Allyl cyanate-to-isocyanate rearrangement for the synthesis of quaternary stereocenter with nitrogen substituent

Article abstract of DOI:10.1271/bbb.69.939

The stereochemistry and efficiency of an allyl cyanate-to-isocyanate rearrangement for the construction of quaternary stereocenter with nitrogen substituent was investigated by the synthesis of (R)-α- methylphenylalanine. The rearrangement was found to be

Full text of DOI:10.1271/bbb.69.939

Biosci. Biotechnol. Biochem., 69 (5), 939–943, 2005
Allyl Cyanate-to-isocyanate Rearrangement for the Synthesis
of Quaternary Stereocenter with Nitrogen Substituent
y
2
Yoshiyasu ICHIKAWA,1; Eiji YAMAUCHI,2 and Minoru ISOBE
1Laboratory of Natural Products, Faculty of Science, Kochi University, 2-5-1 Akebono-cho,
Kochi 780-8520, Japan
2Laboratory of Organic Chemistry, School of Bioagricultural Sciences, Nagoya University,
Chikusa, Nagoya 464-8601, Japan
Received November 8, 2004; Accepted February 24, 2005
The stereochemistry and efficiency of an allyl cyan-
ate-to-isocyanate rearrangement for the construction of
quaternary stereocenter with nitrogen substituent was
investigated by the synthesis of (R)-ꢀ-methylphenylala-
nine. The rearrangement was found to be stereospecific,
and the chirality of allyl carbamate was transferred to
that of the quaternary carbon bearing isocyanate group.
These results establish that an allyl cyanate-to-isocya-
nate rearrangement is a useful method for the synthesis
of natural products, that contain the quaternary carbon
with nitrogen substituent.
Over the last several years, we have been engaged in
the application of [3.3] sigmatropic rearrangement of
allyl cyanate for the synthesis of natural products.1) Allyl
cyanate-to-isocyanate rearrangement begins with dehy-
dration of allyl carbamate A as represented in Scheme 1.
The resulting allyl cyanate B immediately undergoes
[3.3] bond reorganization to give rise to allyl isocyanate
C. Treatment of the resultant allyl isocyanate C with
alcohol affords the corresponding carbamate D in good
yield.2)
During these research efforts, we are most interested in
the construction of quaternary carbon stereocenter bear-
ing nitrogen substituent, because such a structural motif
has been found among many natural products (Fig. 1),
Key words: rearrangement; natural products; amino
acid; methylphenylalanine
Scheme 1. Synthesis of Allyl Carbamate by [3.3] Sigmatropic Rearrangement.
Fig. 1. Representative Natural Products and ꢀ-Alkyl Amino Acid Containing Quaternary Stereocenter with Nitrogen Substituent.
y
To whom correspondence should be addressed. Tel/Fax: +81-88-844-8292; E-mail: ichikawa@cc.kochi-u.ac.jp
Abbreviations: DPMPM, diphenyl(1-methylpyrrolidin-2-yl)methanol; Et2O, ether; KHSO4, potassium hydrogensulfate; NaHCO3, sodium
bicarbonate; MeOH, methanol; CH2Cl2, dichloromethane; EtOH, ethanol; KOH, potassium hydroxide

940
Y. ICHIKAWA et al.
for example, conagenin (1),3) manzacidine A (2),4) and
geranyllinaloisocyanide (3).5,6) In addition, stereoselec-
tive synthesis of nitrogen-substituted quatenary carbon
is one of the most challenging problems for synthetic
chemists.
optical purity. After repeated recrystallization from a
mixture of ether and hexane, the ee value of the resulting
carbamate 7 increased to 90%, as determined by alkaline
hydrolysis (KOH, EtOH, reflux, 3 h) of carbamate 7
followed by esterification of the resulting 6a with MTPA
chloride.
Results and Discussion
Having obtained enantiomerically enriched allyl
carbamate 7, we next focused our attention on the
stereoselectivity and stereochemistry of the rearrange-
ment (Scheme 3). Dehydration of 7 was carried out with
triphenylphosphine, carbon tetrabromide, and triethyl-
amine at 0 ꢀC for 20 min to provide allyl cyanate 8,
which immediately underwent [3.3] sigmatropic rear-
rangement to afford allyl isocyanate 9. Since isolation of
9 using an aqueous work-up is difficult due to hydrolysis
of the isocyanate group, the reaction mixture was treated
in situ with tributyltin methoxide in methanol. Methyl
carbamate 10 was isolated after work-up and chromato-
graphic purification in good yield (85%). In order to
check the level of stereoselectivity of the rearrangement,
allyl carbamate 10 was transformed into alcohol 12a.
Ozonolysis of 10 in dichloromethane at ꢁ78 ꢀC followed
In order to estimate the level of 1,3-chirality transfer
of allyl cyanate for the synthesis of quaternary stereo-
genic center bearing nitrogen, we set up the synthesis of
(R)-ꢀ-methylphenylalanine (4).7,8) The synthesis started
with the enantioselective addition of diethylzinc to the
ꢀ,ꢁ-unsaturated aldehyde 5 using diphenyl(1-methyl-
pyrrolidin-2-yl)methanol (DPMPM) as reported by Soai
(Scheme 2).9) Treatment of the aldehyde 5 with dieth-
ylzinc in the presence of a catalytic amount of (S)-
DPMPM (6 mol %) in cyclohexane at 5 ꢀC for 16 h
provided allyl alcohol 6a in 83% yield. The resulting
allyl alcohol 6a was transformed into the corresponding
(S)- and (R)-2-methoxy-2-phenyl-2-(trifluoromethyl)-
acetic acid (MTPA) esters 6b. The structure for 6a,
initially assigned based on the Soai empirical rule, was
confirmed by a modified Mosher (MTPA ester) analysis,
as represented in Fig. 2.10) Determination of enantio-
1
meric purity was performed by H NMR analysis of the
Mosher ester 6b to show that the enantiomeric excess
(ee) was moderate (80% ee).
Treatment of 6a with trichloroacetyl isocyanate in
dichloromethane at 0 ꢀC and subsequent hydrolysis with
potassium carbonate in aqueous methanol provided allyl
carbamate 7 in 92% yield. Fortunately, the highly
crystalline nature of carbamate 7 led to enhancement of
Fig. 2. Absolute Stereochemistry Determination: ꢀꢂ Values for the
Mosher Ester Derivative.
Scheme 2. Synthesis of Optically Active Allyl Carbamate by Enantioselective Addition of Diethylzinc.
Scheme 3. Stereoselective Construction of Quaternary Carbon Center Bearing Nitrogen Substituent.

Synthesis of Quaternary Stereocenter with Nitrogen Substituent
941
Scheme 4. Synthesis of (R)-ꢀ-Methylphenylalanine.
nuclear magnetic resonance (1H NMR) spectra were
recorded on a Bruker ARX-400 (400 MHz) or a Bruker
Avance E-400 (400 MHz) or a Varian Gemini-2000
(300 MHz) spectrometer. Chemical shifts (ꢂ) are report-
ed in parts per million (ppm) relative to tetramethyl-
silane (TMS, ꢂ 0.00, in CDCl3), benzene-d6 (ꢂ 7.15), t-
BuOH (ꢂ 1.24, in D2O), D2O (ꢂ 4.79) MeOH-d4 (ꢂ 3.34)
as internal standard. Coupling constants (J) are given in
Hz. Data are reported as follows: chemical shift,
integration, multiplicity (s, singlet; d, doublet; t, triplet;
q, quartet; qn, quintet; br, broadened; m, multiplet),
coupling constant, and assignment. Carbon nuclear
magnetic resonance (13C NMR) spectra were recorded
on a Bruker ARX-400 (100 MHz) or a Bruker Avance-
400 (100 MHz) spectrometer. Chemical shifts (ꢂ) are
reported in parts per million (ppm) relative to CDCl3 (ꢂ
77.0), t-BuOH (ꢂ 30.3, 70.1 in D2O) as internal standard.
Reactions were monitored by thin-layer chromatography
(TLC) carried out on 0.25 nm silica gel-coated glass
plates 60 F254 (Merck, Art 1.05715). Reactions were run
under an atmosphere of nitrogen when the reactions
were sensitive to moisture. Cica-Reagent Silica Gel 60
(particle size 0.063–0.2 nm, 70–230 mesh ASTM) was
used for open-column chromatography. Unless other-
wise noted, non aqueous reactions were carried out in
oven-dried (120 ꢀC) or flame-dried glassware under an
nitrogen atmosphere. CH2Cl2 was dried over molecular
Fig. 3. Concerted Six-membered Cyclic Transition State.
by reductive work-up with dimethyl sulfide gave rather
labile aldehyde 11, which was immediately reduced with
sodium borohydride to furnish the alchohol 12a. Trans-
formation of 12a into the corresponding (S)-MTPA ester
12b determined the ee value of 12a to be 84%, which
confirmed that [1.3] chirality transfer of allyl cyanate 8
was achieved with a high degree of selectivity (97%).
The stereochemistry of the quaternary carbon center
in 10 was finally determined by the transformation of
10 into (R)-ꢀ-methylphenylalanine 4, as represented
in Scheme 4. Ozonolysis of 10 followed by sodium
chlorite oxidation of the resulting aldehyde 11 afforded
an 87% yield of carboxylic acid 13. Finally, hydrolysis
of the methyl carbamate in 13 with 6 N hydrogen
chloride followed by ion-exchange chromatography
furnished (R)-ꢀ-methylphenylalanine (4) in 93% yield.7)
The optical rotation of 4 was measured, and the sign of
rotation clearly defined the stereogenic center of our
synthetic amino acid 4 to be the R configuration.
Figure 3 represents the six-membered cyclic transi-
tion state through which allyl cyanate-to-isocyanate
rearrangement might pass. The stereochemistry of the
newly formed stereogenic center in 9 is consistent with
the concerted six-membered cyclic transition state in
which the ethyl group adopts the pseudo-equatorial
position.
ꢁ
sieves 3 A. Triethylamine was dried over anhydrous
KOH. All other commercially available reagents were
used as received.
Allyl alcohol 6a. A solution of (S)-DPMPM (23 mg,
0.086 mmol) and aldehyde 5 (230 mg, 1.44 mmol) in
cyclohexane (5.0 ml) was refluxed for 30 min under a
nitrogen atmosphere and the mixture was cooled to 0 ꢀC.
A solution of diethylzinc (1.01 M, solution in hexane,
3.13 ml, 3.16 mmol) was slowly added. After stirring at
5 ꢀC for 16 h, the reaction mixture was poured into
water. The aqueous layer was extracted with Et2O. The
combined organic layers were washed with aqueous
KHSO4 (1.0 M), saturated aqueous NaHCO3, water, and
brine, and dried over Na2SO4. After concentration, the
resultant residue was purified by silica gel chromatog-
raphy (ethyl acetate/hexane, 1:10) to afford allyl alcohol
6a (226 mg, 1.19 mmol, 83%) as a light-yellow oil;
Conclusion
The present work opens an approach for the stereo-
selective installation of an amino group on the quater-
nary carbon. Further studies towards total synthesis of
natural products are now underway.
Experimental
26
General. Optical rotations were measured on a
JASCO DIP-370 digital polarimeter. Infrared spectra
were recorded on a JASCO FT/IR-8300 spectropho-
tometer and are reported in wave number (cmꢁ1). Proton
½ꢀꢂD ꢁ9:5 (c 0.76, CHCl3). IR (KBr) ꢃmax 3324, 3028,
1
1668 cmꢁ1. H NMR (CDCl3, 400 MHz), ꢂ 0.91 (3H, t,
J ¼ 7:0, CHCH2CH3), 1.42–1.69 (2H, m, CHCH2CH3),
1.62 (3H, s, CH=CCH3), 3.29 (1H, d, J ¼ 13:5, benzyl),

942
Y. ICHIKAWA et al.
3.33 (1H, d, J ¼ 13:5, benzyl), 4.31 (1H, dt, J ¼ 9:0,
7.0, C=CHCH), 5.28 (1H, dm, J ¼ 9:0, C=CH), 7.15–
7.33 (5H, m, Ar–H). 13C NMR (CDCl3, 400 MHz), ꢂ
9.75, 16.4, 30.6, 46.2, 70.1, 126.1, 128.3, 128.9, 129.6,
138.0, 139.6. Anal. Calcd for C13H18O: C, 82.06; H,
9.53. Found: C, 82.00; H, 9.77.
silica gel chromatography (ethyl acetate/hexane, 1:9) to
afford methyl carbamate 10 (70 mg, 0.28 mmol, 85%) as
27
a pale yellow oil; ½ꢀꢂD þ4:4 (c 0.84, CHCl3). IR (KBr)
ꢃmax 3422, 3340, 3030, 1717, 1507 cmꢁ1 1H NMR
.
(CDCl3, 300 MHz), ꢂ 0.97 (3H, t, J ¼ 7:5, CHCH2CH3),
1.37 (3H, s, CHCCH3), 2.05 (2H, dqd, J ¼ 7:5, 6.5, 1.5,
CH=CHCH2), 2.97 (1H, d, J ¼ 13:5, benzyl), 3.08 (1H,
d, J ¼ 13:5, benzyl), 3.65 (3H, s, OCH3), 4.59 (1H, brs,
NHCO), 5.45 (1H, dt, J ¼ 17:0, 6.5, CCH=CH), 5.59
(1H, d, J ¼ 17:0, CCH=CH), 7.07–7.31 (5H, m, Ar–H).
13C NMR (CDCl3, 400 MHz), 13.6, 25.4, 45.5, 51.6,
56.1, 77.8, 126.4, 127.9, 130.4, 130.8, 133.8, 137.2,
155.5. Anal. Calcd for C15H21NO2: C, 72.84; H, 8.56; N,
5.66. Found: C, 72.63; H, 8.73; N, 5.77.
Allyl carbamate 7. To a solution of allyl alcohol 6a
(211 mg, 1.11 mmol) in CH2Cl2 (7.0 ml) cooled to 0 ꢀC
was added Cl3CCONCO (265 ml, 2.22 mmol). After
stirring at 0 ꢀC for 10 min, the reaction mixture was
concentrated under reduced pressure and the resultant
residue was dissolved in MeOH (7.0 ml). To this
solution was added a solution of potassium carbonate
(1.23 g, 8.94 mmol) in water (3.0 ml) at 0 ꢀC. After
stirring at room temperature for 3 h, the mixture was
diluted with Et2O. The separated aqueous layer was
extracted with Et2O, and the combined organic layers
were washed with water, and brine, dried over Na2SO4,
and then concentrated under reduced pressure. The
resultant residue was purified by silica gel chromatog-
raphy (ethyl acetate/hexane = 1:7) to afford allyl
carbamate 7 (239 mg, 1.03 mmol, 92%) as a white solid
Transformation of 10 into (S)-MTPA ester 12b to
determine the ee value. Ozone was bubbled through a
solution of methyl carbamate 10 (11 mg, 0.045 mmol) in
CH2Cl2 (1 ml) with stirring at ꢁ78 ꢀC. The stirring was
continued until the solution turned a blue color. Ozone
addition was stopped and nitrogen was passed through
the solution. Dimethyl sulfide (40 ml, 0.55 mmol) was
added. After stirring at ꢁ78 ꢀC for 10 min, the solution
was concentrated under reduced pressure. The resultant
aldehyde 11 was dissolved in MeOH (2.0 ml), and
sodium borohydride (4.0 mg, 0.11 mmol) was slowly
added at 0 ꢀC. After stirring at 0 ꢀC for 30 min, the
mixture was diluted with Et2O and then poured into
water. The separated aqueous layer was extracted with
Et2O and the combined organic layers were washed with
water and brine, dried over Na2SO4, and concentrated
under reduced pressure. The resultant residue was
purified by silica gel chromatography (ethyl acetate/
hexane, 1:2) to afford alcohol 12a (7.7 mg, 0.035 mmol,
26
{½ꢀꢂD ꢁ18:1 (c 0.96, CHCl3)}. This carbamate was
further purified by recrystallization from a mixture of
Et2O and hexane to afford enantiomerically enriched
25
material 7 {½ꢀꢂD ꢁ25:4 (c 0.80, CHCl3)}; IR (KBr)
ꢃmax 3431, 3029, 1683 cmꢁ1 1H NMR (CDCl3, 300
.
MHz), ꢂ 0.89 (3H, t, J ¼ 8:0, CHCH2CH3), 1.48–1.77
(2H, m, CHCH2 CH3), 1.67 (3H, d, J ¼ 1:5, CH=
CCH3), 3.29 (1H, d, J ¼ 15:5, benzyl), 3.36 (1H, d,
J ¼ 15:5, benzyl), 4.56 (2H, brs, CONH2), 5.21 (1H,
ddt, J ¼ 9:0, 5.0, 1.0, C=CHCH), 5.34 (1H, dt, J ¼ 9:0,
7.0, C=CH), 7.14–7.32 (5H, m, Ar–H). 13C NMR
(CDCl3, 400 MHz), ꢂ 9.41, 16.7, 28.1, 46.1, 73.5,
125.5, 126.1, 128.3, 128.9, 139.4, 139.6, 156.6. Anal.
Calcd for C14H19NO2: C, 72.07; H, 8.21; N, 6.00.
Found: C, 72.05; H, 8.16; N, 5.73.
26
77%) as a colorless oil; ½ꢀꢂD þ56:3 (c 0.40, CHCl3).
IR (KBr) ꢃmax 3414, 3030, 1705 cmꢁ1
.
1H NMR
(CDCl3, 400 MHz), ꢂ 1.13 (3H, s, methyl), 2.85 (1H,
d, J ¼ 14:0, benzyl), 3.09 (1H, d, J ¼ 14:0, benzyl),
3.67 (3H, s, OCH3), 3.69 (2H, br, CCH2OH), 4.69 (1H,
brs, NHCO), 7.14–7.35 (5H, m, Ar–H). 13C NMR
(CDCl3, 400 MHz), 22.8, 41.7, 52.1, 57.3, 69.1, 126.7,
128.3, 130.5, 136.6, 156.9. HRMS (FAB) Calcd for
C12H18NO3 ½M þ Hꢂþ 224.1287, found 224.1293.
Methyl carbamate 10. Allyl carbamate 7 (77 mg,
0.33 mmol) and triphenylphosphine (264 mg, 1.01
mmol) were dissolved in toluene and concentrated
under reduced pressure. The resulting solid was dis-
solved in CH2Cl2 (5.0 ml), and triethylamine (270 ml,
1.94 mmol) was added. After cooling at 0 ꢀC under a
nitrogen atmosphere, carbon tetrabromide (325 mg,
0.98 mmol) in CH2Cl2 (3.0 ml) was added. After stirring
at 0 ꢀC for 20 min, tributyltin methoxide (100 ml,
0.35 mmol) in MeOH (3.0 ml) was added and stirring
was continued at room temperature for 12 h. The
reaction mixture was diluted with Et2O and washed
with KHSO4 (1.0 M), saturated NaHCO3, and water.
After concentration, the resultant residue was dissolved
in a solution of KF in acetonitrile (1.0 M, 5.0 ml). After
stirring for 1.0 h, the suspension was diluted with Et2O
and then filtered. The filtrate was washed with water and
brine, dried over Na2SO4, and concentrated under
reduced pressure. The resultant residue was purified by
A solution of alcohol 12a (7.7 mg, 0.035 mmol),
DMAP (10 mg, 0.082 mmol) and Et3N (50 ml, 0.36
mmol) in CH2Cl2 (2 ml) was cooled to 0 ꢀC, and (R)-
MTPA-Cl (40 ml, 0.21 mmol) was added. After stirring
at 0 ꢀC for 10 min, the mixture was diluted with Et2O,
and then poured into water. The separated aqueous layer
was extracted with Et2O and the combined organic
layers were washed with KHSO4 (1.0 M), saturated
aqueous NaHCO3, water, and brine, and dried over
Na2SO4. Concentration under reduced pressure gave the
crude (S)-MTPA ester 12b (18 mg). NMR analysis (1H,
400 MHz, benzene-d6) of the crude (S)-MTPA ester
determined the diastereomeric ratio to be 92:8. 1H NMR
(benzene-d6 400 MHz), ꢂ 0.82 (3H, s, methyl), 2.50 (1H,

Synthesis of Quaternary Stereocenter with Nitrogen Substituent
943
d, J ¼ 13:0, benzyl), 2.96 (1H, d, J ¼ 13:0, benzyl),
3.37 (3H, s, OCH3), 3.39 (3H, s, OCH3), 4.17 (1H, brs,
NHCO), 4.31 (1H, d, J ¼ 10:5, CH2OC), 4.53 (1H, d,
J ¼ 10:5, CH2OC), 6.89–7.11 (8H, m, Ar–H), 7.65 (2H,
d, J ¼ 8:5, Ar–H).
Ar–H), 7.33–7.42 (3H, m, Ar–H). 13C NMR (D2O,
400 MHz), ꢂ 23.0, 43.3, 62.8, 128.5, 129.6, 130.7, 134.9,
176.8. Anal. Calcd for C10H13NO2: C, 67.02; H, 7.31; N,
7.82. Found: C, 66.94; H, 7.52; N, 7.59.
Acknowledgments
Carboxylic acid 13. Ozone was passed though a
cooled (ꢁ78 ꢀC) solution of methyl carbamate 10
(57 mg, 0.23 mmol) in CH2Cl2 (4.0 ml) until the solution
turned blue. The reaction mixture was purged off excess
ozone employing a stream of nitrogen, and dimethyl
sulfide (200 ml, 2.72 mmol) was added. After stirring at
ꢁ78 ꢀC for 10 min, the solution was concentrated under
reduced pressure. The resultant residue of aldehyde 11
was used directly in the next step without purification.
The residue was dissolved in a mixture of t-butyl
alcohol and water (t-butyl alcohol/water, 5:1, 6.0 ml),
and 2-methyl-2-butene (1 drop), sodium dihydrogen-
phosphate dihydrate (220 mg, 1.41 mmol), and sodium
chlorite (61 mg, 0.66 mmol) were added. After stirring at
room temperature for 2 h, the mixture was diluted with
ethyl acetate, and 0.1 N HCl (10 ml) was added. The
aqueous layer was extracted with ethyl acetate, and the
combined organic layers were washed with brine, dried
over Na2SO4, and concentrated under reduced pressure.
The resultant residue was purified by silica gel chroma-
tography (ethyl acetate/hexane, 1:1, acetic acid, 1%) to
afford carboxylic acid 13 (48 mg, 0.20 mmol, 87%) as a
The authors are grateful for financial support from
MEXT Grant-in-Aid for Specially Promoted Research
(16002007).
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25
light-yellow oil; ½ꢀꢂD ꢁ32:9 (c 0.75, CHCl3). IR (KBr)
1
ꢃmax 3032, 1714 cmꢁ1. H NMR (CDCl3, 400 MHz), ꢂ
1.63 (3H, brs, methyl), 3.26 (1H, brd, J ¼ 13:5, benzyl),
3.35 (1H, brd, J ¼ 13:5, benzyl), 3.71 (3H, s, OCH3),
5.31 (1H, brs, NHCO), 7.10–7.14 (2H, brd, J ¼ 6:5,
Ar–H), 7.22–7.34 (3H, brm, Ar–H). 13C NMR (CDCl3,
400 MHz) ꢂ 23.5, 41.7, 52.2, 60.3, 127.1, 128.4, 130.1,
135.7, 155.8, 178.6. HRMS (FAB) Calcd for
C12H16NO4 ½M þ Hꢂþ 238.1079, found 238.1074.)
(R)-ꢀ-Methylphenylalanine 4. A solution of carboxyic
acid 13 (14 mg, 0.060 mmol) in 6 N HCl (3.0 ml) was
refluxed for 6 h, and the solution was concentrated under
reduced pressure. The residue was dissolved in water
and the solution was evaporated to dryness. The re-
sultant residue was purified by ion exchange chroma-
tography (Dowex 50W ꢃ 2, 100–200 mesh) to afford
(R)-ꢀ-methylphenylalanine 4 (10 mg, 0.056 mmol, 93%)
25
as a white powder; [½ꢀꢂD þ15:1 (c 0.45, H2O)), {lit.7a
17
27
½ꢀꢂD þ21:8 (c 0.73, H2O)}; ½ꢀꢂD þ2:3 (c 0.71, 1 N
HCl), {lit.7b ½ꢀꢂD þ4:2 (c 1, 1 N HCl)}. IR (KBr) ꢃmax
3421, 3033, 1617, cmꢁ1. H NMR (D2O, 400 MHz), ꢂ
1
1.53 (3H, s, methyl), 2.97 (1H, d, J ¼ 14:0, benzyl),
3.28 (1H, d, J ¼ 14:0, benzyl), 7.23–7.28 (2H, m,