Checked by Martin Fox and Larry E. Overman.
1. Procedure
2. Notes
2. A solution of
HBr (30%) in acetic acid (d = 1.31 g/mL) was purchased from Kishida Chemical Co., Ltd. (Japan). When 3 equiv of
HBr rather than 4 equiv was employed, the yield of
2 dropped by more than
40%.
3. Using Merck precoated silica gel plates (0.25-mm thickness) with elution by
hexane-
EtOAc (2:1), after this time period, the starting tartrate ester (R
f = 0.14) was absent. Three spots with R
f values of 0.53 (the largest), 0.36 (half of the largest), and 0.21 (trace) were observed upon visualization. See discussion for the structure of these products.
4.
Commercial reagent grade ethanol was used as received.
5.
Acetyl chloride was purchased from Kishida Chemical Co. Ltd. (Japan), and used as received.
6. A
column (350 mm × 50 mm) packed with Merck silica gel 60 (230–400 mesh ASTM) was used. Elution was facilitated by the action of an
air pump for tropical fish tanks available from supermarkets. After use, the column was washed successively with
methanol (500 mL),
ethyl acetate (400 mL), and
hexane (400 mL). Such a washing operation reactivates the column enough for reuse to purify the epoxide (
3), if necessary (see (Note
15)). Thus the submitters can employ the same column repeatedly for the purification of
2 and
3 (over 10 times). The checkers recommend purification by flash chromatography using a
350-mm × 50-mm column.
8. The spectral data for
2 are as follows:
1H NMR (500 MHz, CDCl
3) δ: 1.31 (t, 6 H, J = 7.1), 3.42 (d, 1 H, J = 7.5), 4.21–4.35 (m, 4 H), 4.66 (dd, 1 H, J = 7.5, 4.1), 4.71 (d, 1 H, J = 4.1);
13C NMR (50 MHz, CDCl
3) δ: 13.7, 13.8, 47.4, 62.3, 62.6, 72.3, 166.5, 170.1; IR (film) cm
−1: 3480, 2909, 2873, 1739, 1371, 1302, 1286, 1220, 1161, 1113, 1024.
9. A Simadzu GC-8A gas chromatograph equipped with a flame ionization detector and ULBON HR-101
capillary column (23 m × 0.25 mm) was used.
11. If it proves difficult to control the rate of addition by adjusting the
nitrogen pressure, a static positive pressure of
nitrogen can be employed and the flask containing the
sodium ethoxide solution can be moved up or down slightly to regulate the rate of addition.
12. More rapid addition of the base results in a lower yield of
3.
13. The spectral data for
3 are as follows:
1H NMR (300 MHz, CDCl3) δ: 1.31 (t, 6 H, J = 7.1), 3.66 (s, 2 H), 4.21–4.32 (m, 4 H);
13C NMR (50 MHz, CDCl
3) δ: 13.9, 51.9, 62.1, 166.6; IR (film) cm
−1: 2988, 1751, 1372, 1330, 1200, 1029.
14. Epoxide
3 should be free from
2 because
2, if subjected to the next step (
3
4), leads to the (2R,3R)-diastereoisomer via an S
N2 displacement process. If
3 is contaminated with
2, the distillate can be purified using the same column as above (Note
6), employing
hexane–
ether (5:1) as eluent and 60-mL fractions. In the checkers' hands a trace of
2 was always present. Therefore, the checkers recommend that the crude product be purified by flash chromatography (as in step A) to remove residual
2 prior to distillation.
15. The literature values
2 for the antipode (95% pure by GLC analysis) are as follows: bp 98–99°C (3 mm) and [α]
23D +105.49° (ether,
c 1.413).
16.
DMAP was purchased from Nacalai Tesque, Inc. (Japan) and used as received.
18.
Azidotrimethylsilane was purchased from Aldrich Chemical Co., Ltd. (95% pure) and used as received.
20.
Commercial, reagent grade chloroform was used as received.
21. The solution was prepared by carefully mixing
3.28 mL acetyl chloride with sufficient dry
ethanol to reach a final volume of 20 mL.
23. The optical rotation of
4 is highly dependent both on solvent and sample concentration. For example, [α]
D values observed in
chloroform vary as follows: +1.43° (
c 3.25) , +3.69° (
c 6.61), and +5.68° (
c 16.7).
24. The spectral data for
4 are as follows:
1H NMR (500 MHz, CDCl
3) δ: 1.30 (t, 3 H, J = 7.1), 1.31 (t, 3 H, J = 7.1), 3.38 (d, 1 H, J = 5.4), 4.20–4.34 (m, 5 H), 4.63 (dd, 1 H, J = 5.4, 2.7);
13C NMR (50 MHz, CDCl
3) δ: 13.90, 13.94, 62.3, 62.6, 64.3, 72.0, 166.9, 170.7; IR (film) cm
−1: 3480, 2989, 2943, 2910, 2877, 2120, 1751, 1724, 1209, 1114, 1028. The signal corresponding to C
3 proton of the (2R,3R) diastereoisomer appears at δ 4.73 (dd, J = 5.6, 2.4).
25.
10% Palladium on carbon catalyst was purchased from Ishizu Seiyaku Co., Ltd. (Japan) and employed as received.
27. An MRK catalytic hydrogenation apparatus (Mitamura Riken Co., Japan) was used.
28.
Di-tert-butyl dicarbonate (97% pure) was purchased from Wako Pure Chemical Industries, Ltd. (Japan) and used as received.
29. The time required for completion of the reaction depends on the activity of the
palladium catalyst employed.
30. This solvent system is convenient to separate less polar contaminants such as tert-butyl acetate or unchanged
di-tert-butyl dicarbonate.
31. The seeds required for crystallization are available by cooling a small portion (
1 mL) of the hexane–ether solution to −78°C and scratching the highly viscous gum that separates with a
glass rod. The rate of crystallization is very slow and additional
ether is sometimes required when an oil phase appears on cooling instead of development of crystals.
32. When commercial
chloroform (stabilized with
0.3–1% of ethanol) was used as received for optical rotation measurements, the submitters obtained
[α]24D +19.3° (
c 6.05). However,
chloroform passed through a silica gel column prior to the measurement gave a much higher value as indicated. The optical rotation of
5 observed with commercial
ethanol was (
[α]24D +19.3° (EtOH,
c 6.32)), while that determined using absolute EtOH [distilled from Mg(OEt)
2] led to a much lower value
[α]24D +7.19° (EtOH,
c 6.32). The spectral properties for pure
5 are as follows:
1H NMR (CDCl
3, 300 MHz) δ: 1.25 (t, 3 H, J = 7.1), 1.32 (t, 3 H, J = 7.1), 1.46 (s, 9 H), 3.47 (s (br), 1 H), 4.14–4.34 (m, 4H), 4.50 (s (br), 1 H), 4.83 (dd, 1 H, J = 7.9, 1.3), 5.51 (d, 1 H, J = 7.9);
13C NMR (CDCl
3, 50 MHz) δ:13.9, 14.0, 28.2, 56.9, 61.8, 62.1, 72.0, 80.3, 155.5, 168.5, 171.5; IR (film) cm
−1: 3450 (br), 2983, 1720, 1507, 1369, 1241, 1218, 1188, 1117, 1059, 1029.
33. After isolation of the second crop, the recovered oily product mixture should be purified, if required, by column chromatography (100 g of silica gel/g oil) using
hexane–
ethyl acetate (8:1). The rate of crystallization for the third crop becomes much slower, requiring 2 to 3 days at −30°C; cooling at −78°C results in oil separation. Careful chromatography on silica gel of the oily residue remaining after concentration of the mother liquors of the third crystallization affords the pure 2R,3R diastereomer. Spectral data for
diethyl (2R,3R)-2-(N-tert-butoxycarbonyl)amino-3-hydroxysuccinate are as follows:
1H NMR (CDCl
3, 500 MHz) δ: 1.30 (t, 3 H, J = 6.9), 1.31 (t, 3 H, J = 7.0), 1.41 (s, 9 H), 3.45 (d, 1 H, J = 5.0), 4.22–4.30 (m, 4 H), 4.68 (d (br), 1 H, J = 3.3), 4.78 (d (br), 1 H, J = 8.3), 5.26 (d (br), 1H, J = 9.3);
13C NMR (CDCl
3, 50 MHz) δ: 13.9, 14.0, 28.0, 56.0, 61.9, 62.4, 71.1, 80.0, 155.2, 169.4, 171.9.
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
The first and second steps are examples of a standard method for the stereospecific synthesis of epoxides via vicinal acetoxy bromides from vicinal diols.
24 25 Based upon kinetic studies, the stereochemical outcome, and the observation of an intermediate carbocation by NMR spectroscopy,
24 the mechanism of the first step has been rationalized to involve monoacetylation of the diol, cyclization to a 1,3-dioxolan-2-ylium ion, and capture of this intermediate by bromide ion. If this mechanism is valid for the present case, the reaction can be illustrated as shown in Scheme 1. The experimental findings (Note
3) correspond reasonably with this mechanistic scheme. Reaction of
1 with
30% HBr in acetic acid proceeded, as shown by both TLC and isolation experiments, with the initial formation of
8 (R
f = 0.53) followed by the gradual increase in the formation of
2 (R
f = 0.36) because of increase in the content of water liberated in the medium. At complete consumption of
1, an additional minor product
6 (R
f = 0.21) was detected by TLC. The presence of
6 may result from competition by the increasing concentration of water as the reaction progresses for
7 relative to bromide. Thus, although
1 had been completely consumed as observed by TLC, the subsequent transesterification process (ethanol/HCl) gives rise to a mixture of
2 and a small amount of
1 (derived from
6) which are easily separated by column chromatography on silica gel.
For the azide cleavage of chiral 2,3-epoxy diester
3, the submitter's earlier procedure
9f was modified to reduce the amount of azide reagent (
azidotrimethylsilane, TMSN
3) and lower the reaction temperature. This effort, coupled with the submitter's recent finding that such a reaction can be accelerated in the presence of amines,
18,
9i led to the use of the system described above. The reaction may proceed by the pathway shown in Scheme 2. The reactive azide species could be DMAPH + N
3− formed from DMAP and HN
3 which are, in turn, initially generated by the exothermic reaction of TMSN
3 and
ethanol, or later catalytically from reaction of TMSN
3 with the desired product
4. The reaction occurs with these reagents at a practical rate at 25°C, in sharp contrast to the previous more vigorous conditions (2 equiv or more of TMSN
3-CH
3OH (1:1) at 60°C in DMF).
9f In addition, this reaction does not require any special precautions other than use of a well-ventilated hood since the generation a high concentration of the hazardous, free HN
3 is avoided.
18,
9i The initial product is a mixture of
4 and its O-silylated derivative (O-TMS-
4). The latter is converted to
4 upon treatment of the mixture with
HCl in
ethanol affording
4 in over 85% yield.
This procedure has been used by Ohfune
26 to convert N-(benzyloxycarbonyl)amino groups to N-(tert-butoxycarbonyl)amino groups in one pot, the Cbz to Boc switching protocol. This procedure is efficient because no tedious isolation of the intermediate amine is required. The following examples illustrate the advantages of this one-pot procedure. In addition, the amount of
palladium catalyst employed controls the chemoselectivity of the transformation. For instance, employing 1–2 wt% Pd/g of substrate, the 1,2-diazide
9 can be changed to the corresponding, protected 1,2-diamine derivative
10, while the O-benzyl group is kept unchanged.
9i On the other hand, employing 30 wt% Pd/g of substrate, both the azido and O-benzyl groups of
11 can be transformed to N-(tert-butoxycarbonyl)amino and hydroxyl groups, (
12) respectively (Scheme 3).
27
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
brine
D-Aspartic acid, N-[(1,1-dimethylethoxy)carbonyl]-3-hydroxy-, diethyl ester, threo-
diethyl erythro-3-hydroxy-N-(tert-butoxycarbonyl)-L-aspartate
Pd-carbon
ethanol (64-17-5)
potassium carbonate (584-08-7)
hydrogen chloride,
HCl (7647-01-0)
acetic acid (64-19-7)
ethyl acetate,
EtOAc (141-78-6)
methanol (67-56-1)
ether (60-29-7)
hydrogen (1333-74-0)
acetyl chloride (75-36-5)
chloroform (67-66-3)
sodium bicarbonate (144-55-8)
sodium chloride (7647-14-5)
HYDROBROMIC ACID,
hydrogen bromide,
HBr (10035-10-6)
sodium sulfate (7757-82-6)
nitrogen (7727-37-9)
carbon (7782-42-5)
potassium hydroxide (1310-58-3)
sodium (13966-32-0)
sodium ethoxide (141-52-6)
palladium (7440-05-3)
L-tartaric acid (87-69-4)
triethyl orthoformate (122-51-0)
dichloromethane (75-09-2)
magnesium sulfate (7487-88-9)
dioxane (5703-46-8)
N,N-dimethylformamide (68-12-2)
magnesium ethoxide (2414-98-4)
benzyltrimethylammonium hydroxide (100-85-6)
hexane (110-54-3)
calcium hydride (7789-78-8)
hydrogen azide
azidotrimethylsilane (4648-54-8)
diethyl L-tartrate
4-(dimethylamino)pyridine (1122-58-3)
Diethyl (2S,3S)-2-bromo-3-hydroxysuccinate (80640-14-8)
Diethyl (2R,3R)-2,3-epoxysuccinate (74243-85-9)
diethyl (2S,3R)-2-bromo-3-hydroxy succinate
Diethyl (2S,3R)-2-azido-3-hydroxysuccinate (101924-62-3)
Diethyl (2S,3R)-2-(N-tert-butoxycarbonyl)amino-3-hydroxysuccinate,
DIETHYL (2S,3R)-2-(N-tert-BUTOXYCARBONYL)AMINO- 3-HYDROXYSUCCINATE (174682-54-3)
ethoxytrimethylsilane (1825-62-3)
diethyl (2S,3R)-2-azido-3-(trimethylsiloxy)succinate
diethyl (2R,3R)-2-(N-tert-butoxycarbonyl)amino-3-hydroxysuccinate
Di-tert-butyl dicarbonate (24424-99-5)
(2S,3S)-2-bromo-3-hydroxysuccinate
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