A stereoselective synthesis of an α-substituted α-amino acid as a substructure for the construction of myriocin

Article abstract of DOI:10.1016/j.tetasy.2012.04.012

A synthetic route to the protected quaternary α-amino acid 2 with a hydroxylated side chain has been achieved. The key transformations are the diastereoselective substrate-controlled epoxidation of allylic alcohol 4; a highly stereoselective oxidation-reduction protocol, and the excellent regioselective isomerization of the oxazolidinone ring to give an oxazinanone skeleton in derivative 3. The carboxylic acid 2 obtained represents the polar substructure, which is present in myriocin 1.

Full text of DOI:10.1016/j.tetasy.2012.04.012

Tetrahedron: Asymmetry 23 (2012) 536–546
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A stereoselective synthesis of an
a-substituted a-amino acid as a
substructure for the construction of myriocin
Miroslava Martinková a, , Jozef Gonda , Jana Špaková Raschmanová , Juraj Kuchár , Jozef Kozíšek
⇑
a
a
b
c
ˇ
a Institute of Chemical Sciences, Department of Organic Chemistry, P.J. Šafárik University, Moyzesova 11, Sk-040 01 Košice, Slovak Republic
b Institute of Chemical Sciences, Department of Inorganic Chemistry, P.J. Šafárik University, Moyzesova 11, Sk-040 01 Košice, Slovak Republic
c Institute of Physical Chemistry and Chemical Physics, Department of Physical Chemistry, Slovak University of Technology, Radlinského 9, Sk-812 37 Bratislava, Slovak Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthetic route to the protected quaternary
a-amino acid 2 with a hydroxylated side chain has been
Received 5 March 2012
Accepted 18 April 2012
Available online 17 May 2012
achieved. The key transformations are the diastereoselective substrate-controlled epoxidation of allylic
alcohol 4; a highly stereoselective oxidation–reduction protocol, and the excellent regioselective isomer-
ization of the oxazolidinone ring to give an oxazinanone skeleton in derivative 3. The carboxylic acid 2
obtained represents the polar substructure, which is present in myriocin 1.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
OH
OH
(+)-Myriocin 1 (also known as thermozymocidine or ISP-I,
Fig. 1) is a natural a-substituted a-amino acid, which was initially
HOOC
NH2 OH
O
myriocin 1
isolated from two fungal sources as an antifungal agent.1 In 1994,
Fujita et al.2 isolated the same molecule from the fermentation
broth of Isaria sinclairii (ATCC 24400) and showed that the immu-
nosuppressive activity of 1 was approximately 10–100 times more
potent than that of cyclosporin A.2 Myriocin 1 has also been re-
ported to have an inhibitory activity3 against serine palmitoyl-
transferase (SPT),4 a key enzyme, which catalyses the first step of
the biosynthesis of the sphingolipids. Due to this activity, the anti-
atherosclerotic properties5 of 1 have been also examined. More-
over, myriocin 1 have been utilized as a lead compound6 for the
development of novel immunosuppressive agents such as
FTY7207 (Fig. 1), which was approved as a new treatment for mul-
tiple sclerosis.
HO
HO
NH2
FTY720
Figure 1. Structures of myriocin 1 and the unnatural immunosuppressant FTY720.
of our previous success in the preparation of substructures pos-
sessing a densely functionalized quaternary stereocentre,10 we
decided to attempt the synthesis of the polar head group of 1.
Herein we report the full details of our strategy based on the retro-
synthetic plan outlined in Scheme 1.
The structure of 1 was established as 2-amino-3,4-dihydroxy-2-
hydroxymethyl-14-oxoeicos-6-enoic acid;1b,c its absolute configu-
ration was assigned by Payette and Just.9b,c Both, the interesting
2. Results and discussion
structure of myriocin, which possesses an
a-substituted a-amino
acid motif, as well as its remarkable bioactivity, have prompted a
number of synthetic studies; several total syntheses8 of 1 and its
analogues8c,e,j,9 have been developed from various starting materi-
als, especially from carbohydrates. From the structural point of
Our analysis, as illustrated in Scheme 1, envisaged that struc-
ture 2, which possesses three requisite asymmetric centres, could
be obtained from the highly functionalized alcohol 3 via an oxida-
tion stereoselective reduction sequence and the base promoted
isomerization of an oxazolidinone ring to an oxazinanone. Com-
pound 3 was planned to be constructed from allylic alcohol 4
through an epoxidation and the reductive regioselective ring-
opening of an epoxide. For the preparation of derivative 4, the
known furanose 511b was used as the appropriate starting material.
As shown in Scheme 2, the synthesis of allylic alcohol 4 started
view, the polar fragment of myriocin 1 contains an
a-substituted
serine scaffold linked to two stereogenic centres bearing hydroxyl
groups and its construction is certainly the most difficult part of
any total synthesis. Prompted by this fact, and in a continuation
⇑
Corresponding author. Tel.: +421 55 6228332; fax: +421 55 62342329.
E-mail address: miroslava.martinkova@upjs.sk (M. Martinková).
with the known and highly functionalized 3-C-hydroxymethyl-a-
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.04.012

M. Martinková et al. / Tetrahedron: Asymmetry 23 (2012) 536–546
537
O
O
O
O
O
OTBDMS
1´
OTBDMS
C-1´
HO2C
BnN
inversion
BnN
O
1
myriocin
O
OH
O
2
3
O
O
O
O
epoxidation
TBDMSO
OH
HN
O
BnN
O
O
O
O
511b
4
Scheme 1. Retrosynthetic analysis.
O
O
O
O
OH
O
TBDMSO
BnN
AcO
BnN
AcO
BnN
d
a
c
b
511b
O
OH
O
O
O
O
O
O
O
6
9
8
OH
OH
OH
OH
OH
OH
AcO
e
f
OH
HO
OH
CO2Et
BnN
O
BnN
O
BnN
O
11
12
10
O
O
O
g
O
O
OH
BnN
O
4
O
Scheme 2. Reagents and conditions: (a) NaH, BnBr, TBAI, 0 °C?rt, 94%; (b) (i) TBAF, THF, 0 °C?rt, 7, 99%; (ii) Ac2O, pyridine, DMAP, rt, 98%; (c) TFA/H2O (85:15), rt, 83%; (d)
Ph3P@CHCO2Et, PhCO2H, CH2Cl2, rt, 68%; (e) DIBAL-H, CH2Cl2, ꢀ78 °C, 88%; (f) (i) NaIO4, CH3OH/H2O, rt; (ii) NaBH4, EtOH, 0 °C?rt, 64% (after two steps); (g) 2,2-DMP, CSA,
40 °C, 86%.
D
-xylofuranose 5,11b which was achieved on a multigram scale
the crucial step, the stereoselective epoxidation. Initially, exposure
of 4 to m-CPBA in CH2Cl2 produced the corresponding epoxy alco-
hols 13 and 14 in 85% yield (Scheme 3) as a readily separable mix-
ture of diastereoisomers (13:14 = 84:16 ratio, determined by 1H
NMR spectroscopy). On the other hand, the epoxidation of the
C@C bond in 13 employing Sharpless asymmetric conditions
(SAE)12 was unsuccessful and afforded an inseparable mixture of
the allylic alcohol 4 and the corresponding epoxides 13 and 14
according to the combined literature protocols.10b,11 Exposure of
5 to benzyl bromide in dry DMF using sodium hydride and cata-
lytic amounts of tetrabutylammonium iodide resulted in the for-
mation of the completely protected derivative 6 in 94% yield
(Scheme 2). After routine deprotection of 6 with TBAF, the alcohol
7 (99%) obtained was converted into acetate 8 in 98% yield by
treatment with Ac2O in dry pyridine. The acetonide group in 8
was removed by acid hydrolysis (TFA/H2O) to afford crystalline
[13:14 = ꢁ80:20 ratio for both auxiliaries used
L-(+)-DET and
D
-(ꢀ)-DET, as determined by 1H NMR]. After 5 days, the reaction
a-D-xylofuranose derivative 9 as the sole product (83%, Scheme 2);
its structure and anomeric configuration were determined by NMR
spectroscopic analysis, including NOE experiments. Wittig reaction
of 9 with a stabilized ylide, Ph3P@CHCO2Et, (CH2Cl2, benzoic acid)
mixture still contained approximately 70–80% of the starting com-
pound 4 (judged by 1H NMR) and thus it could not be utilized pre-
paratively. These results suggest that the stereochemical outcome
of the epoxidation is controlled by the highly hindered substrate
and cannot be overridden by asymmetric conditions.
furnished (E)-a,b-unsaturated ester 10 exclusively in 68% yield
(Scheme 2). The observed coupling constant in 10 (J = 15.6 Hz)
clearly proved the trans-configuration of the C@C bond. Reduction
of both ester groups in 10 with DIBAL-H in CH2Cl2 at ꢀ78 °C gave
the corresponding tetrol 11 (88%), which after rapid 1H NMR anal-
ysis was used immediately in the next reaction. Oxidative cleavage
of 11 with NaIO4 in CH3OH/H2O (1:1), followed by reduction
(NaBH4, EtOH) of the resultant aldehyde group afforded compound
12 in 64% yield after two reaction steps (Scheme 2). Treatment of
12 with 2,2-DMP and catalytic amounts of CSA resulted in the for-
mation of the corresponding isopropylidene derivative 4 (86%).
With allylic alcohol 4 in hand, we were now in a position to explore
In order to rationalize the observed stereoselectivity in the
epoxidation, high-level density functional theory (DFT) calcula-
tions, which included electron correlation effects, were carried
out. Geometries of the transition states were optimized using
B3LYP/6-31G(d,p) with a JAGUAR 7.7 programme.13 The nature of
the vacuum B3LYP transition states was verified with frequency
calculations, yielding only one large imaginary frequency. Har-
monic zero-point energy corrections at B3LYP/6-31G(d,p) obtained
from the frequency calculations of the vacuum transition states
were applied to the transition-state energies. Single-point energies

538
M. Martinková et al. / Tetrahedron: Asymmetry 23 (2012) 536–546
O
O
O
O
OTr
OH
OH
d
O
O
BnN
O
BnN
O
15
O
O
14
O
O
a/b/c
+
OH
BnN
O
O
O
O
O
4
O
g
e
OR
O
BnN
O
BnN
O
OR
13
O
O
16, R = H
17, R = Ac
f
O
O
O
O
O
O
O
OTBDMS
OTBDMS
OTBDMS
BnO
h
j
BnN
O
BnN
O
OH
BnN
O
OH
O
O
3
19
20
O
O
O
O
O
l
OTBDMS
OTBDMS
k
HO
RO2C
BnN
BnN
O
O
22
2,
R = H
R = CH3
O
m
23,
Scheme 3. Reagents and conditions: (a) m-CPBA, CH2Cl2, 0 °C?rt, 85%; (b)
L
-(+)-DET (0.3 equiv), TBHP (1.4 equiv), Ti(OPr-i)4 (0.25 equiv), CH2Cl2, 4 Å MS, ꢀ18 °C; (c) -(ꢀ)-
D
DET (0.12 equiv), TBHP (1.5 equiv), Ti(OPr-i)4 (0.1 equiv), CH2Cl2, 4 Å MS, 18 °C; (d) TrCl, Et3N, DMAP, CH2Cl2, rt, 56%; (e) Red-Al, THF, 0 °C, 62%; (f) Ac2O, pyridine, DMAP, rt,
74%; (g) TBDMSCl, Et3N, DMAP, DMF, rt, 65%; (h) (i) IBX, CH3CN, reflux, 18, 93%; (ii) L-selectride, THF, ꢀ78 °C, 94%; (j) NaH, BnBr, DMF, 0 °C?rt, 89%; (k) (i) H2, Pd(OH)2/C,
EtOH, 10 atm, rt, 21; (ii) TBDMSCl, imidazole, CH2Cl2, 76% (after two steps); (l) (i) IBX, CH3CN, reflux; (ii) NaClO2, CH3CN/t-BuOH/2-methylbut-2-ene (4:4:1), NaH2PO4, 0 °C,
72% (after two steps); (m) CH3I, K2CO3, DMF, rt, 65%.
Figure 2. Transition structures TS1 and TS2 for the rearrangement 4?13. Relative energies of transition states (in kcal/mol) and bond distances (in Å) are shown.

M. Martinková et al. / Tetrahedron: Asymmetry 23 (2012) 536–546
539
were computed with the B3LYP density functional method and the
cc-pvTZ basis set. The solvent effect was taken into account via a
single-point calculation in a dielectric continuum representing
dichloromethane as the solvent. A standard Poisson–Boltzmann
continuum solvation model was applied as implemented in JAGUAR
7.7.13 The epoxidation of allylic alcohol 4 to (20R,30R)-13 occurs
via transition states TS1 and TS2 with relative free energies 0
and 0.083 kcal/mol (Fig. 2); for the conversion of 4 into 14 we have
found other two transition states, TS3 and TS4, with relative free
energies 1.285 and 0.225 kcal/mol (Fig. 3).
The process is concerted but asynchronous, and calculated
geometries were in good agreement with the published results.14
From the calculations, for the pathway 4?TS1?13, the activation
energy was found to be 0.225 kcal/mol lower than for the pathway
4?TS4?14. Thus, the predicted diastereomeric ratio of epoxides
13:14 at 0 °C was 60:40. These results are in relatively good agree-
ment with the experimental data (13:14 = 84:16), with the correct
prediction of epoxide 13 as the predominant diastereoisomer.
These results provide an initial step in understanding the epoxida-
tion; the observed diastereoselectivity seems to depend on many
factors that are still to be explored.
The relative stereochemistry of the isolated epoxides 13 and 14
was assigned by X-ray analysis of the tritylated derivative 15 (56%,
Scheme 3), which was prepared during our search for the optimal
crystalline derivate appropriate for X-ray analysis. This compound
was obtained from the minor epoxy alcohol 14 by the reaction of
triphenylmethyl chloride in the presence of Et3N and DMAP and
afforded crystals suitable for X-ray measurements. From the crys-
tallographic structure shown in Figure 4, it can be seen that the
minor diastereoisomer 14 possesses a (20S,30S)-configuration.
Having incorporated the third stereogenic centre in the key
intermediate 13 and determined its stereochemistry (20R,30R), we
next focused our attention on the finalization of the synthesis of
the polar part of 1. On the basis of our synthetic plan (Scheme 1),
the major epoxy alcohol 13 was reduced with Red-Al15 in THF at
0 °C to give rise to the desired diol 16 (62%, Scheme 3) with excel-
lent regioselectivity (the second possible isomer was not detected,
as determined by 1H NMR analysis of the crude reaction mixture).
The lower 62% yield for this step was most likely due to the forma-
tion of some minor unidentified products. Due to the overlap of
many proton signals in 16, it was not possible to determine all of
the coupling constants and therefore compound 16 was character-
ized in the form of diacetate 17 (Ac2O, pyridine, DMAP, 74%,
Scheme 3). The unmasked hydroxyl group in the resulting diol
16 was selectively silylated (TBDMSCl, Et3N, DMAP and DMF) to af-
ford 3 in 65% yield (Scheme 3). The stereochemistry of the C-10 (S)-
configured secondary alcohol 3 was inverted through an oxida-
tionꢀstereoselective reduction sequence. Thus, the IBX16 mediated
oxidation of 3 resulted in the formation of ketone 18 (93%). Its
reduction with the sterically demanding L-selectride in THF at
ꢀ78 °C gave the requisite C-10 (R)-configured alcohol 19 as a single
diastereomer in 94% yield (Scheme 3). Having successfully estab-
lished the stereochemistry at the C-2 position in 19, our next task
was to develop a suitable synthetic protocol for the base-induced
opening of the oxazolidinone ring in 19, followed by an oxidation
of the released hydroxymethyl moiety. In order to avoid problems
with the protection of the secondary hydroxyl group in 19, we
turned our attention to the isomerization17 of 19 to 20. Interest-
ingly, compound 19 in the presence of sodium hydride and benzyl
bromide was converted into the corresponding oxazinanone deriv-
ative 20 exclusively in 89% yield (Scheme 3). In order to complete
our synthesis, the obtained molecule 20 was then subjected to
hydrogenolysis in EtOH using 20% Pd(OH)2/C (Pearlman’s cata-
lyst);18 however this removed both the O-benzyl and TBDMS group
Figure 3. Transition structures TS3 and TS4 for the rearrangement 4?14. Relative energies of transition states (in kcal/mol) and bond distances (in Å) are shown.

540
M. Martinková et al. / Tetrahedron: Asymmetry 23 (2012) 536–546
Figure 4. ORTEP structure of compound 15 showing the crystallographic numbering.
to furnish compound 21. This product, after a short purification
through a pad of silica gel and a rapid 1H NMR analysis, was selec-
tively protected as a tert-butyldimethylsilyl ether using TBDMSCl
and imidazole in dry CH2Cl2 to produce 22 in 76% yield after a
two-step sequence (Scheme 3). Finally, its oxidation with IBX in
acetonitrile followed by NaClO2 treatment provided the protected
amino acid 2 (72%), which possesses the correct stereochemistry
at all of the stereogenic centres. As an additional confirmation of
structure, we transformed 2 to its ester 23 according to standard
procedure19 (CH3I, K2CO3, DMF, Scheme 3).
plates; detection was carried out with either ultraviolet light
(254 nm), or spraying with a solution of phosphomolybdic acid, a
basic potassium permanganate solution, or a solution of concen-
trated H2SO4, with subsequent heating. 1H NMR and 13C NMR spec-
tra were recorded in CDCl3, CD3OD on a Varian Mercury Plus 400 FT
NMR (400.13 MHz for 1H and 100.6 MHz for 13C) or on a Varian
Premium Compact 600 (599.87 MHz for 1H and 150.84 MHz for
13C) spectrometers using TMS as internal reference. For 1H d are gi-
ven in parts per million (ppm) relative to TMS (d = 0.0) and for 13
C
relative to CDCl3 (d = 77.0), CD3OD (d = 49.05). The multiplicity of
the 13C NMR signals concerning the 13C–1H coupling was deter-
mined by the DEPT method. Chemical shifts (in ppm) and coupling
constants (in Hz) were obtained by first-order analysis; assign-
ments were derived from COSY and H/C correlation spectra. Infra-
red (IR) spectra were measured with a Nicolet Avatar 330 FT-IR
3. Conclusions
In conclusion, a stereoselective approach towards the protected
a-substituted a-amino acid 2, representing the polar head group of
spectrometer as KBr pellets and expressed in
cal rotations were measured on a P-2000 Jasco polarimeter and re-
ported as follows: [ (c in grams per 100 mL, solvent). Melting
points were recorded on a Kofler hot block and are uncorrected.
Small quantities of reagents ( L) were measured with appropriate
v
values (cmꢀ1). Opti-
the natural immunosuppressant myriocin 1, has been developed.
The key transformations of our strategy were the implementation
of a hydroxyl-bearing asymmetric centre into 4 using a diastereose-
lective substrate-controlled epoxidation, oxidation highly stereose-
lective reduction sequence, and the regioselective isomerization of
an oxazolidinone moiety into an oxazinanone in 3 in order to estab-
lish the structure with the free hydroxymethyl functionality as the
source of the carboxylic acid group. The final acid 2 has the pro-
tected primary hydroxyl group as a tool for the construction of a
non-polar side chain with C@O and C@C functionalities at the re-
quired positions via a Wittig reaction or by using Grubb’s cata-
lyst-mediated olefin cross metathesis.
a]
D
l
syringes (Hamilton). All reactions were performed under an atmo-
sphere of nitrogen, unless otherwise noted.
4.2. (3aR,40S,5S,6aR)-30-Benzyl-5-{[(tert-butyldimethylsilyl) oxy]-
methyl}-2,2-dimethyldihydro-3aH-spiro[furo[2,3-d] [1,3]dioxole-
6,40-oxazolidin]-20-one 6
To a solution of 511b (6.35 g, 17.7 mmol) in dry DMF (43.5 mL),
which was pre-cooled to 0 °C, NaH (1.06 g, 44.2 mmol of a 60% dis-
persion in mineral oil) was added and the reaction mixture was
stirred at the same temperature for 10 min. Then, tetrabutylammo-
nium iodide (66 mg, 0.18 mmol) was added followed by dropwise
addition of benzyl bromide (2.54 mL, 21.2 mmol). The resulting
mixture was stirred at 0 °C for 10 min and at room temperature
for another 20 min. The excess hydride was decomposed with
methanol (1.5 mL), and the mixture was partitioned between ice
water (100 mL) and Et2O (75 mL). The aqueous phase was ex-
tracted with an additional portion of Et2O (75 mL), the combined
organic layers were dried over Na2SO4, stripped of solvent, and
the residue was subjected to flash chromatography on silica gel
4. Experimental
4.1. General methods
All commercial reagents were used in the highest available pur-
ity from Aldrich, Fluka, Merck or Acros Organics without further
purification. Solvents were dried and purified before use according
to standard procedures. For flash column chromatography on silica
gel, Kieselgel 60 (0.040–0.063 mm, 230–400 mesh, Merck) was
used. Solvents for flash chromatography (hexane, ethyl acetate,
methanol, dichloromethane) were distilled before use. Thin layer
chromatography was run on Merck silica gel 60 F254 analytical

M. Martinková et al. / Tetrahedron: Asymmetry 23 (2012) 536–546
541
hexane/EtOAc (7:1) to afford 7.47 g (94%) of crystalline compound
(CHPh), 128.9 (2ꢃ CHPh), 137.1 (Ci), 158.3 (C@O), 170.3 (C@O). Anal.
Calcd for C19H23NO7: C, 60.47; H, 6.14; N, 3.71. Found: C, 60.48; H,
6.15; N, 3.76.
6. Mp 105ꢀ106 °C,
½
a 2D5
ꢂ
¼ þ155:3 (c 0.18, CHCl3). 1H NMR
(400 MHz, CDCl3): d 0.07 (s, 6H, 2ꢃ CH3), 0.89 (s, 9H, 3ꢃ CH3),
1.12 (s, 3H, CH3), 1.45 (s, 3H, CH3), 3.71 (dd, 1H, JH,H = 10.4 Hz,
J5,H = 8.3 Hz, CH2O), 3.94 (dd, 1H, JH,H = 10.4 Hz, J5,H = 4.8 Hz,
CH2O), 4.05 (dd, 1H, J5,H = 8.3 Hz, J5,H = 4.8 Hz, H-5), 4.16 (d, 1H,
J6a,3a = 3.8 Hz, H-3a), 4.17 (d, 1H, JH,H = 15.8 Hz, NCH2Ph), 4.26 (d,
4.5. (5R,6S,8S,9R)-6-(Acetoxymethyl)-1-benzyl-8,9-dihydroxy-
3,7-dioxa-1-azaspiro [4.4]nonan-2-one 9
1H, J5 ,5 = 9.5 Hz, H-50), 4.54 (d, 1H, J5 ,5 = 9.5 Hz, H-50), 4.87 (d,
1H, JH,H = 15.8 Hz, NCH2Ph), 5.64 (d, 1H, J6a,3a = 3.8 Hz, H-6a),
7.28ꢀ7.37 (m, 5H, Ph). 13C NMR (100 MHz, CDCl3): d ꢀ5.7 (CH3),
ꢀ5.6 (CH3), 18.2 (Cq), 25.8 (4ꢃ CH3), 26.3 (CH3), 46.8 (NCH2Ph),
60.1 (CH2O), 64.7 (C-50), 70.3 (C-40), 81.9 (C-5), 83.6 (C-3a), 104.0
(C-6a), 112.2 (C-2), 127.7 (2ꢃ CHPh), 128.0 (CHPh), 128.8 (2ꢃ CHPh),
137.5 (Ci), 158.7 (C@O). Anal. Calcd for C23H35NO6Si: C, 61.44; H,
7.85; N, 3.12. Found: C, 61.50; H, 7.80; N, 3.15.
Compound 8 (6.04 g, 16.0 mmol) was treated with a mixture
of 85:15 TFA/H2O (130 mL) for 8.5 h at room temperature. The
solvent was evaporated in vacuo, and the residue was purified
through a short column of silica gel hexane/EtOAc (1:1) to yield
4.48 g (83%) of crystalline compound 9. Mp 162–164 °C,
0
0
0
0
½
a 2D5
ꢂ
¼ þ49:1 (c 0.36, CH3OH). 1H NMR (400 MHz, CD3OD): d
2.06 (s, 3H, CH3), 4.04 (d, 1H, J9,8 = 4.6 Hz, H-9), 4.18ꢀ4.21 (m,
2H, CH2O), 4.23–4.27 (m, 2H, H-4, H-6), 4.37 (d, 1H,
JH,H = 16.3 Hz, NCH2Ph), 4.73 (d, 1H, J4,4 = 9.8 Hz, H-4), 4.75 (d,
1H, JH,H = 16.3 Hz, NCH2Ph), 5.35 (d, 1H, J9,8 = 4.6 Hz, H-8),
7.25ꢀ7.41 (m, 5H, Ph). 13C NMR (100 MHz, CD3OD): d 20.6
(CH3), 47.6 (NCH2Ph), 62.9 (CH2O), 68.3 (C-4), 72.1 (C-5), 75.1
(C-9), 80.9 (C-6), 97.0 (C-8), 128.2 (2ꢃ CHPh), 128.8 (CHPh),
129.8 (2ꢃ CHPh), 139.0 (Ci), 160.8 (C@O), 172.1 (C@O). Anal.
4.3. (3aR,40S,5S,6aR)-30-Benzyl-5-(hydroxymethyl)-2,2-dimethyl-
dihydro-3aH-spiro[furo[2,3-d][1,3]dioxole-6,40-oxazolidin]-20-
one 7
To a solution of 6 (7.46 g, 16.6 mmol) in dry THF (166 mL) was
added dropwise a 1 M solution of TBAF (16.6 mL, 16.6 mmol) in
THF at 0 °C. The resulting reaction mixture was stirred for a further
10 min at 0 °C and then at room temperature for 20 min. The sol-
vent was evaporated in vacuo, and the residue was partitioned be-
tween EtOAc (70 mL) and water (35 mL). The aqueous phase was
washed with further portions of EtOAc (2 ꢃ 30 mL). The organic
layers were combined, dried over Na2SO4 and stripped of solvent.
The crude product was chromatographed on silica gel hexane/
EtOAc (1:1) to give 5.51 g (99%) of compound 7 as a colourless
Calcd for
C16H19NO7: C, 56.97; H, 5.68; N, 4.15. Found: C,
56.92; H, 5.71; N, 4.18.
4.6. Ethyl (4S,2E)-4-{(40R)-40-[(100S)-200-acetoxy-100-hydroxyethyl]-
30-benzyl-20-oxooxazolidin-40-yl}-4-hydroxybut-2-enoate 10
To a solution of 9 (4.48 g, 13.3 mmol) in dry CH2Cl2 (119 mL)
were successively added benzoic acid (0.16 g, 1.33 mmol) and sta-
bilized ylide, Ph3P@CHCO2Et, (8.33 g, 23.9 mmol), and the resulting
mixture was stirred at room temperature. After the starting mate-
rial was completely consumed (3 h, judged by TLC), the reaction
was stopped and the solvent was removed under reduced pressure.
The residue was purified by flash chromatography on silica gel
hexane/EtOAc (1:2) to give 3.68 g (68%) of crystalline ester 10.
oil. ½a 2D5
ꢂ
¼ þ154:0 (c 0.18, CHCl3). 1H NMR (400 MHz, CDCl3): d
1.12 (s, 3H, CH3), 1.45 (s, 3H, CH3), 3.83 (dd, 1H, JH,H = 11.5 Hz,
J5,H = 5.9 Hz, CH2O), 3.94 (dd, 1H, JH,H = 11.5 Hz, J5,H = 6.3 Hz,
CH2O), 4.12ꢀ4.19 (m, 3H, H-5, NCH2Ph, H-3a), 4.23 (d, 1H,
J5 ,5 = 9.8 Hz, H-50), 4.58 (d, 1H, J5 ,5 = 9.8 Hz, H-50), 4.92 (d, 1H,
JH,H = 15.9 Hz, NCH2Ph), 5.67 (d, 1H, J6a,3a = 3.7 Hz, H-6a),
7.29ꢀ7.39 (m, 5H, Ph). 13C NMR (100 MHz, CDCl3): d 25.8 (CH3),
26.3 (CH3), 46.8 (NCH2Ph), 59.6 (CH2O), 64.7 (C-50), 70.2 (C-40),
82.4 (C-5), 83.5 (C-3a), 104.1 (C-6a), 112.4 (C-2), 127.6 (2ꢃ CHPh),
128.2 (CHPh), 128.9 (2ꢃ CHPh), 137.3 (Ci), 158.7 (C@O). Anal. Calcd
for C17H21NO6: C, 60.89; H, 6.31; N, 4.18. Found: C, 60.95; H, 6.27;
N, 4.15.
0
0
0
0
Mp 111ꢀ112 °C,
½
a 2D5
ꢂ
¼ þ167:5 (c 0.23, CHCl3). 1H NMR
(400 MHz, CDCl3): d 1.26 (t, 3H, J = 7.1 Hz, CH3), 2.13 (s, 3H,
CH3CO), 3.29 (m, 1H, OH), 3.91ꢀ3.97 (m, 2H, H-100, H-50), 4.03
(dd, 1H, J2 ,2 = 12.0 Hz, J2 ,1 = 6.8 Hz, H-200), 4.14 (d, 1H,
00 00
00 00
J5 ,5 = 9.4 Hz, H-50), 4.16 (q, 2H, J = 7.1 Hz, CH2), 4.31 (dd, 1H,
0
0
J2 ,2 = 12.0 Hz, J2 ,1 = 2.5 Hz, H-200), 4.65 (d, 1H, JH,H = 15.2 Hz,
NCH2Ph), 4.75 (td, 1H, J4,3 = 4.3 Hz, J4,OH = 4.3 Hz, J4,2 = 1.9 Hz, H-
4), 4.82 (d, 1H, JH,H = 15.2 Hz, NCH2Ph), 6.18 (dd, 1H,
J3,2 = 15.6 Hz, J4,2 = 1.9 Hz, H-2), 6.87 (dd, 1H, J3,2 = 15.6 Hz,
J4,3 = 4.3 Hz, H-3), 7.28ꢀ7.39 (m, 3H, Ph), 7.47ꢀ7.52 (m, 2H, Ph).
00 00
00 00
4.4. (3aR,40S,5S,6aR)-5-(Acetoxymethyl)-30-benzyl-2,2-dimethyldi-
hydro-3aH-spiro[furo[2,3-d][1,3]dioxole-6,40-oxazolidin]-20-
one 8
13C NMR (100 MHz, CDCl3):
d 14.1 (CH3), 20.8 (CH3), 46.3
(NCH2Ph), 60.8 (CH2), 64.7 (C-50), 65.3 (C-200), 68.9 (C-40), 69.2 (C-
4), 72.4 (C-100), 124.2 (C-2), 128.4 (2ꢃ CHPh), 128.4 (CHPh), 129.3
(2ꢃ CHPh), 137.9 (Ci) 142.6 (C-3), 159.0 (C@O), 166.0 (C@O),
171.3 (C@O). Anal. Calcd for C20H25NO8: C, 58.96; H, 6.18; N,
3.44. Found: C, 59.00; H, 6.14; N, 3.48.
To a solution of 7 (5.51 g, 16.4 mmol) in dry pyridine (126 mL)
were successively added Ac2O (2.33 mL, 24.6 mmol) and DMAP
(0.20 g, 1.64 mmol) at room temperature. The resulting mixture
was stirred at the same temperature for 30 min, then poured into
ice water (550 mL) and extracted with CH2Cl2 (3 ꢃ 90 mL). The
combined organic layers were dried over Na2SO4, the solvent was
evaporated, and the residue was purified by flash chromatography
on silica gel hexane/EtOAc (2:1) to afford 6.08 g (98%) of crystalline
4.7. (4R)-3-Benzyl-4-[(10S,20E)-10,400-dihydroxybut-20-enyl]-4-
[(100S)-100,200-dihydroxyethyl]oxazolidin-2-one 11
compound 8. Mp 144ꢀ145 °C, ½a D25
ꢂ
¼ þ123:2 (c 0.21, CHCl3). 1H
Diisobutylaluminum hydride (37.6 mL of a 1.2 M toluene solu-
tion) was added dropwise to a solution of ester 10 (3.68 g,
9.03 mmol) in dry CH2Cl2 (76.5 mL) at ꢀ78 °C. The reaction mix-
ture was stirred at the same temperature for 1 h and then
quenched by the slow addition of cooled acetone (15 mL). To the
resulting solution was added solid Na2SO4.10H2O (45 g) at 0 °C.
After being stirred for 1.5 h at room temperature, the insoluble
parts were filtered off and washed with a mixture of 5:1 CH2Cl2/
MeOH (480 mL). The evaporation of solvents afforded 2.57 g
(88%) of the crude compound 11 as a colourless oil, which was used
immediately in the next step without further purification to avoid
NMR (400 MHz, CDCl3): d 1.12 (s, 3H, CH3), 1.44 (s, 3H, CH3),
2.11 (s, 3H, CH3CO), 4.16 (d, 1H, JH,H = 15.8 Hz, NCH2Ph), 4.17 (d,
1H, J5 ,5 = 10.0 Hz, H-50), 4.17 (d, 1H, J6a,3a = 3.8 Hz, H-3a), 4.19
(dd, 1H, J5,H = 6.8 Hz, J5,H = 5.3 Hz, H-5), 4.25 (dd, 1H, JH,H = 12.0 Hz,
J5,H = 5.3 Hz, CH2O), 4.30 (dd, 1H, JH,H = 12.0 Hz, J5,H = 6.8 Hz, CH2O),
0
0
4.59 (d, 1H, J5 ,5 = 10.0 Hz, H-50), 4.94 (d, 1H, JH,H = 15.8 Hz,
NCH2Ph), 5.69 (d, 1H, J6a,3a = 3.8 Hz, H-6a), 7.29ꢀ7.39 (m, 5H, Ph).
13C NMR (100 MHz, CDCl3): d 20.7 (CH3), 25.7 (CH3), 26.3 (CH3),
46.8 (NCH2Ph), 60.8 (CH2O), 64.4 (C-50), 70.3 (C-40), 80.0 (C-5),
83.3 (C-3a), 104.2 (C-6a), 112.5 (C-2), 127.6 (2ꢃ CHPh), 128.3
0
0

542
M. Martinková et al. / Tetrahedron: Asymmetry 23 (2012) 536–546
problems connected with its hydrophilic nature. 1H NMR
20), 7.19–7.25 (m, 1H, Ph), 7.26–7.32 (m, 2H, Ph), 7.38–7.44 (m,
2H, Ph). 13C NMR (100 MHz, CD3OD): d 19.0 (CH3), 29.4 (CH3),
48.3 (NCH2Ph), 60.0 (C-5), 62.9 (C-30), 66.7 (C-10), 68.5 (C-4),
77.8 (C-6), 100.7 (C-8), 124.4 (C-10), 128.2 (CHPh), 128.8 (2ꢃ CHPh),
129.3 (2ꢃ CHPh), 137.6 (C-20), 139.8 (Ci), 161.2 (C@O). Anal. Calcd
for C18H23NO5: C, 64.85; H, 6.95; N, 4.20. Found: C, 64.87; H,
6.92; N, 4.18.
00 00
00 00
(400 MHz, CD3OD): d 3.55 (dd, 1H, J2 ,2 = 11.7 Hz, J2 ,1 = 5.5 Hz,
H-200), 3.68 (dd, 1H, J2 ,2 = 11.7 Hz, J2 ,1 = 3.0 Hz, H-200), 3.94 (dd,
00 00
00 00
1H, J2 ,1 = 5.5 Hz, J2 ,1 = 3.0 Hz, H-100), 4.01ꢀ4.07 (m, 3H, H-40, H-
5, H-10), 4.35ꢀ4.39 (m, 2H, H-40, H-5), 4.57 (d, 1H, JH,H = 15.6 Hz,
NCH2Ph), 4.64 (d, 1H, JH,H = 15.6 Hz, NCH2Ph), 5.68 (dd, 1H,
00 00
00 00
J3 ,2 = 15.4 Hz, J2 ,1 = 6.4 Hz, H-20), 5.94 (dt, 1H, J3 ,2 = 15.4 Hz,
0
0
0
0
0
0
J4 ,3 = 5.1 Hz, J4 ,3 = 5.1 Hz, H-30), 7.18ꢀ7.23 (m, 1H, Ph),
7.24ꢀ7.31 (m, 2H, Ph), 7.41ꢀ7.47 (m, 2H, Ph). Anal. Calcd for
0
0
0
0
4.10. (5R,6R)-1-Benzyl-6-[(20R,30R)-30-(hydroxymethyl)oxiran-
20-yl]-8,8-dimethyl-3,7,9-trioxa-1-azaspiro[4.5]decan-2-one 13
and (5R,6R)-1-benzyl-6-[(20S,30S)-30-(hydroxymethyl)oxiran-20-
yl]-8,8-dimethyl-3,7,9-trioxa-1-azaspiro[4.5]decan-2-one 14
C
16H21NO6: C, 59.43; H, 6.55; N, 4.33. Found: 59.21; H, 6.73; N,
4.20.
4.8. (4R)-3-Benzyl-4-[(10S,20E)-10,40-dihydroxybut-20-enyl]-4-
(hydroxymethyl)oxazolidin-2-one 12
To a solution of 4 (1.30 g, 3.90 mmol) in dry CH2Cl2 (40 mL),
which was pre-cooled to 0 °C, was added m-chloroperoxybenzoic
acid (57-86%, Aldrich) (1.99 g, 11.53 mmol) in three portions at
10 min intervals. The reaction mixture was stirred for 1 h at 0 °C
and for another 26 h at room temperature. Then, the resulting solu-
tion was treated with saturated aqueous NaHCO3 (75 mL) and
Na2S2O3 (75 mL). The organic layer was dried over Na2SO4, the sol-
vent was evaporated, and the residue was chromatographed on sil-
ica gel hexane/EtOAc (1:2) to afford 0.97 g (71%) of 13 and 0.19 g
A solution of 12 (2.57 g, 7.95 mmol) in a mixture of 1:1 CH3OH/
H2O (29 mL) was treated with solid NaIO4 (2.04 g, 9.54 mmol). The
resulting mixture was stirred at room temperature for 30 min and
then diluted with CH2Cl2 (20 mL). The insoluble materials were re-
moved by filtration, the solvent was evaporated, and the residue
was immediately used in the next step without further purifica-
tion. To a solution of the crude aldehyde (2.31 g, 7.93 mmol) in
EtOH (61.0 mL), which was pre-cooled to 0 °C, was added NaBH4
(0.36 g, 9.52 mmol). The mixture was stirred for 10 min at 0 °C
and then for an additional 20 min at room temperature. The reac-
tion was quenched by neutralization with Amberlite IR-120 (H+),
the solid parts were filtered off, the solvent was evaporated, and
the residue was subjected to flash chromatography on silica gel
CH2Cl2/MeOH (9:1) to give 1.49 g (64%) of compound 12 as a col-
(14%) of 14 as colourless oils. Diastereoisomer 13: ½a D25
¼ þ88:5
ꢂ
(c 0.19, CHCl3). IR (KBr): mmax 3437, 2993, 1743, 1437, 1385,
1263, 1144, 1014, 858, 698. 1H NMR (400 MHz, CDCl3): d 1.45 (s,
3H, CH3), 1.53 (s, 3H, CH3), 2.31 (m, 1H, OH), 3.02 (dd, 1H,
J6,2 = 4.9 Hz, J3 ,2 = 2.1 Hz, H-20), 3.22 (ddd, 1H, J3 ,CH2O = 4.3 Hz,
0
0
0
0
J3 ,CH2O = 3.3 Hz, J3 ,2 = 2.1 Hz, H-30), 3.64 (dd, 1H, JH,H = 12.8 Hz,
0
0
0
0
J3 ,CH2O = 4.3 Hz, CH2O), 3.73 (d, 1H, J4,4 = 9.4 Hz, H-4), 3.76ꢀ3.85
ourless oil. ½a 2D5
ꢂ
¼ þ31:1 (c 0.29), CH3OH). 1H NMR (400 MHz,
(m, 4H, 2ꢃ H-10, H-6, CH2O), 4.21 (d, 1H, J4,4 = 9.4 Hz, H-4), 4.79
(d, 1H, JH,H = 15.3 Hz, NCH2Ph), 4.93 (d, 1H, JH,H = 15.3 Hz, NCH2Ph),
7.24ꢀ7.35 (m, 3H, Ph), 7.44ꢀ7.51 (m, 2H, Ph). 13C NMR (100 MHz,
CDCl3): d 18.4 (CH3), 28.5 (CH3), 47.2 (NCH2Ph), 52.8 (C-20), 55.6 (C-
30), 57.5 (C-5), 61.2 (CH2O), 65.5 (C-10), 66.8 (C-4), 75.3 (C-6), 99.7
(C-8), 127.5 (CHPh), 128.0 (2ꢃ CHPh), 128.4 (2ꢃ CHPh), 138.1 (Ci),
158.6 (C@O). Anal. Calcd for C18H23NO6: C, 61.88; H, 6.64; N,
4.01. Found: C, 61.91; H, 6.58; N, 4.02.
CD3OD):
d 3.50 (d, 1H, JH,H = 11.7 Hz, CH2O), 3.56 (d, 1H,
JH,H = 11.7 Hz, CH2O), 4.01 (m, 2H, 2ꢃ H-40), 4.10 (d, 1H,
J5,5 = 8.7 Hz, H-5), 4.20 (d, 1H, J2 ,1 = 6.8 Hz, H-10), 4.28 (d, 1H,
J5,5 = 8.7 Hz, H-5), 4.47 (d, 1H, JH,H = 15.8 Hz, NCH2Ph), 4.55 (d,
0
0
0
0
1H, JH,H = 15.8 Hz, NCH2Ph), 5.61 (dd, 1H, J3 ,2 = 15.4 Hz,
J2 ,1 = 6.8 Hz, H-20), 5.87 (dt, 1H, J3 ,2 = 15.4 Hz, J4 ,3 = 5.0 Hz,
0
0
0
0
0
0
J4 ,3 = 5.0 Hz, H-30), 7.19ꢀ7.25 (m, 1H, Ph), 7.26ꢀ7.31 (m, 2H, Ph),
7.39ꢀ7.43 (m, 2H, Ph). 13C NMR (100 MHz, CD3OD): d 46.3
(NCH2Ph), 62.8 (C-40), 63.2 (CH2O), 67.5 (C-5), 69.7 (C-4), 72.3 (C-
10), 128.3 (C-20), 128.5 (CHPh), 129.1 (2ꢃ CHPh), 129.4 (2ꢃ CHPh),
135.1 (C-30), 139.6 (Ci), 162.1 (C@O). Anal. Calcd for C15H19NO5:
C, 61.42; H, 6.53; N, 4.78. Found: C, 61.45; H, 6.50; N, 4.80.
0
0
Diastereoisomer 14: ½a D25
ꢂ
¼ þ79:1 (c 0.18, CHCl3). 1H NMR
(400 MHz, CDCl3): d 1.45 (s, 3H, CH3), 1.54 (s, 3H, CH3), 3.10 (dd,
1H, J6,2 = 5.4 Hz, J3 ,2 = 2.3 Hz, H-20), 3.21 (ddd, 1H, J3 ,CH2O = 3.9 Hz,
0
0
0
0
J3 ,CH2O = 2.7 Hz, J3 ,2 = 2.3 Hz, H-30), 3.69–3.78 (m, 5H, CH2O, 2ꢃ H-
0
0
0
0
10, H-6, H-4), 3.90 (dd, 1H, JH,H = 12.9 Hz, J3 ,CH2O = 2.7 Hz, CH2O),
4.04 (d, 1H, J4,4 = 9.6 Hz, H-4), 4.80 (d, 1H, JH,H = 15.5 Hz, NCH2Ph),
4.92 (d, 1H, JH,H = 15.5 Hz, NCH2Ph), 7.25ꢀ7.35 (m, 3H, Ph),
7.44ꢀ7.48 (m, 2H, Ph). 13C NMR (100 MHz, CDCl3): d 18.4 (CH3),
28.4 (CH3), 47.4 (NCH2Ph), 53.3 (C-20), 54.7 (C-30), 57.6 (C-5),
61.0 (CH2O), 64.8 (C-10), 67.6 (C-4), 76.9 (C-6), 99.7 (C-8), 127.5
(CHPh), 127.9 (2ꢃ CHPh), 128.5 (2ꢃ CHPh), 138.2 (Ci), 158.2 (C@O).
Anal. Calcd for C18H23NO6: C, 61.88; H, 6.64; N, 4.01. Found: C,
61.86; H, 6.61; N, 3.95.
4.9. (5R,6S)-1-Benzyl-6-[(E)-30-hydroxyprop-10-enyl]-8,8-dime-
thyl-3,7,9-trioxa-1-azaspiro [4.5]decan-2-one 4
To a solution of 12 (1.49 g, 5.08 mmol) in 2,2-dimethoxypro-
pane (20.8 mL) was added CSA (0.23 g, 0.99 mmol) and the result-
ing mixture was stirred at 40 °C. After the starting material was
completely consumed (1 h, judged by TLC), the reaction was
stopped and allowed to cool to room temperature. The solvent
was evaporated in vacuo, and the residue was partitioned between
CH2Cl2 (35 mL) and a saturated NaHCO3 solution (46 mL). The or-
ganic layer was dried over Na2SO4, the solvent was evaporated,
and the residue was purified by flash chromatography on silica
gel hexane/EtOAc (1:2) to yield 1.46 g (86%) of crystalline alcohol
4.11. (5R,6R)-1-Benzyl-6-[(20S,30S)-30-(trityloxymethyl)oxiran-20-
yl]-8,8-dimethyl-3,7,9-trioxa-1-azaspiro[4.5]decan-2-one 15
To a solution of 14 (49 mg, 0.14 mmol) in dry CH2Cl2 (0.81 mL)
were successively added Et3N (29.5 lL, 0.21 mmol), triphenyl-
4. Mp 132–134 °C, ½a D25
ꢂ
¼ þ18:9 (c 0.28, CH3OH). IR (KBr): mmax
methyl chloride (59 mg, 0.21 mmol) and DMAP (3.4 mg,
0.028 mmol). The resulting mixture was stirred for 92 h at room
temperature, the solvent was evaporated, and the residue was sub-
jected to flash chromatography on silica gel hexane/EtOAc (3:1) to
give 46 mg (56%) of crystalline derivative 15. Mp 173–175 °C,
3417, 3005, 2920, 2854, 1714, 1439, 1352, 1265, 1178, 1059,
972, 945, 854, 702. 1H NMR (400 MHz, CD3OD): d 1.46 (s, 3H,
CH3), 1.49 (s, 3H, CH3), 3.76 (d, 1H, J10,10 = 12.7 Hz, H10), 3.80 (d,
1H, J4,4 = 9.6 Hz, H-4), 3.94 (d, 1H, J10,10 = 12.7 Hz, H-10),
4.06ꢀ4.09 (m, 2H, 2ꢃ H-30), 4.12 (d, 1H, J4,4 = 9.6 Hz, H-4), 4.53
½
a 2D5
ꢂ
¼ þ75:3 (c 0.25, CHCl3). IR (KBr): mmax 2991, 2920, 1751,
0
0
(dd, 1H, J6,1 = 6.2 Hz, J6,2 = 1.2 Hz, H-6), 4.74 (d, 1H, JH,H = 15.7 Hz,
NCH2Ph), 4.91 (d, 1H, JH,H = 15.7 Hz, NCH2Ph), 5.65 (ddt, 1H,
1448, 1385, 1261, 1142, 1052, 883, 764, 700. 1H NMR (600 MHz,
CDCl3): d 1.42 (s, 3H, CH3), 1.54 (s, 3H, CH3), 2.95 (dd, 1H,
J2 ,1 = 15.5 Hz, J6,1 = 6.2 Hz, J3 ,1 = 1.7 Hz, J3 ,1 = 1.7 Hz, H-10), 6.08
J6,2 = 5.4 Hz, J3 ,2 = 2.2 Hz, H-20), 3.11 (ddd, 1H, J3 ,CH2O = 5.7 Hz,
0
0
0
0
0
0
0
0
0
0
0
,20
0
0
0
0
0
0
0
0
(dtd, 1H, J2 ,1 = 15.5 Hz, J3 ,2 = 5.0 Hz, J3 ,2 = 5.0 Hz, J6,2 = 1.2 Hz, H-
J3 ,CH2O = 2.6 Hz, J00 = 2.2 Hz, H-30) 3.16 (dd, 1H, JH,H = 11.1 Hz,
3

M. Martinková et al. / Tetrahedron: Asymmetry 23 (2012) 536–546
543
0
0
J3 ,CH2O = 5.7 Hz, CH2O), 3.41 (dd, 1H, JH,H = 11.1 Hz, J3 ,CH2O = 2.6 Hz,
Et2O (2 ꢃ 20 mL). The organic layers were combined, dried over
Na2SO4, the solvent was evaporated, and the residue was purified
by flash chromatography on silica gel hexane/EtOAc (2:1) to give
0
CH2O), 3.62 (d, 1H, J6,2 = 5.4 Hz, H-6), 3.69 (d, 1H, J10,10 = 12.7 Hz,
H-10), 3.70 (d, 1H, J4,4 = 9.5 Hz, H-4), 3.71 (d, 1H, J10,10 = 12.7 Hz,
H-10), 3.90 (d, 1H, J4,4 = 9.5 Hz, H-4), 4.77 (d, 1H, JH,H = 15.5 Hz,
NCH2Ph), 4.91 (d, 1H, JH,H = 15.4 Hz, NCH2Ph), 7.22ꢀ7.26 (m, 4H,
Ph), 7.27ꢀ7.33 (m, 8H, Ph), 7.42ꢀ7.47 (m, 8H, Ph). 13C NMR
(150 MHz, CDCl3): d 18.8 (CH3), 28.3 (CH3), 47.3 (NCH2Ph), 53.0
(C-20), 53.9 (C-30), 57.6 (C-5), 63.6 (CH2O), 65.2 (C-10), 67.5 (C-4),
76.7 (C-6), 86.9 (CPh3), 99.8 (C-8), 127.1 (3ꢃ CHPh), 127.4 (CHPh),
127.9 (6ꢃ CHPh), 127.9 (2ꢃ CHPh), 128.4 (2ꢃ CHPh), 128.7 (6ꢃ
CHPh), 138.3 (Ci), 143.6 (3ꢃ Ci), 157.8 (C@O). Anal. Calcd for
0.40 g (65%) of compound 3 as a colourless oil. ½a D25
¼ þ39:2 (c
ꢂ
0.16, CHCl3). 1H NMR (400 MHz, CDCl3): d 0.08 (s, 3H, CH3), 0.09
(s, 3H, CH3), 0.90 (s, 9H, 3ꢃ CH3), 1.42 (s, 3H, CH3), 1.45 (s, 3H,
CH3), 1.55–1.67 (m, 1H, H-20), 1.87–1.96 (m, 1H, H-20), 3.66 (d,
1H, J4,4 = 8.4 Hz, H-4), 3.67 (d, 1H, J10,10 = 12.7 Hz, H-10), 3.67 (d,
1H, J6,1 = 8.6 Hz, H-6), 3.70–3.81 (m, 2H, H-10, H-30), 3.84–4.00
0
(m, 2H, H-30, H-10), 4.55 (d, 1H, J4,4 = 8.4 Hz, H-4), 4.71 (d, 1H,
JH,H = 15.4 Hz, NCH2Ph), 4.91 (d, 1H, JH,H = 15.4 Hz, NCH2Ph),
7.19ꢀ7.34 (m, 3H, Ph), 7.45ꢀ7.50 (m, 2H, Ph).13C NMR (100 MHz,
CDCl3): d ꢀ5.6 (CH3), ꢀ5.5 (CH3), 18.1 (Cq), 19.0 (CH3), 25.9 (3ꢃ
CH3), 28.1 (CH3), 34.5 (C-20), 47.0 (NCH2Ph), 58.2 (C-5), 63.1 (C-
30), 67.3 (C-10), 68.5 (C-4), 72.3 (C-10), 77.4 (C-6), 99.3 (C-8),
127.2 (CHPh), 127.9 (2ꢃ CHPh), 128.3 (2ꢃ CHPh), 138.6 (Ci), 159.1
(C@O). Anal. Calcd for C24H39NO6Si: C, 61.90; H, 8.44; N, 3.01.
Found: C, 61.87; H, 8.41; N, 3.06.
C
37H37NO6: C, 75.11; H, 6.30; N, 2.37. Found: C, 75.17; H, 6.27;
N, 2.39.
4.12. (5R,6R)-1-Benzyl-6-[(10S)-10,30-dihydroxypropyl]-8,8-dime-
thyl-3,7,9-trioxa-1-azaspiro[4.5]decan-2-one 16
To a solution of 13 (0.82 g, 2.35 mmol) in dry THF (13.0 mL),
which was pre-cooled to 0 °C, was added Red-Al (1.81 mL of a
65% solution in toluene). After being stirred at 0 °C for 2.5 h, the
reaction mixture was partitioned between ice water (1.1 mL) and
Et2O (26 mL) and then a solid NaF (0.92 g, 21.9 mmol) was added.
The resulting suspension was stirred vigorously at room tempera-
ture for 1 h and filtered through a small pad of Celite. The solvent
was evaporated in vacuo, and the residue was chromatographed on
silica gel hexane/EtOAc (1:5) to afford 0.51 g (62%) of compound 16
as a colourless oil. 1H NMR (400 MHz, CDCl3): d 1.42 (s, 3H, CH3),
1.44 (s, 3H, CH3), 1.55–1.65 (m, 1H, H-20), 1.98–2.06 (m, 1H, H-
20), 3.67 (d, 1H, J10,10 = 12.4 Hz, H-10), 3.67ꢀ3.82 (m, 4H, H-30, H-
6, H-4, H-10), 3.85ꢀ3.99 (m, 2H, H-30, H-10), 4.57 (d, 1H,
J4,4 = 8.6 Hz, H-4), 4.73 (d, 1H, JH,H = 15.4 Hz, NCH2Ph), 4.90 (d,
1H, JH,H = 15.4 Hz, NCH2Ph), 7.23ꢀ7.28 (m, 1H, Ph), 7.29ꢀ7.34 (m,
2H, Ph), 7.42ꢀ7.46 (m, 2H, Ph). Anal. Calcd for C18H25NO6: C,
61.52; H, 7.17; N, 3.99. Found: C, 61.40; H, 7.26; N, 3.87.
4.15. (5R,6R)-1-Benzyl-6-{30-[(tert-butyldimethylsilyl)oxy] pro-
panoyl}-8,8-dimethyl-3,7,9-trioxa-1-azaspiro[4.5]decan-2-one
18
o-Iodoxybenzoic acid (0.35 g, 1.25 mmol) was added to a solu-
tion of 3 (0.29 g, 0.62 mmol) in CH3CN (5.5 mL), and the resulting
mixture was stirred at reflux. After the starting material was com-
pletely consumed (75 min, judged by TLC), the reaction was
stopped and allowed to cool to room temperature. The solid parts
were filtered off, the solvent was evaporated, and the residue was
chromatographed on silica gel hexane/EtOAc (2:1) to afford 0.27 g
(93%) of compound 18 as a colourless oil. ½a D25
¼ þ43:7 (c 0.15,
ꢂ
CHCl3). 1H NMR (400 MHz, CDCl3): d 0.04 (s, 3H, CH3), 0.05 (s,
3H, CH3), 0.87 (s, 9H, 3ꢃ CH3), 1.46 (s, 3H, CH3), 1.55 (s, 3H,
CH3), 2.31 (dt, 1H, J2 ,2 = 17.5 Hz, J3 ,2 = 6.2 Hz, J3 ,2 = 6.2 Hz, H-20),
0
0
0
0
0
0
2.77 (dt, 1H, J2 ,2 = 17.5 Hz, J3 ,2 = 6.6 Hz, J3 ,2 = 6.6 Hz, H-20), 3.68
(d, 1H, J10,10 = 12.6 Hz, H-10), 3.76 (d, 1H, J10,10 = 12.6 Hz, H-10),
3.80 (d, 1H, J4,4 = 8.8 Hz, H-4), 3.67–3.75 (m, 1H, H-30), 3.82–3.85
(m, 1H, H-30), 4.19 (s, 1H, H-6), 4.54 (d, 1H, J4,4 = 8.8 Hz, H-4),
4.62 (d, 1H, JH,H = 15.5 Hz, NCH2Ph), 4.75 (d, 1H, JH,H = 15.5 Hz,
NCH2Ph), 7.21ꢀ7.35 (m, 3H, Ph), 7.36ꢀ7.42 (m, 2H, Ph). 13C NMR
(100 MHz, CDCl3): d ꢀ5.4 (CH3), ꢀ5.4 (CH3), 18.3 (Cq), 18.9 (CH3),
25.9 (3ꢃ CH3), 27.7 (CH3), 41.9 (C-20), 46.9 (NCH2Ph), 58.0 (C-30),
58.5 (C-5), 67.4 (C-10), 68.1 (C-4), 78.8 (C-6), 100.4 (C-8), 127.4
(CHPh), 128.1 (2ꢃ CHPh), 128.3 (2ꢃ CHPh), 137.9 (Ci), 158.5 (C@O),
206.4 (C-10). Anal. Calcd for C24H37NO6Si: C, 62.17; H, 8.04; N,
3.02. Found: C, 62.21; H, 8.01; N, 3.06.
0
0
0
0
0
0
4.13. (5R,6R)-1-Benzyl-6-[(10S)-10,30-diacetoxypropyl]-8,8-dime-
thyl-3,7,9-trioxa-1-azaspiro[4.5]decan-2-one 17
Using the same procedure as described for the preparation of 8,
compound 16 (21 mg, 0.06 mmol), Ac2O (17 lL, 0.18 mmol) an-
d DMAP (1.2 mg, 0.01 mmol) in dry pyridine (0.5 mL) yielded after
flash chromatography on silica gel hexane/EtOAc (1:1) 19 mg (74%)
of derivative 17 as a colourless oil. ½a D25
ꢂ
¼ þ96:2 (c 0.15, CHCl3). 1H
NMR (400 MHz, CDCl3): d 1.44 (s, 3H, CH3), 1.51 (s, 3H, CH3),
1.93ꢀ2.16 (m, 8H, 2ꢃ CH3, 2ꢃ H-20), 3.64 (d, 1H, J10,10 = 12.8 Hz,
0
H-10), 3.69 (m, 2H, H-4, H-10), 3.99 (d, 1H, J6,1 = 7.4 Hz, H-6),
4.06ꢀ4.19 (m, 2H, 2ꢃ H-30), 4.33 (d, 1H, J4,4 = 9.1 Hz, H-4), 4.63
(d, 1H, JH,H = 15.3 Hz, NCH2Ph), 4.91 (d, 1H, JH,H = 15.3 Hz, NCH2Ph),
4.16. (5R,6R)-1-Benzyl-6-{(10R)-30-[(tert-butyldimethylsilyl) oxy]-
10-hydroxypropyl}-8,8-dimethyl-3,7,9-trioxa-1-azaspiro[4.5]-
decan-2-one 19
5.07 (dt, 1H, J6,1 = 7.4 Hz, J2 ,1 = 7.4 Hz, J2 ,1 = 3.7 Hz, H-10),
7.24ꢀ7.34 (m, 3H, Ph), 7.43ꢀ7.48 (m, 2H, Ph). 13C NMR
(100 MHz, CDCl3): d 18.8 (CH3), 20.9 (CH3), 20.9 (CH3), 28.1
(CH3), 29.8 (C-20), 47.1 (NCH2Ph), 57.6 (C-5), 60.3 (C-30), 66.4 (C-
10), 68.1 (C-4), 69.5 (C-10), 76.3 (C-6), 99.8 (C-8), 127.5 (CHPh),
128.0 (2ꢃ CHPh), 128.4 (2ꢃCHPh), 138.1 (Ci), 157.9 (C@O), 169.8
(C@O), 171.0 (C@O). Anal. Calcd for C22H29NO6: C, 60.68; H, 6.71;
N, 3.23. Found: C, 60.71; H, 6.68; N, 3.19.
0
0
0
0
0
L-Selectride (0.78 mL of a 1 M solution in THF) was added drop-
wise to a solution of 18 (0.18 g, 0.39 mmol) in dry THF (9.24 mL),
which was pre-cooled to ꢀ78 °C, and the reaction mixture was stir-
red at ꢀ78 °C for 40 min. After the cautious addition of ice water
(1.6 mL), the mixture was allowed to warm to room temperature
and stirring was continued for another 30 min. The resulting mix-
ture was extracted with EtOAc (2 ꢃ 10 mL), the combined organic
layers were dried over Na2SO4, stripped of solvent, and the residue
was chromatographed on silica gel hexane/EtOAc (2:1) to give
4.14. (5R,6R)-1-Benzyl-6-{(10S)-30-[(tert-butyldimethylsilyl)oxy]-
10-hydroxypropyl}-8,8-dimethyl-3,7,9-trioxa-1-azaspiro[4.5]-
decan-2-one 3
0.17 g (94%) of compound 19 as a colourless oil. ½a D25
¼ þ103:2 (c
ꢂ
To a solution of 16 (0.46 g, 1.31 mmol) in dry DMF (1.44 mL)
were successively added Et3N (0.28 mL, 1.99 mmol), tert-butyldi-
methylsilyl chloride (0.29 g, 1.92 mmol) and DMAP (0.16 g,
1.31 mmol). The resulting mixture was stirred at room tempera-
ture for 1 h, then poured into ice water (15 mL) and extracted with
0.35, CHCl3). 1H NMR (400 MHz, CDCl3): d 0.08 (s, 3H, CH3), 0.08
(s, 3H, CH3), 0.90 (s, 9H, 3ꢃ CH3), 1.45 (s, 3H, CH3), 1.55 (s, 3H,
CH3), 1.68–1.75 (m, 1H, H-20), 1.86–1.94 (m, 1H, H-20), 2.75 (d,
0
1H, J1 ,OH = 5.4 Hz, OH), 3.65–3.73 (m, 3H, 2ꢃ H-10, H-4), 3.75 (d,
1H, J6,1 = 3.1 Hz, H-6), 3.76–3.97 (m, 2H, 2ꢃ H-30), 4.05–4.10 (m,
0

544
M. Martinková et al. / Tetrahedron: Asymmetry 23 (2012) 536–546
1H, H-10), 4.11 (d, 1H, J4,4 = 9.4 Hz, H-4), 4.73 (d, 1H, JH,H = 15.6 Hz,
NCH2Ph), 4.86 (d, 1H, JH,H = 15.6 Hz, NCH2Ph), 7.25ꢀ7.35 (m, 3H,
Ph), 7.46ꢀ7.48 (m, 2H, Ph). 13C NMR (100 MHz, CDCl3): d ꢀ5.5
(CH3), ꢀ5.4 (CH3), 18.3 (Cq), 18.8 (CH3), 25.9 (3ꢃ CH3), 28.4
(CH3), 36.4 (C-20), 47.8 (NCH2Ph), 57.8 (C-5), 60.9 (C-30), 66.4 (C-
10), 67.4 (C-4), 68.2 (C-10), 77.6 (C-6), 99.9 (C-8), 127.2 (CHPh),
127.9 (2ꢃ CHPh), 128.3 (2ꢃ CHPh), 138.8 (Ci), 158.3 (C@O). Anal.
Calcd for C24H39NO6Si: C, 61.90; H, 8.44; N, 3.01. Found: C,
61.92; H, 8.39; N, 2.99.
4.19. (4aS,8R,8aR)-5-Benzyl-8-{20-[(tert-butyldimethylsilyl) oxy]-
ethyl}-4a-(hydroxymethyl)-2,2-dimethyltetrahydro-[1,3] diox-
ino[5,4-d][1,3]oxazin-6(4H)-one 22
To a solution of 21 (35 mg, 99.6 lmol) in dry CH2Cl2 (1.26 mL)
that was pre-cooled to 0 °C, were successively added imidazole
(20 mg, 0.29 mmol) and tert-butyldimethylsilyl chloride (20 mg,
0.13 mmol). After being stirred at 0 °C for 20 min, the solvent
was evaporated and the residue was chromatographed on silica
gel hexane/EtOAc (2:1) to yield 35 mg (76%) of compound 22 as
4.17. (4aS,8R,8aR)-5-Benzyl-8-{20-[(tert-butyldimethylsilyl) oxy]-
ethyl}-4a-(benzyloxymethyl)-2,2-dimethyltetrahydro-[1,3] diox-
ino[5,4-d][1,3]oxazin-6(4H)-one 20
a colourless oil. ½a D25
ꢂ
¼ þ44:8 (c 0.66, CHCl3). 1H NMR (400 MHz,
CDCl3): d 0.06 (s, 3H, CH3), 0.07 (s, 3H, CH3), 0.89 (s, 9H, 3ꢃ CH3),
1.37 (s, 3H, CH3), 1.39 (s, 3H, CH3), 1.77–1.85 (m, 1H, H-10), 2.05–
2.13 (m, 1H, H-10), 3.53 (m, 2H, CH2OH), 3.66 (d, 1H,
J4,4 = 12.3 Hz, H-4), 3.71–3.77 (m, 1H, H-20), 3.78 (d, 1H,
J4,4 = 12.3 Hz, H-4), 3.80–3.85 (m, 1H, H-20), 4.03 (d, 1H,
J8,8a = 1.5 Hz, H-8a), 4.11 (d, 1H, JH,H = 16.2 Hz, NCH2Ph), 4.80
At first, NaH (15 mg, 0.63 mmol of a 60% dispersion in min-
eral oil) was added to a solution of 19 (0.10 g, 0.21 mmol) in
dry DMF (2.0 mL), which was pre-cooled to 0 °C. The resulting
mixture was stirred for 1 h at 0 °C and then benzyl bromide
0
0
(ddd, 1H, J8,1 = 6.8 Hz, J8,1 = 5.0 Hz, J8,8a = 1.5 Hz, H-8), 5.12 (d,
1H, JH,H = 16.2 Hz, NCH2Ph), 7.23ꢀ7.35 (m, 5H, Ph). 13C NMR
(100 MHz, CDCl3): d ꢀ5.4 (CH3), ꢀ5.4 (CH3), 18.2 (Cq), 21.3 (CH3),
25.9 (4ꢃ CH3), 33.0 (C-10), 46.7 (NCH2Ph), 58.8 (C-20), 61.4 (C-4a),
62.6 (C-4), 64.5 (CH2OH), 68.0 (C-8a), 72.4 (C-8), 100.1 (C-2),
126.9 (2ꢃ CHPh), 127.5 (CHPh), 128.8 (2ꢃ CHPh), 138.7 (Ci), 155.3
(C@O). Anal. Calcd for C24H39NO6Si: C, 61.90; H, 8.44; N, 3.01.
Found: C, 61.93; H, 8.39; N, 3.04.
(31 lL, 0.26 mmol) was added, and stirring continued for
10 min at 0 °C and at room temperature for another 23 h. The
mixture was partitioned between ice water (10 mL) and Et2O
(10 mL), and the aqueous phase was extracted with further por-
tions of Et2O (2 ꢃ 10 mL). The organic layers were combined,
dried over Na2SO4, stripped of solvent and the residue was sub-
jected to flash chromatography on silica gel hexane/EtOAc (5:1)
to give 106 mg (89%) of compound 20 as
a colourless oil.
½
a 2D5
ꢂ
¼ þ43:8 (c 0.15, CHCl3). 1H NMR (400 MHz, CDCl3): d 0.05
4.20. (4aS,8R,8aR)-5-Benzyl-8-{20-[(tert-butyldimethylsilyl) oxy]-
ethyl}-2,2-dimethyl-6-oxohexahydro-[1,3]dioxino[5,4-d] [1,3]-
oxazin-4a-carboxylic acid 2
(s, 3H, CH3), 0.05 (s, 3H, CH3), 0.88 (s, 9H, 3ꢃ CH3), 1.35 (s,
6H, 2ꢃ CH3), 1.74–1.83 (m, 1H, H-10), 2.03–2.12 (m, 1H, H-10),
3.28 (d, 1H, JH,H = 10.1 Hz, CH2O), 3.34 (d, 1H, JH,H = 10.1 Hz,
CH2O), 3.65 (d, 1H, J4,4 = 12.4 Hz, H-4), 3.73 (d, 1H,
J4,4 = 12.4 Hz, H-4), 3.73–3.84 (m, 2H, 2ꢃ H-20), 4.01 (d, 1H,
J8,8a = 1.7 Hz, H-8a), 4.18 (d, 1H, JH,H = 12.1 Hz, OCH2Ph), 4.27
(d, 1H, JH,H = 12.1 Hz, OCH2Ph), 4.27 (d, 1H, JH,H = 16.2 Hz,
Using the same procedure as described for the preparation of
18, compound 22 (35 mg, 75.1 lmol), and o-iodoxybenzoic acid
(32 mg, 0.11 mmol) in CH3CN (1.0 mL) afforded, after 30 min, the -
crude aldehyde (35 mg), which was used immediately in the next
0
0
NCH2Ph), 4.80 (ddd, 1H, J8,1 = 8.3 Hz, J8,1 = 4.8 Hz, J8,8a = 1.7 Hz,
H-8), 4.90 (d, 1H, JH,H = 16.2 Hz, NCH2Ph), 7.14ꢀ7.35 (m, 10H,
Ph). 13C NMR (100 MHz, CDCl3): d ꢀ5.4 (2ꢃ CH3), 18.3 (Cq),
21.0 (CH3), 25.9 (3ꢃCH3), 26.3 (CH3), 33.3 (C-10), 47.0 (NCH2Ph),
58.9 (C-20), 60.1 (C-4a), 62.7 (C-4), 67.6 (C-8a), 71.0 (CH2O), 72.1
(C-8), 73.4 (OCH2Ph), 99.9 (C-2), 127.0 (CHPh), 127.1 (2ꢃ CHPh),
127.7 (2ꢃCHPh), 128.0 (CHPh), 128.3 (2ꢃ CHPh), 128.5 (2ꢃ CHPh),
137.0 (Ci), 138.4 (Ci), 154.8 (C@O). Anal. Calcd for C31H45NO6Si:
C, 66.99; H, 8.16; N, 2.52. Found: C, 67.03; H, 8.12; N, 2.49.
reaction without further purification. A solution of NaClO2
(65 mg, 0.72 mmol) and NaH2PO4.2H2O (81 mg, 0.52 mmol) in
water (0.36 mL) was added to the solution of aldehyde (35 mg,
75.1 lmol) in a mixture of 4:4:1 CH3CN/t-butanol/2-methylbut-
2-ene (1.62 mL) at 0 °C. The resulting mixture was stirred at 0 °C
for 1 h, after which the solvent was removed under reduced pres-
sure, and the residue was chromatographed through a short silica
gel column CH2Cl2/CH3OH (9:1) to give 26 mg (72%) of compound
2 as a colourless oil. ½a D25
ꢂ
¼ þ24:3 (c 0.06, CH3OH). 1H NMR
(400 MHz, CD3OD): d 0.03 (s, 3H, CH3), 0.04 (s, 3H, CH3), 0.86 (s,
9H, 3ꢃ CH3), 1.30 (s, 3H, CH3), 1.44 (s, 3H, CH3), 1.73–1.82 (m,
1H, H-10), 1.91–2.01 (m, 1H, H-10), 3.62–3.81 (m, 2H, 2ꢃ H-20),
3.91 (d, 1H, J4,4 = 13.2 Hz, H-4), 4.26 (d, 1H, JH,H = 16.8 Hz, NCH2Ph),
4.34–4.37 (m, 2H, H-8a, H-4), 4.59–4.64 (m, 1H, H-8), 4.91 (d, 1H,
JH,H = 16.8 Hz, NCH2Ph), 7.11ꢀ7.15 (m, 1H, Ph), 7.18ꢀ7.22 (m, 2H,
Ph), 7.32ꢀ7.34 (m, 2H, Ph). 13C NMR (100 MHz, CD3OD): d ꢀ5.3
(CH3), ꢀ5.2 (CH3) 19.2 (Cq), 19.5 (CH3), 26.5 (3ꢃ CH3), 28.7 (CH3),
34.0 (C-10), 51.2 (NCH2Ph), 59.6 (C-20), 63.0 (C-4), 66.1 (C-4a),
67.5 (C-8a), 73.9 (C-8), 100.4 (C-2), 127.8 (CHPh), 128.4 (2ꢃ CHPh),
128.9 (2ꢃ CHPh), 139.1 (Ci), 157.0 (C@O), 173.0 (COOH). Anal. Calcd
for C24H37NO7Si: C, 60.10; H, 7.78; N, 2.92. Found: C, 60.07; H, 7.73;
N, 2.97.
4.18. (4aS,8R,8aR)-5-Benzyl-8-(20-hydroxyethyl)-4a-(hydroxy-
methyl)-2,2-dimethyltetrahydro-[1,3]dioxino[5,4-d] [1,3]oxazin-
6(4H)-one 21
To a solution of 20 (56 mg, 0.10 mmol) in dry EtOH (2.0 mL)
was added Pd(OH)2/C (28 mg, 20% by weight) in one portion
and the resulting mixture was stirred under H2 (10 atm) at room
temperature. After 15 h, no starting material was detected (TLC)
in the mixture, which was then filtered through a small pad of sil-
ica gel. Evaporation of the solvent afforded 35 mg (99%) of com-
pound 21 as a colourless oil, which was used immediately in
the next step without further purification. 1H NMR (400 MHz,
CDCl3): d 1.36 (s, 3H, CH3), 1.39 (s, 3H, CH3), 1.78–1.88 (m, 1H,
H-10), 2.10–2.17 (m, 1H, H-10), 2.56 (m, 1H, OH), 3.51 (d, 1H,
JH,H = 12.4 Hz, CH2O), 3.58 (d, 1H, JH,H = 12.4 Hz, CH2O), 3.62 (d,
1H, J4,4 = 12.6 Hz, H-4), 3.76 (d, 1H, J4,4 = 12.6 Hz, H-4), 3.76–
3.84 (m, 1H, H-20), 3.85–3.93 (m, 1H, H-20), 4.05 (m, 1H, H-8a),
4.31 (d, 1H, JH,H = 16.3 Hz, NCH2Ph), 4.86–4.93 (m, 1H, H-8),
4.94 (d, 1H, JH,H = 16.3 Hz, NCH2Ph), 7.25ꢀ7.38 (m, 5H, Ph). Anal.
Calcd for C18H25NO6: C, 61.52; H, 7.17; N, 3.99. Found: C, 61.43;
H, 7.08; N, 4.05.
4.21. Methyl (4aS,8R,8aR)-5-benzyl-8-{20-[(tert-butyldimethyl-
silyl)oxy]ethyl}-2,2-dimethyl-6-oxohexahydro-[1,3]dioxino-
[5,4-d][1,3]oxazin-4a-carboxylate 23
To a solution of 2 (21 mg, 43.8
successively added K2CO3 (6 mg, 43.4
(4.1 L, 65.9 mol). After being stirred at room temperature for
lmol) in dry DMF (0.16 mL) were
lmol) and methyl iodide
l
l

M. Martinková et al. / Tetrahedron: Asymmetry 23 (2012) 536–546
545
45 min, the solvent was evaporated in vacuo, and the residue was
4.23. Crystallographic data
purified by flash chromatography on silica gel hexane/EtOAc (3:1)
to afford 14 mg (65%) of compound 23 as a colourless oil.
Complete crystallographic data for the structural analysis have
been deposited with the Cambridge Crystallographic Data Centre,
CCDC No. 863786. These data can be obtained free of charge from
the Director, Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge, CB2 1EZ, UK (fax: +44 1223 336033; e-mail: de-
posit@ccdc.cam.ac.uk or via: www.ccdc.cam.ac.uk).
½
a 2D5
ꢂ
¼ þ70:7 (c 0.20, CHCl3). 1H NMR (CDCl3, 400 MHz): d 0.05
(s, 3H, CH3), 0.06 (s, 3H, CH3), 0.88 (s, 9H, 3ꢃ CH3), 1.38 (s, 3H,
CH3), 1.44 (s, 3H, CH3), 1.74–1.83 (m, 1H, H-10), 2.02–2.10 (m,
1H, H-10), 3.59 (s, 3H, OCH3), 3.70 (dt, 1H, J2 ,2 = 10.4 Hz,
0
0
J2 ,1 = 5.3 Hz, J2 ,1 = 5.3 Hz, H-20), 3.81 (ddd, 1H, J2 ,2 = 10.4 Hz,
0
0
0
0
0
0
J2 ,1 = 8.5 Hz, J2 ,1 = 4.3 Hz, H-20), 3.92 (d, 1H, J4,4 = 12.8 Hz, H-4),
4.14 (d, 1H, J8,8a = 1.6 Hz, H-8a), 4.35 (d, 1H, J4,4 = 12.8 Hz, H-4),
4.51 (d, 1H, JH,H = 16.4 Hz, NCH2Ph), 4.58ꢀ4.62 (m, 1H, H-8), 4.78
(d, 1H, JH,H = 16.4 Hz, NCH2Ph), 7.19ꢀ7.24 (m, 1H, Ph), 7.26ꢀ7.30
(m, 2H, Ph), 7.33ꢀ7.35 (m, 2H, Ph). 13C NMR (100 MHz, CDCl3): d
ꢀ5.5 (2ꢃ CH3), 18.2 (Cq), 19.7 (CH3), 25.8 (3ꢃ CH3), 27.4 (CH3),
32.9 (C-10), 49.3 (NCH2Ph), 53.1 (OCH3), 58.4 (C-20), 62.0 (C-4),
64.1 (C-4a), 66.4 (C-8a), 72.2 (C-8), 99.7 (C-2), 127.1 (CHPh),
127.7 (2ꢃ CHPh), 128.1 (2ꢃ CHPh), 137.0 (Ci), 153.9 (C@O), 170.4
(C@O). Anal. Calcd for C25H39NO7Si: C, 60.82; H, 7.96; N, 2.84.
Found: C, 60.79; H, 8.01; N, 2.89.
0
0
0
0
Acknowledgements
The present work was supported by the Grant Agency (Nos. 1/
0568/12 and 1/0433/11) of the Ministry of Education, Slovak
Republic. NMR measurements provided by the Slovak State Pro-
gramme Project No. 2003SP200280203 are gratefully acknowl-
edged. We thank to Professor Radovan Šebesta (Comenius
University, Bratislava) for his excellent assistance in the hydroge-
nation experiments.
References
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4.22. X-ray techniques
Single crystals of 15 suitable for X-ray diffraction were ob-
tained from Et2O by slow evaporation at room temperature.
The intensities were collected at 100 K on an Oxford Diffraction
Gemini
R
0 CCD diffractometer using Mo
K
a
radiation
(k = 0.71073 ÅA). Selected crystallographic and other relevant data
for the compound 15 are listed in Table 1. The structure was
solved by direct methods.20 All non-hydrogen atoms were re-
fined anisotropically by full-matrix least squares calculations
based on F2.20 All hydrogen atoms were included in calculated
positions as riding atoms, with SHELXL9720 defaults. The PLATON
21
programme was used for structure analysis and molecular and
crystal structure drawings.
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2771–2773.
Table 1
Crystal data and structure refinement parameters for compound 15
15
Empirical formula
Formula weight
Temperature, T (K)
Wavelength, k (Å)
Crystal system
Space group
Unit cell dimensions
a (Å)
C37H37NO6
591.69
100(2)
0.71073
Orthorhombic
P212121
9.4578 (3)
10.1086 (3)
32.3811(13)
3095.80 (18)
4
1.269
0.086
1256
b (Å)
c (Å)
V (Å3)
Formula per unit cell, Z
Dcalcd (g/cm3)
Absorption coefficient,
F(000)
Crystal size (mm)
h Range for data collection (°)
Index ranges
l
(mmꢀ1
)
0.649 ꢃ 0.1117 ꢃ 0.0451
3.50–26.50
–11 6 h 6 11
–12 6 k 6 12
–40 6 l 6 40
6390 (0.1298)
Analytical
0.996 and 0.967
Full-matrix least-squares on F2
6390/0/399
10. (a) Gonda, J.; Martinková, M.; Raschmanová, J.; Balentová, E. Tetrahedron:
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2010, 345, 2427–2437.
Independent reflections (Rint)
Absorption correction
Max. and min. transmission
Refinement method
ˇ
11. (a) Martinková, M.; Gonda, J.; Raschmanová, J.; Vojtícková, M. Tetrahedron
Data/restraints/parameters
Goodness-of-fit on F2
0.761
ˇ
2007, 63, 10603–10607; (b) Martinková, M.; Gonda, J.; Uhríková, A.; Kovácová,
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Final R indices [I>2
R indices (all data)
r
(I)]
R1 = 0.0347, wR2 = 0.0528
R1 = 0.0823, wR2 = 0.0579
0.150 and ꢀ0.161
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Largest diff. peak and hole (e/Åꢀ3
)

546
M. Martinková et al. / Tetrahedron: Asymmetry 23 (2012) 536–546
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