Efficient one-step conversion of primary aliphatic amines into primary alcohols: Application to a model study for the total synthesis of (±)-scopadulin

Article abstract of DOI:10.1021/ol006334a

Treatment of primary aliphatic amines with KOH in diethylene glycol at 210°C gives primary alcohols directly in good yields. A synthetic application to a model study of (±)-scopadulin is also described.

Full text of DOI:10.1021/ol006334a

ORGANIC
LETTERS
2000
Vol. 2, No. 18
2893-2895
Efficient One-Step Conversion of
Primary Aliphatic Amines into Primary
Alcohols: Application to a Model Study
for the Total Synthesis of
(±)-Scopadulin
S. M. Abdur Rahman, Hiroaki Ohno, Naoyoshi Maezaki, Chuzo Iwata, and
Tetsuaki Tanaka*
Graduate School of Pharmaceutical Sciences, Osaka UniVersity, 1-6 Yamadaoka,
Suita, Osaka 565-0871, Japan
t-tanaka@phs.osaka-u.ac.jp
Received July 14, 2000
ABSTRACT
Treatment of primary aliphatic amines with KOH in diethylene glycol at 210 °C gives primary alcohols directly in good yields. A synthetic
application to a model study of (±)-scopadulin is also described.
Scopadulin 1, a tetracyclic diterpenoid, was isolated from
the Paraguan plant Scoparia dulcis (fam. Scrophulariaceae)
in 1990, as the first aphidicolane diterpenoid from higher
plants. The structure and the stereochemistry of scopadulin
were determined by T. Hayashi and co-workers.1 Its structural
complexity, due to the presence of three quaternary carbons
and eight stereocenters, along with its notable antiviral and
cytotoxic activities attracted synthetic chemists as a worthy
challenge. However, no synthetic pathway to scopadulin has
been reported to date.2 Although we have established the
construction of a similar C/D ring system in the successful
synthetic study of aphidicolin,3 the progress of a synthetic
study of scopadulin was hampered due to several failed
attempts to construct the A/B ring system with the desired
functionalities. Accordingly, we turned our attention to the
synthesis of model compound 2 bearing the requisite
functionalities and stereochemical configuration prior to the
total synthesis of scopadulin 1.
(1) Hayashi, T.; Kawasaki, M.; Miwa, Y.; Taga, T.; Morita, N. Chem.
Pharm. Bull. 1990, 38, 945.
(2) For a recent example of the synthesis of other aphidicolans, see: (a)
Be´langer, G.; Deslongchamps, P. Org. Lett. 2000, 2, 285. For a review,
see: (b) Toyota, M.; Ihara, M. Tetrahedron 1999, 55, 5641. For the synthesis
of scopadulan diterpenes bearing a similar A/B ring system, see: (c) Ziegler,
F. E.; Wallace, O. B. J. Org. Chem. 1995, 60, 3626. (d) Tagat, J. R.;
McCombie, S. W.; Puar, M. S. Tetrahedron Lett. 1996, 37, 8459. (e) Tagat,
J. R.; Puar, M. S.; McCombie, S. W. Tetrahedron Lett. 1996, 37, 8463. (f)
Overman, L. E.; Ricca, D. J.; Tran, V. D. J. Am. Chem. Soc. 1997, 119,
12031. (g) Fox, M. E.; Li, C.; Marino, P., Jr.; Overman, L. E. J. Am. Chem.
Soc. 1999, 121, 5467.
In the course of our synthetic study, we discovered a novel
method of converting primary amines to alcohols. Although
(3) (a) Tanaka, T.; Murakami, K.; Okuda, O.; Inoue, T.; Kuroda, T.;
Kamei, K.; Murata, T.; Yoshino, H.; Imanishi, T.; Kim, S.-W.; Iwata, C.
Chem. Pharm. Bull. 1995, 43, 193. (b) Tanaka, T.; Okuda, O.; Murakami,
K.; Yoshino, H.; Mikamiyama, H.; Kanda, A.; Kim, S.-W.; Iwata, C. Chem.
Pharm. Bull. 1995, 43, 1407.
10.1021/ol006334a CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/16/2000

conversion of aromatic amines into alcohols via diazonium
salts is a well-known process, that of aliphatic amines is
relatively rare.4 Some of these methods require several steps
for the efficient conversion or suffer from low yields, which
diminishes their synthetic value. However, our newly
invented method is synthetically useful, and herein we
present an application of the new method to the synthesis of
model compound 2 of (()-scopadulin 1.
Scheme 2
Starting from 2-cyclohexen-1-one 3, 6-methylbicyclo-
[4.4.0]dec-1-en-2-one 6 was synthesized in a straightforward
manner as depicted in Scheme 1. Stereoselective cyanation
Scheme 1
reaction under Wolff-Kishner conditions to give the desired
6,10-dimethylated compound.2f However, it was not to be
the case. Unexpectedly, we isolated diol 11 by LiAlH4-
reduction of 10 and subsequent Wolff-Kishner reduction
of the crude mixture. Further investigation revealed that the
diol 11 was formed from the primary amine derived from
10 by a potassium hydroxide-mediated reaction. All our other
efforts to direct reduction of the cyano group to a methyl or
formyl group failed.8,9 Treatment of the nitrile 10 with
DIBAL-H led to complete recovery of the starting material,
presumably due to steric hindrance.
Accordingly, to reveal the utility of the direct synthesis
of the primary alcohols from amines and to optimize the
reaction conditions, we briefly investigated the base-mediated
reaction using simple amines (Scheme 3). We found that
Scheme 3
of 6 gave the trans-fused bicylic ketone 7.5 Reduction of
the ketone 7 and TMS-protection of the resulting alcohol
yielded 8 with the desired stereochemistry.6
Next, construction of a quaternary carbon center at C-10
and conversion of the cyano group into a methyl group were
investigated (Scheme 2).7 Treatment of the nitrile 8 with
LDA and freshly distilled benzyloxymethyl chloride in THF
gave R-alkylated derivative 92g and subsequent deprotection
of the TMS group yielded 10, both in excellent yields.6 Our
expectation was that the partial reduction of 10 would
produce the aminal 12, followed by a reductive ring-opening
(4) (a) Whitmore, F. C.; Langlois, D. P. J. Am. Chem. Soc. 1932, 54,
3441. (b) Streitwieser, A., Jr.; Schaeffer, W. D. J. Am. Chem. Soc. 1957,
79, 2888. (c) Kotani, R. J. Org. Chem. 1965, 30, 350. (d) Fujii, T.; Tashiro,
M.; Ohara, K.; Kumai, M. Chem. Pharm. Bull. 1960, 8, 266. (e) Brasen,
W. R.; Hauser, C. R. In Organic Synthethes; Rabjohn, N., Ed.; John Wiley
and Sons: New York, 1963; Collect. Vol. 4, pp 582-584. (f) Katritzky,
A. R.; Saba, A.; Patel, R. C. J. Chem. Soc., Perkin Trans. 1 1981, 1492.
(5) Slight modifications of the published procedures were applied: see
ref 2g.
(6) Stereochemistries of 8 and 10 were ascertained by NOE analyses.
2894
Org. Lett., Vol. 2, No. 18, 2000

the desired conversion proceeded on heating the amine 13
with KOH in diethylene glycol at 210 °C, yielding the
alcohol 17 as the sole product. When the other amines 14
and 15 were subjected to this condition, the desired alcohols
18 and 19 were isolated in acceptable yields, respectively.
Compound 16, whose amino group is highly hindered due
to the axial 2-hydroxy and 6-methyl groups, similarly gave
11 in 65% yield under identical reaction conditions.10
Encouraged by these results, we explored an alternative
route via the diol 11. Modification of functional groups was
accomplished as shown in Scheme 4. The primary hydroxy
forded 21 in good yield. Benzoylation of 2-OH with BzOTf,13
followed by deprotection of the benzyl group and oxidation,
yielded the model compound 2 with all the desired func-
tionalities.
In conclusion, we have demonstrated a novel and efficient
method for converting primary amines into alcohols mediated
by potassium hydroxide. The new reaction is simple,
performed in one step, and applicable to synthesis of
sterically hindered 1,4-diols from enones in combination with
a cyanation-reduction sequence.14 Application of this method
to the total synthesis of (()-scopadulin is now being
investigated in this laboratory.
Supporting Information Available: Experimental pro-
cedures for synthesis of compounds 6, 7, 9, 20, and 2 as
well as H NMR spectra for compounds 2, 4-11, 16, 20,
Scheme 4
1
and 23. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL006334A
(8) For conversion of the cyano group into a methyl group, see: (a)
Kindler, K.; Luhrs, K. Liebigs Ann. Chem. 1965, 685, 36. (b) Kindler, K.;
Luhrs, K. Ber. 1966, 99, 227.
(9) Attempted conversion of the cyano group into a formyl group using
LiAlH4 was also unsuccessful. See: (a) Nagata, W. Tetrahedron 1961, 13,
287. (b) Nagata, W.; Hirai, S.; Itazaki, H.; Takeda, K. Liebigs Ann. Chem.
1961, 641, 196. (c) Fry, J. L.; Ott, R. A. J. Org. Chem. 1981, 46, 602.
(10) Although these reactions were carried out in the presence of air, a
similar result was obtained when the reaction was carried out under nitrogen
using degassed solvent. Considering these results, the redox mechanism
(proceeding through imines) is unlikely. At our current level of understand-
ing, we speculate that the reaction proceeds via a simple nucleophilic
substitution of amino group by hydroxide at a high temperature.
(11) Tomioka, H.; Takai, K.; Oshima, K.; Nozaki, H. Tetrahedron Lett.
1981, 22, 1605.
(12) (a) Huang-Minlon, J. Am. Chem. Soc. 1946, 68, 2487. (b) Huang-
Minlon, J. Am. Chem. Soc. 1949, 71, 3301.
(13) Brown, L.; Koreeda, M. J. Org. Chem. 1984, 49, 3875.
(14) General procedure for one-step conversion of primary aliphatic
amines into alcohols: synthesis of (2R*,6R*,10R*)-10-(benzyloxy-
methyl)-10-(hydroxymethyl)-6-methylbicyclo[4.4.0]decan-2-ol 11. The
amine 16 (10 mg, 0.0315 mmol), KOH (100 mg, 1.75 mmol, excess), and
diethylene glycol (0.6 mL) were placed in a round-bottom flask equipped
with a refluxing condenser, and the mixture was heated at 210 °C for 3
h.10 The black solution was then cooled to rt, and Et2O (2 mL) and H2O
(1.5 mL) were added. The organic phase was separated, and the aqueous
layer was extracted with EtOAc. The combined organic layers were then
washed with brine, dried (MgSO4), filtered, and concentrated. Purification
of the residue by column chromatography (5:1 hexane/EtOAc) gave 6.5
mg (65%) of the title compound 11. Recrystallization from hexane/Et2O
group of 11 was selectively oxidized by RuCl2(PPh3)3,11 and
subsequent reduction under Huang-Minlon conditions12 af-
(7) Construction of the quaternary carbon center with the desired
stereochemistry has proven to be extremely difficult. Treatment of the
â-methylated enone 24 with Et2AlCN in benzene gave 25 with undesired
stereochemistry. Therefore, we planned to introduce a benzyloxymethyl
group at C-10 that could be converted into a carboxyl group.
provided an analytically pure white solid: mp 139 °C. IR (KBr) cm-1
:
3236 (br). 1H NMR (CDCl3, 500 MHz): 1.33 (s, 3H), 1.06-1.59 (m, 11H),
1.84-1.87 (m, 1H), 1.90-1.99 (m, 1H), 3.39 (d, J ) 9.0 Hz, 1H), 3.47 (d,
J ) 12.5 Hz, 1H), 3.48 (d, J ) 9.0 Hz, 1H), 4.14 (br s, 2H), 4.20 (s, 1H),
4.21 (d, J ) 12.5 Hz, 1H), 4.47 (d, J ) 12.0 Hz, 1H), 4.52 (d, J ) 12.0
Hz, 1H), 7.27-7.37 (m, 5H). 13C NMR (CDCl3, 125 MHz): 16.9, 18.4,
22.3, 34.6, 35.4, 35.6, 42.7, 44.5, 46.2, 52.2, 66.2, 66.3, 73.5, 78.2, 127.5,
127.6, 128.4, 138.3. MS (FAB) m/z (%): 319 (MH+, 25), 91 (100). HRMS
(FAB) Calcd for C20H31O3 (MH+): 319.2273. Found: 319.2269.
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