Synthesis of (3R,4S,5S,9S)-3,5,9-trihydroxy-4-methylundecanoic acid δ-lactone

Article abstract of DOI:10.1016/j.tetlet.2004.08.099

Radical-mediated opening of a chiral trisubstituted epoxy alcohol using cp₂TiCl furnished the '2-methyl-1,3-diol' moiety with the desired stereochemistry, which led to a total synthesis of (3R,4S,5S,9S)-3,5,9- trihydroxy-4-methylundecanoic acid

Full text of DOI:10.1016/j.tetlet.2004.08.099

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7637–7639
Synthesis of (3R,4S,5S,9S)-3,5,9-trihydroxy-4-
methylundecanoic acid d-lactone
Tushar K. Chakraborty* and Rajib K. Goswami
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 13 July 2004; revised 9 August 2004; accepted 17 August 2004
Abstract—Radical-mediated opening of a chiral trisubstituted epoxy alcohol using cp2TiCl furnished the Ô2-methyl-1,3-diolÕ moiety
with the desired stereochemistry, which led to a total synthesis of (3R,4S,5S,9S)-3,5,9-trihydroxy-4-methylundecanoic acid d-lactone
1.
Ó 2004 Elsevier Ltd. All rights reserved.
Biosynthetic engineering is emerging as a powerful tool
to assemble rapidly analogues of natural products in the
search for novel molecular structures,1 which are
increasingly in demand because of the alarming decline
over the past decade in the number of new chemical enti-
ties introduced each year as drugs.2 During the studies
of the biosynthesis of spinosyns, a family of agricultur-
ally important molecules,3 a truncated version of the
spinosyn polyketide synthase was expressed in the
heterologous host Saccharopolyspora erythraea JC2.4
This resulted in the formation of a novel pentaketide
lactone that was identified as (3R,4S,5S,9S)-3,5,9-tri-
hydroxy-4-methylundecanoic acid d-lactone 1. The dis-
covery of this molecule helped in understanding the
crucial steps of spinosyn biosynthesis4 and supported
the widely accepted hypothesis of step-by-step function-
alization of the growing polyketide chain in the biosyn-
thesis of macrolides.5 A general strategy for the
synthesis of this type of lactone would help to prepare
material for use as standards during mechanistic studies
of polyketide synthases and related biological studies.6
In this paper, we describe the total synthesis of lactone
1 following a convergent strategy. Retrosynthetically,
compound 1 could be prepared from a suitably pro-
tected tetrol 2 having a Ô2-methyl-1,3-diolÕ moiety, ubiq-
uitously present in polyketide natural products. The key
feature in our synthesis is the application of a method
developed by us7 for the synthesis of chiral 2-methyl-
1,3-diols by radical-mediated anti-Markovnikov
opening of trisubstituted epoxy alcohol 3 at the more
substituted carbon using cp2TiCl to construct the three
stereocentres of 1. The trisubstituted syn epoxy alcohol
3, in turn, could be synthesized by mCPBA epoxidation
of the unreacted R-allylic alcohol obtained during a
Sharpless kinetic resolution8 of compound 4.
OH
OP1
OH OH
Me
Me
OH
OP2
O
O
2 with "2-methyl-1,3-diol" moiety
1
1. Sharpless kinetic
resolution
OH
Radical-mediated
epoxide opening
OP1
O
OP2
2. mCPBA
Me
3
OP1
OH
[P1, P2 = protective groups]
OP2
Me
4
The synthesis is outlined in Scheme 1. Starting with (S)-
1,3-pentanediol 5,9 the C3-O-Bn protected compound 6
was prepared in three steps in 88% overall yield—pro-
tection of the primary OH as the TBDPS–ether, benzyl-
ation of the secondary hydroxyl group and finally
desilylation using tetra-n-butylammonium fluoride.
Keywords: (3R,4S,5S,9S)-3,5,9-Trihydroxy-4-methylundecanoic acid;
d-Lactone; Sharpless kinetic resolution; Epoxide opening; 2-Methyl-
1,3-diol.
*
Corresponding author. Tel.: +91 402 7193 154; fax: +91 402 7193
108; e-mail: chakraborty@iict.res.in
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.099

7638
T. K. Chakraborty, R. K. Goswami / Tetrahedron Letters 45 (2004) 7637–7639
OH
OBn
OBn
O
OBn
d,e
a-c
f
OH
OH
OEt
OH
7
8
5
6
OBn
OH
O
g-i
OTBDPS
j
OBn
OH
Me
11
OTBDPS
O
O
+
Me
10
(EtO)2P
OTBDPS
OBn
OBn
OH
9
OTBDPS
Me
12
OBn
OH
OH
OH
O
m
k
l
12
OTBDPS
OTBDPS
OBn
Me
14
Me
13
OH
O
Me
OBn
OBn
O
O
O
O
O
s
o-q
r
1
O
OR
OMe
Me
Me
17
18
15: R = TBDPS
n
16: R = H
Scheme 1. Stereoselective synthesis of d-lactone 1. Reagents and conditions: (a) TBDPSCl, Et3N, DMAP (cat.), CH2Cl2, 0°C to rt, 2h, 98%; (b)
BnBr, NaHMDS, THF–DMF (2:1), 0°C, 1.5h, 92%; (c) TBAF, THF, 0°C to rt, 4h, 98%; (d) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 to 0°C, 1h; (e)
Ph3P@CHCO2Et, CH2Cl2, 0°C to rt, 3h, 96% from 6; (f) LiCl, NaBH4, EtOH–THF (1:1), rt, 3d, 62%; (g) same as in step d; (h) compound 9, n-BuLi,
THF, ꢀ78°C, 0.5h, then aldehyde from step g, ꢀ78 to 0°C, 1h, 95% from 8; (i) NaBH4, MeOH, 0°C to rt, 2h, 62%; (j) Ti(OiPr)4, (+)-DIPT, TBHP,
˚
4A MS (20% w/w), CH2Cl2, ꢀ23°C, 40min, 45% of 12; (k) mCPBA, CH2Cl2, 0°C to rt, 45min, 53%; (l) cp2TiCl2, Zn dust, ZnCl2 (freshly fused),
THF, ꢀ20°C to rt, 6h, 60%; (m) Me2C(OMe)2, CSA (cat.), CH2Cl2, 0°C to rt, 45min, 94%; (n) same as in step c, 93%; (o) SO3–py, Et3N, DMSO,
0°C to rt, 1h; (p) NaClO2, NaH2PO4, tBuOH-2-methyl-2-butene (2:1), rt, 1.5h; (q) CH2N2, ether, 0°C, 15min, 84% from 16; (r) AcOH–H2O (4:1),
0°C to rt, 12h, 76%; (s) H2, Pd–C (10%), EtOAc, 2h, 78%.
Swern oxidation10 of the primary hydroxyl group of 6
furnished an aldehyde, which was reacted with the stabi-
lized ylide Ph3P@CHCO2Et to give a,b-unsaturated
ester 7 (96% from 6). Ester 7 was reduced using LiBH4,
prepared in situ from NaBH4 and LiCl, to the saturated
alcohol 8 in 62% yield. Oxidation of 8 to an aldehyde
and subsequent the Horner–Wadsworth–Emmons ole-
fination of the resulting aldehyde with the Li-anion of
ketophosphonate 911 furnished the trisubstituted E-
enone (95% from 8) with complete selectivity and no
Z-olefin was detected. Next the intermediate enone
was reduced with NaBH4 to give the allylic alcohol 10
in 62% yield.
in situ from cp2TiCl2 according to the procedure
described earlier,7 provided the expected all-syn
Ô2-methyl-1,3-diolÕ-containing intermediate 14 in 60%
yield as the only isolable product.
Protection of the diol in 14 as an acetonide gave com-
pound 15 in 94% yield. The 13C NMR spectrum of 15
showed signals due to the acetonide methyls at 30.08
and 19.21ppm and the ketal carbon at 98.8ppm sup-
porting the assigned Ô1,3-synÕ stereochemistry of the diol
3
moiety in 15.14 Furthermore, the J couplings of 5.0Hz
of CH(CH3) with adjacent protons on both sides proved
the Ô1,2- and 2,3-synÕ relationships. Desilylation of 15
furnished the alcohol 16 in 93% yield. Oxidation of the
primary hydroxyl of 16 in two steps gave the acid, which
was esterified with CH2N2 to provide the methyl ester 17
in 84% yield from 16. Treatment of 17 with acid led to
deprotection of the acetonide group with concomitant
cyclization to furnish the six-membered lactone 18 in
76% yield. Finally, hydrogenation of 18, using Pd–C
as catalyst, removed the benzyl-protection resulting in
the successful completion of the first total synthesis of
the target lactone 1 in 78% yield.15 Our synthetic lactone
1 was identical in all respects with that isolated by Mar-
Sharpless kinetic resolution8 of 10 furnished the chiral
unreacted allylic alcohol 12 in 45% yield (92% ee, by
the MosherÕs ester method12). Diastereoselective epoxi-
dation of 12 using m-chloroperbenzoic acid (mCPBA)
gave the syn product 13 as the major product in 53%
yield and the minor anti-isomer could be separated eas-
ily by column chromatography.13 The stereochemistry
of 13 was confirmed at a later stage, after opening of
the epoxide ring and subsequent protection of the result-
ing diol, in the acetonide-protected stage. With the tri-
substituted epoxy alcohol in hand, the stage was now
set to carry out the crucial Ti(III)-mediated epoxide
opening step. Treatment of 13 with cp2TiCl, generated
1
tin et al.4 While the H NMR is consistent with the
reported values, the matching 13C data15 provides strong
evidence that the two materials are the same.

T. K. Chakraborty, R. K. Goswami / Tetrahedron Letters 45 (2004) 7637–7639
7639
9. Compound 5 was prepared from the corresponding chiral
(2S,3S)-epoxy alcohol (Honda, M.; Katsuki, T.; Yama-
guchi, M. Tetrahedron Lett. 1984, 25, 3857) by hydride
opening with Red-Al and subjecting the mixture of
products to an oxidative cleavage reaction using NaIO4
to remove the minor 1,2-diol product.
Acknowledgements
We thank CSIR, New Delhi for a research fellowship
(R.K.G.).
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9
TBDPSO
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27
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