Regioselective nucleophilic ring-opening reaction of chiral epoxyallyl alcohols: A ready access to the pyran core of macrolactin 3

Article abstract of DOI:10.1016/j.tetlet.2014.04.068

Herein we report the synthetic strategy towards the pyran core of macrolactin 3 via Sharpless epoxidation, titanium(IV) mediated regioselective ring-opening reaction of epoxyallyl alcohol/epoxy alcohol and oxa-Michael addition as the key steps.

Full text of DOI:10.1016/j.tetlet.2014.04.068

Accepted Manuscript
Regioselective nucleophilic ring-opening reaction of chiral epoxyallyl alcohols:
A ready access to the pyran core of macrolactin 3
Palakodety Radha Krishna, Rajesh Nomula, Kallaganti V.S. Ramakrishna
PII:
S0040-4039(14)00693-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.04.068
TETL 44530
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 March 2014
16 April 2014
17 April 2014
Please cite this article as: Krishna, P.R., Nomula, R., Ramakrishna, K.V.S., Regioselective nucleophilic ring-opening
reaction of chiral epoxyallyl alcohols: A ready access to the pyran core of macrolactin 3, Tetrahedron Letters (2014),
doi: http://dx.doi.org/10.1016/j.tetlet.2014.04.068
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GRAPHICAL ABSTRACT
Leave this area blank for abstract info.
Regioselective nucleophilic ring-opening reaction of
chiral epoxyallyl alcohols: A ready access to the
pyran core of macrolactin 3
Palakodety Radha Krishnaa∗ Rajesh Nomulaa and Kallaganti V. S. Ramakrishnab
1

Regioselective nucleophilic ring-opening reaction of chiral epoxyallyl
alcohols: A ready access to the pyran core of macrolactin 3
Palakodety Radha Krishnaa∗ Rajesh Nomulaa and Kallaganti V. S. Ramakrishnab
aD-211, Discovery Laboratory, Organic & Biomolecular Chemistry Division; bCenter for
Nuclear Magnetic Resonance
CSIR-Indian Institute of Chemical Technology, Hyderabad-500 007, India.
Abstract: Herein we report the synthetic strategy towards the pyran core of macrolactin 3 via
Sharpless epoxidation, titanium (IV) mediated regioselective ring-opening reaction of epoxyallyl
alcohol/epoxy alcohol and oxa-Michael addition as the key steps.
Keywords: Macrolactins, Sharpless epoxidation, Regioselective epoxide ring-opening, Oxa-
Michael addition.
Disposition of contiguous poly hydroxy stereogenic centers is ubiquitous in many natural
products (Figure 1).1 Accessing such chiral polyols plays a decisive role in achieving the total
synthesis of the parent molecule(s). Earlier, we reported2 titanium(IV) mediated regio- and
stereoselective C5 epoxide ring-opening reaction of chiral epoxyallyl alcohols with acids as a
novel methodology for expedient synthesis of polyol systems. We envisaged a similar
retrosynthetic route to access the C11-C19 segment of macrolactin 3 (1), that was isolated from
the ethyl acetate extract of a marine Bacillus sp.3 and displayed in vitro antimicrobial activity
against both gram-positive and gram-negative pathogens.
The retrosynthetic analysis (Scheme 1, route A) depicts the regioselective epoxide ring-opening
reaction of 7 as the strategic synthetic tool in accessing polyol system and subsequently the
crucial allyl alcohol derivative 4. While 7 could be conceived from divinyl methanol derivative
6, compound 4 upon a few transformations followed by oxa-Michael addition, another key step
for the ring-construction, would lead to the crucial trans-fused pyran fragment 2. Further ahead,
compound 2 could be elaborated to natural product 1 by adopting a convergent strategy.
Alternatively, the crucial intermediate 4, could be accessed from epoxy alcohol 11 (Scheme 1,
route B) by an elimination reaction of the corresponding epoxy iodide derivative under
∗ Corresponding author. Tel.: +91-40-27193518; fax: +91-40-27160387; e-mail: prkgenius@iict.res.in
2

OH
H
OH OH
12
11
O
O
H
HO
OH
O
13
O
23
24
O
17
OH
HO
OH
Macrolactin 3 (1)
Iriomoteolide-4A
O
O
O
HO
OH
O
O
O
OH
O
O
O
O
O
OH
Ph
OH
OH
OH
OH
6-epi goniodiol
OH
Herbarumin I
OH
Herbarumin II
Xyolide
Figure 1: Structures of 1,2,3-polyol containing natural products
conventional reaction conditions.4 It is pertinent to mention that an independent synthesis of the
same intermediate 4 by another route was felt necessary because a chemical correlation of the
product obtained through both pathways would not only prove structure of the compound 4
conclusively but also the regioselectivity of the ring-opening reaction of 7 (route A) obtained by
earlier approach would also be determined unambiguously.
Scheme 2 (route A) depicts the synthesis of crucial fragment 4 and it was accessed from the
known allyl alcohol 5 as the starting material5 by multi-step sequence. Thus, the allyl alcohol 5
3

upon oxidation (IBX/DMSO/CH2Cl2) followed by vinylation (vinylmagnesium bromide/THF)
gave the racemic divinyl methanol 6 (82%). The chiral epoxy allyl alcohol 7 was prepared via
o
Sharpless kinetic resolution6 {(+)-DIPT/Ti(OiPr)4/TBHP/CH2Cl2/-20 C} of the corresponding
racemic divinyl methanol 6. Next, the epoxy alcohol 7 was subjected to regioselective ring-
o
opening (C5-attack) reaction with benzoic acid2 (Bz-OH/Ti(OiPr)4/CH2Cl2/0 C to rt) to afford
1,2,3-triol monoester 8 (83%). Selective mono silylation (TBSCl/Imidazole/CH2Cl2/0 oC to rt) of
compound 8 gave allyl TBS-ether 9 (86%) which was treated with potassium carbonate solid
under methanolic conditions to result in diol 10 (82%). The diol 10 was protected as its acetonide
with 2,2-DMP under acidic conditions to afford the crucial fragment 4 (78%).
OH
OH
O
b
c
a
PMBO
PMBO
OH
PMBO
PMBO
PMBO
PMBO
5
6
7
OBz OH
OBz OTBS
OH OTBS
OH
d
e
f
4
OH
8
OH
9
10
Scheme 2: (a) (i) IBX, DMSO, CH2Cl2, 0 °C to rt, 1h (ii) vinylmagnesium bromide, THF, 0 °C to rt, 1h, 82%; (b)
(+)-DIPT, Ti(OiPr)4, TBHP, 4Å MS, CH2Cl2, -20 °C, 18h, 40%; (c) BzOH, Ti(OiPr)4, CH2Cl2, 0 °C to rt, 5 h,
83%; (d) TBSCl, imidazole, CH2Cl2, 0 °C to rt, 4h, 86%; (e) K2CO3, MeOH, 0 °C to rt, 3h, 82%; (f) 2,2-DMP,
PTSA, CH2Cl2, 0 °C to rt, 4h, 78%.
The same product was realized by an alternative pathway. Accordingly, fragment 4 (Scheme 3,
route B) was accessed from the known epoxy alcohol 115 by reported procedure using the same
starting material 5. Thus, the epoxy alcohol 11 when subjected to the regioselective ring-opening
o
reaction with benzoic acid7 (Bz-OH/Ti(OiPr)4/CH2Cl2/0 C) afforded 1,2 diol 12 (85%). Diol 12
on selective silyl protection (TBSCl/ nBu2SnO/CH2Cl2/0 oC) gave mono silyl ether compound 13
o
(90%) which was subjected to benzoyl group deprotection (K2CO3/MeOH/0 C) resulted in diol
o
14 (85%). Masking of diol 14 as its acetonide with (2,2 DMP/PPTS/CH2Cl2/0 C) gave
compound 15 (80%). Next, deprotection of TBS ether with TBAF gave primary alcohol 16
(86%). The primary alcohol 16 on Swern oxidation afforded the corresponding aldehyde which
on Wittig olefination (PPh3=CHCOOEt/C6H6/reflux) gave α,β-unsaturated ester 17 as a
separable major E-isomer (9:1, 82% over two steps). The major E-isomer 17 on reduction with
4

DIBAL-H gave allyl alcohol 18 (88%). Subsequently, allylic alcohol 18 was converted into
chiral epoxy alcohol 19 under Sharpless conditions7,8 {(-)-DIPT/Ti(OiPr)4/TBHP/4Å
o
MS/CH2Cl2/-20 C}. The epoxy alcohol 19 was converted into the corresponding iodide
(I2/PPh3/imidazole) which on reductive elimination with activated Zn dust (Zn/EtOH/reflux/2 h)
OBz
O
b
c
a
PMBO
OH
PMBO
OH
PMBO
PMBO
OH
11
OH
12
OH
5
OPMB
OBz
d
f
e
OTBS
PMBO
OTBS
OTBS
15
OH
OH
O
14
13
O
OPMB
OPMB
OPMB
OPMB
O
j
i
h
O
g
OH
OEt
OH
OH
O
O
O
O
O
O
O
O
18
17
19
16
OPMB
OH
OPMB
OTBS
k
O
O
O
O
20
4
Scheme 3: (a) (+)-DIPT, Ti(OiPr)4, TBHP, 4Å MS, CH2Cl2, -78 °C, 12h, 83% ; (b) BzOH, Ti(OiPr)4, CH2Cl2, 0 °C to rt, 3 h,
85%; (c) TBSCl, Bu2SnO, imidazole, CH2Cl2, 0 °C to rt, 3h, 90%; (d) K2CO3, MeOH, 0 °C to rt, 2h, 85%; (e) 2,2-DMP, PPTS,
CH2Cl2, 0 °C to rt, 6h, 80%; (f) TBAF, THF, 0 °C to rt, 2h, 86%; (g) (i) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C, 1h; (ii)
PPh3=CHCOOEt, C6H6, reflux (82% over two steps); (h) DIBAL-H, CH2Cl2, 0 °C to rt, 1h, 88%; (i) (-)-DIPT, Ti(OiPr)4,
TBHP, 4Å MS, CH2Cl2, -78 °C, 12h, 85%; (j) (i) I2, TPP, imidazole, THF, 0 °C to rt, 1h; (ii) Zn, EtOH, reflux, 3h (78% over
two steps); (k) TBSCl, imidazole, CH2Cl2, 0 °C to rt, 3h, 91%.
afforded chiral allylic alcohol 20 (78%). The secondary OH group in the allyl alcohol 20 was
o
protected as its TBS-ether ((TBSCl/CH2Cl2/0 C) to result in a fully protected compound 4
(91%). The spectral data of compound 4 thus obtained (route B) was in complete agreement with
the data of the compound 4 obtained by route A.9 Furthermore, while compound 4 was
synthesized in 6 linear steps by route A (overall yield 14.9%), the same was obtained in 11 linear
steps (16.1%) by route B. Interestingly, both the routes used the known allyl alcohol 5 as staring
material.5
5

Next, compound 4 (Scheme 4) was subjected to deprotection of PMB group under DDQ
conditions to afford primary alcohol 21 (86%). The alcohol 21 on Swern oxidation afforded the
corresponding aldehyde which on subsequent Wittig olefination (PPh3=CHCOOEt/C6H6/reflux)
gave the α,β-unsaturated ester 22 (E:Z in 9:1, 80% over two steps) as a separable major E-
isomer. Further, synthesis of the requisite trans-pyran was planned by a step-wise conjugate
addition strategy. Accordingly, deprotection of silyl group (HF.Py/THF/rt/24 h) in compound 22
resulted in allyl alcohol 3 (83%). The resulting alcohol 3 on intramolecular oxa-Michael addition
o
reaction (KOtBu/THF/-78 C)10 led to the trans-pyran 2 (72%) presumably due the steric
crowding posed by the acetonide ring-system, alkyl and alkenyl substituents as well as the
reaction conditions favoring the kinetic product.
This trans-stereochemistry of the newly generated ring-junction was assigned based on 1H NMR
(300 MHz, CDCl3) data and assignments were made with the aid of TOCSY and NOESY
Figure 2. (a) NOESY spectrum (in CDCl3) of 2 (b) energy minimized structure of 2.
experiments. The absence of NOE between C13H/C17H (Figure 2) suggested that both the
protons are anti to each other (trans related) and on opposite faces of the pyran ring system. This
6

was further supported by NOE correlation between C17H/Me-A, C16H/C18H, C13H/C15H and
C15H/Me-B, confirming the structure of 2 (Figure 2). The energy minimized structure is (Figure
2) also shown.
In summary, we have accomplished the synthesis of C11-C19 fragment of bioactive
macrolactin 3 (2) involving Sharpless epoxidation, Ti(IV) promoted nucleophilic regioselective
epoxide ring-opening and oxa-Michael addition as the key steps. Further work towards the total
synthesis of macrolactin 3 is under progress in our laboratory.
Acknowledgements. One of the authors (R. N) thanks the CSIR, New Delhi for the financial
support in the form of a fellowship. All the authors thank CSIR, New Delhi for financial support
as part of XII Five Year plan program under title ORIGIN (CSC-0108).
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