Stereoselective synthesis of highly functionalized 5- A nd 6-membered aminocyclitols starting with a readily available 2-azetidinone

Article abstract of DOI:10.1021/acs.joc.9b00239

Stereoselective transformations of 4-vinyl-2-azetidinone derivative 4 into a variety of highly functionalized 6- A nd 5-membered carbocyclic compounds 7 and 9 were carried out using sequences involving sequential C1-N bond cleavage and Ru-catalyzed ring-closing metathesis. The derived carbocycles were further transformed into polyhydroxylated 6- A nd 5-membered aminocyclitols.

Full text of DOI:10.1021/acs.joc.9b00239

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Article
Stereoselective synthesis of highly functionalized 5- and 6-membered
aminocyclitols starting with a readily available 2-azetidinone
Raghavendra Achary, Hyeong Rae Kim, and Hyeon-Kyu Lee
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00239 • Publication Date (Web): 14 Mar 2019
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Stereoselective Synthesis of Highly Functionalized 5-
and 6-Membered Aminocyclitols Starting with a
Readily Available 2-Azetidinone
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Raghavendra Achary,† Hyeong Rae Kim,†,‡ and Hyeon-Kyu Lee†,‡*
†Korea Chemical Bank, Korea Research Institute of Chemical Technology, PO Box 107, Yuseong, Daejeon 305-
600, Korea; ‡Department of Medicinal Chemistry and Pharmacology, University of Science and Technology,
113 Gwahango, Yuseong, Daejeon 305-333, Korea.
leehk@krict.re.kr
ABSTRACT
O
O
BnO
O
OBn
OBn
and
polyhydroxylated
aminocyclitols
N
NHBoc
NHBoc
Boc
4
7
9
(2R,3S)-
(2R,3S)-
Abstract: Stereoselective transformations of the 4-vinyl-2-azetidinone derivative 4 to a variety of
highly functionalized 6- and 5-membered carbocyclic compounds 7 and 9 were carried out using
sequences involving sequential C1-N bond cleavage and Ru-catalyzed ring-closing metathesis. The
derived carbocycles were further transformed to polyhydroxylated 6- and 5-membered aminocyclitols.
Introduction
Polyhydroxylated amino-cyclohexanes and -cyclopentanes, termed aminocyclitols, constitute
an important class of natural and synthetic products, which display diverse biological
activities.1 In particular, members of the aminocyclitol family serve as aminoglycoside
antibiotics and others are glycosidase inhibitors and antiviral agents.2 Also, aminocyclitols are
carbocyclic analogues of biologically important monosaccharides or aminosugars.3 Because of
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the important characteristics of these substances, many investigations have been conducted
over the past several decades to develop general strategies to produce novel members of this
family, especially those that have enhanced and/or more selective biological profiles.4 In these
investigations it has been recognized that the presence of dense functionality as well as multiple
contiguous chiral centers make aminocyclitols a major synthetic challenge.5
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The 2-azetidinone moiety is a key structural element in a widely employed family of
antibacterial agents known as β-lactam antibiotics.6 Owing to this, many studies, aimed at
developing methods for practical and stereoselective synthesis of 2-azetidinones, have been
carried out.7 Owing to the wealth of approaches that have been devised for their synthesis, 2-
azetidinones are now readily available to the point that they are now being utilized as chiral
synthons in routes for the preparation of other important classes of compounds.8 Examples of
these applications are found in transformations of 2-azetidinones to nonproteogenic amino
acids, peptides9 and other bioactive nitrogen containing heterocycles8d through routes that
employ ring expansion or rearrangement reactions to generate 2-pyrrolidinones10 and 2-
piperidones.8a,8b,11
As part of our recent efforts in this broad area, we developed a new, two-carbon ring
homologation methodology for synthesis of 2-piperidones from readily accessible 2-
azetidinones,11 and routes for preparation of (phyto)sphingosines involving ring opening by
phosphonate stabilized carbanions and subsequent Horner-Wadsworth-Emmons olefination.12
As part of our continuing investigations probing the utilization of 2-azetidinones as chiral
synthons, we envisioned that optically active cyclohexenones and cyclopentenones (A and B)
would be potentially accessible through ring-closing metathesis (RCM)8d,13 of the respective
1,6-dienes and 1,5-dienes (C and D) (Scheme 1). Moreover, we realized the possibility that the
requisite dienes, C and D, could be prepared by using C1-N bond cleavage reactions of
optically active N-Boc-4-vinyl-2-azetidinone (4) with corresponding allyl and vinyl
organometallic reagents (Scheme 1). The investigation, designed to assess the validity of these
proposals led to observations described below, which show that 2-azetidinones 4 can be readily
transformed to highly functionalized 6- and 5-membered carbocyclic products A and B. In
addition, the effort also demonstrated that A and B serve as valuable intermediates in concise
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routes for the preparation of complex polyhydroxylated aminocyclitols.
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9
Scheme 1. Proposed routes for the synthesis of 6- and 5-membered carbocyclic products A and
B from 4-vinyl-2-azetidinone 4 and for transformation of these carbocycles to
polyhydroxylated aminocyclitols.
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BnO
NHBoc
BnO
NHBoc
n=0,1
BnO
O
2
3
2
3
2
1
3
4
1
O
1
O
N
RCM
n
Boc
( )
n
( )
+
C, D
A, B
MgX
n
( )
BnO
NHBoc
OH
BnO
NHBoc
2
3
2 3
and
1
1
HO
HO
polyhydroxylated
aminocyclitols
OH
n
n
( )
( )
N3
OH
Results and Discussion
N-Boc-4-vinyl-2-azetidinone (4), the starting material employed in the new routes developed
for synthesis of functionalized 6- and 5-membered carbocyclic products A and B, was prepared
in enantiomerically pure form using the four-step sequence outlined in Scheme 2. In the route,
the conversion of known optically pure Bose-Manhas 2-azetidinone 1, prepared by Staudinger
reaction of the 4-anisidine imine of (R)-2,3-O-isopropylideneglyceraldehyde with
benzyoxyacetyl chloride in the presence of Et3N,14 to the corresponding diol 2 was
accomplished by using p-TsOH promoted hydrolysis in aqueous THF (89%).15 The resulting
1,2-diol moiety in 2 was then subjected to cleavage reaction with I2 and PPh316 to produce N-
PMP-4-vinyl-2-azetidinone 3 (91%). The PMP (p-methoxyphenyl) protecting group in 3 was
transformed to a N-Boc group in 4 through sequential reactions with cerium(IV) ammonium
nitrate (CAN) and (t-Boc)2O (53%, 4 steps from 1).
Scheme 2. Synthesis of 4-vinyl-2-azetidinone 4 from the Bose-Manhas lactam 1
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O
HO
O
OH
BnO
O
BnO
O
BnO
O
BnO
O
a
c
b
H
H
N
N
N
N
Boc
-4
PMP
PMP
PMP
9
3
1
2
(3R,4S)
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(a) p-TsOH, THF-H2O, reflux, 24 h, 89%; (b) PPh3, I2, imidazole, toluene, reflux, 5 h, 91%; (c) i. CAN,
CH3CN-H2O, rt, 1 h, 71%; ii. (t-Boc)2O, Et3N, DMAP, CH2Cl2, 0 0C to rt, 12 h, 81%.
As stated above, we envisaged that 2-azetidinone 4 would serve as a versatile chiral synthon in
sequences for the preparation of valuable enantiomerically pure substances. Relevant to this
proposal is the expectation that the amide bond in 4 would be readily cleaved in reactions with
various nucleophiles such as amines, alcohols, and organometallic reagents that form
corresponding β–amino-amides, -esters, and -ketones.8a,8b We were aware of the earlier
observation that ring opening reactions of 2-azetidinones with alkyl Grignard reagents
invariably leads to mixtures of β–amino-ketones and -carbinols.17 However, we believed that
formation of undesired carbinols in ring opening reactions of 4 with allyl and vinyl Grignards
would be avoided if it is first converted to the Weinreb amide 5 by treatment with N,O-
dimethylhydroxylamine in the presence of Ti(OPr-i)4 (90%). An extensive optimization
investigation led to the observation that addition of excess amounts of allylmagnesium bromide
to 5 in THF at -30 0C for 2 h using a syringe pump generates the desired 1,6-diene 6 as the sole
product in 95% isolated yield. Similarly, slow addition of vinylmagnesium bromide to 5 in
Et2O at 0 0C produces 1,5-diene 8 in 78% yield (Scheme 3).
Scheme 3. Route for the conversion of 2-azetidinone 4 to functionalized carbocycles 7 and 9
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BnO
O
2
3
1
N
Boc
O
BnO
NHBoc
NHBoc
BnO
NHBoc
NHBoc
4
OBn
c
1
b
2 3
2
3
a
2
3
1
O
1
O
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NHBoc
BnO
NHBoc
7
6
7
2
3
O
1
N
BnO
BnO
1
1
O
O
2
OBn
e
2
3
1
2
5
3
O
O
d
3
NHBoc
8
9
9
(a) CH3ONHCH3∙HCl, Ti(OPr-i)4, dioxane, rt, 12 h, 90%; (b) allylMgBr, THF, -30 0C, 95%; (c) Grubb’s
2nd generation catalyst, toluene, 50 0C, 30 min, 93%; (d) vinylMgBr, Et2O, 0 0C, 78%; (e) Grubb’s 2nd
generation catalyst, toluene, 50 0C, 20 min, 92%.
We next assessed the efficiencies of ring-closing metathesis13 reactions of 6 and 8 using
Grubb’s 2nd generation Ru-catalyst. These processes, carried out in toluene, were observed to
efficiently generate the corresponding (2R,3S)-2-benzyloxy-3-(N-Boc)aminocyclohex-4-en-1-
one 7 (93%) and (2R,3S)-2-benzyloxy-3-(N-Boc)aminocyclopent-4-en-1-one 9 (92%) (Scheme
3).
6-Membered Carbocycles and Aminocyclitols
To demonstrate that 7 and 9 are potentially valuable chiral synthons in synthetic routes to
aminocyclitols, we first explored stereoselective reductions of their carbonyl groups, and then
assessed the outcomes of ensuing reactions that introduce additional functional groups. A
thorough evaluation of stereoselective carbonyl reduction reactions of (2R,3S)-7 led to the
observation that this cyclohexenone can be transformed to either (1S,2R,3S)-10 or
o
(1R,2R,3S)-11 (Scheme 4). Specifically, treatment of 7 with LiEt3BH in THF at -20 C leads
to formation of the 1,2-cis diol 10 in 98% yield, via a process in which hydride transfer from
the bulky superhydride occurs on the carbonyl face that is trans to the neighbouring 2-
benzyoxy group. The absolute stereochemistry of (1S,2R,3S)-10 was assigned by using X-ray
crystallographic analysis of the acetate 12 (CCDC 1848803), which is derived by acetylation
and t-Boc removal (Scheme 5). In contrast, Luche reduction18 (NaBH4, CeCl3∙7H2O in MeOH)
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of 7 forms the 1,2-trans diol, (1R,2R,3S)-11 as the major product (10:11 = 1:9, 81%). It is likely
that in this process cerate ions coordinates to the C-1 carbonyl oxygen and the neighbouring
O-benzyl ether oxygen in 7. In this event, hydride delivery would take place to the carbonyl
face trans to the 3-(t-Boc)amine group.
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Scheme 4. Stereoselective carbonyl reduction of 7 to 10 and 11
O
OH
OH
OBn
OBn
OBn
1
1
2
3
1
2
3
reducing agents
conditions
2
3
+
NHBoc
NHBoc
NHBoc
7
10
11
(1R,2R,3S)-
(2R,3S)-
(1S,2R,3S)-
Reducing
Temp
(oC)
Time
(h)
Yield
(%)
Entry
Solvent
Additive (eq)
-
10:11
Agent (eq)
1
2
LiEt3BH (1.2)
NaBH4 (1.5)
THF
-20
-78
0.5
0.5
98
81
1:0
1:9
.
MeOH
CeCl3 7H2O (1.1)
Scheme 5. Conversion of 10 to 12 for X-ray crystallography analysis
OH
OAc
OBn
OBn
N
O, Et3
1
2
1
2
i) Ac2
3
3
ii) HCl/dioxane
NHBoc
NH
2HCl
12
(1S,2R,3S)-
10
(1S,2R,3S)-
Having demonstrated that 1,2-dihydroxy-3-amino-cyclohex-4-ene derivatives 10 and 11 can
be prepared in an efficient and sterocontrolled manner, we next explored applications of these
substances to the synthesis of 6-membered aminocyclitols. Accordingly, 11 was subjected to
dihydroxylation reaction using standard Upjohn conditions19 (cat. OsO4, 2 equiv NMO,
acetone-H2O-tBuOH). The process forms the (1R,2R,3S,4S,5R)-diol 16 as the predominant
product. The anti-selectivity (to the 3-(N-t-Boc)amino group) of this dihydroxylation reaction
is in accordance with Donohoe’s earlier findings.20To facilitate structural determination, 16
was converted to the corresponding tri-acetate 17 (Scheme 6). The structure and
stereochemistry of 17 were then assigned using 2D-NOESY spectroscopic analysis (see SI).
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Scheme 6. Stereoselective dihydroxylation of 10 and 11 under Upjohn conditions
6
7
8
9
OH
OAc
OH
OBn
OBn
OBn
1
2
3
1
2
3
Ac
N
cat. OsO
4, NMO
2O, Et3
1
2
3
Acetone/H2O/t-BuOH
81%
HO
NHBoc
AcO
NHBoc
10
11
12
13
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17
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NHBoc
rt, 8h
OH
OAc
11
(1R,2R,3S)-
16
17
(1R,2R,3S,4S,5R)-
(1R,2R,3R,4S,5R)-
predominant
OH
OH
OH
OBn
OBn
OBn
1
2
3
1
2
3
cat. OsO
4, NMO
+
1
2
3
Acetone/H2O/t-BuOH
rt, 8h, 70%
HO
NHBoc HO
NHBoc
NHBoc
OH
(1S,2R,3S,4S,5R)-
OH
10
(1S,2R,3S)-
18
19
(1S,2R,3S,4R,5S)-
83%
70:30 mixture
Ac
N,
2O, Et3
OAc
OAc
OAc
OBn
OBn
OBn
1
2
3
1
2
3
1
2
3
cat. OsO
4, NMO
Ac
N
2O, Et3
CH3CN/H
81%
2O, 2,6-lutidine
NHBoc
HO
NHBoc
AcO
NHBoc
rt, 8h, 70%
20
OH
OAc
(1S,2R,3S)-
21
22
(1S,2R,3S,4S,5R)-
(1S,2R,3R,4S,5R)-
predominant
In contrast to the highly stereoselective nature of the reaction of 1,2-anti-11, 1,2-syn-10
undergoes Upjohn dihydroxylation to produce a 7:3 mixture of 18 and 19. However, the acetate
derivative 20, formed by acetylation of 1,2-syn-10, undergoes highly anti-selective
dihydroxylation to form 21 as the major diol product (70%) under slightly modified Upjohn
conditions (cat. OsO4, 2 equiv NMO, 2,6-lutidine, CH3CN-H2O). For simplicity purposes, 21
was converted to the tri-acetate 22 whose structure and stereochemistry were assigned using
2D-NOESY spectroscopy (see SI), (Scheme 6). The observed anti-selective, relative to the 3-
(N-t-Boc)amino group, nature of dihydroxylation of 20 is also in accordance with Donohoe’s
earlier observations.20
To expand the scope of their synthetic applications, the 6-membered carbocycles 10 and 11
were subjected to epoxidation with m-CPBA. Epoxidations of mono N-protected amide and
carbamate derivatives of cyclic allylic amines with peracids are known to occur with high
degrees of syn-selectivity, presumably as a consequence of hydrogen-bonding interactions
between the amide carbonyl groups with the peracid.20b, 21 In fact, epoxidations of 10 and 11
were found to produce the corresponding epoxides 23 (84%) and 24 (86%) stereoselectively
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(Scheme 7). In an effort aimed at determining if more functionally rich aminocyclitols can be
accessed using this chemistry, we observed that epoxides 23 and 24 undergo regioselective
epoxide ring-opening reactions with NaN3 under acidic conditions1a,21a to generate the
functionally more diverse aminocyclitols 25 and 26, respectively (Scheme 7). For example,
treatment of epoxide 23 with NaN3 in the presence of NH4Cl in MeOH forms the highly
functionalized cyclohexane derivatives 25 as the predominant product (78%) via regioselective,
less hindered azide addition at C5. The stereochemical outcome of azide addition to the epoxide
23 affording 4,5-trans-diaxial-4-hydroxy-5-azide 25 is also in accordance with the Furst-
Plattner rule. Moreover, epoxide 24 is transformed to azide 26 under the similar reaction
conditions. The structure and stereochemistry of epoxide 23 was deduced by X-ray crystal
structure analysis (CCDC 1877126) of the corresponding azide-addition product 25 (see below)
and those of 26 were identified by analysis of the the 2D-NOESY and HSQC spectra of di-
acetate derivative 27 (Scheme 7).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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Scheme 7. Transformation of 10 and 11 to polyhydroxylated aminocyclitols through
epoxidation and subsequent azide-induced epoxide ring-opening reactions
OH
OH
OH
OBn
1
OBn
NaN
Cl
3, NH4
MeOH, 80 oC
78%
m-CPBA, NaHCO3
2
3
OBn
1
1
2
3
2
3
CH2Cl2
0 oC to rt, 12h
84%
N3
NHBoc
NHBoc
18h,
NHBoc
OH
O
10
23
25
(1S,2R,3S)-
(1S,2R,3R,4R,5S)-
(1S,2R,3S,4R,5R)-
OH
OAc
OH
OH
OBn
OBn
OBn
OBn
1
2
3
1
2
3
1
m-CPBA, NaHCO3
Ac
N
2O, Et3
NaN
Cl
3, NH4
1
2
3
2
3
,
CH2Cl2
MeOH, 80 oC
N3
NHBoc
N3
NHBoc
NHBoc
24
0 oC to rt, 12h
18h,
NHBoc
75%
O
OH
(1R,2R,3S,4R,5R)-
OAc
86%
11
26
27
(1R,2R,3S)-
(1R,2R,3R,4R,5S)-
(1R,2R,3R,4R,5R)-
5-Membered Carbocycles and Aminocyclitols
The chemical transformations used for stereoselective transformations of the 6-membered
carbocycle 7 to the diverse 6-membered aminocyclitols 10-26 were applied to the 5-membered
analog 9. Firstly, stereoselective reduction of 9 under Luche conditions18 (NaBH4, CeCl3∙7H2O
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in MeOH) produces 1,2-trans diol 13 as the predominant product (96%) (Scheme 8). The
structure and stereochemistry of (1R,2R,3S)-13 were indirectly assigned by employing X-ray
crystallographic analysis of the ester-sulfonamide derivative 15 (CCDC 1867550), formed by
sequential acetylation, t-Boc-deprotection and sulfonylation of 13 (Scheme 9). Similar to
Luche reduction of 7, coordination of cerate ion to the C-1 carbonyl and neighbouring 2-
benzyloxy ether oxygens in 9 likely guides hydride delivery to the carbonyl face opposite side
trans to the 3-(N-t-Boc)-amine group.
10
11
12
13
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21
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40
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Scheme 8. Stereoselective carbonyl reduction of 9 to 13
O
OH
OH
1
1
.7H
1
OBn
OBn
OBn
NaBH4/CeCl3
-78 o
2O, MeOH
+
2
2
2
C, 45 min
96%
3
3
3
NHBoc
NHBoc
NHBoc
14
9
13
(1S,2R,3S)-
(2R,3S)-
(1R,2R,3S)-
predominant
Scheme 9. Conversion of 13 to 15 for X-ray crystallography analysis
OAc
OH
1
N
1
O, Et3
i) Ac2
OBn
O
OBn
2
2
ii) HCl/dioxane
iii) 4-NO2PhSO
3
3
2Cl
N
NO2
S
NHBoc
H
O
13
15
(1R,2R,3S)-
(1R,2R,3S)-
To demonstrate its use in routes for the production of more diversely functionalized 5-
membered aminocyclitols, (1R,2R,3S)-13 was subjected to dihydroxylation reaction under the
Upjohn conditions (Scheme 10). This process stereoselectively generated 28, whose structure
and stereochemistry were assigned by using COSY, HSQC and 2D-NOE spectroscopic
analysis of its tri-acetate derivative 29. Like in the 6-membered series, this dihydroxylation
reaction takes place on the alkene face that is anti to both of 3-(N-t-Boc)-amine and 1-hydroxyl
groups in 13.20 Next, reaction of 13 with m-CPBA was observed to form the corresponding
epoxide 30 (86%) in a manner that is syn to both of 1-hydroxyl and 3-(N-t-Boc)-amine
groups.20b,21
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Finally, to show that more highly functionalized 5-membered aminocyclitols can be accessed
using this protocol, epoxide 30 was subjected to reaction with NaN3 under acidic conditions
(NaN3, NH4Cl in MeOH). However, under these conditions a mixture of regioisomers 31 and
32 was generated. In contrast, treatment of acetylated epoxide 33 with NaN3 under neutral
conditions (NaN3, DMF-H2O, 100 oC) leads to production of the azide 31 as the predominant
product in 85% yield through a pathway involving regioselective epoxide ring-opening
promoted by azide addition to C4 (Scheme 10). The stereochemistry of 31 was assigned by
analysis of the COSY, HSQC and NOE spectra of the corresponding diacetate 34 (see SI).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
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Scheme 10. Transformation of 13 to polyhydroxylated aminocyclitols through
dihydroxylation, epoxidation and subsequent azide-induced epoxide ring-opening
reactions
OH
OH
OAc
1
1
1
OBn
HO
AcO
AcO
OBn
OBn
cat. OsO
4, NMO
Ac
N
2O, Et3
2
2
2
Acetone/H2O/t-BuOH
82%
3
3
3
rt, 5h
NHBoc
HO
NHBoc
NHBoc
13
28
29
(1R,2R,3S)-
(1R,2R,3S,4S,5S)-
(1S,2R,3R,4S,5S)-
OH
1
OH
1
OH
1
OH
1
N3
HO
m-CPBA, NaHCO3
OBn
NaN
MeOH, 80 oC
Cl
3, NH4
HO
OBn
OBn
OBn
2
2
2
+
2
CH2Cl2 0 oC to rt
,
O
3
3
3
3
86%
12h,
NHBoc
NHBoc
N3
NHBoc
31
NHBoc
32
30
13
(1R,2R,3S,4R,5S)-
(1S,2R,3R,4R,5S)-
(1R,2R,3S)-
(1R,2R,3S,4S,5R)-
mixture of regio-isomers
Ac
N
2O, Et3
OH
OAc
OAc
1
1
1
HO
AcO
OBn
OBn
OBn
Ac
2O
NaN
O-DMF
3, H2
2
2
2
30
O
85%
Et
from
3N
3
3
3
N3
NHBoc
N3
NHBoc
NHBoc
31
34
(1S,2R,3S,4S,5R)-
33
(1R,2R,3S,4S,5R)-
(1S,2R,3R,4R,5R)-
predominant
Conclusion
In summary, in the effort described above we developed efficient pathways for stereoselective
transformation of the readily available 4-vinyl-2-azetidinone 4 to highly functionalized 6- and
5-membered carbocycles 7 and 9, through allyl- or vinyl-Grignard addition followed by Ru-
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catalysed ring-closing metathesis of the resulting dienes 6 and 8. In addition, the results
demonstrate that 7 and 9 can be transformed to a variety of highly functionalized
aminocyclitols 10-34 through routes involving stereoselective carbonyl reductions,
dihydroxylation, epoxidation and azide promoted epoxide ring opening.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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29
30
31
32
33
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Experimental Section
General
All commercial reagents were used as obtained from commercial sources unless otherwise specified.
Reactions were performed with reagent grade solvents except dichloromethane (DCM), ether, THF
which were dried and purified using a solvent purification system. The progress of reactions was
monitored using thin layer chromatography (TLC) and visualized using UV light and by staining with
ethanolic phosphomolybdic acid (PMA) solution or KMnO4 solution followed by heating. Flash column
chromatography was carried out on silica gel (38-75 μm). Analytical thin layer chromatography (TLC)
was performed on Merck silica gel 60 F254 plates. Preparative thin layer chromatography (PLC) was
performed on Merck silica gel 60 F254 2mm plates. Nuclear magnetic resonance (NMR) spectra were
recorded using Bruker 500 MHz NMR instrument (1H NMR at 300, 500 MHz and 13C NMR at 75, 125
1
MHz). H NMR data are reported as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, br = broad), integration, coupling constants (Hz). Data
for 13C NMR are reported in terms of chemical shift (δ, ppm). Specific rotations were measured on a
Rudolph Autopol IV (Automatic polarimeter). High-resolution mass spectra and elemental analysis
were obtained from the Korea Research Institute of Chemical Technology. HR-MS were measured with
fast atom bombardment (FAB) ionization via double focusing mass analyzer (magnetic and electric
fields).
(3R,4S)-3-(benzyloxy)-1-(4-methoxyphenyl)-4-vinylazetidin-2-one (3)
A solution of iodine (2.2 g, 8.7 mmol) in toluene (15 mL) was added dropwise to
BnO
a solution of 2 (2.0 g, 5.8 mmol), imidazole (1.6 g, 23.3 mmol), and PPh3 (6.12
N
g, 23.8 mmol) in toluene (20 mL) at reflux temperature. Once the addition was
complete, the mixture was stirred under same temperature for 5 h, allowed to cool
to rt, and quenched with a solution of Na2S2O3 (aq). The mixture was extracted
O
O
with EtOAc (150 mL X 3) and washed with H2O followed by saturated NaCl (aq). The organic layer
was dried over MgSO4 and the solvent was evaporated under reduced pressure. The crude residue was
purified on silica gel column chromatography using EtOAc/hexanes (1:2) as an eluent to afford the title
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compound as a white solid.
Yield: 91% (1.6 g as a white solid); mp: 138.4-140.1 oC; [α]D 23 = +48.5 (c 0.7, CHCl3); 1H NMR (300
MHz, CDCl3) δ 7.42-7.33 (m, 7H), 6.87 (d, J = 9.1 Hz, 2H), 6.03 (ddd, J = 17.3, 10.2, 8.4 Hz, 1H),
5.60-5.49 (m, 2H), 4.88 (d, J = 4.9 Hz, 1H), 4.79-4.70 (m, 2H), 4.62 (dd, J = 8.4, 4.9 Hz, 1H), 3.80 (s,
3H).; 13C{1H} NMR (75 MHz, CDCl3) δ 163.6, 156.4, 136.7, 132.8, 131.1, 128.5, 128.1, 128.1, 121.9,
118.6, 114.3, 82.2, 72.8, 61.1, 55.5.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C19H20NO3
310.1443; Found 310.1449.
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
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(3R,4S)-3-(benzyloxy)-4-vinylazetidin-2-one
A solution of Ammonium cerium(IV) nitrate (5.66 g, 10.3 mmol) in H2O (30 mL) was
BnO
added dropwise to a solution of (3R,4S)-3-(benzyloxy)-1-(4-methoxyphenyl)-4-
NH
vinylazetidin-2-one (1.0 g mg, 3.23 mmol) in CH3CN (60 mL) at 0 oC for 40 min. The
O
reaction mixture was quenched with H2O (100 mL) and extracted with EtOAc (150
mL X 3). The combined organic layer was washed with NaHCO3 (aq) followed by 40% NaHSO3 (aq).
The organic layer was dried over MgSO4 and the solvent was evaporated under reduced pressure. The
crude residue was purified on silica gel column chromatography using EtOAc/hexanes (2:1) as an eluent
to afford the title compound as a white solid.
Yield: 71% (466 mg as a white solid); mp: 91.1-92.2 oC; [α]D 23 = +47.8 (c 0.75, CHCl3); 1H NMR (500
MHz, CDCl3) δ 7.37-7.31 (m, 5H), 6.07 (bs, 1H), 6.05-5.93 (m, 1H), 5.42-5.34 (m, 2H), 4.82-4.79 (m,
1H), 4.70 (dd, J = 19.5, 9.7 Hz, 2H), 4.26 (dd, J = 7.5, 4.8 Hz, 1H).; δ 7.37 – 7.31 (m, 5H), 6.26 (s, 1H),
6.02-5.95 (m, 1H), 5.41 – 5.35 (m, 2H), 4.81-4.79 (m, 1H), 4.70 (q, J = 11.7 Hz, 2H), 4.26 (dd, J = 7.5,
4.8 Hz, 1H).; 13C{1H} NMR (125 MHz, CDCl3) δ 167.8, 136.7, 133.9, 128.4, 128.1, 119.8, 83.9, 72.5,
57.2.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C12H14NO2 204.1025; Found 204.1048.
Tert-butyl (3R,4S)-3-(benzyloxy)-2-oxo-4-vinylazetidine-1-carboxylate (4)
A magnetically stirred mixture of (3R,4S)-3-(benzyloxy)-4-vinylazetidin-2-one (1.0
BnO
g, 4.92 mmol) in dry dichloromethane (10 mL) maintained at 0 oC was treated with
N
di-tert-butyl dicarbonate (1.29 g, 5.90 mmol), Et3N (0.89 mL, 6.39 mmol), and then
DMAP (cat.). The reaction mixture was stirred at rt for 12 h, quenched with H2O and
then extracted with dichloromethane (2 X 50 mL). The combined organic layer was
O
O
O
washed with 1 N HCl (aq) and sat’d NaHCO3 (aq). The organic layer was dried over MgSO4, filtered,
and evaporated under reduced pressure. The crude residue was purified on silica gel column
chromatography using EtOAc/hexanes (1:3) as an eluent to afford the title compound as a white solid.
Yield: 81% (1.21 g as a white solid); mp: 55.1-56.6 oC; [α]D 23 = +65.8 (c 2.1, CHCl3); 1H NMR (500
MHz, CDCl3) δ 7.39-7.33 (m, 5H), 5.98-5.91 (m, 1H), 5.49-5.45 (m, 2H), 4.77-4.67 (m, 3H), 4.52 (dd,
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J = 8.1, 5.8 Hz, 1H), 1.52 (s, 9H).; 13C{1H} NMR (125 MHz, CDCl3) δ 164.4, 147.8, 136.3, 131.1,
128.5, 128.2, 128.1, 121.6, 83.6, 81.6, 72.9, 60.2, 27.9.; HRMS (FAB, double focusing) m/z: [M+H]+
Calcd for C17H22NO4 304.1549; Found 304.1553.
8
9
Tert-butyl((3S,4R)-4-(benzyloxy)-5-(methoxy(methyl)amino)-5-oxopent-1-en-3-yl)carbamate (5)
A magnetically stirred mixture of 4 (1.1 g, 3.63 mmol) in dry 1,4-dioxane (15
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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28
29
30
31
32
33
34
35
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60
BnO
NHBoc
mL) was treated with CH3NH(OCH3).HCl (531 mg, 5.44 mmol) followed by
N
the addition of Ti(OPr-i)4 (5.5 mL). The reaction mixture was stirred at rt for
O
O
12 h, quenched with H2O, and treated with EtOAc (50 mL). The residue was filtered through celite pad
and washed thoroughly with excess of EtOAc. The resulting filtrate was washed with H2O and the
organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue
was purified on silica gel column chromatography using EtOAc/hexanes (2:1) as an eluent to afford the
title compound as colorless oil.
Yield: 90% (1.19 g as a colorless oil); [α]D 23 = +4.9 (c 1.9, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.38-
7.29 (m, 5H), 5.90-5.84 (m, 1H), 5.28-5.18 (m, 2H), 5.14 (d, J = 8.3 Hz, 1H), 4.80 (d, J = 12.1 Hz, 1H),
4.69 (s, 1H), 4.40 (d, J = 12.1 Hz, 1H), 4.31 (d, J = 2.4 Hz, 1H), 3.59 (s, 3H), 3.21 (s, 3H), 1.44 (s, 9H).;
13C{1H} NMR (125 MHz, CDCl3) δ 170.4, 155.5, 137.1, 136.1, 128.4, 128.2, 127.9, 79.4, 71.8, 53.6,
32.8, 28.3.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C19H29N2O5 365.2076; Found
365.2099.
Tert-butyl ((3S,4R)-4-(benzyloxy)-5-oxoocta-1,7-dien-3-yl)carbamate (6)
To a solution of 5 (540 mg, 1.48 mmol) in dry THF (10 mL) was added 1.0 N allyl
BnO
NHBoc
magnesium bromide (10.4 mL, 0.54 mmol) dropwise using syringe pump for 2
O
o
hours at -30 C. The reaction mixture was quenched with sat’d NH4Cl (aq) and
extracted with EtOAc (2 X 50 mL). The combined organic layer was washed with
H2O followed by saturated NaCl (aq). The organic layer was dried over MgSO4, filtered, and evaporated
under reduced pressure. The crude residue was purified on silica gel column chromatography using
EtOAc/hexanes (1:2) as an eluent to afford the title compound as colorless oil.
Yield: 95% (461 mg as a colorless oil); [α]D 23 = -24.8 (c 0.5, CHCl3); 1H NMR (500 MHz, CDCl3) δ
7.40-7.34 (m, 5H), 5.94-5.82 (m, 2H), 5.29-5.12 (m, 5H), 4.73-4.66 (m, 2H), 4.55 (d, J = 11.6 Hz, 1H),
4.01 (s, 1H), 3.41-3.29 (m, 2H), 1.44 (s, 9H).; 13C{1H} NMR (125 MHz, CDCl3) δ 208.2, 155.2, 136.9,
135.1, 129.8, 128.5, 128.2, 128.1, 119.2, 116.5, 84.7, 79.8, 73.0, 53.5, 44.3, 28.3.; HRMS (FAB, double
focusing) m/z: [M+H]+ Calcd for C20H28NO4 346.2018; Found 346.2012.
Tert-butyl ((1S,6R)-6-(benzyloxy)-5-oxocyclohex-2-en-1-yl)carbamate (7)
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To a degassed solution of 6 (210 mg, 0.61 mmol) in dry toluene (20 mL) was added
Grubb’s 2nd generation catalyst (26 mg, 5.0 mol %) and the reaction mixture was
heated to 50 oC for 30 min. The solvent was evaporated under reduced pressure and
the crude residue was purified on silica gel column chromatography using
O
OBn
NHBoc
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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59
60
EtOAc/hexanes (1:2) as an eluent to afford the title compound as a white solid.
o
23
1
Yield: 93% (179 mg as a white solid); mp: 118.3-119.8 C; [α]D = +80.6 (c 1.0, CHCl3); H NMR
(500 MHz, CDCl3) δ 7.37-7.28 (m, 5H), 5.79 (q, J = 10.6 Hz, 2H), 4.85 (d, J = 11.8 Hz, 1H), 4.71 (s,
1H), 4.53 (d, J = 11.8 Hz, 1H), 4.44 (t, J = 7.4 Hz, 1H), 4.21 (s, 1H), 3.05 (s, 2H), 1.47 (s, 9H).; 13C{1H}
NMR (125 MHz, CDCl3) δ 205.7, 155.0, 137.4, 128.5, 128.2, 128.0, 127.9, 124.3, 82.9, 80.0, 72.7, 54.8,
39.7, 28.4.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C18H24NO4 318.1705; Found
318.1698.
Tert-butyl ((3S,4R)-4-(benzyloxy)-5-oxohepta-1,6-dien-3-yl)carbamate (8)
To a solution of 5 (250 mg, 0.68 mmol) in dry diethyl ether (5.0 mL) was added 1.0
N vinyl magnesium bromide (6.9 mL, 6.86 mmol) dropwise at 0 oC. The reaction
mixture was stirred at same temperature for additional 40 min., quenched with
saturated NH4Cl (aq) and extracted with EtOAc (2 X 50 mL). The combined
BnO
NHBoc
O
organic layer was washed with H2O followed by saturated NaCl (aq). The organic layer was dried over
MgSO4, filtered, and evaporated under reduced pressure. The crude residue was purified on silica gel
column chromatography using EtOAc/hexanes (1:2) as an eluent to afford the title compound as
colorless oil.
Yield: 78% (177 mg as a colorless oil); [α]D 23 = -12.7 (c 0.7, CHCl3); 1H NMR (500 MHz, CDCl3) δ
7.40-7.28 (m, 5H), 6.80 (dd, J = 16.5, 10.8 Hz, 1H), 6.39 (d, J = 17.3 Hz, 1H), 5.89-5.82 (m, 1H), 5.79
(dd, J = 10.6, 1.5 Hz, 1H), 5.29-5.20 (m, 2H), 5.09 (s, 1H), 4.70 (d, J = 11.6 Hz, 1H), 4.65 (s, 1H), 4.49
(d, J = 11.6 Hz, 1H), 4.12 (s, 1H), 1.43 (s, 9H).; 13C{1H} NMR (125 MHz, CDCl3) δ 199.1, 155.1, 136.9,
135.2, 131.7, 129.6, 128.5, 128.2, 128.1, 116.4, 84.3, 79.7, 72.8, 54.0, 28.3.; HRMS (FAB, double
focusing) m/z: [M+H]+ Calcd for C19H26NO4 332.1862; Found 332.1883.
Tert-butyl ((1S,5R)-5-(benzyloxy)-4-oxocyclopent-2-en-1-yl)carbamate (9)
To a degassed solution of 8 (90 mg, 0.27 mmol) in dry toluene (12 mL) was added
Grubb’s 2nd generation catalyst (11.5 mg, 5.0 mol %) and the reaction mixture was
heated to 50 oC for 20 min. The solvent was evaporated under reduced pressure and the
crude residue was purified on silica gel column chromatography using EtOAc/hexanes
O
OBn
NHBoc
(1:2) as an eluent to afford the title compound as a white solid.
Yield: 92% (76 mg as a white solid); mp: 96.3-98.8 oC; [α]D 23 = +81.3 (c 0.5, CHCl3); 1H NMR (500
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MHz, CDCl3) δ 7.437.31 (m, 6H), 6.25 (d, J = 5.7 Hz, 1H), 4.97 (d, J = 12.1 Hz, 1H), 4.87 (d, J = 12.1
Hz, 1H), 4.78 (s, 1H), 4.70 (s, 1H), 3.98 (d, J = 3.0 Hz, 1H), 1.48 (s, 9H).; 13C{1H} NMR (125 MHz,
CDCl3) δ 203.0, 159.4, 154.8, 137.3, 132.8, 128.5, 128.1, 128.0, 82.9, 80.5, 72.5, 57.3, 28.3.; HRMS
(FAB, double focusing) m/z: [M+H]+ Calcd for C17H22NO4 304.1549; Found 304.1568.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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27
28
29
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31
32
33
34
35
36
37
38
39
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41
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Tert-butyl ((1S,5S,6R)-6-(benzyloxy)-5-hydroxycyclohex-2-en-1-yl)carbamate (10)
To a solution of 7 (100 mg, 0.32 mmol) in dry THF (5 mL) was added 1.0 M super-
OH
hydride solution in THF dropwise at -20 oC. The reaction mixture was stirred at same
OBn
temperature for additional 30 min and quenched with 20% NaHSO4 (aq). The mixture
NHBoc
was extracted with EtOAc (2 X 25 mL), washed with H2O, and saturated NaCl (aq).
The organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The crude
residue was purified on silica gel column chromatography using EtOAc/hexanes (1:1) as an eluent to
afford the title compound as a white solid.
Yield: 98% (99 mg as a white solid); mp: 166.9-168.7 oC; [α]D 23 = +45.1 (c 0.7, CHCl3); 1H NMR (500
MHz, CDCl3) δ 7.39-7.28 (m, 5H), 5.78-5.76 (m, 1H), 5.58-5.55 (m, 1H), 4.81 (d, J = 12.0 Hz, 1H),
4.69 (d, J = 12.0 Hz, 1H), 4.52 (d, J = 6.1 Hz, 1H), 4.43 (s, 1H), 3.96 (s, 1H), 3.66-3.65 (m, 1H), 2.37-
2.25 (m, 2H), 2.19 (d, J = 6.2 Hz, 1H), 1.50 (s, 9H).; 13C{1H} NMR (125 MHz, CDCl3) δ 155.3, 138.2,
128.5, 128.1, 127.9, 127.7, 125.4, 83.1, 79.6, 73.7, 69.0, 52.1, 31.8, 28.4.; HRMS (FAB, double
focusing) m/z: [M+H]+ Calcd for C18H26NO4 320.1862; Found 320.1854.
Tert-butyl ((1S,5R,6R)-6-(benzyloxy)-5-hydroxycyclohex-2-en-1-yl)carbamate (11)
.
To a solution of 7 (100 mg, 0.32 mmol) in MeOH (5 mL) was added CeCl3 7H2O (141
OH
OBn
mg, 0.38 mmol) followed by the dropwise addition of NaBH4 (18 mg, 0.47 mmol) in
o
MeOH at -78 C. The reaction mixture was stirred at same temperature for 30 min
NHBoc
and quenched with NaHCO3 (aq). The solvents were evaporated under reduced
pressure, treated with H2O and extracted with EtOAc (2 X 25 mL). The combined organic layer was
dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was purified on
silica gel column chromatography using EtOAc/hexanes (1:1) as an eluent to afford the title compound
as a white solid.
Yield: 81% (82 mg as a white solid); mp: 114.7-116.5 oC; [α]D 23 = +54.4 (c 1.0, CHCl3); 1H NMR (500
MHz, CDCl3) δ 7.40-7.28 (m, 5H), 5.69-5.66 (m, 1H), 5.50 (d, J = 9.7 Hz, 1H), 4.88 (d, J = 11.3 Hz,
1H), 4.72-4.68 (m, 2H), 4.38 (s, 1H), 3.94 (q, J = 7.3, 6.6 Hz, 1H), 3.45-3.42 (m, 1H), 2.56-2.51 (m,
1H), 2.48 (s, 1H), 2.16-2.09 (m, 1H), 1.49 (s, 9H).; 13C{1H} NMR (125 MHz, CDCl3) δ 155.1, 138.3,
128.4, 127.8, 127.7, 124.8, 79.7, 79.6, 71.4, 65.6, 48.9, 30.7, 28.4.; HRMS (FAB, double focusing) m/z:
[M+H]+ Calcd for C18H26NO4 320.1862; Found 320.1862.
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(1S,5S,6R)-5-amino-6-(benzyloxy)cyclohex-3-en-1-yl acetate hydrochloride (12)
To a solution of 20 (50 mg, 0.14 mmol) in DCM (5 mL) was added 4 N HCl in 1,4-
6
7
8
OAc
OBn
dioxane (1.0 mL) and the reaction mixture was stirred at rt for 4 h. The solvent was
9
evaporated under reduced pressure and the crude product was recrystallized using
NH
2HCl
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DCM and hexanes to get 12 as colorless crystals.
o
23
1
Yield: 63% (26 mg as a crystal); mp: 208.1-211.7 C; [α]D = +57.8 (c 0.5, CHCl3); H NMR (500
MHz, CD3OD) δ 7.42-7.31 (m, 5H), 5.94-5.90 (m, 1H), 5.69-5.67 (m, 2H), 4.80 (d, J = 11.2 Hz, 1H),
4.57 (d, J = 11.2 Hz, 1H), 3.99-3.96 (m, 1H), 3.78 (dd, J = 9.1, 2.2 Hz, 1H), 2.60-2.54 (m, 1H), 2.45-
13
2.39 (m, 1H), 2.08 (s, 3H).; C{1H} NMR (125 MHz, CD3OD) δ 170.5, 137.3, 128.7, 128.1, 128.0,
127.7, 121.4, 76.5, 70.5, 65.3, 49.9, 30.0, 19.5.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for
C15H20NO3 262.1443; Found 262.1425.
Tert-butyl ((1S,4R,5R)-5-(benzyloxy)-4-hydroxycyclopent-2-en-1-yl)carbamate (13)
.
To a solution of 9 (100 mg, 0.33 mmol) in MeOH (5 mL) was added CeCl3 7H2O (147
mg, 0.38 mmol) followed by the dropwise addition of NaBH4 (25 mg, 0.66 mmol) in
MeOH at -78 oC. The Reaction mixture was stirred at same temperature for 30 min and
quenched with NaHCO3 (aq). The solvents were evaporated under reduced pressure,
OH
OBn
NHBoc
treated with H2O and extracted with EtOAc (2 X 25 mL). The combined organic layer was dried over
MgSO4, filtered, and evaporated under reduced pressure. The crude residue was purified on silica gel
column chromatography using EtOAc/hexanes (1:2) as an eluent to afford the title compound as a white
solid.
Yield: 96% (97 mg as a white solid); mp: 115.7-116.6 oC; [α]D 23 = +42.7 (c 0.8, CHCl3); 1H NMR (500
MHz, CDCl3) δ 7.40-7.28 (m, 5H), 5.90 (s, br, 1H), 5.76 (d, J = 5.6 Hz, 1H), 4.86 (d, J = 7.3 Hz, 1H),
4.79 (d, J = 11.8 Hz, 1H), 4.71 (d, J = 11.8 Hz, 1H), 4.65 (d, J = 7.0 Hz, 1H), 4.43 (d, J = 7.1 Hz, 1H),
3.86 (s, 1H), 2.81 (d, J = 6.9 Hz, 1H), 1.48 (s, 9H).; 13C{1H} NMR (125 MHz, CDCl3) δ 155.1, 138.1,
134.2, 132.6, 128.4, 127.9, 127.7, 93.2, 80.2, 79.9, 71.9, 60.7, 28.4.; HRMS (FAB, double focusing)
m/z: [M+H]+ Calcd for C17H24NO4 306.1705; Found 306.1711.
Tert-butyl ((1S,5R)-5-(benzyloxy)-4-oxocyclopent-2-en-1-yl)carbamate (15)
To a solution of 13 (60 mg, 0.196 mmol) in dry DCM (6 mL) was added
OAc
OBn
O
Ac2O (24 mg, 0.236 mmol), Et3N (0.055 mL, 0.392 mmol), and DMAP
o
(cat.) at 0 C. The reaction mixture was stirred at rt for 2 h and after
HN S
NO2
completion of reaction, it was quenched with 1 N HCl (aq) followed by
saturated NaHCO3 (aq). The combined organic layer was dried over
O
MgSO4, filtered, and evaporated under reduced pressure. The crude residue was dissolved in DCM (5
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9
mL) was added 4 N HCl in 1,4-dioxane (1.5 mL) and the reaction was stirred at rt for 6 h. The reaction
mixture was quenched with saturated NaHCO3 (aq) and extracted with DCM (2 X 25 mL). The organic
layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue (30
mg, 0.121 mmol) was dissolved in dry DCM (3 mL) and 4-nitrobenzenesulfonyl chloride (32 mg, 0.145
mmol), Et3N (0.034 mL, 0.242 mmol), and DMAP (cat.) were added successively to the solution at 0
oC. The reaction mixture was stirred at rt for 8 h and after completion of reaction, it was quenched with
1 N HCl (aq) followed by saturated NaHCO3 (aq). The combined organic layer was dried over MgSO4,
filtered, and evaporated under reduced pressure. The crude residue was purified on silica gel column
chromatography using EtOAc/hexanes (1:1) as an eluent to afford the title compound as a white solid.
Yield: 60% (31 mg as a white solid); mp: 164.4-166.8 oC; [α]D 23 = -19.2 (c 0.5, CHCl3); 1H NMR (500
MHz, CDCl3) δ 8.24 (d, J = 8.9 Hz, 1H), 8.06 (d, J = 8.9 Hz, 1H), 7.37-7.33 (m, 3H), 7.22-7.20 (m,
2H), 5.90-5.88 (m, 1H), 5.77-5.75 (m, 1H), 5.49-5.48 (m, 1H), 4.95 (d, J = 9.6 Hz, 1H), 4.61 (d, J =
11.7 Hz, 1H), 4.45-4.42 (m, 1H), 4.39 (d, J = 11.7 Hz, 1H), 3.92 (t, J = 3.5 Hz, 1H), 2.07 (s, 3H).;
13C{1H} NMR (125 MHz, CDCl3) δ 170.1, 150.0, 146.5, 137.1, 133.4, 132.3, 128.5, 128.3, 128.1, 127.5,
124.3, 89.6, 81.1, 72.1, 63.2.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C20H21N2O7S
433.1069; Found 433.1061.
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60
(1S,2R,4R,5R,6R)-5-(benzyloxy)-6-((tert-butoxycarbonyl)amino)cyclohexane-1,2,4-triyl
triacetate (17)
To an ice cold solution of 11 (30 mg, 0.09 mmol) in acetone:water 9:1, NMO
OAc
OBn
(22 mg, 0.19 mmol) was added followed by an OsO4 (0.6 mg, 2.5 mol%)
t
solution in BuOH, and the reaction was stirred at room temperature for 8 h.
AcO
NHBoc
After completion of the reaction, it was quenched by addition of Na2S2O3 and
OAc
the acetone was evaporated under reduced pressure. The solution was extracted with DCM (2 X 25 mL).
The combined organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure.
The crude residue was dissolved in dry DCM (3.0 mL) and Ac2O (98 mg, 0.38 mmol), Et3N (0.03 mL,
0.24 mmol), and DMAP (cat.) were added successively to the solution. The reaction mixture was stirred
at rt for 2 h and after completion of reaction, it was quenched with 1 N HCl (aq) followed by saturated
NaHCO3 (aq). The combined organic layer was dried over MgSO4, filtered, and evaporated under
reduced pressure. The crude residue was purified on silica gel column chromatography using
EtOAc/hexanes (1:2) as an eluent to afford the title compound as a white solid.
Yield: 81% (36 mg as a white solid); mp: 157.2-159.1 oC; [α]D 23 = +5.7 (c 1.0, CHCl3); 1H NMR (500
MHz, CDCl3) δ 7.37-7.28 (m, 5H), 5.38 (s, 1H), 5.25-5.19 (m, 1H), 5.02 (d, J = 10.6 Hz, 1H), 4.71 (s,
2H), 4.50 (d, J = 8.2 Hz, 1H), 3.99 (q, J = 9.5 Hz, 1H), 3.69 (t, J = 8.9 Hz, 1H), 2.28 (dt, J = 14.1, 4.4
Hz, 1H), 2.14 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H), 1.67-1.58 (m, 1H), 1.46 (s, 9H).; 13C{1H} NMR (125
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MHz, CDCl3) δ 170.5, 170.0, 169.9, 155.3, 137.9, 128.4, 127.9, 127.8, 79.9, 79.8, 74.4, 71.2, 71.1, 67.4,
52.9, 30.8, 28.3, 21.1, 21.0, 20.7.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C18H28NO6
354.1917; Found 354.1929.
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9
(1S,5S,6R)-6-(benzyloxy)-5-((tert-butoxycarbonyl)amino)cyclohex-3-en-1-yl acetate (20)
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To a solution of 10 (150 mg, 0.47 mmol) in dry DCM (10 mL) was added Ac2O (0.09
mL, 0.94 mmol), Et3N (0.16 mL, 1.17 mmol), and DMAP (cat.) at 0 oC. The reaction
mixture was stirred at rt for 6 h and after completion of reaction, it was quenched with
1 N HCl (aq) followed by saturated NaHCO3 (aq). The combined organic layer was
OAc
OBn
NHBoc
dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was purified on
silica gel column chromatography using EtOAc/hexanes (1:2) as an eluent to afford the title compound
as a white solid.
Yield: 83% (141 mg as a white solid); mp: 87.8-89.2 oC; [α]D 23 = +87.5 (c 0.25, CHCl3); 1H NMR (500
MHz, CDCl3) δ 7.39 (d, J = 7.2 Hz, 2H), 7.36 (t, J = 7.4 Hz, 2H), 7.29 (d, J = 7.2 Hz, 1H), 5.78-5.75
(m, 2H), 5.62 (dd, J = 10.0, 3.4 Hz, 1H), 5.18 (t, J = 4.8 Hz, 1H), 4.73 (q, J = 12.2 Hz, 1H), 4.52-4.51
(m, 1H), 4.41 (s, 1H), 3.68 (dd, J = 4.8, 2.1 Hz, 1H), 2.49-2.33 (m, 2H), 2.06 (s, 3H), 1.49 (s, 9H).;
13C{1H} NMR (125 MHz, CDCl3) δ 170.8, 155.1, 138.4, 128.3, 127.8, 127.6, 127.1, 125.4, 79.7, 79.7,
71.4, 68.2, 49.7, 28.4, 27.9, 21.3.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C20H28NO5
362.1967; Found 362.1996.
(1S,2R,3S,4S,5R)-2-(benzyloxy)-3-((tert-butoxycarbonyl)amino)-4,5-dihydroxycyclohexyl acetate
(21)
To an ice cold solution of 20 (41 mg, 0.11 mmol) in CH3CN:H2O (3:1), NMO
(27 mg, 0.23 mmol), and 2,6-lutidine (cat.) were added followed by an OsO4
(1.5 mg, 5 mol%), and the reaction was stirred at water bath for 8 h. After
completion of the reaction, it was quenched by addition of Na2S2O3 and the
OAc
OBn
HO
NHBoc
OH
solvents were evaporated under reduced pressure. The solution was extracted with DCM (2 X 25 mL).
The combined organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure.
The crude residue was purified on silica gel column chromatography using EtOAc/hexanes (2:1) as an
eluent to afford the title compound as a white solid.
Yield: 70% (31 mg as a white solid); mp: 146.8-149.5 oC; [α]D 23 = +13.8 (c 0.5, CHCl3); 1H NMR (500
MHz, CDCl3) δ 7.39-7.28 (m, 5H), 5.44 (s, 1H), 4.74-4.70 (m, 2H), 4.47 (d, J = 11.4 Hz, 1H), 4.02-
4.96 (m, 2H), 3.59 (d, J = 6.3 Hz, 1H), 3.47 (s, 1H), 2.86 (s, 1H), 2.30 (d, J = 14.5 Hz, 1H), 2.11 (s,
3H), 1.72 (d, J = 14.5 Hz, 1H), 1.48 (s, 9H).; 13C{1H} NMR (125 MHz, CDCl3) δ 170.4, 157.5, 137.3,
128.6, 128.2, 128.1, 80.5, 73.9, 71.9, 68.0, 66.9, 52.1, 30.2, 29.7, 28.3, 21.3.; HRMS (FAB, double
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focusing) m/z: [M+H]+ Calcd for C20H30NO7 396.2022; Found 396.1995.
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7
(1S,2R,4S,5R,6R)-5-(benzyloxy)-6-((tert-butoxycarbonyl)amino)cyclohexane-1,2,4-triyl
8
9
triacetate (22)
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To a solution of 21 (30 mg, 0.076 mmol) in dry DCM (4 mL) was added Ac2O
OAc
(0.014 mL, 0.152 mmol), Et3N (0.026 mL, 0.190 mmol), and DMAP (cat.) at
OBn
o
0 C. The reaction mixture was stirred at rt for 4 h and after completion of
AcO
NHBoc
reaction, it was quenched with 1 N HCl (aq) followed by saturated NaHCO3
(aq). The combined organic layer was dried over MgSO4, filtered, and
OAc
evaporated under reduced pressure. The crude residue was purified on silica gel column
chromatography using EtOAc/hexanes (1:2) as an eluent to afford the title compound as a white solid.
Yield: 81% (29 mg as a white solid); mp: 169.3-171.4 oC; [α]D 23 = +9.8 (c 0.5, CHCl3); 1H NMR (500
MHz, CDCl3) δ 7.36-7.28 (m, 5H), 5.47-5.45 (m, 1H), 5.26-5.24 (m, 1H), 4.92-4.90 (m, 1H), 4.71 (d,
J = 12.0 Hz, 1H), 4.46 (d, J = 12.0 Hz, 1H), 4.34 (d, J = 8.7 Hz, 1H), 4.30-4.24 (m, 1H), 3.46 (d, J =
8.8 Hz, 1H), 2.36-2.32 (m, 1H), 2.12 (s, 3H), 2.11 (s, 3H), 2.04 (s, 3H), 1.73-1.68 (m, 1H), 1.47 (s, 9H).;
13C{1H} NMR (125 MHz, CDCl3) δ 170.5, 170.4, 170.2, 155.6, 137.5, 128.5, 128.1, 127.9, 79.7, 97.6,
71.6, 71.1, 67.9, 66.3, 50.1, 28.9, 28.4, 21.2, 21.1, 20.7.; HRMS (FAB, double focusing) m/z: [M+H]+
Calcd for C24H34NO9 480.2234; Found 480.2228.
Tert-butyl((1R,2R,3R,4S,6S)-3-(benzyloxy)-4-hydroxy-7-oxabicyclo[4.1.0]heptan-2-yl)carbamate
(23)
To a solution of 10 (60 mg, 0.19 mmol) in dry DCM (7 mL) was added m-CPBA (84
OH
mg, 0.38 mmol) followed by NaHCO3 (32 mg, 0.38 mmol) and the reaction mixture
was stirred at rt for 12 h. After completion of reaction, it was quenched with Na2SO3
and diluted with H2O. The mixture was extracted with DCM (2 X 25 mL), washed
OBn
NHBoc
O
with H2O, and saturated NaHCO3 (aq). The organic layer was dried over MgSO4, filtered, and
evaporated under reduced pressure. The crude residue was purified on silica gel column
chromatography using EtOAc/hexanes (1:1) as an eluent to afford the title compound as a white solid.
Yield: 84% (53 mg as a white solid); mp: 118.9-120.9 oC; [α]D 23 = +14.1 (c 0.7, CHCl3); 1H NMR (500
MHz, CDCl3) δ δ 7.38-7.28 (m, 5H), 4.88 (d, J = 8.6 Hz, 1H), 4.71 (d, J = 12.0 Hz, 1H), 4.65 (d, J =
12.0 Hz, 1H), 4.39 (dt, J = 7.8, 3.3 Hz, 1H), 3.89 (s, 1H), 3.36-3.32 (m, 3H), 2.22-2.09 (m, 3H), 1.51
(s, 9H).; 13C{1H} NMR (125 MHz, CDCl3) δ 155.4, 137.9, 128.5, 127.9, 127.8, 79.9, 78.5, 54.2, 53.8,
48.0, 29.1, 28.4.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C18H26NO5 336.1811; Found
336.1805.
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Tert-butyl((1R,2R,3R,4R,6S)-3-(benzyloxy)-4-hydroxy-7-oxabicyclo[4.1.0]heptan-2-yl)carbamate
(24)
6
7
8
To a solution of 11 (60 mg, 0.19 mmol) in dry DCM (7 mL) was added m-CPBA (84
OH
9
mg, 0.38 mmol) followed by NaHCO3 (32 mg, 0.38 mmol) and the reaction mixture
was stirred at rt for 12 h. After completion of reaction, it was quenched with Na2SO3
and diluted with H2O. The mixture was extracted with DCM (2 X 25 mL), washed
OBn
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58
59
60
NHBoc
O
with H2O, and saturated NaHCO3 (aq). The organic layer was dried over MgSO4, filtered, and
evaporated under reduced pressure. The crude residue was purified on silica gel column
chromatography using EtOAc/hexanes (1:1) as an eluent to afford the title compound as a white solid.
Yield: 86% (54 mg as a white solid); mp: 148.1-150.2 oC; [α]D 23 = +14.5 (c 0.4, CHCl3); 1H NMR (500
MHz, CDCl3) δ 7.40-7.28 (m, 5H), 4.97 (d, J = 9.4 Hz, 1H), 4.79 (d, J = 11.4 Hz, 1H), 4.61 (d, J = 11.4
Hz, 1H), 4.28 (s, 1H), 3.74 (q, J = 6.9 Hz, 1H), 3.40-3.33 (m, 3H), 2.78 (s, 1H), 2.39 (dt, J = 15.5, 4.7
Hz, 1H), 2.06 (dd, J = 15.5, 7.2 Hz, 1H), 1.50 (s, 9H).; 13C{1H} NMR (125 MHz, CDCl3) δ 155.2, 137.8,
128.5, 128.0, 127.9, 79.9, 79.7, 73.4, 68.6, 55.4, 53.1, 50.4, 31.4, 28.4.; HRMS (FAB, double focusing)
m/z: [M+H]+ Calcd for C18H26NO5 336.1811; Found 336.1831.
Tert-butyl ((1S,2R,3R,5S,6R)-3-azido-6-(benzyloxy)-2,5-dihydroxycyclohexyl)carbamate (25)
To a solution of 23 (30 mg, 0.089 mmol) in MeOH (4 mL) was added NaN3 (58
OH
mg, 0.89 mmol) followed by the addition of 1.2 M NH4Cl solution (1.0 mL). The
OBn
o
reaction mixture was heated to 80 C for 18 h, after completion of reaction, it
N3
NHBoc
was evaporated under vacuum and the residue was diluted with H2O. The
mixture was extracted with DCM (2 X 25 mL) and washed with saturated NaCl
OH
(aq). The combined organic layer was dried over MgSO4, filtered, and evaporated under reduced
pressure. The crude residue was purified on silica gel column chromatography using EtOAc/hexanes
(1:2) as an eluent to afford the title compound as a white solid.
Yield: 78% (26 mg as a white solid); mp: 136.8-138.5 oC; [α]D 23 = -20.8 (c 1.2, CHCl3); 1H NMR (500
MHz, CDCl3) δ 7.38-7.28 (m, 5H), 4.87 (s, 1H), 4.74 (d, J = 11.5 Hz, 1H), 4.64 (d, J = 11.5 Hz, 1H),
4.12 (s, 1H), 4.03-3.96 (m, 3H), 3.60 (s, 1H), 2.36 (s, 1H), 2.12-2.06 (m, 1H), 1.92-1.85 (m, 1H), 1.49
(s, 9H).; 13C{1H} NMR (125 MHz, CDCl3) δ 156.9, 137.7, 128.6, 128.1, 127.8, 80.6, 72.5, 70.9, 66.4,
65.9, 59.7, 51.3, 30.8, 28.3.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C18H27N4O5
379.1981; Found 379.1951.
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Tert-butyl ((1S,2R,3R,5R,6R)-3-azido-6-(benzyloxy)-2,5-dihydroxycyclohexyl)carbamate (26)
6
7
To a solution of 24 (30 mg, 0.089 mmol) in MeOH (4 mL) was added NaN3 (58
OH
OBn
8
9
mg, 0.89 mmol) followed by the addition of 1.2 M NH4Cl solution (1.0 mL). The
o
reaction mixture was heated to 80 C for 18 h, after completion of reaction, it
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N3
NHBoc
was evaporated under vacuum and the residue was diluted with H2O. The mixture
OH
was extracted with DCM (2 X 25 mL) and washed with saturated NaCl (aq). The combined organic
layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was
purified on silica gel column chromatography using EtOAc/hexanes (1:2) as an eluent to afford the title
compound as a white solid.
Yield: 75% (25 mg as a white solid); mp: 122.8-124.4 oC; [α]D 23 = +1.8 (c 1.3, CHCl3); 1H NMR (500
MHz, CDCl3) δ 7.39-7.28 (m, 5H), 5.56 (s, 1H), 4.74 (d, J = 11.5 Hz, 1H), 4.61 (d, J = 11.5 Hz, 1H),
4.06-4.01 (m, 3H), 3.82 (q, J = 7.2 Hz, 1H), 3.68 (s, 1H), 3.56 (s, 1H), 2.30 (s, 1H), 2.06-1.95 (m, 1H),
1.48 (s, 9H).; 13C{1H} NMR (125 MHz, CDCl3) δ 157.2, 137.8, 128.6, 128.0, 127.8, 80.5, 79.2, 73.2,
72.2, 69.3, 58.9, 53.1, 32.0, 28.4.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C18H27N4O5
379.1981; Found 379.2000.
(1R,2R,3S,4R,5R)-5-azido-2-(benzyloxy)-3-((tert-butoxycarbonyl)amino)cyclohexane-1,4-diyl
diacetate (27)
To a solution of 26 (20 mg, 0.05 mmol) in dry DCM (2 mL) was added Ac2O (14
OAc
o
mg, 0.13 mmol), Et3N (0.022 mL, 0.16 mmol), and DMAP (cat.) at 0 C. The
reaction mixture was stirred at rt for 4 h and after completion of reaction, it was
quenched with 1 N HCl (aq) followed by saturated NaHCO3 (aq). The combined
organic layer was dried over MgSO4, filtered, and evaporated under reduced
OBn
N3
NHBoc
OAc
pressure. The crude residue was purified on silica gel column chromatography using EtOAc/hexanes as
an eluent to afford the title compound as a white solid.
Yield: 78% (19 mg as a white solid); mp: 109.9-111.1 oC; [α]D 23 = -6.2 (c 0.34, CHCl3); 1H NMR (500
MHz, CDCl3) δ 7.39-7.31 (m, 5H), 5.19 (q, J = 4.0 Hz, 1H), 5.11 (dd, J = 9.0, 3.9 Hz, 1H), 5.01 (d, J =
8.1 Hz, 1H), 4.75 (d, J = 11.5 Hz, 1H), 4.61-4.57 (m, 2H), 3.92-3.87 (m, 1H), 3.65 (t, J = 4.5 Hz, 1H),
2.13 (s, 3H), 2.11 (s, 3H), 2.06-2.03 (m, 2H), 1.47 (s, 9H).; 13C{1H} NMR (75 MHz, CDCl3) δ 169.8,
168.9, 155.2, 137.2, 128.5, 127.9, 127.9, 79.9, 75.9, 72.8, 72.3, 70.4, 55.1, 49.3, 30.4, 28.3, 21.1, 20.9.;
HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C22H31N4O7 463.2193; Found 463.2171.
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(1S,2S,3S,4R,5R)-4-(benzyloxy)-5-((tert-butoxycarbonyl)amino)cyclopentane-1,2,3-triyl
triacetate (29)
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9
OAc
To an ice cold solution of 13 (40 mg, 0.131) in acetone:water 9:1, NMO (31 mg,
OBn 0.262) was added followed by an OsO4 solution (0.8 mg, 2.5 mol%) in tBuOH,
and the reaction was stirred at room temperature for 5 h. After completion of the
AcO
AcO
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NHBoc
reaction, it was quenched by addition of Na2S2O3 and the acetone was evaporated
under reduced pressure. The solution was extracted with DCM (2 X 25 mL). The combined organic
layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was
dissolved in dry DCM (5 mL) was added Ac2O (0.06 mL, 0.655 mmol), Et3N (0.09 mL, 0.655 mmol),
and DMAP (cat.) at 0 oC. The reaction mixture was stirred at rt for 2 h and after completion of reaction,
it was quenched with 1 N HCl (aq) followed by saturated NaHCO3 (aq). The combined organic layer
was dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue was purified
on silica gel column chromatography using EtOAc/hexanes (1:2) as an eluent to afford the title
compound as a white solid.
o
23
1
Yield: 82% (50 mg as a white solid); mp: 89.9-91.1 C; [α]D = -9.9 (c 0.9, CHCl3); H NMR (500
MHz, acetone-d6) δ 7.35-7.28 (m, 5H), 6.24 (d, J = 8.5 Hz, 1H), 5.49-5.46 (m, 1H), 5.42-5.41 (m, 1H),
5.23 (t, J = 5.7 Hz, 1H), 4.69 (s, 2H), 4.34-4.33 (m, 1H), 4.22-4.19 (m, 1H), 2.06 (s, 3H), 2.04 (s, 3H),
1.99 (s, 3H), 1.43 (s, 9H).; 13C{1H} NMR (125 MHz, CDCl3) δ169.5, 169.3, 169.0, 154.8, 137.5, 128.4,
127.8, 127.7, 86.6, 80.1, 74.7, 71.8, 70.8, 70.4, 54.5, 28.4, 20.6.; HRMS (FAB, double focusing) m/z:
[M+H]+ Calcd for C23H32NO9 466.2077; Found 466.2079.
Tert-butyl((1R,2R,3R,4S,5S)-3-(benzyloxy)-4-hydroxy-6-oxabicyclo[3.1.0]hexan-2-yl)carbamate
(30)
To a solution of 13 (48 mg, 0.157 mmol) in dry DCM (5 mL) was added m-CPBA
(71 mg, 0.314 mmol) followed by NaHCO3 (26 mg, 0.314 mmol) and the reaction
mixture was stirred at rt for 12 h. After completion of reaction, it was quenched with
Na2SO3 and diluted with H2O. The mixture was extracted with DCM (2 X 25 mL),
OH
OBn
O
NHBoc
washed with H2O, and saturated NaHCO3 (aq). The organic layer was dried over MgSO4, filtered, and
evaporated under reduced pressure. The crude residue was purified on silica gel column
chromatography using EtOAc/hexanes (1:1) as an eluent to afford the title compound as a white solid.
Yield: 86% (43.4 mg as a white solid); mp: 136.4-138.2 oC; [α]D 23 = +4.2 (c 0.5, CHCl3); 1H NMR (500
MHz, CDCl3) δ 7.37-7.30 (m, 5H), 4.99 (d, J = 8.3 Hz, 1H), 4.70 (d, J = 11.9 Hz, 1H), 4.64 (d, J = 11.9
Hz, 1H), 4.18 (s, 1H), 3.61 (s, br, 1H), 3.57 (s, br, 1H), 3.31 (t, J = 6.0 Hz, 1H), 2.38 (s, 1H), 1.51 (s,
9H).; 13C{1H} NMR (125 MHz, CDCl3) δ 155.3, 137.9, 128.5, 127.8, 127.8, 85.0, 84.9, 80.0, 72.1, 56.7,
56.3, 55.8, 28.4.; HRMS (FAB, double focusing) m/z: [M+H]+ Calcd for C17H24NO5 322.1654; Found
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322.1658.
Tert-butyl ((1S,2S,3R,4R,5R)-2-azido-5-(benzyloxy)-3,4-dihydroxycyclopentyl)carbamate (31)
8
9
To a solution of 30 (30 mg, 0.09 mmol) in dry DCM (4 mL) was added Ac2O (12
OH
o
HO
mg, 0.12 mmol), Et3N (0.025 mL, 0.19 mmol), and DMAP (cat.) at 0 C. The
OBn
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reaction mixture was stirred at rt for 2 h and after completion of reaction, it was
quenched with 1 N HCl (aq) followed by saturated NaHCO3 (aq). The combined
N3
NHBoc
organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The crude residue
was dissolved in DMF:H2O (5:1) was added NaN3 (60 mg, 0.93 mmol) and heated to 100 oC in sealed
tube for 12 h. The solvent was evaporated under reduced pressure and the crude residue was treated
with H2O. The mixture was extracted with DCM (2 X 25 mL), washed with H2O, and saturated NaHCO3
(aq). The organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The
crude residue was purified on silica gel column chromatography using EtOAc/hexanes (1:1) as an eluent
to afford the title compound as a white solid.
o
23
1
Yield: 85% (29 mg as a white solid); mp: 107.8-109.4 C; [α]D = +24.3 (c 0.85, CHCl3); H NMR
(500 MHz, CDCl3) δ 7.39-7.31 (m, 5H), 5.17 (d, J = 7.1 Hz, 1H), 4.65-4.60 (m, 2H), 4.02-4.95 (m, 3H),
3.87 (s, 1H), 3.72 (s, br, 1H), 3.48-3.42 (m, 1H), 3.03 (s, 1H), 1.48 (s, 9H).; 13C{1H} NMR (125 MHz,
CDCl3) δ 155.6, 137.4, 128.5, 127.9, 127.8, 85.8, 81.1, 75.5, 74.4, 71.9, 68.5, 60.2, 28.3.; HRMS (FAB,
double focusing) m/z: [M+H]+ Calcd for C17H25N4O5 365.1825; Found 365.1803.
(1S,2R,3S,4S,5R)-3-azido-5-(benzyloxy)-4-((tert-butoxycarbonyl)amino)cyclopentane-1,2-diyl
diacetate (34)
To a solution of 31 (15 mg, 0.04 mmol) in dry DCM (2 mL) was added Ac2O (11 mg, 0.10 mmol), Et3N
o
(0.017 mL, 0.12 mmol), and DMAP (cat.) at 0 C. The reaction mixture was
OAc
stirred at rt for 2 h and after completion of reaction, it was quenched with 1 N
AcO
OBn
HCl (aq) followed by saturated NaHCO3 (aq). The combined organic layer was
dried over MgSO4, filtered, and evaporated under reduced pressure. The crude
residue was purified on silica gel column chromatography using EtOAc/hexanes
N3
NHBoc
(1:2) as an eluent to afford the title compound as a white solid.
Yield: 81% (15 mg as a white solid); mp: 100.6-102.8 oC; [α]D 23 = +21.7 (c 0.4, CHCl3); 1H NMR (500
MHz, CDCl3) δ 7.38-7.30 (m, 5H), 5.26 (dd, J = 5.3, 2.2 Hz, 1H), 5.11 (dd, J = 8.7, 5.5 Hz, 1H), 4.80
(s, 1H), 4.70 (d, J = 12.2 Hz, 1H), 4.64 (d, J = 12.2 Hz, 1H), 4.12 (s, br, 1H), 3.86 (s, br, 10H), 3.74 (s,
br, 1H), 2.10 (s, 3H), 2.09 (s, 3H), 1.50 (s, 9H).; 13C{1H} NMR (75 MHz, CDCl3) δ 169.5, 169.4, 154.6,
137.3, 128.5, 127.9, 127.8, 73.4, 71.8, 60.4, 31.6, 28.3, 22.7, 21.1, 20.8, 20.6, 14.2, 14.1.; HRMS (FAB,
double focusing) m/z: [M+H]+ Calcd for C21H29N4O7 449.2036; Found 449.2047.
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Supporting Information. 1H- and 13C-NMR spectra for all new compounds, COSY, HSQC, and 2D-
NOESY spectra for 17, 22, 27, 29, and 34, X-ray crystallographic data in CIF for 12 (CCDC-1848803),
15 (CCDC-1867550), and 25 (CCDC-1877126).
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ACKNOWLEDGMENTS
This research was financially supported by grants from the National Research Foundation (NRF)
funded by the Korea government (MSIT) (2017M3A9A5051181) and Korea Research Institute
of Chemical Technology (SI1807 & SI1951-30).
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