Regioselective base-free intermolecular aminohydroxylations of hindered and functionalized alkenes

Article abstract of DOI:10.1021/jo202375a

Regioselective base-free intermolecular aminohydroxylations of functionalized trisubstituted and 1,1-disubstituted alkenes employing benzoyloxycarbamate 3a and catalytic OsO₄ are described. In all cases, the more substituted alcohol isomer is f

Full text of DOI:10.1021/jo202375a

Note
pubs.acs.org/joc
Regioselective Base-Free Intermolecular Aminohydroxylations of
Hindered and Functionalized Alkenes
Zhiwei Ma, Bradley C. Naylor, Brad M. Loertscher, Danny D. Hafen, Jasmine M. Li, and Steven L. Castle*
Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602, United States
S
* Supporting Information
ABSTRACT: Regioselective base-free intermolecular aminohydroxylations of
functionalized trisubstituted and 1,1-disubstituted alkenes employing benzoylox-
ycarbamate 3a and catalytic OsO4 are described. In all cases, the more
substituted alcohol isomer is favored. Sluggish reactions could be promoted by
gentle heating, the use of amine ligands, or increased catalyst loadings. A
competitive rearrangement was observed with a secondary allylic alcohol
substrate. The adducts serve as useful precursors to dehydroamino acids.
he presence of 1,2-amino alcohols in several natural
products, biologically active compounds, and chiral
tigation of steric effects, electronic effects, and substrate-
directed stereocontrol in base-free aminohydroxylations.
Finally, we demonstrate the utility of this process by converting
an aminohydroxylation adduct into a dehydrovaline-containing
peptide.
T
ligands has spurred the development of numerous methods
for their construction.1 The oxyamination of alkenes provides a
straightforward route to this valuable structural motif.2 In
particular, the Os-catalyzed aminohydroxylation reaction3 is
attractive for its amenability to asymmetric catalysis.4
Unfortunately, problems with regioselectivity have limited the
scope of the Sharpless asymmetric aminohydroxylation.5
Effective solutions for a few specific substrate types have
been devised,6 but a general remedy remains elusive.
Donohoe’s tethered aminohydroxylation of allylic and homo-
allylic alcohols7 constitutes a major advance in this area.
However, tethering of the nitrogen source to the substrate
requires two synthetic steps, and cleavage of the cyclic
carbamate product to reveal the amino alcohol involves
strongly basic conditions. Hence, a need exists for practical
and regioselective aminohydroxylation protocols.
Based on our interest in the synthesis of unusual amino
acids,8 we recognized the potential of regioselective inter-
molecular aminohydroxylations as a means of rapidly accessing
β-hydroxy amino acids and dehydroamino acids. Although
intermolecular aminohydroxylations of trisubstituted alkenes
are rare, the isolated existing examples9 indicate that
regioselectivity is reliable and governed by steric effects. We
were intrigued by the recent report of Luxenburger and co-
workers describing base-free intermolecular aminohydroxyla-
tions of selected mono- and disubstituted alkenes with
benzoyloxycarbamates as the nitrogen source reagents.10 We
recognized that these mild conditions should permit the
aminohydroxylation of functionalized alkenes such as un-
protected allylic alcohols, and we were hopeful that the method
could be adapted to enable regioselective aminohydroxylations
of sterically demanding trisubstituted alkenes. The products of
these reactions would be useful precursors of β-hydroxy amino
acids and dehydroamino acids. Herein, we disclose that simple
modifications to the Luxenburger protocol facilitate efficient
and regioselective aminohydroxylations of several types of
hindered, functionalized alkenes. We also report an inves-
At the outset, we elected to explore ligand-free, racemic
aminohydroxylations. Our initial studies are summarized in
Table 1. Prenol (1) was selected as a test substrate due to its
ready availability and the utility of the expected product 4 as a
precursor to the amino acids of interest. Aminohydroxylations
of the isomeric 1,1-disubstituted alkene isoprenol (2)11 were
also examined. We were pleased to find that 1 afforded the
anticipated adduct 4 in good yield upon exposure to 5 mol % of
OsO4 with benzyl 4-chlorobenzoyloxy carbamate (3a, R = Cbz)
as the nitrogen source.10 No traces of the regioisomeric amino
diol were detected. t-BuOH−H2O and CH3CN−H2O mixtures
were both effective solvent systems (entries 1 and 2), but the
latter was preferred for the homogeneous reaction mixtures that
resulted from its use. The Boc-based reagent 3b was also
effective in the aminohydroxylation of 1 (entry 3), but 3a was
employed in the remainder of our studies due to the
convenience of isolating UV-active products.
In contrast, the aminohydroxylation of 2 was low-yielding,
affording amino diol 5 in 30% yield, albeit as a single
regioisomer (entry 4). Large quantities of benzyl carbamate
(CbzNH2) were obtained; similar results with tethered
aminohydroxylations have been reported by Donohoe.7d This
byproduct could presumably be derived from hydrolysis of an
imidoosmium species, a process that might occur competitively
with a slow aminohydroxylation. Fortunately, two strategies for
increasing the yield of 5 were identified. The use of pyridine or
DABCO as a ligand for Os gave improved results (entries 5 and
6). Interestingly, other amines (i.e., Et3N, DMAP, imidazole)
were not beneficial, demonstrating the subtleties of ligand-
accelerated catalysis.12 Ultimately, mild heating (35 °C) of the
Received: November 17, 2011
Published: December 21, 2011
© 2011 American Chemical Society
1208
dx.doi.org/10.1021/jo202375a | J. Org. Chem. 2012, 77, 1208−1214

The Journal of Organic Chemistry
Note
a
Table 1. Optimization of Reaction Conditions
entry
alkene
R
ligand
none
temp (°C)
product
yield (%)
b
1
1
1
1
2
2
2
2
Cbz
Cbz
Boc
Cbz
Cbz
Cbz
Cbz
rt
rt
rt
rt
rt
rt
35
4a
4a
4b
5
63
62
75
30
61
59
85
2
3
4
5
6
7
none
none
none
py
5
DABCO
none
5
5
a
b
Reaction times were 20−24 h. t-BuOH−H2O 6:1 was used as solvent.
reaction mixture proved most effective, with an 85% yield of 5
obtained under these conditions (entry 7).
Table 2. Regioselective Aminohydroxylations of
Functionalized Alkenes
The scope of the base-free aminohydroxylation was then
explored with allylic alcohols and other functionalized alkenes
that were expected to afford high levels of regioselectivity.
Allylic ether 6, enoate 7, and homoallylic alcohol 8 were each
converted into a single amino alcohol in good yield, although
gentle heating was required (Table 2, entries 1−3). Single
regioisomers were also obtained from aminohydroxylations of
bulkier allylic alcohols 9−11, albeit in moderate yields (entries
4−6). As expected based on our studies with isoprenol,
aminohydroxylation of methallyl alcohol (12) provided amino
diol 20 in good yield, and heating was not required (entry 7).
Allyl alcohol (13) also underwent a regioselective trans-
formation into amino diol 21, but a small amount of the
meso isomer was produced in this case (entry 8). Some of the
lower yielding reactions (i.e., entries 2, 5, and 6) could be
improved significantly by doubling the OsO4 loading. The
aminohydroxylations shown in Table 2 were conducted on
relatively small (0.3−1.0 mmol) scales, but the conversion of
enoate 7 into amino alcohol 15 (entry 2) could be
accomplished on a larger (2.9 mmol) scale with similar results.
To determine the role of steric and electronic effects in base-
free aminohydroxylations, the reactions of trans allylic alcohols
were investigated (Table 3). Poor regioselectivity was observed,
but some interesting patterns emerged. Cinnamyl alcohols
exhibited improved yields and regioselectivities as the electron-
rich nature of the aryl ring was increased. With alkyl-substituted
substrates, an increase in size from methyl to isopropyl caused a
change in preference from the 1,2-diol to the 1,3-diol product,
as well as a slight reduction in yield. These results demonstrate
that both electronic and steric effects can impact the yields and
regioselectivities of base-free aminohydroxylations.
To probe the degree of substrate-directed stereocontrol, we
examined aminohydroxylations of chiral secondary allylic
alcohols. The reaction of ( )-2-cyclohexen-1-ol (32) afforded
regioisomers 33a and 33b as a 1.2:1 mixture in good yield
(Scheme 1, eq 1). The stereoselective addition anti to the allylic
hydroxyl group of 32 is consistent with Kishi’s observations in
related dihydroxylations,13 and the poor regioselectivity is in
harmony with the results shown in Table 3. Interestingly, the
aminohydroxylation of racemic 4-methyl-3-penten-2-ol (34)
produced a 4:1 mixture of diastereomers 35a and 35b, but the
a
b
A 10 mol % loading of OsO4 was used. A 10 mol % loading of OsO4
c
was used, and the reaction was conducted at 35 °C. A 6.7:1 mixture of
regioisomers was obtained.
major product was unexpected regioisomer 35c (Scheme 1, eq
2). Apparently, rearrangement of secondary allylic alcohol 34 is
competitive with aminohydroxylation of this hindered sub-
1209
dx.doi.org/10.1021/jo202375a | J. Org. Chem. 2012, 77, 1208−1214

The Journal of Organic Chemistry
Note
Heating solutions of 34 and 36 at 35 °C in CD3CN−D2O
8:1 did not induce rearrangement or degradation of either
allylic alcohol, indicating that an Os species is playing a role in
the isomerization of 34. Presumably, the mechanism of this Os-
promoted rearrangement is analogous to the [3,3]-sigmatropic
rearrangement pathway proposed for trioxorhenium catalysts.15
We were eager to explore the asymmetric aminohydrox-
ylation of functionalized trisubstituted alkenes. Disappointingly
and in contrast to Luxenburger’s results with disubstituted
alkenes,10 reaction of prenol (1) with 3a and OsO4 in the
presence of (DHQD)2PHAL afforded amino diol 4a in low
(18%) yield as a racemic mixture, and large amounts of benzyl
carbamate were generated. A theoretical study has demon-
strated the acceleration of Os-catalyzed aminohydroxylation by
amine ligands,16 and this finding is supported by our own work
(see Table 1, entries 4−6). Thus, the sluggish and unselective
asymmetric aminohydroxylation of 1 can presumably be
attributed to steric rather than electronic effects, as the
substrate, the dimeric chiral ligand, and the nitrogen source
reagent combine to form a very congested Os center. The small
amount of racemic product 4a may actually be produced by a
less-crowded unligated Os species.
Table 3. Aminohydroxylations of Trans Allylic Alcohols
a
Ratio of regioisomers. The major isomer is drawn in each case.
Scheme 1. Aminohydroxylations of Secondary Allylic
Alcohols
To demonstrate the utility of the aminohydroxylation
adducts, compound 15 was transformed into a dehydroamino
acid as shown in Scheme 2. Hydrogenolysis of the Cbz group
Scheme 2. Conversion into Dehydroamino Acid
followed by coupling of the resulting amine with Cbz-Gly
afforded dipeptide 37. Exposure of 37 to the Martin sulfurane17
facilitated the desired dehydration, producing α,β-dehydrova-
line-containing dipeptide 38 in good yield. α,β-Dehydrovaline
is present in a number of bioactive peptide natural products.18
In summary, we have found that the base-free amino-
hydroxylation protocol developed by Luxenburger10 can be
adapted to permit the use of functionalized trisubstituted and
1,1-disubstituted alkenes as substrates. Most of these hindered
compounds reacted sluggishly under the original conditions,
but three simple strategies (i.e., heating, use of amine ligands,
and higher catalyst loadings) were developed to facilitate
difficult transformations. The reactions are practical and
regioselective, affording the more substituted alcohol isomers
in good yields. We have also discovered an electronic effect in
the aminohydroxylation of cinnamyl alcohols and an Os-
mediated isomerization of a secondary allylic alcohol. The
racemic amino alcohol products have good synthetic utility as
evidenced by the transformation of adduct 15 into a
dehydrovaline derivative. Efforts to expand the scope of this
process and develop a viable enantioselective variant are in
progress and will be disclosed in due course.
strate. Isomerizations of allylic alcohols catalyzed by various
metal−oxo species are known,14 but we are unaware of any
prior examples involving OsO4.
Intrigued by this result, we performed the aminohydrox-
ylation of allylic alcohol 36, which is presumably generated by
the rearrangement of 34. Regioisomers 35a and 35c were
produced in a 1:2 ratio, and 35b was not detected (Scheme 1,
eq 3). Since 35b could only be formed by rearrangement of 36
to 34 prior to aminohydroxylation, its absence suggests that 36
undergoes aminohydroxylation in preference to rearrangement.
This is consistent with the fact that, in the absence of other
factors such as conjugation,14c allylic alcohol rearrangements
catalyzed by metal oxo species tend to proceed in the direction
of the more substituted alcohol.14a,b Using the ratio of 35a and
35c obtained from aminohydroxylation of 36 (eq 3), we
estimate that the majority (14%) of 35a derived from 34 (eq 2)
was produced by the rearrangement pathway, and the
remainder (10%) originated from direct aminohydroxylation
of this substrate. Thus, the rearrangement of 34 is
approximately 2.6 times as fast as its aminohydroxylation, and
the dr of the aminohydroxylation is modest (ca. 1.7:1). We are
unsure why the aminohydroxylation of trisubstituted alkene 34
is higher yielding than that of disubstituted alkene 36.
1210
dx.doi.org/10.1021/jo202375a | J. Org. Chem. 2012, 77, 1208−1214

The Journal of Organic Chemistry
Note
(132 μL, 122 mg, 0.951 mmol) according to the general procedure
with 600 μL of OsO4 solution (0.0944 mmol, 0.10 equiv) and stirring
at 35 °C for 10 h. Flash chromatography (SiO2, 1.5 × 12 cm, 10−50%
EtOAc/hexanes elution) afforded 15 (221.9 mg, 0.751 mmol, 79%) as
EXPERIMENTAL SECTION
■
General Details. Dimethylformamide, methanol, and tetrahydro-
furan were dried by passage through cylinders of activated alumina.
Flash chromatography was conducted using 60−230 mesh silica gel.
1H NMR spectra were acquired on a 500 MHz spectrometer with
chloroform (7.27 ppm), methanol (3.34 ppm), or benzene (7.15 ppm)
as internal reference. Signals are reported as follows: s (singlet), d
(doublet), t (triplet), q (quartet), dd (doublet of doublets), td (triplet
of doublets), br s (broad singlet), m (multiplet). 13C NMR spectra
were acquired on a spectrometer operating at 125 MHz with
chloroform (77.23 ppm), methanol (49.86 ppm), or benzene
(128.62 ppm) as internal reference. Infrared spectra were obtained
on an FT-IR spectrometer. MS data were obtained using ESI
techniques.
General Procedure for Base-Free Aminohydroxylations.
Caution: OsO4 is toxic, and exposure to its vapors can cause damage to
the eyes, respiratory tract, and skin. Solutions of this reagent should be
handled with extreme care inside fume hoods using appropriate protective
clothing. Aqueous waste containing Os should be collected with other
hazardous heavy metals and disposed of in accordance with local
environmental regulations.. A solution of benzyl 4-chlorobenzoyloxy
carbamate10 (3a, 1.7 equiv) in CH3CN (4 mL) at rt was treated with
OsO4 (4 wt % solution in H2O, 100 μL, 0.0157 mmol, 0.05 equiv),
stirred for 10 min, and then treated with the alkene (1 equiv) and H2O
(400 μL). A color change from clear to brown typically acccompanied
alkene addition. The resulting mixture was stirred at either rt, 35 °C, or
45 °C for 20−24 h, treated with satd aq K2S2O5 (400 μL), and stirred
for an additional 5 min. It was then diluted with H2O (15 mL) and
extracted with EtOAc (3 × 15 mL). The combined organic layers were
washed with satd aq NaHCO3 (2 × 15 mL) and brine (15 mL), dried
(MgSO4), and concentrated in vacuo. Flash chromatography afforded
the amino alcohol products.
Benzyl 1,3-Dihydroxy-3-methylbutan-2-ylcarbamate (4a).
Prepared from 3a (168.1 mg, 0.550 mmol) and 1 (32 μL, 27.1 mg,
0.315 mmol) according to the general procedure (rt, 23.5 h). Flash
chromatography (SiO2, 1.5 × 8.5 cm, 5−10% MeOH/CH2Cl2 elution)
afforded 4a19 (49.6 mg, 0.196 mmol, 62%) as a colorless oil.
tert-Butyl 1,3-Dihydroxy-3-methylbutan-2-ylcarbamate
(4b). Prepared from tert-butyl 4-chlorobenzoyloxy carbamate10 (3b,
147.1 mg, 0.541 mmol) and 1 (32 μL, 27.1 mg, 0.315 mmol)
according to the general procedure (rt, 24 h). Flash chromatography
(SiO2, 1.5 × 8 cm, 5−10% MeOH/CH2Cl2 elution) afforded 4b20
(51.6 mg, 0.235 mmol, 75%) as a colorless oil.
1
a colorless oil: H NMR (CDCl3, 500 MHz) δ 7.39−7.31 (m, 5H),
5.62 (br s, 1H), 5.13 (s, 2H), 4.31−4.19 (m, 3H), 2.50 (br s, 1H),
1.34−1.26 (m, 9H); 13C NMR (CDCl3, 125 MHz) δ 171.6, 156.5,
136.1, 128.5 (2C), 128.2, 128.1 (2C), 71.9, 67.2, 61.62, 61.56, 26.8,
26.3, 14.1; IR (film) νmax 3406, 2978, 2922, 1720, 1709, 1512, 1501,
1467, 1452, 1211, 1051, 1027 cm−1; HRMS (ESI) m/z 296.1497
(MH+, C15H21NO5H+ requires 296.1492).
Benzyl (1,4-Dihydroxy-4-methylpentan-3-yl)carbamate (16).
Prepared from 3a (168.8 mg, 0.552 mmol) and 8 (37 μL, 31.7 mg,
0.317 mmol) according to the general procedure (35 °C, 23 h). Flash
chromatography (SiO2, 1.5 × 10 cm, 2−5% MeOH/CH2Cl2 elution)
1
afforded 16 (49.5 mg, 0.185 mmol, 58%) as a colorless oil: H NMR
(CDCl3, 500 MHz) δ 7.37−7.28 (m, 5H), 5.33 (d, J = 9.4 Hz, 1H),
5.13 (d, J = 12.2 Hz, 1H), 5.08 (d, J = 12.2 Hz, 1H), 3.71−3.64 (m,
2H), 3.63−3.56 (m, 1H), 3.38 (br s, 1H), 2.78 (br s, 1H), 1.98−1.89
(m, 1H), 1.57−1.48 (m, 1H), 1.24 (s, 6H); 13C NMR (CDCl3, 125
MHz) δ 157.7, 136.3, 128.6 (2C), 128.2, 128.0 (2C), 72.2, 67.1, 58.6,
56.1, 32.2, 27.6, 27.0; IR (film) νmax 3330, 2973, 1697, 1535, 1258,
1054 cm−1; HRMS (ESI) m/z 268.1561 (MH+, C14H21NO4H+
requires 268.1543).
Benzyl ((2S*,3S*)-1,3-Dihydroxy-3-phenylbutan-2-yl)-
carbamate (17). Prepared from 3a (116.4 mg, 0.381 mmol) and
9
22 (33.2 mg, 0.224 mmol) according to the general procedure (35 °C,
18 h). Flash chromatography (SiO2, 1.5 × 11 cm, 2−5% MeOH/
CH2Cl2 elution) afforded 17 (32.4 mg, 0.103 mmol, 46%) as a
1
colorless oil: H NMR (CDCl3, 500 MHz) δ 7.50−7.42 (m, 3H),
7.41−7.25 (m, 5H), 7.24−7.17 (m, 2H), 5.44 (d, J = 7.6 Hz, 1H), 4.98
(s, 2H), 4.18−4.07 (m, 1H), 4.03−3.91 (m, 2H), 3.37 (br s, 1H), 2.28
(br s, 1H), 1.71 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 156.4, 145.0,
136.3, 128.5 (2C), 128.3 (2C), 128.0, 127.7 (2C), 127.1, 124.7 (2C),
77.0 (obscured by CDCl3), 66.6, 63.1, 58.9, 28.3; IR (film) νmax 3404,
2977, 1701, 1517, 1447, 1251, 1072, 1048 cm−1; HRMS (ESI) m/z
316.1558 (MH+, C18H21NO4H+ requires 316.1543.
Benzyl ((2S*,3S*)-1,3-Dihydroxy-3-methylpentan-2-yl)-
carbamate (18). Prepared from 3a (164.2 mg, 0.537 mmol) and
1023 (37.5 μL, 27.2 mg, 0.316 mmol) according to the general
procedure with 200 μL of OsO4 solution (0.0315 mmol, 0.10 equiv)
and stirring at 35 °C for 23 h. Flash chromatography (SiO2, 1.5 × 11
cm, 0.1−2% MeOH/CH2Cl2 elution) afforded 18 (46.6 mg, 0.174
1
mmol, 55%) as a colorless oil: H NMR (CDCl3, 500 MHz) δ 7.38−
Benzyl (2,4-Dihydroxy-2-methylbutyl)carbamate (5). Pre-
pared from 3a (167.9 mg, 0.549 mmol) and 2 (32 μL, 27.6 mg,
0.321 mmol) according to the general procedure (35 °C, 23 h). Flash
chromatography (SiO2, 1.5 × 10 cm, 2−5% MeOH/CH2Cl2 elution)
7.30 (m, 5H), 5.63 (d, J = 8.1 Hz, 1H), 5.12 (s, 2H), 4.06−4.00 (m,
1H), 3.88−3.82 (m, 1H), 3.62−3.57 (m, 1H), 2.63 (br s, 1H), 2.54 (br
s, 1H), 1.63−1.55 (m, 1H), 1.54−1.45 (m, 1H), 1.29 (s, 3H), 0.89 (t, J
= 7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 156.7, 136.4, 128.5
(2C), 128.1, 128.0 (2C), 75.8, 66.9, 63.6, 56.0, 32.3, 23.9, 8.1; IR
(film) νmax 3400, 2970, 1701, 1529, 1455, 1250, 1061, cm−1; HRMS
(ESI) m/z 268.1557 (MH+, C14H21NO4H+ requires 268.1543.
1
afforded 5 (69.1 mg, 0.273 mmol, 85%) as a colorless oil: H NMR
(CDCl3, 500 MHz) δ 7.38−7.28 (m, 5H), 5.47 (s, 1H), 5.09 (s, 2H),
3.94−3.87 (m, 1H), 3.84−3.78 (m, 1H), 3.73 (br s, 1H), 3.24 (dd, J =
13.8, 6.1 Hz, 1H) 3.18 (dd, J = 13.8, 6.3 Hz, 1H), 3.11 (br s, 1H),
1.85−1.77 (m, 1H), 1.63−1.56 (m, 1H), 1.21 (s, 3H); 13C NMR
(CDCl3, 125 MHz) δ 157.5, 136.4, 128.5 (2C), 128.2, 128.1 (2C),
73.3, 66.9, 59.3, 51.0, 39.4, 24.7; IR (film) νmax 3346, 3066, 2935, 1701,
1535, 1455, 1257, 1144, 1042 cm−1; HRMS (ESI) m/z 254.1406
(MH+, C13H19NO4H+ requires 254.1387).
Benzyl ((2S*,3R*)-1,3-Dihydroxy-3-methylpentan-2-yl)-
carbamate (19). Prepared from 3a (163.7 mg, 0.536 mmol) and
1124 (37 μL, 31.3 mg, 0.312 mmol) according to the General
Procedure with 200 μL of OsO4 solution (0.0315 mmol, 0.10 equiv)
and stirring at 35 °C for 23 h. Flash chromatography (SiO2, 1.5 × 11
cm, 0.1−2% MeOH/CH2Cl2 elution) afforded 19 (48.9 mg, 0.183
Benzyl (3-Hydroxy-1-methoxy-3-methylbutan-2-yl)-
1
mmol, 59%) as a colorless oil: H NMR (CDCl3, 500 MHz) δ 7.40−
carbamate (14). Prepared from 3a (163.5 mg, 0.535 mmol) and
7.30 (m, 5H), 5.69 (br s, 1H), 5.11 (s, 2H), 4.04−3.98 (m, 1H), 3.83−
3.77 (m, 1H), 3.61−3.57 (m, 1H), 2.77−2.55 (m, 2H), 1.77−1.58 (m,
2H), 1.16 (s, 3H), 0.95 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3, 125
MHz) δ 156.7, 136.4, 128.5 (2C), 128.2 (2C), 128.0, 76.1, 66.9, 63.1,
56.6, 32.8, 23.4, 8.3; IR (film) νmax 3401, 2971, 1701, 1522, 1455,
1251, 1062 cm−1; HRMS (ESI) m/z 268.1543 (MH+, C14H21NO4H+
requires 268.1543).
6
21 (34 μL, 31.6 mg, 0.315 mmol) according to the general procedure
(35 °C, 23.5 h). Flash chromatography (SiO2, 1.5 × 12 cm, 10−30%
EtOAc/hexanes elution) afforded 14 (45.3 mg, 0.169 mmol, 54%) as a
colorless oil: 1H NMR (CDCl3, 500 MHz) δ 7.39−7.29 (m, 5H), 5.62
(d, J = 8.3 Hz, 1H), 5.12 (s, 2H), 3.82 (d, J = 7.2 Hz, 1H), 3.60−3.55
(m, 2H), 3.35 (s, 3H), 3.11 (s, 1H), 1.32 (s, 3H), 1.12 (3H); 13C
NMR (CDCl3, 125 MHz) δ 156.5, 136.5, 128.5 (2C), 128.1, 128.0
(2C), 73.7, 72.8, 66.8, 59.4, 57.0, 27.7, 26.9; IR (film) νmax 3322, 2977,
1701, 1522, 1454, 1216, 1117, 1047 cm−1; HRMS (ESI) m/z 268.1560
(MH+, C14H21NO4H+ requires 268.1543).
Benzyl 2,3-Dihydroxy-2-methylpropylcarbamate (20). Pre-
pared from 3a (163.9 mg, 0.536 mmol) and 12 (27 μL, 23.0 mg, 0.319
mmol) according to the general procedure (rt, 23 h). Flash
chromatography (SiO2, 1.5 × 10 cm, 5−10% MeOH/CH2Cl2 elution)
afforded 2025 (47.7 mg, 0.199 mmol, 62%) as a colorless oil.
Ethyl 2-(((Benzyloxy)carbonyl)amino)-3-hydroxy-3-methyl-
butanoate (15). Prepared from 3a (492.8 mg, 1.61 mmol) and 7
1211
dx.doi.org/10.1021/jo202375a | J. Org. Chem. 2012, 77, 1208−1214

The Journal of Organic Chemistry
Note
Benzyl 2,3-Dihydroxypropylcarbamate (21). Prepared from 3a
(164.5 mg, 0.538 mmol) and 13 (21.5 μL, 18.4 mg, 0.316 mmol)
according to the general procedure (rt, 23.5 h). Flash chromatography
(SiO2, 1.5 × 9.5 cm, 5−10% MeOH/CH2Cl2 elution) afforded 2126
(49.6 mg, 0.220 mmol, 70%) as a colorless oil that was a 6.7:1 ratio of
regioisomers.27
(CDCl3, 500 MHz) δ 7.36−7.29 (m, 5H), 5.18 (d, J = 7.9 Hz, 1H),
5.08 (s, 2H), 3.99−3.92 (m, 1H), 3.88−3.81 (m, 1H), 3.61−3.54 (m,
2H), 3.25 (br s, 1H), 2.07 (br s, 1H), 1.19 (d, J = 5.4 Hz, 3H); 13C
NMR (CDCl3, 125 MHz) δ 157.1, 136.3, 128.6 (2C), 128.2, 128.1
(2C), 74.5, 67.0, 63.8, 47.8, 17.7; IR (film, mixture of regioisomers)
νmax 3407, 3066, 2974, 1699, 1519, 1455, 1338, 1294, 1060, 910 cm−1;
HRMS (ESI, mixture of regioisomers) m/z 240.1248 (MH+,
C12H17NO4H+ requires 240.1230).
Benzyl ((1R*,2R*)-1,3-Dihydroxy-1-(4-methoxyphenyl)-
propan-2-yl)carbamate (27a). Prepared from 3a (81.4 mg, 0.266
mmol) and p-methoxycinnamyl alcohol (22,28 25.8 mg, 0.157 mmol)
according to the general procedure, with 50 μL of OsO4 solution
(0.00787 mmol), 200 μL of H2O, 2 mL of CH3CN, and stirring at rt
for 25 h. Flash chromatography (SiO2, 1.5 × 9.0 cm, 2−5% MeOH/
CH2Cl2 elution) afforded a 2.2:1 mixture of 27a and its regioisomer
Benzyl ((2R*,3R*)-1,3-Dihydroxy-4-methylpentan-2-yl)-
carbamate (31a). Prepared from 3a (174.1 mg, 0.569 mmol) and
(E)-4-methyl-2-penten-1-ol (26,32 42 μL, 35.0 mg, 0.350 mmol)
according to the general procedure (rt, 26 h). Flash chromatography
(SiO2, 1.5 × 9.5 cm, 2−10% MeOH/CH2Cl2 elution) afforded a 1.4:1
mixture of regioisomers 31a33 and 31b (66.0 mg, 0.247 mmol, 71%) as
a colorless oil. For 31a: 1H NMR (CDCl3, 500 MHz) δ 7.36−7.31 (m,
5H), 5.59 (d, J = 8.6 Hz, 1H), 5.09 (s, 2H), 3.81−3.71 (m, 3H), 3.51
(d, J = 6.4 Hz, 1H), 3.06 (br s, 2H), 1.76−1.67 (m, 1H), 0.97 (d, J =
6.6 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ
157.6, 136.3, 128.5 (2C), 128.2, 128.0 (2C), 71.0, 67.0, 64.3, 57.4,
29.8, 19.8, 18.8; IR (film, mixture of regioisomers) νmax 3396, 3065,
2960, 1694, 1519, 1246, 1065 cm−1; HRMS (ESI, mixture of
regioisomers) m/z 268.1571 (MH+, C14H21NO4H+ requires
1
27b (39.2 mg, 0.130 mmol, 83%). For 27a: H NMR (CDCl3, 500
MHz) δ 7.37−7.16 (m, 7H), 6.87−6.79 (m, 2H), 5.60 (d, J = 7.6 Hz,
1H), 4.99 (s, 2H), 4.85 (br s, 1H), 3.87−3.80 (m, 1H), 3.76 (s, 3H),
3.69−3.67 (m, 1H), 3.56 (br s, 1H), 3.53−3.43 (m, 1H), 3.13 (br s,
1H); 13C NMR (CDCl3, 125 MHz) δ 159.2, 157.0, 136.2, 133.2, 128.5
(2C), 128.1 (2C), 128.0, 127.2 (2C), 113.8 (2C), 73.3, 66.9, 63.7,
57.7, 55.2; IR (film, mixture of regioisomers) νmax 3400, 3033, 2954,
1701, 1612, 1513, 1454, 1343, 1247, 1031, cm−1; HRMS (ESI, mixture
of regioisomers) m/z 332.1489 (MH+, C18H21NO5H+ requires
1
1
332.1492). For 27b: H NMR (CDCl3, 500 MHz) δ 7.37−7.16 (m,
268.1543). For 31b: H NMR (CDCl3, 500 MHz) δ 7.36−7.31 (m,
7H), 6.87−6.79 (m, 2H), 5.81 (br s, 1H), 4.90 (s, 2H), 4.74 (br s,
1H), 3.87−3.80 (m, 1H), 3.73 (s, 3H), 3.67−3.65 (m, 1H), 3.53−3.43
(m, 1H), 3.35 (br s, 1H), 3.13 (br s, 1H); 13C NMR (CDCl3, 125
MHz) δ 159.1, 156.9, 136.4, 136.15, 128.6 (2C), 128.2, 128.0 (2C),
127.2 (2C), 114.1 (2C), 74.9, 67.1, 67.0, 63.5, 55.3.
5H), 5.20 (d, J = 9.8 Hz, 1H), 5.10 (s, 2H), 3.90−3.86 (m, 1H), 3.86−
3.82 (m, 1H), 3.49−3.46 (m, 1H), 3.37 (td, J = 9.0, 1.9 Hz, 1H), 2.88
(br s, 1H), 2.01 (br s, 1H), 1.91−1.82 (m, 1H), 0.97 (d, J = 6.6 Hz,
3H), 0.94 (d, J = 6.7 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 156.8,
136.3, 128.5 (2C), 128.2, 128.0 (2C), 77.9, 66.9, 65.2, 52.6, 30.9, 19.2,
19.0.
Benzyl ((1R*,2R*)-1,3-Dihydroxy-1-phenylpropan-2-yl)-
carbamate (28a). Prepared from 3a (167.9 mg, 0.549 mmol) and
cinnamyl alcohol (23, 42.3 mg, 0.315 mmol) according to the general
procedure (rt, 24 h). Flash chromatography (SiO2, 1.5 × 9.5 cm, 2−
5% MeOH/CH2Cl2 elution) afforded a 1.9:1 mixture of 28a29 and its
Benzyl ((1S*,2S*,3S*)-2,3-Dihydroxycyclohexyl)carbamate
(33a) and Benzyl (2S*,6S*)-2,6-Dihydroxycyclohexylcarba-
mate (33b). Prepared from 3a (170.4 mg, 0.557 mmol) and
( )-cyclohex-2-enol (32, 30 μL, 28.8 mg, 0.293 mmol) according to
the general procedure (45 °C, 21 h). Flash chromatography (SiO2, 1.5
× 11 cm, 2−5% MeOH/CH2Cl2 elution) afforded 33a (25.4 mg,
0.0957 mmol, 33%) and 33b (20.7, 0.0780 mmol, 27%) as white
solids. For 33a: 1H NMR (CD3OD, 500 MHz) δ 7.40−7.24 (m, 5H),
5.07 (s, 2H), 3.93−3.88 (m, 1H), 3.79−3.75 (m, 1H), 3.65−3.61 (m,
1H), 1.82−1.72 (m, 1H), 1.71−1.58 (m, 2H), 1.57−1.40 (m, 3H); 13C
NMR (CD3OD, 125 MHz) δ 156.9, 137.0, 128.0 (2C), 127.54, 127.45
(2C), 72.0, 69.8, 66.0, 49.8, 27.7, 26.8, 18.4; IR (film) νmax 3402, 2938,
1694, 1531, 1455, 1242, 1075, 1047, 1005 cm−1; HRMS (ESI) m/z
266.1397 (MH+, C14H19NO4H+ requires 266.1387); 2D 1H−1H
COSY NMR (CD3OD, 500 MHz) δ 3.93−3.88/3.65−3.61 (m),
3.93−3.88/1.71−1.58 (s), 3.93−3.88/1.57−1.50 (s), 3.79−3.75/3.65−
3.61 (s), 3.79−3.75/1.82−1.72 (m), 3.79−3.75/1.49−1.40 (s), 1.82−
1.72/1.71−1.58 (m), 1.82−1.72/1.49−1.40 (s), 1.71−1.58/1.57−1.45
1
regioisomer 28b (70.7 mg, 0.235 mmol, 74%). For 28b: H NMR
(CDCl3, 500 MHz) δ 7.38−7.24 (m, 10H), 5.87 (br s, 1H), 5.09−5.01
(m, 2H), 4.79 (br s, 1H), 3.70−3.65 (m, 2H), 3.56−3.44 (m, 2H),
3.17 (br s, 1H); 13C NMR (CDCl3, 125 MHz) δ 156.9, 139.6, 136.1,
128.8 (2C), 128.5 (2C), 128.2, 127.8, 126.8 (2C), 126.0 (2C), 74.7,
67.2, 63.6, 56.3; IR (film, mixture of regioisomers) νmax 3400, 3032,
2950, 1691, 1429, 1347, 1061 cm−1; HRMS (ESI, mixture of
regioisomers) m/z 302.1391 (MH+, C17H19NO4H+ requires
302.1387).
Benzyl ((1R*,2R*)-1-(4-Fluorophenyl)-1,3-dihydroxypropan-
2-yl)carbamate (29a). Prepared from 3a (83.9 mg, 0.274 mmol) and
p-fluorocinnamyl alcohol (24,30 24.3 mg, 0.160 mmol) according to
the general procedure, with 50 μL of OsO4 solution (0.00787 mmol),
200 μL of H2O, 2 mL of CH3CN, and stirring at rt for 23 h. Flash
chromatography (SiO2, 1.5 × 9.5 cm, 2−5% MeOH/CH2Cl2 elution)
afforded a 1.3:1 mixture of 29a and its regioisomer 29b (33.5 mg,
1
(s); 2D H−13C HSQC NMR (CD3OD, 500 MHz) δ 7.40−7.24/
128.0, 7.40−7.24/127.54, 7.40−7.24/127.45, 5.07/66.0, 3.93−3.88/
49.8, 3.79−3.75/69.8, 3.65−3.61/72.0, 1.82−1.72/27.7, 1.71−1.58/
26.8, 1.71−1.58/18.4, 1.57−1.48/26.8, 1.52−1.43/18.4, 1.49−1.40/
27.7; NOE NMR (CD3OD, 500 MHz): irradiation of the signal at
3.93−3.88 enhanced the signals at 3.65−3.61, 1.71−1.58, and 1.57−
1.45; irradiation of the signal at 3.79−3.75 enhanced the signals at
1.82−1.72 and 1.52−1.43; irradiation of the signal at 3.65−3.61
enhanced the signal at 3.93−3.88.
1
0.105 mmol, 66%). For 29a: H NMR (CDCl3, 500 MHz) δ 7.38−
7.20 (m, 7H), 7.06−6.93 (m, 2H), 5.52 (d, J = 7.0 Hz, 1H), 5.04−4.93
(m, 3H), 3.93−3.72 (m, 2H), 3.61−3.49 (m, 1H), 3.44 (br s, 1H),
2.80 (br s, 1H); 13C NMR (CDCl3, 125 MHz) δ 162.3 (d, J = 246.0
Hz), 156.8, 136.7, 136.1, 128.5 (2C), 128.2 (2C), 128.0, 127.6 (d, J =
8.1 Hz, 2C), 115.3 (d, J = 21.4 Hz, 2C), 73.4, 67.0, 63.7, 57.4; IR (film,
mixture of regioisomers) νmax 3401, 3067, 2926, 1697, 1605, 1510,
1455, 1343, 1224, 1061 cm−1; HRMS (ESI, mixture of regioisomers)
m/z 342.1102 (MNa+, C17H18FNO4Na+ requires 342.1112). For 29b:
1H NMR (CDCl3, 500 MHz) δ 7.38−7.20 (m, 7H), 7.06−6.93 (m,
For 33b: 1H NMR (4.5:1 mixture of rotamers, data for major
rotamer, CD3OD, 500 MHz) δ 7.39−7.25 (m, 5H), 5.09 (s, 2H),
4.06−4.00 (m, 1H), 3.67 (td, J = 9.9, 4.2 Hz, 1H), 3.40 (dd, J = 9.6,
2.2 Hz, 1H), 1.98−1.91 (m, 1H), 1.78−1.64 (m, 2H), 1.57−1.49 (m,
2H), 1.38−1.26 (m, 1H); 13C NMR (CD3OD, 125 MHz) δ 157.4,
136.9, 128.0 (2C), 127.53, 127.51 (2C), 68.7, 68.1, 66.1, 59.5, 33.2,
31.2, 18.0; IR (film) νmax 3385, 2938, 1697, 1534, 1454, 1252, 1043
cm−1; HRMS (ESI) m/z 266.1385 (MH+, C14H19NO4H+ requires
2H), 5.76 (br s, 1H), 5.10−5.04 (m, 2H), 4.80 (br s, 1H), 3.93−3.72
(m, 2H), 3.61−3.49 (m, 1H), 3.01 (br s, 1H), 1.83 (br s, 1H); 13C
NMR (CDCl3, 125 MHz) δ 162.2 (d, J = 246.5 Hz), 156.78, 136.14,
136.0, 128.6 (2C), 128.4 (2C), 128.1, 127.6 (d, J = 8.1 Hz, 2C), 115.6
(d, J = 21.9 Hz, 2C), 74.6, 67.3, 63.8, 55.8.
1
266.1387); 2D H−1H COSY NMR (CD3OD, 500 MHz) δ 4.06−
Benzyl ((2R*,3S*)-3,4-Dihydroxybutan-2-yl)carbamate
(30b). Prepared from 3a (164.8 mg, 0.539 mmol) and crotyl alcohol
(25, 27 μL, 22.8 mg, 0.316 mmol) according to the general procedure
(rt, 24.5 h). Flash chromatography (SiO2, 1.5 × 9.5 cm, 5−10%
MeOH/CH2Cl2 elution) afforded a 1.1:1 mixture of 30b and its
4.00/3.40 (s), 4.06−4.00/1.78−1.64 (s), 4.06−4.00/1.57−1.49 (s),
3.67/3.40 (s), 3.67/1.98−1.91 (s), 3.67/1.38−1.26 (s), 1.98−1.91/
1.78−1.64 (s), 1.98−1.91/1.57−1.49 (m), 1.98−1.91/1.38−1.26 (s),
1.78−1.64/1.57−1.49 (s), 1.78−1.64/1.38−1.26 (w), 1.57−1.49/
regioisomer 30a31 (59.0 mg, 0.247 mmol, 78%). For 30b: H NMR
1.38−1.26 (m); 2D H−13C HSQC NMR (CD3OD, 500 MHz) δ
1
1
1212
dx.doi.org/10.1021/jo202375a | J. Org. Chem. 2012, 77, 1208−1214

The Journal of Organic Chemistry
Note
7.39−7.25/128.0, 7.39−7.25/127.53, 7.39−7.25/127.51, 5.09/66.1,
4.06−4.00/68.7, 3.67/68.1, 3.40/59.5, 1.98−1.91/33.2, 1.57−1.49/
31.2 1.57−1.49/18.0, 1.38−1.26/31.2, 1.38−1.26/18.0; NOE NMR
(CD3OD, 500 MHz): irradiation of the signal at 4.06−4.00 enhanced
the signals at 3.40, 1.78−1.64, and 1.57−1.49; irradiation of the signal
at 3.67 enhanced the signals at 1.98−1.91 and 1.78−1.64; irradiation of
the signal at 3.40 enhanced the signals at 4.06−4.00, 1.57−1.49, and
1.38−1.26.
Benzyl ((3S*,4R*)-2,4-Dihydroxy-2-methylpentan-3-yl)-
carbamate (35a), Benzyl (3R*,4R*)-2,4-Dihydroxy-2-methyl-
pentan-3-ylcarbamate (35b), and Benzyl (2R*,3S*)-3,4-Dihy-
droxy-4-methylpentan-2-ylcarbamate (35c). Prepared from 3a
(170.4 mg, 0.557 mmol) and 3434 (37.7 μL, 31.7 mg, 0.317 mmol)
according to the general procedure (45 °C, 25 h). Flash
chromatography (SiO2, 2 × 9.5 cm, 1.5−4% MeOH/CH2Cl2 elution)
afforded 35a (20.6 mg, 0.0771 mmol, 24%), 35b (5.4 mg, 0.0202
mmol, 6%), and 35c (23.9 mg, 0.0894, 28%) as white solids. For 35a:
1H NMR (CDCl3, 500 MHz) δ 7.39−7.29 (m, 5H), 5.57 (d, J = 9.4
4.52 (d, J = 8.8 Hz, 1H), 4.30−4.15 (m, 2H), 3.94 (d, J = 5.4 Hz, 2H),
2.71 (br s, 1H), 1.30 (t, J = 7.2 Hz, 3H), 1.28 (s, 3H), 1.24 (s, 3H);
13C NMR (CDCl3, 125 MHz) δ 171.2, 169.2, 156.6, 136.1, 128.6
(2C), 128.3, 128.1 (2C), 71.9, 67.3, 61.7, 59.8, 44.5, 26.7, 26.6, 14.1;
IR (film) νmax 3342, 2980, 1731, 1531, 1455, 1374, 1261, 1028 cm−1;
HRMS (ESI) m/z 353.1716 (MH+, C17H24N2O6H+ requires
353.1707).
Ethyl 2-(2-(Benzyloxycarbonylamino)acetamido)-3-methyl-
but-2-enoate (38). A solution of alcohol 37 (20.9 mg, 0.059
mmol) in CHCl3 (stored over K2CO3, 250 μL) was treated with a
solution of Martin sulfurane in CHCl3 (0.23 M, 500 μL, 0.117 mmol).
The mixture was stirred at 50 °C for 1 h, cooled to rt, and
concentrated in vacuo. Flash chromatography (SiO2, 1.5 × 7 cm, 0−
1.6% MeOH/CH2Cl2 elution) afforded 38 (15.9 mg, 0.048 mmol,
80%) as a colorless oil: 1H NMR (13.4:1 mixture of rotamers, data for
major rotamer, CDCl3, 500 MHz) δ 7.38−7.32 (m, 5H), 7.15 (br s,
1H), 5.42 (br s, 1H), 5.15 (s, 2H), 4.20 (q, J = 7.1 Hz, 2H), 3.96 (d, J
= 5.7 Hz, 2H), 2.18 (s, 3H), 1.82 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H); 13C
NMR (CDCl3, 125 MHz) δ 167.7, 164.6, 156.7, 146.5, 136.0, 128.6
(2C), 128.3, 128.1 (2C), 120.5, 67.3, 60.9, 44.7, 22.7, 21.4, 14.1; IR
(film) νmax 3316, 2923, 2853, 1714, 1514, 1457, 1309, 1237, 1093
cm−1; HRMS (ESI) m/z 335.1592 (MH+, C17H22N2O5H+ requires
335.1601).
Hz, 1H), 5.13 (s, 2H), 4.42 (q, J = 6.1 Hz, 1H), 3.37 (d, J = 9.8 Hz,
1H), 2.66 (br s, 2H), 1.38 (s, 3H), 1.24 (s, 3H), 1.18 (d, J = 6.4 Hz,
3H); 13C NMR (CDCl3, 125 MHz) δ 157.4, 136.6, 128.5 (2C), 128.1,
127.9 (2C), 74.5, 67.1, 66.8, 60.6, 27.9, 27.7, 20.6; 2D 1H−13C HSQC
NMR (CDCl3, 500 MHz) δ 7.39−7.29/128.5, 7.39−7.29/128.1,
7.39−7.29/127.9, 5.13/66.8, 4.42/67.1, 3.37/60.6, 1.24/27.9, 1.34/
27.7, 1.18/20.6; IR (film) νmax 3407, 2976, 1699, 1515, 1455, 1226,
1056 cm−1; HRMS (ESI) m/z 268.1567 (MH+, C14H21NO4H+
requires 268.1543).
ASSOCIATED CONTENT
■
S
* Supporting Information
Structure proofs of 33a and 33b, stereochemical assignments of
1
For 35b: H NMR (CDCl3, 500 MHz) δ 7.41−7.30 (m, 5H), 5.12
1
35a−c, and copies of H and 13C NMR spectra for all new
(s, 2H), 4.91 (d, J = 9.5 Hz, 1H), 4.03−3.97 (m, 1H), 3.61 (dd, J = 9.9,
6.9 Hz, 1H), 3.13 (br s, 1H), 2.73 (br s, 1H), 1.33 (s, 3H), 1.27 (d, J =
6.2 Hz, 3H), 1.25 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 156.9,
136.3, 128.6 (2C), 128.3, 128.1 (2C), 73.6, 69.5, 67.1, 62.6, 28.5, 26.0,
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
20.8; 2D H−13C HSQC NMR (CDCl3, 500 MHz) δ 7.41−7.30/
AUTHOR INFORMATION
Corresponding Author
*E-mail: scastle@chem.byu.edu.
■
128.6, 7.41−7.30/128.3, 7.41−7.30/128.1, 5.12/69.5, 4.03−3.97/67.1,
1.33/28.5, 1.27/20.8, 1.25/26.0; IR (film) νmax 3416, 2976, 1698,
1544, 1455, 1244, 1027 cm−1; HRMS (ESI) m/z 268.1569 (MH+,
C14H21NO4H+ requires 268.1543).
ACKNOWLEDGMENTS
1
■
For 35c: H NMR (CDCl3, 500 MHz) δ 7.38−7.29 (m, 5H), 5.22
We thank Brigham Young University (Cancer Research Center
Fellowship to Z.M., Undergraduate Research Award to B.C.N.,
Robins Fellowship to B.M.L., Talmadge Fellowship to D.D.H.,
High School Summer Internship to J.M.L.) for support. We
also thank Joseph M. Cardon for assistance in the preparation
of starting materials.
(br s, 1H), 5.13−5.07 (m, 2H), 4.02−3.92 (m, 1H), 3.27−3.24 (m,
1H), 2.81 (br s, 1H), 2.36 (br s, 1H), 1.27−1.22 (m, 9H); 13C NMR
(CDCl3, 125 MHz) δ 156.4, 136.4, 128.5 (2C), 128.2, 128.0 (2C),
79.5, 72.9, 66.9, 46.6, 26.8, 24.9, 21.0; 2D 1H−13C HSQC NMR
(CDCl3, 500 MHz) δ 7.38−7.29/128.5, 7.38−7.29/128.2, 7.38−7.29/
128.0, 5.13−5.07/66.9, 4.02−3.92/46.6, 3.27−3.24/79.5, 1.27/21.0,
1.25/26.8, 1.24/24.9; IR (film) νmax 3421, 2973, 1697, 1512, 1454,
1246, 1100, 1050 cm−1; HRMS (ESI) m/z 268.1560 (MH+,
C14H21NO4H+ requires 268.1543).
REFERENCES
(1) Bergmeier, S. C. Tetrahedron 2000, 56, 2561.
(2) Donohoe, T. J.; Callens, C. K. A.; Flores, A.; Lacy, A. R.; Rathi, A.
■
35a and 35c were also prepared from 3a (170.4 mg, 0.557 mmol)
and 36 (38 μL, 31.7 mg, 0.316 mmol) according to the general
procedure (35 °C, 21 h). Flash chromatography (SiO2, 1.5 × 11 cm,
1.5−4% MeOH/CH2Cl2 elution) afforded 35a (10.7 mg, 0.0400
mmol, 13%) and 35c (21.3 mg, 0.0797 mmol, 25%) as white solids.
Ethyl 2-(2-(((Benzyloxy)carbonyl)amino)acetamido)-3-hy-
droxy-3-methylbutanoate (37). A suspension of 15 (280.4 mg,
0.949 mmol) and Pd/C (10 wt %, 42.6 mg) in MeOH (12 mL) was
stirred at rt under H2 (450 psi) for 23 h. The mixture was filtered
through Celite, and the Celite pad was washed with MeOH (125 mL).
The filtrate was concentrated in vacuo, and the crude amine was
dissolved in THF/DMF (2.5:1, 42.5 mL), cooled to 0 °C under Ar,
and treated with N-Cbz-glycine (370.0 mg, 1.769 mmol), HOBt
(298.9 mg, 1.770 mmol), and EDC·HCl (338.5 mg, 1.766 mmol). The
resulting mixture was allowed to warm to rt and stir for 24 h. The
reaction was quenched with satd aq NaHCO3 (15 mL), and the
precipitate was filtered and washed with EtOAc (15 mL). The aqueous
layer was extracted with EtOAc (3 × 15 mL), and the combined
organic extracts were washed with brine (15 mL), dried (Na2SO4),
filtered, and concentrated in vacuo. Flash chromatography (SiO2, 2.3 ×
17 cm, 1−7% MeOH/CH2Cl2 elution) afforded 37 (286.4 mg, 0.812
H. Chem.Eur. J. 2011, 17, 58.
(3) (a) Sharpless, K. B.; Chong, A. O.; Oshima, K. J. Org. Chem.
1976, 41, 177. (b) Herranz, E.; Sharpless, K. B. J. Org. Chem. 1978, 43,
2544.
(4) Li, G.; Chang, H.-T.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl.
1996, 35, 451.
(5) For a review, see: Bodkin, J. A.; McLeod, M. D. J. Chem. Soc.,
Perkin Trans. 1 2002, 2733.
(6) (a) Reddy, K. L.; Sharpless, K. B. J. Am. Chem. Soc. 1998, 120,
1207. (b) Morgan, A. J.; Masse, C. E.; Panek, J. S. Org. Lett. 1999, 1,
1949. (c) Han, H.; Cho, C.-W.; Janda, K. D. Chem.Eur. J. 1999, 5,
1565. (d) Harding, M.; Bodkin, J. A.; Issa, F.; Hutton, C. A.; Willis, A.
C.; McLeod, M. D. Tetrahedron 2009, 65, 831.
(7) (a) Donohoe, T. J.; Johnson, P. D.; Cowley, A.; Keenan, M. J.
Am. Chem. Soc. 2002, 124, 12934. (b) Donohoe, T. J.; Johnson, P. D.;
Pye, R. J. Org. Biomol. Chem. 2003, 1, 2025. (c) Donohoe, T. J.;
Chughtai, M. J.; Klauber, D. J.; Griffin, D.; Campbell, A. D. J. Am.
Chem. Soc. 2006, 128, 2514. (d) Donohoe, T. J.; Bataille, C. J. R.;
Gattrell, W.; Kloesges, J.; Rossignol, E. Org. Lett. 2007, 9, 1725.
(8) (a) Castle, S. L.; Srikanth, G. S. C. Org. Lett. 2003, 5, 3611.
(b) Mettath, S.; Srikanth, G. S. C.; Dangerfield, B. S.; Castle, S. L. J.
1
mmol, 86%) as a colorless oil: H NMR (CDCl3, 500 MHz) δ 7.40−
7.30 (m, 5H), 6.86 (d, J = 8.2 Hz, 1H), 5.48 (br s, 1H), 5.14 (s, 2H),
1213
dx.doi.org/10.1021/jo202375a | J. Org. Chem. 2012, 77, 1208−1214

The Journal of Organic Chemistry
Note
Org. Chem. 2004, 69, 6489. (c) He, L.; Srikanth, G. S. C.; Castle, S. L.
J. Org. Chem. 2005, 70, 8140. (d) Ma, B.; Parkinson, J. L.; Castle, S. L.
Tetrahedron Lett. 2007, 48, 2083. (e) Banerjee, B.; Capps, S. G.; Kang,
J.; Robinson, J. W.; Castle, S. L. J. Org. Chem. 2008, 73, 8973.
(9) For unfunctionalized alkenes, see ref 3. For electron-rich silyl enol
ethers, see: Phukan, P.; Sudalai, A. Tetrahedron: Asymmetry 1998, 9,
1001.
(10) Harris, L.; Mee, S. P. H; Furneaux, R. H.; Gainsford, G. J.;
Luxenburger, A. J. Org. Chem. 2011, 76, 358.
(11) Recently, regioselective aminohydroxylation of the 1,1-
disubstituted alkene α-methylstyrene was disclosed: Donohoe, T. J.;
Callens, C. K. A.; Flores, A.; Mesch, S.; Poole, D. L.; Roslan, I. A.
Angew. Chem., Int. Ed. 2011, 50, 10957.
(12) For a review of ligand-accelerated catalysis, see: Berrisford, D.
J.; Bolm, C.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1995, 34,
1059.
(13) (a) Christ, W. J.; Cha, J. K.; Kishi, Y. Tetrahedron Lett. 1983, 24,
3947. (b) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron 1984, 40,
2247.
(14) For a review, see: (a) Bellemin-Laponnaz, S.; Le Ny, J.-P.
Compt. Rend. Chim. 2002, 5, 217. (b) V or Mo complexes: Matsubara,
S.; Okazoe, T.; Oshima, K.; Takai, K.; Nozaki, H. Bull. Chem. Soc. Jpn.
1985, 58, 844. (c) Re complexes: Morrill, C.; Grubbs, R. H. J. Am.
Chem. Soc. 2005, 127, 2842.
(15) Bellemin-Laponnaz, S.; Le Ny, J. P.; Dedieu, A. Chem.Eur. J.
1999, 5, 57.
(16) Munz, D.; Strassner, T. J. Org. Chem. 2010, 75, 1491.
(17) Yokokawa, F.; Shioiri, T. Tetrahedron Lett. 2002, 43, 8679.
(18) (a) Morimoto, K.; Shimada, N.; Naganawa, H.; Takita, T.;
Umezawa, H.; Kambara, H. J. Antibiot. 1982, 35, 378. (b) Zenkoh, T.;
Ohtsu, Y.; Yoshimura, S.; Shigematsu, N.; Takase, S.; Hino, M. J.
Antibiot. 2003, 56, 694. (c) Ueoka, R.; Ise, Y.; Ohtsuka, S.; Okada, S.;
Yamori, T.; Matsunaga, S. J. Am. Chem. Soc. 2010, 132, 17692.
(19) Sammakia, T.; Latham, H. A. J. Org. Chem. 1996, 61, 1629.
(20) Dettwiler, J. E.; Lubell, W. D. J. Org. Chem. 2003, 68, 177.
(21) Ramalingam, K.; Zeng, W.; Nanjappan, P.; Nowotnik, D. P.
Synth. Commun. 1995, 25, 743.
(22) Zhang, P.; Le, H.; Kyne, R. E.; Morken, J. P. J. Am. Chem. Soc.
2011, 133, 9716.
(23) Gilbert, J. C.; Kelly, T. A. Tetrahedron 1988, 44, 7587.
́
(24) Shangguan, N.; Joullie, M. Tetrahedron Lett. 2009, 50, 6748.
(25) Tian, S.-K.; Hong, R.; Deng, L. J. Am. Chem. Soc. 2003, 125,
9900.
(26) Schmidt, U.; Meyer, R.; Leitenberger, V.; Stabler, F.;
̈
Lieberknecht, A. Synthesis 1991, 409.
(27) Data for meso isomer of 21: Wharton, T.; Wilson, L. J. Bioorg.
Med. Chem. 2002, 10, 3545.
́
(28) Bouziane, A.; Helou, M.; Carboni, B.; Carreaux, F.;
Demerseman, B.; Bruneau, C.; Renaud, J.-L. Chem.Eur. J. 2008,
14, 5630.
(29) Vatmurge, N. S.; Hazra, B. G.; Pore, V. S. Aust. J. Chem. 2007,
60, 196.
(30) Takeuchi, R.; Ue, N.; Tanabe, K.; Yamashita, K.; Shiga, N. J. Am.
Chem. Soc. 2001, 123, 9525.
(31) Jeffery, A. L.; Kim, J. H.; Wiemer, D. F. Tetrahedron 2000, 56,
5077.
(32) Kennedy, J. P.; Lindsley, C. W. Tetrahedron Lett. 2010, 51, 2493.
(33) Marchand, J.; Rocchiccioli, F.; Pais, M.; Jarreau, F.-X. Bull. Soc.
Chim. Fr. 1972, 4699.
(34) Hatzakis, N. S.; Smonou, I. Bioorg. Chem. 2005, 33, 325.
1214
dx.doi.org/10.1021/jo202375a | J. Org. Chem. 2012, 77, 1208−1214