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

Article abstract of DOI:10.1016/j.tetlet.2006.11.171

A stereoselective synthesis of the pentaketide lactone (3R,4S,5S,9S)-3,5,9-trihydroxy-4-methylundecanoic acid δ-lactone has been achieved.

Full text of DOI:10.1016/j.tetlet.2006.11.171

Tetrahedron Letters 48 (2007) 1037–1039
Stereoselective synthesis of (3R,4S,5S,9S)-3,5,9-trihydroxy-4-
methylundecanoic acid d-lactone
J. S. Yadav,* P. Murali Krishna Reddy and P. Venkatram Reddy
Division of Organic Chemistry-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 18 September 2006; revised 22 November 2006; accepted 29 November 2006
Available online 22 December 2006
Abstract—A stereoselective synthesis of the pentaketide lactone (3R,4S,5S,9S)-3,5,9-trihydroxy-4-methylundecanoic acid d-lactone
has been achieved.
Ó 2006 Published by Elsevier Ltd.
The biosynthesis of macrolides occurs via step-by-step
functionalization of a polyketide chain, which is synthe-
sized in biological systems by enzymes. In the biosynthe-
sis of spinosyn, an agriculturally important polyketide
macrolide,1 a truncated version of the gene of the poly-
ketide synthon was identified and expressed in a hetero-
logous host Saccharopolyspora erythracea, which
resulted in the formation of a novel pentaketide lactone
identified as (3R,4S,5S,9S)-3,5,9-trihydroxy-4-methyl-
undecanoic acid d-lactone 1.2 This experiment demon-
strated that the spinosyn polyketide synthase genes can
be expressed heterologously in S. erythracea and can be
used as the part of a functional hybrid polyketide syn-
thase.3 Thus, by utilizing biosynthetic engineering, one
can access analogues of natural products in the search
for novel and active molecular architectures. Biosyn-
thetic engineering also helps in understanding the bio-
synthetic pathways to natural products.
OH
OH
O
O
1
Ph
OBn
O
O
O
OEt
2
OBn
O
O
+
OEt
4
3
An elegant synthetic approach to this class of lactone
would augment the process of understanding their
biosynthesis, and the mechanisms of the enzyme systems
involved in polyketide synthesis. Herein, we describe the
total synthesis of lactone 1 following a convergent strat-
egy (see Scheme 1).
D-mannitol
Scheme 1. Retrosynthetic analysis.
L-malic acid
chiron approach from L-malic acid, while fragment 3
could be synthesized from a protected chiral glyceralde-
hyde (see Scheme 2).
The retrosynthetic analysis reveals two fragments, 3 and
4, the C1–C6 and C7–C11 skeletons, respectively. It was
envisaged that fragment 4 could be obtained following a
The synthesis began with derivatization of L-malic acid
in dry MeOH and BF3ÆOEt2 to afford the corresponding
dimethyl ester. Subjecting this ester to stereoselective
alkylation following Seebach’s protocol afforded 5 in
an excellent yield with good stereocontrol. The free
Keywords: NaBH4 Mediated epoxidation; One-pot oxidation/olefin-
ation; Oxy-anion Michael addition.
*
Corresponding author. Tel.: +91 27193030; fax: +91 40 27160512;
e-mail: yadavpub@iict.res.in
0040-4039/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.11.171

1038
J. S. Yadav et al. / Tetrahedron Letters 48 (2007) 1037–1039
1.MeOH, BF3.OEt2
98%
OBn
OH
O
n-BuLi, BF3.Et2O
O
OH
MeO
L-malic acid
3
OMe
2.LHMDS, MeI
THF, -78 ºC, 84%
THF, -78 ºC
then 4
OEt
O
5
93%
13
OTs
O
PhCHO, KOtBu
MeOH, 1N HCl
TsCl, Et3N
2
MeO
1
NaBH4
OMe
THF, 0 ºC
78%
Pd/C, H2,85%
DMAP, CH2Cl2
90%
CH2Cl2, MeOH
84%
O
6
Scheme 4. Coupling of fragments 3 and 4.
1.BAIB, TEMPO,
CH2Cl2
O
O
The construction of fragment 3, started from a chiral
glyceraldehyde, which could be prepared easily from
D-mannitol in multigram scale.7 The cyclohexylidene
protected glyceraldehyde 8 was treated with ethylmagne-
sium bromide in ether at 0 °C to yield anti addition
product8 9 (97:3). The hydroxyl group was protected
as its benzyl ether 10 and then the cyclohexylidene group
was removed using a catalytic amount of p-TSA in
methanol to afford the corresponding diol, which was
cleaved to give aldehyde 11 via NaIO4. Dibromoolefin-
ation of the aldehyde using the Corey–Fuchs protocol9
using PPh3 and CBr4 furnished gem-dibromoolefin 12,
which upon treatment with ethylmagnesium bromide
afforded alkyne 3 in a 96% yield.10
O
OH
OEt
2.Ph3P=CHCO2Et
88%
7
4
Scheme 2. Stereoselective synthesis of 4.
hydroxyl group of 5 was converted into the correspond-
ing tosylate 6.4 The next objective was the reduction of
the diester followed by base induced epoxidation.5 Sur-
prisingly, reduction of ester 6 with NaBH4 in dichloro-
methane/methanol (1:1) resulted in epoxy alcohol 7 as
the sole product. The primary hydroxyl of compound
7 was subjected to one-pot oxidation/olefination follow-
ing Vatale’s protocol6 to form a,b-unsaturated ester 4.
Thus, the primary hydroxyl was oxidized with bisacet-
oxyiodobenzene/iodobenzenediacetate (BAIB) and cata-
lytic TEMPO to afford the aldehyde, which was
subsequently subjected to a two-carbon homologation
using ethoxycarbonylmethylene triphenylphosphorane
in dichloromethane to furnish (E)-a,b-unsaturated ester
4 in an excellent yield.
With both fragments 3 and 4 in hand, the stage was set
for assembling11 those fragments. Accordingly, alkyne 3
was treated with n-BuLi to generate the corresponding
lithium-acetylide, to which was added a catalytic
amount of BF3ÆOEt2 and subsequently a solution of 4
in THF to furnish the coupled product 13 in a 93% yield
(see Scheme 3).
Formation of the new C–O bond with a concomitant
new stereocentre was achieved via an oxy-anion assisted
Michael addition12 using KOtBu and benzaldehyde in
THF at 0 °C. A syn 1,3-diol in the form of a benzalde-
hyde acetal (2) was obtained in a 78% yield (see Scheme
4).
EtMgBr
Ref 7
O
D-mannitol
O
Ether, 76%
CHO
Deprotection of the benzylidene acetal led to formation
of a six-membered lactone and saturation of the triple
bond and debenzylation were successfully achieved in
one-pot using Pd/C in acidic methanol to furnish the
target molecule 1 in an 85% yield.13
8
NaH, BnBr
O
O
O
O
THF, 83%
Acknowledgement
OBn
OH
10
(dr 97:3)
9
P.M.K. and P.V.R. thank the UGC, New Delhi, for
financial assistance.
OBn
1.PTSA, MeOH
80%
PPh3, CBr4
H
2.NaIO4
THF, water (7:3)
CH2Cl2, 98%
O
References and notes
11
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S. G.; Wilkinson, B.; Staunton, J.; Leadlay, P. F. Org.
Biomol. Chem. 2003, 1, 4144–4147.
2. Crouse, G. D.; Sparks, T. C. Rev. Toxicol. 1998, 2, 133–
146.
Br
OBn
OBn
EtMgBr
THF, 0 oC
96%
Br
12
3
3. (a) Khosla, C.; Gokhale, R. S.; Jacobsen, J. R.; Cane, D.
E. Ann. Rev. Biochem. 1999, 68, 219–253; (b) Kinoshita,
Scheme 3. Synthesis of fragment 3.

J. S. Yadav et al. / Tetrahedron Letters 48 (2007) 1037–1039
1039
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Tetrahedron 2005, 61, 4341–4346.
6. Vatele, J.-M. Tetrahedron Lett. 2006, 47, 715–718.
7. Chatopadyay, A.; Mamdapur, V. R. J. Org. Chem. 1995,
60, 585–587.
8. Chatopadyay, A. J. Org. Chem. 1996, 61, 6104–6107.
9. Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13,
3769–3772.
10. Gooding, O. W.; Beard, C. C.; Jackson, D. Y.; Wren, D.
L.; Cooper, G. F. J. Org. Chem. 1991, 56, 1083–1088.
11. Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391–
394.
6.81 (dd, 1H, J = 6.7, 9.0 Hz), 5.84 (dd, 1H, J = 1.5,
14.3 Hz), 4.16 (q, 2H, J = 7.5 Hz), 2.81–2.72 (m, 2H),
2.52–2.50 (m, 1H), 2.23–2.14 (m, 1H), 1.32–1.22 (m, 6H).
13C NMR (75 MHz, CDCl3): d 166.2, 148.0, 121.8, 60.3,
54.8, 45.9, 38.8, 15.7, 14.1; IR: 2924, 1720, 1268, 1183,
1036 cmꢁ1; MS (ESI) m/z 193 (M+Na)+. Compound 13:
[a]25 ꢁ4.02 (c 1.6, CHCl3); 1H NMR (300 MHz, CDCl3): d
7.38–7.21 (m, 5H), 6.85 (dd, 1H, J = 8.5, 15.6 Hz), 5.83
(dd, 1H, J = 1.5, 15.6 Hz), 4.73 (d, 1H, J = 11.7 Hz), 4.45
(d, 1H, J = 12.5 Hz) 4.16 (q, 2H, J = 7.0 Hz), 3.98 (tt, 1H,
J = 1.5, 6.2 Hz), 3.63 (q, 1H, J = 6.2 Hz), 2.58–2.30 (m,
3H), 2.23 (br s, 1H), 1.81–1.67 (m, 2H), 1.30 (t, 3H,
J = 7.0 Hz), 1.16 (d, 3H, J = 7.0 Hz), 1.00 (t, 3H,
J = 7.8 Hz); 13C NMR (75 MHz, CDCl3): d 166.5, 138.1,
133.6, 130.1, 128.4, 128.3, 127.8, 127.5, 82.3, 72.3, 70.4,
70.2, 60.3, 41.2 29.0, 25.4, 14.3, 14.2, 9.7; MS (ESI) m/z
345 (M+H)+; IR: 3424, 3030, 2925, 1718, 1276,
12. Evans, D. A.; Gauchet-Prunet, J. A. J. Org. Chem. 1993,
58, 2446–2453.
25
1019 cmꢁ1. Compound 1: Liquid ½aꢀD ꢁ33.8 (c 0.24,
13. Physical and analytical data matched with the reported
data. (a) See Ref. 1. (b) Chakraborty, T. K.; Rajib, K. G.:
Tetrahedron Lett. 2004, 45, 7637. Spectral data for
CHCl3); IR 3445, 2924, 1728, 1459, 1104 cmꢁ1 1H
,
NMR (400 MHz, CDCl3): d 4.71 (ddd, 1H, J = 2.5, 4.7,
8.1 Hz), 4.06 (ddd, 1H, J = 3.2, 3.4, 5.6 Hz), 3.55 (m, 1H),
2.81 (dd, 1H, J = 5.5, 18.5 Hz), 2.53 (ddd, 1H, J = 0.9,
3.2, 18.1 Hz), 1.95 (m, 1H), 1.74 (m, 1H), 1.65 (m, 2H),
1.50 (m, 3H), 1.42 (m, 2H), 0.95 (d, 3H, J = 7.2 Hz), 0.94
(t, 3H, J = 7.3 Hz); 13C NMR (75 MHz, CDCl3): d 170.3,
78.0, 73.0, 68.6, 37.3, 36.4, 35.8, 31.7, 30.3, 21.6, 10.2, 9.8;
MS (ESI) m/z 231 (M+H)+, 253 (M+Na)+.
25
compound 3: ½aꢀD ꢁ98.4 (c 2.2, CHCl3); 1H NMR
(300 MHz, CDCl3): d 7.32–7.23 (m, 5H), 4.75 (d, 1H,
J = 11.3 Hz), 4.44 (d, 1H, J = 11.3 Hz), 3.96 (t, 1H,
J = 6.0 Hz), 2.38 (s, 1H) 1.76 (m, 2H), 1.02 (t, 3H,
J = 6.7 Hz); MS (ESI) m/z 197 (M+Na)+. Compound 4:
25
½aꢀD ꢁ13.2 (c 1.1, CHCl3); 1H NMR (300 MHz, CDCl3): d