Versatile, high 2,4-syn dialkyl diastereoselection in the radical debromination of α-bromo-α-methyl-δ-valerolactones with tri-n-butyltin hydride and a catalytic amount of triethylborane

Article abstract of DOI:10.1016/S0040-4039(01)01507-6

An interesting 2,4-syn dialkyl diastereoselection has been observed in the radical debromination of α-bromo-α-methyl-δ-valerolactones. The reaction of 4-alkyl-2-bromo-3-hydroxy-2-methyl-5-pentanolides with Bu₃SnH and a catalytic amount of Et₃B gave, essentially, a single diastereomer with a 2,4-syn dialkyl relationship, independent of the orientation of the hydroxy substituent at C-3.

Full text of DOI:10.1016/S0040-4039(01)01507-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7299–7301
Versatile, high 2,4-syn dialkyl diastereoselection in the radical
debromination of a-bromo-a-methyl-d-valerolactones with
tri-n-butyltin hydride and a catalytic amount of triethylborane
Syun-ichi Kiyooka,a,* Yong-Nan Li,a Kazi A. Shahid,b Momotoshi Okazakib and Yoshihiro Shutob
aDepartment of Chemistry, Faculty of Science, Kochi University, 2-5-1 Akebono-cho, Kochi 780-8520, Japan
bThe United Graduate School of Agricultural Sciences, Ehime University, 3-5-7 Tarumi, Matsuyama 790-8566, Japan
Received 12 July 2001; revised 14 August 2001; accepted 20 August 2001
Abstract—An interesting 2,4-syn dialkyl diastereoselection has been observed in the radical debromination of a-bromo-a-methyl-
d-valerolactones. The reaction of 4-alkyl-2-bromo-3-hydroxy-2-methyl-5-pentanolides with Bu3SnH and a catalytic amount of
Et3B gave, essentially, a single diastereomer with a 2,4-syn dialkyl relationship, independent of the orientation of the hydroxy
substituent at C-3. © 2001 Elsevier Science Ltd. All rights reserved.
During our studies on the total synthesis of (+)-disco-
dermolide we encountered a problem in which the
acidic deprotection of the TBS function in 2,3-syn
enantiomers 1, which were intended for use in the
preparation of the corresponding syn- and anti-propi-
onate aldol adducts by a reliable methodology involv-
ing highly diastereoselective radical debromination,1
resulted in a facile lactonization to give the d-valerolac-
tones, 2 and 3 (Scheme 1).2 Since a variety of methods
for converting stereochemically regulated d-valerolac-
tones to useful acyclic derivatives are available, an
investigation of the debromination at the stage of d-
valerolactone was deemed to be the method of choice.
Diastereoselection during radical reduction of not only
acyclic but also the cyclic system4,5 might be useful to
synthetic organic chemists, because of the expected
higher selectivity due to the ring system. The reductive
cleavage of the carbonꢀbromine bond in an a-bromo-a-
methylcyclohexanone derivative was reported to give
the 2,4-syn dimethyl compound with moderate stereose-
lection under conditions using tri-n-butyltin hydride
(Bu3SnH) and a catalytic amount of the radical initia-
tor azobisisobutyronitrile (AIBN).3 We disclose herein
a remarkable diastereoselection process which occurs
during the radical debromination of a-bromo-d-
valerolactones.
OH
O
OH
O
PTSA, / MeOH
The preparation of a-bromo-d-valerolactones necessary
for the present study was carried out by using our
chiral oxazaborolidinone-promoted asymmetric aldol
reaction of the racemic aldehyde 4 with bromo silyl
TBSO
OEt
HO
OEt
Br Me
1
Br Me
R
R
versatile intermediates
toward (+)-discodermolide
nucleophile 5 in the presence of
D
-TsVal 6. The reac-
PTSA / M eOH
tion gave a 1:1 mixture of essentially enantiopure aldol
adducts, 7 and 8, with the so-called promoter control
on acyclic stereoselection,6 where the newly generated
stereocenter (C-3) was controlled only by the chiral
center of promoter 6. Deprotection with p-toluenesul-
fonic acid (PTSA) in methanol gave the separable lac-
tones, 2 and 3, as shown in Scheme 2.
H
H
H
OH
Me
O
O
R
HO
H
O
R
Me
H
H
Br
O
H
H
Br
3
2
Debromination reactions of 2 and 3 took place
smoothly in good yields by treatment with 5 mole
equiv. of Bu3SnH and a catalytic amount of Et3B7 in
toluene at −78°C for 2 h. This reaction was accompa-
nied with striking diastereoselection (ꢀ100%) and the
Scheme 1.
* Corresponding author. Tel.: +81-88-844-8295; fax: +81-88-844-8359;
e-mail: kiyo@cc.kochi-u.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01507-6

7300
S. Kiyooka et al. / Tetrahedron Letters 42 (2001) 7299–7301
13 might be reduced because of the larger TMS sub-
O
stituent at C-3. We were actually able to trap the
counter isomer, 2,4-anti 15. However, a considerably
large selection (5:1) was still observed. Thus, it is note-
worthy that the orientation of the substituent at C-4
plays a major role in allowing a preferential approach
of the hydride from the opposite side, compared with
that at C-3. In the case of g-lactones, such superior
2,4-syn diastereoselection could not be observed; the
radical debromination reactions of isomers, 16 and 17,
having a configuration opposite that at C-2, resulted in
the same low selectivity (2:1) of syn- and anti-products,
18 and 19, which suggests that both reactions proceed
via essentially the same transition state assembly
(Scheme 5).
Br
OTMS
OEt
+
TBSO
H
Me
R
5
racemate
4
O
D-TsVal, CH2Cl2
D-TsVal
O
TsN
BH3·THF, -78oC, 16 h
B
H
6
78% yield
OH
O
OH O
OEt
TBSO
OEt +
TBSO
Br Me
Br Me
R
H
R
7
enantiopure
8
H
Me
O
O
H
In conclusion, a very high level of diastereoselection
was observed in the radical debromination of a-bromo-
a-methyl-d-valerolactones and the obtained selectivity
reaches the level of practical use. In addition, the
stereochemically regulated d-valerolactones can be con-
verted to versatile compounds having a simple 2,4-syn
dialkyl unit, e.g. in the case of methyl groups at C-2
and C-4 after dehydroxylation at C-3, where they can
subsequently be converted to a known chiral lactone9
and the Prelog–Djerassi lactonic acid.10 Furthermore,
d-valerolactones having 2,4-syn dialkyl units could be
made generally available for use as precursors for
acyclic segments through ring-opening with various
OH
O
PTSA, MeOH
rt, 2 h
R
HO
H
R
+
Me
H
Br
H
O
H
H
Br
96% yield
Scheme 2.
2
3
debrominated products, 9 and 10,8 were obtained from
the reactions of 2 and 3, respectively, with no detectable
by-products, as shown in Scheme 3 and Table 1. The
distinctive 2,4-syn selection, found in 9 and 10, during
the radical process appears to be affected only by the
chiral center at C-4, completely independent of the
direction of the hydroxy function at C-3. The stereo-
chemical outcome can be rationalized on the basis of
the avoidance of steric hindrance which can be
attributed to the 1,3-interaction produced between the
R substituent at C-4 and the incoming Bu3SnH so that
the hydride can approach the radical center at C-2 from
the opposite side. The above rationalization, however,
is not necessarily sufficient to account for the very high
level diastereoselection.
Table 1. Highly diastereoselective radical and debromina-
tion of a-bromo-a-methyl-d-valerolactones, 2 and 3
(Scheme 3)
Entry
d-valero-
lactones/R
Yields (%)
2,4-syn-diastereo-
selectivity (%)
1
2
3
4
5
6
Me (2-a)
Pr (2-b)
Bn (2-c)
Me (3-a)
Pr (3-b)
Bn (3-c)
78 (9-a)
75 (9-b)
91 (9-c)
75 (10-a)
66 (10-b)
76 (10-c)
ꢀ100
ꢀ100
ꢀ100
ꢀ100
ꢀ100
ꢀ100
In order to estimate the influence of bulkiness at C-3 on
the diastereoselection, the hydroxy function of 2-a and
3-a was protected by a TMS group. The result is shown
in Scheme 4. The radical debromination of 11 remained
unchanged, compared with that of 2-a, and a similar,
high 2,4-syn selectivity was observed for 12 because of
the same orientation of both substituents at C-3 and
C-4. On the other hand, the selectivity in the reaction of
O
O
O
O
Bu3SnH, Et3B
Me
Me
Me
Me
Me
Br
OTMS
toluene, -78ºC, 2 h
OTMS
85% yield
11
12
1
O
O
1
O
O
~100% selection
Bu3SnH, Et3B
Me
4
4
2
2
O
O
R
Me
R
R
Bu3SnH, Et3B
Br
3
Me
3
toluene, -78ºC, 2 h
OH
9 (a-c)
OH
Br
OTMS
toluene, -78ºC, 2 h
2
82% yield
13
O
O
O
O
O
O
O
O
Bu3SnH, Et3B
Me
+
R
Me
Br
Me
Me
Me
Me
toluene, -78ºC, 2 h
OH
OH
OTMS
OTMS
5
:
1
10 (a-c)
3
14
15
Scheme 4.
Scheme 3.

S. Kiyooka et al. / Tetrahedron Letters 42 (2001) 7299–7301
7301
Me
Me
Me
Br
tiopure adducts attributable to the excellent enantioselec-
tivity of the aldol reaction used: (a) Kiyooka, S. -i.; Kira,
H.; Hena, M. A. Tetrahedron Lett. 1996, 37, 2597–2600;
(b) Kiyooka, S. -i.; Goh, K.; Nakamura, Y.; Takesue, H.;
Hena, M. A. Tetrahedron Lett. 2000, 41, 6599–6603.
7. Nozaki, K.; Oshima, K.; Utimoto, K. Tetrahedron 1989,
45, 923–933.
Bu3SnH, Et3B
Toluene, -78oC, 2 h
O
O
16
67-75% yields
Br
Bu3SnH, Et3B
Me Toluene, -78oC, 2 h
O
O
8. Physical data of products. 9-a: [h]2D5 −6.0 (c 1.0%,
CHCl3). IR (neat) 3537, 1716 cm−1. 1H NMR (CDCl3,
400 MHz): l (ppm) 1.07 (d, J=6.8, 3H), 1.40 (d, J=7.1,
3H), 1.97–2.07 (m, 1H), 2.20 (s, 1H), 2.44 (dq, J=9.8,
7.1, 1H), 3.30 (dd, J=9.3, 8.3, 1H), 3.83 (dd, J=11.5,
10.0, 1H), 4.32 (dd, J=11.5, 4.9, 1H). 13C NMR (CDCl3,
100 MHz): l (ppm) 13.5, 13.7, 36.6, 44.2, 70.5, 75.9,
173.6. 9-b: [h]2D4 −19.8 (c 0.96%, CHCl3). IR (neat) 3426,
17
Me
Me
Me
Me
O
+
:
O
O
O
19
18
2
1
Scheme 5.
1
1728 cm−1. H NMR (CDCl3, 400 MHz): l (ppm) 0.95 (t,
J=7.1, 3H), 1.38 (d, J=7.1, 3H), 1.21–1.45 (m, 4H),
1.87–1.93 (m, 1H), 2.21 (d, J=4.9, 1H), 2.49 (dq, J=9.3,
6.8, 1H), 3.37 (ddd, J=9.0, 7.1, 4.9, 1H), 3.95 (dd,
J=11.7, 7.8, 1H), 4.40 (dd, J=11.7, 4.4, 1H). 13C NMR
(CDCl3, 100 MHz): l (ppm) 13.6, 14.1, 19.8, 31.4, 41.7,
43.8, 68.7, 75.1, 173.7. 9-c: [h]1D8 −5.83 (c 1.2%, CHCl3).
types of reagents. A study of the reaction mechanism is
currently underway.
Acknowledgements
1
IR (neat) 3428, 1728 cm−1. H NMR (CDCl3, 400 MHz):
l (ppm) 1.38 (d, J=6.8, 3H), 2.07 (d, J=4.9, 1H),
2.19–2.28 (m, 1H), 2.54 (dq, J=9.3, 6.8, 1H), 2.56 (dd,
J=14.2, 9.3, 1H), 3.03 (dd, J=13.9, 5.6, 1H), 3.74 (ddd,
J=9.3, 7.1, 4.9, 1H), 3.93 (dd, J=11.7, 7.3, 1H), 4.26
(dd, J=11.7, 4.4, 1H), 7.18–7.34 (m, 5H). 13C NMR
(CDCl3, 100 MHz): l (ppm) 13.5, 35.7, 43.6, 43.6, 68.1,
74.4, 126.8, 128.8, 129.0, 137.9, 173.6. 10-a: [h]2D5 +1.0 (c
This work was supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Science,
Sports and Culture of Japan.
References
1.0%, CHCl3). IR (neat) 3435, 1712 cm−1 1H NMR
.
(CDCl3, 400 MHz): l (ppm) 1.02 (d, J=6.8, 3H), 1.32 (d,
J=7.1, 3H), 2.18–2.27 (m, 1H), 2.57 (dq, J=7.1, 3.2,
1H), 3.87 (s, 1H), 4.19 (dd, J=11.0, 5.8, 1H), 4.30 (dd,
J=11.0, 11.7, 1H). 13C NMR (CDCl3, 100 MHz): l
(ppm) 12.8, 12.8, 33.8, 42.3, 70.2, 71.6, 173.1. 10-b: [h]D24
1. (a) Kiyooka, S.-i.; Shahid, K. A.; Hena, M. A. Tetra-
hedron Lett. 1999, 40, 6447–6449; (b) Kiyooka, S.-i.;
Shahid, K. A. Tetrahedron Lett. 2000, 41, 2633–2637.
2. Kiyooka, S.-i. ‘Enantioselective construction of acyclic
segments in natural products based on chiral oxazaboro-
lidinone-mediated aldol reaction under promoter (cata-
lyst) control’; 2000 International Chemical Congress of
Pacific Basin Societies, December, 2000, Honolulu,
Hawaii. Abstract Orgn 9 c562. Discodermolide Synthe-
sis, recent examples: (a) Smith, III, A. B.; Kaufman, M.
D.; Beauchamp, T. J.; LaMarche, M. J.; Arimoto, H.
Org. Lett. 1999, 1, 1823–1826; (b) Paterson, I.; Florence,
G. J.; Gerlach, K.; Scott, J. P. Angew. Chem., Int. Ed.
2000, 39, 377–380.
3. Corey, E. J.; Trybulsky, E. J.; Melvin, Jr., L. S.; Nico-
laou, K. C.; Secrist, J. A.; Lett, R.; Sheldrake, P. W.;
Falck, J. R.; Brunelle, D. J.; Haslanger, M. F.; Kim, S.;
Yoo, S.-E. J. Am. Chem. Soc. 1978, 100, 4618–4620.
4. Guindon, Y.; Jung, G.; Gue´rin, B.; Ogilvie, W. W. Syn-
lett 1998, 213–220 and references cited therein.
−2.5 (c 0.4%, CHCl3). IR (neat) 3437, 1716 cm−1 1H
.
NMR (CDCl3, 400 MHz): l (ppm) 0.95 (t, J=6.8, 3H),
1.33 (d, J=7.1, 3H), 1.23–1.47 (m, 4H), 1.68 (s, 1H),
1.88–2.15 (m, 1H), 2.55 (dq, J=7.3, 3.0, 1H), 3.96 (s,
1H), 4.24 (dd, J=11.0, 6.1, 1H), 4.31 (dd, J=11.7, 11.0,
1H). 13C NMR (CDCl3, 100 MHz): l (ppm) 12.9, 14.1,
19.8, 29.6, 38.6, 42.3, 69.5, 69.7, 173.5. 10-c: [h]2D4 −35.0 (c
0.4%, CHCl3). IR (neat) 3441, 1714 cm−1 1H NMR
.
(CDCl3, 400 MHz): l (ppm) 1.29 (d, J=7.1, 3H), 2.06 (d,
J=3.6, 1H), 2.31–2.39 (m, 1H), 2.49 (dq, J=7.1, 2.9,
1H), 2.64 (dd, J=13.7, 6.6, 1H), 2.75 (dd, J=13.7, 8.8,
1H), 3.82 (s, 1H), 4.24 (dd, J=11.0, 5.9, 1H), 4.43 (t,
J=11.5, 1H), 7.19–7.35 (m, 5H). 13C NMR (CDCl3, 100
MHz): l (ppm) 12.8, 33.8, 40.7, 42.3, 68.8, 69.3, 126.7,
128.7, 128.9, 138.3, 173.2.
9. (a) Nicolaou, K. C.; Pihko, P. M.; Diedrichs, N.; Zou,
N.; Bernal, F. Angew. Chem., Int. Ed. 2001, 40, 1262–
1265; (b) Collum, D. B.; McDonald, III, J. H.; Still, W.
C. J. Am. Chem. Soc. 1980, 102, 2118–2120.
5. Ghosez, A.; Giese, B.; Go¨bel, T.; Zipse, H. In Stereose-
lective Synthesis; Helmchen, G.; Hoffmann, R. W.;
Mulzer, J.; Schaumann, E., Eds.; Houben-Weyl: Stutt-
gart, 1996; Vol. 7, pp. 3913–3924.
6. This process is very practical where racemic starting
compounds can be converted to the corresponding enan-
10. A recent example: Oppolzer, W.; Walther, E.; Balado, C.
P.; De Brabander, J. Tetrahedron Lett. 1997, 38, 809–812.