Multifunctional phosphoramide-(S)-prolinamide derivatives as efficient organocatalysts in asymmetric aldol and Michael reactions

Article abstract of DOI:10.1039/c9nj00300b

The synthesis and evaluation of three novel chiral organocatalysts derived from (S)-proline and containing a bis-amidophosphoryl amine fragment are reported. The structure and conformation of the new compounds were determined by NMR spectroscopy and X-ray crystallographic analysis. The present study represents an effort directed to enhance the performance of (S)-proline-derived organocatalysts in asymmetric aldol and Michael reactions by means of increased steric interactions arising from the incorporation of naphthyl moieties in the catalysts. In the event, the stereoselectivity achieved with naphthyl substituents turned out to be rather similar to that obtained with phenyl analogs. Nevertheless, the new organocatalysts exhibited rather good enantio- and diastereoselectivities in aldol reactions with various isatins and aryl carbaldehydes, affording products with up to 94?:?6 diastereomeric ratios and enantiomeric ratios as high as 95?:?5. Furthermore, products obtained from Michael addition reactions exhibited up to 96?:?4 diastereomeric ratios and enantiomeric ratios as high as 98?:?2.

Full text of DOI:10.1039/c9nj00300b

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Multifunctional phosphoramide-(S)-prolinamide
derivatives as efficient organocatalysts in
asymmetric aldol and Michael reactions†
Cite this:DOI: 10.1039/c9nj00300b
a
a
ab
Carlos Cruz-Hernandez,
Jose M. Landeros
and Eusebio Juaristi
*
´
´
The synthesis and evaluation of three novel chiral organocatalysts derived from (S)-proline and
containing a bis-amidophosphoryl amine fragment are reported. The structure and conformation of the
new compounds were determined by NMR spectroscopy and X-ray crystallographic analysis. The present
study represents an effort directed to enhance the performance of (S)-proline-derived organocatalysts
in asymmetric aldol and Michael reactions by means of increased steric interactions arising from the
incorporation of naphthyl moieties in the catalysts. In the event, the stereoselectivity achieved with
naphthyl substituents turned out to be rather similar to that obtained with phenyl analogs. Nevertheless,
the new organocatalysts exhibited rather good enantio- and diastereoselectivities in aldol reactions with
various isatins and aryl carbaldehydes, affording products with up to 94 : 6 diastereomeric ratios and
enantiomeric ratios as high as 95 : 5. Furthermore, products obtained from Michael addition reactions
exhibited up to 96 : 4 diastereomeric ratios and enantiomeric ratios as high as 98 : 2.
Received 18th January 2019,
Accepted 12th March 2019
DOI: 10.1039/c9nj00300b
rsc.li/njc
bonding play a determining role in the stereochemical outcome
of the organocatalyzed reactions.3,5
Introduction
Organocatalytic strategies were sporadically applied in asym-
In this context, we recently described the synthesis of several
metric synthesis during the XX century;1 nevertheless, this novel organocatalysts based on a proline active moiety and
research area experienced enormous growth following the incorporating a chiral amidophosphoryl scaffold as well as
high-impact work of List, Lerner and Barbas2a as well as that different hydrogen bond donor substituents, which in fact were
of MacMillan and coworkers2b in the year 2000. Nowadays, able to activate asymmetric aldol and Michael reactions with
asymmetric organocatalysis occupies a privileged position as a good stereoselectivity.6 That work was motivated in part by the
practical methodology for the preparation of chiral compounds efforts of Li and coworkers, who evaluated related compounds
in high enantiopurity and good yields, and under unusually as chiral auxiliaries in the stereoselective addition of nucleo-
mild reaction conditions.3 Further development of this area philes to imine functions.7 Also, it was noticed that the side
depends on a proper understanding of the participating catalytic chain of the octahydrobenzodiazaphosphol moiety in Li’s
cycles, and those intrinsic factors responsible for the observed chiral auxiliary could have a direct influence on the observed
stereoinduction. Particularly useful are synergistic collaborative stereoselectivity.7 Additionally, it is worth pointing out that this
efforts between experimental and theoretical researchers,4 moiety has the advantage of separation via GAP (group assisted
which have resulted in the successful development of highly purification) chemistry developed by Li, involving crystalline
efficient organocatalysts for a large diversity of reactions.5 intermediates as was recently corroborated.6a,b
Especially relevant is the observation that steric factors and
In the present work, we report an effort directed to improve
other secondary interactions such as intermolecular hydrogen the stereoinducing performance of our previous catalysts by
means of increased steric hindrance in the chiral framework
of the proline-containing organocatalyst. This possibility was
a
´
´
Departamento de Quımica, Centro de Investigacion y de Estudios Avanzados,
inferred from observations made with the Jørgensen–Hayashi
catalyst, which showed the importance of the steric factor as
related to stereoinduction (Fig. 1a).8 Previous reports9 and our
own results6a,b have demonstrated the dominant influence that
proline’s framework has to direct the stereochemical outcome
of asymmetric aldol and Michael reactions. Nonetheless, taking
into account the general structure of our previously developed
´
Avenida IPN # 2508, 07360 Ciudad de Mexico, Mexico. E-mail: juaristi@relaq.mx,
ejuarist@cinvestav.mx
b
´
´
´
El Colegio Nacional, Luis Gonzalez Obregon 23, Centro Historico, 06020 Ciudad
´
de Mexico, Mexico
† Electronic supplementary information (ESI) available: 1H, 13C, and 31P NMR
spectra, FTIR-ATR spectra and HPLC chromatograms. CCDC 1878183. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c9nj00300b
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Fig. 1 (a) Hydrogen bonding and steric interactions in (S)-proline-promoted
asymmetric organocatalysis. (b) Novel organocatalysts.
organocatalysts (Fig. 1b), where the X segment contains hydrogen
bond donors to activate the electrophilic component and the
octahydrophosphole moiety is responsible for the hydrophobic
properties that make it possible to carry out the reaction in
aqueous media,6 we envisioned that a replacement of the phenyl
group by a naphthyl group in the octahydrophosphole moiety
could enhance the steric hindrance and have a beneficial effect on
the enhancement of the stereoselectivity of the organocatalyzed
reactions.
Scheme 1 Synthesis of
phosphoramides
(1R,2R,10R,20R)-8
and
(1S,2S,10R,20R)-8 incorporating (2-naphthyl)ethyl moieties. Reagents and
conditions: (i) N3, DMF/DMSO (9 : 1), MW, 40 Watts, 60 1C, 1 h. (ii) Pd/C
(10% w/w), H2 (atm), rt, MeOH. 12 h.
could be designated as (1S,2S,10R,20R)-7 when considering the
known configuration of the (naphthyl)ethyl moieties as (R).
This configurational assignment is in line with the results
obtained from the NMR spectroscopic analysis (see the ESI†).
A salient characteristic of the crystallographic structure of azide
(1S,2S,10R,20R)-7 is the syn orientation between the naphthyl
groups, which are also syn to the oxygen of the phosphoryl group.
This conformation is apparently a consequence of a hydrogen
bonding interaction among the ortho hydrogens of the aryl
groups11 with the oxygen of the phosphoryl group. In this regard,
the observed distances (2.69 Å and 3.48 Å) correspond to a strong
and a weak interaction respectively.12
Results and discussion
Synthesis of a bis-amidophosphoryl amine fragment
incorporating the naphthylethyl moiety
Assignment of the corresponding stereochemical descriptors.
To synthesize the desired catalysts we first prepared the required
chiral phosphoramides (1R,2R,10R,20R)-8 according to a general
procedure reported previously6a (Scheme 1, for the complete
synthetic strategy see the ESI†). An unseparable 2 : 1 diastereo-
meric mixture of p-chloro-bis-phosphoramides (1R,2R,10R,20R)-6
and (1S,2S,10R,20R)-6 was treated with azide under microwave
irradiation (see Scheme 1), to obtain the corresponding azides
(1R,2R,10R,20R)-7 and (1S,2S,10R,20R)-7 in good yield. Gratifyingly,
the separation of the diastereomeric azides was easily accomplished
by flash column chromatography. Finally, in order to gain
access to the target phosphoramides containing naphthyl-
ethyl moieties, catalytic hydrogenation of the azido group was
carried out to afford the target molecules (1R,2R,10R,20R)-8 and
(1S,2S,10R,20R)-8 in good yield.
Configurational assignment was accomplished by single
crystal X-ray diffraction analysis of compound (1S,2S,10R,20R)-7
(Fig. 2).10 The absolute configuration of the minor diastereomer
Fig. 2 X-ray crystallographic structure and solid-state conformation of
compound (1S,2S,10R,20R)-7.
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Scheme 2 Synthesis of organocatalyst (1R,2R,10R,20R,200S)-9.
Synthesis and evaluation of organocatalysts derived from
(S)-proline containing the (1S,2S,10R,20R)-8 segment
Catalyst (1R,2R,10R,20R,200S)-9 was synthesised using a two-step
one-pot process according to our previously developed experi-
mental conditions (Scheme 2).6a
The efficiency of organocatalyst (1R,2R,10R20R,200S)-9 was
examined in the asymmetric aldol addition reaction of cyclo-
hexanone to isatins, which is an important synthetic transfor-
mation owing to the value of the corresponding products.13,14
The reaction was carried out using our previously optimized
conditions.6a Thus, 1.0 equivalent of the appropriate isatin,
10 mol% of the catalyst, 10 mol% of benzoic acid as an additive,
7.0 equivalents of cyclohexanone, and 1.0 mL of water were
allowed to react at 3 1C for 48 h. The results shown in Table 1
indicate high diastereo- (dr) and enantiomeric ratio (er) as well
as good yields (79–92%). Nevertheless, it can be appreciated that
catalyst (1R,2R,10R20R,200S)-9 with a naphthyl pendant afforded
rather similar results to those obtained with the phenyl-
containing analog (see the ESI†).6a
Scheme 3 Synthesis of catalyst (1R,2R,10R,20R,200S)-17. Reagents and
conditions: (i) n-BuLi, THF, 0 1C, 20 min, then methyl-2-bromoacetate,
THF, 0 1C to rt, 24 h. (ii) NaN3, DMF/DMSO (9 : 1), rt, 24 h. (iii) H2, Pd/C
(10% w/w), MeOH, rt, 12 h. (iv) T3Ps, NMM, N-Boc-(S)-Pro, ACN, 0 1C
to rt, 24 h. (v) TFA, CH2Cl2, 0 1C to rt, 24 h, then NaOH (1.0 m) or
NH4OH, CH2Cl2.
Derivatives of phosphoramide (1S,2S,10R,20R)-8 containing a
dipeptidic (Pro-Gly) fragment
Evaluation in the aldol addition reaction of cyclohexanone
to aryl-substituted carbaldehydes. It is well established that the
presence of hydrogen bond donor functionalities in proline-
derived organocatalysts usually enhance their performance.15
The synthesis of catalyst (1R,2R,10R,20R,200S)-17 containing
an amidic hydrogen bond donor segment follows a previously
developed strategy (Scheme 3),6b beginning with the nucleophilic
substitution reaction of (1R,2R,10R,20R)-8 with methyl 2-bromo-
acetate to afford bromide (1R,2R,10R,20R)-13. Subsequently,
the bromine atom was displaced by an azide group (SN2
substitution) under mild reaction conditions to afford derivative
(1R,2R,10R,20R)-14. Next, the catalytic reduction of the azide group
to an amino group was carried out to afford (1R,2R,10R,20R)-15
containing a glycine fragment. Finally, coupling of an N-Boc-(S)-
proline residue was carried out under T3Ps activation to
give N-Boc-protected precatalyst (1R,2R,10R,20R,200S)-16, which
was treated with TFA to afford the desired organocatalyst
(1R,2R,10R,20R,200S)-17.
Table 1 Aldol addition reaction between cyclohexanone and substituted
isatins, promoted by organocatalyst (1R,2R,10R,20R,200S)-9
Organocatalyst (1R,2R,10R,20R,200S)-17 was evaluated in the
asymmetric aldol reaction between cyclohexanone and repre-
sentative aryl-substituted carbaldehydes15 under previously reported
conditions,6b and the results are summarized in Table 2. Although
the reaction time varies depending on the aryl substituent
at the aldehyde (24 to 168 h) the yields were good to excellent
(80–99% yield), except for substrates containing 4-CH3 and
4-C6H5 substituents (entries 9 and 10 in Table 2). Furthermore,
diastereomeric and enantiomeric ratios were rather good.
Entrya
R
Yieldb (%)
drc (l mlꢀ1
)
erd
1
2
3
5-NO2
5-Br
7-Cl
92
84
79
90 : 10
91 : 9
84 : 16
90 : 10
73 : 27
66 : 34
a
Reaction conditions: substituted isatin (1.0 mmol, 1.0 equiv.), cyclo-
hexanone (7.0 equiv.), benzoic acid (0.1 equiv.), Cat*9
=
b
(1R,2R,10R,20R,200S)-9 (0.1 equiv.) and water (1 mL) at 3 1C. Isolated
products after chromatographic purification. Determined by 1H NMR
c
d
analysis. Determined by chiral HPLC.
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Table 2 Aldol addition reaction between cyclohexanone and substituted
arylcarbaldehydes, promoted by organocatalyst (1R,2R,10R,20R,200S)-17
Table 3 Michael addition reaction of cyclohexanone to various substituted
b-nitroolefins in the presence of the (1S,2S,10R,20R,200S)-20 organocatalyst
Entrya
R
T (h)
Yieldb (%)
drc (anti/syn)
erd
1
2
3
4
5
6
7
8
9
2-Cl
3-Cl
4-Cl
4-Br
4-NO2
2-CF3
4-CF3
H
4-CH3
4-C6H5
96
96
96
96
30
96
24
168
168
168
99
99
80
85
99
99
99
83
56
54
92 : 8
93 : 7
93 : 7
92 : 8
93 : 7
92 : 8
94 : 6
88 : 12
90 : 10
91 : 9
93 : 7
94 : 6
96 : 4
93 : 7
94 : 6
92 : 8
93 : 7
92 : 8
93 : 7
91 : 9
Entrya
R
Yieldb (%)
drc (syn/anti)
erd
1
2
3
4
5
6
7
8
2-Cl
3-Cl
4-Cl
2-Br
3-Br
4-Br
4-NO2
4-Me
99
32
46
99
33
95
99
77
95 : 5
92 : 8
94 : 6
96 : 4
92 : 8
95 : 5
90 : 10
96 : 4
97 : 3
97 : 3
97 : 3
97 : 3
97 : 3
98 : 2
97 : 3
96 : 4
10
a
a
Reaction conditions: substituted b-nitroolefins (1.0 mmol, 1.0 equiv.),
Reaction conditions: substituted arylcarbaldehyde (1.0 mmol, 1.0 equiv.),
cyclohexanone (7.0 equiv.), benzoic acid (0.07 equiv.), Cat*
=
cyclohexanone (5.0 equiv.), benzoic acid (0.05 equiv.), Cat*
=
(1S,2S,10R,20R,200 S)-20 (7 mol%) and water (1 mL), at room temperature for
16 h. b Isolated products after chromatographic purification. c Determined
by 1H NMR analysis of the crude product. d Determined by chiral HPLC.
b
(1R,2R,10R,20R,200S)-17 (0.05 equiv.) and water (1 mL) at 3 1C. Isolated
products after chromatographic purification based on arylcarb-
aldehyde. Determined by 1H NMR of the crude product. Determined
c
d
by chiral HPLC.
Synthesis of organocatalyst N-phosphoryl-N0-(2S)-[(2-
pyrrolidinyl)methyl]thiourea, (1S,2S,10R,20R,200S)-20, and
catalytic evaluation in Michael addition reactions
Organocatalyst (1S,2S,10R,20R,200S)-20 containing a thiourea
moiety was deemed attractive for asymmetric Michael addition
reactions in view of the hydrogen bond donor capacity of that
functional group.16 It was synthesised by treatment of the
Scheme 5 Evaluation of catalyst (1S,2S,10R,20R,200S)-20 in a cyclization
[3+3] cascade reaction.
lithium amide salt of (1S,2S,10R,20R)-8 with isothiocyanate (S)- benzoic acid as an additive and water solvent.6c Salient results
21 to afford N-Boc protected (1S,2S,10R,20R,200S)-22. Finally, are summarized in Table 3. The best results were obtained with
deprotection was carried out under acid conditions (TFA) to ortho- and para-halide substituted trans-b-nitrostyrenes.
give the active catalyst (1S,2S,10R,20R,200S)-20 (Scheme 4).
The catalytic activity of organocatalyst (1S,2S,10R,20R,200S)-20
was evaluated in the asymmetric Michael addition reaction of
cyclohexanone to trans-b-nitrostyrene,17 in the presence of
Scheme 4 Synthesis of organocatalyst (1S,2S,10R,20R,200S)-20. Reagents
and conditions: (i) n-BuLi, THF, 0 1C, 20 min, then (S)-21, THF, 0 1C to rt,
24 h. (ii) TFA, CH2Cl2, 0 1C to rt, 24 h then NaOH (1.0 M) or NH4OH, CH2Cl2.
Fig. 3 Comparison of stereoinduction observed with chiral moieties
phenyl versus 2-naphthyl.
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Finally, we explored the feasibility of employing Enraf-Nonius CAD-4 X-ray diffractometers. High resolution mass
(1S,2S,10R,20R,200S)-20 as the organocatalyst in a cyclization spectra (HRMS) were measured on a HPLC 1100 coupled to an
[3+3] cascade reaction,18 where methyl arylidenepyruvate MSD-TOF Agilent Technologies HR-MSTOF 1069A. Determination
(0.5 mmol, 1 equiv.) and cyclohexanone (7 equiv.) were allowed of diastereomeric and enantiomeric ratios was carried out on a
to react under standard reaction conditions (see Scheme 5).6c Dionex HPLC Ultimate 3000 apparatus with a UV/Visible detector
Gratifyingly, (1S,2S,10R,20R,200S)-20 efficiently promoted the (210 and 254 nm diode array), using a suitable chiral column.
cascade process affording the desired product with excellent
Synthetic procedures
enantioselectivity (97 : 3 er) and a fair yield of 54%.
Considering all available results and comparison with pre-
Synthesis of (1SR,2SR)-2-((R)-1-(naphthalen-2-yl)ethylamino)-
vious observations (see Fig. 3),6 we conclude that the stereo- cyclohexanol, (1SR,2SR,10R)-3. Under an argon atmosphere,
inducing proline ring is far away from the aryl substituents lithium perchlorate (8.1 g, 75.9 mmol) was suspended in
therefore the steric difference between the aromatic rings does 200 mL of anhydrous acetonitrile before the dropwise addition
not have a significant effect on the observed stereoselectivity. of 7.7 mL (75.9 mmol) of cyclohexene oxide (1). The resulting
This finding is in line with the crystallographic structure mixture was stirred at room temperature until the complete
presented in Fig. 2.
dissolution of LiCIO4 and then it was cooled to 3 1C before the
dropwise addition of 10.0 g (58.4 mmol) of (R)-1-(naphthalen-2-
yl)ethanamine [(R)-2] in 50 mL of anhydrous acetonitrile. The
reaction mixture was heated to reflux for 80 h and then allowed
to cool to room temperature before the addition of 100 mL of
water. The products were extracted with ethyl acetate (3 ꢁ 100 mL),
the organic layer was dried over Na2SO4 and the solvent was
evaporated under reduced pressure to obtain 15.7 g (99% yield)
of a diastereomeric mixture of the expected amine alcohols as a
yellow pale solid. This mixture of products was used in the next
step of the reaction without additional purification.
Synthesis of aziridine 7-[(R)-1-(naphthalen-2-yl)ethyl]-7-azabi-
cyclo[4.1.0]heptane, (R)-4. Under an argon atmosphere, 15.7 g
(58.4 mmol) of the diastereomeric mixture (1SR,2SR,10R)-3 was
dissolved in 250 mL of anhydrous THF before the addition of
28.5 mL (204.4 mmol) of Et3N. The resulting mixture was stirred
for 20 min at room temperature and then cooled to 3 1C before
the slow addition of 6.25 mL (70.1 mmol) of methanesulphonyl
chloride via a syringe (caution: this reaction generates HCl gas,
so the flask should have a pipeline connected to a trap to avoid
pressurization of the system). The resulting reaction mixture was
stirred at room temperature for 36 h, rinsed with methylene
chloride (3 ꢁ 100 mL), dried over Na2SO4 and concentrated
under reduced pressure. The crude product was purified by
column chromatography using silica gel and hexane/EtOAc
(95 : 5 to 100 : 0) as an eluent, to afford 14.5 g (99% yield) of
aziridine (R)-4 as a clear oil. [a]2D5 = +46.41 (c = 0.317, CHCl3),
1H NMR (400 MHz, CDCl3, d = ppm): 7.77–7.90 (m, 4H); 7.53 (dd,
JH–H = 1.5, 8.5 Hz, 1H); 7.40–7.50 (m, 2H); 2.59 (c, JH–H = 6.5 Hz,
1H); 1.83–1.96 (m, 2H); 1.70–1.79 (m, 1H); 1.65–1.69 (m, 1H);
1.57–1.64 (m, 1H); 1.41–1.54 (m, 3H); 1.45 (d, JH–H = 6.5 Hz, 3H);
1.13–1.25 (m, 2H). 13C NMR (100.5 MHz, CDCl3, d = ppm): 143.4,
133.6, 132.8, 128.1, 127.9, 127.8, 126.0, 125.7, 125.5, 125.1, 70.3,
38.6, 38.1, 25.1, 24.8, 23.7, 20.9, 20.8. IR n~max (ATR) cmꢀ1: 3056.0,
Conclusions
In summary, a bis-amidophosphoryl fragment containing a
(2-naphthyl)ethyl moiety was synthetized and used to prepare three
novel organocatalysts (1R,2R,10R,20R,200S)-9, (1R,2R,10R,20R,200S)-17
and (1S,2S,10R,20R,200S)-20 from (S)-proline. The absolute
configuration of these chiral phosphoramides was determined
by single crystal X-ray diffraction analysis and correlated with
1H NMR-spectra. Organocatalysts (1R,2R,10R,20R,200S)-9 and
(1R,2R,10R,20R,200S)-17 (10 and 5 mol%, respectively) were eval-
uated in aldol reactions in the presence of a benzoic acid
additive and water affording the aldol adducts in good yields
and high diastereo- and enantioselectivity. Asymmetric Michael
addition and cascade related reactions were performed using
7 mol% of (1S,2S,10R,20R,200S)-20 and benzoic acid as an additive
in the presence of water at room temperature, affording the
desired products in moderate to good yields and excellent
diastereo- and enantioselectivities.
Experimental
Materials and apparatus
All reagents were purchased from Sigma-Aldrich and used as
received unless otherwise indicated. Solvents were dried by
conventional methods. Reactions under microwave irradiation
were carried out in a single-mode Discover System reactor (CEM
corp.). Column chromatography was performed with a Merck
Silica Gel (0.040–0.063 mm). TLC was run on Merck DC-F254
plates using UV light or iodine vapor.
Compound characterization
NMR spectra were recorded on JEOL Eclipse 400 and JEOL 2965.5, 2928.8, 2851.0, 1600.6, 1506.3, 1437.8, 1412.9, 1366.5,
ECA-500 spectrometers, and chemical shifts were referenced to 1318.6, 1231.1, 1192.2, 1129.8, 1101.2, 1007.5, 950.1, 894.8,
the deuterated solvent peak. Melting points were determined 855.1, 817.2, 776.0, 743.6, 655.4, 622.8, 571.3. HR ESI-TOF
using a Bu¨chi B-540 apparatus and are uncorrected. Optical [M + H]+ (m/z) calcd for [C18H21N + H]+: 252.174676; found:
rotations were determined using an Anton Paar MCP-100 252.174697 (error = 0.082054 ppm).
polarimeter using reagent grade solvents. FTIR spectra were
Opening of aziridine (R)-4 with (R)-1-(naphthalen-2-yl)ethan-
recorded on a Varian 640-IR spectrometer. Crystallographic amine. Under an argon atmosphere, lithium perchlorate
data were determined using Enraf-Nonius Kappa CCD and (5.78 g, 54.3 mmol) in 200 mL of anhydrous acetonitrile was
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treated with 13.7 g (54.3 mmol) of aziridine (R)-4. The resulting 860.9, 826.3, 776.4, 750.1, 707.7, 653.8, 562.0. HR ESI-TOF
mixture was stirred at room temperature until complete dis- [M + H]+ (m/z) calcd for [C30H32ClON2P + H]+: 503.201357; found:
solution of the LiCIO4 salt, and then it was cooled to 3 1C before 503.201248 (error = ꢀ0.215668 ppm).
the dropwise addition of (R)-1-(naphthalen-2-yl)ethanamine
(3aR,7aR)-2-Oxide-2-chlorooctahydro-1,3-bis[(1R)-1-(2-naphthal-
(9.31 g, 54.3 mmol) in 50 mL of anhydrous acetonitrile. The enyl)ethyl]-1H-1,3,2-benzodiazaphosphol, (1R,2R,10R,20R)-6. White
reaction mixture was then heated to reflux for 130 h and was powder, mp = 112.5 1C, [a]2D5 = +44.61 (c = 0.413, CHCl3). 1H NMR
cooled to room temperature, and water (200 mL) was added. (500 MHz, CDCl3, d = ppm): 7.85–7.93 (m, 4H); 7.76–7.84 (m, 5H);
The products were extracted with ethyl acetate (3 ꢁ 100 mL), 7.60 (dd, JH–H = 1.8, 8.5 Hz, 1H); 7.40–7.54 (m, 4H); 5.10 (dc, 3JH–H
=
the combined organic layers were dried over Na2SO4 and the 7.0, 3JP–H = 13.9 Hz, 1H); 4.35 (dc, 3JH–H = 6.6, 3JP–H = 6.5 Hz, 1H);
solvent was evaporated under reduced pressure to obtain 17.9 g 2.96–3.06 (m, 1H); 2.69–2.81 (m, 1H); 1.89 (d, JH–H = 6.9 Hz, 3H);
(78% yield) of the mixture of the diastereomeric diamines 1.85 (d, JH–H = 7.2 Hz, 3H); 1.78–1.82 (m, 1H); 1.37–1.47 (m, 1H);
(1SR,2SR,10R,20R)-5 as a yellowish solid. This mixture of pro- 1.30–1.36 (m, 1H); 1.22 (cd, JH–H = 3.6, 12.1 Hz, 1H); 0.99 (ct, JH–H
ducts was used as such in the next reaction. 3.8, 13.4 Hz, 1H); 0.82–0.90 (m, 1H); 0.72 (ct, JH–H = 4.0, 13.4 Hz,
General procedure for the synthesis of phosphoryl chloride 1H); 0.59 (cd, JH–H = 3.3, 12.3 Hz, 1H). 13C NMR (125.8 MHz, CDCl3,
=
3
3
derivatives, (1R,2R,10R,20R)-6 and (1S,2S,10R,20R)-6. Under an d = ppm): 143.3 (d, JP–C = 10.3 Hz); 137.5 (d, JP–C = 3.5 Hz);
argon atmosphere, 17.5 g (41.4 mmol) of the mixture of 133.5; 133.4; 133.0; 132.9; 128.5; 128.4; 128.3; 128.1;
diastereomeric diamines (1SR,2SR,10R,20R)-5 was dissolved in 127.9; 127.8; 127.0; 126.3; 126.2; 126.1; 126.0; 125.9; 125.1;
200 mL of anhydrous toluene, before the addition of 26.0 mL 124.8; 63.1 (d, JP–C = 11.6 Hz); 61.4 (d, JP–C = 10.1 Hz); 56.6
(204.4 mmol) of Et3N. The resulting mixture was stirred for (d, JP–C = 2.7 Hz); 51.7 (d, JP–C = 5.2 Hz); 31.0 (d, JP–C = 7.5 Hz);
30 min at room temperature, and then phosphorus oxychloride 29.9 (d, JP–C = 11.8 Hz); 24.5; 23.7 (d, JP–C = 1.7 Hz); 23.5 (d, JP–C
=
(5.4 mL, 8.9 g, 58.0 mmol) was slowly added via a syringe 4.5 Hz); 20.1 (d, JP–C = 3.5 Hz). 31P NMR (202.5 MHz, CDCl3,
(caution: this reaction step generates HCl gas, so the flask d = ppm): 29.9 IR n~max (ATR) cmꢀ1: 3050.6, 2935.9, 2856.6,
should have a pipeline connected to a trap to avoid pressuriza- 1634.9, 1600.8, 1506.8, 1449.5, 1378.8, 1331.6, 1293.9, 1267.6,
tion of the system). The reaction mixture was then heated to 1222.8, 1195.0, 1133.7, 1094.9, 1058.4, 1026.1, 964.2, 948.6,
reflux for 24 h and cooled to room temperature before the 929.6, 895.7, 858.1, 820.9, 746.3, 711.1, 658.2, 622.7. HR ESI-TOF
addition of 400 mL of water. The water layer was separated and [M + H]+ (m/z) calcd for [C30H32ClON2P + H]+: 503.201357; found:
extracted with ethyl acetate (3 ꢁ 100 mL). The combined 503.2014 (error = 0.2036 ppm).
organic layer was dried over Na2SO4 and the solvent was
General procedure for the synthesis of azide derivatives,
evaporated under reduced pressure. The crude product was (1S,2S,10R,20R)-7 and (1R,2R,10R,20R)-7. A flask for a MW oven
purified by column chromatography using silica gel with provided with a stirring bar and a condenser was charged with
hexane/EtOAc (85 : 15) as eluent to afford 13.73 g (66% yield) sodium azide (2.0 equiv.) and 25 mL of a solution of DMF–
of the diastereomeric phosphoryl chloride derivatives, the DMSO (9 : 1). The resulting mixture was treated with 1 equiva-
major diastereomer (less polar) (1R,2R,10R,20R)-6 (74%, yield) lent of (1R,2R,10R,20R)-6 [or (1S,2S,10R,20R)-6] and was irradiated
and the minor diastereomer (1S,2S,10R,20R)-6 (26%).
with MW (60 Watts) for 1 h at 60 1C. The reaction mixture was
(3aS,7aS)-2-Oxide-2-chlorooctahydro-1,3-bis[(1R)-1-(2-naphthale- cooled to 3 1C before the addition of distilled water (3 ꢁ 25 mL)
nyl)ethyl]-1H-1,3,2-benzodiazaphosphol, (1S,2S,10R,20R)-6. White (exothermic process). The crude product was extracted with
powder, mp = 153–154 1C, [a]2D5 = +64.21 (c = 0.36, CHCl3). diethyl ether (3 ꢁ 30 mL), the combined organic layers were
1H NMR (500 MHz, CDCl3, d = ppm): 7.76–7.90 (m, 10H); dried over Na2SO4 and concentrated under vacuum. The pro-
3
3
7.42–7.52 (m, 4H); 5.02 (dc, JH–H = 6.8, JP–H = 13.4 Hz, 1H); duct was purified by column chromatography using SiO2 with
3
3
4.78 (dc, JH–H = 7.1, JP–H = 17.2 Hz, 1H); 3.11 (td, JH–H = 2.6, hexane/EtOAc (95 : 5) as eluent.
10.6 Hz, 1H); 2.89 (td, JH–H = 3.0, 10.5 Hz, 1H); 1.97 (d, JH–H (3aS,7aS)-2-Oxide-2-azidooctahydro-1,3-bis[(1R)-1-(2-naphthal-
=
7.1 Hz, 3H); 1.90 (d, JH–H = 7.1 Hz, 3H); 1.69 (br-d, JH–H = 12.3 Hz, enyl)ethyl]-1H-1,3,2-benzodiazaphosphol, (1S,2S,10R,20R)-7. The
1H); 1.60 (br-d, JH–H = 11.9 Hz, 1H); 1.44 (br-d, JH–H = 13.9 Hz, 1H); general procedure for azide synthesis was followed with 2.0 g
1.37 (br-d, JH–H = 13.6 Hz, 1H); 1.05 (ct, JH–H = 3.9, 13.2 Hz, 1H); (3.99 mmol) of (1S,2S,10R,20R)-3 and 0.52 g (7.95 mmol) of
0.97 (cd, JH–H = 3.4, 12.1 Hz, 1H); 0.84 (ct, JH–H = 3.9, 13.2 Hz, 1H); sodium azide to provide 1.47 g (2.88 mmol, 72% yield) of
0.61 (cd, JH–H = 3.3, 12.4 Hz, 1H). 13C NMR (125.8 MHz, CDCl3, (1S,2S,10R,20R)-4 as a white powder, mp = 193–194 1C, [a]D25
=
1
d = ppm): 140.9 (d, 3JP–C = 10.0 Hz); 140.4 (d, 3JP–C = 4.0 Hz); 132.4; +51.31 (c = 0.437, CHCl3). H NMR (500 MHz, CDCl3, d = ppm):
133.2; 133.0; 132.7; 128.7; 128.2; 128.1; 128.0; 127.9; 127.8; 7.77–7.95 (m, 9H); 7.76 (dd, JH–H = 1.8, 8.6 Hz, 1H); 7.42–7.53 (m,
126.6; 126.3; 126.2; 126.1; 126.0; 125.7; 125.5; 124.7; 61.6 (d, JP–C
=
4H); 4.83 (dc, 3JH–H = 6.9, 3JP–H = 13.7 Hz, 1H); 4.65 (dc, 3JH–H = 7.1,
10.8 Hz); 59.0 (d, JP–C = 11.4 Hz); 53.3 (d, JP–C = 4.1 Hz); 50.1 3JP–H =19.2 Hz, 1H); 2.90–2.99 (m, 1H); 2.73–2.83 (m, 1H); 1.93
(d, JP–C = 4.5 Hz); 30.1 (d, JP–C = 12.1 Hz); 29.1 (d, JP–C = 8.2 Hz); (d, JH–H = 7.1 Hz, 3H); 1.88 (d, JH–H = 7.1 Hz, 3H); 1.74–1.80
24.2 (d, JP–C = 1.1 Hz); 24.0 (d, JP–C = 1.5 Hz); 19.4 (d, JP–C
=
(m, 1H); 1.54–1.60 (m, 1H); 1.42–1.48 (m, 1H); 1.34–1.40 (m, 1H);
2.2 Hz); 14.6. 31P NMR (202.5 MHz, CDCl3, d = ppm): 29.7. IR 0.92–1.02 (m, 2H); 0.86 (ct, JH–H = 3.8, 13.0 Hz, 1H); 0.69 (cd,
n~max (ATR) cmꢀ1: 3054.6, 2983.9, 2940.8, 2867.5, 2854.6, 1599.2, JH–H = 3.6, 12.2 Hz, 1H). 13C NMR (125.8 MHz, CDCl3, d = ppm):
1506.4, 1448.7, 1383.3, 1348.3, 1339.3, 1297.9, 1251.5, 1226.8, 140.8 (d, JP–C = 6.7 Hz); 140.4 (d, JP–C = 2.9 Hz); 133.3; 133.0;
3
3
1201.5, 1150.0, 1099.7, 1058.3, 1017.3, 969.9, 947.9, 932.3, 895.5, 132.8; 128.7; 128.2; 128.1; 127.9; 127.8; 126.4; 126.2; 126.1; 126.0;
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125.9; 125.8; 125.7; 124.8; 60.7 (d, JP–C = 11.0 Hz); 60.5 (d, JP–C
=
1.32 g (2.72 mmol, 93%) of (1S,2S,10R,20R)-8 as a white powder,
1
10.3 Hz); 53.5 (d, JP–C = 3.7 Hz); 50.9 (d, JP–C = 3.9 Hz); 29.7 mp = 151–152 1C, [a]2D5 = +103.61 (c = 0.366, CHCl3). H NMR
(d, JP–C = 9.8 Hz); 28.9 (d, JP–C = 8.8 Hz); 24.1 (d, JP–C = 1.3 Hz); 19.9 (500 MHz, CDCl3, d = ppm): 7.88 (dd, JH–H = 1.6, 8.6 Hz, 1H);
(d, JP–C = 2.2 Hz); 17.2. 31P NMR (202.5 MHz, CDCl3, d = ppm): 7.73–7.85 (m, 8H); 7.67 (s, 1H); 7.39–7.47 (m, 4H); 4.80 (dc,
21.3 IR n~max (ATR) cmꢀ1: 3052.4, 2932.6, 2851.5, 2129.9, 1731.3, 3JH–H = 6.8, JP–H = 13.3 Hz, 2H); 3.18 (d, JH–H = 5.0 Hz, 2H);
1598.8, 1506.7, 1449.7, 1383.9, 1353.8, 1297.5, 1259.2, 1244.7, 2.87–2.94 (m, 1H); 2.79–2.86 (m, 1H); 1.90 (d, JH–H = 7.1 Hz, 3H);
1225.5, 1200.9, 1189.6, 1150.5, 1138.2, 1122.3, 1100.6, 1059.3, 1.75 (d, JH–H = 7.0 Hz, 3H); 1.45–1.57 (m, 2H); 1.29–1.37 (m, 2H);
1014.9, 968.8, 932.2, 895.7, 862.5, 828.9, 810.9, 771.2, 750.0, 0.85–0.98 (m, 2H); 0.61–0.74 (m, 2H). 13C NMR (125.8 MHz,
3
2
723.3, 654.6, 619.5, 587.3, 562.6. HR ESI-TOF [M + H]+ (m/z) calcd CDCl3, d = ppm): 142.4 (d, JP–C = 6.4 Hz); 142.2 (d, JP–C
for [C30H32ON5P + H]+: 510.241726; found: 510.241721 (error = 7.1 Hz); 133.4; 133.2; 132.7; 132.6; 128.2; 128.1; 127.9; 127.8;
ꢀ0.009446 ppm). 127.7; 127.2; 126.4; 126.0; 125.9; 125.8; 125.7; 125.0; 124.4; 60.1
(3aR,7aR)-2-Oxide-2-azidooctahydro-1,3-bis[(1R)-1-(2-naphthyl)- (d, JP–C = 10.4 Hz); 59.6 (d, JP–C = 9.9 Hz); 51.4 (d, JP–C = 3.4 Hz);
ethyl]-1H-1,3,2-benzodiazaphosphol, (1R,2R,10R,20R)-7. The general 49.9 (d, JP–C = 5.0 Hz); 30.4 (d, JP–C = 9.2 Hz); 30.2 (d, JP–C
=
3
3
=
procedure for azide synthesis was followed with 2.0 g (3.99 mmol) 10.5 Hz); 24.2; 17.9; 16.2. 31P NMR (202.5 MHz, CDCl3,
of (1R,2R,10R,20R)-6 and 0.52 g (7.95 mmol) of sodium azide in d = ppm): 25.5 IR n~max (ATR) cmꢀ1: 3474.6, 3246.3, 3145.8,
25 mL DMSO/DMF to afford 1.86 g (3.65 mmol, 91% yield) of 3106.6, 3051.9, 2968.1, 2932.9, 1596.5, 1562.9, 1505.8, 1451.7,
(1R,2R,10R,20R)-7 as a white powder, mp = 170 1C, [a]2D5 = +49.51 1379.8, 1299.5, 1278.5, 1212.3, 1179.4, 1154.4, 1118.9, 1093.5,
1
(c = 0.366, CHCl3). H NMR (500 MHz, CDCl3, d = ppm): 7.95 1014.5, 992.1, 949.6, 925.4, 897.5, 859.8, 824.5, 806.8, 760.9,
(s, 1H); 7.79–7.91 (m, 7H); 7.77 (dd, JH–H = 1.7, 8.5 Hz, 1H); 7.65 740.7, 714.5, 648.1, 621.8, 606.1, 572.0, 553.4. HR ESI-TOF
(dd, JH–H = 1.6, 8.5 Hz, 1H); 7.39–7.54 (m, 4H); 4.77 (dc, 3JH–H
7.0, JP–H = 17.7 Hz, 1H); 4.47 (dc, JH–H = 7.0, JP–H = 9.9 Hz, 484.2513 (error = 0.1716 ppm).
1H); 2.89–2.97 (m, 1H); 2.79–2.88 (m, 1H); 1.88 (br-d, JH–H (3aR,7aR)-2-Oxide-2-aminooctahydro-1,3-bis[(1R)-1-(2-naphthy)-
=
[M + H]+ (m/z) calcd for [C30H34ON3P + H]+: 484.251228; found:
3
3
3
=
14.7 Hz, 1H); 1.85 (d, JH–H = 7.0 Hz, 3H); 1.78 (d, JH–H = 7.0 Hz, ethyl]-1H-1,3,2-benzodiazaphosphol, (1R,2R,10R,20R)-8. The general
3H); 1.61 (br-d, JH–H = 10.1 Hz, 1H); 1.52 (br-d, JH–H = 13.0 Hz, procedure for catalytic hydrogenation of azide was followed,
1H); 1.43 (br-d, JH–H = 12.9 Hz, 1H); 1.12 (cd, JH–H = 3.5, 11.9 Hz, with 1.5 g (2.94 mmol) of (1R,2R,10R,20R)-7 and 0.23 g of Pd/C to
1H); 1.00 (ct, JH–H = 3.4, 12.9 Hz, 1H); 0.93 (ct, JH–H = 3.5, afford 1.40 g (2.89 mmol, 98%) of (1R,2R,10R,20R)-8 as a white
13.0 Hz, 1H); 0.79 (cd, JH–H = 3.3, 12.0 Hz, 1H). 13C NMR powder, mp = 185–186 1C, [a]D25 = +66.01 (c = 0.35, CHCl3).
3
(125.8 MHz, CDCl3, d = ppm): 142.3 (d, JP–C = 5.3 Hz); 138.1 1H NMR (500 MHz, CDCl3, d = ppm): 7.77–7.92 (m, 9H); 7.65
(d, 3JP–C = 2.6 Hz); 133.5; 133.4; 133.0; 132.9; 128.4; 128.3; 128.2; (dd, JH–H = 1.4, 8.6 Hz, 1H); 7.40–7.50 (m, 4H); 4.77 (dc, 3JH–H
=
3
3
3
128.1; 127.9; 127.8; 127.1; 126.4; 126.3; 126.2; 126.1; 125.9; 7.1, JP–H = 15.5 Hz, 1H); 4.58 (dc, JH–H = 7.1, JP–H = 9.0 Hz,
2
125.6; 125.0; 63.3 (d, JP–C = 10.6 Hz); 61.4 (d, JP–C = 10.2 Hz); 1H); 2.74–2.83 (m, 1H); 2.65–2.72 (m, 1H); 2.58 (d, JH–H
=
54.7 (d, JP–C = 3.8 Hz); 52.4 (d, JP–C = 4.1 Hz); 30.1 (d, JP–C 4.0 Hz, 2H); 1.80 (d, JH–H = 7.0 Hz, 6H); 1.78 (br, 1H); 1.57–1.66
=
6.5 Hz); 30.0 (d, JP–C = 6.8 Hz); 24.3; 23.9 (d, JP–C = 1.4 Hz); 22.2 (m, 1H); 1.34–1.49 (m, 2H); 0.97–1.08 (m, 1H); 0.83–0.96
(d, JP–C = 3.9 Hz); 19.4 (d, JP–C = 3.4 Hz). 31P NMR (202.5 MHz, (m, 3H). 13C NMR (125.8 MHz, CDCl3, d = ppm): 142.2 (d, 3JP–C
=
3
CDCl3, d = ppm): 20.9 IR n~max (ATR) cmꢀ1: 3054.8, 2980.0, 4.5 Hz); 139.4 (d, JP–C = 2.3 Hz); 133.4; 133.3; 132.7; 132.6;
2941.7, 2870.8, 2855.5, 2129.5, 1600.0, 1506.3, 1448.1, 1380.6, 128.3; 128.1; 128.0; 127.9; 127.8; 127.7; 127.6; 126.4; 126.0;
1352.0,1290.6, 1243.6, 1224.7, 1201.3, 1152.5, 1136.7, 1097.4, 125.9; 125.7; 125.4; 62.7 (d, JP–C = 10.5 Hz); 60.9 (d, JP–C
1065.0, 1025.5, 947.6, 931.0, 897.0, 864.0, 830.5, 809.5, 750.5, 9.9 Hz); 53.5 (d, JP–C = 4.7 Hz); 51.6 (d, JP–C = 3.6 Hz); 30.8
714.3, 652.0, 586.5, 570.0. HR ESI-TOF [M + H]+ (m/z) calcd (d, JP–C = 8.8 Hz); 30.4 (d, JP–C = 10.0 Hz); 24.4; 24.1; 22.4 (d, JP–C
for [C30H32ON5P + H]+: 510.241726; found: 510.2417 (error = 3.7 Hz); 19.7 (d, JP–C = 4.1 Hz). 31P NMR (202.5 MHz, CDCl3,
ꢀ0.0121 ppm).
d = ppm): 24.1 IR n~max (ATR) cmꢀ1: 3187.5, 3136.5, 3087.0, 3052.5,
=
=
General procedure for the catalytic hydrogenation of azides 2931.9, 2863.4, 2819.4, 1630.4, 1598.4, 1560.5, 1505.6, 1448.4,
(1S,2S,10R,20R)-8 and (1R,2R,10R,20R)-8. Under an argon atmo- 1379.4, 1307.4, 1288.7, 1270.2, 1205.3, 1188.4, 1145.6, 1125.3,
sphere, 1 equivalent of azide (1S,2S,10R,20R)-7 [or (1R,2R,10R,20R)- 1094.0, 1073.4, 1060.3, 1024.0, 1008.3, 966.0, 951.1, 922.6, 893.5,
7] was dissolved in methanol, before the addition of 15% w/w of 877.9, 858.3, 819.7, 743.3, 662.3, 645.5, 626.5, 604.6, 580.2. HR
Pd/C (1% Pd/C). Then the system was charged with hydrogen via ESI-TOF [M + H]+ (m/z) calcd for [C30H34ON3P + H]+: 484.251228;
a syringe connected to a rubber balloon (2 ꢁ 500 mL). The found: 484.2514 (error = 0.5454 ppm).
reaction mixture was stirred for 6 h at room temperature and
Synthesis of catalyst (1R,2R,10R,20R,200S)-9. Under an argon
the resulting solution was filtered over Celite, and the solvent atmosphere, 0.3 g (0.62 mmol) of phosphoramide (1R,2R,10R,20R)-8
was evaporated under reduced pressure. The crude product was dissolved in 50 ml of anhydrous THF and cooled to 3 1C before
was purified by column chromatography using silica gel with the slow addition of 0.05 g (0.27 mL, 0.74 mmol) of n-BuLi (2.8 M in
CH2Cl2/MeOH (98: 2) as eluent.
hexanes) via a syringe. The resulting mixture was stirred for
(3aS,7aS)-2-Oxide-2-aminooctahydro-1,3-bis[(1R)-1-(2-naphthyl)- 20 min at 3 1C and then 0.4 g (3.1 mmol) of (S)-proline methyl
ethyl]-1H-1,3,2-benzodiazaphosphol, (1S,2S,10R,20R)-8. The general ester in 25 mL of anhydrous THF was added. The reaction
procedure for catalytic hydrogenation of azides was followed, with mixture was stirred at room temperature for 24 h before
1.5 g (2.94 mmol) of (1R,2R,10R,20R)-7 and 0.23 g of Pd/C to afford quenching and frappe ice was added to quench the reaction
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and extraction with ethyl acetate (3 ꢁ 75 mL). The combined 133.5; 133.3; 132.8; 132.7; 128.3; 128.2; 128.0; 127.9; 127.8;
organic layer was dried over Na2SO4 and the solvent was 127.7; 126.8; 126.2; 126.1; 126.0; 125.7; 125.3; 124.7; 62.6 (d,
evaporated under reduced pressure. The crude product was JP–C = 12.3 Hz); 62.1 (d, JP–C = 11.3 Hz); 55.2 (d, JP–C = 4.8 Hz);
purified by column chromatography using silica gel and 51.8 (d, JP–C = 4.3 Hz); 30.2 (d, JP–C = 8.2 Hz); 29.9 (d, JP–C
=
CH2Cl2/MeOH (95 : 5) as an eluent, to afford 0.26 g (0.45 mmol, 9.7 Hz); 29.7 (d, JP–C = 9.6 Hz); 24.4; 24.1; 22.6 (d, JP–C = 4.3 Hz);
73% yield) of compound (1R,2R,10R,20R,200S)-9 as a white foam. 19.5 (d, JP–C = 3.6 Hz). 31P NMR (202.5 MHz, CDCl3, d = ppm):
[a]2D5 = ꢀ40.91 (c = 0.313, CHCl3). 1H NMR (500 MHz, CDCl3, 14.6 IR n~max (ATR) cmꢀ1: 3061.6, 2932.4, 1702.0, 1600.4, 1478.6,
d = ppm): 7.89 (s, 1H); 7.77–7.86 (m, 8H); 7.68 (dd, JH–H = 1.5, 1446.9, 1377.0, 1296.2, 1195.8, 1142.7, 1096.4, 1060.3, 1023.3,
8.5 Hz, 1H); 7.38–7.48 (m, 4H); 4.68 (dc, 3JH–H = 7.0, 3JP–H = 15.6 965.0, 931.2, 905.5, 856.1, 819.1, 747.8, 713.0, 640.8, 621.8, 579.0,
3
3
Hz, 1H); 4.41 (dc, JH–H = 7.3, JP–H = 7.4 Hz, 1H); 3.77–3.86 556.8. HR ESI-TOF [M + H]+ (m/z) calcd for [C32H35BrO2N3P + H]+:
(m, 1H); 3.58 (dd, JH–H = 5.8, 9.1 Hz, 1H); 2.83–2.90 (m, 1H); 2.80 604.172304 and 606.170823 (1: 1); found: 604.172013 and
(ddd, JH–H = 6.4, 6.4, 10.3 Hz, 1H); 2.43 (ddd, JH–H = 6.6, 6.6, 606.1699 (error = ꢀ0.4810 ppm).
10.4 Hz, 1H); 2.02–2,13 (m, 2H); 1.76 (d, JH–H = 7.0 Hz, 3H); 1.68
Synthesis of azide (1R,2R,10R,20R)-14. Bromide (1R,2R,10R,20R)-13
(d, JH–H = 7.0 Hz, 3H); 1.40–1.53 (m, 4H); 1.33–1.38 (m, 1H); (0.9 g, 1.49 mmol) was dissolved in 20 mL of a DMF/DMSO (9 : 1)
1.25–1.31 (m, 1H); 1.10 (ct, JH–H = 3.6, 13.3 Hz, 1H); 0.79–0.90 mixture before the addition of 0.12 g (1.79 mmol) of sodium
(m, 2H); 0.63 (cd, JH–H = 3.5, 12.4 Hz, 1H). 1H{31P} NMR azide. The reaction mixture was stirred at room temperature for
1
(500 MHz, CDCl3, d = ppm): The same spectrum as H except 24 h, cooled to 3 1C, and treated with distilled water (3 ꢁ 25 mL)
3
3
for; 4.68 (c, JH–H = 6.8 Hz, 1H); 4.41 (c, JH–H = 7.0 Hz, 1H). (caution: exothermic process). The crude product was extracted
13C NMR (125.8 MHz, CDCl3, d = ppm): 177.5; 144.7; 139.5; with diethyl ether (3 ꢁ 40 mL), the organic layers were com-
133.4 (d, 3JP–C = 13.5 Hz); 132.7 (d, 3JP–C = 6.5 Hz); 128.2; 127.9; bined and dried over NaSO3, and the solvent was evaporated
127.8; 127.7; 127.6; 127.2; 126.0; 125.9; 125.5; 125.4; 124.6; 62.7 under reduced pressure. The crude product was purified by
(d, JP–C = 11.8 Hz); 62.2 (d, JP–C = 11.0 Hz); 61.5 (d, JP–C = 6.4 Hz); column chromatography using silica gel and hexane/EtOAc
55.4 (d, JP–C = 3.5 Hz); 52.1 (d, JP–C = 3.0 Hz); 47.2; 30.7; 30.5 (d, (95 : 5) eluent, to afford 0.65 g (1.16 mmol, 78% yield) of
JP–C = 8.5 Hz); 30.0 (d, JP–C = 9.1 Hz); 26.5; 24.4; 24.1; 22.7; 19.7. (1R,2R,10R,20R)-14 as a white foam. [a]D25 = ꢀ25.21 (c = 0.25,
31P NMR (202.5 MHz, CDCl3, d = ppm): 14.5 IR n~max (ATR) cmꢀ1
:
CHCl3). 1H NMR (500 MHz, CDCl3, d = ppm): 8.32 (br, 1H); 7.84
3055.9, 2934.0, 2867.1, 1697.6, 1633.7, 1600.8, 1506.2, 1445.3, (s, 1H); 7.73–7.83 (m, 7H); 7.63 (d, JH–H = 8.5 Hz, 1H); 7.60
3
1421.3, 1382.4, 1298.4, 1178.7, 1149.6, 1099.0, 1053.7, 1018.3, (d, JH–H = 8.3 Hz, 1H); 7.36–7.46 (m, 4H); 4.59 (dc, JH–H = 6.9,
3
3
947.9, 931.0, 900.6, 857.7, 820.8, 747.5, 645.7, 620.9, 595.4, 3JP–H = 18.9 Hz, 1H); 4.38 (dc, JH–H = 7.1, JP–H = 9.3 Hz, 1H);
577.0. HR ESI-TOF [M + H]+ (m/z) calcd for [C35H41O2N4P + H]+: 3.67–3.77 (m, 1H); 3.53 (d, JH–H = 16.8 Hz, 1H); 3.49 (d, JH–H
581.3039; found: 581.3042 (error = 0.378782 ppm). 16.8 Hz, 1H); 2.84–2.93 (m, 1H); 1.76–1.86 (m, 2H); 1.74
=
Synthesis of bromide (1R,2R,10R,20R)-13. Under an argon (d, JH–H = 6.9 Hz, 3H); 1.57 (d, JH–H = 6.5 Hz, 3H); 1.40–1.46
atmosphere, 1.0 g (2.1 mmol) of phosphoramide (1R,2R,10R,20R)-8 (m, 1H); 1.33 (cd, JH–H = 3.4, 12.2 Hz, 1H); 1.10–1.19 (m, 1H);
was dissolved in 50 mL of anhydrous THF and cooled to 3 1C 0.80–0.99 (m, 2H); 0.70 (cd, JH–H = 3.2, 12.3 Hz, 1H). 13C NMR
before the slow addition of 0.17 g (0.98 mL, 2.69 mmol) of n-BuLi (125.8 MHz, CDCl3, d = ppm): 168.5; 143.9; 138.4; 133.5; 133.3;
(2.8 M in hexanes) via a syringe. The resulting mixture was stirred 132.8; 132.7; 128.4; 128.2; 128.0; 127.9; 127.8; 127.7; 127.0;
for 20 min at 3 1C, and then 0.42 g (0.26 mL, 2.73 mmol) of methyl 126.5; 126.4; 126.3; 126.2; 125.8; 125.3; 124.8; 62.6 (d, JP–C
=
2-bromoacetate was added dropwise via a syringe. The reaction 12.1 Hz); 61.9 (d, JP–C = 10.7 Hz); 55.1 (d, JP–C = 4.0 Hz); 52.7
mixture was stirred at room temperature for 24 h and then frappe (d, JP–C = 8.5 Hz); 51.7 (d, JP–C = 3.4 Hz); 30.3 (d, JP–C = 8.4 Hz);
ice was added to quench the reaction. The crude product was 29.9; 29.4 (d, JP–C = 9.0 Hz); 24.5; 24.1; 22.5; 18.4. 31P NMR
extracted with ethyl acetate (3 ꢁ 75 mL), the combined organic (202.5 MHz, CDCl3, d = ppm): 13.3 IR n~max (ATR) cmꢀ1: 3088.6,
layer was dried over Na2SO4 and the solvent was evaporated 3058.5, 2923.3, 2865.3, 2104.4, 1708.2, 1600.6, 1475.6, 1450.3,
under reduced pressure. The crude product was purified by 1376.0, 1295.5, 1180.1, 1135.9, 1096.4, 1069.1, 1023.2, 964.2,
column chromatography using silica gel and with hexane/EtOAc 916.7, 949.1, 856.6, 820.4, 748.6, 698.0, 649.2, 620.6, 574.8. HR
(8: 2 to 7 : 3) as an eluent, to afford 1.05 g (1.73 mmol, 82% yield) ESI-TOF [M + H]+ (m/z) calcd for [C32H35O2N6P + H]+: 567.2631;
of product (1R,2R,10R,20R)-13 as a pale-yellow foam. [a]2D5 = ꢀ32.11 found: 567.263326 (error = 0.2404).
1
(c = 0.437, CHCl3). H NMR (500 MHz, CDCl3, d = ppm): 9.36
Synthesis of amine (1R,2R,10R,20R)-15. The general procedure
(br, 1H); 7.76–7.85 (m, 7H); 7.72 (d, JH–H = 8.0 Hz, 1H); 7.68 (d, for catalytic hydrogenation of azide compounds was followed,
JH–H = 8.4 Hz, 1H); 7.63 (d, JH–H = 8.6 Hz, 1H); 7.34–7.47 (m, 4H); with 0.6 g (1.06 mmol) of azide (1R,2R,10R,20R)-14 in 50 mL of
3
3
3
4.63 (dc, JH–H = 6.9, JP–H = 15.8 Hz, 1H); 4.40 (dc, JH–H = 7.0, methanol, to afford 0.57 g (1.03 mmol, 97% yield) of product
3JP–H = 9.4 Hz, 1H); 3.73–3.79 (m, 1H); 3.72 (d, JH–H = 11.9 Hz, (1R,2R,10R,20R)-15 as a white foam. [a]2D5 = +43.81 (c = 0.29,
1H); 3.64 (d, JH–H = 11.8 Hz, 1H); 2.78–2.91 (m, 1H); 1.75 CHCl3). 1H NMR (500 MHz, CDCl3, d = ppm): 7.94 (s, 1H);
(d, JH–H = 7.0 Hz, 3H); 1.63 (d, JH–H = 7.1 Hz, 3H); 1.46 (br-d, 7.74–7.86 (m, 7H); 7.68 (d, JH–H = 9.2 Hz, 1H); 7.65 (d, JH–H
JH–H = 13.1 Hz, 1H); 1.39 (br-d, JH–H = 13.5 Hz, 1H); 1.20–1.34 8.6 Hz, 1H); 7.36–7.49 (m, 4H); 4.60 (dc, 3JH–H = 6.7, 3JP–H = 21.9
(m, 2H); 1.11 (br-c, JH–H = 13.2 Hz, 1H); 0.76–0.96 (m, 2H); 0.65 Hz, 1H); 4.36 (dc, 3JH–H = 7.0, 3JP–H = 7.4 Hz, 1H); 3.75 (d, JH–H
(cd, JH–H = 3.0, 12.3 Hz, 1H). 13C NMR (125.8 MHz, CDCl3, d = 9.5 Hz, 1H); 3.25–3.55 (m, 2H); 2.98 (t, JH–H = 9.0 Hz, 1H);
=
=
3
3
ppm): 167.9; 144.2 (d, JP–C = 3.8 Hz); 138.8 (d, JP–C = 2.4 Hz); 2.89 (d, JH–H = 17.5 Hz, 1H); 2.84 (d, JH–H = 17.7 Hz, 1H); 1.95
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(d, JH–H = 10.4 Hz, 1H); 1.80 (d, JH–H = 6.8 Hz, 3H); 1.63 (br, 1H); 1365.3, 1297.6, 1235.9, 1159.8, 1133.3, 1094.5, 1024.1, 964.7,
1.59 (d, JH–H = 6.9 Hz, 3H); 1.33–1.47 (m, 2H); 1.0–1.20 (m, 3H); 948.3, 930.5, 901.5, 856.9, 821.9, 748.9, 695.2, 645.8, 578.8. HR
0.67–0.74 (m, 1H). 13C NMR (125.8 MHz, CDCl3, d = ppm): 174.7; ESI-TOF [M + H]+ (m/z) calcd for [C42H52O5N5P + H]+: 738.3778;
144.5 (d, JP–C = 4.1 Hz); 138.6; 133.5; 133.3; 132.7; 128.6; 128.3; found: 738.377711 (error = ꢀ0.2358 ppm).
128.0; 127.8; 127.7; 127.5; 127.4; 126.8; 126.2; 126.0; 125.6;
General procedure for the hydrolysis of the N-Boc group in
125.4; 124.7; 62.6 (d, JP–C = 11.8 Hz); 61.6 (d, JP–C = 10.5 Hz); precatalyst 16 to obtain catalyst (1R,2R,10R,20R,200S)-17. At room
55.4 (d, JP–C = 4.2 Hz); 51.6 (d, JP–C = 3.2 Hz); 45.6 (d, JP–C
temperature, 0.4 g (0.54 mmol) of precatalyst (1R,2R,10R,20R,200S)-16
=
7.5 Hz); 30.4 (d, JP–C = 8.6 Hz); 29.0 (d, JP–C = 9.1 Hz); 24.6; 24.1; was dissolved in 25 mL of anhydrous dichloromethane and the
22.6 (d, JP–C = 3.6 Hz); 17.5. 31P NMR (202.5 MHz, CDCl3, resulting mixture was cooled to 3 1C before the addition of
d = ppm): 13.3. IR n~max (ATR) cmꢀ1: 2934.2, 2857.0, 1697.5, 0.62 g (0.42 mL, 5.42 mmol) trifluoroacetic acid (in 5 mL of
1600.6, 1502.3, 1451.3, 1375.5, 1296.6, 1194.6, 1135.7, 1070.4, dichloromethane). The reaction mixture was warmed to room
1020.3, 963.8, 949.0, 930.8, 857.2, 820.2, 748.5, 567.4, 539.0. HR temperature and stirring was continued for 24 h. The solvent
ESI-TOF [M + H]+ (m/z) calcd for [C32H37O2N4P + H]+: 541.272692; was evaporated at reduced pressure and the resulting residue
found: 541.2730 (error = 0.5844 ppm).
was redissolved in EtOAc (20 mL) and treated with 7.0 mL of a
Synthesis of N-Boc protected precatalyst (1R,2R,10R,20R,200S)-16. solution of NaOH (1.0 M). The resulting mixture was stirred for
Under an argon atmosphere, 0.4 g (1.85 mmol) of N-Boc-(S)-proline 1 h, the layers were separated, the organic layer was dried
was dissolved in 20 mL of anhydrous acetonitrile at room over Na2SO4 and the solvent was evaporated under reduced
temperature before the slow addition of 0.28 g (0.3 mL, pressure. The crude product was purified by column chroma-
2.76 mmol) of N-methylmorpholine via a syringe. The resulting tography on silica gel and hexane/EtOAc (98 : 2 to 95 : 5) as an
mixture was cooled to 3 1C and stirred for 30 min, before the eluent, to afford 0.32 g (0.51 mmol, 94% yield) of compound
addition of 0.7 g (1.4 mL, 2.21 mmol) of 1-propanephosphonic (1R,2R,10R,20R,200S)-17 as a white foam. [a]D25 = +48.61 (c = 0.317,
anhydride solution (T3Ps, 50% w/w in EtOAc). Stirring was CHCl3). 1H NMR (500 MHz, CDCl3, d = ppm): 8.23 (br, 1H);
continued at 3 1C for 30 min and then 0.5 g (0.92 mmol) of 7.75–7.87 (m, 7H); 7.69 (dd, JH–H = 1.5, 8.6 Hz, 1H); 7.65–7.68
compound (1R,2R,10R,20R)-15 in 25 mL of EtOAc was added (m, 2H); 7.64 (dd, JH–H = 1.3, 8.5 Hz, 1H); 7.36–7.46 (m, 4H); 4.60
dropwise. The reaction mixture was allowed to warm to room (dc, 3JH–H = 6.8, 3JP–H = 18.2 Hz, 1H); 4.38 (dc, 3JH–H = 7.0, 3JP–H
=
temperature and stirring was continued for 24 h. Ethyl acetate 9.5 Hz, 1H); 3.88 (dd, JH–H = 6.4, 17.9 Hz, 1H); 3.65–3.75
(150 mL) was added and the resulting mixture was washed with (m, 2H); 3.54 (dd, JH–H = 4.2, 18.0 Hz, 1H); 3.32–3.48 (m,2
a solution of 1.0 M HCl (3 ꢁ 25 mL), potassium sodium tartrate 2H); 2.94–3.01 (m, 1H); 2.82–2.90 (m, 2H); 2.06–2.17 (m, 1H);
(50% w/w, 2 ꢁ 20 mL) and brine (3 ꢁ 20 mL). The organic layer 1.78–1.91 (m, 2H); 1.73 (d, JH–H = 7.0 Hz, 3H); 1.63–1.69 (m, 2H);
was dried over Na2SO4 and the solvent was evaporated under 1.60 (d, JH–H = 7.1 Hz, 3H); 1.48–1.54 (m, 1H); 1.38–1.44 (m, 1H);
reduced pressure. The crude product was purified by column 1.23–1.36 (m, 2H); 1.05–1.18 (m, 3H); 0.85–0.96 (m, 1H); 0.69
chromatography on silica gel and employing hexane/EtOAc (cd, JH–H = 3.2, 12.4 Hz, 1H). 13C NMR (125.8 MHz, CDCl3,
(95 : 5 to 7 : 3) as an eluent, to afford 0.47 g (0.64 mmol, d = ppm): 175.7; 170.7; 144.2 (d, JP–C = 4.2 Hz); 138.7; 133.5;
69% yield) of precatalyst (1R,2R,10R,20R,200S)-16 as a white foam. 133.3; 132.7; 128.3; 128.2; 128.1; 127.9; 127.8; 127.7; 127.2;
1
[a]2D5 = +48.21 (c = 0.303, CHCl3). H NMR (500 MHz, DMSO-d6, 126.2; 126.1; 126.0; 125.6; 125.4; 124.8; 62.5 (d, JP–C
=
100 1C, d = ppm): 8.47 (d, JH–H = 5.4 Hz, 1H); 7.91 (s, 1H); 7.78– 12.1 Hz); 61.8 (d, JP–C = 10.9 Hz); 60.5; 55.2 (d, JP–C = 4.6 Hz);
7.86 (m, 6H); 7.74 (d, JH–H = 8.6 Hz, 1H); 7.67 (d, JH–H = 8.5 Hz, 51.6 (d, JP–C = 4.1 Hz); 47.4; 43.5 (d, JP–C = 9.3 Hz); 30.8; 30.2
1H); 7.53 (s, 1H); 7.38–7.48 (m, 4H); 4.67 (dc, 3JH–H = 7.0, 3JP–H
=
(d, JP–C = 8.6 Hz); 29.5 (d, JP–C = 9.3 Hz); 26.3; 24.4; 24.1; 22.4
14.1 Hz, 1H); 4.40 (dc, JH–H = 7.0, JP–H = 10.7 Hz, 1H); 4.18 (d, JP–C = 3.8 Hz); 18.7. 31P NMR (202.5 MHz, CDCl3, d = ppm):
(dd, JH–H = 3.3, 8.4 Hz, 1H); 3.74 (dd, JH–H = 5.5, 17.1 Hz, 1H); 13.5. IR n~max (ATR) cmꢀ1: 2932.7, 2870.7, 1706.5, 1667.4, 1600.5,
3.66 (dd, JH–H = 5.3, 17.1 Hz, 1H); 3.61–3.63 (m, 1H); 3.31–3.41 1507.7, 1273.7, 1376.7, 1297.0, 1190.3, 1134.1, 1095.8, 1061.0,
(m, 2H); 2.61–2.71 (m, 1H); 2.43–2.49 (m, 2H); 2.06–2.15 (m, 1023.2, 966.1, 947.9, 930.8, 902.3, 857.3, 821.0, 749.6, 648.2,
3
3
1H); 1.81–1.92 (m, 2H); 1.74–1.79 (m, 1H); 1.69–1.73 (m,1H); 5889.9, 569.0. HR ESI-TOF [M
+
H]+ (m/z) calcd for
1.68 (d, JH–H = 7.0 Hz, 3H); 1.62 (d, JH–H = 7.1 Hz, 3H); 1.57 [C37H44O3N5P + H]+: 638.325456; found: 638.326151 (error =
(br, 1H); 1.40 (s, 9H); 1.14–1.18 (m, 1H); 0.99–1.05 (m, 1H); 1.089442 ppm).
0.73–0.92 (m, 2H); 0.60 (cd, JH–H = 2.9, 12.1 Hz, 1H). 13C NMR
Synthesis of N-Boc protected precatalyst (1S,2S,10R,20R,200S)-22.
(125.8 MHz, DMSO-d6, 100 1C, d = ppm): 173.1; 170.9; 154.4; At room temperature and under an argon atmosphere, 0.5 g
144.9; 139.7 (d, JP–C = 2.5 Hz); 133.6 (d, JP–C = 10.2 Hz); 132.9 (1.03 mmol) of phosphoramide (1S,2S,10R,20R)-8 was dissolved
(d, JP–C = 2.4 Hz); 128.4; 128.2; 128.1; 128.0; 127.9; 127.8; 127.4; in 50 mL of anhydrous THF and the resulting mixture was cooled
126.3; 126.2; 126.1; 126.0; 125.9; 125.8; 125.0; 79.5; 62.2 to 3 1C before treatment (slow addition via a syringe) with 0.08 g
(d, JP–C = 10.6 Hz); 62.1 (d, JP–C = 12.2 Hz); 60.6; 54.7 (d, JP–C
=
(0.46 mL, 1.26 mmol) of n-BuLi (2.7 M in hexanes). The resulting
4.6 Hz); 51.8 (d, JP–C = 4.9 Hz); 47.2; 44.0 (d, JP–C = 9.3 Hz); 30.9; mixture was stirred for 20 min at 3 1C and then 0.31 g (1.26 mmol)
30.3 (d, JP–C = 9.2 Hz); 30.2 (d, JP–C = 8.3 Hz); 28.7; 24.6; 24.1; of N-Boc-(S)-proline-isothiocyanate ((S)-20) in 25 mL of anhy-
23.9; 22.2 (d, JP–C = 4.1 Hz); 20.0 (d, JP–C = 4.0 Hz). 31P NMR drous THF was added. The reaction mixture was allowed to
(202.5 MHz, DMSO-d6, 100 1C, d = ppm): 13.4. IR n~max (ATR) cmꢀ1
:
warm to room temperature and stirring was continued for 24 h.
2928.2, 2869.5, 1676.8, 1600.7, 1507.6, 1474.7, 1452.7, 1390.7, Frappe ice was added to quench the reaction and the crude
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product was extracted with ethyl acetate (3 ꢁ 75 mL). The 60366, and also for doctoral and postdoctoral fellowships for
organic layer was dried over anhydrous Na2SO4 and the solvent C. A. C. H. and J. M. L. respectively. Finally, we also thank M. T.
´
´
´
´
was evaporated under reduced pressure. The crude product was Cortez-Picasso, V. M. Gonzalez-Dıaz, and M. L. Rodrıguez-Perez
´
purified by column chromatography on silica gel and using for NMR spectra, and G. Cuellar-Rivera for MS-TOF analysis.
hexane/EtOAc (100 : 0 to 80 : 20) as an eluent, to afford 0.41 g
(0.56 mmol, 54% yield) of precatalyst (1S,2S,10R,20R,200S)-22 as a
white foam. [a]D = + 10.81, c = 0.26 (CHCl3). 1H NMR (400 MHz,
DMSO-d6, 120 1C, d = ppm): 9.91 (a, 1H); 8.73 (a, 1H); 8.03 (a,
Notes and references
1H); 7.94–7.82 (m, 8H); 7.77–7.70 (m, 1H); 7.54–7.43 (m, 4H);
4.72–4.55 (m, 4H); 3.94–3.82 (m, 2H); 3.75–3.62 (m, 1 H); 3.41–
3.22 (m, 4H); 2.74–2.65 (m, 1H); 1.81 (d, JH–H = 7.0 Hz, 3H); 1.77
(d, JH–H = 7.1 Hz, 3H); 1.63–1.49 (m, 2H); 1.40 (s, 9H); 1.23–1.13
1 See, for example: (a) Z. G. Hajos and D. R. Parrish, J. Org.
Chem., 1974, 39, 1615; (b) U. Eder, G. R. Sauer and
R. Wiechert, Angew. Chem., Int. Ed., 1971, 10, 496 (Angew.
Chem, 1971, 83, 492); (c) S. E. Denmark, S. B. D. Winter,
X. Su and K.-T. Wong, J. Am. Chem. Soc., 1996, 118, 7404;
(d) S. E. Denmark, K.-T. Wong and R. A. Stavenger, J. Am.
Chem. Soc., 1997, 119, 2333; (e) S. E. Denmark and R. A.
Stavenger, J. Org. Chem., 1998, 63, 9524; ( f ) M. S. Sigman
and E. N. Jacobsen, J. Am. Chem. Soc., 1998, 120, 4901;
(g) S. E. Denmark, R. A. Stavenger, K.-T. Wong and X. Su,
J. Am. Chem. Soc., 1999, 121, 4982.
(m, 2H); 1.10–0.98 (m, 2H); 0.90–0.76 (m, 4H); 0.65 (cd, JH–H
=
3.3, 12.1 Hz, 1H). 13C NMR (100.5 MHz, DMSO-d6, 120 1C, d =
ppm): 184.2 (d, JP–C = 3.4 Hz), 154.2, 141.8 (d, JP–C = 6.5 Hz),
141.1, 133.6, 133.4, 132.9, 132.7, 128.4, 128.3, 128.2, 127.9,
127.7, 126.5, 126.3, 126.2, 126.1, 126.0, 125.8, 125.0, 79.0,
61.1 (d, JP–C = 10.9 Hz), 58.9 (d, JP–C = 10.8 Hz), 56.7, 53.4,
50.4 (d, JP–C = 4.4 Hz), 47.6, 46.9, 30.2 (d, JP–C = 9.6 Hz), 29.2,
28.7, 28.4 (d, JP–C = 8.5 Hz), 24.2, 24.0, 23.4, 19.8, 16.7 31P NMR
2 (a) B. List, R. A. Lerner and C. F. Barbas III, J. Am. Chem.
Soc., 2000, 122, 2395; (b) K. A. Ahrendt, C. J. Borths and
D. W. C. MacMillan, J. Am. Chem. Soc., 2000, 122, 4243.
3 (a) P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed., 2004,
(161.8.5 MHz, DMSO-d6, 120 1C, d = ppm): 17.4. IR n~max (ATR) cmꢀ1
:
HR ESI-TOF [M + H]+ (m/z) calcd for [C42H52O5N5P + H]+: 738.377885;
found: 738.3777 (error = ꢀ0.2358 ppm).
Synthesis of catalyst (1R,2R,10R,20R,200S)-20. The general
procedure for the hydrolysis of N-Boc groups was followed with
0.35 g (0.48 mmol) of precatalyst (1R,2R,10R,20R,200S)-22 in
10 mL of dichloromethane (reaction time 14 h). The crude
product was purified by column chromatography using silica
gel and CH2Cl2/MeOH (98 : 2 to 90 : 10) as an eluent, to afford
0.29 g (0.46 mmol, 96% yield) of catalyst (1R,2R,10R,20R,200S)-20
43, 5138; (b) A. Erkkila, I. Majander and P. M. Pihko, Chem. Rev.,
¨
2007, 107, 5416; (c) S. Mukherjee, J. W. Yang, S. Hoffmann and
B. List, Chem. Rev., 2007, 107, 5471; (d) T. Akiyama, Chem. Rev.,
2007, 107, 5744; (e) P. Melchiorre, M. Marigo, A. Carlone and
G. Bartoli, Angew. Chem., Int. Ed., 2008, 47, 6138; ( f ) S. Bertelsen
and K. A. Jørgensen, Chem. Soc. Rev., 2009, 38, 2178;
(g) M. Terada, Synthesis, 2010, 1929; (h) M. Rueping,
A. Kuenkel. and I. Atodiresei, Chem. Soc. Rev., 2011, 40, 4539;
(i) T. Akiyama and K. Mori, Chem. Rev., 2015, 115, 9277;
( j) R. Mitra and J. Niemeyer, ChemCatChem, 2018, 10, 1221.
4 (a) S. Bahmanyar and K. N. Houk, J. Am. Chem. Soc., 2001,
123, 12911; (b) S. Bahmanyar, K. N. Houk, H. J. Martin and
B. List, J. Am. Chem. Soc., 2003, 125, 2475; (c) C. Allemann,
R. Gordillo, F. R. Clemente, P. H.-Y. Cheong and K. N. Houk,
Acc. Chem. Res., 2004, 37, 558; (d) P. H.-Y. Cheong and
K. N. Houk, Synthesis, 2005, 1533. See also: (e) R. B. Sunoj,
Wiley Interdiscip. Rev.: Comput. Mol. Sci., 2011, 1, 920.
as a pale-yellow foam. [a]2D5 = +25.81, c = 1.44 (CHCl3). H NMR
1
(400 MHz, CDCl3, d = ppm): 10.2 (a, 1H); 8.00–7.70 (m, 10H);
3
3
7.59–7.38 (m, 4H); 4.81 (dc, JH–H = 6.8, JP–H = 12.5 Hz, 1H);
3
3
4.61 (dc, JH–H = 7.0, JP–H = 19.4 Hz, 1H); 4.00–3.88 (m, 1H);
3.87–3.79 (m, 1H); 3.71–3.60 (m, 2H); 3.53–3.43 (m, 2H);
3.11–2.96 (m, 2H); 2.82–2.70 (m, 1H); 2.01–1.93 (m, 1H); 1.89
(d, JH–H = 7.1 Hz, 3H); 1.86 (d, JH–H = 7.1 Hz, 3H); 1.80–1.76 (m, 1H);
1.60–1.51 (m, 2H); 1.42–1.37 (m, 1H); 1.17–1.12 (m, 3H); 0.92–0.82
(m, 2H); 0.65 (cd, JH–H = 3.0, 12.3 Hz, 1H). 13C NMR (100.5 MHz,
CDCl3, d = ppm): 183.1, 139.9, 133.3, 133.1, 132.8, 132.6, 128.7,
128.1, 128.0, 127.7, 127.6, 126.4, 126.1, 126.0, 125.9, 125.6, 125.3,
124.7, 60.8 (d, JP–C = 11.0 Hz), 59.9 (d, JP–C = 10.4 Hz), 58.0, 54.1,
50.0, 49.1, 46.1, 29.7, 28.7, 28.5, 25.2, 24.0, 23.8, 20.1, 16.7 31P NMR
(161.8 MHz, CDCl3, d = ppm): 16.1. IR n~max (ATR) cmꢀ1: HR
ESI-TOF [M + H]+ (m/z) calcd for [C42H52O5N5P + H]+: 738.377885;
found: 738.377711 (error = ꢀ0.235895 ppm).
5 (a) Comprehensive Enantioselective Organocatalysis: Catalysts,
Reactions and Applications, ed. P. I. Dalko, Wiley-VCH,
Weinheim, 2013, vol. 1–3; (b) Stereoselective Organocatalysis.
´
Bond Formation Methodologies and Activation Modes, ed. R. Rıos
Torres, Wiley, Hoboken, 2013.
´
´
´
6 (a) C. Cruz-Hernandez, P. E. Hernandez-Gonzalez and E. Juaristi,
´
´
Synthesis, 2018, 1827; (b) C. Cruz-Hernandez, P. E. Hernandez-
´
Gonzalez and E. Juaristi, Synthesis, 2018, 3445; (c) C. Cruz-
Conflicts of interest
´
´
´
´
´
Hernandez, E. Martınez-Martınez, P. E. Hernandez-Gonzalez
and E. Juaristi, Eur. J. Org. Chem., 2018, 6890–6900.
There are no conflicts to declare.
7 (a) A. Kattuboina and G. Li, Tetrahedron Lett., 2008, 49, 1573;
(b) J. Han, T. Ai and G. Li, Synthesis, 2008, 2519; (c) P. Kaur,
T. Nguyen and G. Li, Eur. J. Org. Chem., 2009, 912; (d) C. W.
Seifert, S. Pindi and G. Li, J. Org. Chem., 2015, 80, 447;
(e) G. An, C. W. Seifert and G. Li, Org. Biomol. Chem., 2015,
13, 1600; ( f ) S. Qiao, S. Pindi, P. T. Spigener, B. Jiang and
Acknowledgements
´
We thank Consejo Nacional de Ciencia y Tecnologıa (CONACYT,
Mexico) for financial support via grants No. 220945, 130826 and
New J. Chem.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2019

View Article Online
NJC
G. Li, Tetrahedron Lett., 2016, 57, 619; (g) H. Zhang, B. Yang,
Paper
Tetrahedron: Asymmetry, 2015, 26, 517; (g) U. V. S. Reddy,
M. Chennapuram, K. Seki, C. Seki, B. Anusha, E. Kwon,
Y. Okuyama, K. Uwai, M. Tokiwa, M. Takeshita and
H. Nakano, Eur. J. Org. Chem., 2017, 3874.
Z. Yang, H. Lu and G. Li, J. Org. Chem., 2016, 81, 7654;
(h) S. Qiao, C. B. Wilcox, D. K. Unruh, B. Jiang and G. Li,
J. Org. Chem., 2017, 82, 2992; (i) S. Qiao, J. Wu, J. Mo,
P. T. Spigener, B. N. Zhao, B. Jiang and G. Li, Synlett, 2017, 15 (a) Z. Tang, F. Jiang, L.-T. Yu, X. Cui, L.-Z. Gong, A.-Q. Mi,
2483; ( j) S. Qiao, J. Mo, C. B. Wilcox, B. Jiang and G. Li, Org.
Biomol. Chem., 2017, 15, 1718.
8 (a) M. Marigo, T. C. Wabnitz, D. Fielenbach and K. A. Jørgensen,
Y.-Z. Jiang and Y.-D. Wu, J. Am. Chem. Soc., 2003, 125, 5262;
(b) Z. Tang, Z.-H. Yang, X.-H. Chen, L.-F. Cun, A.-Q. Mi,
Y.-Z. Jiang and L.-Z. Gong, J. Am. Chem. Soc., 2005,
127, 9285; (c) M. Raj, S. K. Ginotra and V. K. Singh, Org.
Lett., 2006, 8, 4097; (d) L. He, J. Jiang, Z. Tang, X. Cui,
A.-Q. Mi, Y.-Z. Jiang and L.-Z. Gong, Tetrahedron: Asymmetry,
2007, 18, 265; (e) S. Gandhi and V. K. Singh, J. Org. Chem.,
2008, 73, 9411; ( f ) F. Chen, S. Huang, H. Zhang, F. Liu and
Y. Peng, Tetrahedron, 2008, 64, 9585; (g) M. R. Vishnumaya
and V. K. Singh, J. Org. Chem., 2009, 74, 4289; (h) B. Wang,
G.-H. Chen, L.-Y. Liu, W.-X. Chang and J. Li, Adv. Synth.
Catal., 2009, 351, 2441; (i) E. Tsandi, C. G. Kokotos,
S. Kousidou, V. Ragoussis and G. Kokotos, Tetrahedron,
2009, 65, 1444; ( j) S. Fotaras, C. G. Kokotos, E. Tsandi
and G. Kokotos, Eur. J. Org. Chem., 2011, 1310.
´
Angew. Chem., Int. Ed., 2005, 44, 794; (b) J. Franzen, M. Marigo,
D. Fielenbach, T. C. Wabnitz, A. Kjearsgarrd and K. A. Jørgensen,
J. Am. Chem. Soc., 2005, 127, 18296; (c) Y. Hayashi, H. Gotoh,
T. Hayashi and M. Shoji, Angew. Chem., Int. Ed., 2005, 44, 4212.
See also: (d) K. Soai, A. Ookawa, T. Kaba and K. Ogawa, J. Am.
Chem. Soc., 1987, 109, 7111; (e) E. J. Corey, R. K. Bakshi and
S. Shibata, J. Am. Chem. Soc., 1987, 109, 5551; ( f ) J. Vargas–
Caporali and E. Juaristi, Synthesis, 2016, 3890.
9 (a) M. T. Robak, M. A. Herbage and J. A. Ellman, Tetrahedron,
2011, 67, 4412; (b) W. Wan, W. Gao, G. Ma, L. Ma, F. Wang,
J. Wang, H. Jiang, S. Zhu and J. Hao, RSC Adv., 2014, 4, 26563;
(c) G. Reyes-Rangel, J. Vargas-Caporali and E. Juaristi, Tetra-
hedron, 2017, 73, 4707.
16 (a) M. S. Sigman and E. N. Jacobsen, J. Am. Chem. Soc., 1998,
120, 4901; (b) P. Vachal and E. N. Jacobsen, J. Am. Chem.
Soc., 2002, 124, 10012; (c) P. R. Schreiner, Chem. Soc. Rev.,
2003, 32, 289.
10 Crystallographic data for (1S,2S,10R,20R)-4: C30H32N5OP,
Monoclinic, P21; a = 16.836(17), b = 8.350(8), c = 19.27(2);
a = 901, b = 90.98(3)1, g = 901; V = 2709(5); z = 2, z0 = 1;
R1 = 7.01%. CCDC: 1878183†.
17 (a) B. List, P. Pojarliev and H. J. Martin, Org. Lett., 2001,
3, 2423; (b) T. Ishii, S. Fujioka, Y. Sekiguchi and H. Kotsuki,
J. Am. Chem. Soc., 2004, 126, 9558; (c) Y.-L. Cao, H.-H. Lu,
Y.-Y. Lai, L.-Q. Lu and W.-J. Xiao, Synthesis, 2006, 3795;
(d) Z. Shen, Y. Zhang, C. Jiao, B. Li, J. Ding and Y. Zhang,
Chirality, 2007, 19, 307; (e) Y.-L. Cao, Y.-Y. Lai, X. Wang,
Y.-J. Li and W.-J. Xiao, Tetrahedron Lett., 2007, 48, 21;
( f ) J.-R. Chen, Y.-L. Cao, Y. Q. Zou, F. Tan, L. Fu, X.-Y. Zhu
and W.-J. Xiao, Org. Biomol. Chem., 2010, 8, 1275; (g) D.-Z. Xu.,
Y. Liu, S. Shi and Y. Wang, Tetrahedron: Asymmetry, 2010,
21, 2530; (h) Y.-M. Chuan, L. Y. Yin, Y.-M. Zhang and Y.-G.
Peng, Eur. J. Org. Chem., 2011, 578; (i) J.-R. Chen, L. Fu,
Y.-Q. Zou, N.-J. Chang, J. Rong and W.-J. Xiao, Org. Biomol.
Chem., 2011, 9, 5280; ( j) X. Cao, G. Wang, R. Zhang, Y. Wei,
W. Wang, H. Sun and L. Chen, Org. Biomol. Chem., 2011,
9, 6487; (k) S. Singh and S. S. Chimni, Tetrahedron: Asymmetry,
2012, 23, 1068; (l) H.-W. Zhao, H.-L. Li, Y.-Y. Yue and
Z.-H. Sheng, Eur. J. Org. Chem., 2013, 1740; (m) T. P. Kumar,
L. Radhika, K. Haribabu and V. N. Kumar, Tetrahedron:
Asymmetry, 2014, 25, 1555; (n) H.-W. Zhao, Z. Yang, Y.-Y.
Yue, H.-L. Li, X.-Q. Song, Z.-H. Zheng, W. Meng and W.-Y.
Guo, Synlett, 2014, 293; (o) A. Ruiz-Olalla, M. G. Retamosa and
11 Cf.(a) G. R. Desiraju, S. Kashino, M. M. Coombs and
J. P. Glusker, Acta Crystallogr., Sect. B: Struct. Sci., 1993,
49, 880; (b) G. R. Desiraju, Acc. Chem. Res., 1996, 29, 441.
12 G. A. Jeffrey, An Introduction to Hydrogen Bonding, Oxford
University Press, UK, 1997, p. 12.
13 (a) A. Ricci, L. Bernardi, C. Gioia, S. Verucci, M. Robitzer and
F. Quignard, Chem. Commun., 2010, 46, 6268; (b) C. Shen,
F. Shen, H. Xia, P. Zhang and X. Chen, Tetrahedron: Asym-
metry, 2011, 22, 708; (c) M. Raj, N. Veerasamy and
V. K. Singh, Tetrahedron Lett., 2010, 51, 2157; (d) Q. Guo
and J. C.-G. Zhao, Tetrahedron Lett., 2012, 53, 1768;
(e) Y. Liu, P. Gao, J. Wang, Q. Sun, Z. Ge and R. Li, Synlett,
2012, 1031; ( f ) A. Kumar and S. S. Chimni, Tetrahedron,
2013, 69, 5197; (g) Y. Tanimura, K. Yasunaga and
K. Ishimaru, Eur. J. Org. Chem., 2013, 6535; (h) H. Zhao,
W. Meng, Z. Yang, T. Tian, Z. Sheng, H. Li, X. Song,
Y. Zhang, S. Yang and B. Li, Chin. J. Chem., 2014, 32, 417;
(i) J. Kimura, U. V. S. Reddy, Y. Kohari, C. Seki, Y. Mawatari,
K. Uwai, Y. Okuyama, E. Kwon, M. Tokiwa, M. Takeshita,
T. Iwasa and H. Nakano, Eur. J. Org. Chem., 2016, 3748;
( j) J. Wang, Q. Liu, Y. Sun, Y. Luo and H. Yang, Chirality,
ˇ
´
2015, 27, 314; (k) P. H. Mohite, P. Drabina and F. Bures,
F. P. Cossıo, J. Org. Chem., 2015, 80, 5588; (p) R. Zhang, G. Yin,
Synthesis, 2017, 1613.
Y. Li, X. Yan and L. Chen, RSC Adv., 2015, 5, 3461;
(q) T. P. Kumar, S. S. Prasad, K. Haribabu, V. N. Kumar and
C. S. Reddy, Tetrahedron: Asymmetry, 2016, 27, 1133; (r) J. Du,
B. Shuai, M. Tao, G. Wong and W. Zhang, Green Chem., 2016,
18, 2625; (s) G. Reyes-Rangel, J. Vargas-Caporali and E. Juaristi,
Tetrahedron, 2017, 73, 4707.
14 (a) G. Luppi, P. G. Cozzi, M. Monari, B. Kaptein,
Q. B. Broxterman and C. Tomasini, J. Org. Chem., 2005,
70, 7418; (b) G. S. Singh and Z. Y. Desta, Chem. Rev., 2012,
112, 6104; (c) A. Kumar and S. S. Chimni, RSC Adv., 2012,
´
´
´
2, 9748; (d) J. G. Hernandez, V. Garcıa-Lopez and E. Juaristi,
Tetrahedron, 2012, 68, 92; (e) S. Mohammadi, R. Heiran, 18 (a) C.-L. Cao, X.-L. Sun, Y.-B. Kang and Y. Tang, Org. Lett.,
´
´
´
˜
R. P. Herrera and E. Marques-Lopez, ChemCatChem, 2013,
2007, 9, 4151; (b) A. Obregon-Zu´niga, M. Guerrero-Robles
5, 2131; ( f ) G. M. Ziarani, R. Mirandi and N. Lashgari,
and E. Juaristi, Eur. J. Org. Chem., 2017, 2692.
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