A concise stereoselective total synthesis of Botryolide B

Article abstract of DOI:10.1016/j.tetlet.2010.05.079

The first total synthesis of Botryolide B is described from easily accessible starting materials. The synthetic strategy involves Jacobsen resolution, Sharpless epoxidation, Swern oxidation, Yamaguchi reaction, and ring closing metathesis (RCM).

Full text of DOI:10.1016/j.tetlet.2010.05.079

Tetrahedron Letters 51 (2010) 4020–4022
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A concise stereoselective total synthesis of Botryolide B
*
B. Chennakesava Reddy, H. M. Meshram
Organic Chemistry Division—I, 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:
Received 16 March 2010
Revised 7 May 2010
Accepted 19 May 2010
Available online 25 May 2010
The first total synthesis of Botryolide B is described from easily accessible starting materials. The syn-
thetic strategy involves Jacobsen resolution, Sharpless epoxidation, Swern oxidation, Yamaguchi reaction,
and ring closing metathesis (RCM).
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
by Swern oxidation followed by one-carbon homologation8 with
PPh3CH3I (60% overall yield after two steps). Removal of TBDPS
Natural products containing 10-member framework are found
in plants, insects (pheromones), and bacteria (antibiotics). Natural
products having medium size lactone1 ring possess wide range of
biological activities such as antibacterial and antifungal activities.2
They originate from terrestrial, fungal, or marine sources. Botryo-
lide B was first isolated3 by Gloer and co-workers in 2007 from
the cultures of a fungicolous isolate of Botryotrichum sp. (NRRL
38180). Botryolide B is a 10-membered lactone having a hydroxyl
group, methyl group, epoxide, and cis double bond. During the
course of our studies on asymmetric synthesis for the development
of simple synthetic routes,4 herein we wish to report total synthe-
sis of Botryolide B, and its retrosynthetic analysis is depicted in
Scheme 1.
group with HF–pyridine gave fragment 3 (92%).
The journey for the synthesis of segment 4 began from the
known but-3-en-1-ol 6. Thus, protection of the hydroxyl group
with BnBr in the presence of NaH in THF at 0 °C gave benzyl ether
in 95% yield, which on further epoxidation with m-CPBA in CH2Cl2
gave 16 in 88% yield. A kinetic resolution of racemic epoxide with
(R,R)-Jacobsen catalyst A furnished the optically active epoxide 17
(42%, 99% ee). Treatment of epoxide 17 with trimethylsulfonium
iodide and n-BuLi cleanly afforded secondary allylic alcohol 18 in
85% yield.9 Vinyl alcohol 18 was treated with TBDPSCl to afford
protected TBDPS ether (92%), which was subjected to debenzyla-
tion with DDQ–CH2Cl2 to give 19 (84%).10 Primary alcohol 19 was
As outlined retrosynthetically in Scheme 1, it could be prepared
efficiently by RCM protocol from bis-olefin 2, which in turn could
be realized by Yamaguchi esterification of alcohol 3 and acid 4.
Intermediate 3 can be envisaged from (R)-propylene oxide 7, while
chiral vinyl alcohol 4 could be produced from 3-butene-1-ol 6.
The synthesis of fragment 3 began by the kinetic resolution of 8
(Scheme 2) under Jacobsen reaction conditions5 using the (R,R)-
catalyst A to give chiral epoxide 7 (42%, 99% ee) and diol 9. Epoxide
O
H3C
H3C
O
O
O
OH
O
O
OR
Botryolide B
1
2
7
on treatment with protected 1-methoxy-4-((prop-2-ynyl-
oxy)methyl)benzene 10 in the presence of n-BuLi and BF3ꢀEt2O in
THF at ꢁ78 °C for 3 h afforded 11 (64%). The protection of homo-
propargyl alcohol with TBDPSCl in CH2Cl2 at room temperature
gave TBDPS ether 12. Deprotection of PMB with DDQ in a mixture
of CH2Cl2–H2O (9:1) resulted in primary alcohol 13 in high yield.
Treatment of propargyl alcohol 13 with Ni(OAc)2,6 NaBH4, and eth-
ylenediamine in ethanol at rt under H2 (atm) for 4 h afforded allylic
alcohol 5 in 81% yield, which was then transformed into epoxy
OH
O
O
OR
+
OH
OH
4
6
3
7
*
OR
alcohol 14 (90 %, >20:1 dr) under Sharpless conditions. Conver-
sion of epoxy alcohol 14 into 15 was accomplished in good yield
O
OH
7
5
* Corresponding author. Tel.: +91 40 27160123/2642; fax: +91 40 2716051.
E-mail address: hmmeshram@yahoo.com (H.M. Meshram).
Scheme 1. Retrosynthetic analysis of Botryolide B 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.079

B. C. Reddy, H. M. Meshram / Tetrahedron Letters 51 (2010) 4020–4022
4021
OH
O
O
OH
a
+
8
(40%)
(42%)
9
7
OR
OR
O
b
d
e
OPMB
OH
O
11
R = H (64 %)
7
OPMB
13
10
c
R = TBDPS (94 %)
12
OR
O
OR
OR
f
g
OH
OH
15
5
14
R = TBDPS
R = H
h
3
Scheme 2. Reagents and conditions: (a) (R,R)-Jacobsen catalyst, H2O, rt, 12 h; (b) n-BuLi, BF3ꢀOEt2, THF, ꢁ78 °C, 3 h; (c) TBDPSCl, Imidazole, CH2Cl2, rt, 2 h; (d) DDQ, CH2Cl2–
H2O (9:1), 82%; (e) Ni(OAc)2, (H2NCH2)2, NaBH4, EtOH, rt, H2 (1 atm), 4 h, 88%; (f) (ꢁ)-DIPT, Ti(iOPr)4, TBHP, CH2Cl2, 4AO MS, -20 °C, 90% ; (g) (i) (COCl)2, DMSO, Et3N, CH2Cl2,
ꢁ78 °C, 1 h, 80%; (ii) PPh3CH3I, t-BuOK, THF, ꢁ25 °C, 2 h, 75%; (h) HF–pyridine, THF, rt, 12 h, 92%.
H3C
O
O
O
a, b
d
c
H3C
O
O
O
O
OH
OBn
OR
OBn
c
a
6
16
17
3
+
4
O
OH
O
OH
OR
OR
g
e, f
OBn
1
OH
OH
R = TBDPS
18
19
4
b
R = H
2
Scheme 3. Reagents and conditions: (a) NaH, BnBr, THF, 0 °C, rt 3 h, 95%; (b) m-
CPBA, CH2Cl2, rt, 88%; (c) (R,R)-Jacobsen catalyst, H2O, rt, 12 h, 42%; (d) (CH3)3S+Iꢁ,
n-BuLi, THF, ꢁ10 °C to rt, 85%; (e) TBDPSCl, Imidazole, CH2Cl2, rt, 92%; (f) DDQ,
CH2Cl2–H2O (19:1) reflux, 4 h, 84%; (g) (i) DMP, CH2Cl2, 0 °C to rt, 84%, (ii) NaClO2,
NaH2PO4, 2-methyl-2-butene, 0 °C to rt, 82%.
Scheme 4. Reagents and conditions: (a) 2,4,6-trichlorobenzoyl chloride, THF, Et3N,
rt, 6 h, DMAP, toluene, rt, 14 h, 83%; (b) TBAF, THF, rt, 10 h, 91%; (c) 2nd generation
Grubbs catalyst, CH2Cl2, 25 °C, 65%.
2. Spectral data for selected compounds
oxidized with Dess–Martin periodinane11 (DMP) to afford the cor-
responding aldehyde which on further treatment with NaClO212 in
the presence of NaH2PO4 and 2-methyl-2-butene as a scavenger
gave the required acid 4 in 82% overall yield (Scheme 3).
The esterification of two fragments 3 and 4 was achieved under
Yamaguchi reaction conditions13 using 2,4,6-trichlorobenzoyl
chloride to furnish diene ester 2 (83%). The removal of TBDPS group
with TBAF followed by RCM reaction14 with Grubb’s second-gener-
ation catalyst B (10 mol %) afforded the target molecule 1 as the
2.1. (R)-6-(4-Methoxybenzyloxy)hex-4-yn-2-ol 11
½
a 2D5
ꢂ
ꢁ5.8 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d 1.26 (d,
J = 6.04 Hz, 3H), 2.40 (m, 2H), 3.80 (s, 3H), 3.95 (qt, J = 6.04 Hz,
1H), 4.10 (m, 2H), 4.50 (s, 2H), 6.82 (d, J = 9.06 Hz, 2H), 7.2 (d,
2H, J = 9.06 Hz); 13C NMR (75 MHz, CDCl3): d 22.2, 30.3, 55.2,
57.2, 66.2, 71.3, 83.2, 87.1, 113.7, 129.3, 133.1, 159.2; IR (KBr):
3420, 2935, 2855, 1380, 1272, 1208, 1165, 1120 cmꢁ1; EI-MS: m/z
234 [M+]; ESI-HRMS: calcd for C14H18O3: 234.1255. Found:
234.1250.
sole product in 65%. The prepared synthetic Botryolide B 1 is iden-
13
tical (IR, 1H NMR,
C NMR, and Mass) with the natural product
and also has an optical rotation (½a D25
ꢁ142.1 (c 0.69, CHCl3)) which
ꢂ
is in good agreement with the literature value (½a D25
ꢁ144 (c 0.23,
ꢂ
2.2. (R)-tert-Butyl(6-(4-methoxybenzyloxy)hex-4-yn-2-yloxy)-
diphenylsilane 12
CHCl3))3 (Scheme 4).
½
a 2D5 +12.1 (c 2.0, CHCl3); 1H NMR (300 MHz, CDCl3): d 1.09 (s,
ꢂ
MesN
NMes
9H), 1.20 (d, J = 6.04 Hz), 2.3–2.4 (m, 2H), 3.8 (s, 3H), 3.92 (qt,
J = 6.04 Hz, 1H), 4.05 (t, J = 2.22 Hz, 2H), 4.45 (s, 2H), 6.80 (d,
J = 8.30 Hz), 7.2 (d, J = 8.04 Hz, 2H), 7.3–7.4 (m, 6H), 7.62–7.7 (m,
4H); 13C NMR (75 MHz, CDCl3): d 19.2, 23.0, 27.0, 29.5, 55.1,
55.3, 66.7, 70.7, 73.0, 83.9, 113.7, 127.5, 129.5, 129.6, 134.0,
134.8, 135.8, 159.2; IR (KBr): 3068, 2929, 2857, 1592, 1428,
1260, 1108 cmꢁ1; EI-MS: m/z 495 [M+Na]; ESI-HRMS: calcd for
H
N
H
Cl
Cl
N
Co
Ru
Ph
t-Bu
O
O
t-Bu
OAc
PCy3
t-Bu
t-Bu
2
nd generation Grubbs Catalyst (B)
(R,R) Jacobsen catalyst (A)
C30H36O3Si: 472.2433. Found: 472.2435.
In summary, a concise first total synthesis of Botryolide B was
achieved using inexpensive and commercially available starting
materials. The synthesis is highlighted by Jacobsen resolution,
Sharpless epoxidation, Swern oxidation Yamaguchi reaction, and
RCM reactions as key steps.
2.3. (R)-5-(tert-Butyldiphenylsilyloxy)hex-2-yn-1-ol 13
+26.1 (c 2.0, CHCl3); 1H NMR (300 MHz, CDCl3): d 1.09 (s,
½ ꢂ
a 2D5
9H), 1.20 (d, J = 6.04 Hz), 2.3–2.4 (m, 2H), 3.92 (qt, J = 6.04 Hz,

4022
B. C. Reddy, H. M. Meshram / Tetrahedron Letters 51 (2010) 4020–4022
1H), 4.05 (t, J = 2.07 Hz, 2H), 7.31–7.45 (m, 6H), 7.65–7.7 (m, 4H);
13C NMR (75 MHz, CDCl3): d 19.0, 22.8, 26.4, 29.2, 50.9, 68.1,
79.9, 83.1, 127.4, 129.4, 131.9, 134.6; IR (KBr): 3422, 3069, 2928,
2857, 1643, 1222, 1107 cmꢁ1; EI-MS: m/z 375 [M+Na]; ESI-HRMS:
calcd for C22H28O2Si: 352.1858. Found: 352.1850.
1780, 1589, 1428, 1240 cmꢁ1; EI-MS: m/z 353 [M+1]; ESI-HRMS:
calcd for C21H26O3Si: 354.1651. Found: 354.1652.
2.8. Botryolide B 1
½
a 2D5 -142.1 (c 0.69, CHCl3) 1H NMR (300 MHz, CDCl3): d 1.3 (d,
ꢂ
2.4. ((2R,3S)-3-((R)-2-(tert-Butyldiphenylsilyloxy)propyl)oxiran-
2-yl)methanol 14
J = 6.00 Hz, 3H), 1.3 (m, 2H), 2.5 (d, J = 4.30 Hz, 2H), 3.4–3.5 (m,
2H), 4.7–4.8 (m, 2H), 6.15–6.25 (m, 2H); 13C NMR (75 MHz, CDCl3):
d 20.5, 38.1, 43.4, 53.7, 57.2, 67.7,67.9, 127.9, 135.1, 170.1; IR (KBr):
3542, 3071, 2990, 2857, 1759, 1428, 1260, 1108, 1050 cmꢁ1; EI-
MS: m/z 221 [M+Na]; ESI-HRMS: calcd for C10H14O4: 198.0892.
Found: 198.0890.
½
a 2D5 +0.5 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d 1.05 (s,
ꢂ
9H), 1.1 (d, J = 6.04 Hz, 3H), 2.0 (m, 2H), 2.87–2.96 (m, 2H), 4.05
(m, 1H), 4.4 (d, J = 6.79 Hz, 2H), 7.3–7.42 (m, 6H), 7.6–7.7 (m,
4H); 13C NMR (75 MHz, CDCl3): d 19.1, 24.8, 26.8, 41.2, 50.9,
53.0, 61.3, 66.8, 128.4, 129.4, 130.2, 132.6, 132.4; IR (KBr): 3440,
1590, 1450, 1257, 1050 cmꢁ1; EI-MS: m/z 371 [M+]; ESI-HRMS:
calcd for C22H30O3Si: 370.1964. Found: 370.1965.
Acknowledgments
B.C.K.R. thanks CSIR-UGC for the award of a fellowship and Dr.
J.S. Yadav, Director IICT, for his support and encouragement.
2.5. (R)-1-((2S,3R)-3-Vinyloxiran-2-yl)propan-2-ol 3
References and notes
½
a 2D5
ꢂ
ꢁ8.8 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d 1.2 (d,
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J = 6.20 Hz, 3H), 2.1 (m, 2H), 3.21 (m, 1H), 3.48 (m, 1H), 4.1 (m,
1H), 5.39 (d, J = 9.78 Hz, 1H), 5.48 (d, J = 17.60 Hz, 1H), 5.7 (m,
1H); 13C NMR (75 MHz, CDCl3): d 25.6, 42.1, 57.1, 66.2, 85.8,
118.0, 133.5; IR (KBr): 3377, 2930, 2858, 1641, 1463, 1253, 1100,
837 cmꢁ1; EI-MS: m/z 129 [M+1]; ESI-HRMS: calcd for C7H12O2:
128.0837. Found: 128.0842.
2.6. (R)-5-(Benzyloxy)pent-1-en-3-ol 18
½
a 2D5
ꢂ
ꢁ9.50 (c 2.0, CHCl3); 1H NMR (300 MHz,CDCl3): d 1.63–1.90
(m, 2H), 2.79 (br s, 1H), 3.50–3.74 (m, 2H), 4.20–4.37 (m, 1H), 4.49
(s, 2H), 5.06 (d, J = 10.57 Hz, 1H), 5.23 (d, J = 16.61 Hz, 1H), 5.72–
5.93 (m, 1H), 7.20–7.50 (m, 5H); 13C NMR (75 MHz, CDCl3): d
36.2, 68.1, 71.5, 73.1, 114.2, 127.5, 128.3, 137.8, 140.4; IR (KBr):
3424, 3031, 2920, 2863, 1454, 1364, 1098, 740 cmꢁ1; EI-MS: m/z
215 [M+Na]; ESI-HRMS: calcd for C12H16O2 192.1150. Found:
192.1149.
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2.7. (R)-3-(tert-Butyldiphenylsilyloxy)pent-4-enoic acid 8
½
a 2D5 + 12.1 (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz): d 1.05 (s,
ꢂ
9H), 2.42 (dd, 1H, J = 3.5, 7.00 Hz), 2.61 (dd, 1H, J = 3.0, 6.50 Hz),
4.55 (q, 1H, J = 6.50 Hz), 5.0–5.20 (m, 2H), 5.80–5.90 (m, 1H),
7.35 (m, 6H), 7.65 (m, 4H); IR (neat): 3546, 3070, 2934, 2858,
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