The stereoselective total synthesis of PF1163A

Article abstract of DOI:10.1016/j.tetlet.2014.01.031

A stereoselective total synthesis of 13-membered macrocycle PF1163A, an antifungal agent, has been accomplished for the first time starting from d-xylose. This approach involves a diastereoselective allylation of lactal ether,^3a reductive ring

Full text of DOI:10.1016/j.tetlet.2014.01.031

Tetrahedron Letters 55 (2014) 1519–1522
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The stereoselective total synthesis of PF1163A
⇑
Harish Kumar, A. Srinivas Reddy, B. V. Subba Reddy
Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereoselective total synthesis of 13-membered macrocycle PF1163A, an antifungal agent, has been
Received 2 November 2013
Revised 6 January 2014
Accepted 8 January 2014
Available online 15 January 2014
accomplished for the first time starting from D-xylose. This approach involves a diastereoselective allyla-
tion of lactal ether,3a reductive ring opening of tetrahydrofuran ring,3b asymmetric methylation reaction,
Yamaguchi esterification, and ring closing metathesis as key steps.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Antifungal agent
Evans methylation
Yamaguchi esterification
Ring closing metathesis
PF1163A and PF1163B are potent antifungal agents isolated
from fermentation broths of Penicillium sp. (Fig. 1).1a,b They are po-
tent inhibitors of ergosterol synthesis.1c Ergosterol is a major con-
stituent of plasma membrane of Candida albicans which is
biosynthesized from lanosterol and is responsible for oral and gen-
ital infections in humans and even causes morbidity and mortality
in immunodeficient patients.
O
OH
O
N
O
O
1) R = OH, PF1163A
2) R = H, PF1163B
R
PF1163A shows four times higher antifungal activity than
PF1163B. MIC values of PF1163 A and B were found to be 8 and
Figure 1. Structure of PF1163 A and B.
32 lg/mL respectively against the C. albicans TIMM1768. IC50 val-
ues to inhibit the ergosterol biosynthesis were evaluated to be
13 and 34 ng/mL, respectively. Moreover PF1163A is an almost
equal inhibitor, as fluconazole, of ergosterol synthesis in C. albi-
cans.1a The structure of PF1163B was established by extensive
spectroscopic analysis of degradation products and single crystal
X-ray diffraction analysis while PF1163A was elucidated by its to-
tal synthesis and NMR studies.1c,2 The presence of an extra hydro-
xyl group in the side chain of PF1163A attributes to four fold
enhanced antifungal activity.
asymmetric alkylation,4a Swern oxidation,4b Wittig reaction,4c
Yamaguchi esterification,4d EDCI/HOBT amidation, and RCM reac-
tion.4e This route also provides an easy access to generate various
analogues of PF1163A by simply modifying its side chain in a
highly diastereoselective manner, thus creating a scope of improv-
ing its biological activity. The three points of disconnection are at
the 1,3-anti-diol with an isolated methyl stereocenter 4, substi-
tuted aromatic part 5, and pentenoic acid 6. It was assumed that
a 13-membered macrocycle 1 can be assembled through Yamagu-
chi esterification of alcohol fragment 4 and amino acid fragment 5.
PF1163A is a 13-membered macrocycle comprising a lactam,
lactone, isolated methyl center, hydroxyl group in the side chain,
and an aromatic part derived from L-tyrosine. The enhanced bio-
Alcohol fragment 4 itself was anticipated to be obtained from
D-xy-
lose and fragment 5 could be synthesized from N-boc- -tyrosine
L
logical activity shown by PF1163A has attracted significant interest
methyl ester whereas pent-4-enoic acid is commercially available
(Scheme 1).
Carbohydrates contribute a significant role in chiral pool syn-
thesis (chiron approach) due to the presence of multiple chiral cen-
ters with well defined stereochemistry. The synthesis of fragment
in its synthesis.2
The synthetic approach is focused mainly on showing the appli-
cation of our own strategies like stereoselective allylation of lac-
tals3a and reductive ring opening3b of C-propyl furanosides which
are complimentary for this synthesis. Our approach also involves
4 began with D-xylose, which was converted into compound 7 in
four steps with an overall yield of 65% utilizing the literature
method.3c The lactal 7 was subjected to allylation using allyltri-
methylsilane in the presence of iodine (10 mol%) in DCM at
⇑
Corresponding author. Fax: +91 40 27160512.
E-mail address: basireddy@iict.res.in (B.V.S. Reddy).
0040-4039/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2014.01.031

1520
H. Kumar et al. / Tetrahedron Letters 55 (2014) 1519–1522
O
O
O
O
OMe
OH
OH
a
BnO
BnO
Ref 3c
D-Xylose
Stereoselective
BnO
BnO
allylation
3
7
2
8
O
O
N
N
O1
O
O
O
13
O
OH
OBn
O
8
b
c,d
HO
PMBO
9
e, f
HO
3
HO
Evans methylation
PF1163A (1)
10
Grubbs reaction
9
OH OPMB
OBn OPMB
O
O
O
j, k
g, h, i
OBn
OH
O
OH
+
+
OBn
4
11
12
Boc
O
N
H
5
OH
OBn OPMB
O
OBn OPMB
O
6
O
l
pent-4-enoic acid
N
OH
O
N-Boc-L-tyrosine methyl ester
D-Xylose
13
14
Bn
Scheme 1. Retrosynthetic analysis of PF1163A (1).
OBn OPMB
OBn OPMB
m, n
o, p
OH
16
15
ꢀ78 °C to afford the C-allyl furanoside 8 in 85% yield with high dia-
stereoselectivity (9:1). Reduction of double bond with concomitant
debenzylation of 8 using 10% Pd/C under hydrogen atmosphere in
MeOH gave the saturated 1,3-diol 9 with anomeric propyl chain.
Protection of the diol 9 with p-methoxybenzaldehyde dimethyl-
acetal in the presence of a catalytic amount of CSA in DCM fol-
lowed by reductive cleavage of the p-methoxybenzylidene acetal
with DIBAL-H afforded the alcohol 10 in 70% yield over two steps.
Treatment of 10 with iodine, triphenyphosphine, and imidazole in
dry THF gave the iodo derivative which was then exposed to acti-
vated zinc in refluxing ethanol to afford the key intermediate 11 in
50% yield over two steps. Protection of the alcohol 11 with benzyl
bromide using NaH in dry THF followed by hydroboration5 of the
olefin and Swern oxidation of the alcohol and then C-2 Wittig reac-
tion of the aldehyde gave the unsaturated ester 12 in 60% yield
OBn OH
q
4
Scheme 2. Reagents and conditions: (a) allyltrimethylsilane, I2, DCM, ꢀ78 °C–rt
15 h 85%; (b) H2, Pd/C, MeOH, 24 h, 78%; (c) p-MeO–PhCH(OMe)2, CSA, DCM, 0 °C,
30 min, 89%; (d) DIBAL-H, DCM, 0 °C, 1 h, 78%; (e) Ph3P, I2, imidazole, THF, reflux,
1 h, 74%.; (f) Zn, ethanol, reflux, 12 h, 68%; (g) BnBr, NaH, TBAI, THF 0 °C–rt, 8 h, 90%;
(h) BH3.DMS, THF 0 °C, 8 h then H2O2, aq NaOH, rt, 4 h 80%. (i) (COCl)2, DMSO, Et3N,
CH2Cl2, ꢀ78 °C–rt, 88%, Ph3P@CHCO2Et, 12 h, 82%; (j) NiCl4ꢂ6H2O, NaBH4, MeOH,
0 °C, 2 h, 83%; (k) LiOH, THF/H2O (2:1), 6 h, 75%; (l) PivCl, Et3N, LiCl, (S)-4-benzyl-2-
oxazolidinone, THF, ꢀ20 °C, 4 h, 78%; (m) NaHMDS, MeI, THF, ꢀ78 °C, 1 h, 76%; (n)
LiBH4, MeOH, 0 °C–rt, 10 min, 86%; (o) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 °C–rt, 82%;
(p) CH3PPh3I, LiHMDS, ꢀ78 °C, 60%; (q) DDQ, CH2Cl2/H2O (9:1), rt, 1 h, 74%.
over four steps. Reduction of the
a–b unsaturated ester 12 with
OH
O
NiBH4 in MeOH followed by ester hydrolysis using 2 equiv of LiOH
in THF/water (2:1) gave the acid 13 in 75% yield. N-Acylation of the
acid 13 using chiral (S)-4-benzyl-2-oxazolidinone, PivCl, Et3N, and
LiCl in dry THF afforded the N-acyl derivative 14 in 78% yield. The
diastereoselective alkylation of 14 with MeI in the presence of so-
dium enolate followed by cleavage of the chiral auxiliary using
LIBH4 afforded the alcohol 15 in 68% overall yield.6 Oxidation of
the alcohol 15 under Swern oxidation conditions followed by
homologation using C-1 Wittig salt employing LiHMDS as base at
0 °C gave the olefin 16 in 55% yield over two steps. Oxidative
deprotection of p-methoxybenzyl ether of 16 using DDQ in DCM/
H2O (9:1) system afforded the required fragment 4 in 74% yield
(Scheme 2).
OBn
a
b
O
Boc
O
Boc
N
H
N
H
OMe
OMe
18
17
O
O
OBn
OBn
c
Boc
O
Boc
O
N
H
N
OH
OH
19
5
Scheme 3. Reagents and conditions: (a) BrCH2CH2OBn, K2CO3, DMF, 1 h, 82%; (b)
LiOH, THF/H2O (2:1), 6 h, 85%; (c) MeI, NaH, THF, 0 °C–rt, 24 h, 89%.
Amino acid fragment 5 was prepared from N-Boc-L-tyrosine
methyl ester. Accordingly, compound 17 was treated with 2 equiv
of 2-bromo-O-benzyl-ethanol in the presence of 3 equiv of K2CO3
in dry DMF at room temperature for 1 h that gave the arylalkyl
ether 18 in quantitative yield. Due to the probability of rac-
emization under NaH conditions, the intermediate 18 was initially
hydrolyzed with 1.5 equiv of LiOH and then subjected to N-meth-
ylation with MeI in the presence of NaH to afford the enantiopure
acid 5 in 86% yield (Scheme 3).7,8
The coupling of acid 5 with alcohol 4 under Yamaguchi condi-
tions (through mixed anhydride formation using 2,4,6-trichloro-
benzoyl chloride) afforded the ester 20 in 89% yield.4d Removal
of the Boc group from ester 20 using TFA in DCM and subsequent
N-acylation of free amine with pent-4-enoic acid using EDCI/
HOBT/DIPEA in DCM at 0 °C gave the diene 3 in 75% yield over
two steps. RCM of diene 3 using Grubbs 2nd generation catalyst
in refluxing dichloroethane for 12 h gave the (E)- and (Z)-diaste-
reomers (2:1, respectively).4e Reduction of the double bond and
debenzylation was achieved using Pd/C in MeOH under hydrogen
atmosphere that gave the target molecule (1) in 56% yield over
two steps (Scheme 4). The spectroscopic data and specific rotation
of PF1163A (1) were in good agreement with the data reported in
the literature ½aꢁD ꢀ88.5 (c = 0.93, MeOH).
In conclusion, we have demonstrated a convergent, flexible, and
highly diastereoselective strategy for the total synthesis of
PF1163A. The key reactions employed in this strategy are the Evans
asymmetric alkylation, diastereoselective allylation and reductive

H. Kumar et al. / Tetrahedron Letters 55 (2014) 1519–1522
1521
8. (2R,3R,5S)-3-(4-Methoxybenzyloxy)-5-propyl tetrahydrofuran-2-yl)methanol (10)
O
OBn
a
Rf = 0.50 (30% EtOAc/hexane), pale yellow liquid, ½a D25
ꢁ
ꢀ3.5 (c = 1, CHCl3); 1H
OH
NMR (300 MHz, CDCl3): d 7.16 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.5 Hz, 2H), 4.47 (d,
J = 11.4 Hz, 1H), 4.26 (d, J = 8.5 Hz, 1H), 4.20–4.16 (q, J = 6.1, 6.6 and 12.5 Hz,
1H), 3.83–3.80 (q, J = 5.2, 5.8 and 10.4 Hz, 1H), 3.78–3.71 (m, 6H), 2.24–2.18 (m,
1H), 2.14–2.00 (m, 1H), 1.67–1.53 (m, 2H), 1.52–1.22 (m, 3H), 0.86 (t, J = 7.5 Hz,
3H); 13C NMR (75 MHz, CDCl3): d 159.3, 129.2, 113.9, 80.1, 79.9, 77.7, 71.2, 62.3,
51.3, 38.1, 98.0, 19.3, 14.1; IR (neat): mmax 3398, 2926, 2855, 1733, 1458, 1376,
1267, 1041, 772 cmꢀ1; HRMS (ESI) m/z calcd for C16H24O4: 281.1723, found:
281.1729 [M+H]+.
OBn
O
Boc
+
N
OH
4
5
O
O
OBn
OBn
(5S,7S,E)-Ethyl-7-(benzyloxy)-5-(4-methoxybenzyloxy)dec-2-enoate (12) Rf = 0.60
b,c
(10% EtOAc/hexane), colorless liquid, ½ ꢁ
a 2D5 +26.8 (c = 0.6, CHCl3); 1H NMR
O
O
Boc
N
N
(300 MHz, CDCl3): d 7.35–7.25 (m, 7H), 7.20 (d, J = 8.5 Hz, 2H), 7.02–6.92 (m,
1H), 6.84 (d, J = 8.5 Hz, 2H), 5.87 (d, J = 15.5 Hz, 1H), 4.53 (d, J = 11.4 Hz, 1H),
4.47 (d, J = 10 Hz, 1H), 4.29–4.24 (q, J = 6.7, 4.6 and 11.0 Hz, 2H), 4.22–4.16 (q,
J = 7.0, 7.2 and 14.2 Hz, 2H), 3.82–3.76 (m, 4H), 3.66–3.60 (m, 1H), 2.53–2.35 (m,
2H), 1.69–1.32 (m, 6H), 1.43–1.32 (m, 1H), 1.29 (t, J = 7.2 Hz, 3H), 0.9 (t,
J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 166.3, 159.1, 145.2, 144.9, 138.7,
129.4, 128.3, 127.7, 127.4, 123.6, 113.7, 36.1, 29.6, 18.0, 14.3, 14.2; IR (neat):
mmax 2937, 1718, 1613, 1514, 1458, 1219, 1173, 1056, 772, 699 cmꢀ1; HRMS
(ESI) m/z calcd for C27H36O5: 441.2632, found: 441.2634 [M+H]+.
O
O
O
OBn
O
OBn
20
3
OH
(5S,7S)-7-(Benzyloxy)-5-(4-methoxybenzyloxy)decanoic acid (13) Rf = 0.20 (30%
EtOAc/hexane), colorless liquid, ½a D25
ꢁ
+35.72 (c = 1.8, CHCl3); 1H NMR (300 MHz,
O
CDCl3): d 7.37–7.23 (m, 5H), 7.21 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 8 Hz, 2H), 4.55–
4.25 (m, 4H), 3.77 (s, 3H), 3.67–3.58 (m, 2H), 2.35 (t, J = 7.2 and 14.6 Hz, 2H),
1.78–1.30 (m, 10H), 0.92 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 179.1,
158.9, 138.8, 130.7, 129.4, 128.2, 127.7, 127.3, 113.6, 75.6, 74.8, 70.7, 70.5, 55.1,
39.8, 36.2, 33.9, 33.2, 19.9, 18.0, 14.3; IR (neat): mmax 3031, 2955, 2935, 2871,
N
d,e
O
O
OH
1709, 1612, 1513, 1456, 1353, 1301, 1248, 1172, 1066, 821, 772, 698 cmꢀ1
;
HRMS (ESI) m/z calcd for C25H34O5: 415.2463, found: 415.2467.
(S)-4-Benzyl-3-((5S,7S)-7-(benzyloxy)-5-(4-methoxybenzyloxy)decanoyl)oxazoli-
din-2-one (14): Rf = 0.50 (20% EtOAc/hexane), viscous liquid, +45.28
1
½ ꢁ
a 2D5
Scheme 4. Reagents and conditions: (a) 2,4,6-trichloro-benzoyl chloride, Et3N,
DMAP, toluene, 0 °C–rt, 8 h, 87%; (b) TFA, CH2Cl2, 0 °C–rt, 1 h, 90%; (c) pent-4-enoic
acid, EDCI, HOBT, DIPEA, CH2Cl2, 12 h, 85%; (d) Grubb’s catalyst II (10 mol %), dry
CH2CH2Cl2, reflux, 12 h, 70%; (e) H2, Pd/C, MeOH, 12 h, 79%.
(c = 0.7, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.36–7.17 (m, 12H), 6.84 (d,
J = 8.7 Hz, 2H), 4.68–4.61 (m, 1H), 4.55–4.27 (m, 4H), 4.21–4.12 (m, 2H), 3.76
(s, 3H), 3.71–3.60 (m, 2H), 3.32–3.26 (dd, J = 3 and 13 Hz, 1H), 2.99–2.84 (m,
2H), 2.77–2.70 (m, 1H), 1.81–1.34 (m, 10H), 0.92 (t, J = 7.3 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d 172.9, 158.9, 153.3, 138.9, 135.2, 130.9, 129.3, 128.8, 128.2,
127.7, 127.1, 113.6, 75.7, 74.9, 70.5, 66.0, 55.1, 54.9, 39.9, 37.8, 36.9, 35.5, 33.4,
19.6, 18.1, 14.3; IR (neat): mmax 3029, 2325, 2861, 1781, 1701, 1610, 1512,
1455, 1385, 1353, 1247, 1212, 1069, 821, 770, 700 cmꢀ1; HRMS (ESI) m/z calcd
for C35H43NO6: 574.3161, found: 574.3163 [M+H]+.
ring opening of furanoside. This strategy allows an easy access for
the design and synthesis of various analogues with different side
chain and a variable ring size. This approach may be useful in
improving the antifungal activity of related compounds of its
stereotype.
1-(((3S,6S,8S)-8-(Benzyloxy)-3-methylundec-1-en-6-yloxy)methyl)-4-
methoxybenzene (16) Rf = 0.70 (10% EtOAc/hexane), pale yellow liquid, ½a D25
ꢁ
+13.0 (c = 0.5, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.36–7.27 (m, 5H), 7.25–
7.18 (d, J = 8.3 Hz, 2H), 6.88–6.80 (d, J = 9.1 Hz, 2H), 5.74–5.61 (m, 1H), 5.01–
4.88 (m, 2H), 4.56–4.21 (m, 4H), 3.77 (s, 3H), 3.67–3.56 (m, 2H), 2.15–2.04 (m,
1H), 1.66–1.23 (m, 10 H), 0.99 (d, J = 6.8 Hz, 3H), 0.92 (t, J = 6.8 Hz, 3H); 13C
NMR (75 MHz, CDCl3): d 159.1, 157.1, 147.2, 144.6, 129.4, 128.3, 127.4, 113.7,
75.5, 70.9, 70.5, 55.3, 40.7, 37.9, 31.6, 20.4, 18.2, 14.4; IR (neat): mmax 2924,
2854, 1735, 1512, 1461, 1376, 1249, 1072, 772, 735 cmꢀ1; HRMS (ESI) m/z
calcd for C27H38O3: 411.2874, found: 411.2894 [M+H]+.
Acknowledgements
H.K and A.S.R. thank CSIR, New Delhi, India for the award of fel-
lowships. B.V.S.R. thanks CSIR, New Delhi for the financial support as
a part of XII five year plan program under title ORIGIN (CSC-0108).
(3S,6S,8S)-8-(Benzyloxy)-3-methylundec-1-en-6-ol (4): Rf = 0.40 (10% EtOAc/
hexane), pale yellow liquid, ½a D25
ꢁ
+15.5 (c = 1.8, CHCl3); 1H NMR (300 MHz,
CDCl3): d 7.63–7.2 (m, 5H), 5.75–5.59 (m, 1H), 5.02–4.84 (m, 2H), 4.62–4.47
(m, 2H), 3.9–3.80 (m, 1H), 3.77–3.65 (m, 1H), 2.15–2.03 (m, 1H), 1.8–1.2 (m,
10H), 0.99 (d, J = 6.6 Hz, 3H), 0.93 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 144.6, 138.3, 129.4, 127.8, 127.7, 112.6, 71.8, 68.8, 39.6, 37.9, 35.6, 35.4, 32.6,
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2014.01.031.
20.2, 18.7, 14.2; IR (neat): mmax 3454, 2926, 2855, 1714, 1454, 1277, 1070, 909,
772, 735 cmꢀ1; HRMS (ESI) m/z calcd for C19H30O2: 291.2316, found: 291.2319
[M+H]+.
(S)-((3S,6S,8S)-8-(Benzyloxy)-3-methylundec-1-en-6-yl)-3-(4-(2-
(benzyloxy)ethoxy)phenyl)-2-(tert
butoxycarbonyl(methyl)amino)propanoate
(20): Rf = 0.50 (30% EtOAc/hexane), viscous liquid, ½a D25
ꢁ
+7.2 (c = 1.0, CHCl3);
References and notes
1H NMR (300 MHz, CDCl3): d 7.5–7.2 (m, 10H), 7.15–7.01 (m, 2H), 6.88–6.76
(m, 2H), 5.7–5.6 (m, 1H), 5.24–5.09 (m, 1H), 5.00–4.80 (m, 2H), 4.63 (s, 2H),
4.54–4.25 (m, 2H), 4.15–4.02 (m, 2H), 3.86–3.77 (m, 2H), 3.45–3.11 (m, 2H),
2.98–2.65 (m, 4H), 2.13–1.97 (m, 1H), 1.76–1.45 (m, 5H), 1.44–1.14 (m, 14H),
1.01–0.84 (m, 6H); 13C NMR (75 MHz, CDCl3): d 170.8 (170.6), 157.5 (157.4),
155.6, 144.2 (143.9), 138.7 (138.5), 138.0, 129.8 (129.7), 128.4 (128.3), 128.1
(128.0), 128.7 (127.8), 127.6 (127.5), 114.7 (114.6), 113.1 (113.0), 80.1 (79.8),
75.6 (75.6), 73.3, 72.9, 72.6 (72.5), 71.4, 68.4, 67.5 (67.4), 60.5, 59.6, 39.4
(39.1), 37.8 (37.7), 36.3 (36.0), 34.3 (34.0), 32.6, 31.9 (31.8), 29.6, 28.2, 20.1,
18.2, 14.2; IR (neat): mmax 2924, 2855, 1735, 1698, 1512, 1454, 1247, 1142,
912, 772, 759, 698 cmꢀ1; HRMS (ESI) m/z calcd for C43H59NO7: 702.4369,
found: 702.4364 [M+H]+.
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6. Chakraborty, T. K.; Suresh, V. R. Tetrahedron Lett. 1998, 39, 7775.
7. (a) Malkov, A. V.; Vrankoya, K.; Cerny, M.; Pavel, K. J. Org. Chem. 2009, 74, 8425;
(b) Bouazza, F.; Renoux, B.; Bachmann, C.; Gesson, J. P. Org. Lett. 2003, 5, 4049.
(S)-((3S,6S,8S)-8-(Benzyloxy)-3-methylundec-1-en-6-yl)-3-(4-(2-
(benzyloxy)ethoxy)phenyl)-2-(N-methylpent-4-enamido)propanoate
(3):
Rf = 0.60 (30% EtOAc/hexane), viscous liquid, ½a D25
ꢁ
+6.5 (c = 38.5, CHCl3); 1H
NMR (300 MHz, CDCl3): d 7.4–7.2 (m, 10H), 7.13–6.98 (m 2H), 6.9–6.8 (m, 2H),
5.585–5.52 (m, 2H), 5.4–5.24 (m, 1H), 5.23–5.12 (m, 1H), 5.02-4.85 (m, 4H),
4.63 (s, 2H), 4.55–4.25 (m, 2H), 4.18–4.03 (m, 2H), 3.85–3.77 (m, 2H), 3.44–
3.14 (m, 2H), 3.0–2.74 (m, 4H), 2.37–1.8 (m, 5H), 1.8–1.10 (m, 10H), 0.96 (d,
J = 6.8 Hz, 3H), 0.91 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 172.5,
170.4, 157.4, 144.0, 138.6, 137.8, 137.3, 129.7, 129.2, 128.4, 128.3, 127.9,
127.6, 127.4, 114.9, 114.7, 114.4, 112.9, 75.4, 73.2, 72.6, 71.3, 68.3, 67.2, 58.0,
39.2, 37.7, 36.1, 33.8, 32.6, 31.7, 29.6, 28.7, 20.1, 18.1, 14.2; IR (neat): mmax

1522
H. Kumar et al. / Tetrahedron Letters 55 (2014) 1519–1522
2926, 2863, 1732, 1652, 1512, 1453, 1359, 1247, 1219, 1107, 912, 772,
5.84–5.65 (m, 1H), 5.1–4.9 (m, 1H), 3.98 (s, 2H), 3.88 (s, 2H), 3.54–3.26 (m,
1H), 3.25–3.08 (m, 1H), 3.02–2.5 (m, 4H), 2.4–1.01 (m, 21H), 0.93–0.78 (m,
6H); 13C NMR (75 MHz, CDCl3): d 173.7, 171.8, 157.4, 130.3, 129.7, 129.0,
114.5, 73.0, 69.1, 66.8, 61.5, 55.8, 49.2, 42.3, 39.0, 33.9, 33.1, 29.7, 29.2, 26.8,
698 cmꢀ1; HRMS (ESI) m/z calcd for C43H57NO6: 684.4237, found: 684.4259
[M+H]+.
(3S,10R,13S)-3-(4-(2-Hydroxyethoxy)benzyl)-13-((S)-2-hydroxypentyl)-4,10-
dimethyl-1-oxa-4-azacyclotridecane-2,5-dione (1): Rf = 0.20 (60% EtOAc/
24.1, 20.4, 18.9, 14.1; IR (neat):
1220, 772 cmꢀ1
HRMS (ESI) m/z calcd for C27H43NO6: 478.3159, found:
478.3163 [M+H]+.
mmax 3454, 2924, 2854, 1727, 1628, 1459, 1247,
hexane), viscous liquid,
½
a 2D5
ꢁ
ꢀ42.5 (c = 0.9, CHCl3), and, ꢀ89.5 (c = 0.9,
;
MeOH); 1H NMR (300 MHz, CDCl3): d 7.2–7.0 (m, 2H), 6.82–6.72 (m, 2H),