Synthesis of Carba-Cyclophellitols: a New Class of Carbohydrate Mimetics

Article abstract of DOI:10.1002/ejoc.201701601

Cyclophellitol and cyclophellitol aziridine are potent and irreversible inhibitors of retaining β-glucosidases. They preferentially adopt a ⁴H₃ half-chair conformation, thereby mimicking the substrate-transition-state conformation characteristic of retaining β-glucosidases. As a consequence, both compounds bind tightly to the enzyme active site, and attack of the catalytic nucleophile onto the epoxide/aziridine results in enzyme deactivation. Replacement of the epoxide oxygen in cyclophellitol by a (substituted) carbon yielded carba-cyclophellitols, a conceptually new class of inhibitors of retaining β-glucosidases, as we demonstrated in a recent communication. In this paper, in-depth synthetic studies of this class of compounds are described, and the preparation of a comprehensive set of structurally and configurationally new carba-cyclophellitols is presented.

Full text of DOI:10.1002/ejoc.201701601

A Journal of
Accepted Article
Title: Synthesis of carba-cyclophellitols: a new class of carbohydrate
mimetics
Authors: Thomas J.M. Beenakker, Dennis P.A. Wander, Jeroen D.C.
Codee, Johannes M.F.G. Aerts, Gijsbert A. van der Marel,
and Hermen S. Overkleeft
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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to this Accepted Article as a result of editing. Readers should obtain
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to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701601
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701601
Supported by

10.1002/ejoc.201701601
European Journal of Organic Chemistry
FULL PAPER
Synthesis of carba-cyclophellitols: a new class of carbohydrate
mimetics
Thomas J. M. Beenakker,[a][‡] Dennis P. A. Wander,[a][‡] Jeroen D. C. Codée,[a] Johannes M. F. G.
Aerts,[b] Gijsbert A. van der Marel,[a] and Herman S. Overkleeft*[a]
Abstract: Cyclophellitol and cyclophellitol aziridine are potent and
irreversible retaining β-glucosidase inhibitors. They preferentially
A)
adopt a 4H3 half-chair conformation, thereby mimicking the transition
state conformation that characterizes retaining β-glucosidase-
mediated substrate processing. As a consequence, both compounds
bind tightly to the enzyme active site, after which attack of the
catalytic nucleophile onto the epoxide/aziridine results in enzyme
deactivation. Substitution of the epoxide oxygen in cyclophellitol for
(substituted) carbon yielded carba-cyclophellitols as a conceptually
new class of retaining β-glucosidase inhibitors, as we demonstrated
in a recent communication. Here, in-depth synthesis studies towards
this class of compounds are described, and the preparation of a
comprehensive set of structurally and configurationally new carba-
cyclophellitols is presented.
O
O
O
O
H
4H3
4C1
HO
HO
HO
H
RO
OH
OH
O
O
OR
HO
HO
δ+
HO
O
O
H
δ-
4C1
H
O
O
O
O
O
HO
HO
HO
O
HO
O
O
O
OH
OH
O
O
H
4C1
4H3
OH
HO
HO
HO
OH
O
O
HO
HO
OH
Introduction
δ+
HO
δ-
O
O
O
O
Cyclophellitol (1, Figure 1), isolated in 1990 from the mushroom
Phellinus sp., is a potent mechanism-based covalent retaining β-
glucosidase inhibitor.[1] Following protonation of the epoxide
oxygen by the acid-base catalyst residing within β-glucosidase
active sites and subsequent SN2 displacement by the active site
nucleophile, a covalent enzyme-inhibitor adduct is formed.[2,3]
This adduct is stable over time, leading to irreversible retaining
β-glucosidase inhibition. Cyclophellitol aziridine (2), the
cyclophellitol analogue in which the epoxide oxygen in
cyclophellitol (1) is substituted by nitrogen, proved to inhibit
retaining β-glucosidases covalently and irreversibly as well.[4]
Structural studies have revealed that cyclophellitol and
cyclophellitol aziridine employ a similar mode of action.
B)
O
4H3
O
H
O
O
HO
H
HO
HO
XH
X
HO
OH
X
OH
HO
HO
HO
HO
H
HO
OH
O
O
O
O
1, X = O
2, X = NH
C)
O
OH
4H3
HO
H
X
H
O
HO
HO
OH
N3
X
OH
HO
HO
N
H
H
OH
R1
O
O
3, X = H
4, X = R1
Figure 1. A) Proposed mechanism of retaining β-glucosidases.[5] B)
Cyclophellitol (1) and cyclophellitol aziridine (2) inhibit retaining β-glucosidases
covalently by initial binding in 4H3 conformation, followed by SN2 displacement
of the (protonated) epoxide-oxygen or aziridine-nitrogen. C) Structure of
carba-cyclophellitols 3 and 4. Carba-cyclophellitol 4 is a potent competitive
inhibitor of retaining β-glucosidases and binds to the active site in a 4H3
conformation.[6]
[a]
T. J. M. Beenakker, D. P. A. Wander, J. D. C. Codée, G. A. van der
Marel, H. S. Overkleeft
Department of Bio-Organic Synthesis
Leiden Institute of Chemistry, Leiden University
Einsteinweg 55, 2300 RA Leiden, The Netherlands
E-Mail: h.s.overkleeft@lic.leidenuniv.nl
J. M. F. G. Aerts
Department of Medical Biochemistry
Leiden Institute of Chemistry, Leiden University
Einsteinweg 55, 2300 RA Leiden, The Netherlands
T.J.M. Beenakker and D.P.A. Wander contributed equally to this work.
[b]
[‡]
Cyclophellitol and cyclophellitol aziridine are configurational
analogues of β-glucopyranosides, the substrates of retaining β-
glucosidases, but their conformational behavior is different.
Whereas β-glucopyranoses preferably adopt a 4C1 conformation,
Supporting information for this article is given via a link at the end of the
document.
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10.1002/ejoc.201701601
European Journal of Organic Chemistry
FULL PAPER
HO
BnO
BnO
HO
the epoxide annulation in 1 (and aziridine annulation in 2)
enforces a preferred 4H3 half-chair conformation onto the cyclitol
moiety. A similar half-chair conformation[5] is thought to occur
during hydrolysis of β-glucosidic linkages as effected by
retaining β-glucosidases (Figure 1A) and for this reason,
cyclophellitol and cyclophellitol aziridine are thought to bind well
within β-glucosidase active sites (Figure 1B). This mode of
action of cyclophellitol and cyclophellitol aziridine led us to
postulate that configurational isomeric compounds that would
HO
HO
BnO
H
BnO
BnO
b
a
H
OBn
OBn
OBn
7
5
6
BnO
RO
H
H
BnO
BnO
RO
RO
c
d
4
adopt the H3 half-chair conformation but would not present an
electrophile to the retaining β-glucosidase active site nucleophile,
would act as competitive inhibitors. Substitution of the
cyclophellitol epoxide-oxygen for carbon, as in carba-
cyclophellitol 3, and attachment of an azidoacyl chain (3 to 4)
indeed yielded a remarkably effective competitive retaining β-
glucosidase inhibitor (8.20 nM, Thermotoga maritima TmGH1[6])
(Figure 1C). Emboldened by these initial results, and realizing
that in fact carba-cyclophellitols represent a conceptually new
class of glycosidase inhibitors, and also carbohydrate mimetics,
we decided to investigate broadening the scope of these class of
compounds, starting with investigating their synthetic
accessibility. Here, we report on our in-depth synthesis and
structural analysis studies on carba-cyclophellitols. This work,
besides reporting details on the synthesis of carba-cyclophellitol
4 and some β-glucopyranose-configured isosters, also presents
the synthesis of their α-congeners as well as a set of α- and β-
galactopyranose-configured carba-cyclophellitols.
OBn
OR
9, R = Bn
10, R = H
8
e
Scheme 1. Reagents and conditions: a) (i) TBS-Cl, imidazole, DMF, rt, 1 h (ii)
BnBr, NaH, TBAI, DMF, 0 °C to rt, overnight, (iii) TBAF, THF, rt, 2 h, 83% over
3 steps; b) Et2Zn, CH2I2, 1,2-dimethoxyethane, MeOH, CH2Cl2, rt; c) BnBr,
NaH, TBAI, DMF,
0 °C to rt, overnight, 94%; d) Et2Zn, CH2I2, 1,2-
dimethoxyethane, boron trifluoride diethyl etherate, CH2Cl2, rt, 3 h, 46%; e) (i)
Pd/C, H2, MeOH, rt, overnight, (ii) Ac2O, pyridine, rt, 48 h; (iii) NaOMe, MeOH,
rt, 2 h, 66% over three steps.
We then turned our attention to ethyl diazoacetate (EDA)[10,11] as
the cyclopropanating agent for the synthesis of functionalized
carba-cyclophellitols, employing perbenzylated cyclohexene 8
as the substrate. When the conditions developed for
cyclopropanation of glucals with Rh2(OAc)4 as catalyst[12-14] were
applied to 8, only trace amounts of cyclopropanes 15 and 16
were formed, as detected by TLC-MS analysis of the reaction
mixture. Instead, several other products with higher molecular
masses were detected, corresponding to additional molecules of
EDA having reacted with cyclohexene 8, as compared to the
desired product. We concluded this to be the result of Büchner-
type ring expansion[15,16], in which the benzyl ethers in 8 have
reacted with EDA.[17]
Results and Discussion
In designing a library for this new class of compounds, we
envisioned to include a variety of substituents onto the carba-
cyclophellitol core, varying the electron density on the
cyclopropane ring, steric factors, as well as hydrogen-bonding
capability. For this reason, we selected the ketone,
hydroxymethyl, hydroxymethyl-ethyl ether and carboxamide
functional groups. The latter was appended with an azido-alkyl
tail to allow for further functionalization through click-chemistry.
Based on these initial discouraging results we conducted a
comparative study in which
a number of transition metal
cyclopropanation catalysts that employ EDA as the
cyclopropanylating agents were compared side-by-side
(Scheme 2). Rh2(OAc)4, Cu(acac)2 and Pd(OAc)2 are oft-used
Hashimoto and co-workers[7] were the first to report on the
[18]
synthesis
of
carba-cyclophellitols,
specifically
carba-
catalysts for EDA-mediated cyclopropanation of various
substrates[19-21], and were employed in this study. Bearing in
mind the electrophilic character of copper and rhodium
carbenes[22], the influence of the electron density of the alkene
was studied by comparing peracetyl-cyclohexene 13, per-tert-
butyldimethylsilyl-cyclohexene 14 (which were prepared by
means of standard protective group manipulations from 11 – see
Scheme 2) and perbenzyl-cyclohexene 8.
cyclophellitols 3 and 10. The key step in their synthesis
procedure entails a Simmons-Smith cyclopropanation (Et2Zn,
CH2I2 in DCM) on partially benzylated cyclohexene 6 (prepared
through standard protecting group manipulations from diol 5).
The β-product was reported to emerge as the predominant
isomer when adding DME and MeOH to the standard conditions.
In our hands, however, this did not lead to any conversion of the
cyclohexene. Application of the reported α-selective conditions
.
(DME and BF3 OEt2 as additives) on the fully benzylated
cyclohexene
8 did give us the fully benzylated α-carba-
cyclophellitol 9. This was then debenzylated under palladium-
catalyzed hydrogenolysis, followed by acetylation and de-
acetylation to finally give α-carba-cyclophellitol 10.
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10.1002/ejoc.201701601
European Journal of Organic Chemistry
FULL PAPER
O
O
O
O
a
b
BnO
BnO
BnO
BnO
AcO
AcO
AcO
TBSO
TBSO
TBSO
HO
HO
BnO
NH2 .TFA
NHBoc
5
a
b
OBn
OBn
20
19
OAc
OTBS
OBn
c
5
11
12
O
O
O
O
RO
RO
RO
RO
RO
RO
RO
RO
RO
H
BnO
BnO
BnO
BnO
d
N
N
H
H
H
H
O
O
c
H
OEt
OEt
OBn
OBn
OR
OR
OR
21
22
8, R = Bn
11, R = Ac
12, R = TBS
13, R = Bn
15, R = Ac
17, R = TBS
14, R = Bn
16, R = Ac
18, R = TBS
Scheme 3. Reagents and conditions: a) N-Boc-glycine, DIC, DMAP, rt,
overnight, quant.; b) TFA, CH2Cl2, rt, 45 min, quant.; c) NaNO2, monosodium
citrate, CH2Br2, H2O,
butylsalicylaldiminato)2, toluene, EtOAc or DCE, reflux.
0 °C, 1 h, 99%; d) Cu(acac)2 or Cu(N-tert-
Scheme 2. Reaction conditions: a) (i) Li (s), NH3 (l), THF, -60 °C, 35 min, (ii)
Ac2O, pyridine, rt, overnight, 79% over two steps; b) (i) NaOMe, MeOH, rt,
overnight, (ii) TBS-Cl, imidazole, DMF, rt to reflux temperature, 7 days, 35%
over 2 steps; c) to 0.1 mmol of substrate (8, 11 or 12) and 5 mol% of
(Rh(OAc)2, Cu(acac)2 or Pd(OAc)2) in DCE (200 μL) at reflux was added EDA
(0.3 mmol) in DCE (150 μL) over 6 h.
The combination of Cu(acac)2 as catalyst and tetra-O-benzyl-
cyclohexene 8 as substrate was optimal based on TLC-MS
analysis, even though, in contrast to compounds 11 and 12,
cyclohexene 8 can undergo the aforementioned Büchner-type
reactions. Minimizing such side reactions is best achieved when
EDA is added over time to a mixture of 8 and the copper(II)
catalyst in ethyl acetate. Upon TLC-MS detection of Büchner-
type adducts, the reaction mixture is then concentrated, the
desired product isolated, the side products removed and the
remainder of starting material reused. In this manner and over
two reaction cycles, compounds 13 and 14 were obtained as a
mixture (2:1 α:β, both exo only) in 35% yield. Formation of the
endo-cyclopropanes was not observed, as these place the
largest cyclopropane substituent over/under the carbacycle ring.
An alternative strategy towards bicyclic constructs we
investigated invokes an intra-molecular cyclopropanation
strategy (Scheme 3). This would entail an intramolecular tether
to deliver the carbene to the beta-face of the alkene, to yield a
lactone derivative of the carba-cyclophellitol.
For this purpose, alcohol 5 (derived from cyclohexene 7[8,9]
through standard protecting group manipulations) was
condensed with N-Boc-glycine to obtain 19. Treatment with TFA
gave amine 20, which was subsequently subjected to biphasic
diazotization to give diazoester 21. Following literature
precedents regarding similar intramolecular cyclopropanation by
Corey’s group[23,24], we attempted the cyclisation catalyzed by
their condition of Cu(II)(N-tert-butylsalicylaldiminato)2 in toluene
or our previously used condition of Cu(acac)2 in EtOAc. However,
the major identified product proved to be that of carbene
dimerization. The desired product 23 could not be detected (TLC,
LC/MS) in these experiments.
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10.1002/ejoc.201701601
European Journal of Organic Chemistry
FULL PAPER
RO
RO
RO
RO
H
H
H
H
d
OH
OEt
RO
b
RO
b
OR
OR
27, R = Bn
28, R = H
24, R = Bn
26, R = H
c
BnO
H
BnO
BnO
BnO
H
BnO
O
BnO
BnO
H
O
c
BnO
BnO
crystallisation
e, f
BnO
O
OEt
BnO
OEt
H
OBn
OH
OEt
BnO
H
OBn
H
OBn
OBn
13 + 14
13
25
14
g, h
a
a
RO
RO
RO
RO
RO
RO
H
H
H
H
H
RO
RO
RO
RO
RO
O
O
O
O
NH
NH
RO
H
H
H
OR
OR
OR
OR
22, R = Bn
23, R = H
N3
N3
b
29, R = Bn
30, R = H
b
32, R = Bn
34, R = H
31, R = Bn
33, R = H
h
h
Scheme 4. Reagents and conditions: a) N,O-dimethylhydroxylamine
hydrochloride, EtMgBr, THF, -5 °C, then EtMgBr, THF, rt, overnight, 56% for
15, 45% for 22; b) Pd(OH)2/C, H2, MeOH, rt, overnight, 23 (96%), 26 (90%), 28
(94%), 30 (58%); c) DIBAL, THF, 30 min at 0 °C and then 1 h at rt, (41%, 2:1
24 and 25); d) EtBr, NaH, TBAI, DMF, 0 °C to rt, 4 h, 59%; e) Jones reagent,
Upon diisobutylaluminum hydride (DIBAL-H)-mediated reduction
of the mixture of esters 13 and 14[25], alcohols 24 and 25 were
obtained and could be carefully separated by column
chromatography. Subjection of alcohol 24 to palladium-catalyzed
hydrogenolysis in MeOH gave compound 26. Ether 28 was
obtained by alkylation of alcohol 24 with ethyl bromide followed
by global debenzylation.
acetone,
0 °C, 3 h, 53%; f) EtOH, N,N’-diisopropylcarbodiimide, 4-
dimethylaminopyridine, toluene, rt, 4 h, 62%; g) (i) LiOH, THF, MeOH, H2O, rt,
overnight, 82%; (ii) 1-azido-4-aminobutane, HCTU, DIPEA, DCM, rt, overnight,
78%; h) BCl3, DCM, -78oC, 5h, 33 (88%), 34 (99%).
Pure β-exo alcohol 25 was then used to provide pure ester 14
for further transformations. To this end, 25 was oxidized using
aqueous sodium dichromate-sulfuric acid (Jones reagent) and
esterified to give enantiopure 14. Then, conversion into the
corresponding ketone, as described for its diastereomer,
followed by debenzylation gave 30.
We then explored the versatility of carba-cyclophellitol esters 13
and 14 (Scheme 2) as intermediates for further elaboration
(Scheme 4). Separation of the stereoisomers 13 and 14 by silica
gel column chromatography or HPLC was not successful.
Crystallization of the mixture of compounds from ethanol,
however, resulted in isolation of the pure α-endo ester 13.
Having this versatile functionalized carba-cyclophellitol construct
in hand, the ester was converted into ketone 22. This was
accomplished through direct Weinreb amide formation from the
ester, using ethylmagnesium bromide as the base at low
temperature, followed by Grignard addition at room temperature.
Subsequently, it was subjected to palladium-catalyzed
hydrogenolysis in MeOH to obtain compound 23.
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10.1002/ejoc.201701601
European Journal of Organic Chemistry
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RO
RO
RO
RO
Finally, we prepared the carba-cyclophellitol carboxamides.
Upon saponification of the mixture of 13 and 14 we obtained the
corresponding carboxylic acids, which were subsequently
condensed with 1-azido-4-aminobutane[26]. This resulted into a
mixture of 31 and 32, which were separated by means of HPLC.
The thus purified compounds were treated with BCl3 in
dichloromethane to afford 33 and 34, respectively.
H
H
H
OEt
OEt
RO
b
RO
b
H
OR
OR
44, R = Bn
46, R = H
45, R = Bn
47, R = H
As the next research objective, we set out to investigate whether
the synthesis strategies we identified for the construction of
glucopyranose-configured cyclophellitol cyclopropanes could
also be applied for the construction of some galactopyranose-
c
c
RO
RO
H
H
RO
RO
RO
RO
configured isosters, as potential inhibitors for α- and
β
galactosidases. For this purpose, galacto-configured
OH
OH
H
H
cyclohexene 35 was synthesized in large quantities following our
previously reported strategy[27], which was based on chemistry
developed by Llebaria and co-workers.[28] Simmons-Smith
cyclopropanation of this cyclohexene as described for its
diastereomer afforded α-cyclopropane 37 after global
debenzylation (Scheme 5).
OR
OR
40, R = Bn
42, R = H
41, R = Bn
43, R = H
b
b
a
BnO
RO
RO
RO
BnO
BnO
BnO
BnO
BnO
O
H
H
a
OEt
OBn
38 + 39
e
d
OR
OBn
35
36, R = Bn
37, R = H
b
c
BnO
BnO
BnO
BnO
H
H
H
BnO
BnO
O
O
BnO
BnO
BnO
BnO
BnO
BnO
NH
H
H
H
H
H
OBn
O
OEt
O
OBn
OEt
N3
OBn
OBn
48, R = Bn
50, R = H
52, R = Bn
54, R = H
b
f
38
39
Scheme 5. Reagents and conditions: a) 1,2-dimethoxyethane, boron trifluoride
diethyl etherate, Et2Zn, CH2I2, CH2Cl2, 84%; b) Pd(OH)2/C, H2, MeOH, (99%);
c) EDA, Cu(acac)2, EtOAc, 38 and 39 (2:1, 29%).
BnO
BnO
H
H
BnO
BnO
BnO
BnO
O
O
NH
H
OBn
H
OBn
The optimized conditions for EDA-mediated cyclopropanation of
8 as described before were applied to cyclohexene 35, yielding
N3
38 and 39 after
a single cyclopropanation cycle as an
inseparable mixture (29%, 2:1 α:β, both exo only).
49, R = Bn
51, R = H
53, R = Bn
55, R = H
b
f
DIBAL-mediated reduction of a mixture of esters 38 and 39
provided alcohols 40 and 41 (Scheme 6), which could now be
separated by silica gel column chromatography. Palladium-
catalyzed hydrogenolysis of these alcohols resulted in
compound 42 and 43, respectively. The free alcohols in 40 and
41 were alkylated with ethyl bromide to afford ethers 44 and 45
after debenzylation.
Scheme 6. Reagents and conditions: a) DIBAL, CH2Cl2, 40 (40%) and 41
(36%); b) Pd/C, H2, MeOH, rt, overnight, 42 (quant.), 43 (quant.), 46 (87%), 47
(quant.), 50 (80%), 51 (88%); c) EtBr, NaH, TBAI, DMF, 0 °C to rt, 44 (80%)
45 (74%); d) N,O-dimethylhydroxylamine hydrochloride, EtMgBr, THF, -8 °C to
rt, overnight, 48 (16%) and 49 (21%); e) (i) LiOH, THF, EtOH, H2O, rt,
overnight; (ii) 1-azido-4-aminobutane, HCTU, DIPEA, DCM, rt, overnight, 52
(24%) and 53 (18%); f) BCl3, DCM, 54 (quant.), 55 (70%).
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10.1002/ejoc.201701601
European Journal of Organic Chemistry
FULL PAPER
A mixture of esters 38 and 39 was converted into their
corresponding ketones 48 and 49 according to the previously
described Weinreb conditions and subsequently separated by
HPLC. Deprotection by palladium-catalyzed hydrogenation then
gave compounds 50 and 51. Finally, a mixture of 38 and 39 was
saponified and condensed with 1-azido-4-aminobutane. The
obtained mixture of amides was separated by HPLC to afford 54
and 55 after BCl3 treatment.
D-glucopyranose-configured carba-cyclophellitols
HO
HO
8
H
H
HO
HO
O
R
5
2
7
4
6
1
R
3
HO
HO
H
H
OH
23, R = CH2CH3
33, R = NH(CH2)4N3
OH
10, R = H
26, R = CH2OH
28, R = CH2OCH2CH3
The configuration of the obtained carba-cyclophellitol products
was determined by Nuclear Overhauser Effect SpectroscopY
(NOESY), as exemplified for compounds 13 and 14 (Figure 2).
Spatial couplings between H-1 and H-3, and between H-4 and
H-8 were observed in compound 13. The observed couplings
through space in compound 14, the β-isomer of 13, are between
H-1 and H-6, and between H-3 and H-8. These observations
were consistent throughout the series of compounds reported
herein, and further NOESY data for the final compounds can be
found in the Supporting Information.
HO
H
HO
O
R
HO
H
OH
30, R = CH2CH3
34, R = NH(CH2)4N3
D-galactopyranose-configured carba-cyclophellitols
HO
HO
HO
HO
H-8endo
H-3
H-2
H-1
COOEt
OBn
H
H
H-3
HO
O
R
OBn
H-6
R
OBn
OBn
BnO
BnO
HO
BnO
BnO
H
H
H-6
H-2
H-4
H-1
COOEt
H-8endo
OH
OH
37, R = H
42, R = CH2OH
H-4
50, R = CH2CH3
54, R = NH(CH2)4N3
13
14
46, R = CH2OCH2CH3
Figure 2. Configuration determination by spatial couplings of Nuclear
Overhauser Effect spectroscopY (NOESY) experiments allowed the
assignment of the absolute configuration of compounds 13 and 14.
HO
HO
H
H
HO
HO
O
R
R
HO
HO
H
H
OH
51, R = CH2CH3
55, R = NH(CH2)4N3
OH
Conclusion
43, R = CH2OH
47, R = CH2OCH2CH3
In this work, we reveal in full detail the synthesis of a new class
of carbohydrate mimetics: cyclophellitol cyclopropanes (see
Figure 3 for a full list of the structures prepared here). We
believe such compounds to be of interest as potential inhibitors
of glycoprocessing enzymes, but also as glycomimetics in
general, and we observe that those carboxylate-containing
analogues allow for oligomerization as we and others have
shown in the past for another class of glycomimetics: sugar
amino acids.[29] Thus, our cyclophellitol cyclopropanes represent
yet another addition to the rich and ever-growing, densely
functionalized molecules one can derive from nature’s most
diverse class of compounds: carbohydrates.
Figure 3. Structures of the carba-cyclophellitols that are described in the here
presented synthetic studies.
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10.1002/ejoc.201701601
European Journal of Organic Chemistry
FULL PAPER
crude fully protected cyclohexene, which was continued without further
purification. HRMS: calculated for [C34H44O4SiNa]+ 567.29011, found
567.28989.
Experimental Section
General: All chemicals were purchased from Acros, Sigma Aldrich,
Biosolve, VWR, Fluka, Merck and Fisher Scientific and used as received
unless stated otherwise. N,N-Dimethylformamide (DMF) and toluene
were stored over flame-dried 4 Å molecular sieves before use. Traces of
water from reagents were removed by co-evaporation with toluene in
reactions that require anhydrous conditions. All moisture and/or oxygen
sensitive reactions were performed under inert atmosphere. TLC analysis
was conducted using Merck aluminium sheets (Silica gel 60 F254) with
detection by UV absorption (254 nm), by spraying with a solution of
(NH4)6Mo7O24·4H2O (25 g/L) and (NH4)4Ce(SO4)4·2H2O (10 g/L) in 10%
sulfuric acid or a solution of KMnO4 (20 g/L) and K2CO3 (10 g/L) in water,
followed by charring at ~150 ˚C. Column chromatography was performed
using Screening Device BV Silica Gel (particle size of 40 – 63 µm, pore
diameter of 60 Å) in the indicated solvent systems. For reversed-phase
HPLC purifications, an Agilent Technologies 1200 series instrument
equipped with a semi-prep column (Gemini C18, 250 x 10 mm, 5 µm
particle size, Phenomenex) was used. LC/MS analysis was performed on
a Surveyor HPLC system (Thermo Finnigan) equipped with a C18 column
(Gemini, 4.6 mm x 50 mm, 5 μm particle size, Phenomenex), coupled to
a LCQ Advantage Max (Thermo Finnigan) ion-trap spectrometer (ESI+).
The applied buffers were H2O, MeCN and 1% aqueous TFA. 1H NMR
and 13C NMR spectra were recorded on a Brüker AV-400 (400 and 101
MHz respectively), a Brüker DMX-600 (600 and 151 MHz respectively) or
a Bruker AV-850 (850 and 214 MHz respectively) spectrometer in the
given solvent. Chemical shifts are given in ppm (δ) relative to the residual
solvent peak or to tetramethylsilane (0 ppm) as internal standard.
Coupling constants are given in Hz. High-resolution mass spectrometry
(HRMS) analysis was performed with a LTQ Orbitrap mass spectrometer
(Thermo Finnigan), equipped with an electronspray ion source in positive
mode (source voltage 3.5 kV, sheath gas flow 10 mL/min, capillary
temperature 250 °C) with resolution R = 60000 at m/z 400 (mass range
m/z = 150 – 2000) and dioctyl phthalate (m/z = 391.28428) as a “lock
mass”. The high-resolution mass spectrometer was calibrated prior to
measurements with a calibration mixture (Thermo Finnigan).
This was was then dissolved in THF (8.2 mL), after which TBAF (1 M in
THF, 9.8 mL, 9.8 mmol, 6.0 eq.) was added. After the mixture was stirred
at room temperature for 2 h, it was quenched with 4 drops of H2O and
concentrated in vacuo. Purification by column chromatography (30%
EtOAc in pentane → 50% EtOAc in pentane) gave title compound 6 as a
yellow oil (0.585 g, 1.36 mmol, 83% over 3 steps). 1H NMR (400 MHz,
CDCl3): d (ppm) 7.45 – 7.07 (m, 15H, HaromBn), 5.72 (dt, J = 10.0, 3.0 Hz,
1H, H1/6), 5.53 (dt, J = 10.2, 2.6 Hz, 1H, H1/6), 5.03 – 4.84 (m, 3H,
CH2Bn), 4.74 – 4.57 (m, 3H, CH2Bn), 4.28 – 4.17 (m, 1H, H-3), 3.83 (dd,
J = 10.6, 7.4 Hz, 1H, H-2), 3.68 – 3.50 (m, 3H, H-4 and H-7), 2.46 (ddd, J
= 14.3, 7.4, 3.7 Hz, 1H, H-5). 13C NMR (100 MHz, CDCl3: d (ppm) 138.8,
138.5, 138.4 (4 x Cq Bn), 128.6, 128.5, 128.5, 128.4, 128.3, 128.0, 128.0,
127.9, 127.7, 127.7 (CHarom, C-1 and C-6), 85.2 (C-3), 80.8 (C-2), 78.7
(C-4), 75.3, 75.2, 72.1 (3 x CH2 Bn), 63.1 (H-7), 45.8 (H-5). HRMS:
calculated for [C28H31O4]+ 431.22169, found 431.22174.
((((1R,2R,3S,6R)-6-((benzyloxy)methyl)cyclohex-4-ene-1,2,3-triyl)tris
(oxy))tris(methylene)) tribenzene (8)
Diol 7 (2.21 g, 6.50 mmol) was dissolved in DMF (33 mL) at 0 °C. TBAI
(22.0 mg, 60 µmol, 0.01 eq.), BnBr (1.86 mL, 15.6 mmol, 2.4 eq.) and
NaH (60% dispersion in mineral oil, 0.629 g, 15.7 mmol, 2.4 eq.) were
added. After stirring overnight, additional BnBr (0.93 mL, 7.80 mmol, 1.2
eq.) and NaH (60% dispersion in mineral oil, 0.315 g, 7.68 mmol, 1.0 eq.)
were added at 0 °C. After the mixture was stirred for 4 h, it was quenched
with MeOH (2 mL) and concentrated in vacuo. The crude residue was
redissolved in Et2O (100 mL) and washed with H2O (1 x 100 mL, 3 x 50
mL). The aqueous layers were extracted with Et2O (50 mL) and the
combined organic layers were dried over MgSO4, filtered and
concentrated in vacuo. Purification by column chromatography (3%
EtOAc in pentane → 6% EtOAc in pentane) gave fully benzylated 8 as a
yellow oil (3.17 g, 6.08 mmol, 94%). 1H NMR (400 MHz, CDCl3): δ (ppm)
7.56 – 7.00 (m, 20H, HaromBn), 5.83 – 5.56 (m, 2H, H-1, H-6), 4.98 – 4.86
(m, 3H, CH2Bn), 4.70 (s, 2H, CH2Bn), 4.53 – 4.36 (m, 3H, CH2Bn), 4.31 –
4.22 (m, 1H, H-3), 3.81 (dd, J = 10.1, 7.8 Hz, 1H, H-4), 3.67 (t, J = 9.8
General procedure for global debenzylation
Hz, 1H, H-2), 3.52 (d, J = 4.4 Hz, 2H, H-8), 2.64 – 2.42 (m, 1H, H-5). 13
C
To a solution of the benzyl ether in MeOH was added a catalytic amount
of 10% Pd on carbon or Pd(OH)2 on carbon. The reaction vessel was
purged with hydrogen gas and the mixture was vigorously stirred
overnight. After TLC analysis showed full conversion to a lower running
spot, the palladium catalyst was filtered off over a pad of Celite, followed
by concentration in vacuo, which gave the corresponding product.
NMR (100 MHz, CDCl3): δ (ppm) 129.3, 128.5, 128.2, 128.1, 128.0,
127.9, 127.8, 127.7, 127.0 (CHarom, C-1 and C-6), 85.5 (C-3), 81.0 (C-2),
78.5 (C-4), 75.5, 75.5, 73.2 72.2 (CH2 Bn), 69.3 (C-8), 44.5 (C-5). HRMS:
calculated for [C35H37O4]+ 520.14791, found 521.26883.
(1S,2S,3R,4R,5R,6R)-2,3,4-tris(benzyloxy)-5-((benzyloxy)methyl)
bicyclo[4.1.0]heptane (9)
(1R,2R,5S,6S)-5,6-bis(benzyloxy)-2-(((tert-butyldimethylsilyl)oxy)
methyl)cyclohex-3-en-1-ol (6)
To a solution of 1,2-dimethoxyethane (72 μL) in DCM (0.35 mL) was
added boron trifluoride ethyl etherate (43 μL) and diethyl zinc (1 M in
hexane, 0.7 mL, 0.7 mmol) at room temperature. After stirring for 5 min,
diiodomethane (112 μL, 1.4 mmol) was added and the reaction mixture
was stirred an additional 5 min. Compound 8 (36.3 mg, 70 μmol) was
dissolved in DCM (0.85 mL) and added dropwise to the reaction mixture.
After stirring for 3 h, the reaction mixture was quenched with a saturated
aqueous NH4Cl solution and diluted with EtOAc. The aqueous layer was
extracted with EtOAc (3x) and the combined organic layers were dried
over MgSO4, filtered and concentrated in vacuo. Purification by column
chromatography (pentane → 8% EtOAc in pentane) gave cyclopropane
26 (17.3 mg, 32 μmol, 46%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ
(ppm) 7.40 (d, J = 7.0 Hz, 2H, HaromBn), 7.37 – 7.27 (m, 16H, HaromBn),
7.18 – 7.12 (m, 2H, HaromBn), 4.89 – 4.75 (m, 4H, CH2Bn), 4.69 (d, J = 12
Hz, 1H, CH2Bn), 4.55 – 4.36 (m, 3H, CH2Bn), 4.14 – 4.04 (m, 1H, H-2),
3.59 (d, J = 4.2 Hz, 2H, H-8), 3.46 – 3.24 (m, 2H, H-3 and H-4), 1.93 –
1.85 (m, 1H, H-5), 1.44 – 1.34 (m, 1H, H-1), 1.17 – 1.07 (m, 1H, H-6).
0.82 – 0.74 (m, 1H, H-7), 0.40 – 0.35 (m, 1H, H-7) 13C NMR (101 MHz,
Diol 5 (0.558 g, 1.64 mmol) was dissolved in DMF (8.2 mL), after which
TBS-Cl (0.271 g, 1.80 mmol, 1.1 eq.) and imidazole (0.279 g, 4.10 mmol,
2.5 eq.) were added. The reaction mixture was stirred at room
temperature for 1 h and was then partitioned between Et2O (40 mL) and
H2O (40 mL). The organic layer was separated, washed with H2O (2x),
dried over MgSO4, filtered and concentrated in vacuo to give the crude
silyl ether, which was continued without further purification. HRMS:
calculated for [C27H39O4Si]+ 455.26121, found 455.26129.
This was then dissolved in DMF (8.0 mL) at 0 °C, after which TBAI
(catalytic amount), BnBr (0.23 mL, 1.97 mmol, 1.2 eq.) and NaH (60%
dispersion in mineral oil, 79.2 mg, 1.98 mmol, 1.21 eq.) were added.
After stirring at room temperature overnight, the reaction mixture was
concentrated in vacuo and partitioned between Et2O (25 mL) and H2O
(25 mL). The organic layer was washed with H2O (3x) and the resulting
aqueous layers were extracted with Et2O. The combined organic layers
were dried over MgSO4, filtered and concentrated in vacuo to give the
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10.1002/ejoc.201701601
European Journal of Organic Chemistry
FULL PAPER
CDCl3): δ (ppm) 128.5, 128.5, 128.2, 128.1, 128.0, 127.8, 127.7, 127.6
(CHarom), 84.4 (C-3), 80.5 (C-2), 79.5 (C-4), 75.6, 75.3, 73.3, 71.4 (4 x
CH2 Bn), 71.0 (C-8), 44.1 (C-5), 16.2, 14.2 (C-1 and C-6), 10.4 (C-7).
4), 4.15 (dd, J = 11.3, 4.1 Hz, 1H, H-7), 4.02 (dd, J = 11.3, 5.1 Hz, 1H, H-
7), 2.83 – 2.76 (m, 1H, H-5), 2.03 (s, 12H, 4 x CH3). 13C NMR (100 MHz,
CDCl3): δ (ppm) 170.9, 170.5, 170.3, 170.1 (4 x Cq acetyl), 128.5, 126.5
(C-1 and C-6), 72.8 (C-4), 72.2 (C-3), 69.2 (C-5), 63.1 (C-7), 41.4 (C-5),
21.0, 20.8, 20.8, 20.8 (4 x CH3). HRMS: calculated for [C15H21O8]+
329.12309, found 329.12336.
(1S,2S,3R,4R,5R,6R)-5-(hydroxymethyl)bicyclo[4.1.0]heptane-2,3,4-
triol (10)
Compound 9 (760 mg, 1.4 mmol) was dissolved in MeOH (20 mL). The
reaction mixture was purged with argon gas and 10% palladium on
carbon (373 mg) was added. After the reaction vessel was purged with
hydrogen gas and vigorously stirring overnight, the palladium catalyst
was filtered off over a pad of Celite followed by concentration in vacuo.
Purification by column chromatography (EtOAc → 30% MeOH in EtOAc)
gave a crude product which was dissolved in pyridine (4.2 mL) and acetic
anhydride (0.67 mL, 7.1 mmol) was added. After stirring for 2 days at
room temperature, the reaction mixture was diluted with EtOAc (30 mL)
and washed with H2O (3x). The combined water layers were extracted
with EtOAc (2x) and the combined organic layers were dried over MgSO4,
filtered, concentrated in vacuo. Purification by column chromatography
(pentane → 20% EtOAc in pentane) gave the corresponding acetylated
product 10 (0.36 g, 1.0 mmol, 71%) as a clear oil. 1H NMR (400 MHz,
CDCl3): δ (ppm) 5.39 (dd, J = 8.7, 6.2 Hz, 1H, H-2), 5.00 – 4.84 (m, 2H,
H-3 and H-4), 4.18 – 4.05 (m, 2H, H-8), 2.19 – 2.13 (m, 1H, H-5), 2.09 (s,
3H, Ac), 2.06 (s, 3H, Ac) 2.00 (s, 6H, 2 x Ac), 1.68 – 1.56 (m, 1H, H-6),
1.10 – 1.02 (m, 1H, H-1), 0.93 – 0.85 (m, 1H, H-7), 0.57 – 0.47 (m, 1H,
H-7) 13C NMR (101 MHz, CDCl3): δ (ppm) 171.2, 170.8, 170.2, 169.9 (4 x
Cq Ac), 72.9 (C-3), 71.6 (C-4), 70.2 (C-2), 64.6 C-8), 41.0 (C-5), 21.2,
21.0, 20.8, 20.8 (4 x CH3 Ac), 15.9 (C-6), 13.6 (C-1), 10.7 (C-7). HRMS:
calculated for [C16H22O8Na]+ 365.12069, found 365.12048. The
acetylated product (25 mg, 73 μmol) was dissolved in MeOH (10 mL) and
a catalytic amount of NaOMe was added. After TLC analysis showed full
conversion to a lower running spot, the reaction mixture was neutralized
with Amberlite-H+ IR-120, filtered and concentrated in vacuo to obtain
compound 10 (12 mg, 68 μmol, 93%). 1H NMR (400 MHz, D2O): δ (ppm)
3.99 (dd, J = 8.8, 5.9 Hz, 1H, H-2), 3.83 (dd, J = 10.9, 3.5 Hz, 1H, H-8),
3.70 (dd, J = 10.9, 6.3 Hz, 1H, H-8), 3.18 (t, J = 10.2 Hz, 1H, H-4), 3.09
(dd, J = 10.2, 8.9 Hz, 1H, H-3), 1.77 – 1.66 (m, 1H, H-5), 1.39 – 1.31 (m,
1H, H-6), 1.05 – 0.93 (m, 1H, H-1), 0.79 – 0.72 (m, 1H, C-7), 0.35 – 0.25
(m, 1H, C-7). 13C NMR (101 MHz, D2O): δ (ppm) 74.5 (C-3), 72.1 (C-4),
71.0 (C-2), 63.1 (C-8), 45.1 (C-5), 17.6 (C-6), 12.6 (C-1), 9.2 (C-7).
HRMS: calculated for [C8H14O4Na]+ 197.07843, found 197.07845.
(((1R,2R,3S,6R)-6-(((tert-butyldimethylsilyl)oxy)methyl)cyclohex-4-
ene-1,2,3-triyl)tris(oxy))tris(tert-butyldimethylsilane) (12)
Compound 11 (69.5 mg, 0.434 mmol) was dissolved in MeOH (4.0 mL)
and NaOMe (catalytic amount) was added. After stirring overnight, the
reaction mixture was concentrated in vacuo and dissolved in DMF (3.1
mL). After addition of imidazole (0.708 g, 10.4 mmol, 24 eq.) and a
solution of TBS-Cl (0.864 g, 5.73 mmol, 13.2 eq.) in DMF (2.0 mL) the
mixture was stirred at room temperature for 5 days and subsequently
refluxed over 2 nights. The reaction mixture was partitioned between
Et2O (10 mL) and H2O (10 mL). The organic layer was separated,
washed with H2O (2x), dried over MgSO4, filtered and concentrated in
vacuo. Purification by column chromatography (10% toluene in pentane)
gave title compound 12 as a slightly yellow oil (94.0 mg, 0.152 mmol,
35% over 2 steps). 1H NMR (400 MHz, CDCl3): δ (ppm) 5.74 (d, J = 3.6
Hz, 1H, H-1/H-6), 5.73 (d, J = 3.6 Hz, 1H, H-1/H-6), 3.93 (d, J = 2.5 Hz,
1H, H-2), 3.90 (d, J = 2.0 Hz, H-4), 3.83 (d, J = 3.2 Hz, 1H, H-3), 3.61
(dd, J = 9.6, 8.0 Hz, 1H, H-7), 3.52 (dd, J = 9.2, 7.2, 1H, H-7), 2.35 – 2.30
(m, 1H, H-5), 0.87 (s, 18H, TBS), 0.86 – 0.83 (m, 18H, TBS), 0.10 – 0.05
(m, 18H, TBS), 0.01 (s, 3H, TBS), 0.00 (s, 3H, TBS). 13C NMR (100 MHz,
CDCl3): δ (ppm) 127.3, 127.2 (C-1 and C-2), 76.0 (C-3), 70.5 (C-4), 69.2
(C-2), 65.4 (C-7), 46.4 (C-5), 26.3, 26.3, 26.2, 26.1 (TBS), 18.6, 18.5,
18.2 (Cq TBS), -3.9, -4.1, -4.2, -4.5, -4.6, -5.0, -5.1 (TBS). HRMS:
calculated for [C31H69O8Si4]+ 617.42674, found 617.42689.
ethyl (1R,2S,3R,4R,5R,6R,7R)-2,3,4-tris(benzyloxy)-5-((benzyloxy)
methyl)
bicyclo[4.1.0]heptane-7-carboxylate
(13)
and
ethyl
(1S,2S,3R,4R,5R,6S,7S)-2,3,4-tris(benzyloxy)-5-((benzyloxy)methyl)
bicycle[4.1.0]heptane-7-carboxylate (14)
EtOAc was dried over flame dried 4 Å molsieves overnight before use.
To a solution of cyclic alkene 8 (1.57 g, 3.01 mmol) in EtOAc (2.7 mL) in
a 2-necked pear flask, was added Cu(acac)2 (79.0 mg, 0.301 mmol, 0.1
eq.). The reaction mixture was stirred at 90 °C and a solution of ethyl
diazoacetate (13 wt% DCM, 4.52 mmol, 0.55 mL, 1.5 eq.) in EtOAc (9.0
mL) was added by syringe pump over 6 h. TLC-MS analysis indicated the
presence of starting material, so an equal batch of ethyl diazoacetate
diluted with EtOAc was added. After addition of a total of 6 eq. of ethyl
diazoacetate, the formation of a product with m/z 715 [M + Na]+ was
detected by TLC-MS analysis. The reaction was concentrated in vacuo
and purification by column chromatography (3% EtOAc in pentane → 7%
EtOAc in pentane) to give the desired product as a crude mixture of 2
isomers. In addition, recovered starting material 25 (0.433 g, 0.832 mmol,
28%) was obtained and was subjected to the same conditions as stated
above. After addition of 4.5 eq. of ethyl diazoacetate, significant
byproduct formation was observed by TLC-MS analysis. After this cycle
was repeated a second time a total crude mixture of α-exo-ester 13 and
β-exo-ester 14 (0.642 g, 1.06 mmol, 35%, 2:1, as a mixture of α/β) was
obtained as a light yellow oil. Crystallization of the combined crude
isomeric product mixture from ethanol gave 13 as a white solid (0.274 g,
0.452 mmol, 15%) and a mixture of 13 and 14 as a light yellow oil (0.368
g, 0.606 mmol, 20%). Analytical data for 13: 1H NMR (400 MHz, CDCl3):
δ (ppm) 7.30 (m, 16H, HaromBn), 7.14 (m, 2H, HaromBn), 4.89 – 4.69 (m,
4H, CH2Bn), 4.64 (d, J = 11.8 Hz, 1H, CH2Bn), 4.53 – 4.34 (m, 3H,
CH2Bn), 4.22 – 4.03 (m, 3H, CH2CH3 and H-2), 3.66 – 3.52 (m, 2H, 2 x
H-8), 3.40 (t, J = 10.2 Hz, 1H, H-4), 3.25 (dd, J = 10.1, 8.3 Hz, 1H, H-3),
2.05 – 1.97 (m, 1H, H-1), 1.94 – 1.88 (m, 1H, H-5), 1.76 (ddd, J = 9.5,
4.7, 2.3 Hz, 1H, H-6), 1.67 (t, J = 4.7 Hz, 1H, H-7), 1.27 (t, J = 7.1 Hz,
3H, CH3). 13C NMR (100 MHz, CDCl3): δ (ppm) 173.4 (Cq carbonyl),
(1R,2R,3S,6R)-6-(acetoxymethyl)cyclohex-4-ene-1,2,3-triyl triacetate
(11)
NH3 (20 mL) was condensed at -60 °C. Lithium (250 mg) was added and
the reaction mixture was stirred until the lithium was completely
dissolved. To this solution was added a solution of compound 7 (340 mg,
1.00 mmol) in THF (22.5 mL). The reaction mixture was stirred for 30 min
at -60 °C and subsequently quenched with MeOH (10 mL). The solution
was allowed to come to room temperature and stirred until all NH3 had
evolved. The resulting crude was then dissolved in pyridine (6.0 mL) and
acetic anhydride (5.0 mL) was added. After stirring overnight, additional
acetic anhydride (9.0 mL) was added. The reaction mixture was
partitioned between EtOAc (25 mL) and H2O (10 mL). The organic layer
was washed with H2O (3x), dried over MgSO4 and concentrated in vacuo.
The residue was taken up in pyridine (3.0 mL) and Ac2O (2.0 mL). After
stirring overnight at room temperature, the reaction mixture was
partitioned between EtOAc (25 mL) and H2O (10 mL). The organic layer
was washed with H2O (3x), dried over MgSO4, filtered and concentrated
in vacuo. Purification by column chromatography (10% EtOAc in pentane
→ 40% EtOAc in pentane) and coevaporation with toluene (to remove
any residual pyridine) gave title compound 11 as a yellow oil (0.258 g,
0.786 mmol, 79% over 2 steps). 1H NMR (400 MHz, CDCl3): δ (ppm)
5.72 – 5.68 (m, 1H, H-1/H-6), 5.67 – 5.61 (m, 1H, H-1/H-6), 5.58 – 5.54
(m, 1H, H-2), 5.32 (dd, J = 10.6, 7.9 Hz, 1H, H-3), 5.28 – 5.18 (m, 1H, H-
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10.1002/ejoc.201701601
European Journal of Organic Chemistry
FULL PAPER
139.0, 138.6, 136.6, 138.3 (4 x Cq Bn), 128.5, 128.5, 128.5, 128.4, 128.2,
128.0, 128.0, 127.8, 127.7, 127.6, 127.5 (CHarom), 84.1 (C-3), 79.2 (C-2),
78.5 (C-4), 75.7, 75.4, 73.3, 71.6 (4 x CH2 Bn), 70.2 (C-8), 60.8
(CH2CH3), 43.1 (C-5), 26.9 (C-1), 25.0, 25.0 (C-6 and C-7), 14.4 (CH3).
HRMS: calculated for [C39H43O7]+ 607.30542, found 607.30589.
1-((1R,2S,3R,4R,5R,6R,7R)-2,3,4-tris(benzyloxy)-5-((benzyloxy)
methyl)bicyclo[4.1.0]heptan-7-yl)propan-1-one (22)
Ester 13 (60.8 mg, 0.100 mmol) was added to Me(MeO)NH.HCl (12.2 mg,
0.125 mmol, 1.25 eq.) in THF (0.5 mL). After addition of EtMgBr (0.5 M
in THF, 0.840 mmol, 8.4 eq.) over 2 h at -5 – 0 °C, the reaction mixture
was stirred overnight, quenched with aqueous HCl (3 M, 3 mL) and
extracted with EtOAc (10 mL). The organic layer was dried, concentrated
in vacuo and redissolved in THF (0.8 mL). After addition of EtMgBr (1 M
in THF, 0.300 mmol, 3 eq.) over 2 min at -20 °C, the reaction mixture was
allowed to come to room temperature and was stirred for 75 min before
quenching with aqueous HCl (3 M, 3 mL). The reaction mixture was
extracted with EtOAc (10 mL) after which the organic layer was dried and
concentrated in vacuo. Purification by column chromatography (6%
EtOAc in pentane → 8% EtOAc in pentane) gave compound 22 as a
white solid (32.8 mg, 55.6 µmol, 56%). 1H NMR (400 MHz, CDCl3): d
(ppm) 7.39 – 7.18 (m, 18H, Harom), 7.15 – 7.12 (m, 2H, Harom), 4.92 – 4.76
(m, 3H, CH2 Bn), 4.74 – 4.57 (m, 2H, CH2 Bn), 4.50 – 4.38 (m, 3H, CH2
Bn), 4.06 (dd, J = 7.9, 5.8 Hz, 1H, H-2), 3.61 – 3.50 (m, 2H, H-8), 3.39 (t,
J = 10.0 Hz, 1H, H-4), 3.34 – 3.24 (m, 1H, H-3), 2.58 (dd, J = 14.4, 7.6
Hz, 2H, CH2CH3), 2.09 – 2.00 (m, 1H, H-1), 1.98 (t, J = 4.5 Hz, 1H, H-7),
1.95 – 1.89 (m, 1H, H-5), 1.86 – 1.78 (m, 1H, H-6), 1.08 (t, J = 7.3 Hz,
3H, CH3). 13C NMR (100 MHz, CDCl3): d (ppm) 209.6 (C=O), 139.1,
138.7, 138.6, 138.4 (4 x Cq-arom), 128.6, 128.5, 128.5, 128.2, 128.0,
127.9, 127.8, 127.7 (CHarom), 84.3 (C-3), 79.4 (C-2), 78.7 (C-4), 75.7,
75.5, 73.5, 71.6 (4 x CH2 Bn), 70.4 (C-8), 43.5 (C-5), 37.3 (CH2CH3),
32.6 (C-7), 29.6 (C-1), 27.4 (C-6), 8.2 (CH3). HRMS: calculated for
[C39H42O5Na]+ 613.29245, found 613.29242.
((1R,4S,5R,6R)-4,5,6-tris(benzyloxy)cyclohex-2-en-1-yl)methyl (tert-
butoxycarbonyl) glycinate (19)
Compound 6 (51.9 mg, 0.120 mmol), N-Boc-glycine (31.5 mg, 0.18
mmol, 1.5 eq.) and DMAP (catalytic amount) were dissolved in toluene
(0.6 mL) and DIC (38 µL, 2 eq.) was subsequently added dropwise. After
stirring overnight at room temperature, the reaction mixture was filtered
over Celite, concentrated in vacuo and purified by column
chromatography (8% EtOAc in pentane → 25% EtOAc in pentane) to
give compound 19 as a yellow oil (69.4 mg, 0.120 mmol, quant.). 1H
NMR (400 MHz, CDCl3): d (ppm) 7.42 – 7.21 (m, 15H, HaromBn), 5.72 (dt,
J = 10.2, 2.4 Hz, 1H, H1/6), 5.58 – 5.46 (m, 1H, H1/6), 5.04 – 4.49 (m,
6H, CH2Bn), 4.28 (dd, J = 10.8, 3.2 Hz, 1H, H-8), 4.23 (ddd, J = 7.7, 3.3,
1.9 Hz, 1H, H-2), 4.14 (dd, J = 10.9, 5.0 Hz, 1H, H-8), 3.80 (td, J = 13.3,
11.6, 7.5 Hz, 3H, H-3 and CH2-Glyc), 3.53 (t, J = 9.8 Hz, 1H, H-4), 2.71 –
2.52 (m, 1H, H-5), 1.45 (d, J = 2.5 Hz, 9H, Boc-tBu). 13C NMR (75 MHz,
CDCl3): d (ppm) 170.5 (C=O ester), 138.9, 138.4, 138.0 (3 x Cq Bn),
128.6, 128.6, 128.5, 128.2, 128.0, 128.0, 127.9, 127.8, 127.5 (CHarom),
104.8 (C-1/6), 101.9 (C-1/6), 85.4 (C-3), 80.8 (C-2), 75.4, 75.3, 75.3
(CH2Bn), 72.3 (C-4), 64.5 (C-8), 43.3 (C-5), 42.4 (CH2-Glyc), 28.5 (Boc-
CH3). HRMS: calculated for [C35H42NO7]+ 588.29558, found 588.29600.
(1R,4S,5R,6R)-4,5,6-tris(benzyloxy)cyclohex-2-en-1-yl)methyl 2-
diazoacetate (21)
1-((1R,2S,3R,4R,5R,6R,7R)-2,3,4-trihydroxy-5-(hydroxymethyl)
bicyclo[4.1.0]heptan-7-yl)propan-1-one (23)
To a solution of compound 19 (69.4 mg, 0.120 mmol) in DCM (0.3 mL)
was added TFA (0.3 mL). After stirring for 45 min at room temperature,
the reaction mixture was concentrated in vacuo to give compound 20 as
a light yellow solid which was used without further purification (72.2 mg,
0.120 mmol, quant.). HRMS (as the free amine): calculated for
[C30H34NO5]+ 488.24315, found 488.24285. Compound 20 (60.0 mg,
0.0990 mmol) was suspended in H2O (0.4 mL), after which monosodium
citrate (31.7 mg, 0.149 mmol, 1.5 eq.) and CH2Br2 (0.5 mL) were added.
The reaction was cooled to 0 °C and NaNO2 (8.19 mg, 0.119 mmol, 1.2
eq.) was added. After stirring at 0 °C for 1 h, the reaction mixture was
warmed up to room temperature and the organic layer was removed by
syringe. Additional CH2Br2 was added (0.5 mL) and after stirring for 10
min the organic layer was removed again by syringe. The combined
organic layers were combined and concentrated in vacuo to give
compound 21 as a bright yellow oil (49 mg, 98.0 µmol, 99%). 1H NMR
(400 MHz, CDCl3): d (ppm) 7.45 – 7.16 (m, 15H, Harom), 5.73 (d, J = 10.2
Hz, 1H, H-1/H-6), 5.55 (d, J = 10.2 Hz, 1H, H-1/H-6), 4.96 (d, J = 10.8 Hz,
1H, CH2 Bn), 4.93 – 4.88 (m, 2H, CH2 Bn), 4.69 – 4.62 (m, 3H, CH2 Bn
and H-diazocarbonyl), 4.56 (d, J = 9.2 Hz, 1H, CH2 Bn), 4.33 (dd, J =
10.8, 3.0 Hz, 1H, H-2), 4.23 – 4.18 (m, 2H, H-8), 3.82 (t, J = 8.4 Hz, 1H,
H-3), 3.54 (t, J = 9.8 Hz, 1H, H-4), 2.61 (bs, 1H, H-5). 13C NMR (100 MHz,
CDCl3): d (ppm) 138.9, 138.5, 138.4 (3 x Cq-arom), 128.6, 128.6, 128.4,
128.1, 128.0, 127.9, 127.8, 127.7 (CHarom), 85.3 (C-3), 80.9 (C-2), 77.9
(C-4), 75.5, 74.4, 72.3 (3 x CH2 Bn), 63.9 (C-8), 46.4 (C=N), 43.6 (C-5).
Compound 22 (32.8 mg, 55.6 µmol) was treated according to General
procedure for global debenzylation with Pd(OH)2/C to obtain title
compound 23 as a clear oil (12.3 mg, 53.4 µmol, 96%). 1H NMR (400
MHz, D2O): d (ppm) 4.04 (dd, J = 8.6, 5.5 Hz, 1H, H-2), 3.84 (dd, J = 11.0,
3.6 Hz, 1H, H-8), 3.72 (dd, J = 11.0, 6.2 Hz, 1H, H-8), 3.37 – 3.09 (m, 2H,
H-3 and H-4), 2.72 (dd, J = 7.2, 14.8 Hz, 2H, CH2CH3), 2.25 (t, J = 4.5 Hz,
1H, H-7), 2.11 – 1.98 (m, 1H, H-1), 1.90 – 1.83 (m, 1H, H-5), 1.68 – 1.61
(m, 1H, H-6), 1.04 (t, J = 7.3 Hz, 3H, CH3). 13C NMR (100 MHz, D2O): d
(ppm) 216.1 (C=O), 74.4 (C-3), 70.7 (C-2), 70.4 (C-4), 62.5 (C-8), 44.3
(C-5), 36.6 (CH2CH3), 32.1 (C-7), 31.9 (C-1), 26.8 (C-6), 7.4 (CH3).
HRMS: calculated for [C11H19O5]+ 231.12270, found 231.12270.
((1R,2S,3R,4R,5R,6R,7R)-2,3,4-tris(benzyloxy)-5-((benzyloxy)methyl)
bicyclo[4.1.0]heptan-7-yl)methanol (24) and ((1S,2S,3R,4R,
5R,6S,7S)-2,3,4-tris(benzyloxy)-5-((benzyloxy)methyl)bicyclo
[4.1.0]heptan-7-yl)methanol (25)
A crude mixture of 13 and 14 (0.142 g, 0.234 mmol) was dissolved in
THF (1 mL) at 0 °C, after which DIBAL (1 M in hexanes, 2.1 mL, 2.1
mmol, 9.0 eq.) was added dropwise. After the mixture was stirred for 30
min at 0 °C followed by 1 h at room temperature, the reaction was
quenched with EtOAc. The mixture was concentrated in vacuo and the
residue was partitioned between EtOAc (20 mL) and 1 M aqueous HCl
(20 mL). The aqueous layer was extracted with EtOAc (20 mL) and the
combined organic layers were dried over MgSO4, filtered and
concentrated in vacuo. Purification by column chromatography (20%
EtOAc in pentane → 25% EtOAc in pentane) gave title compounds 24
(36.6 mg, 64.8 µmol, 28%) and 25 (17.1 mg, 30.2 µmol, 13%) as white
solids. Analytical data for 24: 1H NMR (400 MHz, CDCl3): δ (ppm) 7.46 –
7.20 (m, 18H, CHarom), 7.19 – 7.11 (m, 2H, CHarom), 4.96 – 4.64 (m, 5H,
CH2 Bn), 4.55 – 4.29 (m, 3H, CH2 Bn), 4.06 (dd, J = 7.9, 6.2 Hz, 1H, H-
2), 3.59 (d, J = 4.1 Hz, 1H, H-8), 3.51 (dd, J = 11.2, 6.3 Hz, 1H, CHHOH),
3.40 – 3.18 (m, 3H, CHHOH, H-3, H-4), 1.93 – 1.89 (m, 1H, H-5), 1.30 –
1.20 (m, 1H, H-1), 1.12 – 1.03 (m, 2H, H-6 and H-7). 13C NMR (100 MHz,
CDCl3): δ (ppm) 139.2, 139.1, 138.8, 138.5 (4 x Cq-arom), 128.6, 128.5,
Bis(N-tert-butylsalicylaldiminato)copper(II)
Cu(OAc)2 (0.399 g, 2.00 mmol) was dissolved in H2O (5 mL) and a
solution of salicylaldehyde (435 µL, 4.00 mmol, 2 eq.) in EtOH (2 mL)
was added. After stirring for 1h at 55 °C, the precipitate was filtered off
and subsequently suspended in EtOH (2 mL). After addition of tert-
butylamine (525 µL, 5.00 mmol, 2.25 eq.), the reaction mixture was
refluxed for 1.5 h and concentrated in vacuo to give the title compound
as black crystals (0.680 g, 1.64 mmol, 82%). m.p.: 185 °C (literature
values 185-186 °C).[30]
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10.1002/ejoc.201701601
European Journal of Organic Chemistry
FULL PAPER
128.5, 128.2, 128.1, 128.1, 128.0, 127.9, 127.8, 127.8, 127.7 (CHarom),
84.8 (C-3), 80.1 (C-2), 79.3 (C-4), 75.7, 75.4, 73.4, 71.7 (4 x CH2 Bn),
70.9 (C-8), 66.5 (CH2OH), 43.6 (C-5), 26.4 (C-7), 22.0 (C-1), 19.8 (C-6).
HRMS: calculated for [C37H41O6]+ 565.29485, found 565.29462.
Analytical data for 25: 1H NMR (400 MHz, CDCl3): δ (ppm) 7.63 – 6.95
(m, 20H, CHarom), 4.95 – 4.60 (m, 5H, CH2 Bn), 4.53 – 4.31 (m, 3H, CH2
Bn), 3.75 – 3.62 (m, 3H, CHHOH, H-2, H-8), 3.58 – 3.42 (m, 2H, H-3 and
H-8), 3.07 – 2.99 (m, 2H, CHHOH and H-4), 2.41 – 2.30 (m, 1H, H-5),
1.14 (dd, J = 8.2, 4.7 Hz, 1H, H-6), 1.02 (dd, J = 8.9, 4.8 Hz, 1H, H-1),
0.97 – 0.78 (m, 1H, H-7). 13C NMR (100 MHz, CDCl3): δ (ppm) 139.0,
138.6, 138.5, 138.2 (4 x Cq arom) 128.7, 128.6, 128.6, 128.5, 128.3,
128.2, 128.1, 128.1, 128.0, 127.9, 127.9, 127.7, 127.7 (CHarom), 86.4 (C-
3), 82.3 (C-2), 75.5, 75.3, 73.5, 72.5 (4 x CH2 Bn), 71.4 (C-8), 66.7 (CH-
2OH, 40.2 (C-5), 22.9 (C-7), 21.2 (C-6), 20.6 (C-1). HRMS: calculated for
[C37H41O6]+ 565.29485, found 565.29526.
(m, 3H, CH2CH3, CHHOEt), 3.24 – 3.16 (m, 2H CHHOEt and H-4), 3.16 –
3.10 (m, 1H, H-3) 1.83 – 1.72 (m, 1H, H-5), 1.36 – 1.30(m, 1H, H-1), 1.20
(t, J = 7.1 Hz, 3H, CH3), 1.13 – 1.05 (m, 1H, H-7), 1.08 – 0.95 (m, 1H, H-
6). 13C NMR (100 MHz, D2O): δ (ppm) 79.3 (C-3), 78.2 (CH2OEt), 75.8
(C-2), 75.3 (C-4), 70.5 (CH2CH3), 67.3 (C-8), 49.0 (C-5), 27.6 (C-1), 26.6
(C-7), 23.4 (C-6), 18.5 (CH3). HRMS: calculated for [C11H21O6]+
233.13835, found 233.13843.
ethyl (1S,2S,3R,4R,5R,6S,7S)-2,3,4-tris(benzyloxy)-5-((benzyloxy)
methyl)bicyclo[4.1.0]heptane-7-carboxylate (14)
Chromic acid stock solution (1.0 M) was prepared (Caution: Chromic acid
is corrosive, toxic and carcinogenic). Concentrated H2SO4 (2.25 mL, 40.5
mmol) is taken up in H2O (12.5 mL). To this solution was added CrO3
(2.50 g, 25.0 mmol) and the resulting bright red solution was stirred until
all solids were completely dissolved. The solution was then diluted with
H2O to a total volume of 25 mL. Compound 31 (261 mg, 0.462 mmol)
was dissolved in acetone (9.2 mL) and cooled to 0 °C, after which the
chromic acid stock solution (0.92 mL, 0.920 mmol, 2 eq.) was added.
After stirring for 3 h, the reaction mixture was diluted with EtOAc (150
mL) and washed with aqueous HCl (3 M, 2 x 150 mL) and brine (150
mL). The organic layer was dried over MgSO4, filtered and concentrated
in vacuo. Purification by column chromatography (15% EtOAc in pentane
→ 35% EtOAc in pentane) gave the corresponding carboxylic acid as a
white solid (141 mg, 0.244 mmol, 53%). 1H NMR (400 MHz, CDCl3): δ
(ppm) 7.44 – 7.10 (m, 20H, Harom), 4.90 – 4.71 (m, 4H, CH2 Bn), 4.69 –
4.57 (m, 1H, CH2 Bn), 4.54 – 4.34 (m, 3H, CH2 Bn), 3.75 (d, J = 8.1 Hz,
1H, H-2), 3.65 (dd, J = 8.9, 2.7 Hz, 1H, H-8), 3.60 – 3.51 (m, 2H, H-3 and
H-8), 3.11 (t, J = 10.2 Hz, 1H, H-4), 2.45 – 2.33 (m, 1H, H-5), 2.03 – 1.98
(m, 1H, H-6), 1.80 (dd, J = 9.5, 4.5 Hz, 1H, H-1), 1.60 (t, J = 4.6 Hz, 1H,
H-8). 13C NMR (100 MHz, CDCl3): δ (ppm) 179.4 (C=O), 138.9, 138.6,
138.5, 138.1 (4 x Cq-arom), 128.7, 128.6, 128.6, 128.5, 128.5, 128.2, 128.2,
128.1, 128.0, 127.9, 127.7 (CHarom), 85.8 (C-3), 81.3 (C-2), 76.2 (C-4),
75.5, 75.4, 73.3, 72.5 (4 x CH2 Bn), 70.2 (C-8), 40.6 (C-5), 27.3 (C-6),
26.0 (C-1), 22.0 (C-7). HRMS: calculated for [C37H39O6]+ 579.27412,
found 579.27438.
(1R,2S,3R,4R,5R,6R,7R)-5,7-bis(hydroxymethyl)bicyclo[4.1.0]
heptane-2,3,4-triol (26)
Compound 24 (25.6 mg, 45.1 µmol) was treated according to General
procedure for global debenzylation with Pd(OH)2/C to obtain title
compound 26 as a clear oil (8.30 mg, 40.6 µmol, 90%). 1H NMR (400
MHz, D2O): δ (ppm) 4.03 (dd, J = 8.7, 6.0 Hz, 1H, H-2), 3.90 (dd, J =
10.9, 3.5 Hz, 1H, H-8), 3.78 (dd, J = 10.9, 6.1 Hz, 1H, H-8), 3.62 (dd, J =
11.6, 6.1 Hz, 1H, CH2-OH), 3.33 (dd, J = 11.5, 7.7 Hz, 1H, CH2-OH), 3.25
(t, J = 10.1 Hz, 1H, H-4), 3.21 – 3.11 (m, 1H, H-3), 1.86 – 1.77 (m, 1H, H-
5), 1.35 (dt, J = 9.0, 5.5 Hz, 1H, H-1/6), 1.13 (dt, J = 11.3, 5.3 Hz, 1H, H-
7), 1.05 – 0.97 (m, 1H, H-1/H-6). 13C NMR (100 MHz, D2O): δ (ppm) 70.5
(C-3), 67.0 (C-2), 66.5 (C-4), 60.8 (CH2-OH), 58.6 (C-8), 40.2 (C-5), 20.2
(C-7), 18.8 (C-1), 14.1 (C-6). HRMS: calculated for [C9H17O6]+
205.10705, found 205.10701.
(1R,2S,3R,4R,5R,6R,7R)-2,3,4-tris(benzyloxy)-5-((benzyloxy)methyl)-
7-(ethoxymethyl)bicyclo[4.1.0]heptane (27)
Compound 24 (18.0 mg, 32.0 µmol), TBAI (catalytic amount) and NaH
(60%, 2.55 mg, 2.0 eq.) were dissolved in DMF (0.3 mL) at 0 °C. After
stirring for 5 min, ethyl bromide (21 µL, 0.287 mmol, 9.0 eq.) was added
and the reaction mixture was allowed to stir at room temperature for 4 h.
The reaction mixture was partitioned between H2O (10 mL) and EtOAc
(10 mL) and the organic layer was washed with H2O (2x) and all the
aqueous layers were extracted with EtOAc (1x). The combined organic
layers were dried over MgSO4, filtered and concentrated in vacuo.
Purification by column chromatography (10% EtOAc in pentane → 20%
EtOAc in pentane) gave title compound 27 as a clear oil (11.1 mg, 18.7
µmol, 59%). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.48 – 7.11 (m, 20H,
HaromBn), 4.91 – 4.72 (m, 4H, CH2Bn), 4.66 (d, J = 11.7 Hz, 1H, CH2Bn),
4.55 – 4.36 (m, 3H, CH2Bn), 4.07 (dd, J = 8.0, 6.2 Hz, 1H, H-2), 3.66 –
3.60 (m, 2H, H-8), 3.56 – 3.42 (m, 2H, CH2CH3), 3.42 – 3.32 (m, 2H, H-4
and CHHO), 3.32 – 3.22 (m, 2H, H-3, CHHO), 1.89 (dd, J = 6.6, 3.5 Hz,
1H, H-5), 1.34 – 1.28 (m, 1H, H-1), 1.17 (t, J = 7.0 Hz, 3H, CH3), 1.12 –
1.04 (m, 2H, H-6 and H-7). 13C NMR (101 MHz, CDCl3): δ (ppm) 139.3,
139.2, 138.9, 138.6 (4 x Cq-arom),128.6, 128.5, 128.5, 128.2, 128.2, 128.1,
128.0, 127.9, 127.8, 127.7, 127.6, 127.1 (CHarom), 84.9 (C-3), 80.2 (C-2),
79.3 (C-4), 75.7, 75.3 (2 x CH2 Bn), 74.1 (CH2O), 73.3, 71.1 (2 x CH2
Bn), 70.9 (C-8), 65.8 (CH2CH3), 43.6 (C-5), 23.5 (C-7), 21.6 (C-1), 20.4
(C-6), 15.5 (CH3). HRMS: calculated for [C39H45O5]+ 593.32615, found
593.32647.
To a solution of the carboxylic acid (141 mg, 0.244 mmol) in toluene (1.2
mL) was added ethanol (66 µL, 0.488 mmol, 2 eq.) and DMAP (catalytic
amount). After DIC (75 µL, 0.484 mmol, 2.0 eq.) was added dropwise,
the reaction mixture was stirred for 4 h at room temperature. The reaction
mixture was filtered over Celite, concentrated in vacuo and purification by
column chromatography (7% EtOAc in pentane
→ 10% EtOAc in
pentane) gave title compound 14 as a white solid (91.4 mg, 0.151 mmol,
62%). 1H NMR (400 MHz, CDCl3: δ (ppm) 7.44 – 7.14 (m, 20H, Harom),
4.89 – 4.72 (m, 4H, CH2 Bn), 4.64 (d, J = 11.6 Hz, 1H, CH2 Bn), 4.52 –
4.36 (m, 3H, CH2 Bn), 4.15 (d, J = 7.2 Hz, 1H, CHHCH3), 4.12 (d, J = 7.2,
CHHCH3), 3.75 (d, J = 7.8 Hz, 1H, H-2), 3.65 (dd, J = 8.9, 2.7 Hz, 1H, H-
8), 3.61 - 3.48 (m, 2H, H-3 and H-8), 3.14 (t, J = 10.2 Hz, 1H, H-4), 2.45
– 2.29 (m, 1H, H-6), 1.96 - 1.84 (m, 1H, H-6), 1.74 (dd, J = 9.3, 4.5 Hz,
1H, H-1), 1.61 (t, J = 4.7 Hz, 1H, H-7), 1.26 (t, J = 7.1 Hz, 3H, CH3). 13C
NMR (101 MHz, CDCl3): δ (ppm) 173.5 (C=O), 138.9, 138.7, 138.6,
138.2 (4 x Cq-arom), 128.6, 128.5, 128.5, 128.4, 128.2, 128.1, 128.0, 128.0,
127.9, 127.8, 127.8, 127.7, 127.6, 127.5 (CHarom), 85.9 (C-3), 81.5 (C-2),
76.3 (C-4), 75.4, 75.4, 73.3, 72.4 (4 x CH2 Bn), 70.4 (C-8), 60.8 (CH2CH-
3), 40.6 (C-5), 26.4 (C-6), 24.9 (C-1), 22.2 (C-7), 14.4 (CH3). HRMS:
calculated for [C39H43O7]+ 607.30542, found 607.30589.
(1R,2S,3R,4R,5R,6R,7R)-7-(ethoxymethyl)-5-(hydroxymethyl)bicyclo
[4.1.0]heptane-2,3,4-triol (28)
Compound 27 (11.1 mg, 18.7 µmol) was treated according to General
procedure for global debenzylation with Pd(OH)2/C to obtain title
compound 28 as a clear oil oil (4.1 mg, 17.7 µmol, 94%). 1H NMR (400
MHz, D2O): δ (ppm) 4.00 (dd, J = 8.8, 6.0 Hz, 1H, H-2), 3.87 (dd, J =
10.9, 3.5 Hz, 1H, H-8), 3.75 (dd, J = 10.9, 6.0 Hz, 1H, H-8), 3.65 – 3.55
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701601
European Journal of Organic Chemistry
FULL PAPER
1-((1S,2S,3R,4R,5R,6S,7S)-2,3,4-tris(benzyloxy)-5-((benzyloxy)
methyl)bicyclo[4.1.0]heptan-7-yl)propan-1-one (29)
Analytical data for 31: 1H NMR (400 MHz, CDCl3): δ (ppm) 7.38 – 7.10
(m, 20H, HaromBn), 5.66 (t, J = 5.8 Hz, 1H, NH), 4.90 – 4.69 (m, 4H,
CH2Bn), 4.61 (d, J = 11.6 Hz, 1H, CH2Bn), 4.53 – 4.32 (m, 3H, CH2Bn),
4.10 (dd, J = 8.2, 5.9 Hz, 1H, H-2), 3.59 (qd, J = 8.8, 3.8 Hz, 2H, H-8),
3.42 (t, J = 10.1 Hz, 1H, H-4), 3.30 (t, J = 6.1 Hz, 4H, NHCH2, CH2N3),
3.26 – 3.20 (m, 1H, H-3), 2.04 (dt, J = 10.0, 5.2 Hz, 1H, H-1), 1.94 – 1.85
(m, 1H, H-5), 1.82 (ddd, J = 9.2, 4.4, 2.2 Hz, 1H, H-6), 1.65 – 1.57 (m,
4H, NHCH2CH2, CH2CH2N3), 1.35 (t, J = 4.5 Hz, 1H, H-7). 13C NMR (100
MHz, CDCl3): δ (ppm) 172.1 (C=O), 139.1, 138.6 (Cq-Bn), 128.6, 128.6,
128.6, 128.5, 128.3, 128.1, 128.0, 127.9, 127.9, 127.7 (Carom-Bn), 84.4
(C-3), 79.4 (C-2), 78.8 (C-4), 75.7, 75.5, 73.5, 71.6 (CH2-Bn), 70.5 (C-8),
51.3 (CH2N3), 43.4 (C-1), 39.4 (NHCH2), 27.3 (NHCH2CH2), 27.1 (C-5),
26.5 (CH2CH2N3), 25.7 (C-6), 23.8 (C-7). HRMS: calculated for
[C41H47N4O5]+ 675.35410, found 675.35411. Analytical data for 32: 1H
NMR (400 MHz, CDCl3): δ (ppm) 7.45 – 7.12 (m, 20H, CHarom), 5.22 (t, J
= 5.8 Hz, 1H, NH), 4.87 (d, J = 12.3 Hz, 2H, CH2), 4.83 – 4.74 (m, 2H,
CH2), 4.60 (d, J = 11.5 Hz, 1H, CH2), 4.50 (d, J = 11.0 Hz, 1H, CH2), 4.37
(d, J = 2.4 Hz, 2H, CH2), 3.83 (dd, J = 9.1, 3.6 Hz, 1H, H-2), 3.75 (d, J =
7.6 Hz, 1H, H-3), 3.66 – 3.52 (m, 2H, H-8), 3.34 (t, J = 10.2 Hz, 1H, H-4),
3.23 (t, J = 6.7 Hz, 2H, CH2N3), 3.19 – 3.10 (m, 1H, NHCHH), 3.10 – 3.00
(m, 1H, NHCHH), 2.29 – 2.24 (m, 1H, H-5), 1.79 (dd, J = 9. 1, 4.8 Hz, 1H,
H-6), 1.70 – 1.63 (m, 1H, H-1), 1.55 – 1.44 (m, 2H, NHCH2CH2), 1.43 –
1.30 (m, 3H, CH2CH2N3, H-7). 13C NMR (100 MHz, CDCl3) δ (ppm) 172.1
(C=O), 139.0, 139.0, 138.7, 138.3 (Cq-arom), 128.7, 128.6, 128.5, 128.3,
128.1, 128.1, 127.9, 127.9, 127.8, 127.7, 127.4 (CHarom), 86.3 (C-3), 81.6
(C-2), 75.9 (C-4), 75.4, 75.4, 73.2, 71.9 (4 x CH2 arom), 70.3 (C-8), 51.2
(CH2N3), 40.5 (C-1), 39.2 (NHCH2), 27.1 (NHCH2CH2), 26.3 (CH2CH2N3),
25.2 (C-5), 24.5 (C-6), 21.5 (C-7). HRMS: calculated for [C41H47N4O5]+
675.35410, found 675.35436.
Ethyl ester 14 (60.8 mg, 0.100 mmol) was added to Me(MeO)NH.HCl
(12.2 mg, 0.125 mmol, 1.25 eq.) in THF (0.5 mL). Subsequently, EtMgBr
(0.5 M in THF, 0.840 mmol, 8.4 eq.) was added over 2 h at -5 to 0 °C.
After stirring overnight, the reaction mixture was quenched with aqueous
HCl (3 M, 3 mL). The reaction mixture was extracted with EtOAc (10 mL),
after which the organic layer was dried and concentrated in vacuo.
Purification by column chromatography (15% EtOAc in pentane) gave
compound 29 as a white solid (29.4 mg, 47.9 µmol, 48%). 1H NMR (400
MHz, CDCl3): δ (ppm) 7.42 – 7.14 (m, 20H, Harom), 4.95 – 4.69 (m, 4H,
CH2 Bn), 4.60 (d, J = 11.5 Hz, 1H, CH2 Bn), 4.52 – 4.30 (m, 3H, CH2 Bn),
3.72 (d, J = 7.8 Hz, 1H, H-2), 3.69 – 3.46 (m, 3H, H-3 and H-8), 3.26 (t, J
= 10.2 Hz, 1H, H-4), 2.38 (dd, J = 8.7, 7.4 Hz, 2H, CH2CH3), 2.36 – 2.29
(m, 1H, H-5), 1.89 (t, J = 4.7 Hz, 1H, H-7), 1.84 – 1.82 (m, 1H, H-6), 1.82
– 1.79 (m, 1H, H-1), 1.00 (t, J = 7.3 Hz, 3H, CH3). 13C NMR (101 MHz,
CDCl3): δ (ppm) 209.7 (C=O), 139.0, 138.7, 138.6, 138.2 (4 x Cq-arom),
128.6, 128.6, 128.5, 128.5, 128.2, 128.2, 128.1, 127.9, 127.9, 127.8,
127.8, 127.7, 127.6 (CHarom), 86.1 (C-3), 81.6 (C-2), 76.3 (C-4), 75.4,
73.4, 72.2 (4 x CH2 Bn), 70.3 (C-8), 40.7 (C-5), 37.0 (CH2CH3), 29.8 (C-
7), 29.3 (C-6), 26.4 (C-1), 8.0 (CH3). HRMS: calculated for [C39H42O5Na]+
613.29245, found 613.29257.
1-((1S,2S,3R,4R,5R,6S,7S)-2,3,4-trihydroxy-5-(hydroxymethyl)
bicyclo[4.1.0]heptan-7-yl)propan-1-one (30)
Compound 29 (29.4 mg, 49.8 µmol) was treated according to General
procedure for global debenzylation with Pd(OH)2/C to obtain title
compound 30 as a clear oil (6.70 mg, 29.1 µmol, 58%). 1H NMR (400
MHz, D2O): δ (ppm) 3.92 (dd, J = 11.2, 4.0 Hz, 1H, H-8), 3.89 (dd, J = 0.8
Hz, 8.6 Hz, 1H, H-2), 3.60 (dd, J = 10.8, 8.2 Hz, 1H, H-8), 3.28 (dd, J =
10.2, 8.6 Hz, 1H, H-3), 3.05 (t, J = 10.0 Hz, 1H, H-4), 2.69 (dd, J = 14.6,
7.4 Hz, 2H, CH2CH3), 2.21 – 2.15 (m, 1H, H-5), 2.13 (t, J = 4.2 Hz, 1H,
H-7), 1.93 (ddd, J = 9.7, 5.0, 5.0, 1H, H-6), 1.67 (dd, J = 9.2, 4.4 Hz, 1H,
H-1), 1.03 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (100 MHz, D2O): δ (ppm)
216.2 (C=O), 77.3 (C-3), 72.4 (C-2), 68.2 (C-4), 62.7 (C-8), 42.1 (C-5),
36.6 (CH2CH3), 30.1 (C-1), 29.2 (C-7), 28.4 (C-6), 7.4 (CH3). HRMS:
calculated for [C11H19O5]+ 231.12270, found 231.12276.
(1R,2S,3R,4R,5R,6R,7R)-N-(4-azidobutyl)-2,3,4-trihydroxy-5-
(hydroxymethyl)bicyclo[4.1.0]heptane-7-carboxamide (33)
To a cooled (-78 °C) solution of benzylated 31 (12.7 mg, 18.8 µmol) in
DCM (0.2 mL) was added slowly BCl3 (1 M in DCM, 0.400 mL, 0.40
mmol, 20 eq.). After stirring for 5 h at -78 °C, the reaction was quenched
with MeOH (5 mL) and allowed to warm to room temperature overnight.
Concentration in vacuo, co-evaporation with toluene (3x) and purification
by column chromatography (20% MeOH in DCM) gave compound 33 as
a white solid (5.20 mg, 16.5 µmol, 88%). 1H NMR (400 MHz, MeOD): δ
(ppm) 3.81 (dd, J = 8.7, 5.7 Hz, 1H, H-2), 3.72 (dd, J = 10.6, 3.9 Hz, 1H,
H-8), 3.55 (dd, J = 10.5, 6.5 Hz, 1H, H-8), 3.34 – 3.30 (m, 2H, CH2N3),
3.09 (t, J = 6.6 Hz, 2H, CH2N), 3.03 (t, J = 10.1 Hz, 1H, H-4), 2.97 – 2.85
(m, 1H, H-3), 1.85 – 1.80 (m, 1H, H-1), 1.74 – 1.70 (m, 1H, H-5), 1.63 –
1.54 (m, 5H, 2 x CH2 and H-7), 1.53 – 1.49 (m, 1H, H-6). 13C NMR (100
MHz, MeOD): δ (ppm) 174.8 (C=O), 76.5 (C-3), 72.6 (C-4), 72.2 (C-2),
64.7 (C-8), 52.2 (CH2N3), 46.4 (C-5), 40.1 (CH2N), 28.7 (C-1), 27.9 (CH2),
27.3 (CH2), 27.2 (C-7), 23.2 (C-6). HRMS: calculated for [C13H22N4O5]+
315.16630, found 315.16635.
(1R,2S,3R,4R,5R,6R,7R)-N-(4-azidobutyl)-2,3,4-tris(benzyloxy)-5-
((benzyloxy)methyl)bicyclo[4.1.0]heptane-7-carboxamide (31) and
(1S,2S,3R,4R,5R,6S,7S)-N-(4-azidobutyl)-2,3,4-tris(benzyloxy)-5-
((benzyloxy)methyl)bicyclo[4.1.0]heptane-7-carboxamide (32)
To a mixture of 13 and 14 (0.142 g, 0.234 mmol) in THF (8 mL), was
added MeOH (2 mL), H2O (1 mL) and LiOH (22.4 mg, 0.94 mmol, 4 eq.).
After stirring overnight at room temperature, 1 M aqueous HCl solution
was used to acidify the reaction mixture to pH 2. The reaction mixture
was diluted with EtOAc (20 mL) and washed with brine (10 mL). The
aqueous layer was extracted with EtOAc (10 mL) and the combined
organic layers were dried over MgSO4, filtered and concentrated in
vacuo. Purification by column chromatography (30% EtOAc in pentane)
gave the carboxylic acid derivatives as a mixture of α- and β-isomers
(119 mg, 0.206 mmol, 82%) as a clear oil. The carboxylic acid derivatives
(0.346 g, 0.600 mmol) were dissolved in DCM (6.0 mL) and 4-
azidobutan-1-amine (82.2 mg, 0.720 mmol, 1.2 eq.) was added. After
addition of DIPEA (364 µL, 2.10 mmol, 3.5 eq.) and HCTU (298 mg,
0.720 mmol, 1.2 eq.), the reaction mixture was stirred overnight at room
temperature. The reaction mixture was concentrated in vacuo, dissolved
in EtOAc (40 mL) and subsequently washed with aqueous HCl (1 M, 2 x
40 mL), saturated aqueous NaHCO3 (40 mL) and brine (2 x 40 mL), dried
over MgSO4, filtered and concentrated in vacuo. Purification by column
chromatography (30% EtOAc in pentane) gave the mixture of α-exo
isomer 31 and β-exo-isomer 32 (0.341 g, 0.505 mmol, 78%) as a white
solid, which were separated by HPLC purification (C18, linear gradient:
50-90% B in A, solutions used A: H2O, B: acetonitrile, 0.5% TFA, 15 min).
(1S,2S,3R,4R,5R,6S,7S)-N-(4-azidobutyl)-2,3,4-trihydroxy-5-
(hydroxymethyl)bicyclo[4.1.0]heptane-7-carboxamide (34)
To a cooled (-78 °C) solution of benzylated 32 (12.7 mg, 18.8 µmol) in
DCM (0.2 mL) was added slowly BCl3 (1 M in DCM, 0.400 mL, 0.40
mmol, 20 eq.). After stirring for 3 h at -78 °C, additional BCl3 (1 M in
DCM, 0.400 mL, 0.376 mmol, 20 eq.) was added. After stirring overnight
at -20 °C, the reaction was quenched with MeOH (5 mL) and allowed to
warm to room temperature. Concentration in vacuo, co-evaporation with
MeOH (3 x) and purification by column chromatography (20% MeOH in
DCM) gave compound 34 as a slightly yellow solid (5.9 mg, 18.6 µmol,
99%). 1H NMR (400 MHz, MeOD): δ (ppm) 3.80 (d, J = 6.3 Hz, 1H, H-8),
3.53 – 3.44 (m, 2H, H-2 and H-8), 3.17 – 3.01 (m, 3H, H-3 and NHCH2),
2.83 (t, J = 9.7 Hz, 1H, H-4), 2.07 – 1.90 (m, 1H, H-5), 1.76 – 1.61 (m, 1H,
H-1), 1.54 – 1.44 (m, 4H, NHCH2CH2, and CH2CH2N3), 1.44 – 1.38 (m,
1H, H-7), 1.34 – 1.28 (m, 1H, H-6). 13C NMR (100 MHz, MeOD): δ (ppm)
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701601
European Journal of Organic Chemistry
FULL PAPER
79.6 (C-3), 74.5 (C-2), 70.7 (C-4), 65.1 (C-8), 52.3 (CH2N3), 43.8 (C-5),
40.2 (NHCH2), 27.9, 27.9 (CH2CH2N3 and NHCH2CH2), 27.5 (C-7), 25.0
(C-1), 24.5 (C-6). HRMS: calculated for [C13H22N4O5]+ 315.16630, found
315.16635.
CH3). 13C NMR (101 MHz, CDCl3) δ (ppm) 173.50 (Cq carbonyl), 139.2,
139.0, 139.0, 138.4 (4 x Cq Bn), 128.6, 128.4, 128.3, 128.0, 128.0, 127.9,
127.6, 127.5 (CHarom), 82.9 (C-3), 76.2 (C-2), 75.7 (C-4), 74.1, 73.4, 73.0,
71.6 (4 x CH2 Bn), 70.5 (C-8), 60.7 (CH2CH3), 41.4 (C-5), 27.1 (C-1),
26.0 (C-7), 24.5 (C-6), 14.4 (CH3). HRMS: calculated for [C39H43O6]+
607.30542, found 607.30560. Analytical data for 39: 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.40 – 7.24 (m, 20H, HaromBn), 4.87 (d, J = 11.6 Hz, 1H,
CH2Bn) 4.78 – 4.65 (m, 4H, CH2Bn), 4.53 – 4.40 (m, 3H, CH2Bn), 4.14 –
4.08 (m, 2H, CH2CH3), 4.08 – 4.02 (m, 1H, H-4), 4.00 (d, J = 8.8 Hz, 1H,
H-2), 3.66 – 3.58 (m, 1H, H-8), 3.57 – 3.51 (m, 1H, H-8), 3.47 (dd, J =
8.8, 1.7 Hz, 1H, H-3), 2.47 – 2.38 (m, 1H, H-5), 2.09 (t, J = 4.6 Hz, 1H, H-
7), 1.72 (dd, J = 9.4, 4.4 Hz, 1H, H-1/H-6), 1.59 – 1.52 (m, 1H, H-1/H-6),
1.22 (s, 3H, CH3). 13C NMR (101 MHz, CDCl3): δ (ppm) 174.0 (Cq
carbonyl), 139.2, 138.9, 138.6, 138.3 (4 x Cq Bn), 128.6, 128.5, 128.4,
128.3, 128.0, 127.8, 127.8, 127.7, 127.6, 127.6, 127.6, 127.4 (CHarom),
84.3 (C-3), 77.7 (C-2), 74.9 (CH2 Bn), 74.8 (C-4), 73.4, 72.9, 72.7 (3 x
CH2 Bn), 70.4 (C-8), 60.7 (CH2CH3), 38.4 (C-5), 26.1, 23.1 (C-1 and C-6),
22.6 (C-7), 14.4 (CH3). HRMS: calculated for [C39H43O6]+ 607.30542,
found 607.30550.
(1S,2S,3R,4S,5R,6R)-2,3,4-tris(benzyloxy)-5-((benzyloxy)methyl)
bicyclo[4.1.0]heptane (36)
To a solution of DCM (0.5 mL) and 1,2-dimethoxyethane (100 μL) was
added consecutively boron trifluoride ethyl etherate (62 μL) and
diethylzinc (1 M in hexane, 1.0 mL, 1.0 mmol) at room temperature. After
stirring for 5 min, diiodomethane (161 μL, 2.0 mmol) was added and the
reaction mixture was stirred for additional 5 min. Compound 35 (52.0 mg,
0.100 mmol) was dissolved in DCM (1.0 mL) and added dropwise to the
reaction mixture. After stirring overnight, the reaction mixture was
quenched with a saturated aqueous NH4Cl solution and diluted with
EtOAc. The aqueous layer was extracted with EtOAc (3x) and the
combined organic layers were washed with brine, dried over MgSO4,
filtered and concentrated in vacuo. Purification by column
chromatography (pentane → 8% EtOAc in pentane) gave benzylated
cyclopropane 36 (45.1 mg, 84.3 μmol, 84%) as a clear oil. 1H NMR (400
MHz, CDCl3): δ (ppm) 7.47 – 7.21 (m, 20H, Harom Bn), 4.86 (dd, J = 27.0,
11.7 Hz, 2H, CH2 Bn), 4.76 – 4.62 (m, 3H, CH2 Bn), 4.58 (d, J = 11.7 Hz,
1H, CH2 Bn), 4.47 (d, J = 4.4 Hz, 2H, CH2 Bn), 4.39 (dd, J = 8.4, 6.6 Hz,
1H, H-2), 3.90 (s, 1H, H-4), 3.66 – 3.52 (m, 2H, H-8), 3.19 (dd, J = 8.4,
1.1 Hz, 1H, H-3), 1.90 – 1.85 (m, 1H, H-5), 1.55 – 1.40 (m, 1H, H-1), 0.84
– 0.69 (m, 2H, H-6 and H-7), 0.30 (q, J = 5.2 Hz, 1H, H-7). 13C NMR (101
MHz, CDCl3): δ (ppm) 139.4, 139.4, 139.2, 138.4 (Cq Bn), 128.5, 128.4,
128.4, 128.3, 128.1, 128.0, 127.9, 127.8, 127.5, 127.5, 127.4 (Carom Bn),
83.3 (C-3), 76.8 (C-2), 76.3 (C-4), 74.0, 73.3, 72.8, 71.3 (CH2 Bn), 42.4
(C-5), 16.3 (C-1), 14.0 (C-6), 11.5 (C-7). HRMS: calculated for
[C36H39O4]+ 557.26623, found 557.26551.
((1R,2S,3R,4S,5R,6R,7R)-2,3,4-tris(benzyloxy)-5-((benzyloxy)methyl)
bicyclo[4.1.0]heptan-7-yl)methanol (40) and ((1S,2S,3R,4S,5R,6S,
7S)-2,3,4-tris(benzyloxy)-5-((benzyloxy)methyl)bicyclo[4.1.0]heptan-
7-yl)methanol (41)
A mixture of 38 and 39 (0.254 g, 0.420 mmol) was dissolved in DCM (2.1
mL) at 0 °C, after which DIBAL (1 M in hexanes, 1.05 mmol, 2.5 eq.) was
added dropwise. After the mixture was stirred for 1 h at 0 °C the reaction
was quenched with EtOAc, diluted with DCM and washed with 1 M
aqueous HCl. The layers were separated and the aqueous layer was
extracted three times with DCM. The combined organic layers were
washed with saturated aqueous NaHCO3 and brine, dried over MgSO4,
filtered and concentrated in vacuo. Purification by column
chromatography (pentane → 30% EtOAc in pentane) yielded compound
40 (94.5 mg, 0.167 mmol, 40%) and 41 (85.7 mg, 0.152 mmol, 36%) as
yellow oils. Analytical data for 40: 1H NMR (400 MHz, CDCl3): δ (ppm)
7.42 – 7.21 (m, 20H, CHarom), 4.88 (d, J = 11.6 Hz, 1H, CH2 Bn), 4.78 (d,
J = 11.6 Hz, 1H, CH2 Bn), 4.73 – 4.64 (m, 3H, CH2 Bn), 4.57 (d, 11.6 Hz,
1H, CH2 Bn), 4.52 – 4.40 (m, 2H, CH2 Bn), 4.35 (t, J = 8.0 Hz, 1H, H-2),
3.89 (s, 1H, H-4), 3.65 – 3.51 (m, 2H, H-8), 3.44 (dd, J = 11.2, 6.7 Hz,
1H, CHHOH), 3.35 (dd, J = 11.2, 6.8 Hz, 1H, CHHOH), 3.17 (d, J = 8.3
Hz, 1H, H-3), 1.93 – 1.79 (m, 1H, H-5), 1.36 – 1.30 (m, 1H, H-1) 1.07 –
0.99 (m, 1H, H-7), 0.72 – 0.63 (m, 1H, H-6). 13C NMR (101 MHz, CDCl3):
δ (ppm) 139.3, 139.3, 139.0, 138.3 (4 x Cq-arom), 128.5, 128.5, 128.4,
128.3, 128.1, 128.0, 127.9, 127.8, 127.6, 127.5, 127.5 (CHarom), 83.6 (C-
3), 76.9 (C-2), 76.1 (C-4), 74.0, 73.3, 72.9, 71.7 (4 x CH2 Bn), 71.1 (C-8),
66.6 (CH2OH), 41.8 (C-5), 27.4 (C-7), 22.1 (C-1), 19.5 (C-6). HRMS:
(1S,2S,3R,4S,5R,6R)-5-(hydroxymethyl)bicyclo[4.1.0]heptane-2,3,4-
triol (37)
Compound 36 (40.0 mg, 74.8 μmol) was treated according to General
procedure for global debenzylation with Pd(OH)2/C to obtain title
compound 37 as a clear oil (13.0 mg, 74.7 μmol, 99%). 1H NMR (400
MHz, D2O): δ (ppm) 4.20 (dd, J = 9.0, 6.6 Hz, 1H, H-2), 3.80 (s, 1H, H-4),
3.76 – 3.62 (m, 2H, H-8), 3.17 (dd, J = 9.1, 1.7 Hz, 1H, H-3), 1.83 – 1.78
(m, 1H, H-5), 1.42 – 1.32 (m, 1H, H-1), 0.82 – 0.75 (m, 2H, H-6 and H-7),
0.25 – 0.18 (m, 1H, H-7). 13C NMR (101 MHz, D2O): δ (ppm) 73.6 (C-3),
71.8 (C-4), 69.4 (C-2), 62.9 (C-8), 43.3 (C-5), 17.6 (C-1), 12.5 (C-6), 10.4
(C-7). HRMS: calculated for [C8H14O4Na]+ 197.07843, found 197.07839.
(1R,2S,3R,4S,5R,6R,7R)-ethyl 2,3,4-tris(benzyloxy)-5-((benzyloxy)
methyl)bicyclo[4.1.0]heptane-7-carboxylate (38) and (1S,2S,3R,4S,
5R,6S,7S)-ethyl 2,3,4-tris(benzyloxy)-5-((benzyloxy)methyl)bicyclo
[4.1.0]heptane-7-carboxylate (39)
calculated
for
[C37H41O5]+
565.29485,
found
565.29480.
Analytical data for 41: 1H NMR (400 MHz, CDCl3): δ (ppm) 7.41 – 7.20
(m, 20H, CHarom), 4.85 (d, J = 11.6 Hz, 1H, CH2 Bn), 4.78 – 4.67 (m, 4H,
CH2 Bn), 4.53 – 4.41 (m, 3H, CH2 Bn), 4.01 – 3.92 (m, 2H, H-2 and H-4),
3.64 – 3.52 (m, 2H, H-8), 3.50 – 3.41 (m, 2H, H-3 and CHHOH), 3.16
(dd, J = 11.1, 7.7 Hz, 1H, CHHOH), 2.47 – 2.38 (m, 1H, H-5), 1.51 – 1.48
A 2-necked pear flask was charged with cyclic alkene 35 (2.94 g, 5.65
mmol), Cu(acac)2 (153 mg, 0.57 mol, 0.1 eq.) and EtOAc (10 mL, dried
over activated 4 Å molsieves overnight). After stirring under reflux at
90 °C a solution of ethyl diazoacetate (13 wt% DCM, 17.1 mmol, 1.46 mL,
3 eq.) in EtOAc (38 mL) was added by syringe pump over 12 h. The
reaction was concentrated in vacuo and purification by column
chromatography (5% à 7% EtOAc in pentane) gave a mixture of the
desired products 38 (666 mg, 1.10 mmol, 19%) and 39 (333 mg, 0.55
mmol, 10%). Spectral data was obtained from analytical samples of both
products. 38: 1H NMR (400 MHz, CDCl3): δ (ppm) 7.34 – 7.23 (m, 20H,
HaromBn), 4.88 (d, J = 11.6 Hz, 1H, CH2Bn), 4.81 – 4.60 (m, 4H, CH2Bn),
4.56 (d, J = 11.6 Hz, 1H, CH2Bn), 4.50 – 4.40 (m, 2H, CH2Bn), 4.37 (dd,
J = 8.2, 6.4 Hz, 1H, H-2), 4.14 – 4.08 (m, 2H, CH2CH3), 3.91 (s, 1H, H-4),
3.64 (t, J = 9.0 Hz, 1H, H-8), 3.56 (dd, J = 8.6, 6.3 Hz, 1H, H-8), 3.15 (d,
J = 8.2 Hz, 1H, H-3), 2.13 – 2. 04 (m, 1H, H-1), 1.99 – 1.93 (m, 1H, H-5),
1.62 – 1.58 (m, 1H, H-7), 1.40 – 1.34 (m, 1H, H-6), 1.28 – 1.25 (m, 3H,
(m, 1H, H-7), 1.01 – 0.95 (m, 1H, H-1), 0.86 – 0.79 (m, 1H, H-6). 13
C
NMR (101 MHz, CDCl3) δ (ppm) 139.3, 139.1, 139.0, 138.4 (4 x Cq-arom),
128.6, 128.5, 128.4, 128.3, 128.0, 127.9, 127.8, 127.7, 127.6, 127.6,
127.5, 127.4 (CHarom), 84.4 (C-3), 78.2 (C-2), 75.4 (C-4), 74.7, 73.5, 72.8,
72.8 (4 x CH2 Bn), 71.0 (C-8), 67.0 (CH2OH), 37.9 (C-5), 23.2 (C-7), 21.5
(C-1), 18.3 (C-6). HRMS: calculated for [C37H41O5]+ 565.29485, found
565.29472.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701601
European Journal of Organic Chemistry
FULL PAPER
(1R,2S,3R,4S,5R,6R,7R)-5,7-bis(hydroxymethyl)bicyclo[4.1.0]
heptane-2,3,4-triol (42)
(3x) and brine. The combined aqueous layers were extracted with EtOAc
and the combined organic layers were dried over MgSO4, filtered and
concentrated in vacuo. Purification by column chromatography (pentane
→ 20% EtOAc in pentane) gave ether 45 as a yellow oil (29.6 mg, 50.0
µmol, 74%). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.40 – 7.22 (m, 20H,
Harom), 4.87 (d, J = 11.6 Hz, 1H, CH2 Bn), 4.80 – 4.67 (m, 4H, CH2 Bn),
4.49 – 4.44 (m, 3H, CH2 Bn), 4.03 (dd, J = 3.8, 1.7 Hz, 1H, H-4), 3.99 (d,
J = 8.7 Hz, 1H, H-2), 3.68 – 3.61 (m, 1H, H-8), 3.59 – 3.50 (m, 1H, H-8),
3.47 – 3.40 (m, 3H, H-3 and CH2CH3), 3.20 (d, J = 6.8 Hz, 2H, CH2O),
2.40 – 2.37 (m, 1H, H-5), 1.51 – 1.43 (m, 1H, H-7), 1.17 (t, J = 7.0 Hz,
3H, CH3), 0.99 (dd, J = 8.9, 4.4 Hz, 1H, H-6), 0.85 – 0.77 (m, 1H, H-1).
13C NMR (101 MHz, CDCl3): δ (ppm) 139.5, 139.2, 139.0, 138.5 (4 x Cq-
arom), 128.5, 128.4, 128.4, 128.3, 128.3, 128.2, 128.1, 127.9, 127.9,
127.7, 127.6, 127.5, 127.5, 127.5, 127.4, 127.3 (CH Bn), 84.8 (C-3), 78.3
(C-2), 75.4 (C-4), 74.8 (CH2 Bn), 74.4 (CH2O), 73.5, 72.7, 72.4 (3 x CH2
Bn), 71.0 (C-8), 65.6 (CH2CH3), 38.6 (C-5), 21.3 (C-6), 20.5 (C-7), 18.4
(C-1), 15.4 (CH3). HRMS: calculated for [C39H45O5]+ 593.32615, found
593.32603.
Alcohol 40 (30.0 mg, 53 µmol) was treated according to General
procedure for global debenzylation with 10% Pd on carbon to obtain the
title compound 42 (10.9 mg, 53 µmol, quant.) as a clear oil. 1H NMR (400
MHz, D2O): δ (ppm) 4.20 (dd, J = 9.1, 6.6 Hz, 1H, H-2), 3.85 – 3.82 (m,
1H, H-4), 3.78 – 3.66 (m, 2H, H-8), 3.58 (dd, J = 11.6, 6.1 Hz, 1H, C-
HHOH), 3.27 (dd, J = 11.6, 7.8 Hz, 1H, CHHOH), 3.20 (dd, J = 9.1, 1.8
Hz, 1H, H-3), 1.90 – 1.82 (m, 1H, H-5), 1.36 – 1.29 (m, 1H, H-1), 1.05 –
0.97 (m, 1H, H-7), 0.77 – 0.70 (m, 1H, H-6). 13C NMR (101 MHz, D2O): δ
(ppm) 74.0 (C-3), 71.6 (C-4), 68.6 (C-2), 65.3 (CH2OH), 62.7 (C-8), 42.7
(C-5), 25.8 (C-7), 23.2 (C-1), 18.3 (C-6). HRMS: calculated for
[C9H16O5Na]+ 227.08899, found 227.08899.
(1S,2S,3R,4S,5R,6S,7S)-5,7-bis(hydroxymethyl)bicyclo[4.1.0]
heptane-2,3,4-triol (43)
Alcohol 41 (35 mg, 62 µmol) was treated according to General procedure
for global debenzylation with 10% Pd on carbon to obtain the title
compound 43 (11.2 mg, 54 µmol, 87%) as a clear oil. 1H NMR (400 MHz,
D2O): δ (ppm) 4.01 – 3.95 (m, 1H, H-4), 3.83 (d, J = 8 Hz 1H, H-2), 3.78
– 3.64 (m, 2H, H-8), 3.41 – 3.31 (m, 3H, CH2OH and H-3), 2.29 – 2.20 (m,
1H, H-5), 1.31 – 1.21 (m, 1H, H-7), 1.02 – 0.92 (m, 1H, H-6), 0.92 – 0.84
(m, 1H, H-1). 13C NMR (101 MHz, D2O): δ (ppm) 76.0 (C-3), 69.6, 69.5
(C-2 and C-4), 65.6 (CH2OH), 62.4 (C-8), 38.8 (C-5), 22.6 (C-7), 21.9 (C-
1), 17.8 (C-6). HRMS: calculated for [C9H17O5]+ 205.10705, found
205.10753.
(1R,2S,3R,4S,5R,6R,7R)-7-(ethoxymethyl)-5-(hydroxymethyl)bicyclo
[4.1.0]heptane-2,3,4-triol (46)
Ether 44 (20 mg, 34 µmol) was treated according to General procedure
for global debenzylation with 10% Pd on carbon to obtain the title
compound 46 (8.0 mg, 35 µmol, quant.) as a clear oil. 1H NMR (400 MHz,
D2O): δ (ppm) 4.22 – 4.18 (dd, J = 6.4, 9.2 Hz, 1H, H-2), 3.83 (s, 1H, H-
4), 3.75 – 3.67 (m, 2H, H-8), 3.63 – 3.51 (m, 3H, CHHO and CH2CH3),
3.23 – 3.13 (m, 2H, CHHO and H-3), 1.91 – 1.83 (m, 1H, H-5), 1.38 –
1.28 (m, 1H, H-1), 1.17 (t, J = 7.1 Hz, 3H, CH3), 1.05 – 0.96 (m, 1H, H-7),
0.80 – 0.73 (m, 1H, H-6). 13C NMR (101 MHz, D2O): δ (ppm) 73.9, 73.8
(C-3 and CH2O), 71.5 (C-4), 68.6 (C-2), 66.1 (CH2CH3), 62.6 (C-8), 42.6
(C-5), 23.3, 23.2 (C-1 and C-7), 18.7 (C-6), 14.1 (CH3). HRMS:
calculated for [C11H20O5Na]+ 255.12029, found 255.12034.
(1R,2S,3R,4S,5R,6R,7R)-2,3,4-tris(benzyloxy)-5-((benzyloxy)methyl)-
7-(ethoxymethyl)bicyclo[4.1.0]heptane (44)
To a solution of alcohol 40 (33.9 mg, 60.0 µmol) and TBAI (10 mg) in
DMF (0.8 mL) was added NaH (60% dispersion in mineral oil, 19.2 mg,
0.480 mmol 8 eq.) at 0 °C. After stirring the reaction mixture for 5 min,
ethyl bromide (20 µL, 0.36 mmol, 6 eq.) was added and the reaction
mixture was stirred overnight at room temperature. The reaction mixture
was quenched with H2O (3 mL) and diluted with EtOAc (20 mL). The
organic layer was separated and washed with saturated aqueous
NaHCO3, H2O (3x) and brine. The combined aqueous layers were
extracted with EtOAc and the combined organic layers were dried over
MgSO4, filtered and concentrated in vacuo. Purification by column
chromatography (pentane → 20% EtOAc in pentane) gave ether 44 as a
yellow oil (28.5 mg, 48.1 µmol, 80%). 1H NMR (400 MHz, CDCl3): δ
(ppm) 7.43 – 7.21 (m, 20H, Harom), 4.88 (d, J = 11.6 Hz, 1H, CH2 Bn),
4.83 (d, J = 11.6 Hz, 1H, CH2 Bn), 4.77 – 4.61 (m, 3H, CH2 Bn), 4.58 (d,
J = 11.7 Hz, 1H, CH2 Bn), 4.52 – 4.40 (m, 2H, CH2 Bn), 4.39 – 4.33 (m,
1H, H-2), 3.90 (s, 1H, H-4), 3.68 – 3.53 (m, 2H, H-8), 3.52 – 3.37 (m, 2H,
CH2CH3), 3.35 – 3.22 (m, 2H, CH2O), 3.18 (d, J = 8.3 Hz, 1H, H-3), 1.97
– 1.87 (m, 1H, H-5), 1.41 – 1.35 (m, 1H, H-1), 1.15 (t, J = 7.0 Hz, 3H,
CH3), 1.04 (p, J = 6.2 Hz, 1H, H-7), 0.70 – 0.64 (m, 1H, H-6). 13C NMR
(101 MHz, CDCl3): δ (ppm) 139.5, 139.4, 139.2, 138.4 (4 x Cq-arom),
128.5, 128.4, 128.3, 128.3, 128.1, 127.9, 127.8, 127.5, 127.5, 127.4 (CH
Bn), 83.6 (C-3), 76.9 (C-2), 76.2 (C-4), 74.2, 74.0, 73.3, 72.9 (3 x CH2 Bn
and CH2O), 71.1, 71.0 (CH2 Bn and C-8), 65.8 (CH2CH3), 41.8 (C-5),
24.5 (C-7), 21.6 (C-1), 20.0 (C-6), 15.4 (CH3). HRMS: calculated for
[C39H45O5]+ 593.32615, found 593.32617.
(1S,2S,3R,4S,5R,6S,7S)-7-(ethoxymethyl)-5-(hydroxymethyl)bicyclo
[4.1.0]heptane-2,3,4-triol (47)
Ether 45 (23.0 mg, 39 µmol) was treated according to General procedure
for global debenzylation with 10% Pd on carbon to obtain the title
compound 47 (9.0 mg, 39 µmol, quant.) as a clear oil. 1H NMR (400
MHz, D2O): δ (ppm) 4.02 – 3.95 (m, 1H, H-4), 3.84 (d, J = 8.9 Hz, 1H, H-
2), 3.75 – 3.67 (m, 2H, H-8), 3.62 – 3.52 (m, 2H, CH2CH3), 3.42 – 3.33
(m, 2H, H-3 and CHHO), 3.29 – 3.22 (m, 1H, CHHO), 2.31 – 2.21 (m, 1H,
H-5), 1.32 – 1.26 (m, 1H, H-7), 1.18 (t, J = 7.1 Hz, 3H, CH3), 1.02 – 0.96
(m, 1H, H-6), 0.93 – 0.86 (m, 1H, H-1). 13C NMR (101 MHz, D2O): δ
(ppm) 75.9 (C-3), 74.2 (CH2O), 69.5, 69.4 (C-2 and C-4), 65.9 (CH2CH3),
62.3 (C-8), 38.9 (C-5), 22.3 (C-1), 20.1 (C-7), 17.9 (C-6), 14.1 (CH3).
HRMS: calculated for [C11H21O5]+ 233.13835, found 233.13951.
(1R,2S,3R,4S,5R,6R,7S)-1-(2,3,4-tris(benzyloxy)-5-((benzyloxy)
methyl)bicyclo[4.1.0]heptan-7-yl)propan-1-one (48) and (1S,2S,3R,
4S,5R,6S,7S)-1-(2,3,4-tris(benzyloxy)-5-((benzyloxy)methyl)bicyclo
[4.1.0]heptan-7-yl)propan-1-one (49)
To a mixture of 38 and 39 (126 mg, 0.207 mmol) in THF (2.7 mL) was
added Me(MeO)NH.HCl (26.3 mg, 0.270 mmol, 1.3 eq.) at -8 oC.
Subsequently, EtMgBr (1 M in THF, 1.7 mL, 1.7 mmol, 8.4 eq.) was
added over 2 h. After the mixture had stirred overnight, it was quenched
with NaOH (0.5 M). The reaction mixture was extracted with EtOAc (10
mL), after which the organic layer was washed with aqueous HCl (3 M).
The organic layer was dried over MgSO4, filtered, concentrated in vacuo
and co-evaporated with toluene (3x). The residue was dissolved in THF
(1 mL) and EtMgBr (1 M in THF, 0.60 mmol, 3 eq.) was added over 2 min
at -20 oC. After the reaction was allowed to come to room temperature
and stirred for 3 h, the reaction was quenched with a saturated aqueous
NH4Cl solution. After extraction with EtOAc (10 mL), the organic layer
was dried over MgSO4, filtered and concentrated in vacuo. Purification by
(1S,2S,3R,4S,5R,6S,7S)-2,3,4-tris(benzyloxy)-5-((benzyloxy)methyl)-
7-(ethoxymethyl)bicyclo[4.1.0]heptane (45)
To a solution of alcohol 41 (38.0 mg, 67.3 µmol) and a catalytic amount
of TBAI in DMF (0.8 mL) was added NaH (60% dispersion in mineral oil,
21.4 mg, 0.536 mmol 8 eq.) at 0 °C. After stirring the reaction mixture for
5 min, ethyl bromide (50 µL, 0.66 mmol, 10 eq.) was added and the
reaction mixture was stirred overnight. The reaction mixture was
quenched with H2O (3 mL) and diluted with EtOAc (20 mL). The organic
layer was separated and washed with saturated aqueous NaHCO3, H2O
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701601
European Journal of Organic Chemistry
FULL PAPER
column chromatography (8% EtOAc in pentane
→
10% EtOAc in
(1R,2S,3R,4S,5R,6R,7R)-N-(4-azidobutyl)-2,3,4-tris(benzyloxy)-5-
((benzyloxy)methyl)bicyclo[4.1.0]heptane-7-carboxamide (52) and
(1S,2S,3R,4S,5R,6S,7S)-N-(4-azidobutyl)-2,3,4-tris(benzyloxy)-5-
((benzyloxy)methyl)bicyclo[4.1.0]heptane-7-carboxamide (53)
pentane) followed by purification by HPLC (C18, linear gradient: 50-90%
B in A, solutions used A: H2O, B: acetonitrile, 0.1% TFA, 15 min) gave
compound 48 (19.4 mg, 32.8 µmol, 16%) and compound 49 (25.2 mg,
42.6 µmol, 21%). Analytical data for 48: 1H NMR (400 MHz, CDCl3): δ
(ppm) 7.39 – 7.22 (m, 20 H, Harom), 4.88 (d, J = 11.6 Hz, 1H, CH2Bn),
4.76 – 4.52 (m, 5H, CH2Bn), 4.44 (d, J = 3.1 Hz, 2H, CH2Bn), 4.35 (dd, J
= 8.3, 6.3 Hz, 1H, H-2), 3.92 (s, 1H, H-4), 3.63 (t, J = 9.0 Hz, 1H, H-8),
3.57 – 3.50 (m, 1H, H-8), 3.19 (d, J = 7.6 Hz, 1H, H-3), 2.56 (d, J = 8.0
Hz, 1H, CHHCH3), 2.52 (d, J = 8.0 Hz, 1H, CHHCH3), 2.14 – 2.07 (m,
1H, H-1), 1.98 – 1.87 (m, 2H, H-5 and H-7), 1.48 – 1.39 (m, 1H, H-6),
1.06 (t, J = 7.3 Hz, 3H, CH3). 13C NMR (101 MHz, CDCl3) δ (ppm) 209.81
(Cq carbonyl), 139.2, 139.0, 138.9, 138.2 (4 x Cq-arom), 128.6, 128.5,
128.4, 128.3, 128.0, 127.9, 127.9, 127.9, 127.7, 127.5, 127.5 (CH Bn),
83.2 (C-3), 76.5 (C-2), 75.6 (C-4), 74.1, 73.5, 72.9, 71.6 (4 x CH2 Bn),
70.6 (C-8), 41.7 (C-5), 37.1 (CH2CH3), 33.7 (C-7), 29.9 (C-1), 26.6 (C-6),
8.1 (CH3). HRMS: calculated for [C39H43O5]+ 591.31050, found
591.31043. Analytical data for 49: 1H NMR (400 MHz, CDCl3): δ (ppm)
7.39 – 7.22 (m, 20H, Harom), 4.90 (d, J = 11.6 Hz, 1H, CH2Bn), 4.80 –
4.60 (m, 4H, CH2Bn), 4.53 – 4.38 (m, 3H, CH2Bn), 4.07 – 4.01 (m, 1H, H-
4), 3.96 (d, J = 8.7 Hz, 1H, H-2), 3.58 (t, J = 8.8 Hz, 1H, H-8), 3.54 – 3.44
(m, 2H, H-3 and H-8), 2.50 – 2.39 (m, 3H, CH2CH3, H-7), 1.78 (dd, J =
9.2, 4.4 Hz, 1H, H-1/H-6), 1.60 – 1.5 (m, 1H, H-1/H-6), 1.03 (t, J = 7.3 Hz,
3H, CH3). 13C NMR (101 MHz, CDCl3): δ (ppm) 210.38 (Cq carbonyl),
139.4, 138.9, 138.5, 138.3 (4 x Cq-arom), 128.6, 128.5, 128.4, 128.4,
128.0, 127.9, 127.8, 127.7, 127.6, 127.5, 127.4 (CH Bn), 84.2 (C-2), 77.9
(C-3), 75.1 (C-4), 74.9, 73.5, 72.9, 72.5 (4 x CH2 Bn), 70.4 (C-8), 38.5 (C-
5), 37.1 (CH2CH3), 30.0 (C-7), 28.1, 25.9 (C-1 and C-6), 8.2 (CH3).
HRMS: calculated for [C39H43O5]+ 591.31050, found 591.31025.
To a mixture of 38 and 39 (0.260 g, 0.428 mmol) in THF (16 mL), EtOH
(4 mL), H2O (3 mL) and MeOH (0.5 mL), was added LiOH (150 mg, 6.3
mmol, 14.7 eq.). After the mixture was stirred overnight at room
temperature, 1 M aqueous HCl solution was used to acidify to pH 1, and
the reaction mixture was partitioned between EtOAc (125 mL) and brine
(30 mL). The aqueous layer was extracted with EtOAc (50 mL) and the
combined organic layers were dried over MgSO4, filtered and
concentrated in vacuo, resulting in a yellow oil. The crude acid was used
without further purification. HRMS: calculated for [C37H39O6]+ 579.27412,
found 579.27384. The crude acid was dissolved in DCM (7.6 mL) to this
were added 4-azidobutan-1-amine (52 mg, 0.456 mmol, 1.1 eq.), N,N-
diisopropylethylamine (230 µL, 1.33 mmol, 3.1 eq.) and HCTU (188 mg,
0.456 mmol, 1.1 eq.). After stirring overnight at room temperature, the
reaction mixture was concentrated in vacuo, redissolved in EtOAc (40
mL), washed with 1 M aqueous HCl and saturated aqueous NaHCO3,
dried over MgSO4, filtered and concentrated in vacuo. Purification by
column chromatography (pentane → 30% EtOAc in pentane) followed by
purification by HPLC (C18, linear gradient: 70-90% B in A, solutions used
A: H2O, B: acetonitrile, 0.1% TFA, 15 min) afforded compound 52 (68.9
mg, 0.102 mmol, 24%) and compound 53 (51.0 mg, 75.6 μmol, 18%) as
white solids. Analytical data for 52: 1H NMR (400 MHz, CDCl3): δ (ppm)
7.39 – 7.21 (m, 20H, Harom), 5.70 – 5.63 (m, 1H, NH), 4.88 (d, J = 11.6 Hz,
1H, CH2 Bn), 4.75 – 4.55 (m, 5H, CH2 Bn), 4.44 (d, J = 2.7 Hz, 2H, CH2
Bn), 4.39 (dd, J = 8.3, 6.5 Hz, 1H, H-2), 3.93 (s, 1H, H-4), 3.66 (t, J = 8Hz,
1H, H-8), 3.58 – 3.54 (m, 1H, H-8), 3.31 –3.22 (m, 4H, 2 x CH2 amide),
3.13 (d, J = 8.4 Hz, 1H, H-3), 2.15 – 2.05 (m, 1H, H-1), 1.93 – 1.85 (m,
1H, H-5), 1.64 – 1.48 (m, 4H, 2 x CH2 amide), 1.45 – 1.36 (m, 1H, H-6),
1.31 – 1.23 (m, 1H, H-7). 13C NMR (101 MHz, CDCl3): δ (ppm) 172.1
(C=O), 139.2, 138.9, 138.8, 138.2 (4 x Cq), 128.5, 128.4, 128.4, 128.3,
128.1, 127.9, 127.9, 127.7, 127.5, 127.5 (CHarom), 83.1 (C-3), 76.4 (C-2),
75.5 (C-4), 74.1, 73.5, 72.7, 71.5 (4 x CH2 Bn), 70.6 (C-8), 51.1 (CH2
amide), 41.6 (C-5), 39.2 (CH2 amide), 28.1 (C-7), 27.2, 26.3 (2 x CH2
amide), 26.0 (C-1), 23.0 (C-6). HRMS: calculated for [C41H47N4O5]+
675.35410, found 675.35401. Analytical data for 53 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.40 – 7.24 (m, 20H, Harom), 5.56 (t, J = 5.6 Hz, 1H, NH),
4.86 (d, J = 11.2 Hz, 1H, CH2 Bn), 4.81 – 4.61 (m, 4H, CH2 Bn), 4.54 –
4.42 (m, 3H, CH2 Bn), 4.06 – 4.05 (m, 1H, H-4), 3.96 (d, J = 14.8 Hz, 1H,
H-2), 3.60 (t, J = 9.0 Hz, 1H, H-8), 3.56 – 3.52 (m, 1H, H-8), 3.49 (dd, J =
8.7, 1.6 Hz, 1H, H-3), 3.31 – 3.16 (m, 4H, 2 x CH2 amide), 2.51 – 2.42
(m, 1H, H-5), 1.77 – 1.72 (m, 2H, H-1 and H-7), 1.60 – 1.51 (m, 5H, H-6
and 2 x CH2 amide). 13C NMR (101 MHz, CDCl3): δ (ppm) 172.77 (C=O),
139.4, 138.9, 138.6, 138.3 (4 x Cq), 128.5, 128.4, 128.4, 128.4, 128.0,
128.0, 127.9, 127.9, 127.8, 127.8, 127.6, 127.5 (CHarom), 84.3 (C-3), 77.7
(C-2), 75.2 (C-4), 75.1, 73.4, 72.9, 72.2 (4 x CH2 Bn), 70.3 (C-8, 51.1
(CH2 amide), 39.3 (CH2 amide), 38.1 (C-5), 27.1, 26.3 (2 xCH2 amide),
24.5, 24.4 (C-1 and C-7), 21.7 (C-6). HRMS: calculated for [C41H47N4O5]+
675.35410, found 675.35385.
(1R,2S,3R,4S,5R,6R,7R)-1-(2,3,4-trihydroxy-5-(hydroxymethyl)
bicyclo[4.1.0]heptan-7-yl)propan-1-one (50)
Ethyl ketone 48 (14.8 mg, 25 µmol) was treated according to General
procedure for global debenzylation with 10% Pd on carbon to obtain the
title compound 50 (4.6 mg, 20 µmol, 80%) as a white solid. 1H NMR (400
MHz, D2O): δ (ppm) 4.26 (dd, J = 9.0, 6.1 Hz, 1H, H-2), 3.89 (s, 1H, H-4),
3.81 – 3.65 (m, 2H, H-8), 3.29 (dd, J = 9.1, 1.6 Hz, 1H, H-3), 2.74 (d, J =
8.0 Hz, 1H, CHHCH3), 2.70 (d, J = 8.0 Hz, 1H, CHHCH3), 2.18 (t, J = 4.6
Hz, 1H, H-7), 2.11 – 2.04 (m, 1H, H-1), 2.03 – 1.96 (m, 1H, H-5), 1.50 –
1.42 (m, 1H, H-6), 1.04 (t, J = 7.3 Hz, 3H, CH3). 13C NMR (101 MHz,
D2O): δ (ppm) 216.2 (C=O), 73.4 (C-3), 71.1 (C-4), 68.0 (C-2), 62.3 (C-
8), 42.4 (C-5), 36.5 (CH2CH3), 33.2 (C-7), 31.8 (C-1), 26.5 (C-6), 7.4
(CH3). HRMS: calculated for [C11H19O5]+ 231.12270, found 231.12260.
(1S,2S,3R,4S,5R,6S,7S)-1-(2,3,4-trihydroxy-5-(hydroxymethyl)bicycle
[4.1.0]heptan-7-yl)propan-1-one (51)
Ethyl ketone 49 (12.0 mg, 20 µmol) was treated according to General
procedure for global debenzylation with 10% Pd on carbon to obtain the
title compound 51 (4.0 mg, 18 µmol, 88%) as a white solid. 1H NMR (400
MHz, D2O): δ (ppm) 3.93 (t, J = 2.8 Hz, 1H, H-4), 3.81 (d, J = 9.2 Hz, 1H,
H-2), 3.72 – 3.55 (m, 2H, H-8), 3.36 (dd, J = 9.0, 2.3 Hz, 1H, H-3), 2.64 –
2.54 (m, 2H, CH2CH3), 2.37 (t, J = 4.6 Hz, 1H, H-7), 2.30 – 2.21 (m, 1H,
H-5), 1.66 – 1.56 (m, 2H, H-1 and H-6), 0.96 (t, J = 7.4 Hz, 3H, CH3). 13
C
(1R,2S,3R,4S,5R,6R,7R)-N-(4-azidobutyl)-2,3,4-trihydroxy-5-(hydroxy
methyl)bicyclo[4.1.0]heptane-7-carboxamide (54)
NMR (101 MHz, D2O): δ (ppm) 217.1 (C=O), 75.4 (C-3), 69.0, 68.8 (C-2
and C-4), 62.0 (C-8), 38.8 (C-5), 36.5 (CH2CH3), 30.4 (C-1/C-2 and C-8),
26.6 (C-1/C-2), 7.6 (CH3). HRMS: calculated for [C11H19O5]+ 231.12270,
found 231.12283.
To a solution of benzylated 52 (62.5 mg, 93 µmol) in DCM (0.46 mL) was
added slowly BCl3 (1 M in DCM, 1.9 mL, 1.9 mmol, 20 eq.) at -78 °C.
°
After stirring for 4 h at -78 C, the reaction mixture was quenched with
MeOH (3 mL). concentrated in vacuo and co-evaporated with toluene
(3x). Purification by column chromatography (EtOAc → 20% MeOH in
EtOAc) gave title compound 54 (29.0 mg, 93 µmol, quant.) as a white
solid. 1H NMR (400 MHz, D2O): δ (ppm) 4.25 (dd, J = 9.1, 6.3 Hz, 1H, H-
2), 3.85 (s, 1H, H-4), 3.77 – 3.65 (m, 2H, H-8), 3.33 (t, J = 6.2 Hz, 2H,
CH2 amide), 3.28 – 3.14 (m, 3H, CH2 amide and H-3), 1.97 – 1.87 (m,
2H, H-1 and H-5), 1.66 – 1.52 (m, 5H, 2 x CH2 amide and H-7), 1.31 –
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701601
European Journal of Organic Chemistry
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1.25 (m, 1H, H-6). 13C NMR (101 MHz, D2O): δ (ppm) 174.6 (Cq), 73.5
(C-3), 71.1 (C-4), 67.8 (C-2), 62.3 (C-8), 50.8 (CH2 amide), 42.2 (C-5),
39.1 (CH2 amide), 27.0, 27.0 (C-1 and C-7), 25.8 (CH2 amide), 25.4 (CH2
amide), 21.8 (C-6). HRMS: calculated for [C13H23N4O5]+ 315.16630,
found 315.16638.
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T. J. M. Beenakker, D. P. A. Wander, W. A. Offen, M. Artola, L. Raich,
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(1S,2S,3R,4S,5R,6S,7S)-N-(4-azidobutyl)-2,3,4-trihydroxy-5-(hydroxyl
methyl)bicyclo[4.1.0]heptane-7-carboxamide (55)
K.-Y. Li, J. Jiang, M. D. Witte, W. W. Kallemeijn, H. van den Elst, C.-S.
Wong, S. D. Chander, S. Hoogendoorn, T. J. M. Beenakker, J. D. C.
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To a solution of benzylated 53 (45.0 mg, 66 µmol) in DCM (0.50 mL) was
added slowly BCl3 (1 M in DCM, 1.5 mL, 1.5 mmol, 23 eq.). After stirring
°
for 4 h at -78 C, the reaction mixture was quenched with MeOH (3 mL).
concentrated in vacuo and co-evaporated with toluene (3x). Purification
by column chromatography (EtOAc → 20% MeOH in EtOAc) gave title
compound 55 (14.6 mg, 46.4 µmol, 70%) as a white solid. 1H NMR (400
MHz, D2O): δ (ppm) 3.98 (t, J = 4.0 Hz, 1H, H-4), 3.84 (d, J = 9.0 Hz, 1H,
H-2), 3.74 – 3.62 (m, 2H, H-8), 3.41 (dd, J = 9.0, 2.3 Hz, 1H, H-3), 3.31
(t, J = 6.4 Hz, 2H, CH2 amide), 3.18 (t, J = 6.3 Hz, 2H, CH2 amide), 2.34
– 2.25 (m, 1H, H-5), 1.91 (t, J = 4.7 Hz, 1H, H-7), 1.64 – 1.43 (m, 6H, 2 x
CH2 amide, H-1 and H-6). 13C NMR (101 MHz, D2O): δ (ppm) 175.3
(C=O), 75.5 (C-3), 69.0, 68.9 (C-2 and C-4), 61.9 (C-8), 50.7, 38.9 (2 x
CH2 amide), 38.5 (C-5), 25.8 (CH2 amide), 25.7 (C-6), 25.3 (CH2 amide),
24.0 (C-7), 21.4 (C-1). HRMS: calculated for [C13H23N4O5]+ 315.16630,
found 315.16615.
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Supporting Information (see footnote on the first page of this article):
1H NMR and 13C APT NMR spectra for all new compounds.
Acknowledgements: We thank The Netherlands Organization for
Scientific Research (NWO-CW, ChemThem grant to J.M.A. and H.S.O.)
and the European Research Council (ERC-2011-AdG- 290836
“Chembiosphing” to H.S.O.
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Keywords: cyclophellitol • cyclopropanation • conformational
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analysis • carbohydrate mimetic • glucosidase
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10.1002/ejoc.201701601
European Journal of Organic Chemistry
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Entry for the Table of Contents
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HO
HO
HO
HO
HO
BnO
HO
HO
HO
HO
HO
HO
HO
HO
Key Topic* Stereoselective synthesis
H
H
H
H
Thomas J. M. Beenakker[‡], Dennis P. A.
Wander[‡], Jeroen D. C. Codée,
Johannes M. F. G. Aerts, Gijsbert A. van
der Marel and Herman S. Overkleeft*
R
R
R
R
HO
H
H
H
H
OH
OBn
glucose-configured
OH
OH
OH
and galactose-configured
Page No. – Page No.
Synthesis of carba-cyclophellitols: a
new class of cyclophellitol
derivatives
The synthesis towards a new class of glycosidase inhibitors, carba-cyclophellitols, is described. In these cyclophellitol
derivatives the characteristic cyclophellitol epoxide has been replaced by a stable (substituted) methylene group through the
generation of a cyclopropyl moiety. The challenging cyclopropanation of gluco- and galacto-configured cycloalkenes was
achieved using copper catalysis.
This article is protected by copyright. All rights reserved.