Crotylation of (R)-2,3-O-cyclohexylideneglyceraldehyde: a simple synthesis of (+)-trans-oak lactone

Article abstract of DOI:10.1016/j.tetlet.2010.05.070

Crotylations of (R)-2,3-cyclohexylideneglyceraldehyde (1) were utilized in a simple synthesis of trans-oak lactone (I), a representative example of chiral β,γ-disubstituted-γ-butyrolactones. In this endeavor, crotylations of 1 in THF mediated with four low valent metals were studied. All these reactions took place efficiently producing 2 in good yields but with varied stereoselectivities. Each reaction produced the corresponding secondary alcohol adduct 2b and 2c predominantly with diastereoisomer 2a only in trace amounts. Among these four reactions, only Sn-mediated addition yielded 2b as the major products. Later, 2c was converted into 2d through oxidation-reduction. Finally, 2c was transformed into trans-oak lactone I in a few steps. Following this route, 2a, 2b, and 2d would produce other stereoisomers of oak lactone.

Full text of DOI:10.1016/j.tetlet.2010.05.070

Tetrahedron Letters 51 (2010) 3893–3896
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Crotylation of (R)-2,3-O-cyclohexylideneglyceraldehyde: a simple synthesis
of (+)-trans-oak lactone
*
Angshuman Chattopadhyay , Dibakar Goswami, Bhaskar Dhotare
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400 085, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Crotylations of (R)-2,3-cyclohexylideneglyceraldehyde (1) were utilized in a simple synthesis of trans-oak
Received 15 April 2010
Revised 14 May 2010
Accepted 18 May 2010
Available online 24 May 2010
lactone (I), a representative example of chiral b,c-disubstituted-c-butyrolactones. In this endeavor, croty-
lations of 1 in THF mediated with four low valent metals were studied. All these reactions took place effi-
ciently producing 2 in good yields but with varied stereoselectivities. Each reaction produced the
corresponding secondary alcohol adduct 2b and 2c predominantly with diastereoisomer 2a only in trace
amounts. Among these four reactions, only Sn-mediated addition yielded 2b as the major products. Later,
2c was converted into 2d through oxidation–reduction. Finally, 2c was transformed into trans-oak lac-
tone I in a few steps. Following this route, 2a, 2b, and 2d would produce other stereoisomers of oak
lactone.
Keywords:
(R)-2,3-Cyclohexylideneglyceraldehyde
Crotylation
Low valent metal
Stereo-selectivity
Oak lactone
Ó 2010 Elsevier Ltd. All rights reserved.
Chiral b,c-disubstituted-c-butyrolactones
1. Introduction
possessing b,c-disubstituted c-butyrolactone units. So far, several
syntheses of A and B were reported in the literature.7 Among them,
Brown et al.7b synthesized all four stereoisomers of oak lactone. In
our ongoing program on the synthesis of bioactive compounds we
are making versatile use of easily accessible (R)-2,3-cyclohexylid-
eneglyceraldehyde (1)8a to synthesize different molecules possess-
ing varied structural features.8a–h We present herein its another
simple application to develop a simple route for stereodivergent
syntheses of all four stereoisomers of oak lactone. In this Letter,
this has been exemplified by the total synthesis of trans-oak lac-
tone (A).
c
-Butyrolactones are the constituents of many biologically ac-
tive natural products.1 Their enantiopurity and absolute configura-
tion often affect their physiological activities.2 Additionally,
optically active
their versatile application in the synthesis of bioactive com-
pounds.1,3 Chiral b,
-disubstituted- -butyrolactones, due to their
c-butyrolactones are useful as chiral synthons for
c
c
varied biological activities, have drawn considerable attention for
their synthesis over the ages.4 Furthermore, the correlation be-
tween optical rotations and different conformations of trans-b,
c-
disubstituted
c
-lactones drew attention of organic chemists.5
Retrosynthetic analysis (Scheme 1) of A suggested that crotyla-
tion of 1 should be a straightforward approach to begin with. This
would enable us to introduce two contiguous stereo-centers in A
including the methyl branching at its C-4 position at an initial
stage. There are several well-known procedures for stereo-differ-
entiating crotylations9 of aldehydes that are performed in highly
anhydrous conditions. Schlapbach and Hoffman7d synthesized only
(4S,5R)-trans-(A) through asymmetric crotylboration of an alde-
hyde. In recent years, there has been considerable attention on per-
(4S,5R)-trans-(A) and (4S,5S)-cis-(B) 5-butyl-4-methyl butyro-
lactones, known as oak lactones (Fig. 1), are extracted as the major
compounds from wood in alcoholic beverages during fermentation
and/or storage in oak barrels.6 Their corresponding (4R,5S)-trans-
(ent-A) and (4R,5R)-cis-(ent-B) enantiomers are also present in
the same beverages. The aroma of alcoholic beverages is believed
to be due to the presence of pure diastereomers of these lactones.6
Compounds A and B are good examples of chiral trans-b,
c- and cis-
b, -disubstituted -butyrolactones, respectively. Hence, apart from
c
c
obtaining them in sufficient amount for their extensive biological
screening, any synthesis of them assumes good significance from
synthetic viewpoint specially to evaluate the applicability of the
approach for stereo-selective construction of other compounds
O
C4H9
O
C4H9
O
O
A
B
* Corresponding author. Tel.: +91 22 2559 5422; fax: +91 22 2550 5151.
E-mail address: achat@barc.gov.in (A. Chattopadhyay).
Figure 1. Structures of trans-oak lactone (A) and cis-oak lactone (B).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.070

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A. Chattopadhyay et al. / Tetrahedron Letters 51 (2010) 3893–3896
R2
R2
O
R1
R1
crotylation
O
C4H9
O
O
C4H9
O
O
A
OH
COOH
CHO
OH
R1, R2 = Cyclohexylidene
1
Scheme 1. Retrosynthesis of trans-oak lactone (A).
forming organic reactions in wet solvents, aqueous medium, or salt
solutions10 with a view to attaining their practical viability. This
prompted us to give an effort to crotylate 1 in moist reaction con-
ditions mediated with several low valent metals.11 This also gave
us an opportunity to compare the efficacy and stereo-selectivity
(Table 1) of all these low valent metal-mediated reactions with
those observed by us earlier8b for the same reaction using Luche’s
procedure.12 First, 1 was crotylated (Scheme 2) following media-
tion with either of low valent Cu, Co, and Fe that were prepared
in situ by reduction of their salts with Zn11a (Table 1, entries a–
c). Also, the same reaction was performed (Scheme 2) following
mediation with low valent Sn, which was prepared in situ by
3. Stereochemistry
Interestingly, all the reactions yielded the same three (2a, 2b,
and 2c)8b isomers as obtained earlier.8b Of them, 2b and 2c were
produced predominantly and 2a was obtained in trace amount in
all cases (Table 1, entries a–d). While, Co- and Fe-mediated reac-
tions afforded 2c little more than 2b (Table 1, entries a and b),
Cu-mediated reaction produced 2c in much higher amount (Ta-
ble 1, entry c). In sharp contrast with these three cases (Table 1, en-
tries a–c) and also the earlier one,8b low valent Sn-mediated
reaction produced 2b as the major product (Table 1, entry d). This
suggests that each low valent metal mediator has its characteristic
role regarding the stereo-selectivity in crotylation of 1. The easy
separation of the diastereomers 2a–c by column chromatography
enabled us to obtain each of them in homochiral form and deter-
mine the stereo-selectivity of each reaction. The fourth possible
isomer (2d)14 was obtained from 2c following an oxidation–reduc-
tion protocol.8h Thus, PCC oxidation of 2c yielded ketone 3 which
was reduced with K-selectride to obtain 2d (Scheme 3) in good
yield and with absolute stereo-selectivity.
reduction of commercially available SnCl2, 2H2O [E0
¼
2þ
þ0:136 V] with zinc [E0
+2e = +0.761 V] (Table 1S,n¼eSnntrþy2ed).
2+
Zn=Zn
All the four reactions were carried out13 using excess amount of
commercially available crotyl bromide (Fluka make, mixture of
cis and trans, 1:5), the metal salt and reducing metal (zinc) to en-
sure their smooth progress. The results of all crotylation reactions
are given below in Table 1.
The formation of 2,3-anti addition products (2b and 2c) in major
amount in all these additions gave evidence that the reactions took
place following Felkin–Anh model (Fig. 2).15 However, the presence
of 3,4-syn- and 3,4-anti- relationships, respectively, in these two
major products (2b and 2c) suggested the participation of Zimmer-
man–Traxler transition state16 (Fig. 3) during the addition of cro-
tylmetals. Presumably, in each case there has been a substantial
degree of inter conversion between (E)-crotylmetal (X) that was
predominantly formed initially from crotyl bromide (Fluka make,
containing a mixture of cis and trans-bromide: 1:5) and (Z)-crotyl-
metal (Y) prior to the C–C bond formation. Hence, the differences
in the formation of 2b and 2c in all four cases could be explained
from the degree of inter conversion between (E)-crotylmetal (X)
and (Z)-crotylmetal (Y) which was certainly governed by the low
valent metal mediator involved.
2. Results
In all these four cases, reactions progressed smoothly and with
absolute regioselectivity giving only the
c-addition product 2 in
good yields (Table 1). Among the four, the yield of Fe-mediated
reaction was found to be the best (Table 1, entry b) and was even
better than that obtained earlier8b following Luche’s procedure. It
is worthy to note that Fe- and Sn-mediated crotylation of 1 took
place at much faster rates (Table 1, entries b and d) than the other
two (Table 1, entries a and c) and also the earlier one.8b Thus,
employing bimetallic redox strategy11 all the four low valent met-
als (Cu, Fe, Co, and Sn) were found to be good mediators with var-
ied efficacies to crotylate aldehyde 1 and again in wet solvent.
Table 1
Crotylation of (R)-2,3-O-cyclohexylideneglyceraldehyde (1)
To prepare A, compound (2c) was first silylated to obtain 4 in
almost quantitative yield. Regio-selective hydroxylation at its ter-
minal olefin afforded 517 in good yield. Benzoylation of 5 and deke-
talization of the resulting benzoate 6 in acidic condition gave 1,2-
diol 7.18 This was subjected to NaIO4 cleavage to produce aldehyde
8. Wittig olefination of 8 yielded olefin 9 in good yield which was
saturated on catalytic hydrogenation to afford 10. This was deben-
zoylated to give 11.19 PCC oxidation of 11 gave aldehyde 12 which
without being purified further was desilylated to afford the rela-
tively unstable lactol 13. This was quickly oxidized with PCC to fur-
Entry Reagents
Time
Products
Yielda (%) Products
Ratio
a
b
c
CoCl2, 6H2O; Zn 24 h
FeCl3/Zn 10 min 2a, 2b, 2c 87
CuCl2, 2H2O; Zn 15 h 2a, 2b, 2c 79
SnCl2, 2H2O; Zn 45 min 2a, 2b, 2c 80
2a, 2b, 2c 78
2a:2b:2c::
3.8:47.5:48.7
2a:2b:2c::
1.5:48.4: 50.1
2a:2b:2c::
4.2:29.5:66.3
2a:2b:2c::
d
7.1:78.2:14.7
nish trans-oak lactone (I)20 (Scheme 3) whose spectral and
**
a
The nearest rounded figures of all yields were given here.
optical data were in conformity with the reported ones.7a
R2
R2
1
R2
1
R2
1
R1
R1
O
O
2
R1
R1
O
2
O
2
3
5
O
H
O
i
5
3
6
+
O
3
5
O
4
6
+
6
4
4
2a
1
O
OH
OH
2b
OH
2c
R1,R2 = cyclohexylidene
Scheme 2. Crotylation of (R)-2,3-O-cyclohexylideneglyceraldehyde(1). Reagents: (i) E-Crotylbromide, Zn/CuCl2.2H2O, CoCl2.6H2O or FeCl3 or SnCl2.2H2O, THF.

A. Chattopadhyay et al. / Tetrahedron Letters 51 (2010) 3893–3896
3895
R2
R2
R1
ii
R1
O
i
O
2c
O
O
86%
77%
O
OH
3
R1,R2 = cyclohexylidene
2d
R2
R2
R1
O
R1
OH
HO
O
iv, 72%
v, 90%
iii
95%
O
vi
O
OBz
OR
86%
OTPS
7
OTPS
4
5, R = H
OTPS
OBz
6, R = Bz
C4H9
vii
OR
viii
OHC
ix, 96%
x, 78%
C2H5
OBz
OTPS
84%
9
8
90%
OTPS
OH
OTPS
10, R = Bz
11, R = H
i
C4H9
12
CHO
xi
i
C4H9
A
75 %
O
91%
OTPS
56%
13
Scheme 3. Synthesis of trans-oak lactone (A). Reagents and conditions: (i) PCC, CH2Cl2, rt; (ii) K-selectride, THF, ꢀ78 °C; (iii) TBDPSCl, imidazole, CH2Cl2; (iv) Me2SꢁBH3,
hexane, NaOH–H2O2; (v) BzCN, TEA, CH2Cl2; (vi) 80% aq CF3COOH, 0 °C, CH2Cl2; (vii) NaIO4, MeCN/H2O (3:2); (viii) n-C3H7PPh3+Brꢀ, n-BuLi, THF, ꢀ60 °C; (ix) 10% Pd–C, EtOH,
0 °C; (x) K2CO3, MeOH, rt; (xi) TBAF, THF.
ated with four different low valent metals.11 All these crotylation
reactions (Scheme 2 and Table 1) produced 2 in good yields, but
with varied stereo-selectivity, showing the formation of 2b/2c pre-
dominantly and 2a in trace amount. The fourth isomer 2d was later
prepared from 2c using an oxidation-reduction protocol.8h Finally,
one (2c) of the major crotylation products was exploited to prepare
A. Evidently, our route is shorter, more straightforward, and prac-
tically more viable compared to a reported approach7a for the syn-
thesis of the same molecule A staring from 1. Understandably,
employing the same reaction protocol with 2a, 2d, and 2b would
lead to the synthesis of other three diastereomers, namely, (4R,
5S)-trans-(ent-A), (4S, 5S)-cis- (B), and (4R, 5R)- cis-(ent-B), respec-
tively. Hence, the moderate selectivity of these crotylations of 1
and the easy separation of the diastereomers (2a-c) by column
chromatography together enhanced the possibility of obtaining
all four oak lactone stereoisomers and thereby attaining stereo-
divergence in this route.
O
O
H
M
2b & 2c
O
M = Cu, Co, Fe, Sn
1
H
Figure 2. Fekin-Anh model for crotylmetal addition to 1.
4. Conclusion
In summary, (4S,5R)-trans-oak lactone (A), a representative
example of chiral trans-b, -disubstituted -lactone has been syn-
thesized using Barbier type crotylations of 1 in wet media medi-
c
c
M1 (low valent)+ M2X
M1Br
M1X + M2
+ M1
H
M1Br
Z-crotyl metal
Br
H
Y
X
M1Br
E-crotyl metal
H
Me
M1
M1Br
O
O
R
R
Me
R
+
+
O
X
H
H
anti-2c
OH
Me
R
H
H
H
M1Br
M1
R
H
Y
syn-2b
O
OH
R
Me
Figure 3. Zimmerman-Traxler model for crotylmetal addition to 1.

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Roush, W. R. J. Org. Chem. 1991, 56, 4151; (o) Brown, H. C.; Bhat, K. S.; Randad,
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1 (1.7 g, 10 mmol) in THF (50 mL) metal salt
[CuCl2.2H2O (4.25 g, 25 mmol) or CoCl2.6H2O (5.95 g, 25 mmol) or anhydrous
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in Table 1 till the total disappearance of the starting material (TLC). It was then
treated successively with water (25 mL) and EtOAc (50 mL). The mixture was
stirred for 10 min more and then filtered. The filtrate was treated with 2%
aqueous HCl to dissolve a little amount of suspended particles. The organic
layer was separated and the aqueous layer was extracted with EtOAc. The
combined organic extract was washed with water, brine, and then dried.
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chromatography (silica gel, 0-20% EtOAc/Hexane) gave three diastereomers
2a8b [29 mg while using FeCl3/Zn; 74 mg while using CuCl2.2H2O/Zn; 66 mg
while using CoCl2.2H2O/Zn; 129 mg while using SnCl2.2H2O/Zn], 2b8b [950 mg
while using FeCl3/Zn; 525 mg while using CuCl2.2H2O/Zn; 835 mg while using
CoCl2.2H2O/Zn; 1.42 g while using SnCl2.2H2O/Zn], and 2c8b [984 mg while
using FeCl3/Zn; 1.18 g while using CuCl2.2H2O/Zn; 856 mg while using
CoCl2.2H2O/Zn; 267 mg while using SnCl2.2H2O/Zn]
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ꢂ
ꢀ12.3 (c 2.4, CHCl3); 1H NMR (CDCl3, 200 MHz): d 1.1 (d, J
= 6.8 Hz, 3H), 1.4-1.6 (m, 10H), 2.02 (m, 1H), 2.28-2.32 (m, 1H), 3.29 (dd, J = 4.6,
6.8 Hz, 1H), 3.70-3.77 (m, 1H), 3.98 (dd, J = 6.4, 8.0 Hz, 1H), (4.10-4.15 (m, 1H),
5.01-5.07 (m, 2H), 5.6-5.8 (m, 1H); 13C NMR (CDCl3, 50 MHz): d 15.7, 23.7, 23.9,
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Denmark, S. E.; Fu, J. Chem. Rev. 2003, 103, 2763. and references cited therein;
(h) Marshall, J. A. In Lewis Acids in Organic Synthesis; Yamamoto, H., Ed.; Wiley-
VCH: Weinheim, 2000; pp 453–522; (i) Fargeas, V.; Zammattio, F.; Chretien, J-
M.; Bertrans, M.-J.; Paris, M.; Quintard, J-P. Eur. J. Org. Chem. 2008, 1681. and
references cited therein; (j) Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191.
and references cited therein; (k) Roush, W. R. J. Org. Chem. 1991, 56, 4151. and
references cited therein; (l) Brown, H. C.; Ramachandran, P. V. Pure & Appl.
Chem. 1991, 63, 307. and references cited therein; (m) Rauniar, V.; Zhai, H.;
Hall, D. G. J. Am. Chem. Soc. 2008, 130, 8481. and references cited therein; (n)
C
13H22O3: C, 68.99; H, 9.80. Found: C, 69.23; H, 9.56.
15. (a) Cherest, M.; Felkin, H. Tetrahedron Lett. 1968, 9, 2205; (b) Anh, N. T. Top.
Curr. Chem. 1980, 88, 145–170.
16. (a) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920; (b) Evans,
D. A.; Takacs, J. M.; McGee, L. R.; Ennis, M. D.; Mathre, D. J.; Bartroli, J. Pure &
Appl. Chem. 1981, 53, 1109. and references cited therein; (c) Cremler, S. R.;
Roush, W. R. J. Org. Chem. 2003, 68, 1319.
17. Compound 5: ½a D24
ꢂ
+23.2 (c 1.60, CHCl3); 1H NMR (CDCl3, 200 MHz): d 0.91 (d, J
= 6.8 Hz, 3H), 1.05 (s, 9H), 1.35-1.52 (m, 12H), 1.61-1.72 (m, 2H), 3.36-3.48 (m,
2H), 3.62 (t, J=7.2 Hz, 1H), 3.71 (dd, J = 2.2 and 6.4 Hz, 1H), 3.86-3.93 (m, 1H),
4.09-4.16 (m, 1H), 7.25-7.47 (m, 6H), 7.66-7.73 (m, 4H); 13C NMR (CDCl3,
50 MHz): d 15.2, 19.3, 23.7, 23.8, 25.0, 26.9, 33.8, 34.5, 35.2, 35.9, 60.7, 67.4,
75.6, 77.5, 108.9, 127.3, 127.4, 129.5, 129.6, 133.4, 133.5, 135.8. Anal. Calcd. for
C
29H42O4Si: C, 72.15; H, 8.77. Found: C, 72.34; H, 8.52.
18. Compound 7: ½a D24
ꢂ
+6.72 (c 1.61, CHCl3); 1H NMR: 1.03 (d, J = 6.98 Hz, 3H), 1.09
(s, 9H), 1.61-1.66 (m, 1H), 1.9-2.0 (m, 2H), 2.42 (bs, 2H), 3.53-3.61 (m, 1H),
3.69-3.80 (m, 3H), 4.13-4.19 (m, 2H), 7.25-7.45 (m, 9H), 7.65-7.71 (m, 4H),
7.92-7.97 (m, 2H); 13C NMR: 15.1, 19.4, 27.0, 31.3, 34.0, 63.4, 63.9, 72.8, 77.4,
127.4, 127.6, 128.1, 129.3, 129.7, 130.1, 132.6, 133.2, 135.8, 166.5. Anal. Calcd.
for C30H38O5Si: C, 71.11; H, 7.56. Found: C, 71.33; H, 7.39.
19. Compound 11: ½a D24
ꢂ
+ 4.6 (c 1.4, CHCl3); 1H NMR: 0.76 (t, J = 3.2 Hz, 3H), 0.94 (d,
J = 6.8 Hz, 3H), 1.08 (m merged with s, 13H), 1.41-1.46 (m, 4H), 1.50-1.54 (m,
1H), 1.97 (broad s, 1H), 3.50-3.58 (m, 3H), 7.37-7.44 (m, 6H), 7.68-7.73 (m, 4H);
13C NMR: 13.9, 15.5, 19.5, 22.5, 27.1, 28.0, 32.6, 34.3, 34.5, 60.6, 77.4, 127.3,
127.4, 129.4, 129.5, 124.1,134.5, 136.0. Anal. Calcd. for C25H38O2Si: C, 75.32; H,
9.61. Found: C, 75.11; H, 9.77.
20. Compound I: ½a D24
ꢂ
+ 93.5 (c 0.25, CHCl3); Lit7a a D24 + 93 (c 0.2, CHCl3). 1H NMR:
½ ꢂ
0.91 (t, J = 7.2 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H), 1.19-1.65 (m, 6H), 2.16-2.21 (m,
2H), 2.62-2.71 (m. 1H), 3.96-4.02 (m, 1H). 13C NMR: 14.3, 17.2, 22.7, 27.5, 33.8,
36.0, 37.9, 87.6, 176.7.