3996
C. L. Carroll, A. Richard Chamberlin / Tetrahedron Letters 52 (2011) 3995–3997
tain the requisite O-substituted hydroxy carbamate 9 in 96% yield.
O
O
NHCH3
OH
Upon mixing carbamate 9 with potassium osmate, clean conver-
sion to the oxazolidinone 6 was effected in 63–100% yield. While
the amino hydroxylation gave complete conversion by TLC, oxazo-
lidinone 6 proved difficult to purify due to high polarity and low
solubility, which may account for the moderate 63% isolated yield
when column chromatography was applied. Oxazolidinone 6 was
also insoluble in both acetonitrile and water, including mixtures
thereof, which precluded HPLC reverse phase purification. Favor-
ably, the improved NaOH free conditions provided the oxazolidi-
none 6 as a single isomer, without any observed migration of the
cyclic carbamate that proved detrimental when employing the ori-
ginal TAH conditions. The hydroxyl group was then protected as
the TBS ether to give oxazolidinone 10 in 50–72% yield with the
remainder of the mass balance accounted for by the recovered
alcohol 6. The yield was comparable whether purified or crude
oxazolidinone was subjected to silyl protection conditions. Silyla-
tion of the secondary alcohol proved surprisingly tricky; employ-
ment of TBSOTf as the silylation reagent only lead to N-TBS
formation and not the desired O-TBS product, while using N-TBS-
N-methylacetamide showed no significant improvement in yield.9
Treatment of carbamate 10 with methyl iodide in the presence of t-
BuOK afforded N-methyl oxazolidione 11 in 98% yield, with subse-
quent chemoselective cleavage of the primary TBS to complete
construction of the advanced THP core 12.
MeN
O
O
O
O
HO2C
H2N
O
CO2H
BocHN
CO2Me
dysiherbaine (1)
2
O
MeN
O
HO
BnO
O
OTBS
O
4
OH
3
Scheme 1. Retrosynthetic strategy.
O
O
O
O
NH2
O
NH
HN
O
a
75% (1:1)
O
O
OH
HO
+
O
OTBS
OTBS
OTBS
5
6
7
A concise and stereoselective route to the dysiherbaine THP
core employing Donohoe’s improved TAH conditions was success-
fully completed. Alcohol 12 was synthesized in 39% yield over nine
steps from commercially available material, featuring four contig-
uous stereocenters including the methyl amino group. The im-
proved conditions avoided the mixture of alcohol isomers
previously observed, and obviated the need for a chiral amine addi-
tive in the TAH reaction. The THP intermediate could potentially be
applied to a concise total synthesis of dysiherbaine.
O
O
MeN
BnO
6 steps
56%
O
OH
3
Scheme 2. Initial tethered aminohydroxylation: (a) t-BuOCl, NaOH, K2[OsO2(OH)4],
(DHQ)2PHAL, n-PrOH/H2O.
Acknowledgment
The authors are grateful for support from the National Institutes
of Health (NINDS, NS27600 to ARC).
O
H
H
O
N
O
N
HO
OH
O
O
O
C6F5
a
b
Supplementary data
O
O
O
60%
96%
Supplementary data (complete experimental procedures, prod-
uct characterization, and spectral data) associated with this article
OTBS
OTBS
OTBS
4
8
9
10
12
O
O
NH
O
NH
c
O
O
d
References and notes
OH
OTBS
OTBS
63 – 100%
50 – 72%
1. (a) Michaelis, E. K. Prog. Neurobiol. 1998, 54, 369–415; (b) Sakai, R.; Sasaki, M.;
Shimamoto, K.; Kamiya, H. Nerv. Sys. Agents Med. Chem. 2006, 6, 83–108; (c)
Sakai, R.; Swanson, G.; Shimamoto, K.; Green, T.; Contractor, A.; Ghetti, A.;
Tamura-Horikawa, Y.; Owia, C.; Kamiya, H. J. Pharmacol. Exp. Ther. 2001, 296,
650–655; (d) Swanson, G.; Green, T.; Sakai, R.; Contractor, A.; Che, W.; Kamiya,
H.; Heinemann, S. F. Neuron 2002, 34, 589–598; (e) Trist, D. G. Pharma. Acta Helv.
2000, 74, 221–229.
O
OTBS
OTBS
O
6
O
NMe
O
NMe
e
f
O
O
OTBS
2. Sakai, R.; Kamiya, H.; Murata, M.; Shimamoto, K. J. Am. Chem. Soc. 1997, 119,
4112–4116.
98%
91%
3. Total syntheses: (a) Snider, B. B.; Hawryluk, N. A. Org. Lett. 2000, 2, 635–638; (b)
Sasaki, M.; Koike, T.; Sakai, R.; Tachibana, K. Tetrahedron Lett. 2000, 41, 3923–
3926; (c) Masaki, H.; Maeyama, J.; Kamada, K.; Esumi, T.; Iwabuchi, Y.;
Hatakeyama, S. J. Am. Chem. Soc. 2000, 122, 5216–5217; (d) Phillips, D.;
Chamberlin, A. R. J. Org. Chem. 2002, 67, 3194–3201; (e) Sasaki, M.; Akiyama, N.;
Tsubone, K.; Shoji, M.; Oikawa, M.; Sakai, R. Tetrahedron Lett. 2007, 48, 5697–
5700; (f) Sasaki, M.; Tsubone, K.; Aoki, K.; Akiyama, N.; Shoji, M.; Oikawa, M.;
O
OTBS 11
OH
Scheme 3. Synthesis of alcohol 12: (a) (i) CDI, pyridine, 40 °C; (ii) NH2OHÁHCl; (b)
Et3N, F5C6COCl, CH2Cl2, À8 °C; (c) K2[OsO2(OH)4] (1 mol%), t-BuOH/H2O; (d) TBSCl,
imidazole, DMF; (e) t-BuOK, MeI, THF; (f) DOWEX, MeOH.