Diastereo- and enantioselective synthesis of nitroso Diels-Alder-type bicycloketones using dienamine: Mechanistic insight into sequential nitroso aldol/Michael reaction and application for optically pure 1-amino-3,4-diol synthesis

Article abstract of DOI:10.1021/ja066037m

This article presents complete diastereo- and highly enantioselective synthesis of nitroso Diels-Alder-type bicycloketones using dienamine. With the hydrogen bonding of two hydroxyls in the bulky binaphthol 1c, high enantioselectivities and complete diast

Full text of DOI:10.1021/ja066037m

Published on Web 01/12/2007
Diastereo- and Enantioselective Synthesis of Nitroso
Diels-Alder-Type Bicycloketones Using Dienamine:
Mechanistic Insight into Sequential Nitroso Aldol/Michael
Reaction and Application for Optically Pure 1-Amino-3,4-diol
Synthesis
Norie Momiyama, Yuhei Yamamoto, and Hisashi Yamamoto*
Contribution from the Department of Chemistry, UniVersity of Chicago, 5735 South Ellis
AVenue, Chicago, Illinois 60637
Received August 19, 2006; E-mail: yamamoto@uchicago.edu
Abstract: This article presents complete diastereo- and highly enantioselective synthesis of nitroso Diels-
Alder-type bicycloketones using dienamine. With the hydrogen bonding of two hydroxyls in the bulky
binaphthol 1c, high enantioselectivities and complete diastereoselectivity are realized in 2-oxa-3-aza-
bicycloketone synthesis. On the other hand, R,â-unsaturated ketone can be employed as diene precursor,
utilizing readily available tetrazole catalyst 3b, to provide the 3-oxa-2-aza-bicycloketones in moderate yields
with complete enantioselectivities. Investigation into the reaction utilizing 2-morpholino-4,4-diphenylcyclo-
hexadiene 2d clearly indicated that cyclization with the bulky binaphthol 1c is involved in the sequential
process, the N-nitroso aldol reaction, followed by Michael addition. In addition, optically pure 1-amino-3,4-
diol is synthesized from 2-oxa-3-aza-bicycloketones. Use of p-phenoxynitrosobenzene allows access to
protected amino diol via cleavage of the N-Ph bond.
Introduction
Development of enantioselective addition of carbon nucleo-
phile to nitroso compounds (nitroso aldol (NA) reaction) has
been a topic of continued interest during recent years.1 Extension
of this reaction to unsaturated ketone nucleophiles opened a
practical and stereoselective route to aza oxa bicycloketone
synthesis.2 In this article, completely diastereo- and highly
enantioselective synthesis of nitroso Diels-Alder-type bicy-
cloketones is presented including mechanistic insight into
sequential NA-Michael reaction and application for amino diol
synthesis (eqs 1 and 2). This system offers not only a new
comprehensive perspective of diastereoselection in nitroso
Diels-Alder-type bicycloketone synthesis but also new aspects
in the effective design of the enantioselective process mediated
by hydrogen bonding.
In previous studies, we documented that both the appropriate
amine framework of enamine and the proper choice of acidity
of Brønsted acid catalyst play contributing roles in O/N
regioselectivities in NA reaction. In N-NA reaction, the chiral
alcohol exhibits complete N-selection and a high enantioselec-
tion with piperidine or morpholine enamine (eq 3).3 For NdO
group, alcoholic proton reinforces coordination to the mutually
preferred nitroso oxygen.4 In contrast, the chiral carboxylic acid
catalysts or their analogs exhibit uniformly high O selectivity
and enantioselectivity depending on the amine structure of
enamine (eqs 4 and 5). For instance, the reaction of pre-3a or in
(1) For reviews of nitroso aldol reaction, see: (a) Merino, P.; Tejero, T. Angew.
Chem., Int. Ed. 2004, 43, 2995-2997. (b) Janey, J. M. Angew. Chem., Int.
Ed. 2005, 44, 4292-4300. (c) Yamamoto, H.; Momiyama, N. Chem.
Commun. 2005, 3514-3525. (d) Plietker, B. Tetrahedron: Asymmetry 2005,
16, 3453-3459.
(2) (a) Yamamoto, Y.; Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2004,
126, 5962-5963. For examples reported by other groups, see: (b) Hayashi,
Y.; Yamaguchi, J.; Hibino, K.; Sumiya, T.; Urushima, T.; Mitsuru, S.;
Hashizume, D.; Koshino, H. AdV. Synth. Catal. 2004, 346, 1435-1439.
(c) Sunden, H.; Dahlin, N.; Ibrahem, I.; Adolfsson, H.; Cordova, A.
Tetrahedron Lett. 2005, 46, 3385-3389.
(3) (a) Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2005, 127, 1080-
1081. For examples reported by other groups, see: (b) Guo, H. M.; Cheng,
L.; Cun, L. F.; Gong, L. Z.; Mi, A. Q.; Jiang, Y. Z. Chem. Commun. 2006,
429-431. (c) Kano, T.; Ueda, M.; Takai, J.; Maruoka, K. J. Am. Chem.
Soc. 2006, 128, 6046-6047.
(4) a) Olszewska, T.; Milewska, M. J.; Gdaniec, M.; Polon´ski, T. Chem.
Commun. 1999, 1385-1386. (b) Olszewska, T.; Milewska, M. J.; Gdaniec,
M.; Małszynska, H.; Połon´ski, T. J. Org. Chem. 2001, 66, 501-506.
9
1190
J. AM. CHEM. SOC. 2007, 129, 1190-1195
10.1021/ja066037m CCC: $37.00 © 2007 American Chemical Society

Synthesis of Nitroso Diels−Alder-type Bicycloketones
A R T I C L E S
situ5 formed pyrrolidine or piperidine enamines provided
excellent enantioselectivities of the O-NA product.
Table 1. Modification of BINOL Derivatives in Reaction of
Dienamine 2aa
entry
cat.
yield, %b
ee, %c
config.
1
2
3
4
5
6
7
8
9
BINOL
1a
1b
1c
1d
1e
1f
1g
1h
78
31
45
57
74
41
63
80
60
28
46
52
90
25
17
70
43
20
(1S,4R)
(1S,4R)
(1S,4R)
(1S,4R)
(1S,4R)
(1S,4R)
(1R,4S)
(1R,4S)
(1R,4S)
The goal of this investigation is to realize complete diastereo-
and enantioselective nitroso Diels-Alder-type bicycloketone
synthesis. Despite development of a number of chiral auxiliary-
mediated asymmetric nitroso Diels-Alder reactions,6 the cata-
lytic enantioselective version of this process has not been fully
reported.7 The underlying premise for this study is that good
levels of asymmetric induction as well as regioselection might
be anticipated in the sequential NA/Michael process using
dienamine derived from R, â-unsaturated ketones.
a Reactions were conducted with 30 mol % of catalyst, 1.0 equiv of
nitrosobenzene, and 1.5 equiv of dienamine in toluene at -78 °C. b Isolated
yield. c Determined by HPLC (see Supporting Information).
Results and Discussion
Diastereo- and Enantioselective Synthesis of 2-Oxa-3-aza
Bicycloketone. Considering the data profile in N-NA reaction,3a
our preliminary investigation for an enantioselective 2-oxa-3-
aza bicycloketone synthesis rested on finding a suitable hydrogen-
bonding catalyst capable of facilitating reaction of 2-morpholino-
4,4-dimethyl-1,3-cyclohexadiene without protonation or hydration.
The (4S)-trans-1-naphthyl TADDOL was initially evaluated as
a catalyst in the addition of 2-morpholino-1,3-diene to ni-
trosobenzene. Dropwise addition of dienamine to a cooled
solution (-78 °C) of nitrosobenzene with (4S)-trans-1-naphthyl
TADDOL followed by brief treatment of 1 N HCl in THF
produced the expected nitroso Diels-Alder adduct in 36% yield
with 52 % ee.
To achieve higher yields and better enantioselectivities, we
examined a variety of readily accessible chiral binaphthol
derivatives possessing a proper acidity and more flexible chiral
scaffold. While unmodified BINOL proved to afford low
enantioselectivity (Table 1, entry 1), binaphthol possessing a
tris-m-xylylsilyl group at the 3,3′ position provided a single
regioisomer in high enantioselectivity and moderate yield (Table
1, entry 4). Importantly, the size of steric bulkiness in the
triarylsilyl group played an important role in constructing the
chiral environment. For instance, in the case of diol, although
tris-m-xylylsilyl gave the highest enantioselectivity, the more
sterically bulky and crowded substituents tri-o-tolylsilyl and tris-
1-xylylsilyl caused a significant decline of enantioselectivity
(Table 1, entry 5). When the reactions were conducted in the
presence of tetraol-type catalyst,8 the best result was obtained
in triphenylsilyl substituents (Table 1, entry 7). As the trisaryl
group became bulkier and more crowded, the enantioselectivities
were significantly diminished (Table 1, entries 8 and 9).
On the basis of high enantioselectivity in tris(m-xylyl)silyl
binaphthol, we next optimized amino moieties of dienamine and
reaction solvents. While the enantioselectivity in the N-NA
reaction of the piperidine enamine did not differ from that in
N-NA reaction of morpholine enamine,3a the results provided
by piperidine dienamine were distinguishable from that obtained
using morpholine dienamine in the present reaction. When the
(5) (a) Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247-4250. (b) Brown,
S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc.
2003, 125, 10808-10809. (c) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji,
M. Tetrahedron Lett. 2003, 44, 8293-8296. (d) Bøgevig, A.; Sunde´n, H.;
Co´rdova, A. Angew. Chem., Int. Ed. 2004, 43, 1109-1112. (e) Hayashi,
Y.; Yamaguchi, J.; Sumiya, T.; Shoji, M. Angew. Chem., Int. Ed. 2004,
43, 1112-1115. (f) Momiyama, N.; Torii, H.; Saito, S.; Yamamoto, H.
Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5374-5378. (g) Co´rdova, A.;
Sunde´n, H.; Bøgevig, A.; Johansson, M.; Himo, F. Chem. Eur. J. 2004,
10, 3673-3684. (h) Hayashi, Y.; Yamaguchi, J.; Sumiya, T.; Hibino, K.;
Shoji, M. J. Org. Chem. 2004, 69, 5966-5973. (i) Wang, W.; Wang, J.;
Li, H.; Liao, L. Tetrahedron Lett. 2004, 45, 7235-7238. (j) Hayashi, Y.;
Yamaguchi, J.; Hibino, K.; Sumiya, T.; Urushima, T.; Mitsuru, S.;
Hashizume, D.; Koshino, H. AdV. Synth. Catal. 2004, 346, 1435-1439.
(k) Sunden, H.; Dahlin, N.; Ibrahem, I.; Adolfsson, H.; Cordova, A.
Tetrahedron Lett. 2005, 46, 3385-3389.
(6) For review of nitroso Diels-Alder reactions, see: (a) Streith, J.; Defoin,
A. Synthesis 1994, 1107-1117. (b) Vogt, P. F.; Miller, M. J. Tetrahedron
1998, 54, 1317-1348. (c) Yamamoto, Y.; Yamamoto, H. Eur. J. Org.
Chem. 2006, 2031-2043.
(7) (a) Yamamoto, Y.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 4128-
4129. (b) Yamamoto, Y.; Yamamoto, H. Angew. Chem., Int. Ed. 2005, 44,
7082-7085.
(8) (a) Maruoka, K.; Itoh, T.; Shirasaka, T.; Yamamoto, H. J. Am. Chem. Soc.
1988, 110, 310-312. (b) Maruoka, K.; Murase, N.; Yamamoto, H. J. Org.
Chem. 1993, 58, 2938-2939. (c) Ishihara, K.; Kurihara, H.; Matsumoto,
M.; Yamamoto, H. J. Am. Chem. Soc. 1998, 120, 6920-6930.
9
J. AM. CHEM. SOC. VOL. 129, NO. 5, 2007 1191

A R T I C L E S
Momiyama et al.
Table 2. Solvent Effect in 1c Catalyzed Reaction of 2aa
Scheme 1. Reaction of 2-Morpholino-4,4-diphenylcyclohexadiene
2d
Scheme 2. Reaction of Morpholino-4,4-dimethylcyclohexane
Enamine Catalyzed by 1c
entry
solvent
conditions
yield, %b
ee, %c
1
2
3
4
5
6
toluene
CH2Cl2
THF
mesitylene
n-hexane-CH2Cl2 (9/1)
n-pentane-CH2Cl2 (9/1)
-78 °C, 2 h
-78 °C, 2 h
-78 °C, 12 h
-40 °C, 1 h
-78 °C, 12 h
-78 °C, 12 h
57
65
<5
87
93
92
90
28
7
53
87
90
a Reactions were conducted with 30 mol % of catalyst, 1.0 equiv of
nitrosobenzene, and 1.5 equiv of dienamine in corresponding solvent
at -78 °C. b Isolated yield. c Determined by HPLC (see Supporting
Information).
Table 3. Reaction of Various Aromatic Nitroso Compoundsa
4,4-diphenylcyclohexadiene 2d, N-NA adduct was obtained
exclusively in 27% yield with 61 % ee (Scheme 1). It is
noteworthy to point out that no cycloadduct has been observed
during reaction of diene 2d.
Mechanistic Consideration for N-NA/Michael Reaction.
To rationalize the reaction mechanism, the reaction of 4,4-
diphenyl diene 2d was investigated in detail. When the reaction
of diene 2d and nitrosobenzene was conducted in the absence
of binaphthol 1c, nitroso Diels-Alder cyclized product was
cleanly obtained in 57% yield; no NA adduct was detectable.
In contrast, in the presence of 1 equiv of binaphthol catalyst
1c, the reaction provided N-NA adduct exclusively in 70% yield
while the cycloadduct was yielded in less than 5%. Furthermore,
reaction of diene 2d without binaphthol 1c was carried out for
4 h, followed by addition of 1 equiv of binaphthol 1c, which
afforded cycloadduct in 60% yield: there was thus no change
at all from cycloadduct to N-NA by addition of the binaphthol
1c. These data lead to the following insight in this catalysis. (i)
In the presence of binaphthol 1c, the retro Diels-Alder pathway
to N-NA adduct might be excluded. (ii) The binaphthol has the
capability of governing the N-NA pathway but is unable to
facilitate the [4+2] concerted reaction pathway. In addition,
reaction of morpholino 4,4-dimethylcyclohexyl enamine cata-
lyzed by binaphthol 1c revealed that the absolute configu-
ration of the N-NA product was R, which was the same as that
of cycloadduct at the 4 position (Scheme 2). This result may
also support a sequential mechanism N-NA/Michael reaction
for selective nitroso Diels-Alder synthesis in the present
catalysis.
entry
Ar
yield, %b
ee, %c
1
2
3
4
5
Ph
90
65
78
63
52
90
87
90
92
80
4-Br(C6H4)
4-Ph(C6H4)
4-PhO(C6H4)
3,5-Me2(C6H3)
a Reactions were conducted with 30 mol % of catalyst, 1.0 equiv of
aromatic nitroso compounds, and 1.5 equiv of dienamine in n-pentane-
CH2Cl2 (9:1) at -78 °C. b Isolated yield. c Determined by HPLC (see
Supporting Information).
reaction was conducted with piperidine dienamine under the
same reaction condition, the enantioselectivity decreased to 64%.
A survey of reaction solvents revealed that the mixed solvent
of hydrocarbon and CH2Cl2 was quite effective to achieve both
good yield and high enantioselectivity (Table 2). While the 1c-
catalyzed reaction gave only 22 % ee in CH2Cl2, 1c exhibited
the best performance in n-hexane-CH2Cl2 or n-propane-CH2-
Cl2 among the solvents tested.
With the optimized reaction conditions in hand, the substrate
scope in this system was further explored. Reactions of other
aromatic nitroso compounds were examined with 30 mol % of
tris(m-xylyl)silyl binaphthol 1c in n-propane-CH2Cl2 as solvent
using 2-morpholino-4,4-dimethylcyclohexadiene 2a. para-
Substituted aromatic nitroso compounds possessing electron-
withdrawing and -donating groups reacted to afford cycloadducts
in high enantioselectivities and moderate yields (Table 3).
Otherwise, when the reaction was conducted with 2-morpholino-
The transition states in Figures 1 and 2 provide an attempt
to rationalize the observed sense of stereoinduction and trans-
formation. The overall hydrogen-bond network between the two
hydroxyls of 1c via the Brønsted acid assisted Brønsted acid
system and the nitroso oxygen could be the dominant factor
accounting for the observed diastereo- and enantioselectivities.
The bulky arylsilyl group in 1c would not allow it to attack
diene from the si face due to the steric inhibition with
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1192 J. AM. CHEM. SOC. VOL. 129, NO. 5, 2007

Synthesis of Nitroso Diels−Alder-type Bicycloketones
A R T I C L E S
Table 4. Reaction Scope of R,â-Unsaturated Ketones and
Aromatic Nitroso Compoundsa
Figure 1. Possible transition state in 1c-catalyzed reaction.
entry
n
R, R
Ar
3a yield, %b (eec) 3b yield, %b (eec)
1
2
3
4
5
6
7
8
1 H, H
1 Me, Me
1 Ph, Ph
1 -(OCH2CH2O)- Ph
2 H, H
1 Me, Me
1 Me, Me
1 Me, Me
Ph
Ph
Ph
8% (99% ee) 34% (99% ee)
24% (99% ee) 64% (99% ee)
<1%
56% (99% ee)
57% (99% ee) 61% (98% ee)
51% (99% ee) 14% (99% ee)
47% (99% ee)
Ph
4-Me(C6H4)
3,5-Me2(C6H3)
4-Br(C6H4)
52% (98% ee)
50% (99% ee)
a Reactions were conducted with 20 mol % of catalyst, 1.0 equiv of
nitrosobenzene, and 0.5 equiv of enone at 40 °C. b Isolated yield. c Deter-
mined by HPLC (see Supporting Information).
As a result, the reaction proceeded smoothly in the presence of
pyrrolidinyl tetrazole at 40 °C for 20 h in MeCN as solvent
and afforded cycloadduct in moderate yield and 99 % ee.
Reactions with various R,â-unsaturated ketones were surveyed
(Table 4, entries 2-5). The substrate tolerance for this reaction
was broad, and uniformly high levels of enantiomeric excess
were found in the cycloadduct. Alkyl-, aryl-, and alkoxy-
substituted R,â-unsaturated cyclic ketone reacted with ni-
trosobenzene to give cyclized products in over 98 % ee. In 4,4-
diphenyl substituents, the pyrrolidinyl tetrazole-catalyzed reaction
yielded cycloadduct in 56% yield with 99 % ee; in contrast, it
was not possible to facilitate this reaction with proline. When
cycloheptenone was used as amino diene precursor, proline
provided a better yield than did pyrrolidinyl tetrazole. This
catalyst system was further tested for a representative selection
of aromatic nitroso compounds (Table 4, entries 6-8). Various
aromatic nitroso compounds afforded moderate yields and
exceptionally high enantioselectivities.
Figure 2. Mechanistic model for the reaction of dienamine.
substituents of dienamine at the 4 position. As a consequence,
nucleophilic attack of dienamine is postulated to occur from
the re face as described in TS I, which delivers the N-NA
adduct. The following Michael addition occurs in the case of
dimethyl group via conformational change by 60° counterclock-
wise rotation as TS II. In contrast, the sterically more demanding
diphenyl group did not allow the counterclockwise rotation to
receive the subsequent Michael attack. Thus, the N-NA iminium
compound is hydrolyzed during workup to yield the N-NA
product (Figure 2).
Diastereo- and Enantioselective Synthesis of 3-Oxa-2-aza
Bicycloketone. According to the results in O-NA reaction,3a,5
investigations of diastereo- and enantioselective synthesis of
3-oxa-2-aza bicycloketone were preliminarily evaluated by two
kinds of catalyst systems: Brønsted acid catalysis and chiral
enamine catalysis. Reaction between 2-cyclohexen-1-one and
nitrosobenzene at 40 °C revealed that proline afforded a
completely regio- and enantioselective process; however, no
catalyst turnover was observed. When 4,4-dimethyl-2-cyclo-
hexen-1-one was used as the diene precursor, the yield was
increased to 27% with complete enantioselectivity. (R)-Mandelic
acid was also attempted as the catalyst in reactions of either in
situ generated or preformed amino diene; however, these were
totally unsuccessful.
Transformation of 3-Oxa-2-aza Bicycloketone to Protected
1-Amino-3,4-diol. We next applied 3-oxa-2-aza bicycloketone
to synthesis of protected 1-amino-3,4-diol. It is well known that
nitroso Diels-Alder reaction is widely employed in the
convenient assembly of 1-amino-4-ol.6 Thus, the optically pure
aza oxa bicycloketones reflect rapid access to either 1-amino-
2,4-diol or 1-amino-3,4-diol (Scheme 3).
During the course of our interest in this field, we previously
realized catalytic highly diastereo- and enantioselective nitroso
Diels-Alder reaction using nitroso pyridine in the presence of
chiral phosphine-Cu(PF6)(MeCN)4.7 The provided nitroso
Diels-Alder product can be easily transformed to the protected
optically active amino alcohols. Of two prospective chiral amino
diols synthesized from regioisomeric aza oxa bicycloketones,
while 1-amino-2,4-diol may be readily accessible from chiral
phosphine-copper-catalyzed nitroso Diels-Alder reaction of
nitroso pyridine, the approach to 1-amino-3,4-diol has not yet
been fully established. The challenges to be addressed for
1-amino-3,4-diol synthesis include (A) diastereoselective reduc-
tion of 3-oxa-2-aza bicycloketone and (B) cleavage of the N-Ph
bond.
The completely regio- and enantioselectivity with proline as
catalyst prompted us to employ it for the reaction optimization.
The pyrrolidinyl tetrazole exhibited higher reactivity than
proline, affording the cycloadduct in complete enantioselectivity.
Of the examined solvents, employment of those other than
MeCN led to a significant decline in reactivity or no reaction.
9
J. AM. CHEM. SOC. VOL. 129, NO. 5, 2007 1193

A R T I C L E S
Momiyama et al.
Scheme 3. Conversion to Amino Diol
Table 5. Reactions with Various Nitroso Compoundsa
Table 6. Diastereoselective Reduction of 5a
entry
reductant (equiv.)
solvent
conditions
yield, %b
6a/6b
1
2
3
4
5
L-selectride (2)
Super-H (2)
NaBH4 (2)
THF
THF
MeOH
toluene -78 °C, 1 h
toluene -78 °C, ∼rt, 12 h
-78 °C, 15 min
-78 °C, 15 min
0 °C, 1 h
62
64
90
95
95
1/3
1/6
3/1
DIBAL (2)
4/1
>98/2
(10)
entry
RNO
additive
yield, %b
ee, %c
1
2
3
4
5
4a
4b
4c
4d
4d
<1
<1
7
62
74
a Reactions were conducted with corresponding reductant and 5. b Isolated
yield (see Supporting Information).
98
98
98
AcOH (1 equiv)
in a 3:1 ratio (6a:6b). The reaction in the presence of bulky
borane reductants (entries 1 and 2) exhibited a high level of
diastereoselection for 6b. In contrast, when the reductant was
sterically hindered aluminum, the reaction proceeded to give
the opposite diastereomer 6a with complete selectivity. It is
interesting to note that a completely different diastereoselectivity
took place by switching reductant from bulky borane to bulky
aluminum.
a Reactions were conducted with 20 mol % of catalyst, 1.0 equiv of
aromatic nitroso compounds, and 0.5 equiv of enone at 40 °C. b Isolated
yield. c Determined by HPLC (see Supporting Information).
The reported cleavable nitroso compounds, 1-chloro nitroso-
cyclohexane9 and 2-nitrosopyridine,7 were first evaluated for
reaction of 4,4-dimethyl cyclohexenone in the presence of 20
mol % tetrazole catalyst under the optimized conditions.
Disappointingly, these nitroso compounds did not deliver any
of the objective products (Table 5, entries 1 and 2).
In studying the synthesis of amino diol, the pathway to
protected diols is illustrated in Scheme 4. The obtained
diastereoselective 3-oxa-2-aza bicyclo monol 6a was success-
fully protected by benzoyl chloride, which was further trans-
formed to protected diol through cleavage of the N-O bond
by hydrogenation followed by protection of the generated
hydroxyl group in excellent yield.
The need for a more reactive nitroso compound became
apparent during attempts to develop amino diol synthesis via
N-Ph bond cleavage. For example, p-methoxynitrosobenzene
was added to 4,4-dimethylcyclohexenone in the presence of
pyrrolidinyl tetrazole to afford only 7% of desired product (Table
5, entry 3). This observation led us to examine the use of
p-phenoxynitrosobenzene as a more electrophilic reactant.
Gratifyingly, the reaction of p-phenoxynitrosobenzene provided
the objective cyclized product in 98 % ee and 62 %yield (Table
5, entry 4). Also, the reaction of p-phenoxynitrosobenzene in
the presence of 1 equiv of acetic acid as additive produced the
desired product in 74% yield without loss of enantioselectivity
(Table 5, entry 5).
To cleave the N-phenoxyphenyl group of 8a, representative
single-electron-transfer oxidants such as CAN10 or Ag(NO)3-
11
(NH4)S2O8 were employed; however, these systems did not
lead to the desired free amine. To our delight, use of PhI(OAc)2
as an oxidant was found to be an efficient method to remove
the phenoxyphenyl group. Accordingly, oxidation of 8a was
readily accomplished with PhI(OAc)2 to yield phenol and 9a.
Hydrolysis of 9a proceeded at imine, yielding the primary
amine, which was further protected by acetic anhydride
(Scheme 5).
3-Oxa-2-aza bicycloketone 5 derived from p-phenoxyni-
trosobenzene provided the opportunity to study diastereoselec-
tive reduction (Table 6). Reduction with NaBH4 gave alcohol
(10) (a) Kronenthal, D. R.; Han, C. Y.; Taylor, M. K. J. Org. Chem. 1982, 47,
2765-2768. (b) Ha, D. C.; Hart, D. J. Tetrahedron Lett. 1987, 28, 4489-
4492.
(11) Bhattarai, K; Cainelli, G.; Panunzio, M. Synlett 1990, 229-230.
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Oppolzer, W.; Tamura, O.; Sundarababu, G.; Signer, M. J. Am. Chem. Soc.
1992, 114, 5900-5901.
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1194 J. AM. CHEM. SOC. VOL. 129, NO. 5, 2007

Synthesis of Nitroso Diels−Alder-type Bicycloketones
A R T I C L E S
Scheme 4. Cleavage of N-O Bond and Protection of Hydroxyl Group
Scheme 5. Transformation to Protected Amino Diol
provide a valuable contribution to optically pure amino alcohol
synthesis.
Conclusions
Completely regioselective and efficient enantioselective ni-
troso Diels-Alder-type bicycloketone synthesis has been docu-
mented utilizing preformed- or in situ-generated dienamine. We
find that silyl binaphthol possessing a tris-m-xylylsilyl group
at the 3,3′ position provides single regioisomer 2-oxa-3-aza-
bicycloketone with high enantioselectivities. The reaction
proceeds through sequential N-NA reaction followed by Michael
reaction. For 3-oxa-2-aza-bicycloketone synthesis, use of pyr-
rolidine-derived tetrazole has been established as an effective
catalyst. The R,â-unsaturated ketone can be employed as diene
precursor to provide the cycloadducts in moderate yields with
complete enantioselectivities. In addition, we disclose the
synthesis of optically pure 1-amino-3,4-diol from chiral 3-oxa-
2-aza-bicycloketone. We find that use of p-phenoxynitrosoben-
zene allows access to protected amino diol via cleavage of the
N-Ph bond. The study presented here would open a new avenue
of nitroso Diels-Alder-type bicycloketone synthesis as well as
Acknowledgment. We thank Dr. Ian M. Steele for X-ray
crystallographic analysis. Support for this research has been
provided by the National Institutes of Health (NIH) GM068433-
01 and a grant from the University of Chicago. N.M. acknowl-
edges a graduate fellowship from Abbott Laboratories. Y.Y.
thanks Dr. K. Suzuki, BANYU Pharmaceutical Co., Ltd., for
general support.
Note Added after ASAP Publication: After ASAP publica-
tion of this article on January 12, 2007, Schemes 4 and 5 were
updated to show the correct absolute configuration of 8a, 9a,
and 10a. The Supporting Information was also updated. The
corrected version was published ASAP on January 23, 2007.
Supporting Information Available: Experimental details,
optimization data, and NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
JA066037M
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J. AM. CHEM. SOC. VOL. 129, NO. 5, 2007 1195