(R)-2,3-Cyclohexylideneglyceraldehyde, a novel template for facile and simple entry into chiral hydroxy γ-lactones: Synthesis of (-)-muricatacin

Article abstract of DOI:10.1016/j.tetlet.2005.03.002

(R)-2,3-Cyclohexylideneglyceraldehyde 1 has been used in a simple and efficient synthesis of (-)-muricatacin 10. The required chiron, syn-alkanetriol 2a was prepared by the reduction of a ketone 3 derived from 1.

Full text of DOI:10.1016/j.tetlet.2005.03.002

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3103–3105
(R)-2,3-Cyclohexylideneglyceraldehyde, a novel template for
facile and simple entry into chiral hydroxy c-lactones:
synthesis of (ꢀ)-muricatacin
Bhaskar Dhotare and Angshuman Chattopadhyay*
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400 085, India
Received 3 November 2004; revised 24 February 2005; accepted 1 March 2005
Available online 16 March 2005
Abstract—(R)-2,3-Cyclohexylideneglyceraldehyde 1 has been used in a simple and efficient synthesis of (ꢀ)-muricatacin 10. The
required chiron, syn-alkanetriol 2a was prepared by the reduction of a ketone 3 derived from 1.
Ó 2005 Elsevier Ltd. All rights reserved.
Muricatacin was isolated several years ago by
McLaughlin and co-workers from the seeds of Annona
muricata and was found to display cytotoxic activity
against certain tumor cell lines.1 The levorotatory natu-
ral material was shown to be a mixture of (4R,5R)-10
and its enantiomer, with a slight predominance of the
former. Muricatacin is a member of the hydroxy-lactone
class of compounds that are notable for their biological
activity and can be used as building blocks in the synthe-
sis of complex bioactive natural products.2 Further-
alized c-lactones.6 Incidentally, reports are available
on the use of D-mannitol for the synthesis of (ꢀ)-muri-
catacin.3g,5e However, as is evident from the following
discussion our strategy is shorter, more straightforward
and amenable to achieve greater stereochemical flexi-
bility regarding the preparation of functionalized
c-lactones.
Retrosynthetic analysis of 10 (Scheme 1) suggested that
an essential prerequisite was the generation of a func-
tionalized (R,R)-1,2-diol. Earlier, we demonstrated that
the (R,R)-1,2-diol moiety can be obtained from easily
accessible (R)-2,3-cyclohexylideneglyceraldehyde 17a
(Scheme 1) via oxidation of its alkylated products and
syn-selective reduction of the resulting ketones with K-
Selectride.8 Compound 2a was previously prepared from
ketone 3 in high yield and with absolute stereoselectiv-
ity.8b For the present endeavor, reduction of 3 was
carried out with LiAlH4 and NaBH4,9 both of which
afforded the desired products in good yields. From a
more, 10 is
a good target to demonstrate the
applicability of a synthetic methodology for the con-
struction of functionalized c-lactones. Several syntheses
of either enantiomer of this chiral lactone 10 have been
reported employing various strategies, viz the exploit-
ation of chirons,3 application of kinetic resolution,4
stereo differentiating reactions,5 etc. We present herein
the preparation of 10 by a simple and efficient route
starting from D-mannitol, which could also be applied
for stereodivergent syntheses of various other function-
OH
COOR OH
O
O
O
O
O
O
C12H25
C12H25
C12H25
CHO
1
10
OH
OH
Scheme 1.
Keywords: (R)-2,3-Cyclohexylideneglyceraldehyde; LiAlH4; syn-Selective reduction; Functionalized c-lactones; Stereodivergent; (ꢀ)-Muricatacin.
*
Corresponding author. Tel.: +91 22 2557 0015; fax: +91 22 2550 5151; e-mail: achat@apsara.barc.ernet.in
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.002

3104
B. Dhotare, A. Chattopadhyay / Tetrahedron Letters 46 (2005) 3103–3105
stereochemical viewpoint, while NaBH4 reduction took
place with poor selectivity (2a:2b, 55:45, overall
yield 89%), reduction with LiAlH4 resulted in good
syn-selectivity (2a:2b, 85:15, overall yield 94%). High
syn-selectivity has also been observed in the reduction
of an a,b-unsaturated ketone obtained from 1, with
several hydrides.10 The good syn-selectivity in the
LiAlH4 reduction of ketone 3 suggests that hydride
addition takes place via a Felkin–Anh model11 as in
the case of K-Selectride reduction.8 The somewhat lower
syn-selectivity in this case suggests that there is a possi-
bility of an a-chelation controlled reduction12 in the
presence of LiAlH4. However, due to the presence of
the bulky cyclohexylidene moiety in 3, hydride attack
takes place predominantly via the thermodynamically
favorable conformation OC1 of the Felkin–Anh model
rather than the OC2 or a-chelate model in order to avoid
steric interactions (Scheme 2). However, the very poor
selectivity during NaBH4 reduction of 3 suggests an
appreciable degree of a-chelate attack by the reagent.
verted to epoxide 713 in two standard steps. Regioselec-
tive ring-opening of the epoxide 7 with allylmagnesium
bromide produced 8.14 Following a known procedure15
compound 8 was subjected to ozonolysis under basic
conditions to afford the c-lactone 9 directly, in good
yield. This was then desilylated to produce the title com-
pound 10 (Scheme 3) in 72% yield whose spectral and
optical data were in conformity with those reported.3a
Thus a simple and efficient synthesis of 10, a represent-
ative chiral hydroxy c-lactone, has been developed
starting from easily accessible 1, itself derived from
D-mannitol.7a The potential of LiAlH4 and NaBH4 for
syn-selective reduction of ketone 3 was explored with
LiAlH4 proving to be better. Compared to the corre-
sponding isopropylidene derivative,16 the use of 1 is
advantageous due to (i) the better stability of the cyclo-
hexylidene ketal functionality and (ii) easy column chro-
matographic separation of the carbinol epimers 2a and
2b. Furthermore, the easy availability of various anti-al-
kane-1,2,3-triols7 as the major products obtained from 1
and also of (S)-117 would extend the scope of the present
protocol for the synthesis of different stereoisomers of
the hydroxy c-lactones with varied functional features.
Silylation of 2a and deketalization of the resulting silyl
ether 4 afforded diol 5 in high yield, which was con-
M
O
R
O
References and notes
α-chelate model
anti-2b
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H
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()
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O
R
-
H
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()
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O
-
H
H
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1
OC
2
Scheme 2.
iii or iv
i
ii
2a
2b
+
O
O
O
O
O
O
O
O
+
v
R
R
R
CHO
2a
2b
3
1
OH
OH
O
R = C
H
12 25
O
O
OH OH
OTs OH
vi
viii
2a
vii
R
R
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4
5
6
OT BDP S
OT BDP S
OT BDP S
1
OR
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x
ix
xi
R
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8
7
1
OT BDP S
9, R = TBDPS
OT BDP S
xii
1
10, R = H
Scheme 3. Reagents and conditions: (i) RMgBr, 0 °C–rt, 76%; (ii) PCC, rt, 75%; (iii) LiAlH4, THF, 0 °C, 94%; (iv) NaBH4, MeOH, 0 °C, 89%;
(v) column chromatography; (vi) TBDPSCl, Im, rt; (vii) CF3CO2H, H2O, 0 °C, 88% (two steps); (viii) p-TosCl, Py, 0 °C; (ix) K2CO3, MeOH, rt,
85% (two steps); (x) allylMgBr, CuBr, ꢀ40 °C to rt, 78%; (xi) O3, MeOH, NaOH, ꢀ15 °C, 75%; (xii) TBAF, THF, rt, 72%.

B. Dhotare, A. Chattopadhyay / Tetrahedron Letters 46 (2005) 3103–3105
3105
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25
13. Compound 7: ½aꢁD ꢀ15.03 (c 6.5, CHCl3); 1H NMR: d
0.87 (br t, 3H), 1.00–1.25 (m, 20H), 1.07 (s, 9H), 1.40–1.55
(m, 2H), 2.44 (dd, J = 5.0, 2.6 Hz, 1H), 2.70 (t, J = 5.0 Hz,
1H), 3.03 (m, 1H), 3.33 (m, 1H), 7.39 (m, 6H), 7.68 (m,
4H). Anal. Calcd for C31H48O2Si: C, 77.44; H, 10.06.
Found, C, 77.29; H, 10.24.
25
14. Compound 8: ½aꢁD ꢀ11.9 (c 2.8, CHCl3); IR: 3500, 3075,
1
3008, 2859, 1095, 910 cmꢀ1; H NMR: d 0.86 (br t, 3H),
1.00–1.24 (m, 22H), 1.06 (s, 9H), 1.50–1.80 (m, 2H,
overlapped with s at 1.56 for 1H, OH), 1.90–2.20 (m, 2H),
3.40–3.60 (m, 2H), 5.00–5.20 (m, 2H), 5.70–5.90 (m, 1H),
7.40 (m, 6H), 7.65 (m, 4H). Anal. Calcd for C34H54O2Si:
C, 78.10; H, 10.41. Found, C, 78.22; H, 10.55.
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