Construction of the key amino alcohol moiety of the cinchona alkaloids

Article abstract of DOI:10.1055/s-2006-950435

An N-Teoc [CO₂(CH₂)₂TMS] protected form of the amino alcohol moiety found in the cinchona alkaloids was constructed by Curtius rearrangement followed by reaction of the isocyanate intermediate with TMS(CH₂)₂OH in one pot. Deprotection of the TV-Teoc protective group and subsequent piperidine ring formation were easily accomplished with CsF in DMF at 110 °C in one pot to afford model compounds of the alkaloids. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950435

2670
LETTER
Construction of the Key Amino Alcohol Moiety of the Cinchona Alkaloids
Key
Amino
Alcoh
u
ol Moiety of
i
the Cin
c
c
hona Alka
h
loids i Kobayashi, Yuuya Motoyama
Department of Biomolecular Engineering, Tokyo Institute of Technology, B52, Nagatsuta-cho 4259, Midori-ku, Yokohama 226-8501,
Japan
Fax +81(45)9245789; E-mail: ykobayas@bio.titech.ac.jp
Received 3 June 2006
X
Abstract: An N-Teoc [CO2(CH2)2TMS] protected form of the ami-
X
R
aldol
no alcohol moiety found in the cinchona alkaloids was constructed
by Curtius rearrangement followed by reaction of the isocyanate
intermediate with TMS(CH2)2OH in one pot. Deprotection of the
N-Teoc protective group and subsequent piperidine ring formation
were easily accomplished with CsF in DMF at 110 °C in one pot to
afford model compounds of the alkaloids.
CO2R*
OH
+
Ar-CHO
R
CO2R*
Ar
1
2
X
Curtius
rearrangement
Key words: aldol reactions, alkaloids, asymmetric synthesis, re-
arrangements, piperidines
R
R
NH
NHTeoc
OH
8
9
Ar
OH
Ar
4
3
The cinchona alkaloids are an important class of com-
pounds as drugs as well as chiral catalysts.1 To find a more
effective catalyst, a number of analogues has been synthe-
sized by modification of the natural alkaloids,1c,2 while
total synthesis has not exerted its potential on analogue
synthesis due to the lack of an efficient method, though
the synthetic study has a long history of over 50 years.1a,b,3
Recently, stereoselective total syntheses have been report-
ed first by Stork4 in 2001, and then by Jacobsen5 and by
us.6 These methods would contribute to analogue synthe-
sis to some extent. However, we felt the necessity of
developing a new method that would be complementary
to the above methods.
Scheme 1 A construction of the key amino alcohol structure.
Teoc = CO2(CH2)2TMS.
NH
OH
NH
OH
4a
4b
Figure 1 Amino alcohols synthesized by us.
We contemplated aldol reaction and subsequent Curtius
rearrangement for construction of the amino alcohol
functionality at C8 and C9 of the cinchona alkaloids
(Scheme 1). Furthermore, we planned to use
TMS(CH2)2OH as an alcohol to trap the isocyanate inter-
mediate furnishing the Teoc [=CO2(CH2)2TMS] amide 3.
This protective group is chemically stable under acidic
and basic conditions, while it can be easily removed under
the neutral, Teoc-specific conditions (CsF in hot DMF).6b
anhydride formation with PivCl (Piv = t-BuCO) and sub-
sequent reaction with oxazolidinone 8 in the presence of
LiCl.9 Aldol reaction of 9 with PhCHO was successfully
conducted by using the TiCl4/sparteine protocol10
(0 °C, 45 min, CH2Cl2) to produce two syn-isomers, 10
(JHa–Hb = 6 Hz)11 and its diastereomer (structure not
shown; JHa–Hb = 6 Hz), in a 10:1 ratio.12,13 After separation
by chromatography, isomer 10, obtained in 73% yield,
was protected as the THP ether14 in 96% yield and the
oxazolidinone moiety was hydrolyzed to the key acid 11
in 60% yield according to the procedure of Evans15 with
modification.16
To examine the feasibility of this approach, we targeted
two compounds, 4a and 4b (Figure 1), of the quinine/cin-
chonidine type. These compounds have previously been
synthesized, but in low yield and with low enantio- and
diastereoselectivities.7,8 Investigation along this line start-
ed with acid-catalyzed methanolysis of e-caprolactone 5
to produce a hydroxyl ester, which upon protection with
TBDPSCl produced ester 6 in 92% yield. The ester was
hydrolyzed with NaOH in aqueous THF to afford acid 7
in 96% yield, which was converted to oxazolidinone 9 in
87% yield by a two-step sequence consisting of the mixed
An operationally simple procedure for the Curtius re-
arrangement of 11 and further reaction of the resulting
isocyanate 12 with TMS(CH2)2OH were established by
examination of the literature procedures17 using a simple
acid. Thus, a solution of 11, DPPA (1.2 equiv),
TMS(CH2)2OH (2.0 equiv), and Et3N (2.5 equiv) in ben-
zene was heated under gentle reflux for 12 hours to afford
product 13 in 77% yield after chromatography.18,19 The
TBDPS and THP protective groups in 13 were removed in
75% yield under acidic conditions without injuring the
Teoc moiety, and selective tosylation at the primary OH
of the resulting diol 14 gave 15 in 67% yield {[a]D 25 –31
SYNLETT 2006, No. 16, pp 2670–2672
0
4
.1
0
.2
0
0
6
Advanced online publication: 22.09.2006
DOI: 10.1055/s-2006-950435; Art ID: U06406ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Key Amino Alcohol Moiety of the Cinchona Alkaloids
2671
O
1) PivCl
Et3N, THF
O
O
1) p-TsOH, MeOH
O
TBDPSO
TBDPSO
CO2R
6, R = Me
N
O
2) TBDPSCl
imidazole, DMF
O
2)
NaOH
aq THF
Bn
7, R = H
92%
HN
Bn
O
5
9
, LiCl
96%
87% from 7
8
O
O
Ha
Hb
1) TiCl4 (1.1 equiv)
(–)-sparteine (2.5 equiv)
TMS(CH2)2OH
(2 equiv)
1) DHP, H+
TBDPSO
TBDPSO
CO2H
OTHP
N
O
2) LiOH, H2O2
DPPA (1.2 equiv)
Et3N (2.5 equiv)
2) PhCHO (1.5 equiv)
CH2Cl2, 0 °C
OH
aq THF,
70 °C, 24 h
Bn
∆, 12 h
73%
58%
RO
11
10
dry HCl
MeOH–Et2O
NCO
TBDPSO
NHTeoc
NHTeoc
OH
CsF (5 equiv)
4a
DMF
110 °C, 1.5 h
75%
OTHP
OTHP
67%
12
13, 77%
14, R = H
15, R = Ts
TsCl, Et3N
67%
Scheme 2 Synthesis of the phenyl derivative 4a.
(c 1.68, CHCl3)}. Finally, reaction of 15 with CsF in DMF rearrangement of 17 under the conditions mentioned
at 110 °C led to deprotection of the Teoc group and above proceeded smoothly to afford 18 in 57% yield.
subsequent piperidine ring formation to furnish the target Deprotection to diol 19 {[a]D29 –20 (c 0.176, CHCl3)} and
25
24
molecule 4a {[a]D26 –50 (c 0.024, CHCl3); Lit.7c [a]D
tosylation proceeded as well to give 20 {[a]D –21 (c
–50.8 (c 0.4, CHCl3)} in 67% yield. The 1H NMR signal 0.332, CHCl3)} in 60% yield. Finally, exposure of 20 to
for C9–H (d = 4.55 ppm, J = 5.4 Hz) was consistent with CsF in DMF afforded the target 4b {[a]D –73 (c 0.03,
25
that reported previously.7d
CHCl3)}. The H NMR spectrum of 4b (C9–H, d = 5.46
ppm, J = 4.5 Hz) was identical with that reported for the
racemic sample.8,20
1
Next, we applied the above method to the synthesis of the
naphthyl derivative 4b starting with the key oxazolidino-
ne 9 (Scheme 3). Aldol reaction of 9 with 1-naphthalde- In summary, we have shown an approach to the key struc-
hyde furnished aldol 16 (JHa–Hb = 6 Hz) in 63% yield. ture of the cinchona alkaloids, in which the key transfor-
Interestingly, the bulky naphthyl group contributed mation, Curtius rearrangement and subsequent trap with
positively to the high stereoselectivity producing 16 as the TMS(CH2)2OH, were best accomplished by applying the
sole product. Protection of the hydroxyl group as the THP conditions mentioned for 11 to 13 (Scheme 2) and for 17
ether and hydrolysis gave 17 in 61% yield. Curtius to 18 (Scheme 3).
TBDPSO
TBDPSO
O
O
Ha
1) TiCl4 (1.2 equiv)
(–)-sparteine (2.5 equiv)
TMS(CH2)2OH
(5 equiv)
CO2H
OTHP
1) DHP, H+
N
O
9
DPPA (3 equiv)
Et3N (6 equiv)
2)
2) LiOH, H2O2
CHO
OH
Bn
Hb
aq THF,
70 °C, 24 h
∆, 17 h
61%
57%
63%
16
17
TBDPSO
RO
dry HCl
MeOH–Et2O
NHTeoc
OTHP
NHTeoc
OH
CsF (5 equiv)
4b
61%
DMF
110 °C, 2 h
55%
18
19, R = H
20, R = Ts
TsCl, Et3N
60%
Scheme 3 Synthesis of the naphthyl derivative 4b.
Synlett 2006, No. 16, 2670–2672 © Thieme Stuttgart · New York

2672
Y. Kobayashi, Y. Motoyama
LETTER
(13) (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc.
1981, 103, 2127. (b) Evans, D. A. Aldrichimica Acta 1982,
15, 23.
(14) A TBS ether was also synthesized from aldol 10 and
hydrolyzed to acid, in 64% yield for the two steps. However,
subsequent Curtius rearrangement did not take place, even
under more forcing conditions than those used for 11, and
instead gave a mixture of the starting acid and other
unidentified products.
(15) Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett.
1987, 28, 6141.
(16) Probably due to steric hindrance, the hydrolysis with H2O2
and LiOH in aqueous THF required a higher temperature of
70 °C.
(17) (a) Sibi, M. P.; Lu, J.; Edwards, J. J. Org. Chem. 1997, 62,
5864. (b) Jacobi, P. A.; Murphree, S.; Rupprecht, F.; Zheng,
W. J. Org. Chem. 1996, 61, 2413. (c) Sibi, M. P.;
Deshpande, P. K. J. Chem. Soc., Perkin Trans. 1 2000, 1461.
(18) Clean formation of the isocyanate 12 was detectable by
TLC.
Acknowledgment
This work was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Science, Sports, and Culture,
Japan.
References and Notes
(1) (a) Kaufman, T. S.; Rúveda, E. A. Angew. Chem. Int. Ed.
2005, 44, 854. (b) Hoffmann, H. M. R.; Frackenpohl, J. Eur.
J. Org. Chem. 2004, 4293. (c) Kacprzak, K.; Gawroński, J.
Synthesis 2001, 961.
(2) Recent examples: (a) Vakulya, B.; Varga, S.; Csámpai, A.;
Soós, T. Org. Lett. 2005, 7, 1967. (b) Andrus, M. B.; Liu, J.;
Ye, Z.; Cannon, J. F. Org. Lett. 2005, 7, 3861.
(c) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.;
Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219.
(3) (a) Woodward, R. B.; Doering, W. E. J. Am. Chem. Soc.
1944, 66, 849. (b) Gutzwiller, J.; Uskoković, M. R. J. Am.
Chem. Soc. 1978, 100, 576.
(19) To a solution of acid 11 (408 mg, 0.728 mmol) and Et3N
(0.21 mL, 1.49 mmol) in benzene (1.5 mL) were added
DPPA (0.19 mL, 0.891 mmol) and 2-trimethylsilylethanol
(0.21 mL, 1.47 mmol). The solution was heated to reflux for
12 h, cooled to r.t., and diluted with sat. NaHCO3. The
resulting mixture was extracted with EtOAc four times. The
combined extracts were dried over MgSO4 and concentrated
to afford an oil, which was purified by chromatography on
silica gel (hexane–EtOAc) to afford 13 (381 mg, 77%).
(20) The 1H NMR spectral data of selected compounds (300
MHz, CDCl3).
(4) Stork, G.; Niu, D.; Fujimoto, A.; Koft, E. R.; Balkoves, J.
M.; Tata, J. R.; Dake, G. R. J. Am. Chem. Soc. 2001, 123,
3239.
(5) Jacobsen, E. N.; Raheen, I. T.; Goodman, S. N. J. Am. Chem.
Soc. 2004, 126, 706.
(6) (a) Igarashi, J.; Katsukawa, M.; Wang, Y.-G.; Acharya, H.
P.; Kobayashi, Y. Tetrahedron Lett. 2004, 45, 3783.
(b) Igarashi, J.; Kobayashi, Y. Tetrahedron Lett. 2005, 46,
6381.
(7) Synthesis of 4a: (a) Solladié-Cavallo, A.; Roje, M.; Baram,
A.; Sunjić, V. Tetrahedron Lett. 2003, 44, 8501.
(b) Solladié-Cavallo, A.; Marsol, C.; Yaakoub, M.; Azyat,
K.; Klein, A.; Roje, M.; Suteu, C.; Freedman, T. B.; Cao, X.;
Nafie, L. A. J. Org. Chem. 2003, 68, 7308. (c) Bojadziev,
S. E.; Tsankov, D. T.; Ivanov, P. M.; Berova, N. D. Bull.
Chem. Soc. Jpn. 1987, 60, 2651. (d) Meyers, A. I.;Edwards,
P. D.; Bailey, T. R.; Jagdmann, G. E. Jr. J. Org. Chem. 1985,
50, 1019. (e) Fauley, J. J.; LaPidus, J. B. J. Org. Chem.
1971, 36, 3065.
Compound 4a: d = 1.10–1.90 (m, 8 H), 2.61 (dt, J = 3, 12 Hz,
1 H), 2.71–2.79 (m, 1 H), 3.03 (d, J = 11 Hz, 1 H), 4.55 (d,
J = 5.4 Hz, 1 H), 7.19–7.48 (m, 5 H).
Compound 4b: d = 1.10–1.80 (m, 8 H), 2.71 (dt, J = 3, 12
Hz, 1 H), 3.04–3.19 (m, 2 H), 5.46 (d, J = 4.5 Hz, 1 H), 7.42–
7.56 (m, 4 H), 7.73 (d, J = 7 Hz, 1 H), 7.79 (d, J = 8 Hz, 1
H), 7.88 (d, J = 7 Hz, 1 H), 8.08 (d, J = 7 Hz, 1 H).
Compound 10: d = 1.01 (s, 9 H), 1.20–2.10 (m, 6 H), 2.52–
2.62 (m, 2 H), 3.24 (dd, J = 13, 3 Hz, 1 H), 3.61 (t, J = 6 Hz,
2 H), 3.76 (t, J = 9 Hz, 1 H), 3.99 (dd, J = 9, 2 Hz, 1 H),
4.32–4.43 (m, 2 H), 4.91 (dd, J = 6, 3 Hz, 1 H), 7.14–7.48
(m, 16 H), 7.62–7.75 (m, 4 H).
(8) Synthesis of 4b in racemic form: see ref. 7a,b.
(9) Ho, G.-J.; Mathre, D. J. J. Org. Chem. 1995, 60, 2271.
(10) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K.
J. Org. Chem. 2001, 66, 894.
Compound 14: d = 0.05 (s, 9 H), 0.99 (t, J = 8 Hz, 2 H),
1.10–1.70 (m, 7 H), 2.95 (br s, 1 H), 3.56 (t, J = 6 Hz, 2 H),
3.87–4.00 (m, 1 H), 4.17 (t, J = 8 Hz, 2 H), 4.71 (d, J = 8 Hz,
1 H), 4.88 (br s, 1 H), 7.22–7.45 (m, 5 H).
(11) (a) House, H. O.; Crumrine, D. S.; Teranishi, A. Y.;
Olmstead, H. D. J. Am. Chem. Soc. 1973, 95, 3310.
(b) Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem.
Soc. 1974, 96, 7503.
Compound 15: d = 0.05 (s, 9 H), 0.99 (t, J = 8 Hz, 2 H),
1.10–1.70 (m, 6 H), 2.45 (s, 3 H), 2.88 (s, 1 H), 3.60–4.30
(m, 5 H), 4.71 (d, J = 8 Hz, 1 H), 4.85 (br s, 1 H), 7.20–7.46
(m, 7 H), 7.66 (d, J = 7 Hz, 2 H).
Compound 16: d = 1.00 (s, 9 H), 1.10–2.10 (m, 6 H), 2.51
(dd, J = 13, 10 Hz, 1 H), 3.01 (d, J = 3 Hz, 1 H), 3.23 (dd,
J = 13, 3 Hz, 1 H), 3.54–3.65 (m, 3 H), 3.92 (dd, J = 9, 2 Hz,
1 H), 4.05–4.22 (m, 1 H), 4.57–4.68 (m, 1 H), 5.74 (dd,
J = 6, 3 Hz, 1 H), 7.06–8.14 (m, 22 H).
Compound 19: d = 0.05 (s, 9 H), 0.80–1.70 (m, 8 H), 2.53 (br
s, 1 H), 3.45 (t, J = 6 Hz, 2 H), 3.95–4.16 (m, 1 H), 4.23 (t,
J = 8 Hz, 2 H), 5.11 (d, J = 8 Hz, 1 H), 5.78 (s, 1 H), 7.30–
8.30 (m, 7 H).
Compound 20: d = 0.05 (s, 9 H), 1.05 (t, J = 8 Hz, 2 H),
1.10–1.60 (m, 6 H), 2.39 (br s, 1 H), 2.42 (s, 3 H), 3.84 (t,
J = 8 Hz, 2 H), 3.96–4.07 (m, 1 H), 4.23 (t, J = 8 Hz, 2 H),
5.02 (d, J = 8 Hz, 1 H), 5.76 (br s, 1 H), 7.20–8.30 (m, 11 H).
(12) Aldol reaction of a simpler compound i with PhCHO was
preliminarily studied by using the protocols developed by
Evans13 (Bu2BOTf and 9-BBNOTf with Et3N and i-Pr2NEt)
and Crimmins10 (TiCl4 with sparteine). The former was
unsuccessful, while the latter produced aldol ii
(syn:anti = 84:16) in 79% yield (JHa–Hb = 5 Hz for the syn
isomer; JHa–Hb = 8 Hz for the anti isomer; Figure 2).
O
O
O
O
Ha
Hb
RO
RO
N
O
N
O
Ph
OH
i
ii
R = TBDPS
Figure 2
Synlett 2006, No. 16, 2670–2672 © Thieme Stuttgart · New York