A convenient asymmetric synthesis of the octalactin lactone

Article abstract of DOI:10.1016/j.tetlet.2008.04.058

A facile asymmetric synthesis of the octalactin lactone was developed staring from (R)-cyclohexylideneglyceraldehyde (1). The key step of the synthesis is an In-mediated diastereoselective crotylation of 1 in water, which furnished the building blocks with the required stereochemistry under operationally simple conditions. Their conversion to the appropriate intermediates, invertive esterification and a ring closing metathesis reaction furnished the target compound.

Full text of DOI:10.1016/j.tetlet.2008.04.058

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Tetrahedron Letters 49 (2008) 3902–3905
A convenient asymmetric synthesis of the octalactin lactone
Anubha Sharma a, Sunita Gamre a, Siddharth Roy b, Dibakar Goswami a,
Angshuman Chattopadhyay a,b, Subrata Chattopadhyay a,*
a Bio-Organic Division, bNAA Unit, Central Forensic Science Laboratory, Bhabha Atomic Research Centre, Mumbai 400 085, India
b NAA Unit, Central Forensic Science Laboratory, Bhabha Atomic Research Centre, Mumbai 400 085, India
Received 9 February 2008; revised 8 April 2008; accepted 10 April 2008
Available online 12 April 2008
Abstract
A facile asymmetric synthesis of the octalactin lactone was developed staring from (R)-cyclohexylideneglyceraldehyde (1). The key
step of the synthesis is an In-mediated diastereoselective crotylation of 1 in water, which furnished the building blocks with the required
stereochemistry under operationally simple conditions. Their conversion to the appropriate intermediates, invertive esterification and a
ring closing metathesis reaction furnished the target compound.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Asymmetric synthesis; Chiral pool; Crotylation; Octalactin
The medium-size natural lactones, octalactins A and B
(I and II), are polyketide metabolites derived from a mar-
ine Streptomyces sp. found living on the surface of gorgo-
nian coral.1 Compound I, in particular, is noted for its
potent in vitro cytotoxicity towards B-16-F-10 murine mel-
anoma (IC50 = 7.2 lg/mL) and HCT-116 human colon
tumour cell lines (IC50 = 0.5 lg/mL), and has emerged as
a highly promising new anti-cancer agent. Compound II
on the other hand is inactive, indicating that the bioactivity
is linked to the ability for covalent adduct formation at the
epoxy site of I. The combination of their unusual struc-
tures, the challenge associated with the synthesis and the
therapeutic potential of I makes octalactins attractive syn-
thetic targets. Given that the compounds cannot be pro-
duced by fermentation, the availability of their
stereomers would be useful in establishing the unknown
mode of their biological action. The major challenges of
the synthesis lie in the construction of the 8-membered ring
system as well as the structural moiety possessing the adja-
cent asymmetric centres, bearing a hydroxyl group and
methyl branching. Similar chiral building blocks are com-
mon structural elements of other bioactive macrolides
(e.g., tylosin and leucomycins) of interest in pharmacy
and veterinary science.2
Despite the impressive progress,3a the development of
simple and efficient strategies remains a challenging area
in asymmetric synthesis.3b,c To this end, we have recently
endeavoured in formulating reliable routes utilizing inex-
pensive and readily available materials leading to the asym-
metric syntheses4a–f of
a diverse array of natural
compounds using easily accessible (R)-cyclohexylideneglyc-
eraldehyde 1 as a chiral template. This Letter reports an
efficient asymmetric synthesis of the core unit of octalactin
lactone starting from 1.
Retrosynthetic disconnection (Scheme 1) of A1, the ole-
finic precursor of the core lactone A, led to acid A5 and
alcohol A3 or A4 as the key building blocks. Esterification
of A5 with A3, or with A4 under Mitsunobu conditions5
would give the dienic ester A2, while its ring closing metath-
esis (RCM)6a–f to A1 can be used to accomplish the difficult
task7a–c of constructing the eight-membered ring. Based on
this plan, the primary task of the synthesis was to prepare
the building blocks, A3 or A4, and A5. Both these build-
ing blocks possess similar structural features, albeit with
*
Corresponding author. Tel.: +91 22 25593703; fax: +91 22 25505151.
E-mail address: schatt@barc.gov.in (S. Chattopadhyay).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.058

A. Sharma et al. / Tetrahedron Letters 49 (2008) 3902–3905
3903
O
O
HO
O
OH
HO
HO
OH
O
O
O
O
H
H
O
Octalactin B (II)
Octalactin A (I)
O
O
HO
HO
O
O
O
H
R
R
R
H
A1
A
A2
HO
OR1
OR1
O
OR2
A5
OH
OH
A4
A3
Scheme 1.
different relative configurations and variations in the func-
tional groups.
the synthesis was to develop a method for crotylation of
1 to afford 2c and 2b/ 2a selectively, in almost equal yields.
In our approach, the In (2.0 equiv)-mediated reaction9
between 1 and commercially available crotyl bromide
(1.2 equiv) in water produced alcohols 2b and 2c in almost
1:1 ratio in 75% combined yield. The products were sepa-
rated conveniently by column chromatography without
further derivatization. With both 2b and 2c in hand, we
proceeded to the synthesis of the octalactin core as follows
(Schemes 2 and 3). Alcohol 2b was converted to PMB
derivative 3 by reaction with PMB chloride in the presence
of NaH as the base. The acetal group of 3 was hydrolyzed
The homoallylic alcohols 2a–c that can be prepared8a–c
easily by crotylation of aldehyde 1 (Scheme 2) appeared
well suited for the synthesis of A3–A5. Earlier, we repor-
ted8b,c that the Zn-mediated reaction of crotyl bromide
with aldehyde 1 proceeds with moderate stereoselectivity
to furnish the diastereomeric homoallylic alcohols 2a–c in
the ratio 2.4:33.1:64.5. Given that the synthesis required
2c, and 2a or 2b in equal ratio, the Zn-mediated crotylation
protocol was unsuitable, as it did not afford 2a or 2b in
appreciable amounts. Consequently, the initial task for
O
O
O
O
i
+
+
O
O
O
O
CHO
OH
2c
OH
2a
OH
2b
1
OR
O
iii
v,vi
RO
iv
vii
OH
O
CHO
OPMB
OR OH
OPMB
OR
4 R = H
6 R = PMB
7
5 R = Ts
2b R = H
ii
3 R = PMB
viii
ix
OH
OTBDPS
OPMB
8
OR
x
9 R = PMB
10 R = H
Scheme 2. Reagents and conditions: (i) Crotyl bromide/In/H2O (75%); (ii) NaH/PMBCl/DMF/ꢀ10 °C (82%); (iii) CuCl2ꢁ2H2O/MeOH/50 °C (75%); (iv)
p-TsCl/pyridine/0 °C (80%); (v) OsO4/NMO/t-BuOH-H2O(86%); (vi) Zn/NaI/DMF/D (77%); (vii) NaIO4/MeCN–H2O (92%); (viii) NaBH4/MeOH/0 °C
(91%); (ix) TBDPSCl/triethylamine/DMAP/CH2Cl2 (93%); (x) DDQ/aqueous CH2Cl2 (88%).

3904
A. Sharma et al. / Tetrahedron Letters 49 (2008) 3902–3905
OH
OH
O
ii
iii
iv
BzO
HO
O
OBn
13
OBn
12
OR
2c R = H
i
11 R = Bn
vi
v
HO2C
HO
OHC
OBn
16
OBn
15
OBn
14
O
O
BnO
BnO
vii
O
O
viii
OTBDPS
OTBDPS
18
17
Scheme 3. Reagents and conditions: (i) NaH/BnBr/THF/D (91%); (ii) 2% HCl/MeOH (88%); (iii) PhCOCN/triethylamine/CH2Cl2/0 °C (88%); (iv)
MsCl/pyridine/CH2Cl2; LAH/ether/D (65%); (v) PCC/NaOAc/CH2Cl2 (84%); (vi) NaClO2/TEMPO/MeCN-buffer pH 6.5/55 °C (71%); (vii) Ph3P/
DEAD/10/Et2O–PhMe (2:1) (68%); (viii) Grubbs’s II catalyst/CH2Cl2 (84%).
with CuCl2ꢁ2H2O in MeOH10 to give diol 4, which was
ditosylated to furnish 5. Dihydroxylation of the olefin func-
tion followed by detosylation with NaI/Zn afforded diol 6.
Cleavage of the a-diol function with NaIO4 gave aldehyde
7, which was reduced with NaBH4 to give 8 in appreciable
yield. This was silylated to 9, which on DDQ-mediated
deprotection gave alcohol 1011 (an A4 equivalent).
stereoselectivity as required for the synthesis of the octalac-
tin lactone. Overall, our method offers several practical
advantages such as the use of an easily amenable chiral
template 1, inexpensive reagents, operational simplicity
and the possibility of synthesizing all the stereomers of
the octalactin lactone.
For the synthesis of the A5 equivalent (Scheme 3), alco-
hol 2c was benzylated to give 11, which on acidic hydrolysis
furnished diol 12. Regioselective monobenzoylation of its
primary hydroxyl function proceeded smoothly to afford
alcohol 13. Mesylation followed by reduction with lithium
aluminium hydride (LAH) furnished 14. This was oxidized
with pyridinium chlorochromate (PCC) to aldehyde 15,
which on oxidation with NaClO2 gave the required acid 16.
Esterification of 16 with 10 under Mitsunobu conditions
afforded ester 17. This underwent RCM reaction smoothly
with Grubbs’s II catalyst to furnish the target lactone 18
(Scheme 3). Besides being the advanced precursor of oct-
alactins, the PMB (in place of Bn) derivative of 18 is
reported12 to block tubulin polymerization partially, result-
ing in significant antitumour activity. This might be useful
for it to act as a novel mitotic spindle poison.
Acknowledgement
S.R. thanks the Directorate of Forensic Science (DFS),
Ministry of Home Affairs, Government of India, for
awarding the fellowship.
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for the ring construction, while the RCM strategy was used
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3905
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200 MHz): d 0.88 (d, J = 6.8 Hz, 3H), 1.07 (s, 9H), 1.18 (d,
J = 7.0 Hz, 3H), 1.81–2.04 (m, 1H), 2.38–2.45 (m, 1H), 2.68–2.73
(m, 2H), 3.53–3.61 (m, 1H), 3.67–3.72 (m, 2H), 4.28 (d, J = 11.2 Hz,
1H), 4.37–4.44 (m, 1H), 4.55 (d, J = 11.2 Hz, 1H), 5.54–5.68 (m, 2H),
7.27–7.42 (m, 11H), 7.60–7.68 (m, 4H); 13C NMR (CDCl3, 50 MHz):
d 14.1, 18.7, 22.1, 24.0, 26.6, 31.2, 33.8, 38.2, 42.4, 65.7, 71.3, 77.8,
80.8, 118.4, 127.5, 128.6, 128.8, 129.5, 134.2, 135.3, 140.3, 175.2. Anal.
Calcd for C34H42O4Si: C, 75.24; H, 7.80. Found: C, 75.09; H, 7.95.
12. Perchellet, J.-P.; Perchellet, E. M.; Newell, S. W.; Freeman, J. A.;
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´
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11. All the compounds were fully characterized from their spectral,
optical and microanalytical data. Representative data are included.
24
Data for 10: Colourless oil; ½aꢂD ꢀ6.7 (c 0.610, CHCl3); IR (film):
3440, 1162, 915 cmꢀ1 1H NMR (CDCl3, 200 MHz): d 0.85 (d,
;
J = 7.2 Hz, 3H), 1.07 (s, 9H), 1.93–1.98 (m, 1H), 3.12 (br s, 1H), 3.70
(d, J = 6.2 Hz, 2H), 4.32–4.38 (m, 1H), 5.17–5.37 (m, 2H), 5.82–5.99
(m, 1H), 7.39 (m, 10H); 13C NMR (CDCl3, 50 MHz): d 13.3, 19.1,
26.6, 67.7, 75.4, 113.4, 127.8, 129.8, 132.9, 133.0, 134.8, 135.6. Anal.
Calcd for C22H30O2Si: C, 74.53; H, 8.53. Found: C, 74.67; H, 8.35.
24
Data for 16: Colourless oil; ½aꢂD +4.9 (c 0.820, CHCl3); IR (film):
3514, 1731, 912 cmꢀ1 1H NMR (CDCl3, 200 MHz): d 1.04 (d,
;
J = 6.9 Hz, 3H), 1.86–2.02 (m, 1H), 2.45–2.56 (m, 2H), 3.53–3.72 (m,
1H), 4.44–4.67 (m, 2H), 5.03–5.10 (m, 2H), 5.68–5.78 (m, 1H), 7.30 (s,
5H); 13C NMR (CDCl3, 200 MHz): d 14.7, 39.7, 43.8, 71.5, 77.2,
115.8, 127.8, 128.6, 138.3, 140.2, 178.7. Anal. Calcd for C14H18O3: C,
71.77; H, 7.74. Found: C, 71.59; H, 7.57. Data for 18: Colorless oil;
24
½aꢂD ꢀ44.2 (c 1.144, CHCl3); IR (film): 1741 cmꢀ1; 1H NMR (CDCl3,