Carbonylation of functionalized diamine diols to cyclic ureas: Application to derivatives of DMP 450

Article abstract of DOI:10.1016/j.tet.2011.04.015

Synthesis of the cyclic urea core structure of the HIV protease inhibitor DMP 450 has been achieved via W(CO)₆/I₂-catalyzed carbonylation of diamine intermediates. Carbonylations of related functionalized diamines to derivatives of the DMP 450 core structure were also examined. Selected diamine diol substrates could be converted to the cyclic urea core structure by catalytic carbonylation without protection of the diol functionality.

Full text of DOI:10.1016/j.tet.2011.04.015

Tetrahedron 67 (2011) 3976e3983
Contents lists available at ScienceDirect
Tetrahedron
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Carbonylation of functionalized diamine diols to cyclic ureas: application to
derivatives of DMP 450
*
ꢀ
Ampofo K. Darko, F. Chris Curran, Chloe Copin, Lisa McElwee-White
Department of Chemistry and Center for Catalysis, University of Florida, PO Box 117200, Gainesville, FL 32611-7200, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of the cyclic urea core structure of the HIV protease inhibitor DMP 450 has been achieved via
W(CO)6/I2-catalyzed carbonylation of diamine intermediates. Carbonylations of related functionalized
diamines to derivatives of the DMP 450 core structure were also examined. Selected diamine diol sub-
strates could be converted to the cyclic urea core structure by catalytic carbonylation without protection
of the diol functionality.
Received 3 February 2011
Received in revised form 31 March 2011
Accepted 5 April 2011
Available online 13 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Carbonylation
Cyclic ureas
HIV protease inhibitors
Tungsten hexacarbonyl
1. Introduction
to the synthesis of functionalized targets,30e32 including the core
structure of the HIV protease inhibitor DMP 450.33,34
The presence of the urea moiety in various compounds, such as
agrochemicals, pharmaceutical candidates, resins, and dyes1e5 has
prompted the development of methods for the synthesis of ureas.
Classical methods for the preparation of ureas from amines involve
the use of toxic reagents, such as phosgene or isocyanates.6,7 The
use of phosgene or isocyanates poses environmental and health
concerns because of the storage and use of large amounts of chlo-
rine during their manufacture. The high toxicity associated with
these reagents has led to efforts to develop less hazardous reagents
for the synthesis of ureas from amines. Alternatives to phosgene
have included, but are not limited to, the utilization of phosgene
derivatives or the use of carbon monoxide as the carbonyl source.8
An area of considerable interest is catalytic oxidative carbonylation,
which uses amines, an oxidant, and carbon monoxide as starting
materials to afford ureas.9 The only byproducts are the reduced
form of the oxidant and protons, making it appealing by atom
economy10 standards. Various transition-metal catalysts including
Pd,11e16 Co,17e21 Ni,22 Ru,20,23 Mn,24 and Au,25e27 have been shown
to yield at least some urea. However, it is often a minor product.
Additionally, harsh reaction conditions are required, which can
result in complex mixtures of ureas, oxamides, and formamides.
Our prior experiences using tungsten hexacarbonyl [W(CO)6] as
a catalyst for the catalytic oxidative carbonylation of diamines to
ureas with I2 as the oxidant (Scheme 1)28,29 included its application
Scheme 1. Cyclic ureas previously prepared by catalytic carbonylation.
The practical synthesis of DMP 45035 involved the use of phosgene
or a phosgene derivative to install the urea moiety, which required
protection of the diol functionality. In the initial small-scale prepa-
rations, a primary diamine was reacted with the phosgene derivative
1,10-carbonyldiimidazole (CDI), followed by N-alkylation as appro-
priate.34e36 A subsequent approach to the synthesis of DMP 450 an-
alogues involved the use of phosphorus tethers in conjunction with
ring-closing metathesis to afford the diamine precursors but the
urea moiety was also installed by carbonylation with CDI.37
* Corresponding author. Tel.: þ1 352 392 8768; fax: þ1 352 846 0296; e-mail
address: lmwhite@chem.ufl.edu (L. McElwee-White).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.015

A.K. Darko et al. / Tetrahedron 67 (2011) 3976e3983
3977
Since the use of phosgene or its derivatives, such as CDI requires
2. Results and discussion
protection of the diol, an extensive study of protecting groups was
carried out in order to find the best conditions.35,38 Although pro-
tection of the diol functionality was integral to the success of the
catalytic carbonylation reaction using our original reaction condi-
tions, as it had been with stoichiometric use of phosgene and its
derivatives, yields from the carbonylation reaction were comparable
to those obtained using stoichiometric methods (Scheme 2).30
Substrates for the carbonylation study were chosen from a series
of primary and secondary diamine diols that would afford the core
structure of DMP 450 and its derivatives (Scheme 4). In order to
assess the need for protecting group chemistry, the substrates in-
cluded O-protected, as well as unprotected hydroxyl substituents.
All substrates were subjected to W(CO)6/I2 catalyzed oxidative
carbonylation. Depending on the substrate, there were two sets of
reaction conditions for carbonylation, the main differences being in
base and solvent. In one procedure, potassium carbonate was used
as the base with a biphasic solvent system (CH2Cl2/H2O), while in
a second procedure, the preferred base was pyridine with methy-
lene chloride or dichloroethane (at 80 ꢀC) as the solvent.
Scheme 2. Synthesis of the core DMP450 structure by catalytic carbonylation.
Subsequent modification of our reaction conditions led to the
selective catalytic oxidative carbonylation of unprotected amino
alcohols to ureas.31 Using pyridine as the base and changing the
work-up allowed for conversion of a series of 1,2-, 1,3-, 1,4-, and 1,5-
amino alcohols to ureas in good to excellent yields, in preference to
cyclization to the carbamate. Good yields of urea 2 from the 1,2-
amino alcohol 1 (Scheme 3)31 suggested that it could be possible to
synthesize the core structure of DMP 450 by catalytic carbonylation
without protecting group chemistry. We now report the extension
of our original study on the preparation of the core structure of
DMP 450 (primary diamine substrates with protected diols) to
encompass related substrates with secondary diamines and un-
protected diols. Although there are steric limitations to the catalytic
oxidative carbonylation reaction, several of these more challenging
substrates afford the cyclic urea in good to excellent yields.
Scheme 4. Diamine substrates 3 and their respective cyclic ureas.
We began our investigation with the synthesis of primary di-
amines 3aee, starting from the appropriate chiral amino alcohol
(Scheme 5).34,36,39 Swern oxidation of 5a,b followed by vanadium-
mediated coupling affords diols 6a,b. Protection of the diols to
produce 7aed, and hydrogenolysis using cyclohexene as the hy-
drogen source gives O-protected amines 3aed. Unprotected diol 3e
can be obtained by the direct hydrogenolysis of 6b.
For a-methyl diamines 3a and 3c, ureas were obtained in good
yields regardless of whether the protecting group was acetonide or
SEM (Table 1, entries 1 and 3). The protecting group preference was
more apparent with a benzyl group in the alpha position (Scheme 2,
Table 1, entries 2 and 4).30 In addition, urea 4e, the core structure of
DMP 450, could be obtained from diamine 3e in low yield without
protection of the diol (Scheme 6). Optimization experiments on
carbonylation of 3e indicated that this reaction required increased
temperature (80 ꢀC) with dichloroethane as the solvent. However, in
contrast to results with 1,2-amino alcohols,31 formation of the urea
Scheme 3. Carbonylation of 1,2-amino alcohol l.
Scheme 5. Synthesis of bis(amino)hexanediols 3aee.

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A.K. Darko et al. / Tetrahedron 67 (2011) 3976e3983
Table 1
applied to obtain 3h, starting from the appropriate parent tartrate
Carbonylation of diamines 3aeda
12. Due to purification issues, a different route was employed to
synthesize compound 3i. Starting from the ditosylate 13, aminolytic
ring opening of diepoxide 14 provided compound 3i in quantitative
yield (Scheme 8). Results from the carbonylation of amino-
butanediols 3fei are summarized in Table 2.
Entry
Aminohexanediol
Product
Yieldb (%)
O
NH2
O
NH2
O
NH
HN
1
83
O
O
3a
4a
O
NH2
O
NH2
O
Ph
Ph
NH
O
HN
O
Ph
Ph
2
3830
Scheme 8. Synthesis of 3h,i.
3b
4b
O
Table 2
NH2
NH2
Carbonylation of diamines 3feia
NH
OS
HN
Entry
Aminobutanediol
Product
Yieldb (%)
3
75
EM
OS
SEMO
EM
SEMO
O
NH HN
3c
N
O
N
O
4c
O
1
58
O
O
NH2
NH2
O
Ph
Ph
NH
HN
Ph
Ph
4
7530
EM
OS
EM
S
OSEM
EM
O
S
3d
O
4d
Ph
Ph
Ph
Ph
NH HN
Ph
Ph
Ph
Ph
a
Reagents and conditions: W(CO)6, I2, K2CO3, 80 bar CO, CH2Cl2/H2O, 40 ꢀC, 24 h.
Isolated yields.
N
O
N
O
b
2
99d
O
O
O
O
NH HN
N
N
O
3
10
H
H
H
O
O
H
O
H
Scheme 6. Carbonylation of diamine 3e.
was accompanied by cyclization to oxazolidinones 8e and 9e in
roughly equimolar quantities. The reaction also suffered from low
conversion (54% conversion) due to the formation of the amine
hydroiodide from HI generated in the reaction. Although the amine
salt could be recovered and recycled, the formation of a mixture of
products limits the utility of the reaction in the case of 3e.
NH HN
N
O
N
4
42c
O
H
O
H
H
O
To explore the feasibility of the carbonylation of secondary
amines, N-substituted diamines 3fei were synthesized. Amidation
of the starting chiral tartrate40e42 10 followed by reduction by
lithium aluminum hydride42,43 to afford the bis(amino)butanediols
3f and 3g in good yield (Scheme 7). A similar approach can be
a
Reagents and conditions: W(CO)6, I2, pyridine, 80 bar CO, CH2Cl2, 40 ꢀC, 24 h.
Isolated yields.
48 h.
b
c
d
Based on starting material consumed (36%).
From Table 2, it is apparent that the W(CO)6/I2 catalytic car-
bonylation method can be applied to secondary diamines bearing
the seven-membered ring skeleton. Although yields were generally
lower than those from the primary diamines, the tetrasubstituted
ureas were obtained in good yields whether or not the diol was
protected. Protected N-methyl diamine 3f afforded urea 4f in 58%
yield (Table 2, entry 1) and the unprotected N-methyl variant 3i
took 48 h to give a 42% yield of urea (Table 2, entry 4). Urea 4g was
Scheme 7. Synthesis of 3feg.

A.K. Darko et al. / Tetrahedron 67 (2011) 3976e3983
3979
obtained in excellent yields of urea based on the amount of 3g
consumed in the reaction (36%).
such as 3fei yield ureas although they cannot form isocyanates. An
alternative route to formation of tetrasubstituted ureas from sec-
ondary amines is nucleophilic attack of the amine on a carbonyl
ligand to form a carbamoyl complex, followed by a second nucle-
ophilic attack on the carbamoyl.48 Assuming that the cyclic ureas
are formed by intramolecular nucleophilic attack on a carbamoyl
Free diol 3h produced only 10% of the corresponding urea (Table
1, entries 2 and 3). As was also observed for 3e, a portion of 3h (25%)
was recovered in salt form, stemming from the inability of the base,
pyridine, to deprotonate the resulting hydroiodide salt of the sub-
strate. However, substituting pyridine with DMAP or DBU did not
increase the yield. It is possible that because the HI salts of these free
diol substrates are insoluble in the reaction media, they cannot be
deprotonated bythe organicbase. Theimportanceof the solubilityof
complex, we studied the steric implications of N-alkyl and a-alkyl
substituents computationally using molecular modeling for ge-
ometry optimization followed by basic molecular dynamics calcu-
lations with a target temperature of 353 K. The optimized
Fig. 1. Conformations of the postulated carbamate intermediates for ring closure to a
-disubstituted N,N0-dialkyl cyclic ureas.
the HI salt has been discussed previously.44 It is important to note
that the free diol substrates 3h and 3i formed their respective ureas
without competitive formation of the oxazolidinone from reaction
at a hydroxyl group. This is remarkable given the kinetic preference
for the formation of five-membered rings over the desired seven-
membered rings and the behavior of primary diamine diol 3e.
The method was then applied to secondary diamines with al-
kylation at the alpha position, such as compound 3j (Scheme 9).
N-Methylation of 7c followed by deprotection of the Cbz group
afforded 3j in good yields. Attempts at the synthesis of urea 4j by
carbonylation of 3j were met with difficulty. The compound did not
structures show the effect of the additional steric bulk introduced
at the metal center by N-alkyl groups. If there is no substituent in
the
with the ligand when in a pseudo-equatorial position (Fig. 1A).
However, in the presence of both an N-alkyl and an -alkyl group,
the N-alkyl must be in steric conflict with either the ligands or the
-alkyl (Fig.1B and B0). It has also been shown the seven-membered
a-position, the N-alkyl substituent can avoid steric problems
a
a
rings of the urea products can exist in two pseudo-chair confor-
mations. Related conformational analysis of the urea product re-
veals that there is a preferred conformation when the nitrogens are
substituted due to allylic 1,2-strain.34 This provides further evi-
dence that the secondary amines with a-substituents may be un-
able to adopt the necessary conformation to form the urea when
bound to the metal.
3. Conclusion
Building on our previous success with the synthesis of the O-
protected core structure of DMP 450, we have shown that oxidative
catalytic carbonylation can be used to prepare cyclic ureas from
similar functionalized diamine substrates. Furthermore, the cyclic
ureas can be obtained without protection of the diol in several
cases. The synthesis of tetrasubstituted ureas can also be achieved,
although steric constraints tend to lower the yields of the ureas and
Scheme 9. Attempted synthesis of urea 4j.
substitution at the a-carbon was not tolerated. Although there were
limitations, the scope of the W(CO)6/I2-catalyzed carbonylation of
amines to ureas has been extended to include the synthesis of
derivatives of DMP 450.
react using standard conditions from the synthesis of ureas 3fei
(W(CO)6/I2, pyridine, 80 bar CO, CH2Cl2, 40 ꢀC, 24 h). Increasing the
temperature to 80 ꢀC, while using dichloroethane as the solvent,
also proved unsuccessful. In addition, using the stronger base DBU
resulted in decomposition of the starting material.
4. Experimental
4.1. General
It seems that alkylation at both the nitrogen and the a-carbon is
a detriment to the success of the reaction, most likely due to steric
reasons. Catalytic carbonylation of amines is often considered to
involve isocyanate intermediates,26,45e47 but secondary amines,
All experimental procedures were carried out under nitrogen in
oven-dried glassware unless otherwise indicated. Solvents and

3980
A.K. Darko et al. / Tetrahedron 67 (2011) 3976e3983
reagents were obtained from commercial sources in the appropri-
ate grade and used without purification unless otherwise noted.
Carbonylation reactions were conducted in a 300 mL glass liner in
a Parr autoclave behind a blast shield. Carbon monoxide was pur-
chased from Airgas South. Compounds 10, 12, 5a, and 5b were
purchased from SigmaeAldrich. Compound 13 was prepared as
described in the literature.49 1H and 13C NMR spectra were obtained
on Varian Gemini 300 MHz, VXR 300 MHz, and Mercury 300 MHz
spectrometers. 1H spectra were referenced to residual protons in
the deuterated NMR solvents. 13C spectra were referenced to carbon
signals of the solvent. Infrared spectra were measured using a Per-
kineElmer Spectrum One FTIR. High-resolution mass spectrometry
was performed by the University of Florida analytical service. Mo-
lecular modeling was carried out using MM2 energy minimization
followed by MM2 molecular dynamics.50
4.1.6. 1,10-((4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl)bis(N-
methylmethanamine) (3f). Using a variation of the literature pro-
cedure,42 a solution of diamide tartrate 11a (3.51 g, 0.0162 mol) in
dioxane (50 mL) was added slowly to a vigorously stirring sus-
pension of lithium aluminum hydride (1.85 g, 0.0487 mol) in di-
oxane (160 mL) under inert atmosphere. The reaction was refluxed
overnight after addition was complete. After the reaction mixture
cooled, it was quenched by careful addition of 3 mL water, 3 mL 15%
NaOH, and 3 mL water. The solution was opened to air, filtered, and
the filtrate concentrated to afford crude 3f as a pale red oil (3.01 g,
98% yield). The product was identified by comparison with litera-
ture data.53 1H NMR (CDCl3)
4H), 2.46 (s, 6H), 1.40 (s, 6H).
d 3.93e3.88 (m, 2H), 2.76e2.72 (m,
4.1.7. N,N0-(((4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl)bis(-
methylene))bis(1-phenylmethanamine) (3g). The procedure used to
prepare 3f was used with 11b (4.00 g, 0.0109 mol) to obtain 3g in
71% yield (2.62 g) as a pale brown oil after purification by column
chromatography with 99:1 CH2Cl2/CH3OH as eluent. The product
was identified by comparison with literature data.42 1H NMR
4.1.1. (1R,10R)-1,10-((4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl)di-
ethanamine (3a). The procedure was adapted from the literature.36
Compound 7a (0.73 g, 1.6 mmol), 45 mL ethanol, Pd(OH)2/C
(108 mg), and cyclohexene (45 mL) were combined and refluxed
overnight. After cooling to room temperature, the reaction was
filtered through a bed of Celite and the resulting liquor was con-
centrated into an oil. Column chromatography with 9:1 CH2Cl2/
CH3OH provided 3a as a pale brown oil (0.28 g, 93% yield). The
product was identified by comparison with literature data.51 1H
(CDCl3)
d 7.31e7.19 (m, 10H), 3.97e3.90 (m, 2H), 3.79 (s, 4H), 2.77
(dd, J¼2.1, 3.4 Hz, 4H), 1.66 (br s, 2H), 1.38 (s, 6H).
4.1.8. (2S,3S)-1,4-Bis(benzylamino)butane-2,3-diol (3h). Under ni-
trogen, diamide 11c (4.00 g, 0.0122 mol) was placed in a Soxhlet
thimble and extracted into a refluxing suspension of lithium alu-
minum hydride (1.20 g, 0.0316 mol) in 200 mL of tetrahydrofuran.
Refluxing was continued for 72 h and the suspension stirred at
room temperature overnight. Water (3 mL) was then added drop-
wise to the mixture followed by 15% NaOH (3 mL), and additional
water (3 mL). The mixture was opened to air, filtered, and the solids
washed with tetrahydrofuran. The filtrate was concentrated and
the resulting residue was purified by column chromatography with
44:1 CH2Cl2/CH3OH as the eluent to afford 3h (1.36 g, 37% yield) as
a white solid. The product was identified by comparison with lit-
NMR (CDCl3)
(br s, 4H), 1.34 (s, 6H), 1.04 (d, J¼6.6 Hz, 6H).
d
3.55 (d, J¼5.2 Hz, 2H), 2.86 (quint, J¼5.1 Hz, 2H), 2.64
4.1.2. (1R,10R)-1,10-((4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl)
bis(2-phenylethanamine) (3b). The procedure for 3a was used to
produce 3b (730 mg, 99% yield) from 7b (1.32 g, 2.17 mmol). The
product was identified by comparison with literature data.51 1H
NMR (CDCl3)
d
7.38e7.10 (m, 10H), 4.04 (dd, J¼1.4, 2.0 Hz, 2H),
3.08e2.91 (m, 2H), 2.89e2.75 (m, 2H), 2.58 (dd, J¼9.6, 13.1 Hz, 2H),
1.46 (s, 6H).
erature data.54 Mp 82e85 ꢀC. 1H NMR (CDCl3)
d 7.34e7.17 (m, 10H),
4.1.3. (2R,3S,4S,5R)-3,4-Bis((2-(trimethylsilyl)ethoxy)methoxy)hex-
ane-2,5-diamine (3c). The procedure for 3a was used to produce 3c
(1.28 g, 86% yield) from 7c (2.46 g, 3.63 mmol). The product was
identified by comparison with literature data.36 1H NMR (CDCl3)
3.85e3.69 (m, 6H), 3.10 (dd, J¼3.8, 12.0 Hz, 2H), 2.72 (dd, J¼2.1,
12.0 Hz, 2H), 1.54 (br s, 2H).
4.1.9. (2S,3S)-1,4-Bis(methylamino)butane-2,3-diol (3i). Diepoxide
14 (0.232 g, 2.69 mmol) was added to methylamine (11.6 mL of
a 2.0 M solution in methanol, 0.0232 mol) at 0 ꢀC and then stirred at
room temperature overnight under nitrogen. The reaction was then
exposed to air and concentrated to yield 3i as a white solid (0.40 g,
99%). The product was identified by comparison with literature
d
4.73 (d, J¼7.0 Hz, 2H), 4.62 (d, J¼7.0 Hz, 2H), 3.64 (s, 2H),
3.62e3.47 (m, 6H), 1.26 (d, J¼6.7 Hz, 6H), 0.85 (ddd, J¼3.4, 7.3,
9.7 Hz, 4H), 0.00 (s, 18H).
4.1.4. (2R,3S,4S,5R)-1,6-Diphenyl-3,4-bis((2-(trimethylsilyl)ethoxy)
methoxy)hexane-2,5-diamine (3d). The procedure for 3a was used
to produce 3d (0.454 g, 95% yield) from 7d (0.706 g, 0.851 mmol).
The product was identified by comparison with literature data.52 1H
data.54 1H NMR (CDCl3)
12.0 Hz, 2H), 2.65 (dd, J¼2.5, 12.0 Hz, 2H), 2.42 (s, 6H).
d
3.83 (t, J¼2.5 Hz, 2H), 3.05 (dd, J¼3.3,
NMR (CDCl3)
d
7.34e7.23 (m, 10H), 4.80e4.62 (m, 4H), 3.84e3.55
4.1.10. (2R,3S,4S,5R)-N2,N5-Dimethyl-3,4-bis((2-(trimethylsilyl)eth-
oxy)methoxy)hexane-2,5-diamine (3j). The procedure for 3a was
used to produce 3j (450 mg, 75% yield) from 15 (970 mg,
(m, 6H), 3.25e3.20 (m, 2H), 2.94e2.68 (m, 4H), 1.01e0.81 (m, 4H),
0.05 (s, 18H).
1.38 mmol). 1H NMR (CDCl3)
d
4.77 (d, J¼1.1 Hz, 4H), 3.72e3.56 (m,
4.1.5. (2R,3S,4S,5R)-2,5-Diamino-1,6-diphenyl-3,4-hexanediol
(3e). The procedure was adapted from the literature.39 A mixture of
6b (1.33 g, 2.34 mmol), ammonium formate (0.88 g, 0.014 mol), and
10% Pd/C (0.80 g) in DMF (20 mL) was heated to 120 ꢀC under an Ar
atmosphere for 4 h. The reaction was allowed to cool, exposed to
air, and the mixture was filtered through Celite. The filter cake was
rinsed with methanol and the combined filtrates were concen-
trated into a pale yellow oil. The oil was taken up in ethyl acetate
and washed with water, saturated sodium bicarbonate, and satu-
rated sodium chloride, dried over magnesium sulfate, filtered, and
concentrated to obtain 3e (0.40 g, 70% yield). The product was
identified by comparison with literature data.39 1H NMR (CDCl3)
6H), 2.83 (br s, 2H), 2.41 (s, 6H), 1.13 (d, J¼6.5 Hz, 6H), 0.93 (t,
J¼8.6 Hz, 4H), 0.01 (s, 18H). 13C NMR (CDCl3)
d 96.8, 82.9, 66.1, 55.6,
34.1, 18.3, 16.5, ꢁ1.2. HRMS calcd for C20H48N2O4Si2 [MþH]þ
437.3225, found 437.3241.
4.1.11. General procedure A for catalytic oxidative carbonylation of
diamines with W(CO)6/I2: (3aS,4R,8R,8aS)-2,2,4,8-tetramethyltetrahy-
dro-3aH-[1,3]dioxolo[4,5-e][1,3]diazepin-6(7H)-one
(4a). In
air,
a glass-lined 300 mL Parr high-pressure vessel equipped with a stir
bar and containing 40 mL of CH2Cl2 and 10 mL of water was loaded
with diamine 3a (200 mg, 1.06 mmol), W(CO)6 (18.6 mg,
0.0531 mmol), I2 (270 mg, 1.06 mmol), and K2CO3 (587 mg,
4.25 mmol). The vessel was then charged with 80 bar of CO and
heated on a hotplate at 80 ꢀC for 24 h. After cooling to room
d
7.39e7.02 (m, 10H), 3.67 (s, 2H), 3.02 (dd, J¼5.6, 8.9 Hz, 2H), 2.91
(dd, J¼5.8, 13.2 Hz, 2H), 2.71 (dd, J¼8.9, 13.1 Hz, 2H).

A.K. Darko et al. / Tetrahedron 67 (2011) 3976e3983
3981
temperature, the pressure was released and 10 mL of water was
added. The organics were separated and washed with a saturated
solution of Na2SO3 followed by 0.1 M HCl. Each of the collected
aqueous layers was extracted with 3:1 CHCl3/EtOH. The organic
layers were combined, dried over MgSO4, and filtered. The solvents
were removed by evaporation and the residue was purified by col-
umn chromatography using 9:1 CH2Cl2/CH3OH as the eluent to yield
4a as a pale yellow solid. IR (neat) nCO 1639 cmꢁ1. 1H NMR (CDCl3,
(m, 10H), 4.37 (d, J¼5.5 Hz, 1H), 4.26 (dd, J¼12.9, 6.9 Hz, 1H),
3.86e3.68 (m, 1H), 3.15e2.89 (m, 4H), 2.79 (dd, J¼13.5, 7.3 Hz, 2H).
13C NMR (CDCl3 with sufficient CD3OD to dissolve the sample)
d
159.4, 135.3, 134.6, 129.7, 129.5, 129.4, 129.0, 127.8, 127.4, 82.6,
67.8, 55.6, 55.3, 40.9, 36.1. HRMS calcd for C19H23N3O2 [MþH]þ
327.1708, found 327.1714. Carbamate 9e was identified by com-
parison with literature data.55 Mp 159e162 ꢀC. 1H NMR (CDCl3)
d
7.38e7.18 (m, 7H), 7.06 (dd, J¼1.9, 7.5 Hz, 4H), 5.80 (s, 2H), 4.04 (q,
CD3OD)
d
3.97 (d, J¼8.3 Hz, 2H), 3.70 (s, 2H), 1.39 (s, 6H), 1.19 (d,
J¼6.5 Hz, 2H), 3.93 (d, J¼5.3 Hz, 2H), 2.86 (dd, J¼6.7, 13.5 Hz, 2H),
2.70 (dd, J¼7.3, 13.5 Hz, 2H).
J¼6.6 Hz, 6H). 13C NMR (CDCl3, CD3OD)
d 158.2,108.0, 80.3, 44.1, 25.9,
18.5. HRMS calcd for C10H18N2O3 [MþH]þ 215.1390, found 215.1387.
4.1.16. General procedure B for catalytic oxidative carbonylation of
diamines with W(CO)6/I2: (3aS,8aS)-2,2,5,7-tetramethyltetrahydro-
3aH-[1,3]dioxolo[4,5-e][1,3]diazepin-6(7H)-one (4f). In air, a glass-
lined 300 mL Parr high-pressure vessel equipped with a stir bar
and containing CH2Cl2 (40 mL) was loaded with diamine 3f (200 mg,
1.06 mmol), W(CO)6 (18.6 mg, 0.0531 mmol), I2 (270 mg, 1.06 mmol),
and pyridine (336 mg, 4.25 mmol). The vessel was then charged with
80 bar of CO and heated on a hotplate at 40 ꢀC for 24 h. After cooling
to room temperature, the pressure was released and 10 mL of CH2Cl2
was added to further dissolve any crude material. The solution was
washed with a saturated solution of Na2SO3 followed by 0.1 M HCl,
then dried over MgSO4, and filtered. The solvent was removed by
evaporation and the resulting residue was purified by column
chromatography using 9:1 CH2Cl2/CH3OH as the eluent to yield 4f as
a pale brown oil (133 mg, 58% yield). IR (neat) nCO 1637 cmꢁ1. 1H NMR
4.1.12. (3aS,4R,8R,8aS)-4,8-Dibenzyl-2,2-dimethyltetrahydro-3aH-
[1,3]dioxolo[4,5-e][1,3]diazepin-6(7H)-one (4b). Following pro-
cedure A, compound 4b was obtained in 36% yield (46.9 mg) from
3b (120 mg, 0.352 mmol). The product was purified by column
chromatography using 7:3 hexanes/ethyl acetate as the eluent. The
product was identified by comparison with literature data.38 IR
(neat) nCO 1674 cmꢁ1. 1H NMR (CDCl3)
d 7.42e7.16 (m, 10H), 4.97 (d,
J¼6.1 Hz, 2H), 4.26 (s, 2H), 3.62e3.48 (m, 2H), 3.07 (dd, J¼1.2,
13.3 Hz, 2H), 2.91e2.74 (m, 2H), 1.54 (s, 6H). HRMS calcd for
C22H26N2O3 [MþH]þ 503.2752, found 503.2797.
4.1.13. (4R,5S,6S,7R)-4,7-Dimethyl-5,6-bis((2-(trimethylsilyl)ethoxy)
methoxy)-1,3-diazepan-2-one (4c). Following procedure A, 3c
(400 mg, 0.979 mmol) was converted to 4c (320 mg, 75% yield). The
product was identified by comparison with literature data.36 IR
(CDCl3)
d 3.65e3.54 (m, 2H), 3.32e3.17 (m, 4H), 2.91 (s, 6H), 1.45 (s,
(neat) nCO 1683 cmꢁ1. 1H NMR (CDCl3)
d
4.81 (d, J¼7.2 Hz, 2H), 4.70
6H). 13C NMR (CDCl3)
d 165.0, 111.5, 79.5, 51.2, 40.3, 26.9. HRMS calcd
(d, J¼7.0 Hz, 2H), 4.36 (s, 2H), 3.75 (q, J¼6.6 Hz, 2H), 3.65 (dd, J¼7.3,
for C10H18N2O3 [MþNa]þ 237.1210, found 237.1226.
9.6 Hz, 4H), 3.53 (s, 2H), 1.27 (d, J¼6.9 Hz, 6H), 0.93 (dd, J¼7.6,
9.6 Hz, 4H), 0.02 (s, 18H). 13C NMR (CDCl3)
d
164.3, 95.7, 78.1, 65.9,
4.1.17. (3aS,8aS)-5,7-Dibenzyl-2,2-dimethyltetrahydro-3aH-[1,3]di-
oxolo[4,5-e][1,3]diazepin-6(7H)-one (4g). Following procedure B,
urea 4g was obtained in 99% yield (53.2 mg) from 3g (50.0 mg,
0.147 mmol reacted) after column chromatography on silica using
95:5 CH2Cl2/CH2Cl2/ethyl acetate as the eluent. IR (neat) nCO
46.9, 19.4, 18.2, ꢁ1.3. HRMS calcd for C19H42N2O5Si2 [MþNa]þ
457.2525, found 457.2536.
4.1.14. (4R,5S,6S,7R)-4,7-Dibenzyl-5,6-bis((2-(trimethylsilyl)ethoxy)
methoxy)-1,3-diazepan-2-one (4d). Following procedure A, com-
pound 4d was obtained in 75% yield (72.2 mg) from 3d (92.9 mg,
0.164 mmol). The product was identified by comparison with lit-
1638 cmꢁ1. 1H NMR (CDCl3)
d
7.43e7.12 (m, 10H), 4.52 (s, 4H), 3.41
(dd, J¼5.7, 2.8 Hz, 2H), 3.33 (dd, J¼13.1, 2.7 Hz, 2H), 3.23e3.09 (m,
2H), 1.33 (s, 6H). 13C NMR (CDCl3)
d 165.1, 138.3, 128.7, 128.7, 127.6,
erature data.34 IR (neat) nCO 1679 cmꢁ1. 1H NMR (CDCl3)
d
7.37e7.23
111.5, 79.9, 55.5, 48.6, 26.8. HRMS calcd for C22H26N2O3 [MþNa]þ
(m, 10H), 4.81 (d, J¼7.0 Hz, 2H), 4.73 (d, J¼7.0 Hz, 2H), 4.21 (s, 2H),
3.95 (t, J¼7.5 Hz, 2H), 3.71e3.59 (m, 6H), 2.93e2.92 (m, 4H),
0.93e0.91 (m, 4H), 0.05 (s, 18H). HRMS calcd for C31H50N2O5Si2
[MþH]þ 587.3336, found 587.3355.
389.1836, found 389.1853.
4.1.18. (5S,6S)-1,3-Dibenzyl-5,6-dihydroxy-1,3-diazepan-2-one
(4h). Following procedure B, urea 4h was obtained as a clear oil in
10% yield (40.1 mg) from 3h (370 mg, 1.23 mmol) after column
chromatography using 1:1 CH2Cl2/ethyl acetate as the eluent. IR
4.1.15. (4R,5S,6S,7R)-4,7-Dibenzyl-5,6-dihydroxy-1,3-diazepan-2-
one (4e), (4R,5S)-5-((1S,2R)-2-amino-1-hydroxy-3-phenylpropyl)-4-
benzyloxazolidin-2-one (8e), and (4R,40R,5S,50S)-4,40-dibenzyl-[5,
50-bioxazolidine]-2,20-dione (9e). In air, a glass-lined 300 mL Parr
high-pressure vessel equipped with a stir bar and containing 1,2-
dichloroethane (60 mL) was loaded with diamine 3e (610 mg,
2.03 mmol), W(CO)6 (71.0 mg, 0.203 mmol), I2 (515 mg, 2.03 mmol),
and pyridine (642 mg, 8.12 mmol). The vessel was then charged
with 80 bar of CO and heated on a hotplate at 80 ꢀC for 16 h. After
cooling to room temperature, the pressure was released and 10 mL
of CH2Cl2 was added to further dissolve any crude material. The
solution was washed with a saturated solution of Na2SO3 followed
by 0.1 M HCl, then dried over MgSO4, and filtered. The solvent was
removed by evaporation and the resulting residue was purified by
column chromatography using 9:1 CH2Cl2/CH3OH as the eluent to
yield 4e (30 mg, 10% yield), 8e (32 mg, 11% yield), and 9e (42 mg,
13%) based on 54% conversion of 3e. Urea 4e was identified by
comparison with literature data.38 IR (neat) nCO 1662 cmꢁ1. 1H NMR
(neat) nCO 1622 cmꢁ1
.
1H NMR (300 MHz, CDCl3)
d
7.39e7.20 (m,
10H), 4.54, 4.32 (AB, J¼14.7 Hz, 4H), 3.38e3.21 (m, 2H), 3.22e3.02
(m, 4H), 2.39 (s, 2H). 13C NMR (CDCl3)
d 165.9, 138.2, 128.9, 128.7,
127.8, 73.1, 54.3, 51.2. HRMS calcd for C19H22N2O3 [MþNa]þ
349.1523, found 349.1540.
4.1.19. (5S,6S)-5,6-Dihydroxy-1,3-dimethyl-1,3-diazepan-2-one
(4i). Following procedure B, 4i (53.2 mg, 45% yield) was obtained
from 3i (100 mg, 0.675 mmol) after 48 h. IR (neat) nCO 1625 cmꢁ1. 1H
NMR (CDCl3)
d
3.55 (d, J¼7.0 Hz, 2H), 3.40e3.16 (m, 2H), 3.11 (dd,
J¼13.9, 7.9 Hz, 2H), 2.86 (s, 6H). 13C NMR (CDCl3)
d 166.2, 72.7, 53.8,
39.1. HRMS calcd for C7H14N2O3 [MþH]þ 175.1077, found 175.1074.
4.1.20. Dibenzyl
((2R,3S,4S,5R)-3,4-dihydroxyhexane-2,5-diyl)di-
carbamate (6a). Preparation of 6a was adapted from a literature
procedure.56 In a two-necked round-bottom flask equipped with
a stir bar and an addition funnel, a solution of oxalyl chloride
(18.0 mL of 2.0 M solution in CH2Cl2, 0.036 mol) in CH2Cl2 (30 mL)
was cooled to ꢁ78 ꢀC, and anhydrous dimethylsulfoxide (3.40 mL,
0.0478 mol) in CH2Cl2 (53 mL) was added over 20 min while the
temperature was kept near ꢁ78 ꢀC. Immediately thereafter,
(CDCl3 with sufficient CD3OD to dissolve the sample)
d 7.29e7.08
(m, 10H), 3.82 (t, J¼7.6 Hz, 2H), 3.50 (s, 2H), 3.01e2.78 (m, 4H).
Carbamate 8e: IR (neat) nCO 1736 cmꢁ1. Mp 70e74 ꢀC. 1H NMR
(CDCl3 with sufficient CD3OD to dissolve the sample)
d 7.47e6.92

3982
A.K. Darko et al. / Tetrahedron 67 (2011) 3976e3983
a solution of N-Z-
D
-alaninol 5a (5.00 g, 0.0239 mol) in CH2Cl2
in 65 mL CH2Cl2 was added DIPEA (2.94 g, 0.0228 mol) and cooled to
0 ꢀC. SEM chloride (2.78 g, 0.0167 mmol) was then added dropwise
until gas evolution ceased. The mixture was then refluxed overnight
under nitrogen. After cooling to room temperature, cold water was
added and the layers separated. The aqueous layer was extracted
with methylene chloride. The organic layers were combined and
washed with water, dried over magnesium sulfate, and concentrated
into a yellow oil. Column chromatography using 7:3 hexanes/ethyl
acetate afforded pure 7c as a pale yellow oil (2.52 g, 98% yield). The
product was identified by comparison with literature data.36 1H NMR
(70 mL) was added over 30 min, followed by stirring at ꢁ78 ꢀC for
40 min. Triethylamine (9.67 g, 0.0956 mol) was added over 15 min,
followed by stirring for 2 h at ꢁ78 ꢀC to ensure completion of the
reaction. After 20% aqueous KHSO4 (50 mL) was added, the reaction
mixture was allowed to warm to room temperature and water
(45 mL) was added. The aqueous phase was separated and washed
twice with CH2Cl2 (20 mL). The organic layers were combined and
washed with saturated sodium bicarbonate (50 mLꢂ2), water
(50 mLꢂ3), and saturated sodium chloride (50 mLꢂ2), dried over
magnesium sulfate, filtered, and concentrated in vacuo to afford the
resulting aldehyde in quantitative yield as an oil (4.95 g, 99% yield).
The crude aldehyde was used without further purification to pre-
vent possible racemization. Under an inert atmosphere, Zn dust
(0.937 g, 0.0143 mol) was added to a solution of VCl3(THF)3 (9.83 g,
0.0263 mol) in dry CH2Cl2 (55 mL), resulting in a color change from
reddish-brown to green after stirring for 20e30 min. A solution of
the aldehyde (4.95 g, 0.0239 mol) in CH2Cl2 (55 mL) was added via
cannula, causing a color change from green to brown. After being
stirred at room temperature overnight, the reaction was opened to
air and poured into 1 M HCl (125 mL). The two phases were stirred
together overnight resulting in a blue aqueous layer and the pre-
cipitated coupling product in the organic layer. Adding CH2Cl2 and
tetrahydrofuran dissolved all solids. The phases were separated and
the aqueous phase was extracted with CH2Cl2 (85 mL). The com-
bined organic layers were washed with saturated sodium bi-
carbonate (20 mL) and saturated sodium chloride (20 mL), and then
(CDCl3) d 7.47e7.28 (m, 10H), 5.22e4.97 (m, 6H), 4.80e4.62 (m, 4H),
4.09e3.95 (m, 2H), 3.83e3.67 (m, 2H), 3.58e3.39 (m, 4H), 1.21 (d,
J¼6.6 Hz, 6H), 1.01e0.84 (m, 4H), 0.01 (s, 18H).
4.1.25. Dibenzyl
((2R,3S,4S,5R)-1,6-diphenyl-3,4-bis((2-(trime-
thylsilyl)ethoxy)methoxy)-hexane-2,5-diyl)dicarbamate (7d). Using
the same procedure as for 7c, 7d (1.63 g, 77% yield,) was obtained
from 6b (1.45 g, 2.55 mmol). The product was identified by com-
parison with literature data.52 1H NMR (CDCl3)
d 7.43e7.06 (m,
20H), 5.17e4.55 (m, 10H), 4.29e3.60 (m, 4H), 3.55 (s, 4H), 2.79 (d,
J¼7.3 Hz, 4H), 1.09e0.86 (m, 4H), 0.05 (s, 18H).
4.1.26. (4R,5R)-4N,5N,2,2-Tetramethyl-1,3-dioxolane-4,5-dicarbox-
amide (11a). Methylamine (46 mL, 2.0 M in methanol) was added to
dimethyl 2,3-O-isopropylidene- -tartrate 10 (4.20 mL, 22.9 mmol) in
L
methanol (15 mL) and stirred at room temperature for 3 days under
nitrogen. The solution was then concentrated to afford 11a as a white
solid (4.93 g, 99% yield). The compound was identified by compari-
dried, filtered, and evaporated to yield
a white solid. Re-
crystallization from THF and hexanes afforded diol 6a (3.92 g, 84%
yield). The product was identified by comparison with literature
son with literature data.53 Mp 130e132 ꢀC. 1H NMR (CDCl3)
s, 2H), 4.51 (s, 2H), 2.89 (d, J¼4.9 Hz, 6H), 1.49 (s, 6H).
d 7.06 (br
data.36 Mp 170e173 ꢀC. 1H NMR (DMSO-d6)
d 7.38e7.26 (m, 10H),
6.83 (d, J¼8.8 Hz, 2H), 5.08e4.93 (m, 4H), 4.37 (d, J¼5.7 Hz, 2H),
4.1.27. (4R,5R)-4N,5N-Dibenzyl-2,2-dimethyl-1,3-dioxolane-4,5-di-
carboxamide (11b). A mixture of 10 (10.78 g, 49.40 mol), benzyl-
amine (10.32 g, 96.30 mmol), potassium carbonate (0.172 g,
1.24 mmol), and methanol (35 mL) was refluxed overnight under
nitrogen. It was then cooled to room temperature, exposed to air
and the solvent evaporated to afford an orange oil. The oil was
purified by column chromatography (1:1 ethyl acetate/CH2Cl2) to
afford 11b as a pale yellow solid (10.73 g, 67% yield). The compound
was identified by comparison with literature data.42 Mp 82e84 ꢀC.
3.84e3.70 (m, 2H), 3.25e3.14 (m, 2H), 1.00 (d, J¼6.4 Hz, 6H).
4.1.21. (2R,3S,4S,5R)-Bis[N-(benzyloxycarbonyl)amino]-1,6-diphenyl-
3,4-hexanediol (6b). Using the same procedure as for 6a, diol 6b
(3.08 g, 63% yield) was produced from 5b (5.00 g, 0.0175 mol). The
product was identified by comparison with literature data.38 1H
NMR (DMSO-d6)
5.05e4.86 (m, 4H), 4.55 (br s, 2H), 4.29e4.10 (m, 2H), 3.26 (br s, 2H),
2.83e2.66 (m, 2H), 2.59 (dd, J¼5.0, 13.3 Hz, 2H).
d
7.38e7.09 (m, 20H), 6.83 (d, J¼9.6 Hz, 2H),
1H NMR (CDCl3)
4H), 1.46 (s, 6H).
d
7.38e7.24 (m, 10H), 4.63 (s, 2H), 4.50 (d, J¼6.0 Hz,
4.1.22. Dibenzyl ((1R,10R)-((4S,5S)-2,2-dimethyl-1,3-dioxolane-4,5-
diyl)bis(ethane-1,1-diyl))dicarbamate (7a). The procedure was
adapted from the literature.57 To a suspension of diol 6a (1.14 g,
2.74 mmol) in 70 mL CH2Cl2 was added 2,2-dimethoxypropane
(1.99 g, 0.0192 mol) at 0 ꢀC. A catalytic amount of (ꢃ)-camphor-10-
sulfonic acid (50.0 mg) was added and the mixture was stirred
overnight at room temperature under nitrogen. The reaction was
then exposed to air and concentrated into a dark oil. Column
chromatography (7:3 hexanesethyl acetate) afforded 7a as a white
solid (1.18 g, 94% yield). The product was identified by comparison
4.1.28. (2R,3R)-1,4-N,N-Dibenzylamino-2,3-dihydroxysuccinamide
(11c). Using the same procedure as for 11b, diethyl- -tartrate 12
L
(7.00g, 0.0339 mol) was employed to afford 11c as a white solid. The
crude product was filtered, washed with water, and recrystallized
from 50% ethanol in water to obtain pure 11c (10.0 g, 90% yield). The
compound was identified by comparison with literature data.58 Mp
197e199 ꢀC. 1H NMR (DMSO-d6)
d
8.25 (t, J¼6.3 Hz, 2H), 7.39e7.13
(m,10H), 5.74 (d, J¼7.2 Hz, 2H), 4.48e4.17 (m, 6H). 13C NMR (DMSO-
d6)
d 172.1, 139.4, 127.5, 126.5, 72.7, 41.9.
with literature data.51 1H NMR (CDCl3)
d 7.44e7.27 (m, 10H),
5.19e5.01 (m, 4H), 4.95 (d, J¼9.5 Hz, 2H), 4.00e3.82 (m, 2H), 3.61 (s,
4.1.29. (2S,20S)-2,20-Bioxirane (14). In air, compound 1349 (2.62 g,
6.09 mmol) was suspended in 30 mL ether. Pulverized potassium
hydroxide (0.72 g, 0.013 mol) was then added and the mixture
refluxed for 6 h under nitrogen. The reaction was exposed to air,
filtered, and the filtrate concentrated into a colorless oil. The resi-
due was purified by fractional distillation to obtain 14 as an oil
(0.231 g, 44% yield). The product was identified by comparison with
2H), 1.35 (s, 6H), 1.22 (d, J¼6.1 Hz, 6H).
4.1.23. Dibenzyl ((1R,10R)-((4S,5S)-2,2-dimethyl-1,3-dioxolane-4,5-
diyl)bis(2-phenylethane-1,1-diyl))dicarbamate (7b). Using the same
procedure as for 7a, 7b (1.88 g, 84% yield,) was obtained from 6b
(2.09 g, 3.68 mmol). The product was identified by comparison with
literature data.51 1H NMR (CDCl3)
d
7.49e6.97 (m, 20H), 5.07e4.63
literature data.59 1H NMR (CDCl3)
d 2.94e2.88 (m, 2H), 2.87e2.82
(m, 6H), 3.68 (s, 2H), 2.92e2.63 (m, 4H), 1.36 (s, 6H).
(m, 2H), 2.77e2.73 (m, 2H).
4.1.24. Dibenzyl ((2R,3S,4S,5R)-3,4-bis((2-(trimethylsilyl)ethoxy)me-
thoxy)hexane-2,5-diyl)dicarbamate (7c). The procedure was adapted
from the literature.36 To a suspension of diol 6a (1.58 g, 3.79 mmol)
4.1.30. Dibenzyl ((2R,3S,4S,5R)-3,4-bis((2-(trimethylsilyl)ethoxy)me-
thoxy)hexane-2,5-diyl)bis(methylcarbamate) (15). Sodium hydride
(0.472 g, 0.0197 mmol, 60% dispersion in mineral oil) was washed

A.K. Darko et al. / Tetrahedron 67 (2011) 3976e3983
3983
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with dry hexanes. DMF (10 mL) was added, followed by the
N-protected diamine diol 7c (2.22 g, 3.28 mmol) in DMF (10 mL) via
cannula. After 1 h, methyl iodide (2.79 g, 0.0197 mmol) was added
and the reaction was left to stir overnight at room temperature. The
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obtain a crude residue. Flash chromatography using 9:1 hexanes/
ethyl acetate afforded N-methylated compound 15. 1H NMR
(DMSO-d6, 98 ꢀC)
d 7.41e7.22 (m, 10H), 5.09 (s, 4H), 4.68e4.50 (m,
4H), 4.49e4.29 (m, 2H), 3.60 (t, J¼8.1 Hz, 4H), 3.52 (d, J¼4.4 Hz, 2H),
2.82 (s, 6H), 1.11 (d, J¼6.7 Hz, 6H), 0.96e0.75 (m, 4H), 0.00 (s, 18H).
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Acknowledgements
We thank the donors of the American Chemical Society Petro-
leum Research Fund for support of this work through the Green
Chemistry Institute. The research of F.C.C. was supported by the UF
HHMI Science for Life Program. C.C. thanks the Ecole National
ꢀ
Superieure de Chimie de Clermont Ferrand (ENSCCF) for support of
her internship at the University of Florida.
Supplementary data
1H and 13C NMR spectra of compounds 3j, 4a,fei, 8e, and 15.
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2011.04.015.
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