First stereoselective total synthesis of phomonol via oxa-Michael approach

Article abstract of DOI:10.1016/j.tetlet.2013.05.018

Herein we report the first stereoselective total synthesis of phomonol via Sharpless asymmetric dihydroxylation and 6-exo-trig oxa-Michael addition as the key steps.

Full text of DOI:10.1016/j.tetlet.2013.05.018

Tetrahedron Letters 54 (2013) 3788–3790
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
First stereoselective total synthesis of phomonol via oxa-Michael
approach
⇑
Palakodety Radha Krishna , Sunchu Prabhakar
D-211, Discovery Laboratory, Organic & Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein we report the first stereoselective total synthesis of phomonol via Sharpless asymmetric dihydr-
oxylation and 6-exo-trig oxa-Michael addition as the key steps.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 7 March 2013
Revised 3 May 2013
Accepted 5 May 2013
Available online 13 May 2013
Keywords:
Phomonol
cis-2,6-Disubstituted tetrahydropyran
Sharpless asymmetric dihydroxylation
6-exo-Trig oxa-Michael addition
Synthesis of substituted tetrahydropyrans is of considerable
interest due to the presence of either in full or part structure of bio-
logically active natural products.1 Tetrahydropyrans bearing sub-
stituents at the 2,6-positions on the ring are often encountered
in a large number of biologically important natural products like
phorboxazole A,1a laulimalide,1b cyanolide A,1c aspergillides,1d
sorangicin A,1e and amphidinolides.1f The stereoselective synthesis
of 2,3,4,6-tetrasubstituted tetrahydropyrans is an important task
since the cis- or trans-configuration of the 2,6-substitutents on
the tetrahydropyran ring should not only be constructed in a deci-
sive way but also can affect the biological activity of the natural
product. Phomonol (Fig. 1) was isolated from endophytic fungal
strain Phomopsis sp. A 123, along with phomonolides D-H by Shen
and co-workers.2 The strain was isolated from the leaves of the
mangrove species Kandelia candel. Further, the structure of pho-
monol was determined as 1-((2R,3S,4R,6S)-3,4-dihydroxy-6-propyl
tetrahydro-2H-pyran-2yl) propan-2-one.
As a part of our interest in the total synthesis of pyranone and
pyran containing natural products,3 we chose phomonol, which
is endowed with a 2,3,4,6-tetra substituted tetrahydropyran skele-
ton as the next target. Herein we describe the total synthesis of
phomonol by linear synthetic pathway. The envisaged retrosyn-
thetic strategy for phomonol is delineated in Scheme 1; it involves
Sharpless asymmetric dihydroxylation, Wittig olefination, and
intramolecular 6-exo-trig oxa-Michael addition as the key steps
en route to the synthesis of phomonol.
Though a variety of synthetic methods are available for the THP
ring-construction,4 we chose oxa-Michael addition protocol as the
method of choice primarily for its predictable stereochemistry at
the newly created carbon (ring-junction) in accordance with
6-exo-trig mode of cyclization.5 Thus, retrosynthetically, the 2,6-
cis-tetrahydropyran ring could be obtained from the hydroxy a,b-
unsaturated ketone 2 via intramolecular base catalyzed 6-exo-trig
oxa-Michael addition, followed by acid catalyzed acetonide depro-
tection. While compound 2 could be accessed from compound 3 by
oxidation/Wittig olefination/deprotection reaction set, compound
3 in turn could be obtained by Sharpless asymmetric dihydroxyla-
tion followed by protection/deprotection of allylic benzoate 4. Ben-
zoate 4 in turn could be conceived from the commercially available
trans-2-hexen-1-ol by suitable functional group transformations
like Sharpless asymmetric epoxidation/ring-opening/protection/
deprotection/Wittig olefination /reduction/protection reactions.
As outlined in Scheme 2, our synthesis began with known epoxy
alcohol 5,6 which was readily obtained from the commercially
available trans-2-hexen-1-ol. Furthermore, compound 5 on regio-
selective reductive ring-opening reaction with Red-Al led to the
11
3
O
41
2
1
61
21
31
O
51
OH
OH
Figure 1. Phomonol (1).
⇑
Corresponding author. Fax: +91 4027160387.
E-mail address: prkgenius@iict.res.in (P. Radha Krishna).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.018

P. Radha Krishna, S. Prabhakar / Tetrahedron Letters 54 (2013) 3788–3790
3789
O
O
OPMB
O
O
O
PMBO
HO
OBz
O
4
3
2
OH
OH
OH
Phomonol (1)
O
O
OH
Scheme 1. Retrosynthetic analysis.
OCH3
O
PMBO
OH
O
O
c
b
a
OH
OH
OH
5
8
6
7
PMBO
O
PMBO
2
PMBO
e
d
g
f
OEt
OBz
OH
4
3
10
9
O
O
PMBO
OH
11
O
O
PMBO
i
h
OBz
PMBO
OH
12
OH
OBz
O
O
O
O
O
PMBO
O
OH
k
j
l
13
O
2
O
O
O
O
14
m
O
OH
1
OH
Scheme 2. Reagents and conditions: (a) Red-A, dry THF, 0 °C–rt, 3 h, 82%; (b) anisaldehyde dimethyl acetal, PTSA, dry CH2Cl2, 0 °C–rt, 1 h, 94%; (c) DIBAL-H, dry CH2Cl2, 0 °C–
rt, 1 h, 88%; (d) (i) (COCl)2, DMSO, Et3N, dry CH2Cl2, 1 h, (ii) Ph3P@CH2COOEt, benzene, reflux, 8 h, 81% (over two steps); (e) DIBAL-H, dry CH2Cl2, 0 °C, 0.5 h, 90%; (f) Bz-Cl,
Et3N, dry CH2Cl2, 0 °C–rt, 1 h, 86%; (g) Ad-mix b, tBuOH:H2O, 0 °C–rt, 18 h, 76% (major isomer); (h) 2,2-DMP, PPTS, dry CH2Cl2, 0 °C–rt, 1 h, 92%; (i) K2CO3, MeOH, 0 °C–rt, 81%;
(j) (i) TEMPO, BAIB, dry CH2Cl2, 0 °C–rt, 1 h, (ii) 1-(tri phenyl phosphoranylidene)-2-propanone, dry THF, reflux, 8 h 91% (over two steps); (k) DDQ, CH2Cl2:H2O (19:1), 0 °C–rt,
0.5 h, 81%; (l) NaH, dry THF, 0 °C, 0.5 h, 89%; (m) PTSA, MeOH, 0 °C–rt, 0.5 h, 90%.
desired precursor 67 (82%) as the major isomer. The minor 1,2-diol
formed in this case was removed by the NaIO4 mediated oxidative
cleavage. The thus obtained diol 6 was purified and protected as its
PMB-acetal under acidic condition (PTSA) (94%). Later, the acetal
was regioselectively opened with DIBAL-H to afford the corre-
sponding primary alcohol 8 (88%).
Next, the primary alcohol 8 (Scheme 2) was oxidized under
Swern oxidation conditions {(COCl)2/DMSO/Et3N/CH2Cl2/ꢀ78 °C}
to furnish the corresponding aldehyde which was subjected to
Wittig olefination (Ph3P@CH2CO2Et/benzene/reflux/8 h) under re-
flux conditions to afford compound 9 (81%). The unsaturated ester
was reduced with DIBAL-H to result in the allylic alcohol 10 (90%).
The allylic alcohol 10 was protected as its benzoate ester (Bz-Cl/
Et3N/DMAP/CH2Cl2/1 h) to give the allylic benzoate 4 (86%). Next,
the benzoate 4 was exposed to Sharpless asymmetric dihydroxyla-
tion8 (Ad-mix-b/tBuOH/H2O/0 °C–rt/12 h) protocol to afford the
diol 11 (76%) as the separable major isomer (dr 95:5). The resulting
diol 11 was protected as its acetonide 12 (92%). Later, the deprotec-
tion of benzoyl group gave the corresponding alcohol 3 (81%). The
primary alcohol 3 was oxidized under TEMPO/BAIB conditions
followed by Wittig olefination with commercially available
1-(triphenyl phosphoranylidene)-2-propanone ylide under THF
reflux to give the unsaturated ketone 13 (91%). Deprotection of
the PMB ether under DDQ conditions9 (DDQ/CH2Cl2/H2O/0.5 h) re-
sulted in the alcohol 2 (81%).
Subsequently, the key step in the synthesis, base catalyzed
(NaH/THF/0 °C/0.5 h) intramolecular 6-exo-trig oxa-Michael addi-
tion3f,10 of
a,b-unsaturated ketone 2 was conducted to afford the
2,6-cis-tetrasubstituted tetrahydropyran 14 as an exclusive diaste-
reomer (89%). Upon treatment of the latter with catalytic amount
of PTSA in methanol, 1 was obtained in (90%) yield. The structure
and stereochemistry of 2,6-cis-tetrahydropyran were initially as-
signed as 2,6-cis pyran based on the literature11 but further thor-
oughly confirmed by extensive 1H NMR experiments and nuclear
Overhauser effect spectroscopy (2D NOESY). Thus the strong NOE
cross peaks observed between H1b/H21, H1 /H31, H21/H61, H41/
a
H51, H41/H61 and H51/H61 protons are indicative of their relative
spatial orientation, their relation with one another, and their
respective planar arrangement, the observed NOE correlations
are shown in Figure 2. Thus, the relative and absolute stereochem-
istry at the ring-junction was assigned unequivocally as cis to the
existing stereogenic center and hence the structure of the target

3790
P. Radha Krishna, S. Prabhakar / Tetrahedron Letters 54 (2013) 3788–3790
9. Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O. Tetrahedron 1986,
42, 3021–3028.
10. (a) Venkataiah, M.; Somaiah, P.; Gowrisankar, R.; Fadnavis, N. W. Tetrahedron:
Asymmetry 2009, 20, 2230–2233; (b) Janardhan Reddy, P.; Srinivas Reddy, A.;
Yadav, J. S.; Subba Reddy, B. V. Tetrahedron Lett. 2012, 53, 4054–4055.
11. (a) Fuwa, H.; Yamaguchi, H.; Sasaki, M. Org. Lett. 2010, 12, 1848–1851; (b)
Fuwa, H.; Saito, A.; Sasaki, M. Angew. Chem., Int. Ed. 2010, 49, 3041–3044.
O
H
H
21
H
61
11
H
2
O
3
H
12. Spectral data of some selected compounds. Compound 4: Colorless liquid. ½a D25
ꢁ
1
OH
41
51
+0.43 (c 0.24, CHCl3); 1H NMR (600 MHz, CDCl3): d 8.05 (d, J = 7.1 Hz, 2H), 7.55
(t, J = 7.1 Hz, 1H), 7.44 (dd, J = 13.9, 6.4 Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H), 6.84 (d,
J = 8.6 Hz, 2H), 5.93–5.86 (m, 1H), 5.79–5.73 (m, 1H), 4.78 (d, J = 6.4 Hz, 2H),
4.48 (d, J = 10.9 Hz, 1H), 4.43 (d, J = 11.2 Hz, 1H), 3.78 (br s, 3H), 3.44 (qt,
J = 11.2, 5.6 Hz, 1H), 2.33 (t, J = 6.0 Hz, 2H), 1.57–1.50 (m, 1H), 1.49–1.40 (m,
2H), 1.39–1.30 (m, 1H), 0.90 (t, J = 7.1 Hz, 3H); 13C NMR (300 MHz, CDCl3): d
166.4, 159.0, 134.1, 132.9 (2), 132.6, 130.8, 129.6, 129.3, 128.3, 127.9, 126.1,
120.9, 114.0, 113.8, 77.8, 70.6, 65.6, 55.2, 36.9, 36.2, 18.6, 14.2; HRMS: m/z
calcd for C23H29O4 [M+H]+: 369.2060; found: 369.2063. Compound 11: Pale
31
H
H
OH
H
Figure 2. Observed NOE correlations in 1.
yellow liquid. ½a D25
ꢁ
+16.9 (c 0.31, CHCl3); 1H NMR (300 MHz, CDCl3): d 8.05 (d,
molecule. The data of the synthetic sample matched with the
reported values of the natural product.2,12 HRMS spectrum of 1 dis-
played the [M+Na]+ at 239.1252 while calculated gave 239.1253
for the molecular formula C11H20O4Na as an additional support.
In summary, first total synthesis of phomonol (14.2% overall
yield) was accomplished by a linear synthetic strategy using Sharp-
less asymmetric dihydroxylation and 6-exo-trig oxa-Michael reac-
tions as the key steps.
J = 7.1 Hz, 2H), 7.57 (t, J = 7.3 Hz, 1H), 7.43 (t, J = 7.9 Hz, 2H), 7.22 (d, J = 8.6 Hz,
2H), 6.82 (d, J = 8.4 Hz, 2H), 4.55–4.31 (m, 4H), 3.99 (d, J = 10.1 Hz, 1H), 3.77 (br
s, 4H), 3.30 (br s, 1H), 2.85 (br s, 1H), 2.02–1.22 (m, 6H), 0.92 (t, J = 7.1 Hz, 3H);
13C NMR (125 MHz, CDCl3): d 166.8, 159.2, 133.2, 133.1, 133.0, 130.1, 129.8,
129.6, 129.5, 129.4, 128.3, 113.8 (2), 76.3, 72.5, 70.9, 68.2, 66.1, 55.2, 36.4, 35.6,
18.6, 14.2; HRMS: m/z calcd for
C
23H30O6Na [M+Na]+: 425.1934; found:
425.1932. Compound 12: Yellow liquid. ½a D25
ꢁ
+28.2 (c 0.41, CHCl3); 1H NMR
(400 MHz, CDCl3): d 8.03 (d, J = 7.2 Hz, 2H), 7.54 (t, J = 7.2 Hz, 1H), 7.40 (t,
J = 7.6 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H), 4.53–4.43 (m,
2H), 4.40 (d, J = 11.2 Hz, 1H), 4.31 (dd, J = 12.0, 5.6 Hz, 1H), 4.15 (dt, J = 8.8,
2.8 Hz, 1H), 3.96–3.90 (m, 1H), 3.73 (br s, 3H), 3.69–3.60 (m, 1H), 1.85–1.75 (m,
1H), 1.74–1.66 (m, 1H), 1.63–1.32 (m, 4H), 1.42 (br s, 3H), 1.38 (br s, 3H), 0.91
(t, J = 10.9 Hz, 3H); 13C NMR (300 MHz, CDCl3): d 166.2, 158.9, 133.0 (2), 130.8,
129.6 (2), 129.2 (2), 128.2 (2), 113.6 (2), 108.9, 79.1, 75.6, 74.7, 71.1, 64.1, 55.1,
38.4, 36.7, 27.3, 26.8, 18.1, 14.2; HRMS: m/z calcd for C26H35O6 [M+H]+:
Acknowledgment
One of the authors (S.P.) thanks CSIR, New Delhi for the finan-
cial support in the form of a fellowship.
443.2428; found: 443.2429. Compound 3: Colorless liquid. ½a D25
ꢁ
+48.1 (c 0.22,
CHCl3); 1H NMR (300 MHz, CDCl3): d 7.27 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.6 Hz,
2H), 4.53 (d, J = 10.9 Hz, 1H), 4.42 (d, J = 10.9 Hz, 1H), 4.09–3.99 (m, 1H), 3.80
(br s, 3H), 3.77–3.54 (m, 4H), 2.16–2.08 (m, 1H), 1.76–1.65 (m, 2H), 1.64–1.31
(m, 4H), 1.41 (br s, 3H), 1.39 (br s, 3H), 0.93 (t, J = 7.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d 159.1, 130.7, 129.4 (2), 113.7 (2), 108.4, 81.7, 76.0, 74.6,
71.2, 62.0, 55.2, 38.4, 36.7, 27.3, 26.9, 18.1, 14.2; HRMS: m/z calcd for
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.05.
018.
C
19H30O5Na [M+Na]+: 361.1985; found: 361.1981. Compound 13: Pale yellow
liquid. ½a 2D5
ꢁ
+11.67 (c 0.32, CHCl3); 1H NMR (600 MHz, CDCl3): d 7.24 (d,
J = 8.2 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 6.64 (dd, J = 15.8, 5.6 Hz, 1H), 6.29 (d,
J = 16.5 Hz, 1H), 4.52 (d, J = 10.9 Hz, 1H), 4.41 (d, J = 10.9 Hz, 1H), 4.13 (t,
J = 7.5 Hz, 1H), 3.97 (dt, J = 9.4, 3.0 Hz, 1H), 3.80 (br s, 3H), 3.68–3.62 (m, 1H),
2.25 (br s, 3H), 1.76–1.64 (m, 2H), 1.62–1.56 (m, 1H), 1.55–1.46 (m, 1H), 1.44
(br s, 3H), 1.41 (br s, 3H), 1.40–1.35 (m, 2H), 0.93 (t, J = 7.5 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d 197.9, 159.1, 142.4, 131.6, 130.7, 129.3 (2), 113.7 (2), 109.3,
80.6, 77.4, 75.5, 71.3, 55.2, 37.4, 36.7, 29.6, 27.2, 26.6, 18.1, 14.2; HRMS: m/z
calcd for C22H32O5Na [M+Na]+: 399.2141; found: 399.2136. Compound 2: Pale
References and notes
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61, 271–278.
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3907; (b) Radha Krishna, P.; Srinivas Reddy, P. Tetrahedron 2007, 63, 3995–
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(f) Radha Krishna, P.; Rajesh, N.; Ramana, D. V. Tetrahedron Lett. 2012, 53, 3612–
3614.
4. Larrosa, I.; Romea, P.; Urpí, F. Tetrahedron 2008, 64, 2683–2723.
5. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 18, 734–736.
6. (a) Gao, Y.; Hanson, R. M.; Kluder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B.
J. Am. Chem. Soc. 1987, 109, 5765–5780; (b) Brunner, H.; Sicheneder, A. Angew.
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8. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483–
2547.
yellow oil. ½a 2D5
ꢁ
+12.6 (c 0.35, CHCl3); 1H NMR (500 MHz, CDCl3): d 6.70 (dd,
J = 16.0, 5.9 Hz, 1H), 6.34 (d, J = 16.0 Hz, 1H), 4.26–4.21 (m, 1H), 4.06–4.00 (m,
1H), 3.92–3.85 (m, 1H), 2.29 (br s, 3H), 1.72 (t, J = 5.9 Hz, 2H), 1.55–1.32 (m,
5H), 1.46 (br s, 3H), 1.44 (br. s, 3H), 0.94 (t, J = 7.0 Hz, 3H); 13C NMR (300 MHz,
CDCl3): d 198.0, 142.2, 131.5, 109.6, 80.1, 77.7, 68.3, 39.8, 38.3, 29.6, 27.1, 26.6,
18.7, 13.9; HRMS: m/z calcd for C14H25O4 [M+H]+: 257.1747; found: 257.1744.
Compound 14: Yellow oil. ½a D25
ꢁ
+5.8 (c 0.28, CHCl3); 1H NMR (300 MHz, CDCl3):
d 3.92 (dt, J = 9.0, 3.5 Hz, 1H), 3.63–3.53 (m, 1H), 3.49–3.37 (m, 1H), 3.04 (t,
J = 9.0 Hz, 1H), 2.77–2.60 (m, 2H), 2.20 (br s, 3H), 2.12 (qd, J = 6.0, 3.9, 2.0 Hz,
1H), 1.65–1.20 (m, 5H), 1.43 (br s, 6H), 0.89 (t, J = 7.1 Hz, 3H); 13C NMR
(125 MHz, CDCl3): d 208.4, 109.9, 79.8, 78.0, 76.2, 75.4, 73.1, 46.5, 39.0, 37.5,
30.8, 26.7, 18.7, 13.8; HRMS: m/z calcd for C14H24O4Na [M+Na]+: 279.1566;
found: 279.1568. Phomonol 1: Colorless oil. ½a D25
ꢁ
+2.3 (c 0.36, CHCl3); 1H NMR
(500 MHz, CDCl3): d 3.65–3.55 (m, 2H), 3.45–3.38 (m, 1H), 3.10 (t, J = 9.0 Hz,
1H), 2.87 (dd, J = 15.5, 3.9 Hz, 1H), 2.65 (dd, J = 15.4, 8.0 Hz, 1H), 2.22 (br s, 3H),
1.99 (ddd, J = 12.9, 5.0, 1.3 Hz, 1H), 1.54–1.45 (m, 1H), 1.43–1.28 (m, 4H), 0.89
(t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3): d 208.6, 76.3, 75.4 (2), 73.1, 46.2,
39.0, 37.5, 31.0, 18.8, 13.9; HRMS: m/z calcd for
C
11H20O4Na [M+Na]+:
239.1253; found: 239.1252.