Partial racemization occurring in the hydroxylactonization of a δ,ε-Epoxy Amide

Article abstract of DOI:10.1271/bbb.100646

Acid-promoted hydroxylactonization of a δ,ε-epoxy amide took place via both 6-exo-tet and 7-endo-tet processes, causing a considerable degree of racemization of the resulting δ-hydroxyalkyl-δ-lactone.

Full text of DOI:10.1271/bbb.100646

Biosci. Biotechnol. Biochem., 74 (12), 2535–2537, 2010
Note
Partial Racemization Occurring in the Hydroxylactonization
of a ꢀ,"-Epoxy Amide
y
Masaru ENOMOTO and Shigefumi KUWAHARA
Laboratory of Applied Bioorganic Chemistry, Graduate School of Agricultural Science, Tohoku University,
Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan
Received September 6, 2010; Accepted September 22, 2010; Online Publication, December 7, 2010
[doi:10.1271/bbb.100646]
Acid-promoted hydroxylactonization of a ꢀ,"-epoxy
amide took place via both 6-exo-tet and 7-endo-tet
processes, causing a considerable degree of racemiza-
tion of the resulting ꢀ-hydroxyalkyl-ꢀ-lactone.
lactone 6a in an acceptable yield of 54%. Lactone 6a
was obtained as a single diastereomer, and its relative
stereochemistry was confirmed by comparing its 1H- and
13C-NMR spectra with those of an authentic sample
prepared by a different synthetic route.12) Surprisingly,
however, a 1H-NMR analysis of (R)- and (S)-MTPA
esters 6b prepared from 6a indicated the ee of 6a to
be only 55%, down by 33% from the original ee value
(88%) of starting material 2a. As shown in Scheme 2, we
initially expected that the ring opening of protonated
epoxide 7 would proceed via path a (6-exo-tet mode, the
generally favored process from the Baldwin rule),13)
giving desired lactone 6a as a single stereoisomer. The
partial racemization that was observed during the acid-
catalyzed hydroxylactonization process, however, sug-
gests that ring opening also took place through path b (7-
endo-tet mode), affording the enantiomer of 6a (ent-6a)
via hydroxy iminium ion 8 and protonated amino acetal
intermediate 9. We consider that this unexpected result
could be based on the exceptional feature of three-
membered rings (formally belonging to the tetrahedral
system) that they can also behave like the trigonal system
which generally favors both 7-endo and 6-exo ring-
forming modes.13) Some related examples of such endo-
type hydroxylactonization of ꢁ,ꢀ-epoxy esters have in
fact been reported in the literature.14)
Key words: dihydroisocoumarin; epoxy amide; hydro-
xylactonization; racemization; Baldwin rule
Our recently completed total syntheses of bacilosar-
cins A and B,1) herbicidal substances produced by
Bacillus subtilis TP-B0611,2) as well as of two related
natural products3) needed dihydroisocoumarin derivative
1 to be prepared as their common building block
(Scheme 1). Although the preparation of 1 with a high
enantiomeric excess (ee) of 96% was eventually accom-
plished by using an intermolecular epoxide ring-opening
reaction as the key step, our initial approach to 1 via
intramolecular epoxide ring opening of ꢀ,"-epoxy amide
5 to hydroxy lactone 6a suffered from unexpected partial
racemization, forcing us to abandon the original syn-
thetic plan for 1. We disclose in this note our concise
preparation of 5 and propose a plausible mechanism for
the partial racemization.
The preparation of 5 began with the iodination of
epoxy alcohol 2a that had been obtained in 88% ee by
the Sharpless asymmetric epoxidation of (E)-5-methyl-
2-hexen-1-ol according to a reported procedure.4) The ee
of 2a was determined by comparing its specific rotation
In conclusion, we found that the hydroxylactonization
of ꢀ,"-epoxy amide 5 to form lactone 6a can be effected
by its treatment with TFA, but that the reaction was
accompanied by a considerable degree of racemization
ascribable to the concurrent 6-exo-tet and 7-endo-tet
ring-forming processes.
1
with the reported value4) and confirmed by a H-NMR
analysis of corresponding (R)- and (S)-MTPA esters 2b.
Resulting epoxy iodide 3 was converted into epoxy
amide 5 in a 75% yield by treating 3 with the Lipshutz
cuprate prepared from 4 by its successive treatment
with s-BuLi/TMEDA, CuCN, and LiCl.5–8) It is worth
mentioning that 5 was obtained as a 1:1 mixture of
diastereomers ascribable to atropisomerism due to
restricted rotation about the Ar–CO single bond.9)
With 5 in hand, we set about the pivotal transforma-
tion, the hydroxylactonization of 5 into 6a. Although our
literature search revealed that examples of this type of
reaction, intramolecular epoxide ring opening of epoxy
amides to produce hydroxy lactones,10,11) were scarcely
precedented, in contrast to analogous transformations
using epoxy carboxylic acids or epoxy esters as sub-
strates, the conversion of 5 into 6a was successfully
achieved by simply treating 5 with TFA in dichloro-
methane at room temperature, giving desired hydroxy
Experimental
IR spectra were recorded by a Jasco FT/IR-4100 spectrometer,
using an ATR (ZnSe) attachment. NMR spectra were recorded with
TMS as an internal standard in CDCl3 by a Varian Unity Plus-500
spectrometer (500 MHz for 1H and 125 MHz for 13C). Optical rotation
values were measured with a Jasco DIP-371 polarimeter, and mass
spectra were obtained with a Jeol JMS-700 spectrometer. Merck silica
gel 60 (70–230 mesh) was used for column chromatography. CH2Cl2
and THF employed for the reactions were respectively distilled from
CaH2 and Na/benzophenone.
(2R,3R)-2,3-Epoxy-5-methyl-1-hexanol (2a). To a stirred suspen-
sion of D-(ꢀ)-diisopropyl tartrate (70 ml, 0.328 mmol), Ti(OiPr)4
˚
(65 ml, 0.219 mmol) and activated MS 3 A (1.00 g) in CH2Cl2
(3.25 ml) was added TBHP (3.54 M in toluene, 2.60 ml, 9.20 mmol)
at ꢀ25 ꢁC.
A
solution of (E)-5-methyl-2-hexen-1-ol in CH2Cl2
(3.25 ml) was added after 45 min at ꢀ25 ꢁC, and the resulting mixture
y
To whom correspondence should be addressed. Fax: +81-22-717-8783; E-mail: skuwahar@biochem.tohoku.ac.jp
Abbreviations: TMEDA, N,N,N0,N0-tetramethylethylenediamine; TFA, trifluoroacetic acid; MTPA, ꢂ-methoxy-ꢂ-(trifluoromethyl)phenylacetyl

2536
M. ENOMOTO and S. KUWAHARA
Scheme 2. Plausible Mechanism for the Partial Racemization of 6a.
Scheme 1. Preparation of ꢀ,"-Epoxy Amide 5 and Its Hydroxylacto-
nization to 6a.
N,N-Diethyl-2-[(2R,3R)-2,3-epoxy-5-methylhexyl]-6-methoxybenza-
mide (5). To a stirred solution of TMEDA (773 ml, 5.12 mmol) in THF
(20 ml) was added s-BuLi (1.0 M in hexane, 5.12 ml, 5.12 mmol) at
ꢀ78 ꢁC under Ar. After 10 min, a solution of 4 (1.04 g, 5.00 mmol) in
THF (6.0 ml) was added over 15 min, and the resulting mixture was
stirred for 30 min. To the mixture was added a solution of CuCN
(224 mg, 2.50 mmol) and LiCl (212 mg, 5.00 mmol) in THF (8.25 ml)
over 10 min. The mixture was gradually warmed to ꢀ15 ꢁC over
50 min and stirred at ꢀ15 ꢁC for an additional 10 min. A solution of 3
(300 mg, 1.25 mmol) in THF (3.0 ml) was then added to the resulting
yellow suspension at ꢀ78 ꢁC, and the mixture was gradually warmed
to room temperature and stirred overnight. The reaction was quenched
with satd. aq. NH4Cl, and the mixture was extracted with Et2O. The
extract was successively washed with water and brine, dried (Na2SO4)
and concentrated in vacuo. The residue was chromatographed over
was stirred for 16 h at the same temperature. The reaction was
.
quenched by adding FeSO4 7H2O (2.6 g, 9.39 mmol) and 10% w/v aq.
DL-tartaric acid (13 ml) at ꢀ15 ꢁC, and the mixture was filtered through
a pad of Florisil. The resulting filtrate was extracted with Et2O, and
the extract was successively washed with saturated aq. NaHCO3 and
brine, dried (Na2SO4) and concentrated in vacuo. The residue was
chromatographed over SiO2 (hexane/ethyl acetate ¼ 5:1–2:1) to give
22
2a (435 mg, 76%) as a colorless oil. ½ꢂꢂ
þ36.7 (c 0.49, MeOH)
D
20
(lit.4) ½ꢂꢂ
ꢀ36.5 (c 0.053, MeOH) for ent-2 which was estimated
D
to be 88% ee by a chiral GLC analysis); IR ꢃmax: 3449 (s), 2957 (s);
1H-NMR ꢀ: 0.96 (3H, d, J ¼ 3:5 Hz), 0.99 (3H, d, J ¼ 3:5 Hz), 1.29–
1.56 (2H, m), 1.74–1.90 (2H, m), 2.90 (1H, ddd, J ¼ 4:5, 2.7, 2.7 Hz),
2.98 (1H, ddd, J ¼ 6:3, 5.4, 2.7 Hz), 3.64 (1H, ddd, J ¼ 12:5, 6.6,
3.9 Hz), 3.92 (1H, ddd, J ¼ 12:5, 5.4, 2.7 Hz); 13C-NMR ꢀ: 23.0, 23.5,
26.9, 41.3, 55.5, 59.2, 62.3; HRMS (FAB) m=z: calcd. for C7H15O2,
131.1072; found, 131.1080 (½M þ Hꢂþ).
SiO2 (hexane/ethyl acetate ¼ 5:1–4:1) to give 5 (300 mg, 75%) as a
22
colorless oil. ½ꢂꢂ
þ13.8 (c 0.94, CHCl3); IR ꢃmax: 2961 (s), 1631
D
(s); 1H-NMR ꢀ: 0.89 (0:5 ꢃ 3H, d, J ¼ 6:3 Hz), 0.92 (0:5 ꢃ 3H, d,
J ¼ 6:3 Hz), 0.93 (0:5 ꢃ 3H, d, J ¼ 6:5 Hz), 0.94 (0:5 ꢃ 3H, d,
J ¼ 6:5 Hz), 1.02 (0:5 ꢃ 3H, t, J ¼ 7:3 Hz), 1.03 (0:5 ꢃ 3H, t,
J ¼ 7:3 Hz), 1.24 (0:5 ꢃ 3H, t, J ¼ 7:3 Hz), 1.26 (0:5 ꢃ 3H, t,
J ¼ 7:3 Hz) 1.34–1.45 (2H, m), 1.72–1.84 (1H, m), 2.61 (0:5 ꢃ 1H,
dd, J ¼ 14:5, 7.5 Hz), 2.65 (0:5 ꢃ 1H, dd, J ¼ 14:5, 6.0 Hz), 2.74–2.96
(3H, m), 3.07–3.19 (2H, m), 3.43 (1H, dq, J ¼ 20:0, 7.3 Hz), 3.75
(1H, dq, J ¼ 20:0, 7.3 Hz), 3.78 (3H, s), 6.79 (1H, d, J ¼ 7:8 Hz), 6.91
(0:5 ꢃ 1H, d, J ¼ 7:8 Hz), 6.99 (0:5 ꢃ 1H, d, J ¼ 7:8 Hz), 7.25
(0:5 ꢃ 1H, t, J ¼ 7:8 Hz), 7.29 (0:5 ꢃ 1H, t, J ¼ 7:8 Hz); 13C-NMR
ꢀ: 12.8, 13.71/13.73, 22.40/22.43, 22.95/22.97, 26.3/26.4, 35.6, 38.5,
41.0, 42.6/42.7, 55.5, 57.8/58.0, 58.2/58.4, 108.8/108.9, 121.7/122.3,
126.5, 129.3/129.4, 135.3/135.8, 155.3, 167.8/167.9; HRMS (FAB)
m=z: calcd. for C19H30O3N, 320.2226; found, 320.2234 (½M þ Hꢂþ).
(S)-3-[(R)-1-Hydroxy-3-methylbutyl]-8-methoxyisochroman-1-one
(6a). To a stirred solution of 5 (30 mg, 0.0939 mmol) in CH2Cl2
(2.0 ml) was added TFA (7.0 ml, 0.0939 mmol) at room temperature.
After 13.5 h, the reaction was quenched with satd. aq. NaHCO3, and
the mixture was extracted with CH2Cl2. The extract was washed with
brine, dried (Na2SO4) and concentrated in vacuo. The residue was
Determination of the ee of 2a. Compound 2a (2 mg) was treated
with each of (R)- and (S)-MTPA chloride in pyridine to give the
respective (S)- and (R)-MTPA esters (2b) which were then analyzed by
1H-NMR (500 MHz, CDCl3) without chromatographic purification.
The signals for the two protons on the MTPAO-bearing methylene
carbon of the (R)-MTPA ester derived from 2a were observed at ꢀ 4.24
(1H, dd, J ¼ 12:1, 5.8 Hz) and ꢀ 4.58 (1H, dd, J ¼ 12:1, 3.3 Hz), while
those of the MTPA ester formed from ent-2a contained in the sample
of 2a as a small amount of contaminant appeared at ꢀ 4.25 (1H, dd,
J ¼ 12:1, 6.2 Hz) and ꢀ 4.54 (1H, dd, J ¼ 12:1, 3.3 Hz). These
chemical shifts were confirmed by the 1H-NMR spectrum of the (S)-
MTPA esters obtained from 2a. A comparison of the two 1H-NMR
spectra revealed the ee of 2a to be 88%.
(2S,3R)-2,3-Epoxy-1-iodo-5-methylhexane (3). To a stirred solution
of 2a (847 mg, 6.51 mmol), Ph3P (1.88 g, 7.16 mmol) and imidazole
(797 mg, 11.7 mmol) in CH2Cl2 (50 ml) was added iodine (1.82 g,
7.16 mmol) at 0 ꢁC under Ar, and the mixture was stirred at room
temperature for 3 h. To this mixture were added saturated aq. NaHCO3
and satd. aq. Na2S2CO3 at 0 ꢁC, and the resulting mixture was
extracted with Et2O. The extract was successively washed with satd.
aq. Na2SO3, satd. aq. NaHCO3 and brine, dried (Na2SO4) and
concentrated in vacuo. The residue was diluted with hexane/Et2O (3:1)
and filtered though a pad of Celite. The filtrate was concentrated
chromatographed over SiO2 (hexane/ethyl acetate ¼ 4:1) to give 6a
22
(13.4 mg, 54%) as a colorless oil. ½ꢂꢂ
ꢀ64 (c 0.62, CHCl3); IR ꢃmax
:
D
3477 (s), 2955 (s), 1717 (s); 1H-NMR ꢀ: 0.95 (3H, d, J ¼ 6:6 Hz), 0.98
(3H, d, J ¼ 6:6 Hz), 1.21–1.34 (1H, m), 1.52 (1H, ddd, J ¼ 14:4, 10.2,
6.0 Hz), 1.79–1.93 (1H, m), 2.18 (1H, d, J ¼ 3:9 Hz), 2.78 (1H, dd,
J ¼ 16:2, 2.7 Hz), 3.20 (1H, dd, J ¼ 16:2, 12.6 Hz), 3.96 (3H, s), 4.20–
4.12 (1H, m), 4.31 (1H, ddd, J ¼ 12:6, 3.2, 2.7 Hz), 6.85 (1H, d,
J ¼ 7:2 Hz), 6.92 (1H, d, J ¼ 8:7 Hz), 7.47 (1H, d, J ¼ 8:4 Hz);
13C-NMR ꢀ: 21.8, 23.5, 24.6, 28.0, 40.6, 56.2, 69.8, 81.0, 110.8, 113.5,
119.7, 134.7, 142.1, 161.2, 162.4; HRMS (FAB) m=z: calcd. for
C15H21O4, 265.1440; found, 265.1435 (½M þ Hꢂþ).
in vacuo, and the residue was chromatographed over SiO2 (hexane/
22
EtOAc ¼ 4:1) to give 3 (1.284 g, 82%) as a colorless oil. ½ꢂꢂ
ꢀ2.0
D
(c 0.3, CHCl3); IR ꢃmax: 2956 (s), 898 (m); 1H-NMR ꢀ: 0.98 (6H, d,
J ¼ 6:5 Hz), 1.39 (1H, ddd, J ¼ 13:5, 7.5, 5.5 Hz), 1.49 (1H, ddd,
J ¼ 13:5, 6.3, 6.0 Hz), 1.82 (1H, m, J ¼ 5:5, 6.0, 6.5 Hz), 2.83 (1H,
ddd, J ¼ 7:5, 6.3, 2.0 Hz), 2.98 (1H, ddd, J ¼ 7:5, 6.3, 2.0 Hz), 3.05
(1H, dd, J ¼ 10:3, 7.5 Hz), 3.26 ppm (1H, dd, J ¼ 10:3, 6.3 Hz);
13C-NMR ꢀ: 5.1, 22.5, 22.9, 26.3, 40.8, 58.4, 61.7; HRMS (EI) m=z:
calcd. for C7H13OI, 240.0011; found, 240.0014 (Mþ).
Determination of the ee of 6a. Compound 6a (2 mg) was treated
with each of (R)- and (S)-MTPA chloride in pyridine to give the

Racemization in Epoxy Amide Hydroxylactonization
2537
respective (S)- and (R)-MTPA esters (6b) which were then analyzed by
1H-NMR (500 MHz, CDCl3) without chromatographic purification.
The signal for the methine proton on the lactone ring of the (R)-MTPA
ester derived from 6a was observed at ꢀ 4.53 (1H, dt, J ¼ 12:5,
3.0 Hz), while that of the MTPA ester formed from ent-6a contained in
the sample of 6a as a small amount of contaminant appeared at ꢀ 4.39
(1H, ddd, J ¼ 12:4, 4.4, 2.7 Hz). These chemical shifts were confirmed
by the 1H NMR spectrum of the (S)-MTPA esters obtained from 6a.
A comparison of the two 1H-NMR spectra revealed the ee of 6a to
be 55%.
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