Asymmetric syntheses of methyl N, O-diacetyl-d-3-epi-daunosaminide and methyl N, O-diacetyl-d-ristosaminide

Article abstract of DOI:10.1021/jo4020563

Ab initio asymmetric syntheses of methyl N,O-diacetyl-d-3-epi-daunosaminide and methyl N,O-diacetyl-d-ristosaminide, employing diastereoselective epoxidation and dihydroxylation, respectively, of alkyl (3S,αR,Z)-3-[N- benzyl-N-(α-methylbenzyl)amino]hex-4-

Full text of DOI:10.1021/jo4020563

Article
pubs.acs.org/joc
Asymmetric Syntheses of Methyl N,O‑Diacetyl‑D‑3-epi-
daunosaminide and Methyl N,O‑Diacetyl‑D‑ristosaminide
Kristína Csatayova,† Stephen G. Davies,*,† J. Gair Ford,‡ James A. Lee,† Paul M. Roberts,†
́
and James E. Thomson†
†Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
‡AstraZeneca Pharmaceutical Development, Silk Road Business Park, Macclesfield, Cheshire SK10 2QH, U.K.
S
* Supporting Information
ABSTRACT: Ab initio asymmetric syntheses of methyl N,O-diacetyl-D-3-epi-
daunosaminide and methyl N,O-diacetyl-D-ristosaminide, employing diastereose-
lective epoxidation and dihydroxylation, respectively, of alkyl (3S,αR,Z)-3-[N-
benzyl-N-(α-methylbenzyl)amino]hex-4-enoates as the key steps, are reported. The
requisite substrates were readily prepared using the conjugate additions of lithium
(R)-N-benzyl-N-(α-methylbenzyl)amide to methyl and tert-butyl (E)-hexa-2-en-4-
ynoates followed by diastereoselective alkyne reduction. syn-Dihydroxylation using
OsO4 proceeded under steric control on the 4Re,5Re face of the olefin to give the
corresponding diol, which subsequently underwent lactonization. Meanwhile,
epoxidation using F3CCO3H in conjunction with F3CCO2H proceeded on the
opposite 4Si,5Si face of the olefin under hydrogen-bonding control from the in situ
formed ammonium ion. Treatment of the intermediate epoxide with concd aq
H2SO4 promoted highly regioselective ring-opening (distal to the in situ formed
ammonium moiety) to give the corresponding diol (completing overall the formal anti-dihydroxylation of the olefin), which then
underwent lactonization under the reaction conditions. Elaboration of these diastereoisomeric lactones through hydrogenolysis,
N-Boc protection, reduction, methanolysis, and acetate protection gave methyl N,O-diacetyl-D-3-epi-daunosaminide and methyl
N,O-diacetyl-D-ristosaminide.
For example, treatment of 10 with 40% aq HBF4 followed by
m-chloroperbenzoic acid (m-CPBA) gave an ∼70:30 mixture of
lactones 13 and 14. This is consistent with a completely
diastereoselective (>95:5 dr), ammonium-directed epoxida-
tion18,19 of the 4Si,5Re face20 of 10 to give epoxide 11, followed
by regioselective ring-opening at the C(5)-oxirane carbon atom
(distal to the in situ formed ammonium moiety) to give the
corresponding diol 12 (overall a formal anti-dihydroxylation of
the olefin). Lactonization of 12 under the acidic reaction
conditions upon attack of either the C(4)-hydroxyl group or
the C(5)-hydroxyl group at the carbonyl group gives γ-lactone
13 or δ-lactone 14, respectively. The mixture of lactones 13 and
14 was converted to the corresponding 2,3,6-trideoxy-3-
aminohexose, viz. L-acosamine 4, which was isolated as the
corresponding N,O-diacetyl-protected methyl glycoside 15 in
only seven steps and 15% overall yield from sorbic acid15
(Scheme 1).
INTRODUCTION
■
An amino sugar is any species resulting from the formal
replacement of any of the nonglycosidic hydroxyl groups of a
monosaccharide with an amino group. The amino sugar family
of compounds comprises a structurally diverse array of species,
and an important, specific subclass of these are the 2,3,6-
trideoxy-3-aminohexoses: daunosamine 1,1 3-epi-daunosamine
2,2 ristosamine 3,3,4 and acosamine 4.5 These compounds have
attracted considerable interest, mainly due to their occurrence
as the glycosidic fragment of a variety of naturally occurring and
synthetic anthracycline antibiotics,6 for example, naturally
occurring daunorubicin 5,7 doxorubicin 6,8 and carubicin 79
and the synthetic analogues idarubicin 810 and epirubicin 911
(Figure 1).
As a result of these potential therapeutic applications, a range
of approaches to enable syntheses of the 2,3,6-trideoxy-3-
aminohexoses have been developed,12 with the majority of
these commencing with carbohydrate-derived starting materials
as the sources of chirality.13 In contrast, relatively few
asymmetric syntheses have been reported.14 We have shown
that (E)-configured β-amino-γ,δ-unsaturated esters such as 10,
which are readily derived from conjugate addition of lithium
(R)-N-benzyl-N-(α-methylbenzyl)amide to the requisite ester
of (E,E)-hexa-2,4-dienoic acid (sorbic acid), are valuable
precursors for the synthesis of amino sugars through their
oxidative functionalization in a diastereoselective manner.15−17
Herein, efficient asymmetric syntheses of methyl N,O-
diacetyl-D-3-epi-daunosaminide and methyl N,O-diacetyl-D-
ristosaminide are reported, which employ highly diastereose-
lective epoxidation and dihydroxylation, respectively, of (Z)-
configured β-amino-γ,δ-unsaturated esters 16 as the key steps.
From the outset of these studies, it was expected that these
Received: September 16, 2013
Published: November 20, 2013
© 2013 American Chemical Society
12397
dx.doi.org/10.1021/jo4020563 | J. Org. Chem. 2013, 78, 12397−12408

The Journal of Organic Chemistry
Article
intermediate epoxide 17 was expected to occur at C(5), distal
to the ammonium moiety where its destabilizing electron-
withdrawing influence on the transition state is less
pronounced,25 to give the corresponding diol 18. This
transformation constitutes a formal anti-dihydroxylation of
the olefin. Diols 18 and 19 represent precursors to the
corresponding 2,3,6-trideoxy-3-amino sugars, viz. D-3-epi-
daunosamine 2 and D-ristosamine 3, respectively (Figure 2).
RESULTS AND DISCUSSION
■
A scalable synthesis of the requisite β-amino esters 25 (R =
t
Me) and 26 (R = Bu) was first developed. A one-pot Swern/
Wittig reaction26 of propargylic alcohol 20 using
Ph3PCHCO2Me as the ylide resulted in the formation of
an 80:20 mixture of enyne diastereoisomers, from which the
major product (E)-21 (3J2,3 = 15.9 Hz) was isolated in 64%
yield as a single diastereoisomer (>99:1 dr). Conjugate addition
of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to (E)-21
gave the corresponding β-amino ester 23 in 61% isolated yield
and 93:7 dr. The absolute (3S,αR)-configuration within 23 was
assigned by reference to the transition-state mnemonic
developed by us to rationalize, and reliably predict, the very
high levels of diastereoselectivity observed upon conjugate
addition of this class of lithium amide.27 Subsequent reduction
of β-amino ester 23 upon treatment with Lindlar’s catalyst28
gave β-amino ester 25 in 95:5 dr [(Z):(E) ratio], which was
isolated in 83% yield and >95:5 dr (Scheme 2). The relative
configuration within 25 was unambiguously established by
single crystal X-ray diffraction analysis,29 with the absolute
(3S,αR,Z)-configuration being assigned from the known (R)-
configuration of the α-methylbenzyl fragment. The predicted
solution-phase conformation was consistent with the observed
solid-state conformation of 25. From this solid-state analysis,
the assigned absolute configuration within β-amino ester 23
was also confirmed. In a directly analogous manner, the
corresponding tert-butyl β-amino ester (3S,αR,Z)-26 was
prepared from propargylic alcohol 20 in 35% overall yield
and >95:5 dr (Scheme 2).
Figure 1. Structures of L-daunosamine 1, L-3-epi-daunosamine 2, L-
ristosamine 3, L-acosamine 4, and the anthracycline antibiotics
daunorubicin 5, doxorubicin 6, carubicin 7, idarubicin 8, and
epirubicin 9.
substrates would favor a conformation with the C(5)−C(6)
bond parallel to the C(3)−H bond to minimize 1,3-allylic
strain.21 In this conformation, the (bulky) N-benzyl-N-(α-
methylbenzyl)amino substituent is placed above one face of the
olefin. Invoking this as the reactive conformation, dihydroxyl-
ation using OsO4 under either Upjohn22 or Donohoe23
conditions was expected to proceed, in both cases, on the
sterically more accessible 4Re,5Re face20 of the olefin (opposite
to the amino group) owing to the absence of any potential
hydrogen-bond donors.24 This would result in the formation of
diol 19. In contrast, sequential treatment with a strong
Brønsted acid and a peracid (e.g., 40% aq HBF4 and m-
CPBA, as employed with 10) was anticipated to result in
ammonium-directed epoxidation on the opposite 4Si,5Si face20
of the olefin. Subsequent regioselective ring-opening of the
Asymmetric Synthesis of Methyl N,O-Diacetyl-D-3-epi-
daunosaminide. Treatment of 25 with 40% aq HBF4
followed by m-CPBA under our previously reported con-
a
Scheme 1
a
Reagents and conditions: (i) 40% aq HBF4, m-CPBA, CH2Cl2, rt, 48 h; (ii) H2, Pd(OH)2/C, Boc2O, EtOAc, rt, 48 h; (iii) DIBAL-H, CH2Cl2, −78
°C, 30 min; (iv) MeOH, HCl, rt, 48 h; (v) Ac2O, pyridine, DMAP, rt, 30 min.
12398
dx.doi.org/10.1021/jo4020563 | J. Org. Chem. 2013, 78, 12397−12408

The Journal of Organic Chemistry
Article
Figure 2. Proposed synthesis of the 2,3,6-trideoxy-3-aminohexoses D-3-epi-daunosamine 2 and D-ristosamine 3 via diastereoselective epoxidation and
dihydroxylation, respectively, of β-amino esters 16.
a
a
Scheme 2
Scheme 3
a
Reagents and conditions: (i) (ClCO)2, DMSO, Et3N, −78 °C to rt, 1
h, then Ph3P=CHCO2R, rt, 18 h; (ii) lithium (R)-N-benzyl-N-(α-
methylbenzyl)amide, THF, −78 °C, 2 h; (iii) Pd/CaCO3, quinoline,
H2 (1 atm), EtOAc, rt, 2 h. bCrude ratio 80:20 [(E):(Z)]. cCrude ratio
90:10 [(E):(Z)]. dCrude ratio 95:5 [(Z):(E)]. eCrude ratio 96:4 [(Z):
(E)].
a
Reagents and conditions: (i) 40% aq HBF4, m-CPBA, CH2Cl2, rt, 48
h.
product and a minor product assigned as the corresponding δ-
lactone 31, which were isolated as a 93:7 mixture in 72%
combined yield (Scheme 4). The presence of δ-lactone 31 was
ditions15 resulted in complete conversion of starting material to
a complex mixture of products, of which the three major
components were identified as epoxide 27, diol 28, and γ-
lactone 2916 in the ratio 21:51:28, respectively. Chromato-
graphic purification of these polar compounds proved difficult,
but nonetheless samples of 27, 28, and 29 were isolated in 19,
38, and 10% yield, respectively, and in >95% purity (Scheme
3). The relative configuration within lactone 29 was confirmed
unambiguously by single-crystal X-ray diffraction analysis,29
with the absolute (3S,4S,5S,αR)-configuration following from
the known (R)-configuration of the α-methylbenzyl group. The
stereochemistry within diol 28 was initially tentatively assigned
by comparison of its 1H NMR spectrum with that of the known
tert-butyl ester analogue:17 the chemical shifts corresponding to
the protons on the carbon backbone and the N-benzyl-N-α-
methylbenzyl fragment of these two species were essentially
identical; however the configurations within both epoxide 27
and diol 28 were subsequently assigned unambiguously by
chemical correlation (vide infra).
supported by H and 13C NMR chemical shift, H−1H J
coupling constant, and COSY analyses. In addition, analysis of
the mixture of 30 and 31 by IR absorption spectroscopy
revealed bands consistent with the presence of both a γ-lactone
(νmax 1773 cm−1) and a δ-lactone (νmax 1728 cm−1). Formation
of γ-lactone 30 as the major product in this reaction allowed
unambiguous assignment of the stereochemistry within diol 28.
When epoxide 27 was treated with 40% aq HBF4 in CH2Cl2,
a 45:51:4 mixture of γ-lactone 29,16 γ-lactone 30,16 and δ-
lactone 31, respectively, was produced. Purification and
1
1
3
a
Scheme 4
In order to probe the origin of the products of this oxidation
reaction, the behavior of epoxide 27 and diol 28 under the
acidic conditions of the reaction was next studied. Treatment of
diol 28 with 40% aq HBF4 in CH2Cl2 resulted in the formation
of an 88:12 mixture of the known γ-lactone 3016 as the major
a
Reagents and conditions: (i) 40% aq HBF4, CH2Cl2, rt, 48 h.
12399
dx.doi.org/10.1021/jo4020563 | J. Org. Chem. 2013, 78, 12397−12408

The Journal of Organic Chemistry
Article
a
Scheme 5
a
Reagents and conditions: (i) 40% aq HBF4, CH2Cl2, rt, 48 h; (ii) MsCl, Et3N, CH2Cl2, 0 °C to rt, 1 h; (iii) K2CO3, MeOH, rt, 12 h.
separation via chromatography gave 29 in 32% yield and >99:1
dr, and 30, also in 32% yield and >99:1 dr. Treatment of a
sample of γ-lactone 30 with mesyl chloride (MsCl) gave the
corresponding mesylate 32, which upon treatment with K2CO3
in MeOH gave complete conversion to epoxide 27, which was
isolated in 26% yield and >99:1 dr, thus unambiguously
establishing its stereochemistry (Scheme 5).
on the 4Si,5Si face),20 consistent with an ammonium-directed
process proceeding via transition-state model 33 (Scheme 6).
a
Scheme 6
The production of a mixture of γ-lactones 29 and 30 upon
treatment of epoxide 27 with 40% aq HBF4 suggests two
competing mechanisms for lactone formation are occurring
under these conditions. SN2-type ring-opening of epoxide 27
upon attack of H2O at C(5), distal to the in situ formed
ammonium moiety,25,30 gives the intermediate diol 28.
Subsequent lactonization of 28 through attack of the C(4)-
hydroxyl group at the ester carbonyl gives γ-lactone 30.
Alternatively, ring-opening of epoxide 27 may occur via a
formal 5-exo-trig31 cyclization by attack of the ester carbonyl
group at C(4), followed by hydrolysis to give γ-lactone 29
directly. The conformational bias of 27 may serve to promote
this latter pathway: the ester functionality would presumably be
held in relatively close proximity to the approach trajectory
necessary to effect attack at C(4). The production of γ-lactone
29 from β-amino ester 25 may therefore be attributable solely
to the fate of a single intermediate epoxide 27 under the
reaction conditions. However, the possibility that 29 arises
from the corresponding diastereoisomeric epoxide undergoing
SN2-type ring-opening upon regioselective attack of H2O at
C(5) followed by lactonization cannot be excluded from the
data available. Hence, this precludes assessment of the
diastereoselectivity of epoxidation of 25 under these conditions.
In order to probe the levels of diastereoselectivity in the
epoxidation process, reaction of 25 under conditions which
enabled isolation of the intermediate epoxide in a directly
analogous system15 was investigated. Treatment of 25 with
F3CCO3H32 in the presence of F3CCO2H gave complete
conversion to a 75:25 mixture of epoxide 27 and diol 28. The
formation of 28 in this reaction can be rationalized by
regioselective SN2-type ring-opening of 27 occurring in situ
upon attack of trifluoroacetate anion at C(5), followed by
hydrolysis of the labile trifluoroacetate functionality upon basic
aqueous workup.33 Chromatographic purification of the crude
reaction mixture allowed isolation of 27 in 51% yield and >99:1
dr, although 28 did not elute from the column in this case.
From all these data it could be concluded that the epoxidation
diastereoselectivity is complete (>95:5 dr in favor of reaction
a
Reagents and conditions: (i) F3CCO2H, F3CCO3H, CH2Cl2, 0 °C to
rt, 16 h.
With an efficient method for the preparation of epoxide 27 in
hand, a method to effect its regioselective ring-opening was
examined. Treatment of 27 with concd aq H2SO4 in 1,4-
dioxane resulted in the formation of a 65:35 mixture of γ-
lactone 3016 and δ-lactone 31, which were isolated as a 65:35
mixture in 43% combined yield. This product distribution is
consistent with initial formation of diol 28 being followed by
lactonization and, indeed, treatment of a sample of 28 with
concd aq H2SO4 under identical conditions gave a 65:35
mixture of 30 and 31, which were isolated as a 65:35 mixture in
56% combined yield. Although formed as a mixture,
importantly the stereochemistries within 30 and 31 are
identical and so both these lactones would converge upon
the same final 2,3,6-trideoxy-3-amino sugar product (Scheme
7).
Hydrogenolysis of the 65:35 mixture of γ-lactone 30 and δ-
lactone 31 in the presence of di-tert-butyl dicarbonate (Boc2O)
in EtOAc gave a 65:35 mixture of two species, assigned as the
corresponding N-Boc protected lactones 3416 and 35.
Chromatographic purification allowed isolation of 34 in 58%
yield and >99:1 dr, although 35 did not elute from the column
and so was not isolated. Treatment of γ-lactone 34 with
diisobutylaluminum hydride (DIBAL-H) gave a mixture of the
corresponding lactols (as mixtures of anomers), which were
12400
dx.doi.org/10.1021/jo4020563 | J. Org. Chem. 2013, 78, 12397−12408

The Journal of Organic Chemistry
Article
a
80:20 mixture of two species, which were identified as diol 37
and γ-lactone 38. Chromatography on silica gel allowed the
isolation of 37 in 52% yield and >99:1 dr, and 38 in 24% yield
and >99:1 dr (Scheme 9). The relative configuration within 37
was unambiguously established via single crystal X-ray
diffraction analysis,29 with the absolute (3S,4S,5R,αR)-config-
uration being assigned from the known absolute (R)-
configuration of the α-methylbenzyl fragment. The isolated
yield of 38 (24%) is greater than the theoretical maximum
suggested by the crude product ratio, which suggests that 37
undergoes partial lactonization during chromatography to give
38. In support of this assertion, treatment of 37 with F3CCO2H
resulted in formation of 38 as the only product, which was
isolated in 69% yield. Therefore, the absolute (3S,4S,5R,αR)-
configuration within 38 was unambiguously established. From
this result, the diastereofacial selectivity of the dihydroxylation
reaction in favor of reaction on the 4Re,5Re face20 can be
inferred as >95:5. The procedure reported by Donohoe et al.
for syn-dihydroxylation using OsO4 in conjuction with
N,N,N′,N′-tetramethylethylenediamine (TMEDA) was also
investigated,23 and cleavage of the intermediate osmate ester
using tris(hydroxymethyl)phosphine36 gave γ-lactone 38 as the
only product in 40% isolated yield after chromatography. The
stereochemical outcome of the Upjohn dihydroxylation is
known to be controlled by steric and/or stereoelectronic
factors,24 and in the absence of any potential hydrogen-bond
donors, the Donohoe procedure23 should also result in
dihydroxylation of the sterically more accessible face of the
expected solution-phase conformation of β-amino ester 26
(Scheme 9).
Scheme 7
a
Reagents and conditions: (i) concd aq H2SO4, 1,4-dioxane, H2O, rt,
12 h.
treated with HCl in MeOH followed by peracetylation to give
the known methyl N,O-diacetyl-α-D-3-epi-daunopyranosami-
nide 36,34 which was isolated in 40% yield and 93% purity35
over three steps from 34. The 1H and 13C NMR spectroscopic
data for this sample of 36 were entirely consistent with those
previously reported,34 thus confirming the stereochemical
assignments of all intermediates (Scheme 8).
Asymmetric Synthesis of Methyl N,O-Diacetyl-D-
ristosaminide. Using the protocol originally reported by the
Upjohn Company,22 treatment of 26 with 0.1 equiv of OsO4
and 4 equiv of N-methylmorpholine-N-oxide (NMO) gave an
a
Scheme 9
a
Scheme 8
a
Reagents and conditions: (i) OsO4, NMO, THF, H2O, rt, 16 h; (ii)
OsO4, TMEDA, CH2Cl2, −78 °C, 1 h, then P(CH2OH)3, CH2Cl2,
Et3N, SiO2, rt, 48 h; (iii) F3CCO2H, CH2Cl2, rt, 12 h.
Hydrogenolysis of γ-lactone 38 in the presence of Boc2O
gave N-Boc-protected γ-lactone 3937 in 92% isolated yield and
>99:1 dr (Scheme 10). The relative configuration within 39 was
unambiguously confirmed by single-crystal X-ray diffraction
analysis.29 Sequential reduction of 39 with DIBAL-H, treatment
with HCl in MeOH, and peracetylation resulted in equilibration
to give an approximate 10:15:65:10 mixture of the α- and β-
anomers of the furanose and pyranose forms of methyl N,O-
diacetyl-D-ristopyranosaminide 40−43, respectively (i.e., all
possessing the same stereochemistry at all nonanomeric
a
Reagents and conditions: (i) Boc2O, H2, Pd(OH)2/C, MeOH, rt, 48
h; (ii) DIBAL-H, CH2Cl2, −78 °C, 30 min; (iii) HCl, MeOH, rt, 16 h;
(iv) Ac2O, pyridine, DMAP, rt, 12 h.
12401
dx.doi.org/10.1021/jo4020563 | J. Org. Chem. 2013, 78, 12397−12408

The Journal of Organic Chemistry
Article
39), in >99:1 dr and 95% purity,38 and methyl N,O-diacetyl-α-
D-ristopyranosaminide 42 in 48% overall yield (three steps from
39) and >99:1 dr, along with a 70:30 mixture of methyl N,O-
diacetyl-α-D-ristofuranosaminide 40 and methyl N,O-diacetyl-β-
D-ristopyranosaminide 43 in 11% combined yield (3 steps from
39). The identities of and relative configurations within 40−43
a
Scheme 10
1
were established by H and 13C NMR spectroscopic analyses
1
(COSY, HSQC, HMBC, and NOE). Furthermore, the H and
13C NMR spectroscopic data for our sample of methyl N,O-
diacetyl-α-D-ristopyranosaminide 43 were entirely consistent
with those previously reported39 (Scheme 10).
CONCLUSION
■
In conclusion, efficient asymmetric syntheses of methyl N,O-
diacetyl-D-3-epi-daunosaminide and methyl N,O-diacetyl-D-
ristosaminide have been developed that utilize a highly
diastereoselective conjugate addition and a highly diastereose-
lective epoxidation or dihydroxylation, respectively, as the key
steps to introduce the stereochemistry. Conjugate addition of
lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to α,β-unsatu-
rated esters facilitates the preparation of alkyl (3S,αR,Z)-3-[N-
benzyl-N-(α-methylbenzyl)amino]hex-4-enoates 25 and 26.
These systems favor a solution-phase conformation with the
C(5)−C(6) bond parallel to the C(3)−H bond in order to
minimize 1,3-allylic strain. In this conformation, the (bulky) N-
benzyl-N-(α-methylbenzyl)amino substituent is placed above
one face of the olefin, which allows for its oxidative
functionalization in a diastereoselective manner, under either
steric control or hydrogen-bonding control. syn-Dihydroxyla-
a
Reagents and conditions: (i) Boc2O, H2, Pd(OH)2/C, MeOH, rt, 48
t
h; (ii) DIBAL-H, CH2Cl2, −78 °C, 30 min; (iii) HCl, MeOH, rt, 16 h;
(iv) Ac2O, pyridine, DMAP, rt, 12 h.
tion of 26 (R = Bu) using OsO4 (under Upjohn or Donohoe
conditions) proceeded on the least hindered 4Re,5Re face of the
olefin (opposite the amino group) to give the corresponding
diol 37, which upon lactonization results in γ-lactone 38 only.
Meanwhile, epoxidation of 25 (R = Me) using F3CCO3H in
conjunction with F3CCO2H proceeded on the 4Si,5Si face
under hydrogen-bonding control from the in situ formed
ammonium ion. Subsequent regioselective ring-opening of the
intermediate epoxide 27 in concd aq H2SO4 proceeded at the
carbon atom distal to the ammonium moiety to give the
corresponding diol 28 (a formal anti-dihydroxylation process),
which lactonized under the reaction conditions to give a
stereocenters). In a related approach, Sibi reported the
formation of a mixture of all four possible α- and β-anomers
of the furanose and pyranose forms of methyl N-benzoyl-D-
ristosamide, although the relative amount of each of these
components was not quantified and their identities were not
assigned.37 However, in our study, partial separation of the
mixture of 40−43 was achieved via chromatography, enabling
the isolation of a sample of methyl N,O-diacetyl-β-D-
ristofuranosaminide 41 in 15% overall yield (three steps from
a
Scheme 11
a
Reagents and conditions: (i) OsO4, NMO, THF, H2O, rt, 16 h; (ii) F3CCO2H, CH2Cl2, rt, 12 h; (iii) F3CCO2H, F3CCO3H, CH2Cl2, rt, 16 h; (iv)
concd aq H2SO4, 1,4-dioxane, H2O, rt, 12 h; (v) Boc2O, H2, Pd(OH)2/C, MeOH, rt, 48 h; (vi) DIBAL-H, CH2Cl2, −78 °C, 30 min; (vii) HCl,
MeOH, rt, 16 h; (viii) Ac2O, pyridine, DMAP, rt, 12 h.
12402
dx.doi.org/10.1021/jo4020563 | J. Org. Chem. 2013, 78, 12397−12408

The Journal of Organic Chemistry
Article
vacuo to give a 90:10 mixture of (E):(Z) diastereoisomers. Purification
via flash column chromatography (eluent 30−40 °C petroleum ether/
Et2O, 99:1) gave 22 as a yellow oil (3.00 g, 64%, >99:1 dr): νmax (film)
2222 (CC), 1717 (CO); δH (400 MHz, CDCl3) 1.44 (9H, s,
CMe3), 1.97 (3H, dd, J 2.5, 0.6, C(6)H3), 6.02 (1H, dd, J 15.8, 0.6,
C(3)H), 6.58 (1H, dq, J 15.8, 2.5, C(2)H); δC (100 MHz, CDCl3) 4.7
(C(6)), 27.9 (CMe3), 80.7 (CMe3), 95.4 (C(4), C(5)), 124.9 (C(2)),
131.3 (C(3)), 165.4 (C(1)); m/z (ESI+) 167 ([M + H]+, 100); HRMS
mixture of γ-lactone 30 and δ-lactone 31 (both possessing the
same stereochemistry). Elaboration of either the mixture of
lactones 30 and 31, or γ-lactone 38 via hydrogenolysis, N-Boc
protection, reduction with DIBAL-H, methanolysis, and
peracetylation gave mixtures of the α- and β-anomers of the
pyranose and furanose forms of methyl N,O-diacetyl-D-3-epi-
daunosaminide 36 and methyl N,O-diacetyl-D-ristosaminide
40−43, respectively (Scheme 11). The ready availability of the
enantiomeric β-amino ester starting materials [i.e., derived from
conjugate addition of lithium (S)-N-benzyl-N-(α-
methylbenzyl)amide] renders these strategies equally applicable
to the syntheses of either enantiomeric form of this important
product class, and further applications of this methodology will
be reported in due course.
+
(ESI+) C10H15O2 ([M + H]+) requires 167.1067; found 167.1068.
Methyl (3S,αR)-3-[N-Benzyl-N-(α-methylbenzyl)amino]hex-
4-ynoate 23. n-BuLi (2.50 M in hexanes, 11.9 mL, 24.5 mmol)
was added dropwise via syringe to a stirred solution of (R)-N-benzyl-
N-(α-methylbenzyl)amine (5.99 g, 28.4 mmol) in THF (30 mL) at
−78 °C. After the solution was stirred for 30 min, a solution of 21
(2.20 g, 17.9 mmol) in THF (10 mL) at −78 °C was added dropwise
via cannula. The reaction mixture was allowed to stir for a further 2 h
before addition of satd aq NH4Cl (10 mL). The resultant mixture was
allowed to warm to rt and then extracted with CH2Cl2 (3 × 40 mL).
The combined organic extracts were washed sequentially with 10% aq
citric acid (30 mL) and satd aq NaHCO3 (30 mL), dried (Na2SO4),
and concentrated in vacuo. Purification via flash column chromatog-
raphy (eluent 30−40 °C petroleum ether/Et2O, 19:1) gave 23 as a
colorless oil (3.62 g, 61%, 93:7 dr): [α]2D0 −136.5 (c 1.0 in CHCl3);
νmax (film) 2233 (CC), 1731 (CO); δH (500 MHz, CDCl3) 1.51
(3H, d, J 6.9, C(α)Me), 1.89 (3H, d, J 2.4, C(6)H3), 2.48 (1H, dd, J
14.6, 6.6, C(2)HA), 2.59 (1H, dd, J 14.6, 8.5, C(2)HB), 3.47 (3H, s,
OMe), 3.74 (1H, d, J 14.3, NCHA), 3.88 (1H, d, J 14.3, NCHB), 3.98
(1H, q, J 6.8, C(α)H), 4.00 (1H, ddq, J 8.6, 6.6, 2.2, C(3)H), 7.18−
7.41 (10H, m, Ph); δC (125 MHz, CDCl3) 3.6 (C(6)), 13.4 (C(α)Me),
41.0 (C(2)), 46.6 (C(3)), 51.4 (NCH2), 51.5 (OMe), 57.2 (C(α)),
77.2, 81.1 (C(4), C(5)), 126.7, 126.8 (p-Ph), 127.9, 128.0, 128.2, 128.9
(o,m-Ph), 140.4, 143.9 (i-Ph), 170.9 (C(1)); m/z (ESI+) 336 ([M +
H]+, 100); HRMS (ESI+) C22H26NO2+ ([M + H]+) requires 336.1958,
found 336.1953.
EXPERIMENTAL SECTION
■
General Experimental Details. All reactions involving organo-
metallic or other moisture-sensitive reagents were carried out under a
nitrogen or argon atmosphere using standard vacuum line techniques
and glassware that was flame-dried and cooled under nitrogen before
use. Solvents were dried according to the procedure outlined by
Grubbs and co-workers.40 m-CPBA was supplied as a 70−77% slurry
in water and titrated according to the procedure of Swern41
immediately before use. Water was purified by an Elix UV-10 system.
Organic solvents were used as supplied (analytical or HPLC grade)
without prior purification. Organic layers were dried over Na2SO4 or
MgSO4, as stated. Thin layer chromatography was performed on
aluminum plates coated with 60 F254 silica. Plates were visualized using
UV light (254 nm) or 1% aq KMnO4. Flash column chromatography
was performed on Kieselgel 60 silica on a glass column.
Melting points are uncorrected. IR spectra were recorded using an
ATR module. Selected characteristic peaks are reported in cm−1. NMR
spectra were recorded in the deuterated solvent stated. The field was
locked by external referencing to the relevant deuteron resonance.
tert-Butyl (3S,αR)-3-[N-Benzyl-N-(α-methylbenzyl)amino]-
hex-4-ynoate 24. n-BuLi (2.50 M in hexanes, 0.75 mL, 1.86
mmol) was added dropwise via syringe to a stirred solution of (R)-N-
benzyl-N-(α-methylbenzyl)amine (406 mg, 1.93 mmol) in THF (4.0
mL) at −78 °C. After the solution was stirred for 30 min, a solution of
22 (200 mg, 1.20 mmol) in THF (2 mL) at −78 °C was added
dropwise via cannula. The reaction mixture was allowed to stir for a
further 2 h before addition of satd aq NH4Cl (3 mL). The resultant
mixture was allowed to warm to rt and then extracted with CH2Cl2 (3
× 20 mL). The combined organic extracts were washed sequentially
with 10% aq citric acid (10 mL) and satd aq NaHCO3 (10 mL), dried
(Na2SO4), and concentrated in vacuo. Purification via flash column
chromatography (eluent 30−40 °C petroleum ether/Et2O, 19:1) gave
24 as a colorless oil (318 mg, 70%, 92:8 dr): [α]2D0 −66.5 (c 1.0 in
CHCl3); νmax (film) 2230 (CC), 1727 (CO); δH (500 MHz,
CDCl3) 1.40 (9H, s, CMe3), 1.50 (3H, d, J 6.9, C(α)Me), 1.87 (3H, d,
J 2.2, C(6)H3), 2.37−2.42 (2H, m, C(2)H2), 3.71 (1H, d, J 14.5,
NCHA), 3.83 (1H, d, J 14.5, NCHB), 3.96 (1H, q, J 6.9, C(α)H),
4.00−4.03 (1H, m, C(3)H), 7.17−7.37 (10H, m, Ph); δC (125 MHz,
CDCl3) 3.6 (C(6)), 14.8 (C(α)Me), 28.0 (CMe3), 42.2 (C(2)), 47.3
(C(3)), 51.6 (NCH2), 57.9 (C(α)), 78.1 (CMe3), 80.2, 80.7 (C(4),
C(5)), 126.6, 126.7 (p-Ph), 127.8, 127.9, 128.0, 128.6 (o,m-Ph), 140.9,
144.2 (i-Ph), 170.1 (C(1)); m/z (ESI+) 378 ([M + H]+, 100); HRMS
1
1H−1H COSY and H−13C HMQC analyses were used to establish
atom connectivity. Accurate mass measurements were run on a
MicroTOF instrument internally calibrated with polyalanine.
Methyl (E)-Hex-2-en-4-ynoate 21. DMSO (2.6 mL, 37.1 mmol)
was added to a stirred solution of (COCl)2 (2.9 mL, 34.2 mmol) in
CH2Cl2 (224 mL) at −78 °C. After 5 min, a solution of 20 (2.00 g,
28.5 mmol) in CH2Cl2 (10 mL) was added. The resultant mixture was
stirred at −60 °C for a further 1 h before the addition of Et3N (7.95
mL, 57.1 mmol). The resultant mixture was allowed to warm to rt, and
Ph3PCHCO2Me (9.54 g, 28.5 mmol) was added. The reaction
mixture was stirred for 18 h at rt. Saturated aq Na2CO3 (200 mL) was
then added, and the resultant mixture was extracted with CH2Cl2 (3 ×
100 mL). The combined organic extracts were washed with brine (200
mL), dried (MgSO4), and concentrated in vacuo to give an 80:20
mixture of (E):(Z) diastereoisomers. Purification via flash column
chromatography (eluent 30−40 °C petroleum ether/Et2O, 99:1) gave
21 as a yellow oil (2.27 g, 64%, >99:1 dr): νmax (film) 2222 (CC),
1719 (CO); δH (400 MHz, CDCl3) 2.01 (3H, dd, J 2.4, 0.6,
C(6)H3), 3.73 (3H, s, OMe), 6.13 (1H, dd, J 15.9, 0.6 C(3)H), 6.74
(1H, dq, J 15.9, 2.4, C(2)H); δC (100 MHz, CDCl3) 4.6 (C(6)), 51.6
(OMe), 96.4 (C(4), C(5)), 126.3 (C(2)), 128.9 (C(3)), 166.5 (C(1));
+
+
m/z (FI+) 124 ([M]+, 100); HRMS (FI+) C7H8O2 ([M]+) requires
(ESI+) C25H32NO2 ([M + H]+) requires 378.2428, found 378.2429.
124.0524; found 124.0523.
Methyl (3S,αR,Z)-3-[N-Benzyl-N-(α-methylbenzyl)amino]-
hex-4-enoate 25. A mixture of 23 (2.60g, 7.75 mmol), Pd/CaCO3
(5 wt % Pd, 780 mg, 30% w/w of substrate) and quinoline (27 μL,
6.08 mmol) in degassed EtOAc (15 mL) was stirred under H2 (1 atm)
at rt for 2 h. The reaction mixture was then filtered through a short
plug of Celite (eluent EtOAc) and concentrated in vacuo to give a
95:5 mixture of (Z):(E) diastereoisomers. Purification via flash column
chromatography (eluent 30−40 °C petroleum ether/Et2O, 19:1) gave
25 as a white solid (2.17 mg, 83%, >95:5 dr); mp 43−46 °C; [α]D20
+24.0 (c 1.0 in CHCl3); νmax (film) 1740 (CO); δH (500 MHz,
CDCl3) 1.36 (3H, d, J 6.8, C(α)Me), 1.58 (3H, d, J 5.5, C(6)H3), 2.24
(1H, dd, J 13.9, 7.7, C(2)HA), 2.58 (1H, J 13.9, 5.3, C(2)HB), 3.49
tert-Butyl (E)-Hex-2-en-4-ynoate 22. DMSO (2.6 mL, 37.1
mmol) was added to a stirred solution of (COCl)2 (2.9 mL, 34.2
mmol) in CH2Cl2 (224 mL) at −78 °C. After 5 min, a solution of 20
(2.00 g, 28.5 mmol) in CH2Cl2 (10 mL) was added. The resultant
mixture was stirred at −60 °C for a further 1 h before the addition of
Et3N (7.95 mL, 57.1 mmol). The resultant mixture was allowed to
t
warm to rt, and Ph3PCHCO2 Bu (10.7 g, 28.5 mmol) was added.
The reaction mixture was stirred for 18 h at rt. Saturated aq Na2CO3
(200 mL) was then added, and the resultant mixture was extracted
with CH2Cl2 (3 × 100 mL). The combined organic extracts were
washed with brine (200 mL), dried (MgSO4), and concentrated in
12403
dx.doi.org/10.1021/jo4020563 | J. Org. Chem. 2013, 78, 12397−12408

The Journal of Organic Chemistry
Article
(3H, s, OMe), 3.70 (1H, d, J 14.8, NCHA), 3.88 (1H, d, J 14.8,
NCHB), 4.00 (1H, q, J 6.8, C(α)H), 4.09 (1H, dt, J 8.9, 7.3, C(3)H),
5.54−5.64 (2H, m, C(4)H, C(5)H), 7.19−7.39 (10H, m, Ph); δC (125
MHz, CDCl3) 13.4 (C(6)), 14.8 (C(α)Me), 39.6 (C(2)), 50.2
(NCH2), 51.3 (OMe), 51.5 (C(3)), 56.3 (C(α)), 126.0, 126.6, 127.8,
127.9, 128.1, 128.4, 130.3 (o,m,p-Ph, C(4), C(5)), 141.2, 144.3 (i-Ph),
171.9 (C(1)); m/z (ESI+) 338 ([M + Na]+, 100); HRMS (ESI+)
column chromatography (eluent PhMe/EtOAc, 4:1) gave 27 as a
colorless oil (18 mg, 19%, >99:1 dr). Further elution gave 29 as white
solid (9 mg, 10%, >99:1 dr):16 mp 129−134 °C (lit.16 mp 132−136
°C); [α]2D0 +112.6 (c 1.0 in CHCl3) [lit.16 [α]2D6 +101.2 (c 1.6 in
CHCl3)]; δH (500 MHz, CDCl3) 1.37 (3H, d, J 6.6, C(6)H3), 1.42
(3H, d, J 7.0, C(α)Me), 2.02 (1H, dd, J 18.6, 9.1, C(2)HA), 2.11 (1H,
dd, J 18.6, 7.3, C(2)HB), 3.66 (1H, d, J 14.8, NCHA), 3.74 (1H, d, J
14.8, NCHB), 3.83 (1H, q, J 7.0, C(α)H), 4.01−4.05 (2H, m, C(3)H,
C(5)H), 4.12 (1H, dd, J 6.0, 2.8, C(4)H), 7.27−7.43 (10H, m, Ph).
Further elution gave 28 as colorless oil (37 mg, 38%, >99:1 dr): [α]D20
+36.7 (c 1.0 in CHCl3); νmax (film) 3428 (O−H), 3062, 3029, 2973,
2933, 2848 (C−H), 1730 (CO); δH (500 MHz, CDCl3) 1.32 (3H,
d, J 6.6, C(6)H3), 1.47 (3H, d, J 7.1, C(α)Me), 1.80 (1H, dd, J 16.9,
1.7, C(2)HA), 2.14 (1H, dd, J 16.9, 9.0, C(2)HB), 3.26 (1H, d, J 7.6,
C(4)H), 3.54 (1H, d, J 13.9, NCHA), 3.62 (3H, s, OMe), 3.70−3.78
(2H, m, C(3)H, C(5)H), 3.86 (1H, d, J 13.9, NCHB), 3.92 (1H, q, J
7.1, C(α)H), 7.27−7.43 (10H, m, Ph); δC (125 MHz, CDCl3) 19.6
(C(α)Me), 20.2 (C(6)), 32.0 (C(2)), 51.4 (NCH2), 51.8 (OMe), 54.1
(C(3)), 56.9 (C(α)), 66.6 (C(5)), 74.4 (C(4)), 127.4, 127.7 (p-Ph),
128.1, 128.4, 128.7, 128.8 (o,m-Ph), 138.7, 139.7 (i-Ph), 173.3 (C(1));
m/z (ESI+) 372 ([M + H]+, 100); HRMS (ESI+) C22H30NO4 ([M +
H]+) requires 372.2169, found 372.2165.
(3S,4S,5S,αR)-3-[N-Benzyl-N-(α-methylbenzyl)amino]-5-hy-
droxy-4-hexanolactone 29 and (3S,4R,5R,αR)-3-[N-Benzyl-N-
(α-methylbenzyl)amino]-5-hydroxy-4-hexanolactone 30. HBF4
(40% aq, 44 μL, 0.28 mmol) was added to a stirred solution of 27 (20
mg, 0.06 mmol) in CH2Cl2 (0.1 mL), and the resultant solution was
stirred at rt for 48 h. Saturated aq NaHCO3 (0.5 mL) was added, and
the resultant mixture was extracted with EtOAc (3 × 1 mL). The
combined organic extracts were dried (Na2SO4) and concentrated in
vacuo to give a 45:55 mixture of 29 and 30, respectively. Purification
via flash column chromatography (eluent 30−40 °C petroleum ether/
EtOAc, 3:1) gave 29 as a white solid (6 mg, 32%, >99:1 dr).16 Further
elution gave 30 as a white solid (6 mg, 32%, >99:1 dr):16 mp 133−135
°C (lit.16 mp 132−136 °C); [α]D25 +75.8 (c 1.0 in CHCl3) [lit.16 [α]2D6
+101.2 (c 1.6 in CHCl3)]; δH (500 MHz, CDCl3) 1.42 (3H, d, J 6.1,
C(6)H3), 1.47 (3H, d, J 7.1, C(α)Me), 1.98 (1H, dd, J 17.8, 6.5,
C(2)HA), 2.16 (1H, dd, J 17.8, 8.4 C(2)HB), 3.77 (2H, app s, NCH2),
3.95 (1H, q, J 7.1, C(α)H), 4.05 (1H, dt, J 8.4, 6.6, C(3)H), 4.35 (1H,
dd, J 6.6, 5.8, C(4)H), 4.40 (1H, app quintet, J 5.8, C(5)H), 7.15−7.41
(10H, m, Ph).
+
C22H28NO2 ([M + H]+) requires 338.2115, found 338.2112.
tert-Butyl (3S,αR,Z)-3-[N-Benzyl-N-(α-methylbenzyl)amino]-
hex-4-enoate 26. A mixture of 24 (130 mg, 0.34 mmol), Pd/
CaCO3 (5 wt % Pd, 26 mg, 20% w/w of substrate), and quinoline (27
μL, 0.07 mmol) in degassed EtOAc (5 mL) was stirred under H2 (1
atm) at rt for 1 h 20 min. The reaction mixture was then filtered
through a short plug of Celite (eluent EtOAc) and concentrated in
vacuo to give a 96:4 mixture of (Z):(E) diastereoisomers. Purification
via flash column chromatography (eluent 30−40 °C petroleum ether/
Et2O, 19:1) gave 26 as a colorless oil (102 mg, 78%, >95:5 dr): [α]D20
−24.5 (c 1.0 in CHCl3); νmax (film) 1784 (CO); δH (500 MHz,
CDCl3) 1.36 (9H, s, CMe3), 1.38 (3H, d, J 6.6, C(α)Me), 1.56 (3H, d,
J 5.0, C(6)H3), 2.18 (1H, dd, J 13.6, 9.1, C(2)HA), 2.50 (1H, J 13.6,
5.2, C(2)HB), 3.70 (1H, d, J 14.8, NCHA), 3.80 (1H, d, J 14.8, NCHB),
4.01−4.09 (2H, m, C(α)H, C(3)H), 5.52−5.61 (2H, m, C(4)H, C(5)
H), 7.15−7.42 (10H, m, Ph); δC (125 MHz, CDCl3) 13.6 (C(6)), 16.4
(C(α)Me), 28.0 (CMe3), 40.6 (C(2)), 50.5 (NCH2), 52.0 (C(3)), 57.1
(C(α)), 80.0 (CMe3), 126.2, 126.5, 126.9, 127.8, 127.9, 128.0, 128.2,
130.5 (o,m,p-Ph, C(4), C(5)), 141.7, 144.6 (i-Ph), 171.0 (C(1)); m/z
+
(ESI+) 402 ([M + Na]+, 100); HRMS (ESI+) C25H33NaNO2 ([M +
Na]+) requires 402.2404, found 402.2405.
Methyl (3S,4R,5S,αR)-3-[N-Benzyl-N-(α-methylbenzyl)-
amino]-4,5-epoxyhexanoate 27. (F3CCO)2O (0.33 mL, 2.37
mmol) was added to a stirred solution of urea hydrogen peroxide
(836 mg, 8.89 mmol) and CH2Cl2 (3 mL) at 0 °C, and the resultant
solution was stirred for 30 min at 0 °C. A solution of 25 (200 mg, 0.52
mmol) and F3CCO2H (0.12 mL, 1.48 mmol) in CH2Cl2 (3 mL) was
then added, and the resultant mixture was stirred for 16 h at rt. The
reaction mixture was then cooled to 0 °C, and satd aq Na2SO3 (∼3
mL) was added until starch iodide paper indicated no remaining
oxidant. The resultant mixture was then diluted with CH2Cl2 (10 mL)
and washed with 2.0 M aq NaOH (2 × 10 mL). The combined
aqueous washings were extracted with CH2Cl2 (2 × 10 mL), and the
combined organic extracts were dried (Na2SO4) and concentrated in
vacuo to give a 75:25 mixture of 27 and 28, respectively. Purification
via flash column chromatography (eluent PhMe/EtOAc, 4:1) gave 27
as a colorless oil (107 mg, 51%, >99:1 dr): [α]2D0 +8.8 (c 1.0 in
CHCl3); νmax (film) 3062, 3028, 2973, 2251 (C−H), 1737 (CO);
δH (500 MHz, CDCl3) 1.18 (3H, d, J 5.4, C(6)H3), 1.49 (3H, d, J 6.6,
C(α)Me), 2.24 (1H, dd, J 14.0, 6.5, C(2)HA), 2.51 (1H, dd, J 14.0, 7.6,
C(2)HB), 3.04−3.12 (2H, m, C(4)H, C(5)H), 3.14−3.19 (1H, m,
C(3)H), 3.50 (3H, s, OMe), 3.86 (1H, d, J 14.2, NCHA), 3.95 (1H, d, J
14.2, NCHB), 4.09 (1H, q, J 6.9, C(α)H), 7.21−7.41 (10H, m, Ph); δC
(125 MHz, CDCl3) 13.4 (C(6)), 16.8 (C(α)Me), 36.5 (C(2)), 50.4
(NCH2), 51.5 (OMe), 52.8 (C(3)), 53.0 (C(5)), 56.4 (C(4)), 57.0
(C(α)), 126.7, 126.8 (p-Ph), 127.9, 128.0, 128.1, 128.7 (o,m-Ph),
140.7, 144.0 (i-Ph), 171.4 (C(1)); m/z (ESI+) 354 ([M + H]+, 100);
(3S,4R,5R,αR)-3-[N-Benzyl-N-(α-methylbenzyl)amino]-5-hy-
droxy-4-hexanolactone 30 and (3S,4R,5R,αR)-3-[N-Benzyl-N-
(α-methylbenzyl)amino]-4-hydroxy-5-hexanolactone 31.
Method A. H2SO4 (concd aq, 37 μL, 0.71 mmol) and H2O (2
drops) were added to a stirred solution of 27 (50 mg, 0.14 mmol) in
1,4-dioxane (0.5 mL). The reaction mixture was stirred at rt for 16 h
and then concentrated in vacuo. Saturated aq NaHCO3 (1 mL) was
added to the residue, and the resultant mixture was extracted with
EtOAc (3 × 2 mL). The combined organic extracts were dried
(Na2SO4) and concentrated in vacuo to give a 65:35 mixture of 30 and
31, respectively. Purification via flash column chromatography (eluent
30−40 °C petroleum ether/EtOAc, 4:1) gave a 65:35 mixture of 30
and 31 as a colorless oil (21 mg, 43% combined yield).16 Data for
mixture: νmax (film) 3419 (O−H), 3061, 3028, 2975, 2930, 2850
(C−H), 1773 (CO, γ-lactone), 1728 (CO, δ-lactone); m/z (ESI+)
+
HRMS (ESI+) C22H28NO3 ([M + H]+) requires 354.2064, found
354.2062.
+
340 ([M + H]+, 100); HRMS (ESI+) C21H26NO3 ([M + H]+)
Methyl (3S,4R,5S,αR)-3-[N-Benzyl-N-(α-methylbenzyl)-
amino]-4,5-epoxyhexanoate 27, Methyl (3S,4R,5R,αR)-3-[N-
Benzyl-N-(α-methylbenzyl)amino]-4,5-dihydroxyhexanoate
28, and (3S,4S,5S,αR)-3-[N-Benzyl-N-(α-methylbenzyl)amino]-
5-hydroxy-4-hexanolactone 29. HBF4 (40% aq, 0.23 mL, 1.48
mmol) was added to a stirred solution of 25 (100 mg, 0.29 mmol) in
CH2Cl2 (0.9 mL), and the resultant solution was stirred at rt for 5 min.
Then m-CPBA (75%, 272 mg, 1.19 mmol) was added, and stirring was
continued for 48 h at rt. The reaction mixture was then diluted with
CH2Cl2 (3 mL) and washed sequentially with satd aq Na2SO3 (2 × 5
mL) and satd aq NaHCO3 (10 mL). The combined aqueous washings
were extracted with CH2Cl2 (3 × 5 mL), and the combined organic
extracts were dried (Na2SO4) and concentrated in vacuo to give a
21:51:28 mixture of 27, 28 and 29, respectively. Purification via flash
requires 340.1907, found 340.1912. Data for 31: δH (500 MHz,
CDCl3) 1.35 (3H, d, J 6.7, C(6)H3), 1.44 (3H, d, J 6.4, (C(α)Me),
2.14 (1H, dd, J 17.0, 6.3, C(2)HA), 2.25 (1H, dd, J 17.0, 10.8, C(2)
HB), 3.36 (1H, ddd, J 10.8, 7.8, 6.3, C(3)H), 3.70 (1H, d, J 14.5,
NCHA), 3.79 (1H, d, J 14.5, NCHB), 3.84 (1H, dd, J 7.8, 4.4, C(4)H),
3.90−3.92 (1H, m, C(α)H), 4.54 (1H, dq, J 6.7, 4.4, C(5)H), 7.15−
7.41 (10H, m, Ph); δC (125 MHz, CDCl3) 15.5 (C(6)), 21.4 (C(α)
Me), 30.9 (C(2)), 50.3 (NCH2), 54.7 (C(3)), 57.8 (C(α)), 68.2
(C(4)), 75.7 (C(5)), 127.4, 127.5 (p-Ph), 128.1, 128.2, 128.8, 129.0
(o,m-Ph), 137.8, 141.7 (i-Ph), 170.7 (C(1)).
Method B. HBF4 (40% aq, 63 μL, 0.40 mmol) was added to a
stirred solution of 28 (30 mg, 0.08 mmol) in CH2Cl2 (0.2 mL), and
the resultant solution was stirred at rt for 48 h. Saturated aq NaHCO3
12404
dx.doi.org/10.1021/jo4020563 | J. Org. Chem. 2013, 78, 12397−12408

The Journal of Organic Chemistry
Article
(0.5 mL) was added, and the resultant mixture was extracted with
EtOAc (3 × 2 mL). The combined organic extracts were dried
(Na2SO4) and concentrated in vacuo to give an 88:12 mixture of 30
and 31, respectively. Purification via flash column chromatography
(eluent 30−40 °C petroleum ether/EtOAc, 4:1) gave a 93:7 mixture
of 30 and 31 as a colorless oil (22 mg, 72% combined yield).
Method C. H2SO4 (concd aq, 14 μL, 0.27 mmol) and H2O (1 drop)
were added to a stirred solution of 28 (20 mg, 0.05 mmol) in 1,4-
dioxane (0.1 mL). The reaction mixture was stirred at rt for 16 h and
then concentrated in vacuo. Satd aq NaHCO3 (1 mL) was added to
the residue and the resultant mixture was extracted with EtOAc (3 × 2
mL). The combined organic extracts were dried (Na2SO4) and
concentrated in vacuo to give a 65:35 mixture of 30 and 31,
respectively. Purification via flash column chromatography (eluent
30−40 °C petroleum ether/EtOAc, 4:1) gave a 65:35 mixture of 30
and 31 as a colorless oil (10 mg, 56% combined yield).
(3S,4R,5R,αR)-4-[N-Benzyl-N-(α-methylbenzyl)amino]-5-
(methanesulfonyloxy)-4-hexanolactone 32. MsCl (33 μL, 0.42
mmol) was added dropwise to a stirred solution of 30 (90 mg, 0.42
mmol) and Et3N (74 μL, 0.53 mmol) in CH2Cl2 (2 mL) at 0 °C. The
resultant solution was stirred at rt for 1 h, washed with satd aq CuSO4
(5 mL), dried (MgSO4), and concentrated in vacuo to give 32 as a
yellow oil (110 mg). Purification of an aliquot via flash column
chromatography (eluent CHCl3/iPrOH, 95:5) gave an analytical
sample (>95% purity): [α]2D0 +117.1 (c 1.0 in CHCl3); νmax (ATR)
3029, 2975, 2938 (C−H), 1786 (CO); δH (500 MHz, CDCl3) 1.45
(3H, d, J 7.2, C(α)Me), 1.71−1.74 (1H, m, C(2)HA), 1.74 (3H, d, J
6.3, C(6)H3), 2.21 (1H, dd, J 18.4, 8.0, C(2)HB), 2.97 (3H, s, SO2Me),
3.70 (1H, d, J 14.5, NCHA), 3.82 (1H, d, J 14.5, NCHB), 3.89 (1H, q, J
7.2, C(α)H), 4.07−4.10 (1H, m, C(3)H), 4.41 (1H, dd, J 8.9, 6.3,
C(4)H), 5.17 (1H, dq, J 8.9, 6.3, C(5)H), 7.19−7.45 (10H, m, Ph); δC
(125 MHz, CDCl3) 18.2 (C(6)), 18.4 (C(α)Me), 32.2 (C(2)), 38.6
(SO2Me), 51.8 (NCH2), 53.9 (C(3)), 56.7 (C(α)), 77.8 (C(5)), 84.6
(C(4)), 127.7, 127.8, 128.0, 128.7, 128.8, 129.1 (o,m,p-Ph), 137.7,
139.2 (i-Ph), 175.1 (C(1)); m/z (ESI+) 418 ([M + H]+, 100); HRMS
(ESI+) C22H27NNaO5S+ ([M + Na]+) requires 440.1502, found
440.1492.
K2CO3 (182 mg, 1.32 mmol) was added to a solution of 32 (90 mg,
0.22 mmol) in MeOH (2 mL). The reaction mixture was stirred at rt
for 16 h and then concentrated in vacuo. The residue was partitioned
between CH2Cl2 (5 mL) and H2O (5 mL). The aqueous layer was
extracted with CH2Cl2 (3 × 5 mL), and the combined organic extracts
were dried (Na2SO4) and concentrated in vacuo. Purification via flash
column chromatography (eluent CHCl3/iPrOH, 95:5) gave 27 as oil
colorless oil (24 mg, 26% from 30, >99:1 dr).
(3S,4R,5R)-3-(N-tert-Butoxycarbonylamino)-5-hydroxy-4-
hexanolactone 34. Boc2O (92 mg, 0.42 mmol) and Pd(OH)2/C
(50% w/w of substrate, 65 mg) were added sequentially to a solution
of a 65:35 mixture of 30 and 31 (130 mg, 0.38 mmol) in MeOH (2
mL). The resultant suspension was placed under H2 (1 atm) and
stirred vigorously at rt for 48 h. The reaction mixture was then filtered
through a short plug of Celite (eluent MeOH) and concentrated in
vacuo to give a 65:35 mixture of 34 and 35, respectively. Purification
via flash column chromatography (eluent 30−40 °C petroleum ether/
EtOAc, 1:1) gave 34 as a white solid (54 mg, 58%, >99:1 dr):16 mp
156−161 °C (lit.16 mp 159−162 °C); [α]D20 −39.2 (c 1.0 in CHCl3)
[lit.16 [α]D25 −52.5 (c 2.1 in CHCl3)]; δH (500 MHz, CDCl3) 1.38 (3H,
d, J 6.6, C(6)H3), 1.45 (9H, s, CMe3), 2.59 (1H, dd, J 17.8, 8.2,
C(2)HA), 2.82 (1H, dd, J 17.8, 9.4, C(2)HB), 4.08−4.12 (1H, m,
C(5)H), 4.45 (1H, d, J 7.5, C(4)H), 4.76 (1H, app quintet, J 8.5,
C(3)H), 5.47 (1H, d, J 8.2, NH).
(0.2 mL), and HCl (1.25 M in MeOH, 0.4 mL) was added. The
resultant solution was stirred at rt for 48 h before being concentrated
in vacuo. The residue was dissolved in pyridine (0.3 mL), Ac2O (0.3
mL) and DMAP (1 mg) were added, and the resultant solution was
stirred at rt for 12 h. The reaction mixture was then diluted with
CH2Cl2 (2 mL), EtOAc (2 mL), and satd aq CuSO4 (2 mL). The
resultant solution was extracted with EtOAc (3 × 2 mL), and the
combined organic extracts were washed with satd aq NaHCO3 (2 × 2
mL), dried (Na2SO4), and concentrated in vacuo. Purification via flash
column chromatography (eluent PhMe/iPrOH, 4:1) gave 36 as a
colorless oil (10 mg, 40% from 34, 93% purity):34,35 νmax (film) 3407
(N−H), 2973, 2941, 2857, 2831 (C−H), 1739 (CO, ester), 1693
(CO, amide); δH (500 MHz, CDCl3) 1.12 (3H, d, J 6.5, C(6)H3),
1.62 (1H, dd, J 14.5, 0.9, C(2)HA), 1.99 (3H, s, COMe), 2.13 (3H, s,
COMe), 2.15−2.20 (1H, m, C(2)HB), 3.41 (3H, s, OMe), 4.10 (1H, q,
J 6.5, C(5)H), 4.15 (1H, ddt, J 7.2, 5.0, 2.4, C(3)H), 4.80−4.82 (2H,
m, C(1)H, C(4)H), 6.82 (1H, br d, J 6.9, NH); δC (125 MHz, CDCl3)
16.7 (C(6)), 20.9, 23.5 (COMe), 28.3 (C(2)), 44.5 (C(3)), 55.3
(OMe), 61.3 (C(5)), 69.1 (C(4)), 98.6 (C(1)), 169.0, 169.8 (COMe);
+
m/z (ESI+) 268 ([M + Na]+, 100); HRMS (ESI+) C11H19NNaO5
([M + Na]+) requires 268.1155, found 268.1158.
Data for minor (7%) component:35 δH (500 MHz, CDCl3) 1.19
(3H, d, J 6.6, C(6)H3), 1.95 (1H, d, J 13.6 C(2)HA), 2.05−2.09 (1H,
m, C(2)HB), 2.10 (3H, s, COMe), 2.17 (3H, s, COMe), 3.38 (3H, s,
OMe), 3.95−3.97 (1H, m, C(5)H), 4.20−4.23 (1H, m, C(3)H), 5.02−
5.04 (1H, m, C(4)H), 5.41 (1H, d, J 3.5, C(1)H), 6.47 (1H, br d, J
10.1, NH); δC (125 MHz, CDCl3) 16.8 (C(6)), 21.4, 23.7 (COMe),
30.8 (C(2)), 44.4 (C(3)), 55.0 (OMe), 60.0 (C(5)), 69.2 (C(4)), 99.1
(C(1)), 168.9, 170.5 (COMe).
tert-Butyl (3S,4S,5R,αR)-3-[N-Benzyl-N-(α-methylbenzyl)-
amino]-4,5-dihydroxyhexanoate 37 and (3S,4S,5R,αR)-3-[N-
Benzyl-N-(α-methylbenzyl)amino]-5-hydroxy-4-hexanolactone
38. Donohoe Oxidation. OsO4 (147 mg, 0.58 mmol) was added to a
stirred solution of 26 (200 mg, 0.53 mmol) and TMEDA (111 μL,
0.74 mmol) in CH2Cl2 (8 mL) at −78 °C. The reaction mixture was
stirred at −78 °C for 1 h and then allowed to warm to rt over a further
15 min before being concentrated in vacuo. The residue was dissolved
in CH2Cl2 (20 mL), the resultant solution was stirred, and
P(CH2OH)3 (6.56 g, 52.6 mmol) and Et3N (1.47 mL, 10.6 mmol)
were added sequentially. After the mixture was stirred for 5 min, excess
silica gel (∼5 g) was added, and stirring was continued at rt for a
further 48 h. The resultant suspension was concentrated in vacuo.
Purification via flash column chromatography (eluent 30−40 °C
petroleum ether/EtOAc, 1:1) gave 38 as a colorless oil (72 mg, 40%
from 26, >99:1 dr): [α]D20 +109.1 (c 1.0 in CHCl3); νmax (film) 3422
(O−H), 1777 (CO); δH (500 MHz, CDCl3) 1.32 (3H, d, J 6.6,
C(6)H3), 1.44 (3H, d, J 7.3, C(α)Me), 1.95−2.01 (1H, m, C(2)HA),
2.04−2.09 (1H, m, C(2)HB), 2.47 (1H, br s, OH), 3.65 (1H, d, J 14.5,
NCHA), 3.75 (1H, d, J 14.5, NCHB), 3.83 (1H, q, J 7.3, C(α)H),
4.01−4.05 (1H, m, C(3)H), 4.05−4.10 (1H, m, C(5)H), 4.23 (1H, dd,
J 4.7, 3.5, C(4)H), 7.23−7.45 (10H, m, Ph); δC (125 MHz, CDCl3)
18.3 (C(6)), 19.2 (C(α)Me), 30.1 (C(2)), 50.4 (NCH2), 53.4 (C(3)),
57.8 (C(α)), 68.4 (C(5)), 87.2 (C(4)), 127.3, 127.7 (p-Ph), 127.7,
127.9, 128.5, 128.6 (o,m-Ph), 139.3, 140.8 (i-Ph), 176.6 (C(1)); m/z
+
(ESI+) 362 ([M + Na]+, 100); HRMS (ESI+) C21H25NNaO3 ([M +
Na]+) requires 362.1727, found 362.1727.
Upjohn Oxidation. OsO4 (13 mg, 0.03 mmol) was added to a
stirred solution of 26 (200 mg, 0.58 mmol) in THF (4 mL) and H2O
(1 mL), followed by a solution of NMO (246 mg, 2.10 mmol) in H2O
(0.5 mL). The reaction mixture was stirred at rt for 12 h. Saturated aq
Na2SO3 (2 mL) was then added, and the resultant mixture was allowed
to stir at rt for a further 1 h. The mixture was then extracted with
EtOAc (3 × 5 mL), and the combined organic extracts were dried
(Na2SO4) and concentrated in vacuo to give 80:20 mixture of 37 and
38, respectively. Purification via flash column chromatography (eluent
30−40 °C petroleum ether/EtOAc, 4:1) gave 37 as a yellow oil that
crystallized upon standing (113 mg, 52%, >99:1 dr): mp 80−82 °C;
[α]2D0 +53.7 (c 1.0 in CHCl3); νmax (film) 3452 (O−H), 1740 (CO);
δH (500 MHz, CDCl3) 1.26 (3H, d, J 6.3, C(6)H3), 1.41 (9H, s,
CMe3), 1.48 (3H, d, J 6.3, C(α)Me), 1.79 (1H, dd, J 16.7, 1.3,
Methyl N,O-Diacetyl-D-3-epi-α-daunopyranosaminide 36.
DIBAL-H (1.0 M in CH2Cl2, 0.5 mL, 0.5 mmol) was added dropwise
via syringe (over 1 min) to a stirred solution of 34 (35 mg, 0.14
mmol) in CH2Cl2 (3 mL) at −78 °C. The resultant mixture was
stirred for 30 min at −78 °C. MeOH (∼0.5 mL) was then added
dropwise until effervescence ceased. Saturated aq Rochelle salt (10
drops) was then added, and the resultant suspension was stirred at rt
for 16 h before being filtered through Celite (eluent MeOH) and
concentrated in vacuo. The residue was dissolved in anhydrous MeOH
12405
dx.doi.org/10.1021/jo4020563 | J. Org. Chem. 2013, 78, 12397−12408

The Journal of Organic Chemistry
Article
C(2)HA), 2.21 (1H, dd, J 16.7, 9.5, C(2)HB), 2.24 (1H, d, J 8.5,
C(4)OH), 3.37−3.45 (1H, m, C(4)H), 3.52 (1H, d, J 13.9, NCHA),
3.69 (1H, td, J 9.5, 1.3, C(3)H), 3.85−3.90 (3H, m, C(5)H, C(α)H,
NCHB), 5.44 (1H, br s, C(5)OH), 7.25−7.44 (10H, m, Ph); δC (100
MHz, CDCl3) 19.3 (C(6)), 19.6 (C(α)Me), 28.0 (CMe3), 34.5 (C(2)),
51.9 (NCH2), 56.9 (C(3)), 57.3 (C(α)), 72.4 (C(5)), 75.9 (C(4)),
81.0 (CMe3), 127.4, 127.6 (p-Ph), 128.1, 128.5, 128.8, 129.0 (o,m-Ph),
138.7, 140.3 (i-Ph), 173.7 (C(1)); m/z (ESI+) 436 ([M + Na]+, 60);
C(3)H), 4.72 (1H, d, J 3.2, C(1)H), 6.79 (1H, br d, J 8.5, NH); δC
(125 MHz, CDCl3) 17.4 (C(6)), 20.8, 23.6 (COMe), 33.1 (C(2)),
43.5 (C(3)), 55.2 (OMe), 61.6 (C(5)), 72.9 (C(4)), 98.2 (C(1)),
169.6, 170.2 (COMe); m/z (ESI+) 268 ([M + Na]+, 100); HRMS
+
(ESI+) C11H19NNaO5 ([M + Na]+) requires 268.1155, found
268.1159. Further elution gave methyl N,O-diacetyl-β-D-ristofurano-
saminide 41 as a colorless oil (10 mg, 15% from 39, 95% purity);38
[α]2D0 +37.8 (c 0.5 in CHCl3); νmax (film) 3283 (N−H), 2938, 2857,
2827 (C−H), 1736 (CO, ester), 1672 (CO, amide); δH (500
MHz, CDCl3) 1.29 (3H, d, J 6.5, C(6)H3), 1.78 (1H, app d, J 13.4,
C(2)HA), 1.97 (3H, s, COMe), 2.06 (3H, s COMe), 2.11−2.16 (1H,
m, C(2)HB), 3.38 (3H, s, OMe), 3.83 (1H, dd, J 4.1, 2.5, C(4)H),
4.59−4.63 (1H, m, C(3)H), 4.99 (1H, qd, J 6.5, 4.1, C(5)H), 5.07
(1H, d, J 4.4, C(1)H), 6.24 (1H, br d, J 8.8, NH); δC (125 MHz,
CDCl3) 16.2 (C(6)), 21.3, 23.5 (COMe), 39.0 (C(2)), 48.6 (C(3)),
54.8 (OMe), 70.3 (C(5)), 88.3 (C(4)), 105.3 (C(1)), 168.7, 170.4
(COMe); m/z (ESI+) 268 ([M + Na]+, 100); HRMS (ESI+)
+
HRMS (ESI+) C25H36NO4 ([M + H]+) requires 414.2639, found
414.2632. Further elution gave 38 as a colorless oil (43 mg, 24%,
>99:1 dr).
Lactonization of 37. F3CCO2H (0.5 mL) was added to a stirred
solution of 37 (100 mg, 0.24 mmol) in CH2Cl2 (2.5 mL) at rt. The
resultant solution was stirred for 12 h at rt before being neutralized (to
pH 7) by the dropwise addition of satd aq NaHCO3 (∼2 mL). The
resultant mixture was extracted with EtOAc (3 × 5 mL) and the
combined organic extracts were dried (Na2SO4) and concentrated in
vacuo. Purification via flash column chromatography (eluent 30−40
°C petroleum ether/EtOAc, 1:1) gave 38 as a colorless oil (57 mg,
69%, >99:1 dr).
(3S,4S,5R)-3-(N-tert-Butoxycarbonylamino)-5-dihydroxy-4-
hexanolactone 39. Boc2O (141 mg, 0.65 mmol) and Pd(OH)2/C
(50% w/w of substrate, 100 mg) were added sequentially to a solution
of 38 (200 mg, 0.59 mmol) in MeOH (3 mL). The resultant
suspension was placed under H2 (5 atm) and stirred vigorously at rt
for 48 h. The reaction mixture was then filtered through a short plug of
Celite (eluent MeOH) and concentrated in vacuo. Purification via
flash column chromatography (eluent 30−40 °C petroleum ether/
EtOAc, 1:1) gave 39 as a white solid (132 mg, 92%, >99:1 dr):37 mp
104−107 °C (lit.37 108−110 °C); [α]D20 −24.4 (c 1.0 in CHCl3) [lit.37
[α]2D5 −24.5 (c 0.4 in CH2Cl2)]; δH (500 MHz, CDCl3) 1.33 (3H, d, J
6.3, C(6)H3), 1.46 (9H, s, CMe3), 2.46 (1H, dd, J 18.2, 5.7, C(2)HA),
2.75 (1H, br s, OH), 3.02 (1H, dd, J 18.2, 9.0, C(2)HB), 3.98−4.02
(1H, br m, C(5)H), 4.10−4.16 (1H, m, C(4)H), 4.35−4.42 (1H, m,
C(3)H), 4.87 (1H, d, J 5.4, NH).
Methyl N,O-Diacetyl-D-ristofuranosaminide 40−43. DIBAL-H
(1.0 M in CH2Cl2, 1.42 mL, 1.42 mmol) was added dropwise via
syringe (over 1 min) to a stirred solution of 39 (100 mg, 0.41 mmol)
in CH2Cl2 (6 mL) at −78 °C. The resultant mixture was stirred for 30
min at −78 °C. MeOH (∼1 mL) was then added dropwise until
effervescence ceased. Saturated aq Rochelle salt (20 drops) was then
added, and the resultant suspension was stirred at rt for 16 h before
being filtered through Celite (eluent MeOH) and concentrated in
vacuo. The residue was dissolved in anhydrous MeOH (1 mL), and
HCl (1.25 M in MeOH, 1 mL) was added. The resultant solution was
stirred at rt for 48 h before being concentrated in vacuo. The residue
was dissolved in pyridine (0.5 mL), Ac2O (0.5 mL) and DMAP (1
mg) were added, and the resultant solution was stirred at rt for 12 h.
The reaction mixture was then diluted with CH2Cl2 (3 mL), EtOAc (3
mL) and satd aq CuSO4 (5 mL). The resultant solution was extracted
with EtOAc (3 × 2 mL), and the combined organic extracts were
washed with satd aq NaHCO3 (2 × 3 mL), dried (Na2SO4), and
concentrated in vacuo to give a 10:15:65:10 mixture of 40, 41, 42, and
43 respectively. Purification via flash column chromatography (eluent
PhMe/iPrOH, 4:1) gave methyl N,O-diacetyl-α-D-ristopyranosami-
nide 42 as a colorless oil (30 mg, 48% from 39, >99:1 dr):4,34f,39 [α]D20
+173.9 (c 1.0 in CHCl3) [lit.4 for enantiomer [α]2D1 −134 (c 0.5 in
CHCl3); lit.34f for enantiomer [α]D25 −130.4 (c 0.49 in CHCl3); lit.39a
for enantiomer [α]D25 −130.8 (c 0.5 in CHCl3); lit.39b [α]D20 +134.5 (c
0.92 in CHCl3); lit.39c for enantiomer [α]D20 −130.1 (c 1.2 in CHCl3);
lit.39d for enantiomer [α]D25 −132 (c 0.62 in CHCl3); lit.39e for
enantiomer [α]D20 −126 (c 1.27 in CHCl3); lit.39f,g [α]2D3 +127.6 (c 0.3
in CHCl3); lit.39h for enantiomer [α]D23 −141 (c 0.35 in CHCl3); lit.39i
for enantiomer [α]2D5 −134 (c 2.0 in CHCl3); lit.39j for enantiomer
[α]2D6 −136 (c 0.02 in CHCl3)]; νmax (film) 3413 (N−H), 2937, 2872,
2833 (C−H), 1737 (CO, ester), 1655 (CO, amide); δH (500
MHz, CDCl3) 1.18 (3H, d, J 6.3, C(6)H3), 1.83 (1H, ddd, J 14.7, 2.8,
1.1, C(2)HA), 1.97 (3H, s, COMe), 1.98 (3H, s, COMe), 2.03 (1H, dt,
J 14.7, 4.2, C(2)HB), 3.39 (3H, s, OMe), 3.91 (1H, dq, J 10.1, 6.3,
C(5)H), 4.51 (1H, dd, J 10.1, 3.8, C(4)H), 4.57 (1H, qd, J 8.0, 4.1,
+
C11H19NNaO5 ([M + Na]+) requires 268.1155, found 268.1157.
Further elution gave a 70:30 mixture of methyl N,O-diacetyl-α-D-
ristofuranosaminide 40 and methyl N,O-diacetyl-β-D-ristopyrano-
saminide 43 as a colorless oil (7 mg, 11% from 39). Data for mixture:
νmax (film) 3286 (N−H), 2937 (C−H), 1735 (CO, ester), 1653
(CO, amide); m/z (ESI+) 268 ([M + Na]+, 100); HRMS (ESI+)
+
C11H19NNaO5 ([M + Na]+) requires 268.1155; found 268.1154.
Data for 40: δH (500 MHz, CDCl3) 1.30 (3H, d, J 6.6, C(6)H3), 1.88−
1.94 (1H, m, C(2)HA), 1.98 (3H, s, COMe), 2.07 (3H, s, COMe), 2.35
(1H, d, J 13.3, 7.3, 1.4, C(2)HB), 3.35 (3H, s, OMe), 3.79 (1H, t, J 5.5,
C(4)H), 4.58 (1H, dd, J 7.9, 6.0, C(3)H), 5.00 (1H, dd, J 6.6, 5.5,
C(5)H), 5.04 (1H, dd, J 5.7, 1.4, C(1)H), 5.55 (1H, br d, J 5.4, NH);
δC (125 MHz, CDCl3) 15.8 (C(6)), 21.3, 23.4 (COMe), 39.7 (C(2)),
50.5 (C(3)), 55.2 (OMe), 71.0 (C(5)), 86.1 (C(4)), 105.0 (C(1)),
169.5, 170.6 (COMe). Data for 43:34b δH (500 MHz, CDCl3) 1.38
(3H, d, J 6.9, C(6)H3), 1.85−1.87 (1H, m, C(2)HA), 2.00 (3H, s,
COMe), 2.02−2.05 (1H, m, C(2)HB), 2.10 (3H, s, COMe), 3.44 (3H,
s, OMe), 3.91−3.96 (1H, m, C(5)H), 4.63−4.69 (2H, m, C(1)H,
C(3)H), 4.73−4.75 (1H, m, C(4)H), 6.41 (1H, d, J 4.7, NH); δC (125
MHz, CDCl3) 18.8 (C(6)), 21.1, 23.5 (COMe), 33.1 (C(2)), 42.1
(C(3)), 55.8 (OMe), 70.5 (C(5)), 73.0 (C(4)), 99.2 (C(1)), 169.0,
170.2 (COMe).
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H and 13C NMR spectra and crystallographic
information files (for structures CCDC 953270−953273). This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: steve.davies@chem.ox.ac.uk.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Astra-Zeneca for a studentship (K.C.).
■
REFERENCES
■
(1) (a) Arcamone, F.; Franceschi, G.; Orezzi, P.; Babier, W.;
Mondelli, R. J. Am. Chem. Soc. 1964, 86, 5334. (b) Arcamone, F.;
Cassinelli, G.; Orezzi, P.; Franceschi, G.; Mondelli, R. J. Am. Chem. Soc.
1964, 86, 5335.
(2) 3-epi-Daunosamine is the only member of the 2,3,6-trideoxy-3-
aminohexose family that has not been isolated from natural sources.
(3) (a) Gauze, G. F.; Kudrina, E. S.; Ukholina, R. S.; Gavrilina, G. V.
Antibiotiki 1963, 8, 387. (b) Brazhnikova, M. G.; Lomakina, N. N.;
Lavrova, M. F.; Tolstykh, I. V.; Yurina, M. S.; Kluyeva, L. M. Antibiotiki
1963, 8, 392.
12406
dx.doi.org/10.1021/jo4020563 | J. Org. Chem. 2013, 78, 12397−12408

The Journal of Organic Chemistry
Article
(4) Bognar, R.; Sztaricskai, F.; Munk, M. E.; Tamas, J. J. Org. Chem.
1974, 39, 2971.
(23) (a) Donohoe, T. J.; Moore, P. R.; Waring, M. J.; Newcombe, N.
J. Tetrahedron Lett. 1997, 38, 5027. (b) Donohoe, T. J.; Blades, K.;
Moore, P. R.; Winter, J. J. G.; Helliwell, M.; Stemp, G. J. Org. Chem.
1999, 64, 2980. (c) Donohoe, T. J. Synlett 2002, 1223. (d) Donohoe,
T. J.; Blades, K.; Moore, P. R.; Waring, M. J.; Winter, J. J. G.; Helliwell,
M.; Newcombe, N. J.; Stemp, G. J. Org. Chem. 2002, 67, 7946.
(24) The diastereoselectivity of the Upjohn dihydroxylation is usually
a result of oxidation under steric or stereoelectronic control; see:
(a) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron Lett. 1983, 24, 3947.
(b) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron 1984, 40, 2247.
(c) Cha, J. K.; Kin, N.-S. Chem. Rev. 1995, 95, 1761. Meanwhile, the
OsO4/TMEDA complex is known to participate as a hydrogen-bond
acceptor, allowing substrate directed dihydroxylation in the presence
of potential hydrogen-bond donors (e.g., allylic hydroxyl groups); see
ref 23.
(25) (a) Parker, R. E.; Isaacs, N. S. Chem. Rev. 1959, 59, 737.
(b) Addy, J. K.; Parker, R. E. J. Chem. Soc. 1963, 915.
(26) Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E.; Yin, J.
Org. Lett. 2012, 14, 218.
(27) Costello, J. F.; Davies, S. G.; Ichihara, O. Tetrahedron:
Asymmetry 1994, 5, 1999.
(28) (a) Lindlar, H. Helv. Chim. Acta 1952, 35, 446. (b) Lindlar, H.;
Dubuis, R. Org. Synth. 1966, 46, 89.
(29) Crystallographic data (excluding structure factors) have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication numbers CCDC 953720 (25), 953721
(29), 953722 (37), and 953273 (39).
(30) The regioselectivity of this epoxide ring-opening reaction is
entirely consistent with our and others’ previous observations in
several related systems. See refs 15, 18, and: (a) Wolinsky, J.;
Thorstenson, J. H.; Killinger, T. A. J. Org. Chem. 1978, 43, 875.
(b) Calvani, F.; Crotti, P.; Gardelli, C.; Pineschi, M. Tetrahedron 1994,
50, 12999.
(31) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
(32) Emmons, W. D.; Pagano, A. S. J. Am. Chem. Soc. 1955, 77, 89.
(33) Alternatively, formation of diol 28 is also accounted for by
simple regioselective SN2-type ring-opening of epoxide 27 upon attack
of H2O at C(5) during aqueous workup.
(34) (a) Cheung, T.-M.; Horton, D.; Sorenson, R. J.; Weckerle, W.
Carbohydr. Res. 1978, 63, 77. (b) Boivin, J.; Pais, M.; Monneret, C.
Carbohydr. Res. 1978, 64, 271. (c) Cheung, T.-M.; Horton, D.;
Weckerle, W. Carbohydr. Res. 1979, 74, 93. (d) Dyong, I.; Wiemann,
R. Chem. Ber. 1980, 113, 1592. (e) Danishefsky, S.; Maring, C. J. Am.
Chem. Soc. 1985, 107, 1269. (f) Suami, T.; Tadano, K.; Suga, A.; Ueno,
Y. J. Carbohydr. Chem. 1984, 3, 429 Also see ref 14a.
(35) The minor (7%) component was methyl N,O-diacetyl-β-D-3-epi-
daunopyranosaminide or either anomer of methyl N,O-diacetyl-D-3-
epi-daunofuranosaminide, although an unambiguous structural assign-
ment could not be made.
(36) Davies, S. G.; Fletcher, A. M.; Foster, E. M.; Lee, J. A.; Roberts,
P. M.; Thomson, J. E. J. Org. Chem. 2013, 78, 2500. Use of
tris(hydroxymethyl)phosphine to remove ruthenium residues after
olefin metathesis reactions was first reported by Grubbs; see: Maynard,
H. D.; Grubbs, R. H. Tetrahedron Lett. 1999, 40, 4137.
(37) Sibi, M. P.; Lu, J.; Edwards, J. J. Org. Chem. 1997, 62, 5864.
(38) The minor (5%) component was methyl N,O-diacetyl-α-D-
ristopyranosaminide 41.
(39) (a) Lee, W. W.; Wu, H. Y.; Marsh, J. J., Jr.; Mosher, C. W.;
Acton, E. M.; Goodman, L.; Henry, D. W. J. Med. Chem. 1975, 18, 767.
(b) Horton, D.; Weckerle, W. Carbohydr. Res. 1976, 46, 227.
(c) Heyns, K.; Lim, M.; Park, J. I. Tetrahedron Lett. 1976, 18, 1477.
(5) (a) Lomakina, N. N.; Spiridonova, I. A.; Sheinker, Y. N.; Vlasova,
T. F. Khim. Prir. Soedin. 1973, 9, 101. (b) Spiridonova, I. A.; Yurina, M.
S.; Lomakina, N. N.; Sztaricskai, F.; Bognar, F. Antibiotiki 1976, 21,
304. (c) Harada, K.; Ito, S.; Suzuki, M. Carbohydr. Res. 1979, 75, C17.
(6) For a review concerning the role of carbohydrates in natural
products, including the anthracycline antibiotics, see: Weymouth-
Wilson, A. C. Nat. Prod. Rep. 1997, 14, 99.
(7) Di Marco, A.; Gaetani, M.; Dirogotti, L.; Soldati, M.; Bellini, O.
Nature 1964, 201, 706.
(8) Arcamone, F.; Cassinelli, G.; Fantani, G.; Grein, A.; Orezzi, P.;
Pol, C.; Spalla, C. Biotechnol. Bioeng. 1969, 11, 1101.
(9) (a) Gause, G. F.; Sveshnikova, M. A.; Ukholina, R. S.; Gavirilina,
G. A.; Filicheva, V. A.; Gladkikh, E. G. Antibiotiki 1973, 18, 675.
(b) Brazhnikova, M. G.; Zbarsky, V. B.; Pnomarenko, V. I.; Potapova,
N. P. J. Antibiot. 1974, 27, 254. (c) Arcamone, F.; Cassinelli, G.;
DiMatteo, F.; Forenza, S.; Ripamonete, M. C.; Rivola, G.; Vigevani, A.;
Clardy, J.; McCabe, T. J. Am. Chem. Soc. 1980, 102, 1462.
(10) Arcamone, F.; Bernardi, L.; Giardino, P.; Patelli, B.; DiMarco,
A.; Casazza, A. M.; Pratesi, G.; Reggiani, P. Cancer Treat. Rep. 1976,
60, 829.
(11) (a) Arcamone, F.; Franceschi, P.; Penco, S. Cancer Chemother.
Pharmacol. 1975, 6, 123. (b) Zaya, M. J.; Hines, R. N.; Stevens, J. C.
Drug Metab. Dispos. 2006, 34, 2097.
(12) For reviews, see: (a) Hauser, F. M.; Ellenberger, S. R. Chem. Rev.
1986, 86, 35. (b) Ding, F.; Cai, S.; William, R.; Liu, X.-W. RSC Adv.
2013, 3, 13594.
(13) For selected examples, see: (a) Wovkulich, P. M.; Uskovic,
R. Tetrahedron 1985, 41, 3455. (b) Hirama, M.; Shigemoto, T.; Ito
́
M.
, S.
̂
J. Org. Chem. 1987, 52, 3342. (c) Roger, P.; Monneret, C.; Fournier, J.-
P.; Choay, P.; Gagnet, R.; Gosse, C.; Letourneux, Y.; Atassi, G.;
Gouyette, A. J. Med. Chem. 1989, 32, 16. (d) Konradi, A. W.; Pedersen,
S. F. J. Org. Chem. 1990, 55, 4506. (e) Hatanaka, M.; Ueda, I. Chem.
Lett. 1991, 61. (f) Kovacs, I.; Herczegh, P.; Sztaricskai, J. Tetrahedron
1991, 37, 7837. (g) Renneberg, B.; Ling, Y.-M.; Laatsch, H.; Fiebig,
H.-H. Carbohydr. Res. 2000, 329, 861. (h) Sugiura, M.; Hirano, K.;
Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 7182. (i) Matsushima, Y.;
Kino, J. Tetrahedron Lett. 2005, 46, 8609. (j) Parker, K. A.; Chang, W.
Org. Lett. 2005, 7, 1785. (k) Doi, T.; Shibata, K.; Kinbara, A.;
Takahashi, T. Chem. Lett. 2007, 36, 1372. (l) Shi, W.; Coleman, R. S.;
Lowary, T. L. Org. Biomol. Chem. 2009, 7, 3709. (m) Ding, F.; William,
R.; Wang, F.; Ma, J.; Ji, L.; Liu, X.-W. Org. Lett. 2011, 13, 652.
́ ̀
(14) For selected examples, see: (a) Ginesta, X.; Pasto, M.; Pericas,
M. A.; Riera, A. Org. Lett. 2003, 5, 3001. (b) Matsushima, Y.; Kino, J.
Tetrahedron Lett. 2006, 47, 8777. (c) Matsushima, Y.; Kino, J. Eur. J.
Org. Chem. 2010, 2206.
(15) Bagal, S. K.; Davies, S. G.; Fletcher, A. M.; Lee, J. A.; Roberts, P.
M.; Scott, P. M.; Thomson, J. E. Tetrahedron Lett. 2011, 52, 2216.
(16) Davies, S. G.; Smyth, G. D.; Chippindale, A. M. J. Chem. Soc.,
Perkin Trans. 1 1999, 3089.
́
(17) Csatayova, K.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Russell,
A. J.; Thomson, J. E.; Wilson, D. L. Org. Lett. 2011, 13, 2606.
(18) (a) Aciro, C.; Claridge, T. D. W.; Davies, S. G.; Roberts, P. M.;
Russell, A. J.; Thomson, J. E. Org. Biomol. Chem. 2008, 6, 3751.
(b) Aciro, C.; Davies, S. G.; Roberts, P. M.; Russell, A. J.; Smith, A. D.;
Thomson, J. E. Org. Biomol. Chem. 2008, 6, 3762. (c) Bond, C. W.;
Cresswell, A. J.; Davies, S. G.; Kurosawa, W.; Lee, J. A.; Fletcher, A.
M.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E. J. Org.
Chem. 2009, 74, 6735.
(19) For the application of this methodology to the asymmetric
synthesis of imino sugars, see: Bagal, S. K.; Davies, S. G.; Lee, J. A.;
Roberts, P. M.; Scott, P. M.; Thomson, J. E. J. Org. Chem. 2010, 75,
8133.
(20) Hanson, K. R. J. Am. Chem. Soc. 1966, 88, 2731.
(21) Hoffman, R. W. Chem. Rev. 1989, 89, 1841.
́ ́
(d) Pelyvas, I.; Sztaricskai, F.; Bognar, R. Carbohydr. Res. 1979, 76,
257. (e) McGahren, W. J.; Martin, J. H.; Morton, G. O.; Hargreaves, R.
T.; Leese, R. A.; Lovell, F. M.; Ellestad, G. A.; O’Brien, E.; Holker, J. S.
E. J. Am. Chem. Soc. 1980, 102, 1671. (f) Hamada, Y.; Kawai, A.;
Shioiri, T. Chem. Pharm. Bull. 1985, 33, 5601. (g) Hamada, Y.; Kawai,
A.; Matsui, T.; Hara, O.; Shioiri, T. Tetrahedron 1990, 46, 4823.
(h) Pauls, H. W.; Fraser-Reid, B. Carbohydr. Res. 1986, 150, 111.
(i) Barco, A.; Benetti, S.; De Risi, C.; Pollini, G. P.; Spalluto, G.;
(22) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
17, 1973.
12407
dx.doi.org/10.1021/jo4020563 | J. Org. Chem. 2013, 78, 12397−12408

The Journal of Organic Chemistry
Article
Zanirato, V. Tetrahedron 1996, 52, 4719. (j) Tsuda, M.; Sato, H.;
Tanaka, Y.; Yazawa, K.; Mikami, Y.; Sasaki, T.; Kobayashi, J. J. Chem.
Soc., Perkin Trans. 1 1996, 1773.
(40) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J. Organometallics 1996, 15, 1518.
(41) Swern, D. Org. React. 1953, VII, 392.
12408
dx.doi.org/10.1021/jo4020563 | J. Org. Chem. 2013, 78, 12397−12408