Stereoselective Synthesis of the β-Amino Acid Moiety of Fijiolide A

Article abstract of DOI:10.1002/ejoc.201801623

An enantioselective synthesis of the β-amino acid moiety of fijiolide A is described. Starting from eugenol, two sulfamates could be obtained on gram scale as substrates for an enantioselective C–H amination using Rh₂(R/S-nap)₄. Acylation and ring opening of the resulting oxathiazinanes, followed by stepwise oxidation of the corresponding amino alcohol and TES-protection of the catechol gave rise to Cramer's amino acid fragment from the total synthesis of fijiolide A.

Full text of DOI:10.1002/ejoc.201801623

DOI: 10.1002/ejoc.201801623
Full Paper
Amino Acid Synthesis
Stereoselective Synthesis of the ꢀ-Amino Acid Moiety of
Fijiolide A
Timon Kurzawa,[a] Eric Kerste,[a] Paul Nikodemiak,[a] Daniel Bothe,[a] Klaus Harms,[a] and
Ulrich Koert*[a]
Abstract: An enantioselective synthesis of the ꢀ-amino acid ation and ring opening of the resulting oxathiazinanes, fol-
moiety of fijiolide A is described. Starting from eugenol, two lowed by stepwise oxidation of the corresponding amino alco-
sulfamates could be obtained on gram scale as substrates for hol and TES-protection of the catechol gave rise to Cramer's
an enantioselective C–H amination using Rh2(R/S-nap)4. Acyl- amino acid fragment from the total synthesis of fijiolide A.
Introduction
Here, a stereoselective synthesis of compound 3, the ꢀ-amino
acid moiety of fijiolide A is described starting from readily avail-
able eugenol.
C-1027 chromophore (1) and its cyclization derived counter-
parts fijiolide A and B (2) are highly bioactive compounds which
are furthermore intriguing due to their unique geometric com-
plexity. While the biological activity of 1 can be mainly attrib-
uted to the DNA-damaging abilities of a biradical intermediate
resulting via Bergmann-cyclization,[1] the fijiolides A and B were
found to be potent inhibitors of TNF-α-induced NFκB activa-
tion.[2] Structurally, they both consist of an enediyne (derived)
core, a glycosylated amino sugar and a 3′-chloro-5′-hydroxy-ꢀ-
tyrosine, while C-1027 also features a benzoxazinone moiety at
the diol ansa-bridge (Figure 1).
The stereoselective synthesis of ꢀ-amino acids is an inten-
sively studied area.[4] Previous synthetic work by Hirama[5] and
Cramer[6] relied on diastereomeric 1,4-addition of Davies lithium
amide to cinnamic acid ester 4 to yield 5 or asymmetric hyd-
rogenation of respective enamine 6 which was transformed
into amino acid 3 (Scheme 1). Our synthetic plan for amino acid
3 is based on oxidative ring opening of oxathiazinane 9, which
could be obtained by enantioselective C–H amination of sulf-
Figure 1. The C-1027 chromophore, the fijiolides and their ꢀ-tyrosine unit.
A stereoselective route to the benzodihydropentalene core
of the fijiolides was published recently from this laboratory.[3]
[a] Fachbereich Chemie, Philipps-Universität Marburg,
35032 Marburg, Hans-Meerwein Strasse 4, D
E-mail: koert@chemie.uni-marburg.de
https://www.uni-marburg.de/fb15/ag-koert
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201801623.
Scheme 1. Previous synthetic strategies and present approach.
1 © 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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amate 8. Sulfamate 8 itself origins from eugenol (7) via chlorin-
Table 1. Optimization of the enantioselective nitrene insertion.
ation, hydroboration and subsequent sulfamoylation.
Results and Discussion
Synthesis of the sulfamate started with oxychlorination of
eugenol (7), following a procedure of Gusevskaya.[7] For the
purpose of orthogonal protection of the amino acids' catechol,
the remaining phenol was TBS-protected to yield 10a. Subse-
quent hydroboration with oxidative work up gave the corre-
sponding alcohol, which was sulfamoylated with in situ formed
sulfamoyl chloride[8] 11 to furnish sulfamate 12a in 49 % yield
on gram-scale starting from eugenol (7). Cramer's synthesis of
fijiolide A (2a) demonstrated that the best atropselectivities in
the cyclophane formation were obtained with the unprotected
catechol.[6] Therefore a second methyl ether was installed onto
the chlorinated eugenol for simultaneous catechol deprotec-
tion. Analogous transformations 7 → 12b yielded methylated
sulfamate 12b in 52 % overall yield starting from 7 (Scheme 2).
Entry
Catalyst
Oxidating
agent
Additive
Yield[a]
(ee)[b] [%]
12a → 13a
1[c]
2[c]
3[c]
4[d]
5[d]
6[c]
7[d]
8[c]
A
PhI(OPiv)2
PhI(OPiv)2
PhI(OPiv)2
PhI(OPiv)2
PhIO
PhIO
PhIO
PhIO
MgO
MgO
90
B
B
B
C
B
B
B
82 (44,R)
98 (37,R)
99 (53,R)
77 (12,S)
37 (82,R)
30 (87,R)
66 (84,R)
MgO, 4 Å MS
MgO, 4 Å MS
MgO, 4 Å MS
MgO, 4 Å MS
MgO, 4 Å MS
MgO, 3 Å MS
(powdered)
MgO, 3 Å MS
(powdered)
9[d]
B
PhIO
45 (79,R)
12b → 13b
10[c]
11[c]
A
B
PhI(OPiv)2
PhIO
MgO
99
62 (81,R)
MgO, 3 Å MS
(powdered)
MgO, 3 Å MS
(powdered)
MgO, 3 Å MS
(powdered)
MgO, 3 Å MS
(powdered)
12[c,e]
13[c]
B
B
D
PhIO
14
60 (88,R)
0
14[c,e]
PhIO
63 (87,S)
52 (> 99,S)[f]
Scheme 2. Synthesis of sulfamates 12a and 12b from eugenol (7). a)
CuCl2·2H2O, LiCl, O2, AcOH, 80 °C, 6 h, 85 %; b) R = TBS: TBSCl, NEt3, DMAP,
CH2Cl2, 0 °C → r.t., 12 h, 97 %; R = Me: NaH, MeI, DMF, 0 °C → r.t., 12 h, 99 %;
c) R = TBS, 10a: i) BH3·SMe2, THF, 0 °C → r.t., ii) NaOH, H2O2, 0 °C → r.t., 2 h,
74 %; R = Me, 10b: i) 9-BBN, THF, 0 °C → r.t., 1 h, ii) NaOH, H2O2, 0 °C → r.t.,
2 h, 87 %; d) 11, py, CH2Cl2, 0 °C → r.t., 12 h, R = TBS, 12a: 80 %; R = Me,
12b: 70 %.
[a] Isolated yields. [b] ee was determined by HPLC. [c] Reaction performed in
CH2Cl2. [d] Reaction performed in benzene; reactions were performed at
25 °C, except. [e] Reaction was performed at 0 °C. [f] After recrystalliza-
tion from CH3Cl; catalyst A: Rh2(esp)2; B: Rh2(S-nap)4; C: Rh2(S-dosp)4;
D: Rh2(R-nap)4.
The crystal structure[10] of oxathiazinane 13b (Figure 2) re-
vealed the (R)-enantiomer had been formed which is in contrast
to the original paper by Du Bois.[9c] The prediction of enantio-
selective C–H aminations using Rh2(S-nap)4 has already been
observed and corrected by others.[11] The respective (S)-
enantiomer could be obtained in similar yield and enantioselec-
tivity by employing Rh2(R-nap)4.
The transition metal-catalyzed C–H amination is a powerful
method to convert ubiquitous C–H bonds into valuable C-N
bonds.[9a] In particular, Du Bois' contributions using carbamates
and sulfamates as nitrene sources for intramolecular C–H amin-
ations have received considerable attention.[9b]
With sulfamate 12a in hand, the rhodium-catalyzed
C–H amination using Rh2(esp)2 gave racemic oxathiazinane 13a
in 90 % yield (Table 1, entry 1). Using Rh2(S-nap)4,[9c] 13a was
obtained in 82 % with 44 % ee (entry 2). Addition of molecular
sieves increased the yield but did not improve the enantioselec-
tivity (entry 3). Using benzene as solvent slightly enhanced the
ee to 53 % (entry 4). Rh2(S-dosp)4 showed only poor enantio-
induction with 12 % in favor of the opposite enantiomer (entry
5). Since it was hypothesized that the carboxylate moieties re-
leased from the oxidation agent undertook a ligand exchange
with the catalyst, iodosobenzene was employed for activation
of the substrate, which gave 13a in 37 % yield with 82 % ee in
CH2Cl2 and 87 % ee in benzene (entries 6 and 7). By shortening
the reaction time to 2 h and using powdered 3 Å molecular
Figure 2. Crystal structures of oxathiazinanes (S)- and (R)-13b.
For sulfamate 12b using optimized reaction conditions gave
sieves the yield of 13a could be increased to 66 % without a oxathiazinane 13b in 62 % yield with 81 % ee (entry 11); by
significant loss of enantioselectivity (entries 8 and 9).
decreasing the temperature to 0 °C (R)-13b could be obtained
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Other solvents were distilled by rotary evaporation prior to use. 1H-
NMR spectra were recorded at 300 or 500 MHz, 13C-NMR at 75 or
125 MHz, the solvent residue signals were used as internal standard
and all spectra are reported in ppm. Mass spectra were recorded
with a LTQ-FT or AccuTOF-GCv mass spectrometer. Melting points
were recorded with a Mettler Toledo MP70 by using one side open
capillary tubes. More details regarding experimental procedures are
specified in the Supporting Information.
in 60 % yield with 88 % ee (entry 12). Application of soluble
iodine(III) oxidation agent 14 gave no conversion at all (en-
try 13). Performing the reaction under optimized conditions
with Rh2(R-nap)4 gave (S)-13b in similar yield and enantioselec-
tivity which could be further increased to 99 % ee by recrystalli-
zation from CHCl3 (entry 14). The formation of both (R) and (S)-
13b could be secured via X-ray crystallography (Figure 2).[11]
With a solution found for the asymmetric C–H amination the
conversion of the oxathiazinane into the amino acid was inves-
tigated next. Acetylation of 13b with acetyl chloride under care-
ful adjustment of reaction conditions to prevent deacetylation
during the ring opening lead to amino acid 16 in 70 % yield
over 2 steps. Employing acetic anhydride as acylation agent
resulted in ring opening without acylation, which could prove
useful for synthesis of the amino acid moiety of C-1027. Analo-
gous to Cramer's strategy in their synthesis of fijiolide A depro-
tection of 16 using AlBr3/EtSH followed by double TES-protec-
tion yielded the desired amino acid 3 with 61 % yield over two
steps (Scheme 3).
(4-Allyl-2-chloro-6-methoxyphenoxy)(tert-butyl)dimethylsilane
(10a): Under Ar-atmosphere 6-chloroeugenol (17, 4.88 g,
24.6 mmol, 1.00 equiv.) was dissolved in CH2Cl2 (100 mL). At 0 °C
DMAP (1.50 g, 12.3 mmol, 0.50 equiv.), NEt3 (4.26 mL, 31.9 mmol,
1.30 equiv.) and TBSCl (4.42 g, 29.5 mmol, 1.20 equiv.) were added
and the mixture was stirred at r.t. for 4 h. The reaction mixture was
diluted with CH2Cl2 (100 mL), washed with H2O (50 mL), brine
(50 mL) and dried with Na2SO4. All volatiles were removed in vacuo.
After column chromatography (n-pentane/EtOAc, 40:1) TBS-pro-
tected chloroeugenol 10a (7.43 g, 23.7 mmol, 97 %) was obtained
as colorless oil.
TLC: Rf = 0.65 (n-pentane/EtOAc, 40:1). 1H-NMR: 300 MHz, CDCl3;
δ = 0.19 (s, 6 H, TBS), 1.04 (s, 9 H, TBS), 3.29 (d, J = 6.7 Hz, 2 H, 1-
H), 3.78 (s, 3 H, OMe), 5.04–5.13 (m, 2 H, 3-H), 5.93 (ddt, J = 6.7, 9.6,
17.4 Hz, 1 H, 2-H), 6.56 (d, J = 2.0 Hz, 1 H, Ar), 6.77 (d, J = 2.0 Hz,
1 H, Ar) ppm. 13C-NMR: 75 MHz, CDCl3; δ = –4.0 (TBS), 19.0 (TBS),
26.1 (TBS), 39.8 (C1), 55.5 (OMe), 110.7 (Ar), 116.4 (C3), 122.0 (Ar),
125.7 (Ar), 133.4 (Ar), 137.1 (C2), 140.1 (Ar), 151.5 (Ar) ppm. HR-MS:
(ESI+): m/z calc. for C16H25ClO2Na [M – Na]+ 564.1244, found
564.1249. FT-IR: (neat): ν = 2937 (w), 1598 (w), 1572 (m), 1490 (s),
˜
1461 (w), 1415 (m), 1273 (m), 1235 (m), 1181 (w), 1140 (m), 1051
(s), 1001 (s), 968 (w), 913 (m), 837 (m), 778 (m), 686 (m), 598 (w),
3078 (w), 3002 (w), 2830 (w), 1639 (w) cm–1
.
3-{4′-[(tert-Butyldimethylsilyl)oxy]-3′-chloro-5′-methoxy-
phenyl}propanol (18): Under Ar-atmosphere olefin 10a (7.43 g,
23.7 mmol, 1.00 equiv.) was dissolved in THF (120 mL). At 0 °C
BH3·SMe2 (2.25 mL, 23.7 mmol, 1.00 equiv.) was added, the mixture
was stirred at this temperature for 10 min and at r.t. for 1 h. Aq.
NaOH (8.20 mL, 35.6 mmol, 15wt.-%, 1.50 equiv.) and aq. H2O2
(4.90 mL, 47.4 mmol, 30 %, 2.00 equiv.) were added at 0 °C and the
reaction mixture was stirred for 2 h at r.t. The reaction was
quenched with brine (100 mL), extracted with Et2O (3 × 50 mL),
dried with MgSO4 and concentrated in vacuo. After column chroma-
tography (n-pentane/EtOAc, 1:1) the alcohol (5.82 g, 17.6 mmol,
74 %) was obtained as colorless oil.
Scheme 3. Conversion of oxathiazinane 13b into amino acid 16 and synthesis
of amino acid building block 3. a) KOtBu, AcCl, THF, r.t., 8 h, 74 %; b) i) MeCN/
H2O, 50 °C, 4 h; ii) TEMPO, NaOCl, NaClO2, 35 °C, 16 h, 64 %; c) AlBr3, EtSH,
0 °C → r.t., 24 h; d) TESCl, NEt3, DMAP, DMF, r.t., 8 h, 61 %, 2 steps.
Conclusions
In summary, a stereoselective synthesis of the ꢀ-amino acid
moiety of the fijiolides was achieved. The stereocenter was con-
trolled via Du Bois' asymmetric C–H amination of a sulfamate
using Rh2(S-nap)4 and Rh2(R-nap)4 respectively. Ring opening
of the resulting oxathiazinane led to the target ꢀ-amino acid
substructure in protected form that corresponds to Cramer's
intermediate. In combination with earlier synthesis of the di-
hydrobenzopentalene core[3] this work paves the way for a total
synthesis of the fijiolides and structurally related natural prod-
ucts.
TLC: Rf = 0.65 (EtOAc). 1H-NMR: 300 MHz, CDCl3; δ = 0.18 (s, 6 H,
TBS), 1.03 (s, 9 H, TBS), 1.71 (s, 1 H, OH), 1.84 (dt, J = 6.4, 13.5 Hz,
2 H, 2-H), 2.60 (dd, J = 6.8, 8.6 Hz, 2 H, 3-H), 3.65 (t, J = 6.4 Hz, 2 H,
1-H), 3.77 (s, 3 H, OMe), 6.58 (d, J = 2.0 Hz, 1 H, Ar), 6.77 (d, J =
2.0 Hz, 1 H, Ar) ppm. 13C-NMR: 75 MHz, CDCl3; δ = –4.0 (TBS), 19.1
(TBS), 26.1 (TBS), 31.8 (C2), 34.2 (C3), 55.5 (OMe), 62.2 (C1), 110.6
(Ar), 121.7 (Ar), 125.7 (Ar), 135.1 (Ar), 139.9 (Ar), 151.5 (Ar) ppm.
Experimental Section
General Methods: All nonaqueous reactions were carried out by
using Schlenk technique with freshly dried and distilled solvents.
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HR-MS: (ESI+): m/z calc. for C16H28ClO3Si [M – H]+ 331.1491, found 14.3 Hz, 1 H, 5-HA), 2.22 (dtd, J = 5.0, 12.4, 14.3 Hz, 1 H, 5-HB), 3.82
331.1502. FT-IR: (neat): ν = 3337 (w), 2931 (m), 2885 (w), 2857 (w),
(s, 3 H, OMe), 4.39 (d, J = 9.6 Hz, 1 H, NH), 4.64 (ddd, J = 1.7, 5.0,
11.7 Hz, 1 H, 6-HA), 4.75 (ddd, J = 2.5, 9.0, 12.4 Hz, 1 H, 4-H), 4.85
(dd, J = 2.3, 11.7 Hz, 1 H, 6-HB), 6.78 (d, J = 2.2 Hz, 1 H, Ar), 6.91 (d,
J = 2.2 Hz, 1 H, Ar) ppm. 13C-NMR: 75 MHz, CDCl3; δ = –3.9 (TBS),
19.0 (TBS), 26.0 (TBS), 30.1 (C5), 55.7 (OMe), 58.6 (C4), 71.9 (C6),
108.6 (Ar), 119.7 (Ar), 126.2 (Ar), 131.1 (Ar), 142.4 (Ar), 152.1 (Ar)
ppm. HR-MS: (ESI+): m/z calc. for C24H32ClNO7SSiNa [M – Na]+
˜
1571 (w), 1495 (s), 1466 (w), 1415 (w), 1391 (w), 1361 (w), 1321 (w),
1249 (s), 1187 (w), 1149 (m), 1055 (s), 1010 (w), 906 (s), 837 (s), 804
(w), 782 (m), 738 (w), 695 (w), 660 (w), 600 (w) cm–1
.
3-{4′-[(tert-Butyldimethylsilyl)oxy]-3′-chloro-5′-methoxy-
phenyl}propyl sulfamate (12a): Under Ar-atmosphere formic acid
(0.99 mL, 26.4 mmol, 1.50 equiv.) was added dropwise to neat
chlorosulfonyl isocyanate (2.29 mL, 26.4 mmol, 1.50 equiv.) at 0 °C.
After 5 min of vigorous stirring, CH2Cl2 (15 mL) was added and the
mixture was stirred at 0 °C for 1 h and at r.t. for 8 h. At 0 °C the
alcohol (5.82 g, 17.6 mmol, 1.00 equiv.) and pyridine (2.13 mL,
26.4 mmol, 1.50 equiv.) in CH2Cl2 (15 mL) were added dropwise.
The reaction mixture was slowly warmed to r.t. and stirred for 12 h.
The mixture was diluted with EtOAc (60 mL), quenched with H2O
(60 mL) and the layers were separated. The aq. layer was extracted
with EtOAc (2 × 30 mL) and the combined org. layers were washed
with brine (2 × 20 mL), dried with MgSO4 and concentrated under
reduced pressure. After column chromatography (n-pentane/EtOAc,
2:1) sulfamate 12a (5.80 g, 14.2 mmol, 80 %) was isolated as color-
less solid.
564.1249, found 564.1248. FT-IR: (neat): ν = 3262 (w), 2931 (w), 2896
˜
(w), 2857 (w), 1573 (w), 1500 (m), 1467 (w), 1420 (w), 1360 (w), 1333
(w), 1306 (w), 1251 (m), 1188 (s), 1155 (w), 1055 (m), 1022 (w), 988
(w), 909 (w), 884 (w), 870 (w), 840 (m), 782 (s), 742 (w), 714 (w), 742
(w), 714 (w), 681 (w), 600 (w), 579 (w) cm–1. m.p.: 169 °C (EtOAc).
HPLC: (Chiralpac IC, n-hexane/EtOAc, 9:1, 0.7 mL/min, 254 nm)
tR(major) = 31.1 min, tR(minor) = 21.9 min. [α]2D3 : –7.3 (c 0.5, EtOAc,
for a sample with 84 %ee).
rac-Benzyl-4-{4′-[(tert-butyldimethylsilyl)oxy]-3′-chloro-5′-meth-
oxy-phenyl}-1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide
(19): Under Ar-atmosphere oxathiazinane 13a (36.7 mg, 90.0 μmol,
1.00 equiv.) was dissolved in THF (1.5 mL). KOtBu (15.1 mg,
135 μmol, 1.50 equiv.) was added and the mixture was stirred at r.t.
for 1.5 h. Benzyl chloroformate (32.0 μL, 225 μmol. 2.50 equiv.) was
added and the mixture was stirred at r.t. for 12 h. H2O (3 mL) was
added to quench the reaction, it was extracted with EtOAc (3 ×
2 mL), washed with brine (2 mL), dried with MgSO4 and filtered.
All volatiles were removed under reduced pressure. After column
chromatography (n-pentane/CH2Cl2, 1:1) Cbz-N-protected oxathiazi-
nane (45.0 mg, 83.0 μmol, 92 %) was isolated as colorless oil.
TLC: Rf = 0.48 (n-pentane/EtOAc, 1:1). 1H-NMR: 300 MHz, CDCl3;
δ = 0.18 (s, 6 H, TBS), 1.02 (s, 9 H, TBS), 2.01 (ddt, J = 4.9, 7.3, 8.4 Hz,
2 H, 2-H), 2.63 (dd, J = 6.7, 8.4 Hz, 2 H, 3-H), 3.78 (s, 3 H, OMe), 4.18
(t, J = 6.2 Hz, 2 H, 1-H), 6.58 (s, 1 H, Ar), 6.76 (s, 1 H, Ar) ppm. 13C-
NMR: 75 MHz, CDCl3; δ = –4.0 (TBS), 19.0 (TBS), 26.0 (TBS), 30.4 (C2),
31.1 (C3), 55.5 (OMe), 70.4 (C1), 110.8 (Ar), 121.6 (Ar), 125.7 (Ar),
133.7 (Ar), 140.1 (Ar), 151.5 (Ar) ppm. HR-MS: (ESI+): m/z calc. for
C
16H28ClNO5SSiNa [M – Na]+ 432.1038, found 432.1049. FT-IR: (neat):
ν = 3282 (w), 2931 (m), 2895 (w), 2857 (w), 1570 (w), 1495 (s), 1466
˜
TLC: Rf = 0.10 (n-pentane/CH2Cl2, 1:1). 1H-NMR: 300 MHz, CDCl3; δ =
0.19 (s, 6 H, TBS), 1.03 (s, 9 H, TBS), 2.40 (dddd, J = 2.3, 3.5, 6.2,
14.7 Hz, 1 H, 5-HA), 2.90 (dddd, J = 4.9, 7.4, 10.8, 14.7 Hz, 1 H, 5-HB),
3.71 (s, 3 H, OMe), 4.46 (td, J = 6.2, 10.8 Hz, 1 H, 6-HA), 4.70 (ddd,
J = 2.3, 7.4, 10.8 Hz, 1 H, 6-HB), 5.32 (s, 2 H, Cbz), 5.64 (t, J = 5.6 Hz,
1 H, 4-H), 6.78 (d, J = 2.2 Hz, 1 H, Ar), 6.91 (dd, J = 0.7, 2.2 Hz, 1 H,
Ar), 7.31–7.38 (m, 5 H, Ph) ppm. 13C-NMR: 75 MHz, CDCl3; δ = –3.9
(TBS), 19.0 (TBS), 26.0 (TBS), 28.5 (C5), 55.5 (OMe), 60.4 (ArCN), 69.8
(C4), 70.1 (C6), 107.8 (Ar), 119.1 (Ar), 126.3 (Ar), 128.0 (Ph), 128.7
(Ph), 128.8 (Ph), 130. 9 (Ar), 134.8 (Ph), 151.8 (Ar), 152.2 (NCO2) ppm.
HR-MS: (ESI+): m/z calc. for C24H32ClNO7SSiNa [M – Na]+ 564.1249,
(w), 1416 (w), 1360 (m), 1324 (w), 1272 (w), 1249 (s), 1179 (s), 1149
(w), 1054 (m), 1010 (w), 905 (m), 836 (m), 804 (w), 781 (s), 740 (w),
694 (w), 662 (w), 593 (w), 662 (w) cm–1. m.p.: 46 °C (EtOAc).
(R)-4-{4′-[(tert-Butyldimethylsilyl)oxy]-3′-chloro-5′-methoxy-
phenyl}-1,2,3-oxathiazinane 2,2-dioxide (13a): Under Ar-atmos-
phere sulfamate 12a (96.3 mg, 235 μmol, 1.00 equiv.), MgO
(19.0 mg, 470 μmol, 2.00 equiv.), 3 Å molecular sieves (40.0 mg)
and Rh2(S-nap)4 (6.00 mg, 4.70 μmol, 0.02 equiv.) were dissolved in
CH2Cl2 (1 mL). Iodosobenzene (67.2 mg, 306 μmol, 1.30 equiv.) was
added and the mixture was stirred at r.t. for 2 h. CH2Cl2 (3 mL) was
added and the reaction mixture was filtered through a pad of Celite.
The crude product was concentrated in vacuo. After column chro-
matography (n-pentane/EtOAc, 4:1) oxathiazinane 13a (63.2 mg,
155 μmol, 66 %, 84 % ee) was isolated as colorless solid.
found 564.1248. FT-IR: (neat): ν = 3246 (s), 2943 (s), 2836 (m), 1601
˜
(m), 1576 (s), 1496 (s), 1461 (s), 1423 (s), 1362 (m), 1305 (m), 1286
(m), 1241 (s), 1187 (s), 1147 (s), 1053 (m), 1023 (m), 993 (s), 922 (s),
871 (w), 785 (w), 618 (w), 573 (w), 549 (w), 522 (w) cm–1. The
Cbz-protected oxathiazinane was synthesized using racemic oxa-
thiazinane 13a, therefore no measurement of optical rotation was
performed.
5-Allyl-1-chloro-2,3-dimethoxybenzene (10b): Under Ar-atmos-
phere 6-chloroeugenol (1.05 g, 5.28 mmol, 1.00 equiv.) was dis-
solved in DMF (100 mL). At 0 °C NaH (290 mg, 6.34 mmol,
1.20 equiv.) was added. After 15 min MeI (1.50 mL, 21.1 mmol,
4.00 equiv.) was added and the mixture was stirred at r.t. for 16 h.
The reaction was quenched with H2O (150 mL) and extracted with
cyclohexane (3 × 40 mL), dried with Na2SO4, filtered and concen-
TLC: Rf = 0.33 (n-pentane/EtOAc, 4:1). 1H-NMR: 300 MHz, CDCl3;
δ = 0.19 (s, 6 H, TBS), 1.02 (s, 9 H, TBS), 1.99 (ddd, J = 2.3, 4.2,
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trated in vacuo. After column chromatography (n-pentane/EtOAc, separated. The aq. layer was extracted with EtOAc (3 × 50 mL) and
8:1) 5-allyl chloro-2,3-dimethoxybenzene 10b (1.12 g, 5.26 mmol,
99 %) was isolated as colorless oil.
the combined org. layers were washed with brine (2 × 20 mL), dried
with MgSO4 and concentrated under reduced pressure. After col-
umn chromatography (n-pentane/EtOAc, 2:1) sulfamate 12b (1.65 g,
5.40 mmol, 70 %) was isolated as colorless oil.
TLC: Rf = 0.55 (n-pentane/EtOAc, 8:1). 1H-NMR: 300 MHz, CDCl3;
δ = 3.31 (dd, J = 1.4, 6.8 Hz, 2 H, 1-H), 3.84 (s, 3 H, OMe), 3.86 (s,
3 H, OMe), 5.07–5.14 (m, 2 H, 3-H), 5.92 (ddt, J = 6.8, 9.6, 17.4 Hz,
1 H, 2-H), 6.63 (d, J = 1.9 Hz, 1 H, Ar), 6.81 (d, J = 1.9 Hz, 1 H, Ar)
ppm. 13C-NMR: 75 MHz, CDCl3; δ = 39.9 (C1), 56.2 (OMe), 60.8 (OMe),
111.6 (Ar), 116.6 (C3), 121.9 (Ar), 128.2 (Ar), 136.7 (C2), 143.9 (Ar),
153.8 (Ar) ppm. HR-MS: (ESI+): m/z calc. for C11H13ClO2Na [M – Na]+
TLC: Rf = 0.33 (n-pentane/EtOAc, 2:1). 1H-NMR: 300 MHz, CDCl3;
δ = 2.00–2.09 (m, 2 H, 2-H), 2.68 (t, J = 7.5 Hz, 2 H, 3-H), 3.85 (s,
3 H, OMe), 3.86 (s, 3 H, OMe), 4.21 (t, J = 6.2 Hz, 2 H, 1-H), 4.74 (sbr,
1 H, NH), 6.65 (d, J = 1.8 Hz, 1 H, Ar), 6.80 (d, J = 1.8 Hz, 1 H, Ar)
ppm. 13C-NMR: 75 MHz, CDCl3; δ = 30.4 (C2), 31.4 (C3), 56.3 (OMe),
60.8 (OMe), 70.4 (C1), 111.7 (Ar), 121.7 (Ar), 128.3 (Ar), 137.2 (Ar),
144.1 (Ar), 154.0 (Ar) ppm. HR-MS: (ESI+): m/z calc. for
C11H16ClNO5SNa [M – Na]+ 332.0330, found 332.0333. FT-IR: (neat):
235.0496, found 235.0497. FT-IR: (neat): ν = 3078 (w), 3001 (w), 2934
˜
(w), 2832 (w), 1681 (w), 1639 (w), 1598 (w), 1572 (m), 1490 (s), 1459
(w), 1415 (m), 1273 (m), 1235 (m), 1182 (w), 1140 (m), 1051 (s), 1001
(m), 968 (w), 913 (m), 837 (m), 777 (w), 745 (w), 686 (w), 598 (w),
548 (w) cm–1
.
ν = 3361 (w), 3270 (w), 3106 (w), 2940 (w), 1599 (w), 1572 (m), 1492
˜
3-(3′-Chloro-4′,5′-dimethoxyphenyl) propanol (20): Under Ar-at-
mosphere 5-allyl-1-chloro-2,3-dimethoxybenzene (10b) (1.12 g,
5.27 mmol, 1.00 equiv.) was dissolved in THF (20 mL). At 0 °C 9-BBN
(m), 1459 (w), 1416 (w), 1360 (s), 1309 (w), 1277 (w), 1234 (w), 1176
(s), 1141 (m), 1083 (w), 1048 (m), 996 (w), 927 (s), 818 (m), 777 (w),
734 (w), 657 (w), 590 (w), 552 (s) cm–1. m.p.: 66 °C (EtOAc).
(11.1 mL, 5.53 mmol, 0.5
M in THF, 1.05 equiv.) was added and the
mixture was stirred at 0 °C for 10 min and at r.t. for 1 h. 15 % aq.
NaOH (1.80 mL, 7.90 mmol, 1.50 equiv.) and aq. H2O2 (1.08 mL,
10.5 mmol, 30 %, 2.00 equiv.) were added at 0 °C and the reaction
mixture was stirred at r.t. for 2 h. The reaction was quenched with
brine (40 mL), extracted with Et2O (3 × 20 mL), dried with MgSO4,
filtered and concentrated in vacuo. After column chromatography
(n-pentane/EtOAc, 1:1) the respective alcohol (1.05 g, 4.56 mmol,
87 %) was obtained as colorless oil.
(R)-4-(3′-Chloro-4′,5′-dimethoxyphenyl)-1,2,3-oxathi-
azinane 2,2-dioxide (R-13b): Under Ar-atmosphere sulfamate 12b
(200 mg, 646 μmol, 1.00 equiv.), MgO (52.1 mg, 1.29 mmol,
2.00 equiv.), 3 Å molecular sieves (120 mg) and Rh2(S-nap)4
(16.5 mg, 12.9 μmol, 0.02 equiv.) were dissolved in CH2Cl2 (5 mL).
Iodosobenzene (156 mg, 710 μmol, 1.10 equiv.) was added and the
mixture was stirred at 0 °C for 3 h. CH2Cl2 (10 mL) was added and
the reaction mixture was filtered through a pad of Celite. The crude
product was concentrated in vacuo. After column chromatography
(n-pentane/EtOAc, 2:1) oxathiazinane (R)-13b (119 mg, 387 μmol,
60 %, 88 % ee) was isolated as colorless solid.
TLC: Rf = 0.30 (EtOAc). 1H-NMR: 300 MHz, CDCl3; δ = 1.82–1.91 (m,
2 H, 2-H), 2.65 (dd, J = 6.7, 8.7 Hz, 2 H, 3-H), 3.67 (t, J = 6.4 Hz, 2 H,
1-H), 3.85 (s, 3 H, OMe), 3.86 (s, 3 H, OMe), 6.58 (d, J = 2.0 Hz, 1 H,
Ar), 6.77 (d, J = 2.0 Hz, 1 H, Ar) ppm. 13C-NMR: 75 MHz, CDCl3; δ =
31.0 (C2), 34.1 (C3), 56.3 (OMe), 60.8 (OMe), 62.2 (C1), 111.5 (Ar),
121.7 (Ar), 128.2 (Ar), 138.6 (Ar), 143.8 (Ar), 153.8 (Ar) ppm. HR-MS:
(ESI+): m/z calc. for C11H15ClO3Na [M – Na]+ 253.0602, found
TLC: Rf = 0.28 (n-pentane/EtOAc, 2:1). 1H-NMR: 300 MHz, CDCl3;
δ = 2.02 (ddd, J = 2.3, 2.5, 14.4 Hz, 1 H, 5-HA), 2.22 (ddt, J = 5.0,
12.5, 14.4 Hz, 1 H, 5-HB), 3.86 (s, 3 H, OMe), 3.88 (s, 3 H, OMe), 4.40
(d, J = 9.3 Hz, 1 H, NH), 4.66 (ddd, J = 1.7, 5.0, 11.7 Hz, 1 H, 6-HA),
4.78 (ddd, J = 2.5, 9.3, 12.5 Hz, 1 H, 4-H), 4.85 (dd, J = 2.3, 11.7 Hz,
1 H, 6-HB), 6.82 (d, J = 2.0 Hz, 1 H, Ar), 6.93 (d, J = 2.0 Hz, 1 H, Ar)
ppm. 13C-NMR: 75 MHz, CDCl3; δ = 29.9 (C5), 56.4 (OMe), 58.3 (C4),
60.9 (OMe), 71.8 (C6), 109.5 (Ar), 119.6 (Ar), 128.8 (Ar), 134.6 (Ar),
145.7 (Ar), 154.3 (Ar) ppm. HR-MS: (ESI+): m/z calc. for
C11H14ClNO5SNa [M – Na]+ 330.0173, found 330.0171. FT-IR: (neat):
253.0603. FT-IR: (neat): ν = 3387 (w), 3054 (w), 2939 (w), 2877 (w),
˜
1599 (w), 1572 (m), 1491 (m), 1457 (w), 1414 (m), 1307 (w), 1270
(m), 1234 (m), 1183 (w), 1141 (m), 1049 (s), 1001 (m), 963 (w), 916
(w), 852 (m), 774 (w), 733 (s), 702 (w), 655 (w), 610 (w), 573 (w), 512
(w), 472 (w) cm–1
.
3-(3′-Chloro-4′,5′-dimethoxyphenyl) propyl sulfamate (12b): Un-
der Ar-atmosphere formic acid (0.75 mL, 19.8 mmol, 2.50 equiv.)
was added dropwise to neat chlorosulfonyl isocyanate (1.72 mL,
19.8 mmol, 2.50 equiv.) at 0 °C. After 5 min of vigorous stirring,
CH2Cl2 (8 mL) was added and the mixture was stirred at 0 °C for
ν = 3246 (w), 2943 (w), 2836 (w), 1601 (w), 1576 (w), 1496 (w), 1461
˜
(w), 1423 (m), 1362 (m), 1305 (w), 1286 (w), 1241 (w), 1187 (s), 1147
1 h and at r.t. for 8 h. At 0 °C the alcohol (1.82 g, 7.90 mmol, (w), 1053 (m), 1023 (w), 993 (m), 922 (w), 871 (w), 785 (m), 618 (w),
1.00 equiv.) and pyridine (1.59 mL, 19.8 mmol, 2.50 equiv.) in CH2Cl2
(10 mL) were added dropwise. The reaction mixture was slowly
warmed to r.t. and stirred for 12 h. The mixture was diluted with
EtOAc (100 mL), quenched with H2O (100 mL) and the layers were
573 (w), 549 (w), 522 (w) cm–1. HPLC: (Chiralpac IC, n-hexane/EtOAc,
3:2, 0.7 mL/min, 277 nm) tR(major) = 8.357, tR(minor) = 7.127 min.
[α]2D3 : –6.4 (c 0.6, EtOAc, for a sample with 88 % ee). m.p.: 66 °C
(EtOAc).
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(S)-4-(3′-Chloro-4′,5′-dimethoxyphenyl)-1,2,3-oxathi-
azinane 2,2-dioxide (S-13b): Under Ar-atmosphere sulfamate 12b
(1.27 g, 4.10 mmol, 1.00 equiv.), MgO (328 mg, 8.20 mmol,
2.00 equiv.), 3 Å molecular sieves (300 mg) and Rh2(R-nap)4
(105 mg, 82.0 μmol, 0.02 equiv.) were dissolved in CH2Cl2 (40 mL).
Iodosobenzene (992 mg, 4.51 mmol, 1.10 equiv.) was added and
(ddd, J = 2.3, 7.4, 10.8 Hz, 1 H, 6-HB), 5.89 (t, J = 4.6 Hz, 1 H, 4-H).
6.80 (d, J = 2.1 Hz, 1 H, Ar), 6.94 (dd, J = 0.8, 2.1 Hz, 1 H, Ar) ppm.
13C-NMR: 75 MHz, CDCl3; δ = 24.8 (Me), 28.2 (C5), 56.3 (OMe), 57.7
(C4), 60.8 (OMe), 70.9 (C6), 108.9 (Ar), 119.3 (Ar), 128.9 (Ar), 134.3
(Ar), 145.2 (Ar), 154.2 (Ar), 168.6 (CO) ppm. HR-MS: (ESI+): m/z calc.
for C13H16ClNO6SNa [M – Na]+ 372.0279, found 372.0276. FT-IR:
the mixture was stirred at 0 °C for 3 h. CH2Cl2 (40 mL) was added (neat): ν = 2937 (w), 1705 (m), 1601 (w), 1574 (w), 1495 (m), 1463
˜
and the reaction mixture was filtered through a pad of Celite. The
crude product was concentrated in vacuo. After column chromatog-
raphy (n-pentane/EtOAc, 2:1) oxathiazinane 13b (794 mg,
2.58 mmol, 63 %, 87 % ee) was isolated as colorless solid. Recrystalli-
zation from CHCl3 gave (S)-13b with 52 % yield and 99 % ee.
(w), 1414 (w), 1370 (s), 1261 (s), 1176 (s), 1144 (m), 1112 (w), 1047
(m), 988 (s), 958 (w), 925 (m), 888 (m), 790 (s), 755 (w), 731 (w), 583
(s), 544 (w), 506 (w), 479 (w) cm–1. m.p.: 95 °C (EtOAc). [α]2D3 : –13.8
(c 0.1, EtOAc, for a sample with 99 %ee).
(S)-3-Acetamido-3-(3′-chloro-4′,5′-dimethoxyphenyl)propanoic
Acid (S-16b): Acylated oxathiazinane 15b (277 mg, 792 mmol,
1.00 equiv.) was dissolved in MeCN/H2O (4.8 mL, 4:3) and the mix-
ture was stirred at 50 °C for 4 h. The mixture was cooled to 35 °C
and Na2HPO4·12H2O (397 mg, 1.11 mmol, 1.40 equiv.) was added
to reach pH ≈ 4. TEMPO (11.0 mg, 71.3 μmol, 0.09 equiv.) was
added, aq. NaOCl (8.00 μL, 15.8 μmol, 12wt.-%, 0.02 equiv.) and
NaClO2 (143 mg, 1.58 mmol, 2.00 equiv.) were added in 7 portions
over 3 h and the mixture was stirred at this temperature for 16 h.
Aq. NaOH (2.0 M) was added to reach pH ≈ 8, aq. Na2SO3 (240 mg,
TLC: Rf = 0.27 (n-pentane/EtOAc, 2:1). 1H-NMR: 300 MHz, CDCl3;
δ = 2.03 (ddd, J = 2.4, 4.2, 14.4 Hz, 1 H, 5-HA), 2.22 (dtd, J = 5.0,
12.6, 17.4 Hz, 1 H, 5-HB), 3.87 (s, 3 H, OMe), 3.89 (s, 3 H, OMe), 4.30
(d, J = 9.2 Hz, 1 H, NH), 4.67 (ddd, J = 1.5, 5.0, 11.7 Hz, 1 H, 6-HA),
4.87 (ddd, J = 2.9, 7.3, 12.1 Hz, 1 H, 4-H), 4.87 (dd, J = 2.4, 11.8 Hz,
1 H, 6-HB), 6.83 (d, J = 1.9 Hz, 1 H, Ar), 6.93 (d, J = 1.6 Hz, 1 H, Ar)
ppm. 13C-NMR: 75 MHz, CDCl3; δ = 29.9 (C5), 56.4 (OMe), 58.4 (C4),
60.9 (OMe), 71.8 (C6), 109.5 (Ar), 119.5 (Ar), 128.9 (Ar), 134.5 (Ar),
145.9 (Ar), 154.4 (Ar) ppm. HR-MS: (ESI–): m/z calc. for C11H13ClNO5S
1.90 mmol, 2.40 equiv.) was added and stirring was continued at
r.t. for 30 min. The reaction mixture was washed with EtOAc (20 mL),
the pH was adjusted to ≈ 3 by addition of HCl (1.0 M) and the layers
were separated. The aq. layer was extracted with EtOAc (3 × 20 mL),
the combined org. layers were dried with Na2SO4, filtered and con-
centrated in vacuo. The crude product was recrystallized from Et2O
to yield clean 16 (152 mg, 0.504 mmol, 64 %) as colorless solid.
[M – H] 306.0208, found 306.0210. FT-IR: (neat): ν = 3248 (w), 2943
˜
(w), 2836 (w), 1601 (w), 1576 (w), 1496 (w), 1462 (w), 1423 (m), 1362
(m), 1306 (w), 1286 (w), 1241 (w), 1187 (s), 1147 (w), 1053 (m), 1023
(w), 992 (m), 922 (w), 890 (w), 871 (w), 786 (m), 732 (w), 618 (w),
574 (w), 549 (w), 523 (w) cm–1. HPLC: (Chiralpac IC, n-hexane/EtOAc,
3:2, 0.7 mL/min, 277 nm) tR(major) = 7.212 min, tR(minor) =
8.555 min. [α]2D3 : +17.5 (c 0.1, EtOAc, for a sample with 99 %ee).
m.p.: 194 °C (CHCl3).
TLC: Rf = 0.29 (CH2Cl2/MeOH/AcOH, 100:20:1). 1H-NMR: 300 MHz,
[D4]DMSO; δ = 1.82 (s, 3 H, Me), 2.65 (d, J = 7.5 Hz, 2 H, 2-H), 3.71
(s, 3 H, OMe), 3.82 (s, 3 H, OMe), 5.11 (q, J = 7.5 Hz, 1 H, 3-H), 6.93
(d, J = 2.0 Hz, 1 H, Ar), 6.99 (d, J = 2.0 Hz, 1 H, Ar), 8.34 (d, J =
8.4 Hz, 1 H, NH), 12.17 (sbr, 1 H, CO2H) ppm. 300 MHz, [D4]MeOD;
δ = 1.96 (s, 3 H, Me), 2.76 (dd, J = 4.6, 7.4 Hz, 2 H, 2-H), 3.78 (s, 3
H, OMe), 3.87 (s, 3 H, OMe), 5.25 (t, J = 7.4 Hz, 1 H, 3-H), 6.96 (sbr,
2 H, Ar) ppm. 13C-NMR: 75 MHz, [D4]MeOD; δ = 22.6 (Me), 41.4 (C2),
51.2 (C3), 56.7 (OMe), 60.9 (OMe), 111.3 (Ar), 120.7 (Ar), 129.0 (Ar),
139.9 (Ar), 145.8 (Ar), 155.2 (Ar), 171.4 (Ac), 173.8 (CO2H) ppm. HR-
MS: (ESI+): m/z calc. for C13H16ClNO5Na [M – Na]+ 324.0609, found
(S)-1-[4-(3′-Chloro-4′,5′-dimethoxyphenyl)-2,2-dioxido-1,2,3-
oxathiazinan-3-yl]ethan-1-one (S-15): Under Ar-atmosphere oxa-
thiazinane 13b (64.0 mg, 208 μmol, 1.00 equiv.) was dissolved in
THF (6 mL). KOtBu (46.7 mg, 416 μmol, 2.00 equiv.) was added and
the mixture was stirred at r.t. for 2 h. Acetyl chloride (37.7 μL,
520 μmol, 2.50 equiv.) was added and the mixture was stirred at r.t.
for 10 h. H2O (6 mL) was added to quench the reaction, it was
extracted with EtOAc (2 × 10 mL), dried with Na2SO4 and all volatile
compounds were removed under reduced pressure. After column
chromatography (n-pentane/EtOAc, 2:1) N-acylated oxathiazin-
ane 15 (54.0 mg, 154 μmol, 74 %) was isolated as colorless solid.
324.0605. FT-IR: (neat); ν = 3313 (w), 2937 (w), 2828 (w), 2567 (w),
˜
2504 (w), 1692 (s), 1612 (m), 1555 (s), 1493 (m), 1451 (w), 1428 (w),
1408 (m), 1377 (w), 1340 (w), 1272 (m), 1235 (s), 1214 (w), 1184 (m),
1141 (m), 1114 (w), 1069 (w), 1048 (m), 991 (s), 909 (m), 856 (m),
833 (w), 793 (w), 716 (w), 631 (w), 613 (s), 517 (m), 481 (w), 442 (w)
cm–1. m.p.: 154 °C (Et2O). [α]2D3 : –29.9 (c 0.1, MeOH, for a sample
with 99 %ee).
(S)-3-Acetamido-3-{3′-chloro-4′,5′-bis[(triethylsilyl)oxy]-
phenyl}propanoic Acid (3): Under Ar-atmosphere amino acid 16
(33.0 mg, 109.0 μmol, 1.00 equiv.) was suspended in CH2Cl2 (0.5 mL)
and added to a solution of AlBr3 (233 mg, 875 μmol, 8.00 equiv.) in
EtSH (580 μL, 7.65 mmol, 70.0 equiv.) at 0 °C. The mixture was
TLC: Rf = 0.20 (n-pentane/CH2Cl2, 2:1). 1H-NMR: 300 MHz, CDCl3; warmed to r.t. and stirred for 18 h at this temperature. The reaction
δ = 2.47 (dddd, J = 2.3, 3.5, 6.2, 14.7 Hz, 1 H, 5-HA), 2.59 (s, 3 H,
Me), 2.87 (dddd, J = 4.6, 7.4, 10.8, 14.7 Hz, 1 H, 5-HB), 3.85 (s, 3 H,
OMe), 3.86 (s, 3 H, OMe), 4.51 (td, J = 6.2, 10.8 Hz, 1 H, 6-HA), 4.73
was quenched by addition of 1.0 M HCl (1.0 mL) and diluted with
EtOAc (1.0 mL). NaCl was added to saturate the aq. layer and it was
extracted with EtOAc (4 × 3.0 mL). The combined org. layers were
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dried with Na2SO4, filtered and all volatile compounds were re-
moved in vacuo to yield the crude deprotected catechol (30.0 mg),
which was directly used for the next step without further purifica-
tion.
(s), 871 (s), 785 (w), 618 (s), 573 (s), 549 (s), 522 (w) cm–1. [α]D23
–56.5 (c 1.0, CHCl3, for a sample with 99 %ee).
:
Acknowledgments
Under Ar-atmosphere crude amino acid, NEt3 (0.12 mL, 887 μmol,
8.00 equiv.) and DMAP (2.00 mg, 16.0 μmol, 0.15 equiv.) were dis-
solved in DMF (1.0 mL). At 0 °C TESCl (138.0 μL, 822 μmol,
7.50 equiv.) was added and the mixture was stirred at r.t. for 7 h.
Sat. aq. NH4Cl (3.0 mL) was added to quench the reaction, it was
extracted with Et2O (3 × 7 mL), the combined layers were dried
with Na2SO4 and all volatile compounds were removed in vacuo.
After column chromatography (CH2Cl2/MeOH/AcOH, 100:2:1) TES-
protected amino acid 3 (33.6 mg, 66.9 μmol, 61 %) was isolated as
colorless oil.
Financial support by the Deutsche Forschungsgemeinschaft is
gratefully acknowledged.
Keywords: C–H Amination · Nitrene insertion · Fijiolide A ·
Amino acids
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[10] CCDC 1850089 (for 13a) and 1850090 (for 13b) contain the supplemen-
tary crystallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre.
[11] S. Kang, H.-K. Lee, J. Org. Chem. 2010, 75, 237–240.
TLC: Rf = 0.11 (CH2Cl2/MeOH/AcOH, 100:2:1). 1H-NMR: 300 MHz,
CDCl3; δ = 0.72–0.80 (m, 12 H, TES), 0.96 (td, J = 6.0, 7.8 Hz, 1 H,
TES), 2.03 (s, 3 H, Me), 2.80 (dd, J = 5.8, 16.1 Hz, 1 H, 2-HA), 2.91 (dd,
J = 5.8, 16.1 Hz, 1 H, 2-HB), 5.30 (dt, J = 5.8, 8.5 Hz, 1 H, 3-H), 6.48
(d, J = 8.5 Hz, 1 H, NH), 6.67 (d, J = 2.3 Hz, 1 H, Ar), 6.86 (d, J =
2.3 Hz, 1 H, Ar) ppm. The carboxylic acid proton could not be
detected. 13C-NMR: 75 MHz, CDCl3; δ = 5.2 (TES), 5.6 (TES), 6.7 (TES),
6.8 (TES), 23.4 (Me), 39.5 (C2), 48.8 (C3), 116.6 (Ar), 120.0 (Ar), 126.8
(Ar), 133.4 (Ar), 143.6 (Ar), 148.4 (Ar), 170.1 (Ac), 174.8 (CO2H) ppm.
HR-MS: (ESI+): m/z calc. for C23H40ClNO5Si2H [M – H]+ 502.2212,
found 502.2206. FT-IR: (neat); ν = 3246 (s), 2943 (m), 2836 (s), 1601
˜
(s), 1576 (s), 1496 (s), 1461 (m), 1423 (m), 1362 (m), 1305 (s), 1286
(m), 1241 (m), 1187 (s), 1147 (s), 1053 (m), 1023 (m), 993 (m), 922
Received: November 1, 2018
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Amino Acid Synthesis
T. Kurzawa, E. Kerste,
P. Nikodemiak, D. Bothe, K. Harms,
U. Koert* ............................................... 1–8
Stereoselective Synthesis of the ꢀ-
Amino Acid Moiety of Fijiolide A
A stereoselective synthesis of the ꢀ- Du Bois' asymmetric C–H amination of
amino acid moiety of the fijiolides was a sulfamate.
achieved using an intramolecular
DOI: 10.1002/ejoc.201801623
Eur. J. Org. Chem. 0000, 0–0
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