Carboxy mediated stereoselective reduction of ketones with sodium triacetoxyborohydride: Synthesis of novel 3,4-fused tetrahydropyran and tetrahydrofuran prolines

Article abstract of DOI:10.1016/j.tetlet.2004.06.070

In the presence of a carboxyl group positioned for participation, NaBH(OAc)₃ will reduce the usually unreactive ketones in a stereoselective manner. This reaction was applied in a key step to prepare precursors 7 and 15 toward the title compounds 1 and 2. These results are consistent with the exchange of one of the acetoxy groups in the reducing agent with the carboxy group followed by intramolecular delivery of the hydride.

Full text of DOI:10.1016/j.tetlet.2004.06.070

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6097–6100
Carboxy mediated stereoselective reduction of ketones with sodium
triacetoxyborohydride: synthesis of novel 3,4-fused tetrahydropyran
and tetrahydrofuran prolinesq
Yi-Tsung Liu, Jesse K. Wong, Meng Tao, Rebecca Osterman, Mousumi Sannigrahi,*
Viyyoor M. Girijavallabhan and Anil Saksena
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Received 11 June 2004; accepted 16 June 2004
Abstract—In the presence of a carboxyl group positioned for participation, NaBH(OAc)3 will reduce the usually unreactive ketones
in a stereoselective manner. This reaction was applied in a key step to prepare precursors 7 and 15 toward the title compounds 1 and
2. These results are consistent with the exchange of one of the acetoxy groups in the reducing agent with the carboxy group followed
by intramolecular delivery of the hydride.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Due to their unique conformational properties, substi-
tuted prolines have been used extensively to influence
the conformation of peptide backbones and to induce
desired turns in host structures.1 These nonproteino-
genic amino acids are also incorporated into peptide
molecules in an attempt to improve their pharmaco-
logical properties, and this methodology continues to be
a powerful tool for identifying and elucidating struc-
ture–activity relationships.2 In the course of our
medicinal chemistry program, we desired to prepare and
incorporate into a peptide molecule the substituted
novel prolines 1 and 2 (Fig. 1).
Me
2
Me Me
Me
3
3
3a
2
O
6a
4
O
4a
7a
7
6
COOMe
4
N
COOMe
5
N
Cbz
Cbz
2
1
Figure 1.
O
Me
Prenylation of enamine 4 derived from the ketone 33
proceeded smoothly and the prenylated product 5 was
isolated in ꢀ50% yield in addition to unreacted starting
material (Scheme 1).
N
Me
O
b
a
COOMe
N
COOMe
Cbz
N
COOMe
Cbz
N
5
3
4
Cbz
Reduction of 5 with NaBH4 gave three products, 6, 7,
and 8 in the increasing order of polarity and in a ratio of
11:18:24. Compound 6 has the stereochemistry as cis, cis
Scheme 1. Reagents and conditions: (a) pyrrolidine, MS4A, toluene,
D; (b) prenyl bromide, K2CO3, MeCN, then H3Oþ.
Keywords: Sodium triacetoxyborohydride; Stereoselective reduction;
Tetrahydropyran and tetrahydrofuran proline.
across C-2, C-3, and C-4 because it is derived from the
hydride attack solely from the a-side of the molecule.
Compounds 7 and 8 are the corresponding a- and b-
hydroxy isomers of the major 2,3-trans prenylation
product (Scheme 2).
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.06.070
* Corresponding author. Tel.: +1-908-740-4403; fax: +1-908-740-7512;
e-mail: mousumi.sannigrahi@spcorp.com
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.070

6098
Y.-T. Liu et al. / Tetrahedron Letters 45 (2004) 6097–6100
Me
Me
Me
Me
Me
Me
Me
Me
HO
O
O
O
a
a
COOMe
COOMe
COOH
COOMe
N
N
N
N
Cbz
Cbz
5
Cbz
Cbz
6
+
5
10
b
Me
Me
Me
Me
HO
Me
HO
Me
Me
+
Me
HO
O
H7a
c
H4a
COOMe
COOMe
COOMe
N
N
Cbz
Cbz
8
N
COOR
N
H5
7
Cbz
Cbz
1
11 (R = H)
7 ( R = Me)
Scheme 2. Reagents and conditions: (a) NaBH4, MeOH, THF.
CH2N2
H4a H7a8%
H5 H4a1.5%
Scheme 4. Reagents and conditions: (a) 1 N LiOH, dioxane; (b)
NaBH(OAC)3, cat. AcOH then TMSCHN2; (c) BF3ÆMe2O, CH2Cl2.
Me
Me
O
HO
a
keto ester 5 with NaBH4. Cyclization of 7 by BF3ÆMe2O
21
D
COOMe
COOMe
N
N
gave the title compound 1, ½aŠ )50.81 (c 1.0, CHCl3) in
Cbz
Cbz
92% yield. The stereochemistry of 1 is clearly confirmed
as trans, cis across C-2, C-3, and C-4 by PMR–NOE
experiments.
9
8
O
H7a
H4a
The same strategy was applied toward the synthesis of 2.
Thus, treatment of the enamine 4 with methallyl chlo-
ride in the presence of NaI and Na2CO3 followed by
acidic work-up provided the alkylation product 12 in
ꢀ50% yield in addition to unchanged starting material.
H7b
N
COOMe
H5
Cbz
H7b 3.7%
H5 + H7a 14%
H7a
H4a
H7a
Basic hydrolysis of 12 then provided the thermody-
21
namically more preferred 2,3-trans acid 13, ½aŠ )39.16
Scheme 3. Reagents and conditions: (a) BF3ÆMe2O, CH2Cl2.
D
(c 1.0, CHCl3) in 77% yield. Reduction of 13 with
NaBH(OAc)3 gave the C-2, C-3, C-4 trans, cis hydr-
21
D
Treatment of 14 with CH2N2 followed by reaction of 15
Upon treatment of 8 with BF3ÆMe2O the cyclization
product 9 was obtained. PMR analysis through COSY
and NOE experiments unambiguously established a
trans, trans relationship between the substituents of C-2,
C-3, and C-4 (Scheme 3).
oxy acid 14, ½aŠ À 12:31 (c 1.0, CHCl3) in 98% yield.5
with BF3ÆMe2O provided the title compound 2,
21
D
½aŠ À 40:32 (c 1.0, CHCl3) in 84% yield (Scheme 5).
In order to understand the aforementioned processes,
the reaction of NaBH(OAc)3 with 4-ketoproline 19 was
studied. Reaction of N-Cbz 4-ketoproline methyl ester 3
with NaBH(OAc)3 failed to provide any product. Its
reaction with NaBH4 provided three products, the
known 4-cis and 4-trans alcohols 16 and 17 as well as
the over reduced 4-cis diol 18 in a 53:17:30 ratio
(Scheme 6).
In the meantime, saponification of esters 5 gave the acid
10, a single product, in ꢀ95% yield. It is reasoned that
during ester hydrolysis, equilibration occurs at C-3 and
the thermodynamically more preferred product 10 is
obtained (Scheme 4).
Interestingly, reduction of the C-4 carbonyl group with
NaBH(OAc)3 gave 11 with an a-hydroxyl at C-4 as the
sole product in 93% yield. This result is consistent with
the exchange of one of the acetoxy groups of
NaBH(OAc)3 with the carboxyl group, which in turn
donates hydride from the b-side of the molecule. This
effect has been previously observed in the context of
hydroxy ketones.4 Some additional examples of this
unprecedented stereoselective reduction of ketoacids
with NaBH(OAc)3 are described below. Treatment of 11
with CH2N2 gave the same C-2, C-3, C-4 trans, cis hy-
droxy ester 7 obtained above by direct reduction of the
When the 4-ketoproline 19 was reacted with
NaBH(OAc)3 followed by treatment of 20 with CH2N2,
the 4-trans hydroxy acid 17 was isolated in 95% yield
(Scheme 7). As depicted in [I] this result is consistent
with exchange of one of the acetoxy groups in
NaBH(OAc)3 with the carboxylic group in 4-ketopro-
line, which delivers the hydride from the b-face of the
molecule. In a related example, reduction of pinonic
acid methyl ester 21 with NaBH4 gave as expected a
mixture of R and S alcohols 226 (Scheme 8).

Y.-T. Liu et al. / Tetrahedron Letters 45 (2004) 6097–6100
6099
Me Me
O
OMe
HO
a
N
O
a
O
21
COOMe
COOMe
N
N
Me Me
Cbz
Cbz
OMe
4
12
b
O
22
Scheme 8. Reagents and conditions: (a) NaBH4, aq. THF.
HO
O
c
COOH
COOH
N
N
Me Me
O
Cbz
14
Cbz
13
OH
a, b
d
O
23
Me Me
H2'
H5
S
HO
Me
O
HO
OMe
e
H2
O
COOMe
N
COOMe
N
24
Cbz
15
Cbz
2
Scheme 9. Reagents and conditions: (a) NaBH(OAc)3, cat. AcOH; (b)
TMSCHN2, Et2O, MeOH.
Scheme 5. Reagents and conditions: (a) methallyl chloride, NaI,
K2CO3; (b) 1 N LiOH, dioxane; (c) NaBH(OAc)3, cat. AcOH; (d)
TMSCHN2, Et2O, MeOH; (e) BF3ÆMe2O, CH2Cl2.
In contrast, reaction of pinonic acid 23 with large excess
of NaBH(OAc)3 gave in modest (12%) yield a single 5S
21
D
hydroxy compound 24, ½aŠ )21.86 (c 1.0, MeOH)
(Scheme 9). The absolute configuration at C-5 was
determined using J-coupling and NOE data, which
revealed spatial proximity between Me (C-5) and H-2
and H-20. The modest yield in this case suggests that a 6
carbon spatial distance between the participating car-
boxy group and the keto functionality is likely a limiting
factor for the intramolecular hydride delivery. From the
discussed examples it appears that a 4 carbon distance
between the carboxy group and the site of hydride
delivery, as in the rigid proline system, is optimal.7
O
HO
a
COOMe
COOMe
N
N
Cbz
Cbz
3
16
+
HO
HO
+
OH
COOMe
N
N
Cbz
17
Cbz
18
Supplementary data
Scheme 6. Reagents and conditions: (a) NaBH4, aq. THF.
Information available: Experimental procedures and
Characterization for 1, 2, and 24.
Na+
AcO OAc
-
B
O
References and notes
H
O
O
a
O
1. (a) Beausoleil, E.; L’Archeveque, B.; Belec, L.; Atfani, M.;
Lubell, W. D. J. Org. Chem. 1996, 61, 9447–9454; (b) Del
Valle, J. R.; Goodman, M. J. Org. Chem. 2003, 68, 3923–
3931; (c) Del Valle, J. R.; Goodman, M. Angew. Chem., Int.
Ed. 2002, 41(9), 1600–1602; (d) Trabocchi, A.; Cini, N.;
Menchi, G.; Guarna, A. Tetrahedron Lett. 2003, 44, 3489–
3492, and references cited therein.
COOH
N
N
Cbz
Cbz
19
I
HO
2. West, M. L.; Fairlie, D. P. Trends Pharm. Sci. 1995, 16, 67–
75.
3. Holladay, M. W.; Lin, C. W.; May, C. S.; Garvey, D. S.;
Witte, D. G.; Miller, T. R.; Wolfram, C. A. W.; Nadzan, A.
M. J. Med. Chem. 1991, 455–457.
20 (R = H)
17 (R = Me)
COOR
N
Cbz
Scheme 7. Reagents and conditions: (a) NaBH(OAc)3.

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Y.-T. Liu et al. / Tetrahedron Letters 45 (2004) 6097–6100
4. (a) Saksena, A. K.; Mangiaracina, P. Tetrahedron Lett.
1983, 24, 273–276; (b) Evans, D. A.; Chapman, K. T.;
Carriera, E. M. J. Am. Chem. Soc. 1988, 110, 560–3578.
5. Representative procedure to obtain 15. To a stirred
suspension of NaBH(OAc)3 (125 g; 589 mmol) in of CH2Cl2
(1.4 L) was added with cooling (ice bath) a solution of 13
(66.6 g; 210 mmol) in CH2Cl2 (400 mL) over 40 min. Glacial
acetic acid (67 mL) was then added and the reaction
mixture stirred for ꢀ20 h at room temperature. The
reaction mixture was poured onto ice (2 L) and stirred for
1 h. CH2Cl2 (2 L) as added and the organic phase washed
with brine (1 L · 2), dried over Na2SO4, and evaporated to
dryness in vacuo to provide 14 as a syrupy liquid (70 g). It
was dissolved in Et2O/MeOH (930/270 mL), cooled to
)5 ꢁC and TMSCHN2 (186 mL; 2 M in hexane) was added
over 1 h. The reaction was kept at 0 ꢁC for 1 h then stirred at
room temperature for 3.5 h and evaporated to dryness in
vacuo to provide almost pure 15 (71 g) as an oil. It was
purified on a silica gel column using 10–30% ethyl acetate in
hexane as eluent to provide pure 15 (65 g).
6. Kergomard, A. Bull. Soc. Chim. Fr. 1957, 9, 1161–1166.
1
7. All new compounds were characterized by H, 13C NMR,
and high resolution mass spectra. When necessary 1D NOE
and 2D NOESY NMR spectra were obtained to confirm
relative stereochemistry. Elemental analyses were obtained
for crystalline compounds only. Yields refer to isolated
products and have not been optimized. Selective spectral
data is given here.