Enantioselective total syntheses and determination of absolute configuration of marine toxins, oxazinins

Article abstract of DOI:10.1039/c3ra44631j

The enantioselective total syntheses of natural marine toxins, oxazinin-1, -2, -4, -5, -6 and linear precursor preoxazinin-7 are described. The synthetic highlights include Sharpless asymmetric aminohydroxylation and dihydroxylation, oxa-Michael reaction and intramolecular diastereoselective addition of an appropriate hydroxyl substituent to a 3-methyleneindolenine for the construction of the morpholine ring as key steps. The synthetic route also allowed the synthesis of the epi-preoxazinin and a structurally related secondary metabolite bursatellin isolated in 1980 from sea hare Bursatella leachii pleii and its epimer.

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ARTICLE TYPE
Enantioselective total Syntheses and determination of absolute
configuration of marine toxins, oxazinins.
Dattatraya H. Dethe,* and Alok Ranjan
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
The enantioselective total syntheses of natural marine toxins, oxazininꢀ1, ꢀ2, ꢀ4, ꢀ5, ꢀ6 and linear
precursor preoxazininꢀ7 are described. The synthetic highlights include Sharpless asymmetric
aminohydroxylation and dihydroxylation, OxaꢀMichael reaction and intramolecular diastereoselective
addition of an appropriate hydroxyl substituent to a 3ꢀmethyleneindolenine for the construction of
10 morpholine ring as key steps. The synthetic route also allowed the synthesis of the epiꢀpreoxazinin and a
structurally related secondary metabolite bursatellin isolated in 1980 from sea hare Bursatella leachii pleii
and its epimer.
lot of efforts are directed towards structure elucidation and
Introduction
synthetic confirmation of these toxins3. These marine biotoxins
are found to be polyether compounds such as okadaic acid4,
yessotoxin5 etc. During their investigation of toxic Adriatic
25 mussels, Ciminiello et al have also isolated new type of toxins,
which are completely different from polyether biotoxins isolated
so for, but can raise further alarm for Sea life and public health.
The Marine biotoxins pose serious threats to both human health
15 and fishery resources throughout the world1. The problem has
aggrevated in last two decades, earlier only few regions were
affected in scattered locations, now in essence every costal region
is affected, not only fish and shellfish but life of marine
mammals, seabirds and other animal is also in danger due to the
20 toxic algal species2. In order to prevent or minimize such damage,
30
Figure 1. Structures of Oxazininꢀ1, ꢀ2, ꢀ3, ꢀ4, ꢀ5, ꢀ6, Preoxazininꢀ7 and Bursatellin
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In 2001, Fattorusso and Ciminiello et al reported the isolation of
Oxazininꢀ1 (1), ꢀ2 (2), and ꢀ3 (3)6 from the digestive glands of
Mytilus galioprovincialis from northern Andriatic Sea.
Subsequentaly in 2006 cimminello et al reported isolation of
another natural product Oxazininꢀ4 (4)7 from toxic mussels
collected along the Emilia Romagna coasts, Italy. Again in 2007
same group reported isolation of three new natural products,
namely, oxazininꢀ5 (5), ꢀ6 (6), and a linear precursor preoxazininꢀ
60 Results and discussion.
5
Retrosynthetic analysis of oxazinins is depicted in scheme 1. It
was envisaged that oxazininꢀ1 (1), ꢀ2 (2), and ꢀ4 (4) could be
obtained from intermediate 12 by intramolecular regioselective
addition of secondary hydroxyl group at –CꢀX position to 3ꢀ
65 methyleneindolene moiety while oxazininꢀ5 (5) and ꢀ6 (6) could
be prepared from same intermediate 12 by regioselective
intramolecular addition of primary alcohol to 3ꢀ
methyleneindolene. Key intermediate 12 in turn could be
generated in situ from chemoselective reduction of preoxazininꢀ7
70 (7) via 3ꢀhydroxymethylindole intermediate. Preoxazininꢀ7 (7)
could be easily obtained by coupling of 3ꢀindoleglyoxylic acid
chloride 14 and tyrosine derivative 13. To unambiguously
establish the relative as well as absolute configuration of all
oxazinin natural products, both (R, R) and (R, S) diastereomers of
75 unnatural amino acid derivative could be synthesized from ethyl
cinnamate 15 by Sharpless asymmetric dihydroxylation17 and
Sharpless asymmetric aminohydroxylation18 respectively.
10 7 (7)8. The structural elucidation of these oxazinins has been
determined by extensive 2D NMR analysis and Molecular
Mechanics and dynamics calculations. The absolute configuration
of oxazininꢀ1 was established by application of the 9ꢀAMA shift
correlation method for βꢀchiral primary alcohols9. Possible
15 biogenetic pathway was proposed by Ciminiello et al leading to
these novel class of cytotoxic marine natural products8.
Oxazininꢀ1 (1) was shown to inhibit the proliferation of
fibrosarcoma cell (WEHIꢀ164) and J774 macrophages in vitro6.
The originally assigned cisꢀstereochemistry at Cꢀ2 and Cꢀ6 centre
20 in oxazininꢀ1 (1) and oxazininꢀ2 (2) was latter corrected as trans
by Ciminiello et al. in 20067. Because of their potential risk, these
novel class of cytotoxic natural products could represent for
human health and fish industries, comprehensive toxicological
studies are needed. However their evaluation is hampered by the
25 limited availability of oxazinins from isolation, therefore efficient
total synthesis of these natural products and their analogues are
necessary.
In this direction, Couladouros has reported total synthesis of a
simple member of this family, oxazininꢀ3 (3) containing two
30 stereocentres10. Subsequently in 2007, Baran group11 also
reported a 4 step synthesis of oxazininꢀ3 (3) using the direct
coupling of indole to carbonyl compound under basic condition
as key step. In 1980 Schmitz et al isolated a metabolite
bursatellin12 from the sea hare Bursatella leachii pleii. Initially
35 Schmitz et al proposed structure 812 for bursatellin, later in 1987
research group of G. Sodano13 collected two Mediterranean sea
hares, Bursatella leachii leachii and Bursatella leachii
savignyana, and isolated from them a compound that exhibited
1H NMR spectral data nearly identical with that reported for
40 bursatellin except for one additional lowꢀfield singlet observed at
8.20 ppm, this eventually lead to the revision of originally
proposed structure of bursatellin 8 to structure 9. Structurally
bursatellin 9 is similar to preoxazininꢀ7 (7) except that the indole
glyoxylic amide functionality in preoxazininꢀ7 (7) is replaced by
45 formamide group. In 1990 Sodano et al14 reported the
semisynthesis of bursatellin 9 from chloramphenicol, and later in
1991 Hiroshi et al15 reported the total synthesis of bursatellin 9 in
16 steps starting from Lꢀtryptophan, both these syntheses are
tedious and very low yielding.
50 We recently initiated a research program directed towards the
total synthesis of oxazinins. In preliminary communication16 we
have reported the first total synthesis of oxazininꢀ5 (5), ꢀ6 (6),
and their biogenetic precursor preoxazininꢀ7 (7). Prior to our
report there were no reports of synthesis of oxazinins except for
55 oxazininꢀ2 as described earlier. In this article we describe further
studies in this area that include enantioselective total synthesis of
oxazininꢀ1 (1) ꢀ2 (2), ꢀ4 (4) as well as epiꢀpreoxazininꢀ7 (10) and
epiꢀbursatellin 11.
80 Scheme 1. Retrosynthetic Analysis
To begin with the cinnamate 15 was prepared in two step from pꢀ
hydroxybenzaldehyde 16 by first protection of hydroxyl group as
its benzyl ether followed by treatment of resultant aldehyde with
PPh3=CHCO2Et. As discussed in retrosynthetic analysis
85 cinnamate 15 was subjected to Sharpless asymmetric
hydroxylation and Sharpless asymmetric aminohydroxylation,
independently. Treatment of cinnamate 15 with AD mixꢀβ gave
diol 17 in 94% yield and 98% ee. Nosylation (Nscl, Et3N, 92%
Yield) of the diol 17 followed by treatment with sodium azide
90 furnished hydroxyl azide 19 in 90% yield via nosylate 18. SnCl2
mediated reduction of the azido group within 19, followed by in
2
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situ trapping of the resulting amine with (Boc)2O furnished amino
derivative 20 in 80% overall yield. On the other hand Sharpless
indoleglyoxylic chloride. Accordingly reduction of ester in
30 compound 26 using LiBH4 followed by deprotection of boc group
using TFA/CH2Cl2 afforded the amine 27. Coupling of amine 27
Table 1 : Optimization of oxaꢀMichael reaction
Base
Reagent
solvent
Temp
(°C)
60
Product
NaHCO3
NaH
MeOH/THF
THF
No reaction
No reaction
No reaction
No reaction
RT
60
K2CO3
NaH
MeOH/THF
THF
RT
Ph3P
Ph3P
CH3CN
ꢀ
reflux
reflux
Complex
mixture
Complex
mixture
30%
TritonꢀB
TritonꢀB
CH3CN/THF
ꢀ
reflux
reflux
92%
35
with indoleglyoxylic chloride [prepared in one step by treatment
of indole with oxalyl chloride] followed by TBSꢀdeprotection
using TBAF afforded epiꢀpreoxazinin (10). On the other hand
amine 27 on refluxing with ethyl formate followed by TBSꢀ
40 deprotection generated epiꢀbursatellin (11) in 80% over all yield
(Scheme 3).
After making epimers 10 and 11, we next turned our attention
towards syntheses of preoxazininꢀ7 (7) and bursatellin 9. Oxaꢀ
Michael reaction of phenol 25 with acrylonitrile using 20 mol%
45 of tritonꢀB under reflux condition as described earlier for
diastereomer 24 generated the desired oxaꢀMichael product 13 in
92% yield. Reduction of ester 13 generated the primary alcohol
28 in 83% yield. Unlike the diastereomer 24, boc deprotection of
compound 28 proved to be more complex and led to multiple
50 products and decomposition under various conditions such as
Scheme 2. Synthesis of diastereomers of tyrosine derivative
t
5
asymmetric aminohydroxylation18 [NaOH, BocNH2 , BuOCl,
(DHQD)2AQN, K2OsO2(OH)4, nPrOH/H2O (1:1)], of substrate
15 afforded directly boc protected amino alcohol 21 in 45% yield
and 98% ee. Finally silylation of 20 and 21 (TBSCl, imidazole,
98% yield) gave the targeted (R, R) 22 and (R, S) 23 phenyl
10 alanine derivatives respectively. Hydrogenolysis of benzyl ether
in 22 and 23 using Pd/C afforded phenols 24 and 25 respectively
(Scheme 2).
TFA/CH2Cl219a, TFAꢀTriethylsilane19b, 4M HCl in dioxane19c
,
19f
CAN19d
,
TMSOTf19e
,
and 10% H2SO4
and TMSI19g
.
Interestingly treatment of 28 with stoichiometric amount of
Yb(OTf)3 under CH2Cl2 reflux conditions generated bocꢀ
55 deprotected amine 29 in excellent yield. Amine 29 on treatment
with ethyl formate under reflux condition followed by TBS
deprotection afforded the natural product bursatellin 9 in 80%
yield (Scheme 4).
It was envisioned that amine 29 on coupling with indoleglyoxalic
60 chloride 14 would generate the key intermediate 30, which will
eventually lead to synthesis of oxazinin 5 (5), ꢀ6 (6) and
preoxazininꢀ7 (7). On the other hand, bocꢀdeprotection of amino
group in compound 13 followed by coupling with indoleglyoxylic
acid and further functional group transformation would generate
65 oxazininꢀ1 (1), ꢀ2 (2) and ꢀ4 (4). Accordingly coupling of amine
29 with indoleglyoxylic acid afforded ketoamide 30 in 70% yield.
TBSꢀdeprotection of compound 30 generated the natural product
preoxazininꢀ7 (7) in excellent yield (Scheme 5).
Next we turned our attention towards the cyanoethylation of the
phenolic hydroxyl group in compound 24 using oxaꢀMichael
15 reaction, our initial efforts using several standard bases failed to
facilitate this reaction possibly due to retroꢀMichael
fragmentation, as mentioned by the two independent groups of
Sodano et al14 and Hiroshi et al15 in their synthesis of bursatellin
9, a metabolite isolated in 198012. Sodano et al.14 have also
20 shown that bursatellin 9 on treatment with dil. aq. Na2CO3
undergoes retroꢀMichael fragmentation reaction to generate the
corresponding phenol derivative. After trying several different
conditions (table 1), finally to our delight treatment of
aminophenol 24 with acrylonitrile using 20 mol% of tritonꢀB
25 under reflux condition generated the desired oxaꢀMichael product
26 in 92% yield.
After having fully functionalized amino ester derivative 26 in
hand the stage was set for coupling reaction using
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Reduction of ketone functionality in 3ꢀindoleglyoxylic amide 30
separated by careful silica gel column chromatography. The
using sodium borohydride generated the diastereomeric mixture 30 treatment of oxazininꢀ1(1) with 1.0 N aq. NaOH solution
of diols 31a,b Which was then further treated with 10 mol% of
PPTS in refluxing acetonitrile without further purification to
furnish morpholinones 32a and 32b as a 3:1 mixture of Cꢀ2
diastereomers. The two diastereomers 32a and 32b were
generated another natural product oxazininꢀ2 (2) by retroꢀMichael
fragmentation reaction in 85% yield (Scheme 7). All the synthetic
oxazinins exhibited IR, 1H and 13C NMR, mass as well as sign of
5
OH
CO2Et
TBSO
TBSO
NHBoc
NH2
1. LiBH4, 4 h, 83%
2. TFA, CH2Cl2
O
O
CN
CN
26
27
35
1. HCO2Et, reflux
6h, 70%,
2. TBAF/THF, 80%
OH
Scheme 5. Synthesis of preoxazininꢀ7
OH
OH
H
N
O
HO
NHCHO
O
O
HN
CN
O
CN
epi-preoxazinin-7(10)
epi-bursatellin (11)
Scheme 3. Synthesis of epiꢀpreoxazininꢀ7 and (+)ꢀepiꢀbursatellin
Scheme 6. synthesis of Oxazininꢀ5 and ꢀ6
10 Scheme 4. Synthesis of (ꢀ) bursatellin
separated by preparative TLC. Finally TBSꢀdeprotection of major
32a and minor 32b diastereomers provided natural products
oxazininꢀ5 (5) and oxazininꢀ6 (6) respectively along with minor
amount of cyanoethyl side chain cleaved compound 33a and 33b
15 (Scheme 6). On the other hand, for the syntheses of oxazininꢀ1
(1), ꢀ2 (2) and ꢀ4 (4), boc group in compound 13 was deprotected
using Yb(OTf)3 under CH2Cl2 reflux conditions. The resultant
amine was then coupled with indoleglyoxylic chloride using Et3N
to generate the intermediate 34 in excellent yield. TBSꢀ
20 deprodection of compound 34 using TBAF/THF afforded the
alcohol 35 in 78% yield. To our surprise NaBH4 reduction of
indoleglyoxylic amide 35 not only reduced the ketone
functionality but also the ester group to afford diastereomeric
mixture of diols 36a,b. This is one of the rare example of ester
25 reduction using NaBH4. The mixture of diols 36a,b on treatment
with 10 mol% PPTS in refluxing acetonitrile furnished the natural
products oxazininꢀ1 (1) and ꢀ4 (4) along with small amount of
oxazininꢀ5 (5) (3%) and oxazininꢀ6 (6) (2%) which were
40
Scheme 7. Synthesis of Oxazininꢀ1 (1),ꢀ2 (2) and ꢀ4 (4)
4
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CD curves (for oxazininꢀ5,ꢀ6 and preoxazininꢀ7) identical with 55 added PPh3=CHCO2Et salt (19.7 g, 56.5 mmol) and heated it to
the natural oxazininꢀ1 (1), ꢀ2 (2), ꢀ4 (4), ꢀ5 (5), ꢀ6 (6) and
preoxazininꢀ7 (7) reported in literature, thus confirming the
structure of the natural products as well as their relative and
absolute stereochemistry.
90 °C for 2h. The reaction mixture was cooled to RT and
extracted with CH2Cl2 (3 x 80 ml), washed with brine and dried
over Na2SO4. Evaporation of the solvent and purification of the
residue on a silica gel column using EtOAcꢀpetroleum ether (1:9)
60 as eluent furnished the ester 15 (E/Zꢀratio : 95/5, 10.0 g, 94%), Rf
= 0.30 (EtOAcꢀpetroleum ether, 1:9). IR (neat): νmax/cmꢀ1 3282,
1682 (C=O), 1632, 1603, 1585, 1515, 1439, 1371, 1279, 1189,
5
Conclusions
In summary, we have completed the first enantioselective total
syntheses of oxazininꢀ1, ꢀ2, ꢀ4, ꢀ5, ꢀ6 and their biogenetic linear
precursor preoxazininꢀ7 along with structurally related metabolite
1
1033, 830; H NMR (200 MHz, CDCl3): δ 7.64 (d, J 16.0 Hz,
1H) 7.53ꢀ7.29 (m, 7H), 6.97 (dt, J 8.7 and 2.0 Hz, 2H) , 6.31 (d,
65 J 16.0 Hz, 1H), 5.10 (s, 2H), 4.25 (q, J 14.3 and 7.1 Hz, 2H),
1.33 (t, J 7.1 Hz, 3H); 13C NMR (50 MHz, CDCl3): δ 167.3,
160.5, 144.2, 136.5, 129.7, 128.6, 128.1, 127.4, 115.9, 115.2,
70.1, 60.3, 14.3; HRMS (ESI): m/z calcd for C18H19O3 (M+H)
283.1334; found 283.1330.
10 bursatelline and its epimer using, aminohydroxylation and oxaꢀ
Michael reaction as the key steps, in a longest linear sequence of
8 steps, from the cinnamate 15 with excellent overall yields. In
addition, the absolute configuration of stereogenic center were
firmly established by the total synthesis to be (2S, 5R, 6R) for
15 oxazininꢀ1 and ꢀ2, (2R, 5R, 6R) and for oxazininꢀ4, (2R, 5R, 7R)
for oxazininꢀ5, (2S, 5R, 7R) for oxazininꢀ6 and (4R, 5R) for
preoxazininꢀ7. The synthetic route developed here is general and
efficient and could also be applied to the syntheses of other
substituted morpholine related natural products.
70
(2R,3R)-ethyl 3-(4-benzyloxy)phenyl)-2,3-dihydroxypropano-
ate (17): To a solution of ADꢀmix β (86.6 g) in t-BuOH/H2O
(1:1, 800.0 ml) was added MeSO2NH2 (5.9 g, 61.9 mmol) at RT.
The mixture was cooled to 0 °C, and ethyl cinnamate 15 (17.5 g,
75 61.9 mmol) was added dropwise. The resulting mixture was
warmed to RT over a period of 16 h before it was quenched with
Na2SO3 (200 ml, sat. aq. solution), extracted with EtOAc (3 ×
200 ml). The combined organic layers were washed with brine
(200 ml), dried over Na2SO4. Evaporation of the solvent and
80 purification of the residue on silica gel column using ethyl
acetateꢀpetroleum ether (1:2) as eluent furnished the diol 17 (16.9
20 Experimental section
General Information
All reactions were carried out under nitrogen or argon
atmosphere with dry solvents under anhydrous conditions, unless
otherwise mentioned. Anhydrous THF and diethyl ether were
25 distilled from sodiumꢀbenzophenone and dichloromethane was
25
g, 86%); Rf = 0.40 (EtOAcꢀpetroleum ether, 1:2). [α]D = ꢀ10.6
(c 4.7, CHCl3); IR (neat): νmax/cmꢀ1 3438, 3019, 1727, 1613,
distilled
from
calcium
hydride.
Yields
refer
to
1
1585, 1513, 1455, 1216, 1106, 1026, 747, 697; H NMR (200
chromatographically pure material, unless otherwise stated.
Reactions were monitored by thinꢀlayer chromatography (TLC)
carried out on 0.25 mm Merck silica gel plates (60Fꢀ254) using
30 UV light as a visualizing agent and an pꢀanisaldehyde or
ninhydrin stain, and heat as developing agents. Merck silica gel
(particle size 100ꢀ200 and 230ꢀ400 mesh) was used for flash
column chromatography. Reagents were purchased at the highest
commercial quality and used without further purification, unless
35 otherwise stated. NMR spectra were recorded on either a Bruker
Avance 200 (1H: 200 MHz, 13C: 50MHz), Bruker Avance 400
(1H: 400 MHz, 13C: 100MHz), Bruker Avance 500 (1H: 500
MHz, 13C: 125 MHz), JEOL ECX 400 (1H: 400 MHz, 13C: 100
MHz) JEOL ECX 500 (1H: 500 MHz, 13C: 125 MHz). Mass
40 spectrometric data were obtained using WATERSꢀQꢀTof
PremierꢀESIꢀMS. Optical rotations were measured on a Rudolph
and JASCO using a 6.0 ml and 1.0 ml cell with a 100 and 50 mm
85 MHz, CDCl3): δ 7.44ꢀ7.30 (m, 7H), 6.98 (d, J 8.7 Hz, 2H), 5.06
(s, 2H), 4.95 (dd, J 5.8 and 3.0 Hz, 1H), 4.33–4.29 (m, 1H), 4.25
(q, J 12.1 and 4.9 Hz, 2H), 3.17 (d, J 6.0 Hz, 1H), 2.75 (d, J 6.7
Hz, 1H), 1.25 (t, J 7.0 Hz, 3H); 13C NMR (50 MHz, CDCl3): δ
172.7, 158.6, 136.9, 132.3, 128.6, 127.9, 127.6, 127.4, 114.7,
90 74.7, 74.2, 70.0, 62.1, 14.1; HRMS (ESI): m/z calcd for
C18H20O5Na (M+Na) 339.1208; found 339.1204.
(2S,3R)-ethyl-(4-(benzyloxy)phenyl)-3-hydroxy-2-(4nitrophe-
nylsulf onyloxy)propanoate (18): To a solution of diol 17 (11.2
95 g, 35.4 mmol) in CH2Cl2 (85 ml) were added NsCl (8.7g, 35.4
mmol) and Et3N (7.4 ml, 53.1 mmol) at 0 °C. The reaction
mixture was stirred for 6 h before it was quenched with HCl (20.0
ml, 5 % aq). Water was added to the reaction mixture, extracted
with CH2Cl2 (3 x 100 ml), washed with brine and dried over
100 Na2SO4. Evaporation of the solvent and purification of the
residue on a silica gel column using ethyl acetateꢀpetroleum ether
(1:4) furnished the nosylate 18 (16.3 g, 92% ); Rf = 0.40 (EtOAcꢀ
25
path length are reported as [α]D (c in g per ml solvent) at 25
°C. Enantiomeric ratios (er) were determined by HPLC using
45 grace denali RPꢀ18 250 x 4.6 and kromasil 5ꢀ cellucoat 0.46cm x
25cm (detection at 230 nm). Diastereomeric ratios (dr) were
determined by crude 1H NMR. The following abbreviations were
used to explain the multiplicities: s = singlet, d = doublet, t =
triplet, q = quartet, dd = doublet of doublet, dt = doublet of triplet,
50 ddd = doublet of a doublet of a doublet, dm = doublet of a
multiplet, m = multiplet, br = broad.
25
petroleum ether 1:4). [α]D = ꢀ40.0 (c 0.9, CHCl3); IR (neat):
νmax/cmꢀ1 3437, 2926, 1760, 1610, 1532, 1455, 1378, 1350, 1188,
1
105 1094, 1026, 744, 617; H NMR (200 MHz, CDCl3): δ 8.23 (dt, J
9.1 and 4.3 Hz, 2H), 7.85 (dt, J 9.2 and 4.3 Hz, 2H) , 7.45ꢀ7.32
(m, 5H), 7.13 (d, J 8.7 Hz, 2H), 6.80 (dt, J 8.8 and 4.8 Hz, 2H),
5.14 (d, J 4.2 Hz, 1H), 5.00 (s, 2H), 4.95 (d, J 4.0 Hz, 1H), 4.15
(q, J 14.3 and 7.2 Hz, 2H), 2.60 (s, 1H), 1.17 (t, J 7.2 Hz, 3H);
110 13C NMR (50 MHz, CDCl3): δ 166.4, 158.9, 150.5, 141.4, 136.4,
129.5, 129.1, 128.6, 128.1, 127.5, 127.4, 124.0, 114.7, 82.4, 73.0,
69.9, 62.5, 13.8; HRMS (ESI): m/z calcd for C24H23NO9SNa
Experimental procedures
(E)-ethyl 3-(4-(benzyloxy)phenyl)acrylate (15): To a solution
of the aldehyde 16a (8.0 g, 37.7 mmol) in water (150 ml) was
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(M+Na) 524.0991; found 524.1001.
22 (2.3 g, 92%) as colorless oil, Rf = 0.40 (EtOAcꢀpetroleum
25
60 ether 1:9). [α]D = ꢀ57.9 (c 11.8, CHCl3); IR (neat): νmax/cmꢀ1
(2S,3R)-ethyl-2-azido-3-(4-(benzyloxy)phenyl)-3-hydroxypro-
panoate (19): To a solution of nosylate 18 (15.0 g, 29.8 mmol) in
DMF (80.0 ml) was added sodium azide (11.6 g, 179.7 mmol) at
RT. The resulting reaction mixture was heated at 50 °C for 38h.
3446, 2931, 2858, 1718, 1611, 1511, 1367, 1250, 1170, 1094,
1050, 939, 837; H NMR (200 MHz, CDCl3): δ 7.36ꢀ7.18 (m,
7H), 6.85 (d, J 8.7 Hz, 2H), 5.22 (d, J 8.3 Hz, 1H), 4.94 (s, 3H),
4.43 (dd, J 8.3 and 4.2 Hz, 1H), 3.98 (q, J 14.2 and 7.1 Hz, 2H),
1
5
After cooled to RT, the reaction mixture was concentrated in 65 1.35 (s, 9H), 1.05 (t, J 7.1 Hz, 3H), 0.84 (s, 9H), 0.00 (s, 3H), ꢀ
vacuo, extracted with ethyl acetate (3 x 100 ml), washed with
brine and dried over Na2SO4. Evaporation of the solvent and
10 purification of the residue on a silica gel column using ethyl
0.19 (s, 3H); 13C NMR (50 MHz, CDCl3): δ 169.7, 158.1, 154.6,
136.8, 132.7, 128.3, 127.7, 127.2, 114.0, 79.3, 74.9, 69.7, 60.8,
60.6, 28.1, 25.5, 17.9, 13.8, ꢀ5.0, ꢀ5.5; HRMS (ESI): m/z calcd for
C29H44NO6 (M+H) 530.2938; found 530.2944.
acetateꢀpetroleum ether (2:3) furnished azide 19 (9.2 g, 90%), Rf
25
= 0.40 (EtOAcꢀpetroleum ether 2:3). [α]D = +63.8 (c 6.0,
70
CHCl3); IR (neat): νmax/cmꢀ1 3443, 2112, 1574, 1397, 1115, 618,
(2R,3R)-ethyl
2-(tert-butoxycarbonylamino)-3-(tert-
1
536; H NMR (200 MHz, CDCl3): δ 7.43ꢀ7.30 (m, 8H), 7.00 (dt,
butyldimethylsilyloxy)-3-(4-hydroxyphenyl)propanoate (24):
To a solution of the ester 22 (2.0 g, 3.8 mmol) in methanol was
added 5% Pd/C (40.0 mg) and shaken in hydrogenation
15 J 8.8 and 5.1 Hz, 2H), 4.98 (dd, J 7.0 and 4.4 Hz, 1H), 4.26 (q, J
14.3 and 7.0 Hz, 2H), 4.10 (d, J 7.0 Hz, 1H), 2.78 (d, J 4.4 Hz,
1H), 1.58 (s, 1H), 1.28 (t, J 7.1 Hz, 3H); 13C NMR (50 MHz, 75 atmosphere at RT for 12 h. The reaction mixture was filtered on
CDCl3): δ 170.0, 159.0, 136.7, 131.3, 128.6, 128.0, 127.9, 127.4,
114.9, 73.6, 69.9, 66.8, 62.1, 14.0; HRMS (ESI): m/z calcd for
20 C18H19N3O4Na (M+Na) 364.1273; found 364.1282.
celite using ethyl acetate. Evaporation of the solvent and
purification of the residue on a silica gel column using ethyl
acetateꢀpetroleum ether (1:4) as eluent furnished hydroxy ester 24
(1.6 g, 97%) as a colorless oil, Rf = 0.30 (EtOAcꢀpetroleum ether
25
(2S,3R)-ethyl 3-(4-(benzyloxy)phenyl)-2-(tert-butoxycarbonyl- 80 1:4). [α]D = ꢀ50.3 (c 9.7, CHCl3); IR (neat): νmax/cmꢀ1 3434,
1
amino)-3-proxypropanoate (20): To a solution of azide 19 (4.0
g, 11.7 mmol) in dioxane (60.0 ml) was added a solution of
25 SnCl2•2H2O (13.2 g, 58.5 mmol) in H2O/dioxane (4:1, 100.0 ml)
at 0 °C. The resulting mixture was warmed to RT over a period of
3020, 2859, 1694, 1616, 1516, 1369, 1169, 1084, 834; H NMR
(200 MHz, CDCl3): δ 7.49 (br s, 1H), 7.11 (d, J 8.6 Hz, 2H), 6.73
(d, J 8.5 Hz, 2H), 5.26 (d, J 8.6 Hz, 1H), 4.91 (d, J 4.2 Hz, 1H),
4.44 (dd, J 8.5 and 4.4 Hz, 1H), 4.05 (q, J 14.2 and 7.0 Hz, 2H),
5 h before it was cooled to 0 °C. Solid NaHCO3 was slowly 85 1.37 (s, 9H), 1.12 (t, J 7.0 Hz, 3H), 0.84 (s, 9H), 0.00 (s, 3H), ꢀ
added until pH 8ꢀ9 was reached. Boc2O (3.8 g, 17.6 mmol) was
added at 0 °C and the reaction mixture was warmed to RT over a
30 period of 15 h before it was acidified by slow addition of HCl (2
N) until pH 5ꢀ6 was reached. The reaction mixture was filtered
through a mixture of silica gel and celite, and the filtrate was
extracted with EtOAc (4 × 30 ml). The combined organic layers
were dried over Na2SO4. Evaporation of the solvent and
35 purification of the residue on silica gel column using ethyl
acetateꢀpetroleum ether (1:3) as eluent furnished the Bocꢀ
0.19 (s, 3H); 13C NMR (50 MHz, CDCl3): δ 170.4, 156.0, 155.1,
131.3, 127.4, 114.9, 80.1, 75.1, 61.2, 60.3, 28.2, 25.5, 17.9, 13.8,
ꢀ4.9, ꢀ5.5; HRMS (ESI): m/z calcd for C22H38NO6Si (M+H)
440.2468; found 440.2475.
90
(2R,3R)-ethyl
2-(tert-butoxycarbonylamino)-3-(tert-
butyldimethylsilyloxy)-3-(4-(2-
cyanoethoxy)phenyl)propanoate (26): To a solution of the
phenol 24 (1.0 g, 2.3 mmol) in acrylonitrile (10.0 ml) was added
carbamate 20 (3.1 g, 80%). Rf = 0.40 (EtOAcꢀpetroleum ether, 95 catalytic amount of triton B and refluxed for 8 h. Excess
1:3). [α]D = ꢀ50.2 (c 9.6, CHCl3); IR (neat): νmax/cmꢀ1 3436,
acrylonitrile was removed under reduced pressure and the
reaction mixture was diluted with water, extracted with CH2Cl2,
washed with brine and dried over Na2SO4. Evaporation of the
solvent and purification of the residue on silica gel column using
25
2979, 2932, 1715, 1612, 1586, 1511, 1455, 1369, 1243, 1170,
40 1114, 1025, 864, 752; H NMR (200 MHz, CDCl3): δ 7.43ꢀ7.30
(m, 5H), 7.20 (d, J 8.6 Hz, 2H), 6.94 (dt, J 8.7 and 2.8 Hz, 2H) ,
1
5.32 (br d, J 7.5 Hz, 1H), 5.12 (br s, 1H), 5.04 (s, 2H), 4.65 (dd, J 100 ethyl acetateꢀpetroleum ether (1:4) as eluent furnished the
7.6 and 3.9 Hz, 1H), 4.13 (q, J 14.3 and 7.2 Hz, 2H), 4.04 (br s,
1H), 1.43 (s, 9H), 1.19 (t, J 7.2 Hz, 3H); 13C NMR (100 MHz,
45 CDCl3): δ 169.8, 158.5, 156.3, 136.8, 131.6, 128.5, 127.9, 127.4,
127.3, 114.5, 80.5, 74.6, 69.9, 61.6, 59.7, 28.2, 14.0 HRMS
cyanoester 26 (1.0 g, 92%). Rf = 0.40 (EtOAcꢀpetroleum ether,
25
1:4). [α]D = ꢀ53.3 (c 10.7, CHCl3); IR (neat): νmax/cmꢀ1 3444,
3020, 2931, 2240, 1712, 1612, 1510, 1250, 1170, 1115, 1080,
1
1056, 930, 757, 669; H NMR (200 MHz, CDCl3): δ 7.23 (d, J
(ESI): m/z calcd for C23H30NO6 (M+H) 416.2073; found 105 8.6 Hz, 2H), 6.80 (d, J 8.7 Hz, 2H), 5.20 (d, J 8.3 Hz, 2H), 4.95
416.2065.
(d, J 3.8 Hz, 1H), 4.40 (dd, J 8.3 and 4.0 Hz, 1H), 4.13 (t, J 6.3
Hz, 2H), 4.03 (q, J 14.4 and 7.3 Hz), 2.77 (t, J 6.3 Hz, 2H), 1.36
(s, 9H), 1.10 (t, J 7.2 Hz, 3H), 0.84 (s, 9H), 0.00 (s, 3H), ꢀ0.19 (s,
3H); 13C NMR (50 MHz, CDCl3): δ 169.6, 157.0, 154.7, 133.9,
50 (2S,3R)-ethyl 3-(4-(benzyloxy)phenyl)-2-((tert-butoxycarbon-
yl)amino)-3-(tert-butyldimethylsilyloxy)propanoate (22): To a
solution of the alcohol 20 (2.0 g, 4.8 mmol) in DMF (15.0 ml) 110 127.5, 117.1, 113.9, 79.6, 75.0, 62.5, 61.0, 60.7, 28.2, 25.5, 18.5,
were added TBSCl (1.0 g, 6.2 mmol), imidazole (0.5 g, 7.2
mmol) and stirred magnetically at RT for 12 h. Water was added
55 to the reaction mixture, extracted with ethyl acetate (3 x 20 ml),
washed with brine and dried over Na2SO4. Evaporation of the
18.5, 17.9, 13.9, ꢀ4.9, ꢀ5.4; HRMS (ESI): m/z calcd for
C25H41N2O6Si (M+H) 493.2734; found 493.2735.
tert-butyl
(1R,2S)-1-(tert-butyldimethylsilyloxy)-1-(4-(2-
solvent and purification of the residue on a silica gel column 115 cyanoethoxy)phenyl)-3-hydroxypropan-2-ylcarbamate (26a):
using ethyl acetateꢀpetroleum ether (1:9) furnished the TBS ether
To a magnetically stirred solution of the cyanoester 26 (2.0 g, 4.1
6
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DOI: 10.1039/C3RA44631J
mmol) in ether/methanol (20:10 ml) was added LiBH4 (0.45 g,
20.5 mmol) and stirred for 4 h at RT. Solvent was evaporated
18.7;
60
under reduced pressure, water (15.0 ml) was added to the residue
and extracted with ether (3 x 20 ml). The combined extract was
washed with brine (15.0 ml) and dried over Na2SO4. Evaporation
of the solvent and purification of the residue on a silica gel
N-((1R,2R)-1-((tert-butyldimethylsilyl)oxy)-1-(4-(2-cyanoeth-
oxy)phenyl)-3-hydroxypropan-2-yl)-2-(1H-indol-3-yl)-2-oxoa-
cetamide (27b): To a solution of indole (1.0 g, 8.6 mmol) in
anhydrous diethyl ether (15.0 ml) at 0 °C, freshly distilled oxalyl
5
column using ethyl acetateꢀpetroleum ether (1:2) as eluent 65 chloride (0.8 ml, 9.5 mmol) was added dropwise. The reaction
furnished the alcohol 26a (1.5 g, 83%), Rf = 0.30 (EtOAcꢀ
mixture was stirred at 0 °C for 0.5 h and then allowed to warm to
RT. The resulting yellow crystals of indoleglyoxylic chloride 14
were collected by filtration, washed with cold anhydrous diethyl
ether and dried under vacuum (1.6 g, 15.7 mmol). The compound
25
petroleum ether, 1:2). [α]D = ꢀ17.9 (c 4.3, CHCl3); IR (neat):
10 νmax/cmꢀ1 3445, 2930, 2260, 1701, 1510, 1392, 1367, 1246, 1170,
1086, 868, 557; 1H NMR (200 MHz, CDCl3): δ 7.25 (d, J 8.5 Hz,
2H), 6.81 (d, J 8.6 Hz, 2H), 5.39 (d, J 7.8 Hz, 1H), 5.06 (br s, 70 14 was used without further purification in next step. To a
1H), 4.12 (t, J 6.3 Hz, 2H), 3.75 (dd, J 11.5 and 2.5 Hz, 1H),3.48ꢀ
3.34 (m, 2H), 2.76 (t, J 6.3, Hz, 2H), 1.38 (s, 9H), 0.84 (s, 9H),
15 0.00 (s, 3H), ꢀ0.18 (s, 3H); 13C NMR (50 MHz, CDCl3): δ 156.9,
155.5, 134.3, 127.1, 117.1, 114.3, 79.4, 76.8, 62.5, 60.9, 56.5,
solution of bocꢀamine 26a (100 mg, 0.2 mmol) in CH2Cl2 (5.0
ml) was added TFA (0.15 ml, 2.0 mmol) and stirred for 2 h. aq.
NaHCO3 was added to the reaction mixture and extracted with
CH2Cl2 (3 x 10 ml). The organic layer was washed with brine and
28.3, 25.7, 18.5, 18.0, ꢀ5.0, ꢀ5.5; HRMS (ESI): m/z calcd for 75 dried over Na2SO4. After evaporation of the solvent, the residue
C23H39N2O5Si (M+H) 451.2628; found 451.2628.
was dissolved in CH2Cl2, cooled to 0 °C. To the cold solution was
added Et3N (17.0 mg, 0.16 mmol) followed by 3ꢀindoleglyoxalyl
chloride 14 (40.0 mg, 0.14 mmol) and stirred magnetically at RT
for 12 h. Water (10.0 ml) was added to the reaction mixture and
20 N-((1R,2R)-1-(4-(2-cyanoethoxy)phenyl)-3-hydroxy-1-((trim-
ethylsilyl) oxy) propan-2-yl)formamide (27a) : To a solution of
bocꢀamine 26a (90.0 mg, 0.20 mmol) in CH2Cl2 (4.0 ml) was 80 extracted with CH2Cl2 (3 x 10 ml). Combined organic layers were
added TFA (0.19 ml, 2.00 mmol) at 0 °C and stirred for 8 h at
RT. It was quenched with NaHCO3 and concentrated on vacuo.
25 The residue was dissolved in ethyl formate (6.0 ml) and refluxed
for 6 h. Evaporation of the solvent and purification of the residue
washed with brine and dried over anhydrous Na2SO4.
Evaporation of the solvent and purification of the residue on a
silica gel column using MeOH:CH2Cl2 (1:19) furnished the TBSꢀ
25
protected preoxazinin 27b (73 mg, 70%). [α]D = +24.3 (c 1.4,
on a silica gel column using MeOHꢀCH2Cl2 (1:19) furnished 85 CHCl3); IR (neat): νmax/cmꢀ1 3436, 3010, 2930, 2400, 2280,
1
TBSꢀprotected bursatellin 27a (50.0 mg, 70%, 2 steps) as
1611, 1511, 1438, 1214, 1124, 1045, 929, 756, 618; H NMR
(200 MHz, CDCl3): δ 9.27 (s, 1H), 8.88 (d, J 3.3 Hz, 1H), 8.41ꢀ
8.45 (m, 1H), 8.13 (d, J 8.6 Hz, 1H), 7.45ꢀ7.29 (m, 5H), 6.86 (d, J
8.7 Hz, 2H), 5.05 (d, J 4.0 Hz, 1H), 4.16 (t, J 6.3 Hz, 2H), 4.07ꢀ
25
colorless oil, Rf = 0.30 (MeOHꢀCH2Cl2 1:19). [α]D = +13.0 (c
30 1.1, CHCl3); IR (neat): νmax/cmꢀ1 3357, 2928, 2856, 2280,1746,
1
1670, 1512, 1381, 1245, 1080, 1040, 837; H NMR (200 MHz,
CDCl3, peaks due to major rotamer): δ 8.21 (s, 1H), 7.26 (d, J 8.6 90 3.94 (m, 2H), 3.71ꢀ3.60 (m, 1H), 3.04 (d, J 7.2 Hz, 1H), 2.82 (t, J
Hz, 2H), 6.84 (d, J 8.7 Hz, 2H), 6.44 (d, J 7.6 Hz, 1H), 5.05 (d, J
2.7 Hz, 1H), 4.14 (t, J 6.3 Hz, 2H), 3.93ꢀ3.82 (m, 2H), 3.45ꢀ3.36
35 (m, 1H), 2.78 (t, J 6.3 Hz, 2H), 0.85 (s, 9H), 0.00 (s, 3H), ꢀ0.20
(s, 3H); 13C NMR (125 MHz, CDCl3): δ 161.0, 157.3, 134.0,
6.2 Hz, 2H), 1.75 (s, 1H), 0.92 (s, 9H), 0.07 (s, 3H), ꢀ0.15 (s, 3H);
13C NMR (50 MHz, CDCl3): δ 180.4, 162.5, 157.2, 138.1, 135.7,
134.2, 127.5, 126.5, 124.2, 123.3, 122.4, 117.4, 144.4, 113.2,
111.7, 75.8, 62.5, 61.0, 56.2, 25.7, 18.6, 18.0, ꢀ4.9, ꢀ5.3; HRMS
128.0, 127.3, 117.1, 114.5, 62.6, 60.7, 54.6, 25.8, 18.6, 17.9, ꢀ4.9, 95 (ESI): m/z calcd for C28H36N3O5Si (M+H) 522.2424; found
ꢀ5.3; HRMS (ESI): m/z calcd for C19H30N2O4SiNa (M+Na)
522.2424.
401.1873; found 401.1867;
40
Synthesis of epi-preoxazinin-7 (10): To the solution of 27b
Synthesis of epi-bursatellin (11): To a magnetically stirred
(60.0 mg, 0.15 mmol) in THF (4.0 ml) was added TBAF (1.0 M
solution of the TBS protected bursatellin 27a (30.0 mg, 0.08 100 in THF, 0.15 ml, 0.15 mmol). The resulting mixture was stirred
mmol) in THF (2.0 ml) was added 1 M solution of TBAF in THF
(0.08 ml, 0.08 mmol) and stirred for 1 h at 0 °C. Solvent was
45 evaporated under reduced pressure, water (3.0 ml) was added to
the residue and extracted with CH2Cl2 (3 x 10 ml). The combined
for 1 h at 0 °C, before it was concentrated in vacuo. Water (5.0
ml) was added to the residue and extracted with ether (3 x 20 ml).
The combined extract was washed with brine (13.0 ml) and dried
over Na2SO4. Evaporation of the solvent and purification of the
extract was washed with brine (6.0 ml) and dried over Na2SO4. 105 residue on a silica gel column using ethyl acetateꢀpetroleum ether
Evaporation of the solvent and purification of the residue on a
silica gel column using MeOHꢀCH2Cl2 (1:9) as eluent furnished
50 the (+)ꢀbursatellin 11 (16.8 mg, 80%), Rf = 0.40 (MeOH:CH2Cl2,
(9:1) as eluent furnished the epiꢀpreoxazininꢀ7 10 (27.0 mg, 80
25
%). Rf = 0.30 (EtOAcꢀpetroleum ether, 9:1). [α]D = +40.4 (c
0.25, MeOH); IR (neat): νmax/cmꢀ1 3434, 3340, 3162, 2977,
25
1
1:9). [α]D = +7.1 (c 0.4, MeOH); IR (neat): νmax/cmꢀ1 3362,
2270, 1662, 1622, 1450, 1377, 1113, 1089, 929, 757; H NMR
1
2977, 2243, 1660, 1450, 1377, 1174, 1099; H NMR (400 MHz, 110 (400 MHz, CD3CN): δ 10.19 (br s, 1H), 8.78 (d, J 3.3 Hz, 1H),
CDCl3): δ 8.27 (s, 1H), 7.37 (d, J 8.3 Hz, 2H), 6.94 (d, J 8.5 Hz,
2H), 6.42 (br d, J 6.8 Hz, 1 H), 5.06 (d, J 3.3 Hz, 1H), 4.22 (t, J
55 6.5 Hz, 2H), 4.14 (dd, J 7.5 and 3.8 Hz,1H), 3.90 (dd, J 10.8 and
2.8 Hz, 1H), 3.66 (d, J 11.0 Hz, 1H), 3.06 (br s, 1H) 2.85 (t, J 6.3
8.27 (dd, J 5.8 and 2.0 Hz, 1H), 7.71 (d, J 9.5 Hz, 1H), 7.54 (dd,
J 7.5 and 4.0 Hz, 1H), 7.36ꢀ7.25 (m, 4H), 6.87 (dt, J 8.7 and 2.0
Hz, 2H), 4.82 (dd, J 6.4 and 5.0 Hz, 1H), 4.19ꢀ4.07 (m, 3H), 3.92
(d, J 4.8 Hz, 1H), 3.84ꢀ3.60 (m, 2H), 3.23 (t, J 5.8 Hz, 1H), 2.81
Hz, 2H), 2.57 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 161.3, 115 (t, J 6.1 Hz, 2H); 13C NMR (100 MHz, CD3CN): δ 182.4, 163.7,
157.5, 133.9, 127.2, 117.1, 114.8, 75.4, 62.7, 61.4, 54.2, 29.7,
158.7, 140.1, 137.5, 136.3, 129.3, 127.8, 125.1, 124.2, 122.9,
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DOI: 10.1039/C3RA44631J
119.6, 115.5, 113.6, 74.3, 64.3, 62.2, 57.5, 19.5; HRMS (ESI): 60 purification of the residue on a silica gel column using ethyl
m/z calcd for C22H21N3O5Na (M+Na) 430.1379; found 430.1370.
acetateꢀpetroleum ether (1:4) as eluent furnished hydroxy ester 25
(1.6 g, 97%) as a colorless oil, Rf = 0.30 (EtOAcꢀpetroleum ether
25
(2S,3R)-ethyl 3-(4-(benzyloxy)phenyl)-2-((tert-butoxycarbony-
l)amino)-3-hydroxypropanoate (21): A round bottom flask was
1:4). [α]D = ꢀ17.8 (c 2.3, CHCl3); IR (neat): νmax/cmꢀ1 3434,
1
5
3020, 2859, 1694, 1616, 1516, 1369, 1169, 1084, 834; H NMR
charged with sodium hydroxide (30.5 ml of 1 N solution) and 65 (400 MHz, CDCl3): δ 7.22 (d, J 8.5 Hz, 2H), 6.97 (s, 1H), 6.79
diluted with water (45.0 ml) in a dark fume hood. Part of this
alkaline solution (5.0 ml) was transferred into a vial to dissolve
K2[OsO2(OH)4] (147 mg, 0.4 mmol). With vigorous stirring, nꢀ
(d, J 8.5 Hz, 2H), 5.50 (br d, J 9.3 Hz, 1H), 5.22 (s, 1H), 4.30ꢀ
4.05 (m, 3H), 1.36 (s, 9H), 1.27 (t, J 7.0 Hz, 3H), 0.89 (s, 9H),
0.01 (s, 3H), ꢀ0.15 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 172,
157.9, 156.9, 133.7, 129.1, 116.0, 80.4, 75.6, 62.6, 62.3, 28.9,
10 propanol (40.0 ml) and tertꢀbutylcarbamate (3.6 g, 31.0 mmol)
were added to the flask, followed by dropwise addition of freshly 70 26.4, 19.0, 14.8, ꢀ4.0, ꢀ4.8; HRMS (ESI): m/z calcd for
prepared tertꢀbutyl hypochlorite (3.5 ml, 3.05 mmol). After five
minutes, nꢀpropanol solution (35.0 ml) of (DHQD)2AQN (343
mg, 0.4 mmol) and ethyl cinnamate 15 (2.82 g, 1.0 mmol), and
15 the aqueous K2[OsO2(OH)4] solution were added. After 2 h, the
C22H38NO6Si (M+H) 440.2468; found 440.2467.
(2S,3R)-ethyl
2-(tert-butoxycarbonylamino)-3-(tert-
butyldimethylsilyloxy)-3-(4-(2-
solution was quenched with 5.0 g sodium bisulfite, added water 75 cyanoethoxy)phenyl)propanoate (13) : To a solution of the
and extracted with ethyl acetate (3 x 50 ml), washed with brine
and dried over Na2SO4. Evaporation of the solvent and
purification of the residue on a flash silica gel column using ethyl
phenol 25 (1.0 g, 2.3 mmol) in acrylonitrile (10.0 ml) was added
catalytic amount of triton B and refluxed for 8 h. Excess
acrylonitrile was removed under reduced pressure and the
reaction mixture was diluted with water, extracted with CH2Cl2,
80 washed with brine and dried over Na2SO4. Evaporation of the
solvent and purification of the residue on silica gel column using
20 acetateꢀpetroleum ether (1:4) furnished the hydroxy ester 21 (2.14
25
g, 45%, 98% ee), Rf = 0.30 (EtOAcꢀpetroleum ether 1:4). [α]D
=
ꢀ12.8 (c 4.0, CHCl3); IR (neat): νmax/cmꢀ1 3421, 2930, 1716,
1690, 1512, 1392, 1244, 1162, 1025; 1H NMR (200 MHz,
CDCl3): δ 7.50ꢀ7.20 (m, 7H), 6.94 (td, J 8.7 and 2.0 Hz, 2H) ,
25 5.35 (d, J 8.8 Hz, 1H), 5.12 (t, J 3.4 Hz, 1H), 5.04 (s, 2H), 4.45
ethyl acetateꢀpetroleum ether (1:4) as eluent furnished the ester
25
13 (1.0 g, 92%). Rf = 0.40 (EtOAcꢀpetroleum ether, 1:4). [α]D
=
ꢀ15.6 (c 2.0, CHCl3); IR (neat): νmax/cmꢀ1 3447, 3020, 2931, 2240,
1
(br d, J 7.4 Hz, 1H), 4.18 (q, J 14.3 and 7.2 Hz, 2H), 2.9 (br s, 85 1712, 1612, 1510, 1215, 1171, 1086, 757, 669; H NMR (200
1H), 1.35 (s, 9H), 1.22 (t, J 7.1 Hz, 3H); 13C NMR (50 MHz,
CDCl3): δ 171.0, 158.6, 155.8, 136.9, 132.4, 128.6, 128.0, 127.5,
127.4, 114.7, 80.1, 73.7, 70.0, 61.7, 59.7, 28.2, 14.1; HRMS
30 (ESI): m/z calcd for C23H30NO6 (M+H) 416.2073; found
416.2086.
MHz, CDCl3): δ 7.30 (d, J 8.3 Hz, 2H), 6.87 (d, J 8.4 Hz, 2H),
5.35ꢀ5.00 (m, 2H), 4.40ꢀ4.05 (m, 5H), 2.82 (t, J 6.3 Hz, 2H), 1.35
(s, 9H), 1.32 (t, J 7.2 Hz, 3H), 0.89 (s, 9H), 0.00 (s, 3H), ꢀ0.15 (s,
3H); 13C NMR (50 MHz, CDCl3): δ 170.5, 157.1., 155.3, 133.9,
90 127.5, 117.1, 114.1, 79.5, 74.2, 62.5, 61.3, 60.5, 28.1, 25.5, 18.4,
17.9, 13.9, ꢀ4.8, ꢀ5.7; HRMS (ESI): m/z calcd for C25H41N2O6Si
(M+H) 493.2734; found 493.2727.
(2S,3R)-ethyl 3-(4-(benzyloxy)phenyl)-2-((tert-butoxycarbon-
yl)amino)-3-((tert-butyldimethylsilyl)oxy)propanoate (23):
35 To a solution of the alcohol 21 (4.0 g, 9.6 mmol) in DMF (25.0
tert-butyl
(1R,2R)-1-(tert-butyldimethylsilyloxy)-1-(4-(2-
ml) were added TBSCl (1.9 g, 12.5 mmol), imidazole (0.9 g, 14.4
mmol) and stirred magnetically at RT for 12 h. Water was added
to the reaction mixture, extracted with ethyl acetate (3 x 20 ml),
washed with brine and dried over Na2SO4. Evaporation of the
40 solvent and purification of the residue on a silica gel column
using ethyl acetateꢀpetroleum ether (1:9) furnished the TBS ether
23 (4.9 g, 98%) as colorless oil, Rf = 0.40 (EtOAcꢀpetroleum
95 cyanoethoxy)phenyl)-3-hydroxypropan-2-ylcarbamate (28):
To a magnetically stirred solution of the cyano ester 13 (2.0 g, 4.1
mmol) in ether/methanol (20:10 ml) was added LiBH4 (0.5 g,
20.5 mmol) and stirred for 4 h at RT. Solvent was evaporated
under reduced pressure, water (15.0 ml) was added to the residue
100 and extracted with ether (3 x 20 ml). The combined extract was
washed with brine (15.0 ml) and dried over Na2SO4. Evaporation
of the solvent and purification of the residue on a silica gel
column using ethyl acetateꢀpetroleum ether (1:2) as eluent
furnished the alcohol 28 (1.5 g, 83%), Rf = 0.30 (EtOAcꢀ
25
ether 1:9). [α]D = ꢀ16.5 (c 5.4, CHCl3); IR (neat): νmax/cmꢀ1
1
2930, 1720, 1643, 1510, 1367, 1250, 830, 778; H NMR (200
45 MHz, CDCl3): δ 7.50ꢀ7.20 (m, 7H), 6.94 (dt, J 8.7 and 2.0 Hz,
2H), 5.30ꢀ5.10 (m, 2H), 5.05 (s, 2H), 4.38 (dd, J 7.5 and 2.5 Hz,
1H), 4.30ꢀ4.10 (m, 2H), 1.35 (s, 9H), 1.31 (t, J 7.1 Hz, 3H), 0.89
(s, 9H), 0.00 (s, 3H), ꢀ0.15 (s, 3H); 13C NMR (50 MHz, CDCl3): δ
170.0, 158.3, 154.9, 137.1, 133.0, 128.6, 127.9, 127.5, 114.3,
50 79.6, 75.2, 69.9, 61.0, 60.9, 53.5, 28.4, 25.8, 18.2, 14.1, ꢀ4.8, ꢀ5.3;
HRMS (ESI): m/z calcd for C29H44NO6Si (M+H) 530.2938; found
530.2941.
25
105 petroleum ether, 1:2). [α]D = ꢀ22.2 (c 4.2, CHCl3); IR (neat):
νmax/cmꢀ1 3442, 3020, 2931, 2255, 1700, 1510, 1392, 1367, 1216,
1
1172, 1086, 838; H NMR (200 MHz, CDCl3): δ 7.25 (d, J 8.6
Hz, 2H), 6.86 (d, J 8.6 Hz, 2H), 5.0ꢀ4.8 (m, 2H), 4.18 (t, J 6.3 Hz,
2H), 3.75ꢀ3.50 (m, 3H), 2.83 (t, J 6.3, Hz, 2H), 1.37 (s, 9H), 0.90
110 (s, 9H), 0.06 (s, 3H), ꢀ0.16 (s, 3H); 13C NMR (50 MHz, CDCl3): δ
156.9, 156.1, 135.0, 127.6, 117.2, 114.2, 79.5, 72.9, 62.7, 62.5,
58.5, 28.2, 25.7, 18.5, 18.0, ꢀ4.7, ꢀ5.3; HRMS (ESI): m/z calcd for
C23H39N2O5Si (M+H) 451.2628; found 451.2620.
(2S,3R)-ethyl
2-(tert-butoxycarbonylamino)-3-(tert-
55 butyldimethylsilyloxy)-3-(4-hydroxyphenyl)propanoate (25):
To a solution of the ester 23 (2.0 g, 3.8 mmol) in methanol was
added 5% Pd/C (40.0 mg) and shaken in hydrogenation
atmosphere at RT for 12 h. The reaction mixture was filtered on
celite using ethyl acetate. Evaporation of the solvent and
115 N-((1R,2R)-1-(tert-butyldimethylsilyloxy)-1-(4-(2-
cyanoethoxy)phenyl)-3-hydroxypropan-2-yl)formamide (28a):
To a solution of bocꢀamine 28 (80.0 mg, 0.2 mmol) in CH2Cl2
8
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DOI: 10.1039/C3RA44631J
(8.0 ml) was added Yb(OTf)3 (110.0 mg, 0.2 mmol) and refluxed
9.58 (s, 1H), 8.71 (dd, J 5.1 and 3.4 Hz, 1H), 8.39 (d, J 7.5 Hz,
for 8 h. It was quenched with NaHCO3 and concentrated on 60 1H), 7.92 (d, J 9.0 Hz, 1H), 7.40ꢀ7.20 (m, 5H), 6.73 (d, J 8.7 Hz,
vacuo. The residue was dissolved in ethyl formate (6.0 ml) and
refluxed for 6 h. Evaporation of the solvent and purification of
the residue on a silica gel column using MeOHꢀCH2Cl2 (1:19)
furnished TBSꢀprotected bursatellin 28a (47.6 mg, 71%, 2 steps)
2H), 5.00 (d, J 3.1 Hz, 1H), 4.15ꢀ4.05 (m, 1H), 4.02 (t, J 6.2 Hz,
2H), 3.85ꢀ3.70 (m, 2H), 2.72 (t, J 6.2 Hz, 2H), 0.92 (s, 9H), 0.07
(s, 3H), ꢀ0.15 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 180.3,
163.0, 157.0, 138.5, 135.8, 134.7, 127.4, 126.5, 124.1, 123.3,
5
as colorless oil, Rf = 0.30 (MeOHꢀCH2Cl2 1:19). [α]D25 = -15.1 (c 65 122.2, 117.4, 114.2, 112.9, 111.9, 72.73, 62.73, 62.36, 58.1, 25.8,
4.4, CHCl3); IR (neat): νmax/cmꢀ1 3358, 2928, 2856, 2280, 1746,
18.6, 18.1, ꢀ4.61, ꢀ5.25; HRMS (ESI): m/z calcd for
C28H36N3O5Si (M+H) 522.2424; found 522.2424.
1
1672, 1512, 1389, 1245, 1080, 1047, 837; H NMR (500 MHz,
10 CDCl3, peaks due to major rotamer): δ 8.14 (s, 1H), 7.25 (d, J
15.0 Hz, 2H), 6.86 (d, J 8.8 Hz, 1H), 6.10 (d, J 7.3 Hz, 1H), 4.97
Synthesis of preoxazinin-7 (7): To the solution of 30 (80.0 mg,
(d, J 3.3 Hz, 1H), 4.19 (t, J 6.5 Hz, 2H), 4.07ꢀ4.01 (m, 1H), 3.68 70 0.2 mmol) in THF (5.0 ml) was added TBAF (1.0 M in THF, 0.2
(d, J 5.8 Hz, 2H), 2.84 (t, J 6.0 Hz, 2H), 0.91 (s, 9H), 0.08 (s,
3H), ꢀ0.14 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 165.0, 161.6,
15 157.3, 134.7, 127.8, 127.4, 117.2, 114.5, 114.5, 73.5, 72.3, 63.0,
62.6, 60.8, 57.2, 25.8, 25.8, 18.7, 18.2, ꢀ4.6, ꢀ5.2; HRMS (ESI):
ml, 0.2 mmol). The resulting mixture was stirred for 1 h at 0 °C,
before it was concentrated in vacuo. Water (5.0 ml) was added to
the residue and extracted with ether (3 x 20 ml). The combined
extract was washed with brine (15.0 ml) and dried over Na2SO4.
m/z calcd for C19H30N2O4SiNa (M+Na) 401.1873; found 75 Evaporation of the solvent and purification of the residue on a
401.1869.
silica gel column using ethyl acetateꢀpetroleum ether (9:1) as
eluent furnished the preoxazininꢀ7 7 (48.7 mg, 78 %). Rf = 0.30
25
20 Synthesis of (-)-bursatellin (9): To a magnetically stirred
solution of the TBS protected bursatellin 28a (20.0 mg, 0.05
(EtOAcꢀpetroleum ether, 9:1). [α]D = ꢀ11.0 (c 0.6, MeOH); IR
(neat): νmax/cmꢀ1 3480, 3340, 3162, 2977, 2270, 1660, 1622, 1450,
mmol) in THF (2.0 ml) was added 1 M solution of TBAF in THF 80 1377, 1174, 1089, 929; H NMR (400 MHz, CD3CN): δ 10.12
1
(0.05 ml, 0.05 mmol) and stirred for 1 h at 0 °C. Solvent was
evaporated under reduced pressure, water (3.0 ml) was added to
25 the residue and extracted with CH2Cl2 (3 x 8 ml). The combined
extract was washed with brine (6.0 ml) and dried over Na2SO4.
(br s , 1H), 8.81 (s, 1H), 8.31 (d, J 9.1 Hz, 1H), 7.79 (br s, 1H),
7.54 (d, J 9.1 Hz, 1H), 7.30 (dd, J 9.1 and 7.3 Hz, 2H), 7.29 (dd,
J 9.1 and 7.3 Hz, 2H), 6.88 (d, J 8.9 Hz, 2H), 5.00 (t, J 3.6 Hz,
1H), 4.14 (t, J 6.2 Hz, 2H), 4.10ꢀ4.00 (m, 1H), 3.86 (d, J 4.0 Hz,
Evaporation of the solvent and purification of the residue on a 85 1H), 3.70 (dd, J 11.4 and 5.6 Hz, 1H), 3.63 (dd, J 11.4 and 5.6
silica gel column using MeOHꢀCH2Cl2 (1:9) as eluent furnished
the (ꢀ)ꢀbursatellin 9 (11.2 mg, 80%), Rf = 0.40 (MeOH:CH2Cl2,
30 1:9). [α]D25 = ꢀ8.6 (c 0.6, MeOH); IR (neat): νmax/cmꢀ1 3360, 2977,
2240, 1660, 1450, 1377, 1174, 1089; 1H NMR (400 MHz,
Hz, 2H), 2.81 (t, J 6.2 Hz, 2H); 13C NMR (100 MHz, CD3CN): δ
181.8, 163.6, 158.4, 139.9, 137.2, 136.5, 128.5, 127.6, 124.9,
124.0, 122.7, 119.3, 115.3, 113.5, 113.3, 72.5, 64.0, 63.1, 57.8,
19.2, HRMS (ESI): m/z calcd for C22H21N3O5Na (M+Na)
CD3OD): δ 7.90 (s, 1H), 7.23 (d, J 8.5 Hz, 2H), 6.82 (d, J 8.5 Hz, 90 430.1379; found 430.1382.
2H), 4.80 (d, J 3.6 Hz, 1H), 4.07 (t, J 6.0 Hz, 2H), 4.01ꢀ3.96 (m,
1H), 3.54 (dd, J 10.8 and 6.2 Hz, 1H), 3.38 (dd, J 10.8 and 6.0
35 Hz, 1H), 2.80 (t, J 6.0 Hz, 2H); 13C NMR (100 MHz, CD3OD): δ
164.0, 159.0, 136.7, 128.6, 119.0, 115.4, 71.9, 64.2, 62.5, 57.1,
19.0;
3-(4-((S)-((3S,6R)-6-(1H-indol-3-yl)-5-oxomorpholin-3-yl)(tert-
butyldimethylsilyloxy)methyl)phenoxy)propanenitrile (32a) &
3-(4-((S)-((3S,6S)-6-(1H-indol-3-yl)-5-oxomorpholin-3-yl)(tert-
95 butyldimethylsilyloxy)methyl)phenoxy)propanenitrile (32b):
To a cold solution (0 °C) of 30 (104.0 mg, 0.2 mmol) in MeOH
was added NaBH4 (40.0 mg, 1 mmol) and stirred vigorously at
the same temperature for 30 min. Excess MeOH was removed
from reaction mixture under reduced pressure. Added water (10.0
40 N-((1R,2R)-1-((tert-butyldimethylsilyl)oxy)-1-(4-(2-cyanoetho-
xy)phenyl)-3-hydroxypro-pan-2-yl)-2-(1H-indol-3-yl)-2-oxoa-
cetamide (30): To a solution of bocꢀamine 28 (100 mg, 0.2 100 ml), extracted with ethyl acetate (3 x 8 ml), washed with brine
mmol) in CH2Cl2 (10.0 ml) was added Yb(OTf)3 (138 mg, 0.2
mmol) and refluxed for 8 h. Aq. NaHCO3 was added to the
45 reaction mixture and extracted with CH2Cl2 (3 x 10 ml). The
organic layer was washed with brine and dried over Na2SO4.
(10.0 ml) and dried over Na2SO4 and concentrated. To the crude
alcohol was added acetonitrile (50.0 ml), catalytic (10.0 mg)
pyridine paraꢀtoluene sulfonate (PPTS) and refluxed for 1 h. The
reaction mixture was quenched with aq. NaHCO3 (20.0 ml),
After evaporation of the solvent, the residue was dissolved in 105 extracted with ethyl acetate (3 x 8 ml), washed with brine and
CH2Cl2, cooled to 0 °C. To the cold solution was added Et3N
(17.0 mg, 0.16 mmol) followed by 3ꢀindoleglyoxalyl chloride 14
50 (40.0 mg, 0.14 mmol) and stirred magnetically at RT for 12 h.
Water (10.0 ml) was added to the reaction mixture and extracted
with CH2Cl2 (3 x 10 ml). Combined organic layers were washed 110
with brine and dried over anhydrous Na2SO4. Evaporation of the
solvent and purification of the residue on a silica gel column
55 using MeOH:CH2Cl2 (1:19) furnished the TBSꢀprotected
dried over Na2SO4. Evaporation of the solvent and purification of
the residue using preparative thin layer chromatography furnished
the diastereomers 32a (23.0 mg) and 32b (58.0 mg) (yield 78%
for two steps).
25
TBS-protected oxazinin-5 (32a): [α]D = +19.1 ( c 2.0 CHCl3);
IR (neat): νmax/cmꢀ1 3396, 3269, 2928, 2856, 1668(C=O), 1612,
1512, 1462, 1238, 1105, 858, 839, 780, 744, 618; 1H NMR
(CDCl3, 400 MHz): δ 8.35 (br s, 1H), 7.68 (d, J 7.8 Hz, 1H),
25
preoxazininꢀ7 30 (73.0 mg, 70%). [α]D = ꢀ24.0 (c 0.9, CHCl3);
IR (neat): νmax/cmꢀ1 3392, 3020, 2930, 2400, 2280, 1635, 1511, 115 7.35ꢀ7.00 (m, 6H), 6.89 (d, J 8.6 Hz, 1H), 6.55 (br s, 1H), 5.51 (s,
1423, 1215, 1045, 929, 758, 669; 1H NMR (400 MHz, CDCl3): δ
1H), 4.63 (d, J 8.3 Hz, 1H), 4.18 (t, J 6.3 Hz, 2H), 3.70ꢀ3.55 (m,
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DOI: 10.1039/C3RA44631J
2H), 3.41 (dd, J 11.5 and 5.0 Hz, 1H), 2.83 (t, J 6.3 Hz, 2H), 1.64
hydroxyphenyl)methyl)-2-(1H-indol-3-yl)morpholin-3-one
(br s, 1H), 0.91 (s, 9H), 0.10 (s, 3H), ꢀ0.19 (s, 3H); 13C NMR 60 (33b): To an ice cold (0 °C) solution of the compound 32b (20.0
(CDCl3, 100 MHz): δ 169.4, 157.8, 136.4, 133.7, 128.2, 126.1,
124.6, 122.4, 120.0, 119.5, 117.1, 114.7, 111.3, 76.2, 73.8, 62.6,
61.5, 58.6, 25.8, 18.6, 18.1, ꢀ4.5, ꢀ5.0; HRMS (ESI): m/z calcd for
C28H36N3O4Si (M+H) 506.2475; found 506.2486.
mg, 0.04 mmol) in anhydrous THF (2.0 ml) was added dropwise
1 M solution of TBAF in THF (0.08 ml, 0.08 mmol) and stirred
magnetically for 1 h. The reaction mixture was quenched with aq.
NaHCO3 (5.0 ml), extracted with ethyl acetate (5 ml x 3), washed
65 with brine and dried over Na2SO4. Evaporation of the solvent and
purification of the residue using preparative TLC furnished
oxazininꢀ6 6 (9.3 mg, 60%) and the diol 33b (3.7 mg, 24%).
5
Synthesis of TBS-protected oxazinin-6 (32b): [α]D25 = ꢀ28.4 (c
4.5, CHCl3); IR (neat): νmax/cmꢀ1 3398, 2927, 2856, 1668 (C=O),
10 1611, 1511, 1459, 1248, 1097, 859, 838, 779, 743, 617; 1H NMR
(CDCl3, 500 MHz): δ 8.65 (br s, 1H), 7.71 (d, J 7.6 Hz, 1H),
[α]D = +9.0 (c 0.5, MeOH); IR (neat): νmax/cmꢀ1 3360 (OH),
25
3163, 2924, 2857, 2256 (CN), 1661 (C=O), 1618, 1513, 1456,
1
7.35ꢀ7.00 (m, 6H), 6.81 (d, J 8.6 Hz, 2H), 6.62 (s, 1H), 5.51 (s, 70 1306, 1241, 1177, 1107, 1051, 838, 749, 618; H NMR (CD3CN,
1H), 4.61 (d, J 8.5 Hz, 1H), 4.12 (t, J 6.1 Hz, 2H), 3.70ꢀ3.50 (m,
2H), 3.50ꢀ3.40 (m, 1H), 2.79 (t, J 6.1 Hz, 2H), 0.90 (s, 9H), 0.09
15 (s, 3H), ꢀ0.21 (s, 3H).13C NMR (CDCl3, 125 MHz): δ 169.7,
157.7, 136.5, 133.5, 128.2, 126.2, 124.9, 122.3, 119.9, 119.4,
400 MHz): δ 9.37 (br s, 1H), 7.62 (d, J 7.8 Hz, 1H), 7.43 (d, J 8.0
Hz, 1H), 7.35ꢀ7.26 (m, 2H), 7.25ꢀ7.20 (m, 1H), 7.18ꢀ7.14 (m,
1H), 7.09ꢀ7.05 (m, 1H), 6.92 (d, J 8.3 Hz, 2H), 6.86 (br s, 1H),
5.38 (s, 1H), 4.71 (dd, J 7.8 and 3.9 Hz, 1H), 4.17 (t, J 6.1 Hz,
117.1, 114.6, 111.5, 110.9, 76.1, 73.8, 62.5, 61.1, 58.6, 25.8, 75 2H), 3.91 (d, J 3.9 Hz, 1H), 3.68ꢀ3.52 (m, 3H), 2.84 (t, J 6.1 Hz,
18.6, 18.1, ꢀ4.5, ꢀ5.0; HRMS (ESI): m/z calcd for C28H36N3O4Si(
M+H) 506.2475; found 506.2463.
2H); 13C NMR (CD3CN, 100 MHz): δ 170.1, 158.8, 137.3, 135.4,
129.3, 127.3, 126.3, 122.7, 120.6, 120.2, 119.2, 115.6, 112.7,
112.5, 75.3, 74.5, 64.2, 62.7, 58.2, 19.0.
20
Oxazinin-5
(5)
and
(2R,5S)-5-((S)-hydroxy(4-
hydroxyphenyl)methyl)-2-(1H-indol-3-yl)morpholin-3-one
(33a): To an ice cold (0 °C) solution of the compound 32a (22.0
mg, 0.043 mmol) in anhydrous THF (2.0 ml) was added dropwise
25 1 M solution of TBAF in THF (0.08 ml, 0.08 mmol) and stirred
magnetically for 1 h. The reaction mixture was quenched with aq.
80 (2S,5S)-5-((S)-hydroxy(4-hydroxyphenyl)methyl)-2-(1H-
indol-3-yl)morpholin-3-one (33b): [α]D25 = +7.0 (c 0.6, MeOH);
IR (neat): νmax/cmꢀ1 3360 (OH), 2923, 2853, 1652 (C=O), 1613,
1457, 1182, 1108, 966, 838, 745, 618; 1H NMR (CDCl3, 400
MHz): δ 9.38 (br s, 1H), 7.63 (d, J 7.6 Hz, 1H), 7.43 (d, J 8.1 Hz,
NaHCO3 (5.0 ml), extracted with ethyl acetate (5 ml x 3), washed 85 1H), 7.30ꢀ7.00 (m, 6H), 6.87 (br s, 1H), 6.85ꢀ9.70 (m, 2H), 5.38
with brine and dried over Na2SO4. Evaporation of the solvent and
purification of the residue using preparative TLC furnished
30 oxazininꢀ5 5 (11.0 mg, 65%) and the diol 33a (2.5 mg, 15%).
(s, 1H), 4.70ꢀ4.60 (m, 1H),3.83 (br s, 1H), 3.65ꢀ3.50 (m, 3H).13C
NMR (CDCl3, 100 MHz): δ 170.2, 157.8, 137.5, 133.4, 129.2,
127.5, 126.4, 122.9, 120.5, 120.4, 116.2, 112.7, 112.6, 75.6, 74.5,
62.8, 58.6; HRMS (ESI): m/z calcd for C19H18N2O4Na (M+Na)
25
[α]D = + 6.9 (c 0.4, MeOH); IR (neat): νmax/cmꢀ1 3360, 3302,
2924, 2853, 2257, 1660, 1609, 1513, 1456, 1306, 1240, 1177, 90 361.1164; found 361.1158.
1
1106, 1049, 838, 749, 618; H NMR (CDCl3, 400 MHz): δ 9.29
(br s, 1H), 7.58 (d, J 8.1 Hz, 1H), 7.40 (d, J 8.3 Hz, 1H), 7.34 (d,
35 J 8.5 Hz, 2H), 7.27 (d, J 2.7 Hz, 1H), 7.15 (dd, J 8.1 and 7.1 Hz,
1H), 7.05 (dd, J 8.1 and 7.1 Hz, 1H), 6.96 (d, J 8.8 Hz, 1H), 5.29
(2S,3R)-ethyl
2-(2-(1H-indol-3-yl)-2-oxoacetamido)-3-(tert-
butyldimethylsilyloxy)-3-(4-(2-cyanoethoxy)phenyl)propanea-
te (34): To a solution of bocꢀamine 13 (100 mg, 0.2 mmol) in
(s, 1H), 4.58 (dd, J 8.1 and 4.2 Hz, 1H), 4.19 (t, J 6.1 Hz, 2H), 95 CH2Cl2 (10.0 ml) was added Yb(OTf)3 (138 mg, 0.2 mmol) and
3.86 (d, J 4.1 Hz, 1H), 3.85ꢀ3.70 (m, 1H), 3.59 (dd, J 12.0 and
3.9 Hz, 1H), 3.50 (dd, J 12.0 and 7.6 Hz, 1H), 2.85 (t, J 6.1 Hz,
40 2H); 13C NMR (CDCl3, 100 MHz): δ 169.2, 158.0, 136.5, 134.1,
128.1, 126.1, 125.3, 121.8, 119.4, 118.2, 114.6, 112.0, 111.5,
refluxed for 8 h. aq. NaHCO3 was added to the reaction mixture
and extracted with CH2Cl2 (3 x 10 ml). The organic layer was
washed with brine and dried over Na2SO4. After evaporation of
the solvent, the residue was dissolved in CH2Cl2, cooled to 0 °C.
73.9, 73.6, 63.1, 63.0, 57.5, 18.1; HRMS (ESI): m/z calcd for 100 To the cold solution was added Et3N (17.0 mg, 0.16 mmol)
C22H21N3O4Na (M+Na) 414.1430; found 414.1418.
followed by 3ꢀindoleglyoxalyl chloride 14 (40.0 mg, 0.14 mmol)
and stirred magnetically at RT for 12 h. Water (10.0 ml) was
added to the reaction mixture and extracted with CH2Cl2 (3 x 10
ml). Combined organic layers were washed with brine and dried
45 (2R,5S)-5-((S)-hydroxy(4-hydroxyphenyl)methyl)-2-(1H-
indol-3-yl)morpholin-3-one (33a): [α]D25 = +5.3 (c 0.6, MeOH);
IR (neat): νmax/cmꢀ1 3362, 3169, 2923, 2853, 1653, 1612, 1463, 105 over anhydrous Na2SO4. Evaporation of the solvent and
1
1186, 1108, 967, 838, 745, 618; H NMR (CDCl3, 400 MHz): δ
9.30 (br s, 1H), 7.58 (d, J 8.0 Hz, 1H), 7.39 (d, J 8.0 Hz, 1H),
50 7.25 (s, 1H), 7.20 (d, J 7.3 Hz, 2H), 7.18ꢀ7.00 (m, 3H), 6.85ꢀ6.75
(m, 2H), 5.28 (s, 1H), 4.49 (dd, J 8.1 and 3.9 Hz, 1H), 3.85ꢀ3.75
purification of the residue on a silica gel column using (EtOAcꢀ
petroleum ether, 1:1) furnished the TBSꢀprotected compound 34
(114 mg, 80%). [α]D25 = ꢀ50.0 (c 1.5, CHCl3); IR (neat): νmax/cmꢀ1
3393, 3313, 3060, 2954, 2929, 2856, 2255, 1738, 1686, 1511,
(m, 2H), 3.56 (dd, J 12.0 and 3.9 Hz, 1H), 3.47 (dd, J 11.7 and 110 1472, 1340, 1052, 939, 780, 651; 1H NMR (500 MHz, CDCl3): δ
7.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ 169.3, 156.9, 136.4,
132.2, 128.0 (2C), 126.2, 125.3, 121.8, 119.4 (2C), 115.2 (2C),
55 111.9, 74.1, 73.6, 63.2, 57.6; HRMS (ESI): m/z calcd for
C19H18N2O4Na (M+Na) 361.1164; found 361.1181.
9.43 (s, 1H), 8.54 (d, J 3.4 Hz, 1H), 8.11 (d, J 8.1 Hz, 1H), 7.34
(d, J 7.9 Hz, 1H), 7.31ꢀ7.24 (m, 4H), 6.74 (d, J 8.8 Hz, 2H), 5.39
(d, J 2.0 Hz, 1H), 4.69 (dd, J 9.8 and 2.1 Hz, 1H), 4.31ꢀ4.17 (m, 2
H), 4.07ꢀ4.00 (m, 2H), 2.73 (t, J 6.1 Hz, 2H), 0.91 (s, 9H), 0.02
115 (s, 3H), ꢀ0.15 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 179.9,
169.5, 162.3, 157.2, 138.2, 135.8, 133.7, 127.5, 126.4, 124.0,
Oxazinin-6
(6)
and
(2S,5S)-5-((S)-hydroxy(4-
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123.2, 122.2, 117.5; 114.2, 112.9, 11.8, 74.3, 62.4, 61.9, 59.4,
MHz): δ 9.28 (br s, 1H), 7.68 (d, J 7.2 Hz, 1H), 7.41 (d J 8.0 Hz,
29.7, 25.7, 18.6, 18.0, 14.1, ꢀ4.6, ꢀ5.5; HRMS (ESI): m/z calcd for 60 2 H), 7.36 (d, J 8.5 Hz, 2H), 7.32 (d, J 2.6 Hz, 1H), 7.15 (t, J 7.1
C30H37N3O6SiNa (M+Na) 586.2349; found 586.2345.
Hz, 1H), 7.07 (t, J 8.0 Hz, 1H), 6.93 (, J 6.3 Hz, 2H), 6.68 (s,
1H), 5.43 (s, 1H), 4.74 (d, J 9.7 Hz, 1H), 4.16 (t, J 6.3 Hz, 2H),
3.89ꢀ3.86 (m, 1H), 3.43 (dd, J 11.4 and 2.6 Hz, 1H), 3.31 (dd, J
10.8 and 6.1 Hz, 1H), 3.10 (br s, 1H), 2.82 (t, J 6.0 Hz, 2H); 13C
5
(2S,3R)-ethyl
2-(2-(1H-indol-3-yl)-2-oxoacetamido)-3-(4-(2-
cyanoethoxy)phenyl)-3-hydroxypropanoate (35): To the
solution of 34 (80.0 mg, 0.14 mmol) in THF (5.0 ml) was added 65 NMR (CD3CN, 125 MHz): δ 170.8, 158.3, 137.6, 132.1, 129.9,
TBAF (1.0 M in THF, 0.20 ml, 0.2 mmol). The resulting mixture
was stirred for 1 h at 0 °C, before it was concentrated in vacuo.
10 Water (5.0 ml) was added to the residue and extracted with ether
(3 x 20 ml). The combined extract was washed with brine (15.0
127.1, 126.4, 122.9, 120.6, 120.5, 119.3, 115.7, 113.4, 112.6,
78.0, 75.7, 64.1, 62.0, 60.8, 19.2; HRMS (ESI): m/z calcd for
C22H21N3O4Na (M+Na) 414.1430; found 414.1439
ml) and dried over Na2SO4. Evaporation of the solvent and 70 Oxazinin-2 (2): To the solution of 1 (35.0 mg, 0.1 mmol) in THF
purification of the residue on a silica gel column using ethyl
(2.0 ml) was added 1N NaOH solution (1.0 N in H2O, 0.4 ml, 0.4
mmol). The resulting mixture was stirred for 1 h at RT, before it
was quenched with 1N HCl. Water (5.0 ml) was added to the
residue and extracted with ethyl acetate (3 x 20 ml). The
acetateꢀpetroleum ether (7:3) as eluent furnished the 35 (49.7 mg,
25
15 78 %). Rf = 0.40 (EtOAcꢀpetroleum ether, 7:3). [α]D = ꢀ59.0 (c
0.25, MeOH); IR (neat): νmax/cmꢀ1 3377, 2926, 2854, 2255, 1736,
1
1680, 1632, 1458, 1371, 1157, 1050, 751; H NMR (500 MHz, 75 combined extract was washed with brine (15.0 ml) and dried over
CD3CN): δ 10.14 (s, 1H), 8.68 (d, J 3.4 Hz, 1H), 8.27ꢀ8.25 (m,
1H), 7.95 (d, J 8.8 Hz, 1H), 7.52ꢀ7.49 (m, 1H), 7.32ꢀ7.26 (m,
20 4H), 6.85ꢀ6.83 (m, 2H), 5.27 (s, 1H), 4.67 (dd, J 9.1 and 3.4 Hz,
1H), 4.20ꢀ4.08 (m, 5H), 2.78 (t, J 6.0 Hz, 2H), 1.21 (t, J 7.1 Hz,
Na2SO4. Evaporation of the solvent and purification of the
residue on a silica gel column using ethyl acetateꢀpetroleum ether
25
(9:1) as eluent furnished the 2 (22 mg, 80 %). [α]D = +6.0 (c
0.1, MeOH); IR (neat): νmax/cmꢀ1 3318, 2923, 1651, 1613, 1515,
1
3H); 13C NMR (125 MHz, CD3CN): δ 181.6, 171.0, 163.7, 159.0, 80 1456, 1377, 1172, 1086, 1057, 976, 754; H NMR (CD3CN, 500
140.2, 137.5, 135.1, 128.8, 127.8, 125.3, 124.4, 123.1, 119.6,
115.6, 113.7, 73.6, 64.3, 62.8, 59.9, 19.5, 14.8; HRMS (ESI): m/z
25 calcd for C24H23N3O6Na (M+Na) 472.1485; found 472.1489;
MHz): δ 9.37 (br s, 1H), 7.59 (d, J 7.7 Hz, 1H), 7.43 (d J 8.3 Hz,
2 H), 7.29 (d, J 2.6 Hz, 1H), 7.16 (t, J 7.1 Hz, 1H), 7.09 (d, J 8.5
Hz, 2H), 7.00 (, J 6.8 Hz, 1H), 6.74(d, J 8.5 Hz, 2H), 6.63 (s, 1H),
5.57 (s, 1H) 4.57 (d, J 9.2 Hz, 1H), 3.73ꢀ3.69 (m, 1H), 3.44 (dd, J
Synthesis of oxazinin 1 and 4: To a cold solution (0 °C) of 35 85 11.4 and 2.6 Hz, 1H), 3.26 (br s, 1H), 3.03 ( br s, 1H); 13C NMR
(110 mg, 0.25 mmol) in MeOH was added NaBH4 (80.0 mg, 2
mmol) and stirred vigorously at the same temperature for 30 min.
30 Excess MeOH was removed from reaction mixture under reduced
pressure. Added water (10.0 ml), extracted with ethyl acetate (3 x
8 ml), washed with brine (10.0 ml) and dried over Na2SO4 and
concentrated. To the crude alcohol was added acetonitrile (50.0
ml), catalytic (15.0 mg) pyridine paraꢀtoluene sulfonate (PPTS)
35 and refluxed for 1 h. The reaction mixture was quenched with aq.
NaHCO3 (20.0 ml), extracted with ethyl acetate (3 x 8 ml),
washed with brine and dried over Na2SO4. Evaporation of the
solvent and purification of the residue using preparative thin layer
chromatography furnished the diastereomers 1 (23 mg) and 4 (57
40 mg) (yield 60% for two steps).
(125 MHz, CD3CN): δ 170.2, 158.0, 137.4, 130.0, 129.9, 127.5,
126.1, 122.8, 120.3, 120.1, 116.0, 112.4, 112.4, 72.9, 71.2, 62.1,
59.9; HRMS (ESI): m/z calcd for C19H19N2O4 (M+H) 339.1345;
found 339.1343.
90 Acknowledgements
AR thanks CSIR, New Delhi, for a senior research fellowship.
This work was funded by IIT Kanpur startup grant.
Notes and references
95 a Department of Chemistry, Indian Institute of Technology kanpur,
Kanpur, 208016, India
25
Oxazinin-1 (1): [α]D = +28.6 (c 0.28 MeOH); IR (neat):
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
100 DOI: 10.1039/b000000x/
νmax/cmꢀ1 3421, 2923, 2852, 2253(CN), 1660(C=O), 1614, 1540,
1514, 1458, 1384, 1177, 1050, 830, 839, 780, 746; 1H NMR
45 (CD3CN, 500 MHz): δ 9.39 (br s, 1H), 7.59 (d, J 7.9 Hz, 1H),
7.43 (d, J 7.9 Hz, 1H), 7.30 (d, J 2.1 Hz, 1H) 7.21 (d, J 8.8 Hz,
2H), 7.14 (t, J 7.3, 1H), 7.00 (t, J 7.3 Hz, 1H), 6.88 (d, J 8.8 Hz,
2H), 6.69 (s, 1H), 5.59 (s, 1H), 4.62 (d, J 8.3 Hz, 1H), 4.15 (t, J
6.1 Hz, 2H), 3.74ꢀ3.71 (m, 1H), 3.41 (dd, J 11.3 and 3.0 Hz, 1H),
50 3.28 (dd J 11.3 and 5.8 Hz, 1H), 2.82 (t, J 6.1 Hz, 2H); 13C NMR
(CD3CN, 125 MHz): δ 170.2, 159.0, 137.4, 131.8, 130.0, 127.5,
126.1, 122.8, 120.4, 120.0, 119.1, 115.4, 112.4, 112.3, 72.9, 71.0,
63.9, 61.9, 59.9, 19.0; HRMS (ESI): m/z calcd for C22H21N3O4Na
(M+Na) 414.1430 found 414.1439.
‡
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Graphical Abstract :
OH
H
N
3
O
5
2
6
O
1
HN
OR
O
H
OH
BocHN
TBSO
CO2Et
2
4
6
N
3
5
1
Oxazinin-1/2/4
O
OH
N
OR
H
OR
OH
H
3
O
N
7
5
2
O
1
OR
HN
Oxazinin-5/6