Organocatalytic Enantioselective Michael-Acetalization-Henry Reaction Cascade of 2-Hydroxynitrostyrene and 5-Oxohexanal for the Entry to the Hexahydro-6H-benzo[c]chromenones with Four Consecutive Stereogenic Centers and an Approach to Aflatoxin Analogues

Article abstract of DOI:10.1021/acs.joc.7b02178

A domino reaction with the organocatalytic enantioselective Michael-acetalization-Henry reaction of 2-hydroxynitrostyrene and 5-oxohexanal was developed for the synthesis of hexahydro-6H-benzo[c]chromenones with four consecutive stereogenic centers and high enantioselectivity (up to >99% ee). The transformation of a NaBH₄-reduced adduct to the aflatoxin system via the Nef-cyclization process was achieved by the assistant of ZnBr₂.

Full text of DOI:10.1021/acs.joc.7b02178

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Note
Organocatalytic Enantioselective Michael-Acetalization-Henry Reaction
Cascade of 2-Hydroxynitrostyrene and 5-Oxohexanal for the Entry
to the Hexahydro-6H-benzo[c]chromenones with Four Consecutive
Stereogenic Centers and an Approach to Aflatoxin Analogues
Yu-You Hsieh, Arun Raja, Bor-Cherng Hong, Prakash Kotame, Wan-Chen Chang, and Gene-Hsiang Lee
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02178 • Publication Date (Web): 25 Oct 2017
Downloaded from http://pubs.acs.org on October 27, 2017
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Organocatalytic Enantioselective Michael−Acetalization−Henry Reaction
Cascade of 2-Hydroxynitrostyrene and 5-Oxohexanal for the Entry to
the Hexahydro-6H-benzo[c]chromenones with Four Consecutive Stereo-
genic Centers and an Approach to Aflatoxin Analogues
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Yu-You Hsieh,† Arun Raja,† Bor-Cherng Hong,*,† Prakash Kotame,† Wan-Chen Chang,† and Gene-
Hsiang Lee‡
† Department of Chemistry and Biochemistry, National Chung Cheng University, Chia-Yi, 621, Taiwan, R.O.C., and
‡ Instrumentation Center, National Taiwan University, Taipei, 106, Taiwan, R.O.C.
ABSTRACT: A domino reaction with the organocatalytic enan-
tioselective Michael−acetalization−Henry reaction of 2-
hydroxynitrostyrene and 5-oxohexanal was developed for the
synthesis of hexahydro-6H-benzo[c]chromenones with four con-
secutive stereogenic centers and high enantioselectivity (up to
>99% ee). The transformation of a NaBH4-reduced adduct to the
aflatoxin system via the Nef-cyclization process was achieved by
the assistant of ZnBr2.
The chroman motif is an important scaffold found in natural and reaction selectivities, and consequently, the development of
products which widely occur in natural resources and have a related studies for easy access to other derivatives is still a com-
broad spectrum of biological activities. Among them, hexahy- pelling subject. Herein, we report the details of our extension
dro-6H-benzo[c]chromene emerges as a peculiar representative works, the various domino Michael–acetalization–Henry reac-
in this family. Many of chromans have attracted considerable tions of 5-oxohexanal and 2-hydroxynitrostyrenes, which afford
attention owing to their promising pharmacological activities, the hexahydro-6H-benzo[c]chromenones with four consecutive
Figure 1.1 As the result, the total syntheses of the natural prod- stereogenic centers, and also an approach to the aflatoxin sys-
ucts of this family as well as their derivatives have garnered tem via a sequence of reduction-Nef-acetalization reactions.
significant research interest.2 One of the investigations success-
fully delivered an FDA approved therapeutic drug, nabilone,
which was used as an antiemetic and as an adjunct analgesic in
the treatment of neuropathic pain (for example, the symptoms
caused by fibromyalgia and multiple sclerosis), Figure 1. Mo-
rover, several intricate total syntheses of the naturally-occurring
hexahydro-6H-benzo[c]chromene have been revealed. For ex-
ample, a short and divergent total synthesis of (+)-machaeriol B,
(+)-Machaeriol D, and (+)-∆8-THC has been developed by Stu-
der and coworkers, with the key step being the stereospecific
palladium-catalyzed decarboxylative arylation.3 Moreover, a
tandem 5-exo, 6-exo radical cyclization was introduced by Par-
ker et al. as the pivotal step in the total synthesis of (±)-
bisabosqual A.4 Since the turn of this century, many domino
organic reactions with the organocatalyts have been developed
and have enriched the synthetic methodologies. In 2011, Gong
and coworkers reported an asymmetric organocatalytic tandem
Michael–hemiacetalization for the synthesis of chiral dihydro-
coumarins, chromanes, and 4H-chromenes (Scheme 1).5 Coin-
cidentally and almost concurrently, an asymmetric synthesis of
cis-3,4-disubstituted chromans and dihydrocoumarins by the aid
of an organocatalytic Michael–hemiacetalization reaction was
developed by Enders et al., Scheme 1.6 Compellingly, within
six weeks after Gong’s publication, our group revealed a related
organocatalytic Michael–hemiacetalization reaction “on water”,
where the reactions were dramatically accelerated, and with the
extension of the domino Michael–acetalization–Henry reactions
of 2-hydroxynitrostyrenes and glutaraldehyde for the prepara-
tion of hexahydro-6H-benzo[c]chromenones, with the tricyclic
chromane scaffold (Scheme 1).7 Despite the aforementioned
advances in the synthesis of chromanes, a few extensions of the
synthetic methods are as yet required in terms of substrate scope
Figure 1. Naturally-occurring and synthetic bioactive hexahydro-
6H-benzo[c]chromenes.
Scheme 1. Selected examples of the synthesis of the chromanes by
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the aid of asymmetric organocatalysis cascade.
5-oxohexanal (2), followed by the oxidation with PCC to give
the lactone derivatives 4 and 5 (Table 2). For example, to a so-
lution of catalyst I (20 mol %) and HOAc (20 mol %) in water
was added nitrostyrene 1a and ketoaldehyde 2, and the solution
was stirred at ambient temperature (~25 °C) for 28 h, until the
completion of the reaction, followed by dilution with CH2Cl2.
To this reaction mixture was added PCC (3 equiv), and the solu-
tion was stirred at room temperature for 12 h. After the regular
3
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extraction-concentration work up, the diastereomeric ratio of the
1
product was determined by the crude H NMR spectrum of the
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residue and was found to have a ratio of 79:21. The crude prod-
uct was purified by silica-gel chromatography to give lactones
4a and 5a in a total yield of 59% (Table 2, entry 1). As shown
in Table 2, the reaction was quite general with respect to the
various hydroxynitrostyrene derivatives and gave good yields.
The enantioselectivities of the major diastereomeric products
were high with up to 99% ee, (Table 2, entries 1 and 2). The
reason for the inconsistent phenomenon currently is unclear. In
addition, the first step the Michael-acetalization-Henry reaction
was slightly faster and was completed in 18 h when the hy-
droxynitrostyrene 1 bore an electron-withdrawing substituent on
the aromatic ring, e.g., NO2 group (Table 2, entry 5), whereas
the reaction was slightly slower when the electron-donating
groups were presented on the aromatic ring, e.g., OMe, OBn
group (Table 2, entries 4, 7, 8, and 11). The structures and the
absolute configurations of the products (+)-4b and (–)-4c was
unambiguously characterized by single-crystal X-ray analysis
(Figure 2).10
At the outset, a solution of hydroxynitrostyrene 1a and 5-
oxohexanal (2) in 95% ethanol was employed with Jørgensen–
Hayashi catalyst I–PhCO2H (20 mol %) for 96 h, providing
43% yield of the Michael-acetalization-Henry product 3a (Table
1, entry 1).8 In order to find the best reaction media providing
the highest yield, the reaction was screened in a series of sol-
vents (Table 1, entries 2–8). The reactions conducted in THF,
toluene, DMF, and CH3CN were sluggish, giving lesser yields
(22–32%) after a 7-day reaction period (Table 1, entries 2–5).
Additionally, the reaction performed in CHCl3 and CH2Cl2
somewhat expedited the process and afforded higher yields
(Table 1, entries 6–7). Encouragingly and as expected, the reac-
tion of hydroxynitrostyrene 1a and six equivalents of 5-
oxohexanal (2) “on water”9 not only facilitated the reaction,
which was completed in 28 h, but also furnished a higher yield
of the domino Michael-acetalization-Henry product (74% yield,
Table 1, entry 8).
Table 2. Examples of the one-pot Michael−acetalization−Henry
reaction of 1 and 2
entry
product
time
(h)b
28/12
yield
(%)c (4:5)
drd
ee (%)e
1
a. R1=H, R2=H, R3=H
b. R1=Br, R2=H, R3=H
c. R1=Cl, R2=H, R3=H
d. R1=OMe, R2=H, R3=H
e. R1= NO2, R2=H, R3=H
f. R1=CH3, R2=H, R3=H
g. R1=H, R2=OMe, R3=H
h. R1=OBn, R2=H, R3=H
i. R1=H, R2=H, R3=Br
j. R1=H, R2=H, R3=Cl
k. R1=H, R2=H, R3=OMe
59 f 79：21 99
61 88：12 99
59 79：21 99 (96)g
Table 1. Screening of additives and solvents for the domino reac-
2
20/12
22/16
28/16
18/13
24/15
26/17
30/15
26/18
26/19
28/18
tion.a
3
4
61 94：6
99
5
52 90：10 99
6
64 92：8
63 87：13 99 (97)g
99 (99)
7
entry
solvent
additive
(20 mol %)
PhCO2H
time
(h)
96
168
168
168
168
68
yieldb
(%)
43 %
22 %
24 %
30 %
32 %
54 %
59 %
74 %
8
54 90：10 99
54 79：21 99 (92)g
51 80：20 99 (94)g
1
2
3
4
5
6
7
8c
EtOHd
THF
Toluene
DMF
CH3CN
CHCl3
CH2Cl2
H2O
9
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
AcOH
10
11
55 96：4
99
a The reaction was performed on a 0.6 M scale of 1 and 2 (6 equiv) “on
H2O” at ambient temperature (~25 °C). b Reaction time for the Michael-
acetalization-Henry reaction / reaction time for the PCC oxidation. c Yield of
1
the product 4 and 5 isolated. d Determined by H NMR of the crude product
68
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of 4 and 5. e Unless otherwise noted, ee was determined by HPLC with a
f
chiral column (Chiralpak IA); ee of the minor products 5 in parentheses.
a
Isolated yields for the cascade reaction and oxidation was found to be 74%
Unless otherwise noted, the reaction was performed on a 0.6 M
scale of 1a and 2, with the addition of 0.2 equiv of 2 in a 24-h inter-
g
and 86%, respectively. ee was determined by HPLC with a chiral column
b
c
(Chiralpak IC)
val. Yields of 3a isolated. Ketoaldehyde 2 (6 equiv) was added at
once in the beginning of the reaction. d 95% EtOH was used.
With the optimized reaction conditions in hand, the transfor-
mation was studied with a series of hydroxynitrostyrenes 1 and
Consequently, in the attempt to expand the structural diversity
of the prepared product and to broaden the synthetic applica-
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tions, we envisaged that the nitroalkane 6, which could be gen-
2
yamine E would be transformed to nitroso intermediate F, and
erated from the reduction of lactol 3a, could be transformed to
the tetrahydrofuro[2,3-b]benzofuran systems 8, i.e., the aflatox-
in skeleton, since the nitro group could serve as the carbonyl
equivalent by the Nef reaction,11 and with the intramolecular
acetalization-cyclization, Scheme 2.12
the subsequent cyclization via G to afford tetrahydrofuro[2,3-
b]furan 10. An observation supports the intramolecular hy-
droxy-assisted ZnBr2-mediated Nef-cyclization reaction: the
same reaction conditions applied to alcohol 9 analog, 12a and
12b, which lacked the additional hydroxy group on the tether,
gave a tiny amount of the product (Figure 3). In addition, the
reaction of 12c led to the formation of tiny amount of products,
with recovery of most of the starting compound. Thus, the two
alkoxy groups on the benzene moiety increased the nucleo-
philicity of phenolic hydroxyl groups, and hence, triggered the
reaction.
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(+)-4b
(–)-4c
(–)-10
Scheme 3. Expanded application of the reaction sequence.
Figure. 2 Stereo plots of the X-ray crystal structures of (+)-4b,(–)-4c
and (–)-10: C, gray; O, red; N, blue; Br, purple; Cl, green.
Scheme 2. Retrosynthetic analysis of the tetrahydrofuro[2,3-b]benzofurans
with Nef-acetalization transformation.
Scheme 4. Proposed reaction mechanism.
In this context, treatment of nitroalkene 1l13 and 5-oxohexanal
(2) with the preceeding Michael–acetalization–Henry reaction,
followed by the reduction of the acetal intermediate with
NaBH4 in MeOH at 0 °C for 30 min gave the triol 9 in 55 %
yield (Scheme 3). During this process, in addition to the reduc-
tion of the acetal group on intermediate 3l, the ring opening and
reduction of the cyclic tert-β-nitroalcohol group was observed
in the NaBH4 reduction reaction.14,15 Zinc-catalyzed organic
reactions have been applied in many organic syntheses.16
Among them, ZnBr2 has been used for many synthetic trans-
formations.17 Owing to its Lewis-acid property, we suspect that
the Nef reaction of 9 could be achieved by the ZnBr2-mediated
process, which will be a process with less basic or acidic reac-
tion conditions than the traditional Nef process conditions, e.g.,
KOH, HCl, TiCl4, SnCl4, etc. To our delight, treatment of 9 with
1.5 equivalent of ZnBr2 in CH2Cl2 for 30 h gave the expected
tetrahydrofuro[2,3-b]benzofuran 10 in 61% yield. Oxidation of
10 with PCC afforded a 78% yield of ketone 11, which was
analyzed by HPLC with a chiral column, affording 99% ee. It is
noteworthy that the mild Lewis acid ZnBr2 was first successful-
ly applied in the Nef-acetalization reactions, without the need of
treatment with strong base and acid conditions.18 The structure
and the absolute configuration of 10 was revealed by X-ray
diffraction analysis of its single crystal (Figure 2). To account
for the retro-Henry–reduction process as well as the ZnBr2-
mediated Nef-cyclization reaction, a plausible mechanism has
been proposed as depicted in Scheme 4. Initial treatment of
intermediate 3l with NaBH4 would lead to the formation of ke-
tone B intermediate via the retro-Henry–reduction of A, fol-
lowed by the reduction of ketone and acetal to give triol 9. Re-
action of 9 with ZnBr2 would promote the formation of nitro-
nate D, via the neighboring group participation of ZnBr2 with
the hydroxyl group on the tether, followed by cyclization of
phenol to give dihydroxyamine E. After dehydration, dihydrox-
Figure. 3 Alcohol 9 analogs.
CONCLUSION
In summary, a domino Michael–acetalization–Henry reaction
of 5-oxohexanal and 2-hydroxynitrostyrenes has been devel-
oped
for
the
synthesis
of
the
hexahydro-6H-
benzo[c]chromenones with four consecutive stereogenic centers
and high enantioselectivity (up to >99% ee). The structures and
absolute configurations of the products (+)-4b, (–)-4c, and (–)-
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10, have been unambiguously confirmed by single-crystal X-ray 277.0951. HPLC (Chiralcel IA, 8% i-PrOH/hexane, 1.0
crystallographic analyses. Transformation of alcohol 9 to an mL/min, UV λ = 254 nm) tR(major) = 8.51 min, tR(minor) = 11.84
aflatoxin system via the key step of the Nef-cyclization process min.
was achieved with the mild Lewis acid, ZnBr2. Given the wide-
(6aS,9R,10S,10aS)-9-hydroxy-9-methyl-10-nitro-
spread occurrence in nature and the intriguing biological activi- 6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one
(5a):
26
ties of the chromanes and the aflatoxins, these adequate asym- Mp: 139–140 °C; [α]D –31.4 (c 1, CHCl3); 1H NMR (500
metric processes could become a conventional means to the MHz, CDCl3): δ 7.32 – 7.28 (m, 1 H), 7.11 – 7.07 (m, 2 H),
synthesis of related compounds.
7.00 (dd, J = 7.0, 1.0 Hz, 1 H), 4.76 (d, J = 11.0 Hz, 1 H ), 3.95
(dd, J = 13.5, 11.5 Hz, 1 H), 2.41 – 2.34 (m, 1 H), 2.21 – 2.09
(m, 4 H), 1.60 – 1.48 (m, 1 H), 1.41 (s, 3 H); 13C NMR (125
MHz, CDCl3): δ 169.0 (C), 150.9 (C), 129.2 (CH), 125.1 (CH),
124.8 (C), 122.9 (CH), 117.6 (CH), 93.8 (CH), 70.0 (C), 40.7
(CH), 36.4 (CH2), 34.9 (CH), 27.5 (CH3), 20.1 (CH2).
10
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█ EXPERIMENTAL SECTION
General information. All solvents were reagent grade. Re-
actions were normally carried out under nitrogen atmosphere in
glassware. Merck silica gel 60 (particle size 0.04-0.063 mm)
was employed for flash chromatography. Melting points are
(6aR,9R,10S,10aS)-2-bromo-9-hydroxy-9-methyl-10-
1
nitro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one
(4b). White solid. Yield: 57.9 mg (54%). Column chromatog-
raphy eluents: 15% EtOAc–hexane (TLC: Rf = 0.35 developed
twice in 20% EtOAc–hexane). m.p. 213–214 °C; [α]D26 +18.8 (c
uncorrected. H NMR spectra were obtained in CDCl3 unless
otherwise noted at 400 MHz (Bruker DPX-400) or 500 MHz
(Varian-Unity INOVA-500). 13C NMR spectra were obtained at
100 MHz or 125 MHz. E.e. values were measured by HPLC on
a chiral column (chiralpak IC, IA, or IB, 0.46 cm ID x 25 cm,
particle size 5 µ) by elution with IPA–hexane or EtOAc–
hexane. The flow rate of the indicated elution solvent is main-
tained at 1 mL/min, and the retention time of a compound is
recorded accordingly. HPLC was equipped with the ultraviolet
and refractive index detectors. The melting point was recorded
on a melting point apparatus (MPA100 – Automated melting
point system, Stanford Research Systems, Inc.) and is uncor-
rected. The optical rotation values were recorded with a Jasco-
P-2000 digital polarimeter.
General Procedure for the Synthesis of Product 4 and 5. To
a solution of catalyst I (19.5 mg, 0.06 mmol, 0.2 equiv) and
acetic acid (3.6 mg, 0.06 mmol, 0.2 equiv) in H2O (0.5 mL) was
added (E)-2-(2-nitrovinyl)phenol (1a, 50 mg, 0.30 mmol, 1.0
equiv) and 5-oxohexanal (205.5 mg, 1.8 mmol, 6.0 equiv). The
resulting solution was stirred at room temperature (~25 °C) for
28 h until the completion of the reaction, monitored by TLC.
The resulting mixture was extracted with EtOAc (15 mL x 3),
washed with brine (10 mL), dried over MgSO4, and concentrat-
ed in vacuo to give the crude product. A solution of the crude
product in CH2Cl2 (15 mL) and PCC (194.0 mg, 0.9 mmol, 3.0
equiv) and Celite® 545 (400 mg) was stirred at ambient temper-
ature for 12 h until the completion of the reaction, monitored by
TLC. The reaction mixture was diluted with EtOAc (50 mL),
and filtered through Celite® 545. The filtrate was concentrated
in vacuo to give the crude product. The residue was purified by
flash column chromatography with 15% EtOAc–hexane (Rf =
0.46 for 4a and Rf = 0.41 for 5a in 30% EtOAc–hexane) to give
4a (43.9 mg, 47 % yield) and 5a (11.7 mg, 12 % yield) as white
solids.
1
1.0, CHCl3); IR (neat): 3552, 1760, 1548, 1362 cm-1; H NMR
(500 MHz, CDCl3): δ 7.43 (dd, J = 9.0, 2.5 Hz, 1 H), 7.17 (d, J
= 2.5 Hz, 1 H), 6.95 (d, J = 8.5 Hz, 1 H), 4.36 (d, J = 12 Hz, 1
H), 3.94 (dd, J = 12, 6 Hz, 1 H), 3.09 – 3.07 (m, 1 H), 2.81(d, J
= 2.5 Hz, 1 H), 2.34 – 2.29 (m, 1 H), 2.19 – 2.11 (m, 1 H), 1.92
– 1.89 (m, 1 H), 1.69 – 1.62 (m, 1 H), 1.28 (s, 3 H); 13C NMR
(125 MHz, CDCl3): δ 167.7 (C), 150.2 (C), 133.3 (CH),
131.1(CH), 123.1 (C), 119.0 (CH), 117.7 (C), 93.8 (CH), 70.2
(C), 38.5 (CH), 36.9 (CH), 33.8 (CH2), 27.1 (CH3), 19.4 (CH2);
MS (m/z, relative intensity): 357 (M++2, 38), 355 (M+, 39), 310
(24), 308 (24), 295 (95), 293 (100); exact mass calculated for
C14H14BrNO5 (M+): 355.0055; found: 355.0058. HPLC (Chiral-
cel IA, 16% i-PrOH/hexane, 1.0 mL/min, UV λ = 254 nm)
tR(major) = 10.67 min, tR(minor) = 30.83 min.
(6aS,9R,10S,10aS)-2-bromo-9-hydroxy-9-methyl-10-
nitro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one
(5b). White solid. Yield: 7.9 mg, (7 %). Column chromatog-
raphy eluents: 15% EtOAc–hexane (TLC: Rf = 0.32 developed
twice in 20% EtOAc–hexane). m.p. 149–150 °C; [α]D24 –36.2 (c
1
1.0, CHCl3); H NMR (500 MHz, CDCl3): δ 7.42 (dd, J = 8.5,
2.0 Hz, 1 H), 7.11 (d, J = 1.0 Hz, 1 H), 6.98 (d, J = 8.5 Hz, 1 H),
4.74 (d, J = 11.0 Hz, 1 H), 3.95 (dd, J = 14.0., 110 Hz, 1 H),
2.37 – 2.31 (m, 1 H), 2.19 – 2.05 (m, 4 H), 1.42 (s, 3 H); 13C
NMR (125 MHz, CDCl3): δ 168.4 (C), 149.9 (C), 132.3 (CH),
127.0 (C), 126.1 (CH), 119.3 (CH), 117.9 (C), 93.4 (CH), 70.0
(C), 40.3 (CH), 36.3 (CH2), 34.8 (CH), 27.5 (CH3), 20.0 (CH2).
(6aR,9R,10S,10aS)-2-chloro-9-hydroxy-9-methyl-10-
nitro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one
(4c). White solids. Yield: 40.6 mg (43%). Column chromatog-
raphy eluents: 15% EtOAc–hexane (TLC: Rf = 0.50 developed
27
twice in 20% EtOAc–hexane). m.p. 206–207 °C; [α]D1 –6.1 (c
(6aR,9R,10S,10aS)-9-hydroxy-9-methyl-10-nitro-
1, CHCl3); IR (neat): 3550, 1762, 1542, 1362 cm-1; H NMR
(500 MHz, CDCl3): δ 7.28 (dd, J = 9.0, 2.5 Hz, 1 H), 7.02 (d, J
= 2.5 Hz, 1 H), 7.00 (d, J = 9.0 Hz, 1 H), 4.38 (d, J = 12.5 Hz, 1
H), 3.94 (dd, J = 11.8, 6.0 Hz, 1 H), 3.09 – 3.07 (m, 1 H), 2.82
(d, J = 2.0 Hz, 1 H), 2.33 – 2.29 (m, 1 H), 2.19 – 2.10 (m, 1 H),
1.91 – 1.88 (m, 1 H), 1.69 – 1.63 (m, 1 H), 1.28 (s, 3 H); 13C
NMR (125 MHz, CDCl3): δ 167.8 (C), 149.7 (C), 130.30 (CH),
130.28 (C), 128.2 (CH), 122.7 (C), 118.7 (CH), 93.8 (CH), 70.2
(C), 38.5 (CH), 37.0 (CH), 33.7 (CH2), 27.1 (CH3), 19.4 (CH2);
MS (m/z, relative intensity): 313 (M++2, 1.1), 311 (M+, 3.2),
264 (2), 251 (3), 58 (100); Exact mass calculated for
C14H14ClNO5 (M+): 311.0561; found: 311.0559. HPLC (Chiral-
6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one
(4a).
26
m.p. 198–200 °C; [α]D –56.9 (c 1, CHCl3); IR (neat): 3540,
1
1767, 1545, 1362 cm-1; H NMR (500 MHz, CDCl3): δ 7.31
(dd, J = 8.0, 7.5 Hz, 1 H), 7.10 – 7.00 (m, 3 H), 4.39 (d, J = 12.0
Hz, 1 H), 3.96 (dd, J = 12.0, 6.0 Hz, 1 H), 3.12 (s, 1 H), 2.92 (s,
1 H), 2.32 (dd, J = 14.0, 2.0 Hz, 1 H), 2.20 – 2.11 (m, 1 H), 1.89
(d, J = 14.0 Hz, 1 H), 1.70 – 1.60 (m, 1 H), 1.27 (s, 3 H); 13C
NMR (125 MHz, CDCl3): δ 168.4 (C), 151.1 (C), 130.2 (CH),
128.3 (CH), 125.2 (CH), 121.1 (C), 117.3 (CH), 94.2 (CH), 70.1
(C), 38.8 (CH), 37.2 (CH), 33.8 (CH2), 27.1 (CH3), 19.5 (CH2);
MS (m/z, relative intensity): 277 (M+, 14), 230 (21), 215 (100);
exact mass calculated for C14H15NO5 (M+): 277.0950; found:
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cel IA, 16% i-PrOH/hexane, 1.0 mL/min, UV λ = 254 nm) 3.89 (dd, J = 12.0, 5.5 Hz, 1 H), 3.09 – 3.06 (m, 1 H), 2.92 (d, J
tR(major) = 10.92 min, tR(minor) = 37.79 min.
(6aS,9R,10S,10aS)-2-chloro-9-hydroxy-9-methyl-10-
nitro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one
= 3.0 Hz, 1 H), 2.33 – 2.28 (m, 1 H), 2.26 (s, 3 H), 2.17 – 2.09
(m, 1 H), 1.91 – 1.86 (m, 1 H), 1.70 – 1.62 (m, 1 H), 1.27 (s, 3
H); 13C NMR (125 MHz, CDCl3): δ 168.6 (C), 149.0 (C), 134.9
3
4
5
6
7
8
9
(5c). White solid. Yield: 15.0 mg (16 %). Column chromatog- (C), 130.7 (CH), 128.5 (CH), 120.7 (C), 117.0 (CH), 94.2 (CH),
raphy eluents: 15% EtOAc–hexane (TLC: Rf = 0.45 developed 70.1 (C), 38.8 (CH), 37.2 (CH), 33.8 (CH2), 27.1 (CH3), 20.7
twice in 20% EtOAc–hexane). m.p. 120–121 °C; [α]D27 –49.7 (c (CH3), 19.5 (CH2); MS (m/z, relative intensity): 291 (M+, 35),
1
0.5, CHCl3); H NMR (500 MHz, CDCl3): δ 7.27 (dd, J = 9.0, 244 (15), 229 (100); exact mass calculated for C15H17NO5 (M+):
2.0 Hz, 1 H), 7.04 (d, J = 9.0 Hz, 1 H), 6.98 (s, 1 H), 4.74 (d, J 291.1107; found: 291.1110. HPLC (Chiralcel IA, 16% i-
= 11.0 Hz, 1H), 3.94 (dd, J = 14.0 , 11.5 Hz, 1H), 2.39 – 2.31 PrOH/hexane, 1.0 mL/min, UV λ = 254 nm) tR(major) = 9.55 min,
(m, 1 H), 2.20 – 2.05 (m, 5 H), 1.42 (s, 3 H); 13C NMR (125 tR(minor) = 23.04 min.
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MHz, CDCl3): δ 168.4 (C), 149.4 (C), 130.5 (C), 129.2 (CH),
126.6 (C), 123.3 (CH), 118.9 (CH), 93.4 (CH), 70.0 (C), 40.3 6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one
(CH), 36.3 (CH2), 34.9 (CH), 27.5 (CH3), 20.0 (CH2). HPLC White solids. Yield: 4.5 mg (5%). Column chromatography
(Chiralcel IC, 14% EtOAc/hexane, 1.0 mL/min, UV λ = 280 eluents: 15% EtOAc–hexane (TLC: Rf = 0.38 developed three
nm) tR(major) = 11.26 min, tR(minor) = 14.37 min.
(6aR,9R,10S,10aS)-9-hydroxy-2-methoxy-9-methyl-10-
nitro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one
(6aS,9R,10S,10aS)-9-hydroxy-2,9-dimethyl-10-nitro-
(5f).
times in 20% EtOAc–hexane). m.p. 144–145 °C; [α]D26 –59.5 (c
0.5, CHCl3); 1H NMR (500 MHz, CDCl3): δ 7.08 (d, J = 8.5 Hz,
1 H), 6.98 (d, J = 8.5 Hz, 1 H), 6.79 (s, 1 H), 4.75 (d, J = 11.5
(4d). White solids. Yield: 55.9 mg (61%). Column chromatog- Hz, 1 H), 3.92 (dd, J = 13.5, 11.5 Hz, 1H), 2.37 – 2.31 (m, 1 H),
raphy eluents: 15% EtOAc–hexane (TLC: Rf = 0.34 developed 2.27 (s, 3 H), 2.20 – 2.07 (m, 4 H), 1.41 (s, 3 H); 13C NMR (125
27
in 30% EtOAc–hexane). m.p. 178–179 °C; [α]D1 –14.4 (c 1, MHz, CDCl3): δ 169.3 (C), 148.7 (C), 134.8 (C), 129.6 (CH),
CHCl3); IR (neat): 3552, 1760, 1542, 1369 cm-1; H NMR (500 124.5 (C), 123.2 (CH), 117.4 (CH), 93.8 (CH), 70.0 (C), 40.7
MHz, CDCl3): δ 6.98 (d, J = 9.0 Hz, 1 H), 6.82 (dd, J = 9.0, 3.0 (CH), 36.4 (CH2), 34.8 (CH), 27.6 (CH3), 21.1 (CH3), 20.0
Hz, 1 H), 6.53 (d, J = 3.0 Hz, 1 H), 4.38 (d, J = 12.0 Hz, 1 H), (CH2). HPLC (Chiralcel IA, 16% i-PrOH/hexane, 1.0 mL/min,
3.90 (dd, J = 12.0, 6.0 Hz, 1 H), 3.73 (s, 3 H), 3.09 – 3.07 (m, 1 UV λ = 238 nm) tR(major) = 11.17 min, tR(minor) = 21.21 min.
H), 2.87 (d, J = 3.0 Hz, 1 H), 2.34 – 2.29 (m, 1 H), 2.17 – 2.10
(6aR,9R,10S,10aS)-9-hydroxy-3-methoxy-9-methyl-10-
(m, 1 H), 1.91 – 1.87 (m, 1 H), 1.70 – 1.62 (m, 1 H), 1.27 (s, 3 nitro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one
H); 13C NMR (125 MHz, CDCl3): δ 168.5 (C), 156.5 (C), 144.9 (4g). White solids. Yield: 50.7 mg (55%). Column chromatog-
(C), 121.9 (C), 118.1 (CH), 115.4 (CH), 113.1 (CH), 94.1 (CH), raphy eluents: 15% EtOAc–hexane (TLC: Rf = 0.42 developed
26
70.1 (C), 55.7 (CH3), 38.7 (CH), 37.5 (CH), 33.8 (CH2), 27.1 three times in 20% EtOAc–hexane). m.p. 224–225 °C; [α]D
–
(CH3), 19.5 (CH2); MS (m/z, relative intensity): 308 (M++1, 18), 54.7 (c 0.5, CHCl3); IR (neat): 3567, 1766, 1546, 1361 cm-1; 1H
307 (M+, 100), 260 (17); Exact mass calculated for C15H17NO6 NMR (500 MHz, CDCl3): δ 6.91 (d, J =8.5 Hz, 1 H), 6.62 (d, J
(M+): 307.1056; found: 307.1055. HPLC (Chiralcel IA, 16% i- = 2.5 Hz, 1 H), 6.60 (s, 1 H), 4.34 (d, J = 12.0 Hz, 1 H), 3.90
PrOH/hexane, 1.0 mL/min, UV λ = 254 nm) tR(major) = 11.08 (dd, J = 12.0, 6.0 Hz, 1 H), 3.76 (s, 3 H), 3.10 – 3.09 (m, 1 H),
min, tR(minor) = 28.97 min.
(6aR,9R,10S,10aS)-9-hydroxy-9-methyl-2,10-dinitro-
6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one
2.89 (s, 1 H), 2.33 – 2.28 (m, 1 H), 2.20 – 2.10 (m, 1 H), 1.88
(d, J = 14.5 Hz, 1 H), 1.68 – 1.60 (m, 1 H), 1.26 (s, 3 H); 13C
(4e). NMR (125 MHz, CDCl3): δ 168.4 (C), 161.0 (C), 152.0 (C),
White solids. Yield: 50 mg (52%). Column chromatography 128.8 (CH), 112.8 (C), 111.0 (CH), 102.9 (CH), 94.6 (CH), 70.1
eluents: 15% EtOAc–hexane (TLC: Rf = 0.50 developed three (C), 55.5 (CH3), 39.0 (CH), 36.7 (CH), 33.8 (CH2), 27.1 (CH3),
times in 20% EtOAc–hexane). m.p. 207–208 °C; [α]D26 +68.2 (c 19.5 (CH2); MS (m/z, relative intensity): 307 (M+, 16), 260 (18),
1
1, CHCl3); IR (neat): 3552, 1760, 1542, 1369 cm-1; H NMR 245 (100); exact mass calculated for C15H17NO6 (M+):
(500 MHz, CDCl3): δ 8.23 (d, J = 9.0, 2.5 Hz, 1 H), 7.97 (d, J = 307.1056; found: 307.1056. HPLC (Chiralcel IA, 16% i-
2.5 Hz, 1 H), 7.22 (d, J = 9.0 Hz, 1 H), 4.38 (d, J = 12.0 Hz, 1 PrOH/hexane, 1.0 mL/min, UV λ = 280 nm) tR(major) = 8.66 min,
H), 4.12 (dd, J = 12.0, 6.0 Hz, 1 H), 3.17 – 3.14 (m, 1 H), 2.79 tR(minor) = 20.34 min.
(d, J = 3.0 Hz, 1 H), 2.36 – 2.31 (m, 1 H), 2.25 – 2.16 (m, 1 H),
(6aS,9R,10S,10aS)-9-hydroxy-3-methoxy-9-methyl-10-
1.96 – 1.92 (m, 1 H), 1.71 – 1.64 (m, 1 H), 1.31 (s, 3 H); 13C nitro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one
NMR (125 MHz, CDCl3): δ 166.7 (C), 155.5 (C), 144.5 (C), (5g). White solids. Yield: 7.6 mg (8%). Column chromatog-
126.1 (CH), 124.3 (CH), 122.3 (C), 118.3 (CH), 93.6 (CH), 70.2 raphy eluents: 15% EtOAc–hexane (TLC: Rf = 0.35 developed
27
(C), 38.3 (CH), 37.0 (CH), 33.8 (CH2), 27.0 (CH3), 19.3 (CH2); three times in 20% EtOAc–hexane). m.p. 117–118 °C; [α]D
–
MS (m/z, relative intensity): 322 (M+, 3), 307 (11), 59 (100); 90.5 (c 1, CHCl3); H NMR (500 MHz, CDCl3): δ 6.89 (d, J =
exact mass calculated for C14H14N2O7 (M+): 322.0801; found: 8.5 Hz, 1 H), 6.65 (d, J = 2.5 Hz, 1 H), 6.62 (dd, J = 8.5, 2.5 Hz,
322.0800. HPLC (Chiralcel IA, 25% i-PrOH/hexane, 1.0 1 H), 4.71 (d, J = 11.0 Hz, 1 H), 3.88 (dd, J = 13.5, 11.5 Hz, 1
mL/min, UV λ = 280 nm) tR(major) = 9.03 min, tR(minor) = 63.01 H), 3.76 (s, 3 H), 2.37 – 2.31 (m, 1 H), 2.22 – 2.08 (m, 4 H),
1
min.
1.39 (s, 3 H); 13C NMR (125 MHz, CDCl3): δ 169.0 (C), 160.1
(C), 151.7 (C), 123.5 (CH), 116.5 (C), 110.5 (CH), 103.5 (CH),
(4f). 94.2 (CH), 70.0 (C), 55.6 (CH3), 41.1 (CH), 36.4 (CH2), 34.5
(6aR,9R,10S,10aS)-9-hydroxy-2,9-dimethyl-10-nitro-
6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one
White solids. Yield: 51.2 mg (59%). Column chromatography (CH), 27.5 (CH3), 20.0 (CH2). HPLC (Chiralcel IC, 20%
eluents: 15% EtOAc–hexane (TLC: Rf = 0.45 developed three EtOAc/hexane, 1.0 mL/min, UV λ = 280 nm) tR(major) = 9.41
26
times in 20% EtOAc–hexane). m.p. 218–219; [α]D –23.8 (c 1, min, tR(minor) = 13.55 min.
1
CHCl3); IR (neat): 3543, 1757, 1548, 1367 cm-1; H NMR (500
(6aR,9R,10S,10aS)-2-(benzyloxy)-9-hydroxy-9-methyl-
MHz, CDCl3): δ 7.10 (dd, J = 8.5, 2.0 Hz, 1 H), 6.94 (d, J = 8.5 10-nitro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-
Hz, 1 H), 6.80 (d, J = 2.0 Hz, 1 H), 4.37 (d, J = 12.5 Hz, 1 H), one (4h). White solids. Yield: 62.7 mg (54%). Column chroma-
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tography eluents: 15% EtOAc–hexane (TLC: Rf = 0.55 devel- 147.1(C), 131.0 (CH), 126.6 (CH), 125.4 (CH), 122.8 (C), 122.4
oped three times in 20% EtOAc–hexane). m.p. 163–164 °C; (C), 93.9 (CH), 70.1 (C), 38.6 (CH), 37.5 (CH), 33.7 (CH2),
[α]D25 +8.6 (c 1, CHCl3); IR (neat): 3540, 1759, 1549, 1375 cm- 27.1 (CH3), 19.4 (CH2); MS (m/z, relative intensity): MS (m/z,
1
1; H NMR (500 MHz, CDCl3): δ 7.38 – 7.31 (m, 5 H), 6.98 (d, relative intensity): 313 (M++2, 6), 311 (M+, 20), 264 (11), 251
J = 9.0 Hz, 1 H), 6.89 (dd, J = 8.5, 2.5 Hz, 1 H), 6.61 (d, J = 2.5 (28), 249 (100); exact mass calculated for C14H14ClNO5 (M+):
Hz, 1 H), 4.97 (s, 2 H), 4.38 (d, J = 11.5 Hz, 1 H), 3.89 (dd, J = 311.0561; found: 311.0563. HPLC (Chiralcel IA, 16% i-
12.0, 6.0 Hz, 1 H), 3.07 (s, 1 H), 2.86 (d, J = 2.5 Hz, 1 H), 2.35 PrOH/hexane, 1.0 mL/min, UV λ = 238 nm) tR(major) = 9.00 min,
– 2.28 (m, 1 H), 2.18 – 2.10 (m, 1 H), 1.90 – 1.85 (m, 1 H), 1.70 tR(minor) = 34.26 min.
– 1.60 (m, 1 H), 1.23 (s, 3 H); 13C NMR (125 MHz, CDCl3): δ
(6aS,9R,10S,10aS)-4-chloro-9-hydroxy-9-methyl-10-
10
11
12
13
14
15
16
17
18
19
20
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22
23
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33
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35
36
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168.5 (C), 155.6 (C), 145.1 (C), 136.3 (C), 128.7 (2CH), 128.1 nitro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one
(CH), 127.5 (2CH), 121.9 (C), 118.2 (CH), 116.5 (CH), 114.1 (5j). White solids. Yield: 9.5 mg (10%). Column chromatog-
(CH), 94.1 (CH), 70.6 (CH2), 70.2 (C), 38.7 (CH), 37.5 (CH), raphy eluents: 15% EtOAc–hexane (TLC: Rf = 0.40 developed
26
33.8 (CH2), 27.1 (CH3), 19.5 (CH2); MS (m/z, relative intensi- three times in 20% EtOAc–hexane). m.p. 173–174 °C; [α]D
–
ty): 384 (M++1, 3), 383 (M+, 11), 91 (100) exact mass calculat- 74.3 (c 0.3, CHCl3); 1H NMR (500 MHz, CDCl3): δ 7.37 (d, J =
ed for C21H21NO6 (M+): 383.1369; found: 383.1367. HPLC 8.0 Hz, 1 H), 7.04 (dd, J = 8.0, 8.0 Hz, 1 H), 6.91 (d, J = 7.5 Hz,
(Chiralcel IA, 16% i-PrOH/hexane, 1.0 mL/min, UV λ = 254 1 H), 4.75 (d, J = 11.5 Hz, 1 H), 3.97 (dd, J = 13.0, 12.5 Hz, 1
nm) tR(major) = 17.33 min, tR(minor) = 38.37 min.
H), 2.42 – 2.35 (m, 1 H), 2.21 – 2.11 (m, 4 H), 1.42 (s, 3 H); 13
C
(6aR,9R,10S,10aS)-4-bromo-9-hydroxy-9-methyl-10-
nitro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one
NMR (125 MHz, CDCl3): δ 167.7 (C), 146.9 (C), 130.1 (CH),
126.8 (C), 125.3 (CH), 123.0 (C), 121.1 (CH), 93.6 (CH), 70.0
(4i). White solids. Yield: 45.6 mg (43%). Column chromatog- (C), 40.3 (CH), 36.3 (CH2), 35.3 (CH), 27.5 (CH3), 20.0 (CH2).
raphy eluents: 15% EtOAc–hexane (TLC: Rf = 0.50 developed HPLC (Chiralcel IC, 15% EtOAc/hexane, 1.0 mL/min, UV λ =
26
three times in 20% EtOAc–hexane). m.p. 206–207 °C; [α]D
–
254 nm) tR(major) = 10.65 min, tR(minor) = 10.34 min.
1
97.5 (c 1, CHCl3); IR (neat): 3531, 1769, 1549, 1368 cm-1; H
(6aR,9R,10S,10aS)-9-hydroxy-4-methoxy-9-methyl-10-
NMR (500 MHz, CDCl3): δ 7.55 (dd, J = 7.5, 2.5 Hz, 1 H), 6.99 nitro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one
– 6.93 (m, 2 H), 4.38 (d, J = 12.0 Hz, 1 H), 3.98 (dd, J = 12.0, (4k). White solids. Yield: 50.3 mg (55%). Column chromatog-
6.0 Hz, 1 H), 3.13 (dd, J = 5.5, 4.0 Hz, 1 H), 2.87 (d, J = 3.0 Hz, raphy eluents: 15% EtOAc–hexane (TLC: Rf = 0.32 developed
26
1 H), 2.36 – 2.30 (m, 1 H), 2.21 – 2.13 (m, 1 H), 1.93 – 1.88 (m, in 30% EtOAc–hexane). m.p. 183–184 °C; [α]D1 –63.6 (c 1,
1 H), 1.70 – 1.66 (m, 1 H), 1.28 (s, 3 H); 13C NMR (125 MHz, CHCl3); IR (neat): 3528, 1759, 1549, 1368 cm-1; H NMR (500
CDCl3): δ 167.2 (C), 148.2 (C), 134.1 (CH), 127.4 (CH), 125.9 MHz, CDCl3): δ 7.03 (dd, J = 8.0, 8.0 Hz, 1 H), 6.91 (d, J = 8.0
(CH), 122.8 (C), 111.1 (C), 93.9 (CH), 70.1 (C), 38.6 (CH), Hz, 1 H), 6.59 (d, J = 7.5 Hz, 1 H), 4.38 (d, J = 12.0 Hz, 1 H),
37.6 (CH), 33.7 (CH2), 27.1 (CH3), 19.3 (CH2); MS (m/z, rela- 3.94 (dd, J = 12.0, 6.0 Hz, 1 H), 3.87 (s, 3 H), 3.12 (s, 1 H),
tive intensity): 357 (M++2, 32), 355 (M+, 32), 310 (16), 308 2.93 (d, J = 2.0 Hz, 1 H), 2.32 (d, J = 14.5 Hz, 1 H), 2.19–2.11
(17), 295 (91), 293 (100); exact mass calculated for (m, 1 H), 1.89 (d, J = 14.5 Hz, 1 H), 1.69 – 1.63 (m, 1 H), 1.27
C14H14O5NBr (M+): 355.0055; found: 355.0057. HPLC (Chiral- (s, 3 H); 13C NMR (125 MHz, CDCl3): δ 167.8 (C), 147.7(C),
cel IA, 16% i-PrOH/hexane, 1.0 mL/min, UV λ = 238 nm) 140.3(C), 125.2 (CH), 122.0 (C), 119.5 (CH), 112.7 (CH), 94.1
tR(major) = 9.21 min, tR(minor) = 30.59 min.
(CH), 70.1 (C), 56.1 (CH3), 38.6 (CH), 37.4 (CH), 33.8 (CH2),
27.1 (CH3), 19.5 (CH2); MS (m/z, relative intensity): 308
(M++1, 17), 307 (M+, 100); exact mass calculated for
(6aS,9R,10S,10aS)-4-bromo-9-hydroxy-9-methyl-10-
nitro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one
(5i). White solids. Yield:12.1 mg (11%). Column chromatog- C15H17NO6 (M+): 307.1056; found: 307.1057. HPLC (Chiralcel
raphy eluents: 15% EtOAc–hexane (TLC: Rf = 0.46 developed IA, 32% i-PrOH/hexane, 1.0 mL/min, UV λ = 238 nm) tR(major)
=
26
three times in 20% EtOAc–hexane). m.p. 166–167 °C; [α]D
–
7.53 min, tR(minor) = 29.33 min.
(R)-2-((S)-1-(2-hydroxy-4,6-bis(methoxymethoxy)phenyl)-
1
56.5 (c 0.4, CHCl3); H NMR (500 MHz, CDCl3): δ 7.53 (dd, J
= 7.5, 2.0 Hz, 1 H), 6.99 – 6.94 (m, 2 H), 4.75 (d, J = 11.0 Hz, 1 2-nitroethyl)hexane-1,5-diol (9). Colorless oil. Yield: 66.6 mg
H), 3.98 (dd, J = 13.5, 11.0 Hz, 1 H), 2.41 – 2.35 (m, 1 H), 2.24 (55%). Column chromatography eluents: 70% EtOAc–hexane
– 2.09 (m, 4 H), 1.42 (s, 3 H); 13C NMR (125 MHz, CDCl3): δ (TLC: Rf = 0.21 developed in 70% EtOAc–hexane). IR (neat):
167.8 (C), 147.9 (C), 133.1 (CH), 126.8 (C), 125.7 (CH), 121.9 3332, 1549, 1378 cm-1; 1H NMR (500 MHz, CDCl3, * de-
(CH), 111.8 (C), 93.6 (CH), 70.0 (C), 40.4 (CH), 36.3 (CH2), notes the isomeric peak): δ 6.34 (s, 1 H), 6.19 (s, 1 H), 5.11 (s, 2
35.3 (CH), 27.5 (CH3), 20.0 (CH2). HPLC (Chiralcel IC, 15% H), 5.06 (s, 2 H), 4.91 – 4.85 (m, 1 H), 4.21 – 4.15 (m, 1 H),
EtOAc/hexane, 1.0 mL/min, UV λ = 254 nm) tR(major) = 11.43 3.73 – 3.64 (m, 2 H), 3.60 – 3.58 (m, 1 H), 3.47 (s, 3 H), 3.44 (s,
min, tR(minor) = 14.46 min.
(6aR,9R,10S,10aS)-4-chloro-9-hydroxy-9-methyl-10-
nitro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one
3 H), 2.18 – 2.02 (m, 1 H), 1.52 – 1.30 (m, 4 H), 1.09 (d, J= 6
Hz, 3 H)*, 1.06 (d, J= 6.5 Hz, 3 H)*; 13C NMR (125 MHz,
CDCl3, * denotes the isomeric peak): δ 157.6 (C)*, 157.5 (C)*,
(4j). White solids. Yield: 37.9 mg (41%). Column chromatog- 156.4 (C), 107.5 (C), 97.9 (CH)*, 97.8 (CH)*, 95.9 (CH)*, 95.8
raphy eluents: 15% EtOAc–hexane (TLC: Rf = 0.48 developed (CH)*, 94.8 (CH2)*, 94.3 (CH2)*, 77.6 (CH2), 68.4 (CH)*, 68.3
26
three times in 20% EtOAc–hexane). m.p. 205–206 °C; [α]D
–
(CH)*, 68.0 (CH), 63.3 (CH2)*, 62.7 (CH2)*, 56.4 (CH3)*, 56.1
1
86.4 (c 1, CHCl3); IR (neat): 3742, 1757, 1548, 1368 cm-1; H (CH3)*, 41.9 (CH), 36.0 (CH2)*, 35.8 (CH)*, 24.5 (CH2), 23.4
NMR (500 MHz, CDCl3): δ 7.39 (dd, J = 8.0, 1.5 Hz, 1 H), 7.02 (CH3)*, 23.1 (CH3)*; MS (m/z, relative intensity): 403 (M+, 3),
(dd, J = 8.0, 7.5 Hz, 1 H), 6.93 (dd, J = 8.0, 1.5 Hz, 1 H), 4.38 385 (7), 267 (9), 354 (100); exact mass calculated for
(d, J = 12.0 Hz, 1 H), 3.99 (dd, J = 12.5, 6.0 Hz, 1 H), 3.13 (dd, C18H29NO9 (M+): 403.1842; found: 403.1849.
J = 4.5, 4.0 Hz, 1 H), 2.86 (d, J = 2.5 Hz, 1 H), 2.36 – 2.31 (m,
4-[(2S,3R,6R)-10,12-bis(methoxymethoxy)-5,7-
1 H), 2.21 – 2.13 (m, 1 H), 1.93 – 1.89 (m, 1 H), 1.71 – 1.63 (m, dioxatricyclo[6.4.0.02,6]dodeca-1(12),8,10-trien-3-yl]butan-2-ol
1 H), 1.28 (s, 3 H); 13C NMR (125 MHz, CDCl3): δ 167.1 (C), (10). To a solution of alcohol 9 (15 mg, 0.037 mmol) in dry
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CH2Cl2 (4 mL) was added ZnBr2 (12.6 mg, 0.056 mmol, 1.5 matography with 20% EtOAc-hexane (Rf = 0.5 for 1b in 30 %
equiv) at ambient temperature. The resulting solution was EtOAc-hexane) to afford product 1b (214.5 mg, 88% yield) as a
stirred at room temperature for 30 h until the completion of the yellow solid.
reaction, monitored by TLC. The reaction was quenched by the
(E)-4-bromo-2-(2-nitrovinyl)phenol (1b). Yellow solids.
addition of aqueous NaHCO3 solution (3 mL). The reaction Yield: 214.5 mg (88%). Column chromatography eluents: 20%
mixture was extracted with EtOAc (20 mL x 2), washed with EtOAc–hexane (TLC: Rf = 0.5 in 30% EtOAc–hexane). m.p.
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brine (10 mL), dried over MgSO4, and concentrated in vacuo to 117–118 °C; IR (neat): 3324, 1620, 1554, 1334 cm-1; H NMR
give the crude product. The residue was purified by flash col- (500 MHz, acetone-d6): δ 10.02 (brs, 1 H), 8.14 (d, J = 14 Hz, 1
umn chromatography with 30% EtOAc–hexane (Rf = 0.65 in H), 8.09 (d, J = 14 Hz, 1 H), 7.84 (d, J = 2.5 Hz, 1 H), 7.48 (dd,
70% EtOAc–hexane), to give alcohol 10 (8 mg, 61%) as a white J = 9.0, 2.5 Hz, 1 H), 7.01 (d, J = 9.0 Hz, 1 H);19 13C NMR (125
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solid. Select data for 10: m.p. 74–75 °C; [α]D 1 –22.5 (c 1, MHz, acetone-d6): δ 157.8 (C), 139.8 (CH), 136.5 (CH), 134.7
CHCl3); IR (neat): 3421, 1609, 1143, 1049 cm-1; H NMR (500 (CH), 134.5 (CH), 120.6 (C), 119.2 (CH), 112.5 (C); EI-MS
MHz, CDCl3, *denotes the isomeric peak): δ 6.29 – 6.27 (m, 2 (m/z, relative intensity): 245 (M++3, 21), 243 (M++1, 22), 198
H), 6.22 (s, 1 H), 5.18 – 5.13 (m, 2 H), 5.08 (s, 2 H), 3.86 – 3.84 (100), 196 (100); exact mass calculated for C8H6O3NBr (M+):
(m, 1 H), 3.78 (d, J = 3.0 Hz, 2 H), 3.63 (dd, J = 6.0, 3.0 Hz, 1 242.9531; found: 242.9536.
H), 3.47 (s, 3 H), 3.46 (s, 3 H), 3.44 (s, 6 H), 2.35 – 2.32 (m, 1
(E)-4-chloro-2-(2-nitrovinyl)phenol (1c). Yellow-orange
H), 1.63 – 1.49 (m, 4 H), 1.23 (d, J = 3.5 Hz, 3 H)*, 1.21 (d, J = solid. Yield: 171.6 mg (86%). Column chromatography eluents:
3.5 Hz, 3H)*; 13C NMR (125 MHz, CDCl3
*
de- 20% EtOAc–hexane (TLC: Rf = 0.50 in 30% EtOAc–hexane).
1
notes the isomeric peak): δ 160.81 (C)*, 160.79 (C),* 159.2 (C), m.p. 162–163 °C; IR (neat): 3514, 1622, 1487, 1337 cm-1; H
153.92 (C)*, 153.88 (C),* 111.7 (CH),* 111.6 (CH),* 108.7 NMR (500 MHz, acetone-d6): δ 10.00 (brs, 1 H), 8.16 (d, J = 14
(C)*, 108.6 (C),* 95.69 (CH)*, 95.68 (CH),* 94.7 (CH2), 94.2 Hz, 1 H), 8.10 (d, J = 14 Hz, 1 H), 7.73 (d, J = 2.5 Hz, 1 H),
(CH2),* 94.1 (CH2)*, 91.95 (CH)*, 91.92 (CH),* 71.96 (CH2)*, 7.36 (dd, J = 8.5, 2.5 Hz, 1 H), 7.06 (d, J = 8.5 Hz, 1 H);19 13
C
71.88 (CH2),* 67.96 (CH)*, 67.84 (CH), 56.3 (CH3),* 56.2 NMR (125 MHz, acetone-d6): δ 157.4 (C), 139.9 (CH), 134.6
(CH3),* 56.1 (CH3), 50.43 (CH)*, 50.41 (CH),* 44.9 (CH)*, (CH), 133.6 (CH), 131.7 (CH), 125.5 (C), 120.0 (C), 118.8
44.8 (CH),* 37.0 (CH2), 30.1 (CH2)*, 30.0 (CH2),* 23.8 (CH3)*, (CH); EI-MS (m/z, relative intensity): 201 (M++2, 4), 199 (M+,
23.6 (CH3)*; MS (m/z, relative intensity): 355 (M++1, 20), 354 13), 154 (26), 153 (6), 152 (100); exact mass calculated for
(M+, 100), 322 (19), 292 (53); exact mass calculated for C8H6O3NCl (M+): 199.0036; found: 199.0037.
C18H26O7 (M+): 354.1679; found: 354.1672.
(E)-4-methoxy-2-(2-nitrovinyl)phenol (1d). Yellow solids.
4-[(2S,3R,6R)-10,12-bis(methoxymethoxy)-5,7-
Yield: 173.5 mg (89%). Column chromatography eluents: 20%
dioxatricyclo[6.4.0.02,6]dodeca-1(12),8,10-trien-3-yl]butan-2-
EtOAc–hexane (TLC: Rf = 0.45 in 30% EtOAc–hexane). m.p.
one (11). To a solution of alcohol 10 (8.4 mg, 0.024 mmol) in 152–153 °C; IR (neat): 3148, 1612, 1495, 1347 cm-1; H NMR
CH2Cl2 (5 mL) was added pyridinium chlorochromate (15.5 mg, (500 MHz, acetone-d6): δ 9.29 (brs, 1 H), 8.22 (d, J = 13.5 Hz, 1
0.072 mmol, 3 equiv) and Celite® 545 (31 mg) at ambient tem- H), 8.07 (d, J = 13.5 Hz, 1 H), 7.24 (s, 1 H), 7.00 – 6.96 (m, 2
perature. The resulting solution was stirred at room temperature H), 3.79 (s, 3 H);5 13C NMR (125 MHz, acetone-d6): δ 154.2
for 2 h until the completion of the reaction, monitored by TLC. (C), 153.0 (C), 138.9 (CH), 136.0 (CH), 121.5 (CH), 118.4 (C),
The reaction mixture was diluted with EtOAc (25 mL) and fil- 118.2 (CH), 115.2 (CH), 56.1 (CH3); EI-MS (m/z, relative in-
tered through Celite® 545. The filtrate was concentrated in vac- tensity): 196 (M+ +1, 4), 195 (M+, 39), 149 (16), 148 (100); ex-
uo to give the crude product. The residue was purified by flash act mass calculated for C9H9O4N (M+): 195.0532; found:
column chromatography with 15% EtOAc–hexane (Rf = 0.55 in 195.0533.
1
30% EtOAc–hexane), to give 11 (6.5 mg, 78%) as a colorless
(E)-4-nitro-2-(2-nitrovinyl)phenol (1e). Yellow solids.
26
oil. Select data for 11: [α]D –26.6 (c 0.54, CHCl3); IR (neat): Yield: 147.2 mg (70%). Column chromatography eluents: 30%
1
1712, 1612, 1219, 1014 cm-1; H NMR (500 MHz, CDCl3): δ EtOAc–hexane (TLC: Rf = 0.2 in 30% EtOAc–hexane). m.p.
6.29 (d, J = 2.0 Hz, 1 H), 6.28 (d, J = 6.0 Hz, 1 H), 6.22 (d, J = 181–182 °C; IR (neat): 2900–3300, 1617, 1518, 1341 cm-1; H
1
2.0 Hz, 1 H), 5.14 (dd, J = 13.5, 6.5 Hz, 2 H), 5.07 (s, 2 H), 3.77 NMR (500 MHz, acetone-d6): δ 8.54 (d, J = 3.0 Hz, 1H), 8.20 –
(d, J = 3.5 Hz, 2 H), 3.60 (d, J = 6.0 Hz, 1 H), 3.46 (s, 3 H), 8.13 (m, 3 H), 7.18 (d, J = 9.0 Hz, 1 H);20 13C NMR (125 MHz,
3.44 (s, 3 H), 2.62 – 2.53 (m, 2 H), 2.35 – 2.32 (m, 1 H), 2.17 (s, acetone-d6): δ 163.5 (C), 141.9 (C), 140.8 (CH), 133.9 (CH),
3 H), 1.78 – 1.73 (m, 2 H); 13C NMR (125 MHz, CDCl3): δ 128.9 (CH), 128.7 (CH), 119.0 (C), 117.7 (CH); EI-MS (m/z,
208.0 (C), 160.8 (C), 159.3 (C), 153.9 (C), 111.6 (CH), 108.3 relative intensity): 211 (M+ +1, 1), 210 (M+, 12), 182 (12), 165
(C), 95.7 (CH), 94.7 (CH2), 94.2 (CH2), 91.9 (CH), 71.7 (CH2), (15), 163 (100); exact mass calculated for C8H6O5N2 (M+):
56.3 (CH3), 56.1 (CH3), 50.2 (CH), 44.2 (CH), 41.3 (CH2), 30.0 210.0277; found: 210.0279.
(CH3), 27.5 (CH2); MS (m/z, relative intensity): 353 (M++1, 20),
(E)-4-methyl-2-(2-nitrovinyl)phenol (1f). Yellow solids.
352 (M+, 100), 307 (12), 294 (44); exact mass calculated for Yield: 150.1 mg (84%). Column chromatography eluents: 20%
C18H24O7 (M+): 352.1522; found: 352.1524. HPLC (Chiralcel EtOAc–hexane (TLC: Rf = 0.55 in 30% EtOAc–hexane). m.p.
1
IB, 10% i-PrOH/hexane, 1.0 mL/min, UV λ = 238 nm) tR(major)
10.39 min, tR(minor) = 12.22 min.
=
164–165 °C; IR (neat): 3407, 1627, 1586, 1330 cm-1; H NMR
(500 MHz, acetone-d6): δ 9.52 (brs, 1 H), 8.17 (d, J = 13.5 Hz,
General Procedure for the Synthesis of Nitroalkene 1. 1H ), 8.04 (d, J = 13.5 Hz, 1 H), 7.46 (d, J = 1.0 Hz, 1 H), 7.19
A solution of 5-bromo-2-hydroxybenzaldehyde (201 mg, 1.0 (dd, J = 8.5, 1.5 Hz, 1 H), 6.94 (d, J = 8.5 Hz, 1 H), 2.26 (s, 3
mmol) and ammonium acetate (115.7 mg, 1.5 mmol, 1.5 equiv) H);21 13C NMR (125 MHz, acetone-d6): δ 156.8 (C), 138.6
in nitromethane (5 mL) was heated to reflux for 12 h until the (CH), 136.2 (CH), 135.1 (CH), 132.9 (CH), 130.4 (C), 118.1
completion of reaction, as monitored by TLC. Then the reaction (C), 117.2 (CH), 20.3 (CH3); EI-MS (m/z, relative intensity):
mixture was directly concentrated in vacuo to give the crude 179 (M+, 31), 132 (100), 131 (42); exact mass calculated for
residue. The crude product was purified by flash column chro- C9H9O3N (M+): 179.0582; found: 179.0585.
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(E)-5-methoxy-2-(2-nitrovinyl)phenol (1g). Yellow solids.
Procedure for the Synthesis of nitroalkene 1l. To a so-
Yield: 153.8 mg (79%). Column chromatography eluents: 30% lution of 2,4,6-trihydroxybenzaldehyde (929.6 mg, 6.03 mmol)
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EtOAc–hexane (TLC: Rf = 0.35 in 30% EtOAc–hexane). m.p. and N,N-diiospropylethylamine (DIPEA, 5.3 mL, 30.4 mmol,
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146–147 °C; IR (neat): 3334, 1609, 1338, 1099 cm-1; H NMR 5.0 equiv) in CH2Cl2 (20 mL) was added bromoethyl methyl
(500 MHz, acetone-d6): δ 8.15 (d, J = 13.5 Hz, 1 H), 7.95 (d, J = ether (1.46 mL, 17.9 mmol, 3.0 equiv) at 0 °C. The resulting
13.5 Hz, 1 H), 7.56 (dd, J = 7.5, 2.5 Hz, 1 H), 6.58 – 6.55 (m, 2 solution was stirred at 0 °C for 3.5 h until the completion of the
H), 3.82 (s, 3 H);22 13C NMR (125 MHz, acetone-d6): δ 165.3 reaction, as monitored by TLC. The solution was extracted with
(C), 160.6 (C), 136.43 (CH), 136.38 (CH), 134.7 (CH), 111.6 EtOAc (40 mL x 3), and the combined organic solution was
(C), 108.0 (CH), 102.4 (CH), 55.9 (CH3); EI-MS (m/z, relative washed with brine, dried over MgSO4 and concentrated in vac-
intensity): 195 (M+, 24), 178 (8), 149 (15), 148 (100); exact uo to give a residue. The crude product was purified by flash
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mass calculated for C9H9O4N (M+): 195.0532; found: 195.0531.
(E)-4-(benzyloxy)-2-(2-nitrovinyl)phenol (1h). Yellow 10%
column chromatography with 15% EtOAc–hexane (Rf = 0.14 in
EtOAc–hexane) to afford 2-hydroxy-4,6-
solids. Yield: 217.2 mg (80%). Column chromatography elu- bis(methoxymethoxy)benzaldehyde (1110 mg, 76%) as a white
ents: 20% EtOAc–hexane (TLC: Rf = 0.48 in 30% EtOAc– solid. Selected data m.p. 68–69 °C; 1H NMR (500 MHz,
hexane). m.p. 127–128 °C; IR (neat): 3375, 1589, 1498, 1347 CDCl3): δ 12.26 (s, 1 H), 10.14 (s, 1 H), 6.23 (d, J = 2.0 Hz, 1
1
cm-1; H NMR (500 MHz, acetone-d6): δ 9.31 (brs, 1 H), 8.23 H), 6.20 (d, J = 2.0 Hz, 1 H), 5.21 (s, 2 H), 5.15 (s, 2 H), 3.48
(d, J = 14.0 Hz, 1 H), 8.08 (d, J = 14.0 Hz, 1 H), 7.48 (dd, J = (s, 3 H), 3.45 (s, 3 H); 13C NMR (125 MHz, CDCl3): δ 192.1
7.5, 1.5 Hz, 2 H), 7.42 – 7.36 (m, 3 H), 7.35 – 7.30 (m, 1 H), (CH), 165.6 (C), 165.5 (C), 161.2 (C), 106.9 (C), 96.6 (CH),
7.08 (dd, J = 8.5, 3.0 Hz, 1 H), 6.99 (d, J = 8.5 Hz, 1 H), 5.12 94.6 (CH2), 94.10 (CH), 94.05 (CH2), 56.6 (CH3), 56.5 (CH3);24
(s, 2 H); 13C NMR (125 MHz, acetone-d6): δ 153.4 (C), 153.2 EI-MS (m/z, relative intensity): 243 (M++1, 13), 242 (M+, 100),
(C), 138.9 (C), 138.4 (CH), 135.9 (CH), 129.4 (2CH), 128.8 229 (9), 214 (16), 197 (55); exact mass calculated for C11H14O6
(CH), 128.6 (2CH), 122.5 (CH), 118.6 (C), 118.3 (CH), 116.7 (M+): 242.0790; found: 242.0796.
(CH), 71.3 (CH2); EI-MS (m/z, relative intensity): 271 (M+, 4),
A solution of ammonium acetate (537 mg, 7.0 mmol, 1.6
92 (5), 91 (100); exact mass calculated for C15H13O4N (M+): equiv) and 2-hydroxy-4,6-bis(methoxymethoxy)benzaldehyde
271.0845; found: 271.0844. (1026 mg, 4.2 mmol) in MeNO2 (30 mL) was heated to reflux
(E)-2-bromo-6-(2-nitrovinyl)phenol (1i). Yellow solids. for 24 h. The resulting solution was concentrated in vacuo to
Yield: 185.6 mg (76%). Column chromatography eluents: 20% give a residue. The crude product was purified by flash column
EtOAc–hexane (TLC: Rf = 0.65 in 30% EtOAc–hexane). m.p. chromatography with 15% EtOAc–hexane (Rf = 0.41 in 50%
1
120–121 °C; IR (neat): 3420, 1626, 1510, 1333 cm-1; H NMR EtOAc–hexane) to afford (E)-3,5-bis(methoxymethoxy)-2-(2-
(500 MHz, acetone-d6): δ 8.23 (d, J = 13.5 Hz, 1 H), 8.03 (d, J = nitrovinyl)phenol (1l, 723 mg, 60%) as a bright yellow solid.12
13.5 Hz, 1 H), 7.73 – 7.67 (m, 2 H), 6.96 (dd, J = 8.0, 8.0 Hz, 1 Selected data: m.p. 109–110 °C; IR (neat): 3329, 1612, 1151
1
H); 13C NMR (125 MHz, acetone-d6): δ 154.5 (C), 139.9 (CH), cm-1; H NMR (500 MHz, acetone-d6): δ 9.88 (brs, OH), 8.51
137.0 (CH), 135.1 (CH), 131.8 (CH), 122.8 (CH), 120.7 (C), (d, J = 13.5 Hz, 1 H), 8.07 (d, J = 13.5 Hz, 1 H), 6.46 (d, J = 2.0
112.4 (C); EI-MS (m/z, relative intensity): 245 (M++2, 27), 243 Hz, 1 H), 6.42 (d, J = 2.0 Hz, 1 H), 5.38 (s, 2 H), 5.21 (s, 2 H),
(M+, 29), 199 (16), 198 (100), 196 (100); exact mass calculated 3.51 (s, 3 H), 3.44 (s, 3 H); 13C NMR (125 MHz, acetone-d6): δ
for C8H6BrNO3 (M+): 242.9531; found: 242.9532.
163.3 (C), 161.3 (C), 160.5 (C), 137.3 (CH), 130.9 (CH), 103.2
(E)-2-chloro-6-(2-nitrovinyl)phenol (1j). Yellow solids. (C), 97.6 (CH), 96.1 (CH), 95.7 (CH2), 95.1 (CH2), 56.8 (CH3),
Yield: 188.6 mg (74%). Column chromatography eluents: 15% 56.5 (CH3); MS (m/z, relative intensity): 286 (M++1, 4), 285
EtOAc–hexane (TLC: Rf = 0.62 in 30% EtOAc–hexane). m.p. (M+, 27), 208 (4), 195 (10), 194 (100); exact mass calculated for
1
126–127 °C; IR (neat): 3460, 1627, 1515, 1335 cm-1; H NMR C12H15NO7 (M+): 285.0849; found: 285.0843.
(500 MHz, acetone-d6): δ 8.24 (d, J = 13.5 Hz, 1 H), 8.08 (d, J =
13.5 Hz, 1 H), 7.70 (dd, J = 7.5, 1.5 Hz, 1 H), 7.56 (dd, J = 8.0,
█ ASSOCIATED CONTENT
1.5 Hz, 1 H), 7.02 (dd, J = 8.0, 7.5 Hz, 1 H); 13C NMR (125
MHz, acetone-d6): δ 153.9 (C), 139.9 (CH), 135.1 (CH), 133.8
(CH), 131.3 (CH), 122.6 (C), 122.1 (CH), 120.7 (C); EI-MS
(m/z, relative intensity): 201 (M++2, 9), 199 (M+, 32), 154 (40),
152 (100); exact mass calculated for C8H6O3NCl (M+):
199.0036; found: 199.0037.
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.joc.xxxxxxx. H and 13C
1
NMR spectra, HPLC analysis data (PDF), X-ray crystallographic
data (cif).
(E)-2-methoxy-6-(2-nitrovinyl)phenol (1k). Yellow solids.
Yield: 315.7 mg (82%). Column chromatography eluents: 25%
EtOAc–hexane (TLC: Rf = 0.45 in 30% EtOAc–hexane). m.p.
■ AUTHOR INFORMATION
1
129–130 °C; IR (neat): 3409, 1622, 1473, 1335 cm-1; H NMR
Corresponding Author
* E-mail: chebch@ccu.edu.tw
(500 MHz, acetone-d6): δ 8.22 (d, J = 13.5 Hz, 1 H), 8.06 (d, J =
13.5 Hz, 1 H), 7.25 (dd, J = 8.0, 1.0 Hz, 1 H), 7.13 (dd, J= 8.0,
Notes
1.0 Hz, 1 H), 6.91 (dd, J = 8.0, 8.0 Hz, 1 H), 3.90 (s, 3 H);23 13
C
The authors declare no competing financial interest.
NMR (125 MHz, acetone-d6): δ 148.8 (C), 148.5 (C), 139.0
(CH), 135.8 (CH), 123.9 (CH), 120.8 (CH), 117.9 (C), 115.4
(CH), 56.7 (CH3); EI-MS (m/z, relative intensity): 196 (M++1,
5), 195 (M+, 60), 149 (11), 148 (100); exact mass calculated for
C9H9O4N (M+): 195.0532; found: 195.0531.
■ ACKNOWLEDGMENT
We acknowledge the financial support for this study from the Min-
istry of Science and Technology (MOST, Taiwan) and thank the
instrument center of MOST for analyses of compounds. Thanks to
Mr. Wei-Lun Huang (NCCU) for his help in the related work.
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Song, C. E. ACS Catal. 2015, 5, 3613–3619. (b) Jimeno, C. Org. Bio-
■ DEDICATION
This paper is dedicated to Professor Elias J. Corey on the occasion
of his 90th birthday.
mol. Chem. 2016, 14, 6147–6164. (c) Mase, N.; Barbas III, C. F. Org.
Biomol. Chem. 2010, 8, 4043–4050. (d) Butler, R. N.; Coyne, A. G.
Chem. Rev. 2010, 110, 6302−6337. (e) Chanda, A.; Fokin, V. V. Chem.
Rev. 2009, 109, 725–748. (f) Hayashi, Y. Angew. Chem., Int. Ed. 2006,
45, 8103–8104. (g) Brogan, A. P.; Dickerson, T. J.; Janda, K. D. An-
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