as above for the preparation of (S,R,R)-6 from 5; yield:
65%; Rf = 0.24 (SiO2, hexanes–EtOAc, 9:1); mp 185–187 °C;
[a]D25 +10.2 (c 1.00, CHCl3).
IR (film): 3240, 2958, 1682, 1524, 1455, 1366, 1250, 1162, 1074,
1045, 1019, 876, 815, 750 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.46 (s, 9 H), 1.50–1.56 (m, 1 H),
1.66–1.75 (m, 1 H), 2.02–2.11 (m, 1 H), 2.24–2.36 (m, 1 H), 2.65
(dd, J = 11.1, 8.7 Hz, 2 H), 3.06 (d, J = 10.2 Hz, 1 H), 3.41–3.45 (m,
1 H), 3.88–3.95 (m, 1 H), 4.56 (br s, 1 H), 5.01 (br s, 1 H), 5.91 (dd,
J = 9.9, 4.2 Hz, 1 H), 6.61 (dd, J = 9.6, 1.5 Hz, 1 H), 7.07–7.10 (m,
1 H), 7.22–7.25 (m, 2 H), 7.33–7.36 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 155.41, 135.55, 132.60, 129.75,
128.43, 128.28, 127.62, 126.96, 126.61, 79.79, 64.79, 57.91, 56.83,
49.11, 48.85, 35.14, 28.66, 25.32.
IR (film): 3239, 2935, 2797, 1689, 1673, 1558, 1451, 1317, 1266,
1248, 1172, 1067, 757, 741 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.50 (s, 9 H), 1.52–1.57 (m, 1 H),
1.64–1.79 (m, 2 H), 1.99–2.08 (m, 1 H), 2.09–2.23 (m, 2 H), 2.55 (t,
J = 10.2 Hz, 1 H), 2.68 (t, J = 10.2 Hz, 1 H), 2.75–3.05 (m, 4 H),
3.90–4.00 (m, 1 H), 4.56–4.64 (m, 1 H), 4.86 (t, J = 9.7 Hz, 1 H),
7.03–7.07 (m, 1 H), 7.11–7.20 (m, 2 H), 7.36–7.41 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 156.7, 137.8, 136.2, 128.3, 128.0,
126.8, 126.1, 79.0, 66.9, 60.6, 56.9, 51.2, 45.8, 35.7, 29.2, 28.5,
25.6, 21.8.
HRMS (EI): m/z calcd for C20H27N2O2 [M + H+]: 327.2072; found:
327.2070.
+
HRMS (EI): m/z calcd for C20H28N2O2 [M ]: 328.2151; found:
328.2146.
(4aS,10bS,12aS)-2,3,4a,10b,12,12a-Hexahydro-1H-ben-
zo[f]pyrrolo[1,2-a]quinoxalin-11-carboxylic Acid tert-Butyl
Ester (5¢)
The cyclic compound 5¢ was prepared from 3c¢ following the same
procedure as above for the preparation of 5 from 3c; yield: 210 mg
(75%); [a]D25 +315.6 (c 1.00, CHCl3); mp 141–143 °C.
(1S,2S)-(2-Benzoylamino-1,2,3,4-tetrahydronaphthalen-1-
yl)carbamic Acid tert-Butyl Ester (9)
To a stirred solution of (R,S,S)- 8¢ (200 mg, 0.42 mmol) in EtOAc
(10 mL) and MeOH (20 mL) was added ammonium formate (268
mg, 4.25 mmol) and 30 mol% of Pd/C (10 wt%, 136 mg, 0.13
mmol). The mixture was heated at reflux for 25 min and was cooled
to r.t. The resulting black suspension was filtered through Celite and
the cake was washed with Et3N–MeOH (1:1, v/v, 2 × 15 mL). The
filtrate was concentrated under reduced pressure and the residue
was dissolved in anhyd THF (5.0 mL), and pyridine (0.1 mL, 1.27
mmol) was added. Benzoyl chloride (60 mL, 0.50 mmol) was then
slowly added at 0 ° C and the mixture was stirred at r.t. for 15 h un-
der N2. The resulting mixture was quenched with aq 1 N NaOH (20
mL) and extracted with Et2O (3 × 15 mL). The combined organic
extracts were dried (MgSO4), filtered, and evaporated under re-
duced pressure. Flash column chromatography on silica gel (hex-
ane–EtOAc, 70:30) gave 75 mg (55%) of (1S,2S)-9;
IR (film): 3241, 2957, 2935, 2804, 1693, 1675, 1550, 1327, 1309,
1250, 1183, 1169, 1047, 977, 877, 776, 758, 746 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.46 (s, 9 H), 1.47–1.53 (m, 1 H),
1.70–1.77 (m, 1 H), 2.05–2.18 (m, 1 H), 2.32 (t, J = 10.2 Hz, 1 H),
2.49 (dt, J = 10.8, 2.7 Hz, 1 H), 2.75 (d, J = 11.7 Hz, 1 H), 2.97 (d,
J = 11.7 Hz, 1 H), 3.41–3.45 (m, 1 H), 3.82–3.90 (m, 1 H), 4.57 (br
s, 1 H), 4.98 (br s, 1 H), 5.93 (dd, J = 9.6, 4.5 Hz, 1 H), 6.63 (d,
J = 10.8 Hz, 1 H), 7.08–7.10 (m, 1 H), 7.22–7.25 (m, 2 H), 7.33–
7.36 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 155.48, 135.37, 132.54, 129.85,
128.47, 128.32, 127.71, 126.99, 125.73, 79.71, 64.63, 57.50, 56.80,
49.15, 48.91, 35.40, 28.64, 25.52.
>99% ee by HPLC analysis with a chiral column (Chiralcel AD,
hexane–propan-2-ol, 90:10, 1.0 mL/min): tR (R,R)-(–)-, 9.4 min
(minor); (S,S)-(+)-, 11.5 min (major); [a]D25 +53.1 (c 0.90, CHCl3)
{Lit.15 [a]D25 +58.2 (c 1.00, CHCl3) for (1S,2S)-9 of >99% ee}.
1H NMR (300 MHz, CDCl3): d = 1.38 (s, 9 H), 1.80 (dq, J = 12.3,
5.1 Hz, 1 H), 2.43–2.49 (m, 1 H), 2.87 (dd, J = 17.3, 3.2 Hz, 1 H),
3.07 (ddd, J = 17.3, 12.3, 5.1 Hz, 1 H), 4.11–4.22 (m, 1 H), 4.97–
5.02 (m, 2 H), 7.10–7.13 (m, 1 H), 7.18–7.25 (m, 3 H), 7.38–7.50
(m, 4 H), 7.88 (d, J = 6.9 Hz, 2 H).
HRMS (EI): m/z calcd for C20H27N2O2 [M + H+]: 327.2072; found:
327.2077.
Catalytic Hydrogenation of 5 and 5¢
To a solution of 5 (80 mg, 0.25 mmol) in EtOAc (10 mL) and
MeOH (30 mL) was added Degussa E1 catalyst (53 mg, 0.025
mmol). The mixture was allowed to stir at r.t. for 1 h under 1 atm of
H2 in a Parr hydrogenation apparatus. The resulting mixture was
then filtered through Celite. The filtrate was concentrated under re-
Synthesis 2008, No. 15, 2467–2475 © Thieme Stuttgart · New York

2474
Y.-H. Cho et al.
PAPER
13C NMR (75 MHz, CDCl3): d = 28.5, 28.7, 29.0, 54.3, 55.0, 80.5,
126.5, 127.1, 127.3, 127.7, 128.6, 129.1, 131.6, 134.3, 135.4, 136.9,
158.0, 167.5.
126.60, 126.50, 79.23, 60.66, 60.29, 54.51, 51.21, 50.29, 28.38,
14.07.
HRMS (EI): m/z calcd for C26H32N2O4 [M+]: 436.2362; found:
436.2354.
(1S,2S)-1,2,3,4-Tetrahydronaphthalen-1,2-diamine (R,R)-Tar-
trate (10)
Diamide 9 (1.0 g, 2.7 mmol, >99% ee) was treated with 50% HCl
(80 mL) at 100 °C for 48 h. The mixture was cooled to r.t. and the
acidic solution was washed with Et2O (3 × 20 mL). To the combined
aqueous solution was slowly added aq 4 N NaOH at 0 °C over 30
min and its pH was adjusted to approximately pH 11. The mixture
was extracted with CH2Cl2 (3 × 20 mL) and the combined CH2Cl2
layers were dried (MgSO4). After concentration under reduced pres-
sure, the residue was dissolved in EtOH (40 mL) and H2O (5 mL),
and a solution of L-(+)-tartaric acid (0.3 g, 1.82 mmol) in EtOH (10
mL) was added. The mixture was heated at reflux for 12 h and was
cooled to r.t. The precipitate was collected by filtration and the col-
lected solid was dried under vacuum. The enantiomerically pure di-
amine tartrate 1015 (1.7 g) was obtained in 72% yield (2 steps);
[a]D25 +27.0 (c = 1.00, H2O).
Acknowledgment
We gratefully acknowledge the financial support of the Natural
Sciences and Engineering Research Council (NSERC) of Canada,
the Ontario Research and Development Challenge Fund (ORDCF),
and the University of Toronto. We also thank Dr. Alan J. Lough for
his assistance with crystallographic analysis.
References
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1H NMR (400 MHz, DMSO-d6): d = 1.70–1.82 (m, 1 H), 2.05–2.13
(m, 1 H), 2.80–2.86 (m, 2 H), 2.98–3.05 (m, 1 H), 3.70 (d, J = 9.4
Hz, 1 H), 3.76 (s, 2 H), 7.09 (d, J = 7.4 Hz, 1 H), 7.18 (td, J = 7.2,
1.6 Hz, 1 H), 7.22 (td, J = 7.4, 1.6 Hz, 1 H), 7.59 (d, J = 7.4 Hz, 1
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trans-{2-[N-Benzyl-N-(2-hydroxyethyl)amino]-1,2-dihydro-
naphthalen-1-yl}carbamic Acid tert-Butyl Ester (13) (Scheme 7)
Prepared by the asymmetric ring-opening of 1 (1 equiv) using N-
benzylethanolamine (11, 3 equiv) in the presence of [Rh(cod)Cl]2
(0.5 mol%), dppf (1.5 mol%), Et3NHI (10 mol%), and i-Pr2NEt (3.0
equiv) to give 13 in 95% yield in a similar manner as described in
our previous work.15
IR (film): 3401, 3337, 1694, 1514, 1454, 1391, 1366, 1251, 1170,
1045, 1021, 782, 747 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.51 (s, 9 H), 2.65 (dt, J = 13.5,
4.5 Hz, 1 H), 2.90 (dt, J = 13.5, 4.5 Hz, 1 H), 3.17 (br s, 1 H), 3.52–
3.59 (m, 4 H), 3.81 (d, J = 12.3 Hz, 1 H), 4.53 (d, J = 8.7 Hz, 1 H),
5.12 (t, J = 8.7 Hz, 1 H), 5.96 (dd, J = 9.9, 3.6 Hz, 1 H), 6.57 (dd,
J = 9.9, 1.5 Hz, 1 H), 7.03–7.05 (m, 1 H), 7.18–7.34 (m, 8 H).
13C NMR (75 MHz, CDCl3): d = 156.01, 139.40, 134.72, 132.47,
129.52, 129.10, 128.25, 128.09, 127.97, 127.10, 126.71, 126.15,
79.79, 60.95, 59.19, 54.85, 52.09, 50.16, 28.42.
HRMS (EI): m/z calcd for C24H30N2O3 [M+]: 394.2256; found:
394.2257.
trans-{2-[N-Benzyl-N-(ethoxycarbonylmethyl)amino]-1,2-dihy-
dronaphthalen-1-yl}carbamic Acid tert-Butyl Ester (14)
(Scheme 7)
Prepared by the asymmetric ring-opening of 1 (1 equiv) using N-
benzylglycine ethyl ester (12, 1.1 equiv) in the presence of
[Rh(cod)Cl]2 (1 mol%), dppf (3 mol%), Et3NHI (20 mol%), and i-
Pr2NEt (1.1 equiv) to give 14 in 88% yield in a similar manner as
described in our previous work.15
IR (film): 3358, 1731, 1713, 1505, 1454, 1391, 1366, 1250, 1171,
1046, 1028, 976 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.22 (t, J = 7.2 Hz, 3 H), 1.48 (s,
9 H), 3.31 (s, 2 H), 3.65 (br s, 1 H), 3.82 (d, J = 13.9 Hz, 1 H), 3.97
(d, J = 13.9 Hz, 1 H), 4.06 (q, J = 7.6 Hz, 2 H), 4.91 (d, J = 7.6 Hz,
1 H), 5.07 (t, J = 7.6 Hz, 1 H), 6.04 (dd, J = 9.8, 4.2 Hz, 1 H), 6.61
(dd, J = 9.8, 1.5 Hz, 1 H), 7.05–7.18 (m, 1 H), 7.18–7.29 (m, 5 H),
7.33–7.38 (m, 3 H).
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1224. (b) Yoshioka, H.; Aoki, T.; Goko, H.; Nakatsu, K.;
Noda, T.; Sakakibara, H.; Take, T.; Nagata, A.; Abe, J.;
13C NMR (75 MHz, CDCl3): d = 172.01, 155.57, 139.28, 135.19,
132.20, 129.73, 128.79, 128.10, 128.05, 127.79, 127.69, 126.94,
Synthesis 2008, No. 15, 2467–2475 © Thieme Stuttgart · New York

PAPER
Rhodium-Catalyzed Ring-Opening of N-Boc-azabenzonorbornadiene
2475
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additional 1 h. After filtration to remove the NaCl, the
solution was concentrated and the residue was dissolved in
CH2Cl2 and the insoluble precipitate was filtered off again.
After removal of all volatile substrates, the corresponding
iodide (quantitative yield) was obtained.
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A. R.; Rees, C. W.; Scriven, E. F. V., Eds.; Elsevier:
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(23) Crystal data for 4: C15H16N2O, M = 240.30, orthorhombic,
space group P212121, a = 7.3032 (2) Å, b = 12.2966 (6) Å,
c = 13.5897 (6) Å, a = 90°, b = 90°, g = 90°, V = 1220.42 (9)
Å3, Z = 4, Dc = 1.308 Mg/m3, m(Cu-Ka) = 0.083 mm–1,
F(000) = 512 reflections were collected, of which 9593 were
considered to be observed with I > 2s(I). The structure was
determined by direct methods using the SHELXTLTM suite
of programs. Hydrogen atoms were placed in calculated
positions. Full-matrix least squares refinement based on F2
with anisotropic thermal parameters for the non-hydrogen
atoms led to agreement factors R1 = 0.0360 and
wR2 = 0.0887. Crystallographic data for the structure 4
reported in this paper have been deposited at the Cambridge
Crystallographic Data Centre as supplementary material No.
CCDC-639749. Copies of the data may be obtained, free of
charge, on application to CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK (fax: +44 1223 33603 or e-mail:
deposit@ccdc.cam.ac.uk).
(24) Chiral stationary phase columns (Chiralcel AS for 3b and
AD for 3b¢).
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(25) Crystal data for 3b: C21H30N2O3, M = 358.47, monoclinic,
space group P21, a = 9.4130 (4) Å, b = 19.6173 (12) Å,
c = 11.8127 (7) Å, a = 90°, b = 110.225 (3)°, g = 90°,
V = 2046.81 (19) Å3, Z = 4, Dc = 1.163 Mg/m3, m(Cu-Ka) =
0.078 mm–1, F(000) = 776 reflections were collected, of
which 111510 were considered to be observed with I > 2s(I).
Full-matrix least squares refinement based on F2 with
anisotropic thermal parameters for the nonhydrogen atoms
led to agreement factors R1 = 0.0491 and wR2 = 0.1115.
Crystallographic data for the structure 3b reported in this
paper have been deposited at the Cambridge
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Ferriphos would be required to ensure high enantio-
selectivity in the catalytic ring-opening reaction.
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Crystallographic Data Centre as supplementary material No.
CCDC-639748. Copies of the data may be obtained, free of
charge, on application to CCDC, 12 Union Road,
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(22) To a solution of (S)-proline methyl ester hydrochloride in
MeOH (0.5–1.0 M) was added 1.0 equiv of NaI solution in
(29) Chiral stationary phase columns (Chiralcel AD for 9).
Synthesis 2008, No. 15, 2467–2475 © Thieme Stuttgart · New York