1892
Y. Kothapalli et al. / Tetrahedron Letters 53 (2012) 1891–1893
H
2 equiv. of lithium diisopropylamide followed by reaction with
H
O
H
OH
a
b
OH
O
oxygen and subsequent reduction of the intermediate peroxide
with sodium sulfite, we obtained the desired product 17 with new-
ly incorporated hydroxyl group. To our surprise in the case of 17,
the hydroxyl group was further oxidized to give directly pheno-
pyrrozin (+)-1, an optical antipode of natural (ꢀ)-1. The physical
and spectral data10 of compound (+)-1 were found to be identical
N
Boc
N
Boc
N
H
O
O
O
6
7
5
c
H
O
H
Grignard
Triflation
Low yield
d
O
N
N
H
with those of the reported natural phenopyrrozin (ꢀ)-1 {½a D27
ꢁ
O
O
O
a 2D5
4
+9.7 (c 0.3, MeOH), reported1
½ ꢁ : ꢀ10.2 (c 0.6, MeOH)}.
8
After accomplishing the synthesis of (+)-1, the focus was turned
toward the synthesis of 2 by employing a similar strategy. Accord-
ingly, base mediated oxygenation of 16 provided the compound 18,
which was found to be very stable (in sharp contrast to unstable 17)
and could be isolated by chromatography and stored for several
days without any signs of aerial oxidation. For the oxidation of
18, initially a few notable conditions9 were tried based on the
assumption that highly conjugated product would drive the reac-
tion to forward direction; but they were unsuccessful in giving even
traces of the desired product. Most of the methods either resulted in
the formation of very complex reaction mixture or the recovery of
unreacted starting material. However, later it was found that ruthe-
nium(III) chloride mediated procedure has worked well to give the
desired oxidized product. Accordingly, oxidation of 18 was carried
out at ꢀ10 °C by employing catalytic amounts of ruthenium(III)
chloride hydrate in the presence of sodium periodate in a mixture
of CCl4, acetonitrile, and water (1:1:1) for 2 h to obtain 19. Finally,
desilylation was carried out by using 1 M tetrabutyl ammonium
fluoride in THF to afford 7a(S)-p-hydroxyphenopyrrozin (+)-2,
whose spectral and physical data10 are in good agreement with
Scheme 2. Reagents and conditions: (a) Boc anhydride, 10% aq. NaHCO3, 1,4-
dioxane, 0 °C?rt, 6 h, 90%; (b) (i) CDI, THF, 0 °C?rt, 2 h; (ii) KO2CCH2CO2Et, MgCl2,
THF, 50 °C, 6 h, then 16 h, 65%; (c) 80% aq. TFA, DCM, rt, 3 h; (d) 70% aq. K2CO3,
60 °C, 1 h, 11% (from 7).
yield. In addition, the ketolactam 4 was found to be unstable4 and
several purification trials were unsuccessful. Unfortunately,
attempts toward the conversion of semi-pure 4 to the corresponding
enol triflate were also unsuccessful. Even aryl Grignard reaction also
resulted only in the formation of a complex mixture. To overcome
this difficulty in handling unstable lactam 4, an alternate strategy
has been investigated via the introduction of aromatic moiety at
an earlier stage before the cyclization as illustrated in Scheme 3.
The ketoester 7 was then carefully converted5 to enol triflate 9
using triflic anhydride at ꢀ65 °C in the presence of triethylamine.
After careful isolation of triflate 9, it was coupled with appropriate
arylboronic acid5 under Suzuki reaction conditions to generate an
E/Z mixture of 10 (7:3) and 11 (7:3). In one direction, the deprotec-
tion of Boc group in 10 was carried out and subsequently several
methods were screened for cyclization. However we found out that
only traces of cyclized product were forming, presumably due to
the higher ratio of E isomer, which is not favorable for the cycliza-
tion. Since the double bond is not required at the later stages, we
considered to reduce the double bond, which would eventually in-
crease the feasibility of cyclization reaction. Accordingly, catalytic
hydrogenation of 10 and 11 afforded 12 and 13 as a diastereomeric
mixture. Deprotection of Boc group in 12 and 13 followed by
cyclization using aqueous ammonia led to the formation of 14
and 15 as a mixture of diastereomers6 in 3:2 and 4:1 ratios, respec-
tively. The hydroxyl group in 15 was protected with TBDMS group
to obtain 16. Next attention was turned toward the introduction of
oxygen functionality on 14 and 16. Initially, few notable oxidative
methods7 were tried for the C-oxidation in 14 and 16 but failed to
give the desired product. Later, the oxidation was successfully car-
ried out by employing a well known base mediated oxygenation
method.8 Under these conditions, the deprotonation of 14 using
the literature values.2a {½a D25
ꢁ
+31.7 (c 0.34, MeOH), Reported2a
½
a 2D5
+34.0 (c 0.34, MeOH)}.
ꢁ
In conclusion, we have accomplished the enantiospecific first
total synthesis of natural enantiomer of the 7a(S)-p-hydrox-
yphenopyrrozin 2 and optical antipode of phenopyrrozin 1 starting
from abundantly available L-proline by employing base mediated
cyclization and base mediated oxygenation as the key steps. The
present sequence in addition to confirming the stereo structure,
also established the absolute configuration of natural products.
Acknowledgments
We thank management, GVK Biosciences Private Limited for the
financial support and encouragement. Help from the analytical
department for the analytical data is appreciated.
R
R
H
OTf
H
O
a
c or d
H
H
b
OEt
N
OEt
N
Boc
OEt
OEt
N
N
Boc
Boc
O
Boc
O
O
O
9
7
12
13
10
11
R=H
R=H
e, f
R=OH
R-OH
OTBDMS
i
R
R
H
H
H
j
h
(+)-2
N
19
N
N
O
OH
OH
18 R=OTBDMS
O
O
14
15
R=H
R= OH
17 R=H
g
16 R= OTBDMS
(+)-1
Scheme 3. Reagents and conditions: (a) Tf2O, Et3N, THF, ꢀ65 °C to ꢀ40 °C, 4 h, 65%; (b) phenyl boronic acid or p-hydroxyphenyl boronic acid, 2 M aq. Na2CO3, 1,4-dioxane,
Pd(PPh3)4, 0 °C?60 °C, 40 min, 80% (for 10) and 86% (for 11); (c) Pd-BaSO4, EtOAc, H2 (balloon), rt, 97% (for 12); (d) PtO2, H2 (balloon), MeOH, EtOAc (1:1), rt, 6 h, 93% (for 13);
(e) 80% aq. TFA, DCM, 2 h; (f) aq. NH3, sealed tube, 75 °C, 40 min, 76% (for 14) and 86% (for 15); (g) AgNO3, pyridine, THF, TBDMSCl, rt, 5 h, 87%; (h) LDA, HMPA, P(OMe)3, dry
O2, THF, ꢀ75 °C ?ꢀ65 °C, 4 h, 62% (for 18) and 21% (for 1); (i) RuCl3, NaIO4, CCl4, MeCN, water (1:1:1), ꢀ10 °C to ꢀ5 °C, 2 h, 77%; (j) TBAF, ꢀ40 °C, 30 min, THF, 53%.
Kothapalli, Yugandhar
