Toward the synthesis of brevipolide H

Article abstract of DOI:10.1016/j.tetlet.2014.12.125

A linear diastereoselective synthesis of C₁-C₁₂ fragment of brevipolide H is described. The key reactions include J?rgensen's asymmetric epoxidation, palladium-catalyzed regioselective opening of α,β-unsaturated γ,δ-epoxide, Charette's modified Simmons-Smith cyclopropanation, anti-selective reduction of cyclopropyl containing α,β-unsaturated ketone, Brown allylation, and ring-closing metathesis reaction.

Full text of DOI:10.1016/j.tetlet.2014.12.125

Tetrahedron Letters 56 (2015) 1041–1044
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Toward the synthesis of brevipolide H
⇑
Debendra K. Mohapatra , Suresh Kanikarapu, P. Ramesh Naidu, Jhillu S. Yadav
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 5000 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A linear diastereoselective synthesis of C1–C12 fragment of brevipolide H is described. The key reactions
Received 18 November 2014
Revised 24 December 2014
Accepted 26 December 2014
Available online 3 January 2015
include Jørgensen’s asymmetric epoxidation, palladium-catalyzed regioselective opening of
rated ,d-epoxide, Charette’s modified Simmons–Smith cyclopropanation, anti-selective reduction of
cyclopropyl containing
a,b-unsatu-
c
a
,b-unsaturated ketone, Brown allylation, and ring-closing metathesis reaction.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Jørgensen’s asymmetric epoxidation
Palladium-catalyzed regioselective opening
of epoxide
Charette’s modified Simmons–Smith
cyclopropanation
anti-Selective reduction
Brown allylation
Ring-closing metathesis
In 2009, Douglas Kinghorn,1 isolated brevipolides A–F from
the entire plant of Hyptis brevipes, an invasive plant species
which belongs to the genus Hyptis (Lamiaceae), distributed
mainly in the tropical region around the world. Recently,
Miranda2 and co-workers also isolated related compounds bre-
vipolides A–J (Fig. 1) from the same species and the absolute
configuration was assigned as 5R, 6S, 7S, 9S, and 11S which
was confirmed by the combination of X-ray diffraction analysis,
chiroptical measurements, chemical correlations, and Mosher’s
ester analysis. The structural features of the brevipolides A–J
family contain the cyclopropyl group attached to b-substituted
cinnamylcarboxyketo unit on one side and on the other side a
hydroxymethine containing an unsaturated d-lactone. Brevipo-
lides (A–J) showed excellent biological activity which includes
inhibitory activity against bacterial, fungal growth, DNA interca-
lation activity, cytotoxicity against HT-29 and the MCF-7 human
breast cancer cell line. In particular, compounds 7, 8, and 9 were
isolated from Peruvian plant Lippia alva sp. (Verbenaceae),3
which was identified as an inhibitory of chemokine receptor 5
(IC50 values CCR5, IC50 = 5.5, 6.0 and 7.2
for inhibiting HIV infection. Additionally, Compound 7 was also
found to be active in an enzyme-based ELISA NF-jB assay.
l
g mLꢀ1) and it leads
R3
5'
R1
6
O
R1
6
O
3'
1'
7'
R2
R3
5
9
O
5
11
7
9'
O
11
R2
9
7
9'
7'
1'
O
O
1
5'
O
O
1
3'
O
O
1
Brevipolide A, R1 = OAc
R2 = H
R3 = OH
R3 = OH
R3 = OH
R3 = OH
R3 = OMe
R3 = OMe
2 Brevipolide C, R1 = OH
3 Brevipolide E, R1 = OAc
7 Brevipolide G, R1 = OH
Brevipolide H, R1 = OH
Brevipolide J, R1 = OH
R2 = OH
R2 = OH
R2 = H
4
5
6
9
Brevipolide B, R1 = OAc
Brevipolide D, R1 = OH
Brevipolide F, R1 = OAc
Brevipolide I, R1 = OH
R2 = H
R2 = OH
R2 = H
R2 = H
R3 = OH
R3 = OH
R3 = OH
R3 = OMe
8
10
R2 = H
R2 = OH
Figure 1. Structure of brevipolides A–J.
⇑
Corresponding author. Tel.: +91 40 27193128; fax: +91 40 27160512.
E-mail address: mohapatra@iict.res.in (D.K. Mohapatra).
http://dx.doi.org/10.1016/j.tetlet.2014.12.125
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

1042
D. K. Mohapatra et al. / Tetrahedron Letters 56 (2015) 1041–1044
Charette's modified
Ph
Ph
Brown asymmetric
allylation
(10 mol%)
O
Simmons-Smith
cyclo propanation
O
N
H
(i)
OTMS
O
b
d
OHC
O
HO
6
EtO
11
O
O
a
14
15
5
O
1
8
OH
OMe
O
OTBS
Jorgensen
c
- selective
anti
O
epoxidation
EtO
EtO
Ring-closing
reductions
OPMB
OPMB
metathesis
16
17
TBDPSO
OH
O
OTBS
OTBS
OPMB
OTBS
OPMB
e
f
TBDPSO
HO
OMOM
O
12
OMOM
11
O
19
18
OTBS
OTBS
OTBS
g
TBDPSO
OHC
TBDPSO
TBDPSO
OH
OH
trans-crotonaldehyde
OH
13
20
13
14
Scheme 2. Reagents and conditions: (a) (i), H2O2 (1.3 equiv), CH2Cl2, rt, 24 h,
PPh3 = CHCO2Et, CH2Cl2, 2 h, 78% (over two steps); (b) PMBOH, Pd(PPh3)4, (PhO)3B,
THF, 0 °C to rt, 3 h, 96%; (c) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C to rt, 30 min, 95%; (d)
DIBAL-H, CH2Cl2, ꢀ78 °C to 0 °C, 2 h, 95%; (e) TBDPSCl, imidazole, CH2Cl2, 0 °C to rt,
1 h, 98%; (f) DDQ, pH 7 buffer, CH2Cl2, 0 °C to rt, 2 h, 86%; (g) Et2Zn, CH2I2, CH2Cl2,
ꢀ78 °C to 0 °C, 4 h, 97%.
Scheme 1. Retrosynthesis of brevipolide H (8).
The attractive structural features and the versatile biological
profiles showing significant activity prompted us to initiate the
synthesis of brevipolide H (8).
As a part of our work, the synthesis of novel biologically active
compounds,4 we have ventured into the total synthesis of pharma-
cological active cyclopropane containing natural products.
Very recently, Hou and co-workers reported the total synthesis
of ent-brevipolide H and Kumaraswamy et al. reported the studies
toward diastereoselective synthesis of derivative of 110-epi-bre-
vipolide H.5 Herein, we report a diastereoselective synthesis of
C1–C12 fragment of brevipolide H. According to our retrosynthetic
analysis of brevipolide H (8) as illustrated in Scheme 1, the lactone
11 could be achieved through ring-closing metathesis reaction of
corresponding diolefinic ester. Fragment 12 could be obtained by
Charette’s modified Simmons–Smith cyclopropanation from olefin
fragment 13, which in turn could be derived from commercially
available achiral starting material trans-crotonaldehyde 14.
The synthesis of lactone fragment 11 began with commercially
available trans-crotonaldehyde 14. Following Jørgensen’s chiral
epoxidation6 protocol aldehyde 14 was enantioselectively
Δδ>0
Δδ< 0
OMTPA
+70
+110
MOMO
9
5
-50
-60
4
8
6
C7
H
3
-120
-110
1
-130
+110
-120
2
-90
OTBS
Figure 2. (
D
d = dS ꢀ dR) ꢁ 103 for (S) and (R)-MTPA ester of compound 23.
yield. Selective deprotection of 1° TBDPS ether in the presence
of 2° TBS ether with NH4F10 in methanol at 0 °C afforded
primary alcohol 22 in 92% yield, which was then oxidized to
aldehyde using Dess–Martin periodinane11 in CH2Cl2 with 95%
yield. The resulting aldehyde was then subjected to vinyl magne-
sium bromide in THF at ꢀ78 °C to afford the diastereomers 23
and 24 (dr 2:3) in 90% yield, which was easily separated by col-
umn chromatography.
epoxidized by using (S)-(ꢀ)-
a,a-diphenyl-2-pyrrolidinemethanol
trimethylsilyl ether as the chiral catalyst to afford chiral epoxide
followed by two carbon homologation using stable Wittig ylide
to form a,b-unsaturated epoxy ester 15 in 78% yield over two steps
with dr 95:5 (by 1H NMR analysis) and with 93:7 enantiomeric
ratio (by HPLC). Palladium(0) catalyzed regioselective opening of
the resulting epoxide compound 15 by p-methoxy benzyl alcohol
afforded secondary homoallylic alcohol 16 in 96% yield.7 The
secondary alcohol 16 was protected as its TBS ether using tert-
butyldimethylsilyl trifluoromethanesulfonate and 2,6-lutidine as
Stereochemical assignment at the newly created hydroxy
bearing center was confirmed by the modified Mosher’s method.12
Thus, esterification of the isomer 23 with both (S)- and (R)-meth-
oxy-
a (trifluoromethyl)phenylacetic acid (MTPA) showed positive
base in CH2Cl2 to obtain the compound 17 in 95% yield. The
a,b-
chemical shift difference [(
D
d = dS ꢀ dR) ꢁ 103] for protons on C8
unsaturated ester 17 was converted to primary alcohol 18 using
diisobutylaluminium hydride in CH2Cl2 at ꢀ78 °C in 95% yield.
The protection of primary alcohol 18 with tert-butylchlorodiphen-
ylsilane resulted in TBDPS protected product 19 in 98% yield. At
this stage, we performed Simmons–Smith cyclopropanation
reaction but the reaction was unsuccessful. PMB-ether group in
compound 19 was oxidatively cleaved by using DDQ in CH2Cl2:
pH 7 buffer solution (9:1) to obtain secondary alcohol 13 in 86%
yield.8 Following Charette’s modified9 Simmons–Smith cycloprop-
anation, treatment of allylic alcohol 13 with Et2Zn and CH2I2 in
CH2Cl2 at ꢀ78 °C afforded cyclopropyl alcohol 20 as a major
diastereomer (de. 99% by HPLC) in 97% yield (Scheme 2).
through C9 (Fig. 2), while protons on C1 through C6 showed
negative chemical shift differences, which is the indicative of C7
bearing an R-configuration. Therefore, the absolute configuration
of C7 was assigned as R.
Inversion of C7 center of isomer 24 under Mitsunobu condi-
tions13 gave desired isomer 23 in low yield. To improve the yield
and selectivity of required isomer, the two diastereomers were
treated with Dess–Martin periodinane11 in CH2Cl2 to afford the
a
,b-unsaturated ketone 12 in 93% yield (Scheme 3). Diastereoselec-
tive reduction of cyclopropyl enone 12 was screened under various
reducing agents and conditions (depicted in Table 1). Among the
selected reagents, lithium tri-tert-butoxyaluminumhydride14 in
ethanol ꢀ78 °C gave the desired anti alcohol 23 in 94% yield as a
single isomer.
Secondary alcohol 20 was protected as its MOM ether using
MOM-Cl and DIPEA as a base to furnish compound 21 in 96%

D. K. Mohapatra et al. / Tetrahedron Letters 56 (2015) 1041–1044
1043
OTBDPS OTBS
OTBS
OTBS
OTBDPS OTBS
a
b
HO
20
TBDPSO
a
b
26
OMOM
OTBS
OMOM
O
OMOM
21
22
OH
OMOM
O
27
29
OH
OH
OTBS
c
+
OTBDPS OH
OTBDPS OTBS
OMOM
23
OMOM
24
d
c
d
O
OMOM
O
OMOM
O
OTBS
e
O
O
23
24
30
+
11
OMOM
12
Scheme 5. Synthesis of lactone fragment 11. Reagents and conditions: (a) (+)-
(Ipc)2BCl, allylmagnesium bromide, Et2O, ꢀ90 °C, 4 h, 81%; (b) acryloyl chloride,
Et3N, cat. DMAP, 0 °C to rt, 0 °C, 2 h, 85%; (c) Grubbs 1st generation catalyst, CH2Cl2,
5 h, 88%; (d) PPTS, MeOH, 50 °C, 4 h, 81%.
Scheme 3. Reagents and conditions: (a) DIPEA, MOMCl, CH2Cl2, 0 °C to rt, 12 h, 96%
(b) NH4F, MeOH, 0 °C to rt, 24 h, 92%; (c) (i) DMP, NaHCO3, CH2Cl2, 0 °C to rt, 2 h,
95%, (ii) vinylmagnesiumbromide, THF, ꢀ78 °C to rt, 2 h, 90% (d) (i) TPP, DIAD,
AcOH, THF, 0 °C to rt, 12 h, (ii) K2CO3, MeOH, rt, 3 h, 50% over two steps; (e) DMP,
NaHCO3, CH2Cl2, 0 °C to rt, 1 h, 93%.
After separation of both the isomers, stereochemistry of the
hydroxy center in the major isomer 28 was assigned by modified
Mosher’s ester method12 and was found to be unrequired (Fig. 3).
To obtain the required isomer 27 as a major product, Brown’s
protocol17 proved useful here. Thus, an allylating reagent ally-
lB(Ipc)2, prepared from allylmagnesium bromide and (+)-DIP-Cl
(diisopinocampheylboron chloride), reacted with aldehyde 26 in
anhydrous ether at ꢀ90 °C furnished the desired homo allylic alco-
hol 27 and 28 in 81% yield with high diastereoselectivity (85:15), in
favor of the required isomer 27. The alcohol 27 was acrylated with
acrolyl chloride, Et3N as base and catalytic amount of DMAP in
CH2Cl2 at 0 °C to give the acrylated product 29 in 85% yield.
Ring-closing metathesis of acryloyl ester 29 was achieved
smoothly with 10 mol % of Grubbs 1st generation catalyst under
refluxing conditions in CH2Cl2 for 5 h to furnish 30 in 88% yield.18
Selective desilylation of TBS ether in the presence of TBDPS
ether using PPTS19 in MeOH under refluxing conditions afforded
fragment 1120 in 81% yield (Scheme 5). To achieve the complete
synthesis of brevipolide H, we performed the standard Mitsunobu
protocol conditions to couple p-methoxy cinnamic acid and alcohol
11. Unfortunately, the reaction was unable to give the desired
inverted product.13
Table 1
Hydride reduction of cyclopropyl enone 12
Sr. no.
Conditions
23/24a
Yield (%)
1
2
3
4
5
(R)-CBS, THF, ꢀ25 °C, 12 h
85:15
62:38
90:10
94:06
100:0
74
72
87
82
94
DIBAL-H, ether, ꢀ78 °C, 1 h
NaBH4, CeCl3ꢂ7H2O, MeOH, ꢀ78 °C, 1 h
Zn(BH4)2, ether, ꢀ78 °C, 6 h
Li(Ot-Bu3)AlH, ethanol, ꢀ78 °C, 1 h
a
As per isolated yield.
OTBDPS OTBS
OH
OTBS
OTBDPS OTBS
H
a
b
O
OMOM
OMOM
OMOM
26
23
25
OTBDPS OTBS
OTBDPS OTBS
c
+
OH
OMOM
OH
OMOM
In summary, a linear diastereoselective synthesis of C1–C12 frag-
ment of brevipolide H was synthesized in 18 steps with 12.5%
overall yield, starting from commercially available trans-crotonal-
dehyde. Efforts to complete the total synthesis of brevipolide H
are in progress and will be reported in due course.
27
28
Scheme 4. Synthesis of homo allylic alcohols 27 and 28. Reagents and conditions:
(a) TBDPSCl, imidazole, CH2Cl2, 0 °C to rt, 3 h, 92%; (b) OsO4, 2,6-lutidine, NaIO4,
dioxane, H2O, rt, 4 h, 76%; (c) allyl bromide, Zn dust, aq NH4Cl, ꢀ20 °C, 2 h, 76%.
Acknowledgments
The allylic alcohol 23 was protected as its TBDPS ether 25 using
TBDPSCl and imidazole as base in CH2Cl2 at 0 °C in 92% yield. At
this stage, Jin’s one step dihydroxylation–oxidation protocol15 fol-
lowed by Barbier’s allylation16 using allyl bromide in the presence
of zinc and aq NH4Cl in THF at ꢀ20 °C furnished diastereomeric
homoallylic alcohols 27 and 28 (dr = 2:3) in 76% yield (Scheme 4).
The authors thank CSIR, New Delhi, India for financial support
as part of XII Five Year plan programme under title ORIGIN (CSC-
0108). K.S. and P.R.N. thank Council of Scientific and Industrial
Research (CSIR), New Delhi, India for financial assistance in the
form of fellowships.
Supplementary data
Δδ< 0 Δδ>0
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.12.
125.
OTBDPS
+490
MTPAO
OTBS
+240
-90
+200
+160
-190
C
References and notes
+50
+50
-170
+60
+180
-20
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H
OMOM
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Miranda, R. J. Nat. Prod. 2013, 76, 72.
Figure 3. (
D
d = dS ꢀ dR) ꢁ 103 for (S) and (R)-MTPA ester of compound 28.

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D. K. Mohapatra et al. / Tetrahedron Letters 56 (2015) 1041–1044
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25
20. Spectral data of compound 11: [
a
]
D
+32 (c 0.3, CHCl3); IR (KBr): 2927, 2855,
1726, 1464, 1385, 1254, 1108 cmꢀ1 1H NMR (500 MHz, CDCl3): d 7.78–7.73
;
(m, 4H), 7.49–7.35 (m, 6H), 6.96–6.90 (m, 1H), 6.01 (dd, J = 9.7, 2.5 Hz, 1H),
4.50 (d, J = 6.5 Hz, 1H), 4.46 (dt, J = 11.7, 2.8 Hz, 1H) 4.38 (d, J = 6.5 Hz, 1H),
3.42–3.33 (m, 2H), 3.33 (s, 3H), 2.96–2.86 (m, 1H), 2.76 (dd, J = 6.5, 4.1 Hz, 1H),
2.96–2.86 (m, 2H), 1.02 (s, 9H), 0.99–0.94 (m, 1H), 0.92 (d, J = 6.4 Hz, 3H), 0.56–
0.49 (m, 1H), 0.30–0.23 (m, 1H), 0.15–0.10 (m, 1H); 13C NMR (125 MHz, CDCl3):
d 163.9, 145.2, 136.0, 135.8, 130.0, 129.7, 127.8, 127.6, 121.0, 97.4, 83.8, 80.7,
76.9, 70.0, 55.6, 26.8, 23.6, 19.6, 18.6, 18.1, 16.4, 5.1; HRMS (ESI) m/z: calcd for
13. (a) Mitsunobu, O.; Yamada, M.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1967, 40,
935; (b) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380; (c)
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Vladimir, S. Org. Lett. 2006, 8, 3315.
C
30H41O6Si [M+H]+.525.2666; found: 525.2676.