Selective one-pot conversion of carboxylic acids into alcohols

Article abstract of DOI:10.1021/jo9520699

Carboxylic acids are converted into alcohols by chemoselective reduction of their corresponding fluorides with sodium borohydride and dropwise addition of methanol. The method is general and mild and displays a high level of functional group compatibility. N-Protected amino and peptide alcohols, bearing varieties of protecting groups, are prepared in the same way from their corresponding amino acids and peptides without racemization.

Full text of DOI:10.1021/jo9520699

6
994
J . Org. Chem. 1996, 61, 6994-6996
Selective On e-P ot Con ver sion of Ca r boxylic Acid s in to Alcoh ols
George Kokotos* and Caterina Noula
Department of Chemistry, University of Athens, Panepistimiopolis, Athens 15771, Greece
Received November 22, 1995 (Revised Manuscript Received J uly 12, 1996X)
Carboxylic acids are converted into alcohols by chemoselective reduction of their corresponding
fluorides with sodium borohydride and dropwise addition of methanol. The method is general and
mild and displays a high level of functional group compatibility. N-Protected amino and peptide
alcohols, bearing varieties of protecting groups, are prepared in the same way from their
corresponding amino acids and peptides without racemization.
In tr od u ction
Reduction of carboxylic acids into alcohols is a useful
Sch em e 1
and important transformation in synthetic organic chem-
istry. Methods for the conversion of carboxylic acids and
derivatives into primary alcohols have been summarized
by Larock.1 More recent methods for the reduction of
carboxylic acids utilize aluminum hydride and triethyl-
amine,2 Zn(BH
trolysis in the presence of NaBH
)
2
and trifluoroacetic anhydride, elec-
3
4
Ta ble 1. Red u ction of Ca r boxylic Acid s to Alcoh ols
4
5
4
, and NaBH
or catechol-TFA. Primary alcohols may also be ob-
tained by (a) reduction of esters with ZnBH under
and
SiH, electroreduction of esters, and (b) reduction
of acyl chlorides with Zn(BH and N,N,N′,N′-tetra-
4 2
with I
6
4
7
sonication, reduction of esters with Ti(OPr-i)
4
8
9
(EtO)
3
4 2
)
methylethylenediamine.10 However, many of these meth-
ods have limited use if the substrate contains sensitive
functional groups. Thus, efforts are still directed toward
the development of selective and more convenient meth-
ods. One such method, the conversion of carboxylic acids
to alcohols by chemoselective reduction of their corre-
sponding fluorides with sodium borohydride, is reported
here.
Resu lts a n d Discu ssion
Acyl fluorides have been rarely used in organic syn-
thesis. They have greater stability than the correspond-
ing chlorides toward neutral oxygen nucleophiles such
as water and methanol, yet appear to be of equal
1
1
reactivity toward anionic nucleophiles and amines.
1
2
13
Recently, R-Fmoc, Boc, or Z amino acid fluorides have
X
Abstract published in Advance ACS Abstracts, September 1, 1996.
(1) Larock, R. C. Comprehensive Organic Transformations; VCH:
New York, 1989; pp 548-552.
(
(
2) Cha, J . S.; Brown, H. C. J . Org. Chem. 1993, 58, 3974-3979.
3) Ranu, B. C.; Das, A. R. J . Chem. Soc., Perkin. Trans. 1 1992,
been found to be stable rapid-acting acylating reagents
for peptide bond formation. Cyanuric fluoride is a mild
reagent that is suitable for the preparation of acyl
fluorides even when unsaturated double bonds, hydroxyl
1
561-1562.
4) Shundo, R.; Matsubara, Y.; Nishiguchi, I.; Hirashima, T. Bull.
Chem. Soc. J pn. 1992, 65, 530-534.
(
(
5) (a) Kanth, J . V. B.; Periasamy, M. J . Org. Chem. 1991, 56, 5964-
5
1
965. (b) Prasad, A. S. B.; Kanth, J . V. B.; Periasamy, M. Tetrahedron
992, 48, 4623-4628.
14
groups, or aromatic rings are found in the molecule.
(
(
(
(
6) Suseela, Y.; Periasamy, M. Tetrahedron 1992, 48, 371-376.
7) Ranu, B. C.; Basu, M. K. Tetrahedron Lett. 1991, 32, 3243-3246.
8) Berk, S. C.; Buchwald, S. L. J . Org. Chem. 1992, 57, 3751-3753.
9) Shono, T.; Masuda, H.; Murase, H.; Shimomura, M.; Kashimura,
Carboxylic acids were converted into the corresponding
fluorides by treatment with cyanuric fluoride in the
presence of pyridine (Scheme 1). Acyl fluorides were
reduced in situ to primary alcohols by sodium borohy-
dride with dropwise addition of methanol at room tem-
perature. A variety of acids, namely decanoic, palmitic,
benzoic, 1-naphthoic, o-nitrobenzoic, and phenylacetic,
were converted into alcohols in very high yield (Table 1).
S. J . Org. Chem. 1992, 57, 1061-1063.
10) Kotsuki, H.; Ushio, Y.; Yoshimura, N.; Ochi, M. Tetrahedron
Lett. 1986, 27, 4213-4214.
(
(
11) (a) Bender, M. L.; J ones, J . M. J . Org. Chem. 1962, 27, 3771-
3
2
774. (b) Swain, C. G.; Scott, C. B. J . Am. Chem. Soc. 1953, 75, 246-
48.
(
12) Carpino, L. A.; Sadat-Aalaee, D.; Chao, H. G.; DeSelms, R. H.
J . Am. Chem. Soc. 1990, 112, 9651-9652.
13) Carpino, L. A.; Mansour, E.-S. M. E.; Sadat-Aalaee, D. J . Org.
Chem. 1991, 56, 2611-2614.
(
(14) Olah, G. A.; Nojima, M.; Kerekes, I. Synthesis 1973, 487-488.
S0022-3263(95)02069-X CCC: $12.00 © 1996 American Chemical Society

One-Pot Conversion of Carboxylic Acids into Alcohols
J . Org. Chem., Vol. 61, No. 20, 1996 6995
Ta ble 2. Red u ction of N-P r otected Am in o Acid s to Am in o Alcoh ols
The polyunsaturated acids arachidonic and linoleic were
reduced in good yields, as was camphanic acid. Under
the conditions described, the double bonds, the nitro
group, and the lactone group remained unaffected.
N-Protected amino alcohols are important synthetic
intermediates, particularly useful in the synthesis of
peptide aldehydes that are potent inhibitors of pro-
teases.15 They can also be incorporated at the C-terminal
of biologically active peptides, e.g., enkephalins, to modify
the biological activity.16 The conversion of N-protected
amino acids and peptides into alcohols by chemoselective
reduction of their corresponding mixed anhydrides and
N-carboxyanhydrides18 with sodium borohydride has also
been reported. In the present work, a variety of N-
protected amino acids were converted rapidly into alco-
hols by in situ reduction of their corresponding fluorides
with sodium borohydride in high yields (Table 2). How-
ever the yield of the reduction for the dipeptide 1p was
moderate. The peptide bond and the N-terminal ure-
thane bonds of benzyloxycarbonyl (Z), tert-butoxycarbonyl
values with those reported in the literature (Table 2). To
verify this point the enantiomeric purities of 2j, 2m , and
2p were checked by NMR analysis of their esters with
(R)-(+)-R-methoxy-R-(trifluoromethyl)phenylacetic acid
(Mosher esters).20 The H NMR spectrum (CDCl
1
, 500
3
MHz) of the Mosher ester of 2j was compared with the
spectra of the Mosher esters of (R)-Boc-phenylalaninol
and (RS)-Boc-phenylalaninol. Enantiomeric excess >95%
was indicated for 2j by the absence of any diastereomeric
proton signal in the spectrum of its Mosher ester since
the NH proton, the methoxy protons, and the methylene
protons of the hydroxymethyl group are well resolved in
the spectrum of the Mosher ester of (RS)-Boc-phenyl-
alaninol. Furthermore, no absorptions caused by the
presence of the other enantiomer could be observed for
the Mosher esters of 2m and 2p .
1
7
The method described herein has the advantage of
chemoselectivity in comparison with the I
2
-NaBH
4
method,21 which cannot be applied to N-protected pep-
tides and to substates containing N-acyl-type protecting
groups or ester protective groups. The borane-tetrahy-
drofuran method22 is only applied to N-protected amino
acids giving products of lower chemical and optical purity,
as is concluded by comparison of the determined values
of specific rotations (Table 2) with those reported for the
(Boc), and 9-fluorenylmethoxycarbonyl (Fmoc) protective
groups are not reduced. Moreover, the benzyl ether and
benzyl ester groups used for the protection of the side
chain of serine and glutamic acid remained inert.
The present method proceeds with retention of optical
purity as indicated by comparison of the specific rotation
borane-tetrahydrofuran method [2j, [R] ) -0.80 (1.1,
D
2
2
CHCl
3
); 2m , [R]
D
) +0.25 (1, CHCl
3
)].
(
15) (a) Thompson, R. Methods Enzymol. 1977, 46, 220-225. (b)
Sharma, R. P.; Gore, M. G.; Akhtar, M. J . Chem. Soc., Chem. Commun.
979, 875-877. (c) Bakker, A. V.; J ung, S.; Spencer, R. W.; Vinick, F.
J .; Faraci, W. S. Biochem. J . 1990, 271, 559-562.
16) Pless, J .; Bauer, W.; Cardinaux, F.; Closse, A.; Hauser, D.;
In conclusion, the cyanuric fluoride-NaBH
4
-MeOH
1
procedure provides a general, rapid, and convenient
method for the reduction of carboxylic acids into alcohols.
Its compatibility with a variety of normally reducible
(
Huguenia, R.; Roemer, D.; Buescher, H.-H.; Hill, R. C. Helv. Chim.
Acta 1979, 62, 398-411.
(17) (a) Kokotos, G. Synthesis 1990, 299-301. (b) Rodriguez, M.;
Linares, M.; Doulut, S.; Heitz, A,; Martinez, J . Tetrahedron Lett. 1991,
2, 923-926.
18) Fehrentz, J .-A.; Califano, J .-C.; Amblard, M.; Loffet, A.; Mar-
tinez, J . Tetrahedron Lett. 1994, 35, 569-571.
19) Soai, K.; Oyamada, H.; Takase, M. Bull. Chem. Soc. J pn. 1984,
7, 2327-2328.
(20) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543-2549.
3
(
(21) McKennon, M. J .; Meyers, A. I.; Drauz, K.; Schwarm, M. J . Org.
Chem. 1993, 58, 3568-3571.
(
(22) Stanfield, C. F.; Parker, J . E.; Kanellis, P. J . Org. Chem. 1981,
46, 4799-4800.
5

6
996 J . Org. Chem., Vol. 61, No. 20, 1996
Kokotos and Noula
functional groups makes it more useful for selective
carboxylic acid reduction in polyfunctional molecules.
7 Hz, 2H), 7.55 (d, J ) 7 Hz, 2H), 7.42-7.25 (m, 9H), 5.12-
5
2
1
.05 (m, 3H), 4.42-4.15 (m, 3H), 3.78-3.52 (m, 3H), 2.44 (m,
H), 2.23 (m, 1H), 1.88 (m, 2H); MS (FAB) m/ e 468 (M + Na,
00). Anal. Calcd for C27H27NO : C, 72.79; H, 6.11; N, 3.14.
5
Exp er im en ta l Section
Found: C, 72.49; H, 6.21; N, 3.26.
Gen er a l P r oced u r es. Melting points are uncorrected.
Optical rotations were measured at 25 °C. All asymmetric
amino acid derivatives were of the L-configuration and were
purchased from Fluka Chemical Co. Cyanuric fluoride was
purchased from Lancaster. All solvents and chemicals were
of reagent grade and used without further purification. Silica
gel 60 (70-230 mesh, Merck) was used for column chroma-
tography.
(S)-2-[N-(9H -flu or en ylm et h oxyca r b on yl)a m in o]p en -
ta n e-1,5-d iol (2o) was purified by column chromatography
3 3
using CHCl OD) δ 7.80
/MeOH (95:5) as eluent: 1H NMR (CD
(d, J ) 7 Hz, 2H), 7.68 (d, J ) 7 Hz, 2H), 7.45-7.28 (m, 4H),
4.42-4.20 (m, 3H), 3.62-3.48 (m, 5H), 1.65-1.15 (m, 4H); MS
(FAB) m/ e 364 (M + Na, 100). Anal. Calcd for C H23NO4:
2
0
C, 70.36; H, 6.79; N, 4.10. Found: C, 70.12; H, 6.93; N, 4.11.
Gen er a l P r oced u r e for th e P r ep a r a tion of Mosh er
Ester s of N-P r otected Am in o Alcoh ols. To a stirred
solution of N-protected amino alcohol (0.20 mmol) in dichlo-
romethane (3 mL) were added 4-(dimethylamino)pyridine (5
mg, 0.04 mmol), (R)-(+)-R-methoxy-R-(trifluoromethyl)pheny-
lacetic acid (82 mg, 0.35 mmol), and dicyclohexylcarbodiimide
Gen er a l P r oced u r e for th e P r ep a r a tion of Alcoh ols.
Pyridine (80 µL,1 mmol) and subsequently cyanuric fluoride
(
180 µL, 2 mmol) were added to a stirred solution of the acid
or N-protected amino acid or dipeptide (1 mmol) in CH Cl (2.5
mL), kept under a N atmosphere, at -20 to -10 °C. Precipi-
2
2
2
tation of cyanuric acid occurred and increased gradually as
the reaction proceeded. After the mixture was stirred at -20
to -10 °C for 1 h, ice-cold water was added along with 15 mL
(78 mg, 0.38 mmol) at 0 °C. The reaction mixture was stirred
at 0 °C for 30 min and at room temperature overnight. After
removal of the solvents the mixture was separated by column
of additional CH
the aqueous layer was extracted once with CH
combined organic layers were washed with ice-cold water (10
mL), dried (Na SO ), and concentrated under reduced pressure
to a small volume (2 mL). NaBH (76 mg, 2 mmol) was added
2
Cl
2
. The organic layer was separated, and
chromatography using CHCl
3
as eluent. The product was used
, 500 MHz) analysis.
2
2
Cl (5 mL). The
for 1H NMR (CDCl
3
1
Ch a r a cter istic H NMR Ch em ica l Sh ifts (in p p m ). (S)-
ter t-Bu toxyca r bon yl)p h en yla la n in ol Mosh er ester : 4.53
d, J ) 6.5 Hz, 1H), 4.30 (dd, J ) 3.5 Hz, J gem ) 11 Hz, 1H),
2
4
(
(
4
4
in one portion, and MeOH (2 mL) was then added dropwise
over a period of 10-15 min at rt. The reaction mixture was
2 4
neutralized with 1 N H SO , and the organic solvents were
.21 (dd, J ) 3.9 Hz, J gem ) 11 Hz, 1H), 3.55 (s, 3H).
(R)-(ter t-Bu t oxyca r b on yl)p h en yla la n in ol Mosh er
evaporated under reduced pressure. The residue was treated
with EtOAc (10 mL) and H O (5 mL); the organic layer was
separated, and the aqueous layer was extracted with EtOAc
2 × 8 mL). The combined organic layers were washed
consecutively with 1 N H SO (5 mL) and H
O (2 × 10 mL)
and dried (Na SO ), and the solvent was evaporated under
ester : 4.47 (d, J ) 6.5 Hz, 1H), 4.36 (dd, J ) 3.8 Hz, J gem )
10.6 Hz, 1H), 4.16 (dd, J ) 4.4 Hz, J gem ) 10.6 Hz, 1H), 3.56
2
(s, 3H).
(
2
4
2
Ack n ow led gm en t. Financial support from the Eu-
ropean Community (BIO2-CT943041) is gratefully ac-
knowledged.
2
4
reduced pressure. The residue was purified by distillation or
column chromatography using EtOAc/petroleum ether (bp 40-
6
0 °C) (1:1) as eluent.
1S)-1-H yd r oxym et h yl-4,7,7-t r im et h yl-2-oxa b icyclo-
(
2
5
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
Mosher esters of 2j, (S)-Boc-Phe-ol, (RS)-Boc-Phe-ol, 2m , and
2p (9 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
[
2.2.1]h ep ta n -3-on e (2i): mp 178-181 °C; [R]
D
) +1.6 (c 1,
1
CHCl ); H NMR (CDCl ) δ 4.00 (dd, J ) 6 Hz, J gem ) 18 Hz,
3
3
1
1
9
H), 3.83 (dd, J ) 8.5 Hz, J gem ) 18 Hz, 1H), 2.00 (m, 1H),
.88-1.78 (m, 2H), 1.71 (m, 1H), 1.12, 0.98 and 0.95 (s, s, s,
H); MS (FAB) m/ e 207 (M + Na, 100). Anal. Calcd for
10 16 3
C H O : C, 65.19; H, 8.75. Found: C, 65.23; 8.90.
Ben zyl (S)-4-[N-(9H-flu or en ylm eth oxycar bon yl)am in o]-
1
5
-h yd r oxyp en ta n oa te (2n ): H NMR (CDCl
3
) δ 7.75 (d, J )
J O9520699