Efforts toward the total synthesis of a jatrophane diterpene

Article abstract of DOI:10.1016/j.tetlet.2012.03.080

A significant effort toward the model study of jatrophane skeleton has been made. To synthesize an important synthon, Horner-Emmons-Wadsworth olefination was attempted.

Full text of DOI:10.1016/j.tetlet.2012.03.080

Tetrahedron Letters 53 (2012) 2730–2732
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Tetrahedron Letters
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Efforts toward the total synthesis of a jatrophane diterpene
⇑
Priya Mohan , Krishna Koushik, Michael J. Fuertes
Department of Chemistry & Biochemistry, Texas Tech University, Lubbock, TX 79409, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A significant effort toward the model study of jatrophane skeleton has been made. To synthesize an
important synthon, Horner–Emmons–Wadsworth olefination was attempted.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 3 March 2012
Revised 21 March 2012
Accepted 21 March 2012
Available online 29 March 2012
Keywords:
Model study
Multidrug resistance
Horner–Emmons–Wadsworth olefination
Introduction
carbonyl-ene reaction was utilized to synthesize the highly substi-
tuted cyclopentane fragment.
It has been found that certain cancer cells naturally become
resistant to chemotherapeutic drugs when exposed to drug over
a period of time. Scientists have identified small pumps on the sur-
face of cancer cells that actively extrude the chemotherapeutic
drug from inside the cancer cell ultimately leading to the failure
of chemotherapy. The developed resistance of disease-causing mi-
crobes or cells against varying drugs is commonly known as mul-
tidrug resistance (MDR).1 Jatrophane diterpenes were isolated in
1970 by Kupchan et al. from Euphorbia gossypiifolia2 which have
shown potential as Pgp inhibitor. Since then a large number of
jatrophane diterpenes have been isolated. Most of the jatrophane
Results and discussion
We assume that a bulky base-promoted hydrogen-abstraction
can lead to a regioselective opening of an epoxide to furnish an
exo-double bond. Hence the synthesis of jatrophane analogue 1
was targeted. In pursuit of a reliable synthetic pathway to access
a jatrophane skeleton such as 4, one of our main goals was to
establish a reliable methodology to construct the C11–C12 trisub-
stituted double bond. The structural architecture of this molecule
consists of a 5-membered ring trans-fused to a 12-membered ring.
diterpenes feature
framework.
a characteristic bicyclic[10.3.0]pentadecane
O
O
O
The structural complexity of this molecule can be estimated by
the numbers of stereocenters. They possess as many as 9 stereo-
genic centers along with C11–C12 double bond, and C6–C17 exo-
double bond. The first total synthesis of a jatrophane diterpene
was accomplished by Smith and co-workers in 1981.3 The key step
in this synthesis of normethyljatrophone was a TiCl4-mediated
intramolecular Mukaiyama cyclization. Stille and co-workers re-
ported another synthetic route for the total synthesis of jatrophone
in 1990.4 The key step in their total synthesis was the intramolec-
ular palladium-catalyzed carbonylative coupling between vinyl
stannane and vinyl triflate. However, the first asymmetric total
synthesis of 15-acetyl-3-propionyl-characiol was achieved by
Hiersemann et al., demonstrating a reliable synthetic strategy
toward the jatrophane framework.5 A thermal intramolecular
AcO
AcO
AcO
Epoxide
formation
Base
H
H
AcO
H
ONic
ONic
ONic
AcO
AcO
AcO
O
AcO
R2
R2
AcO
R2
AcO
2
3
1
HO
HO
MOMO
MOMO
12
11
RCM
5
6
O
4
O
5
HEW
OMOM
O
O
MOMO
P
EtO
EtO
+
O
7
6
⇑
Corresponding author.
E-mail address: pmohan.eburonorganics@gmail.com (P. Mohan).
Scheme 1. Retrosynthetic analysis of model substrate 4.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.080

P. Mohan et al. / Tetrahedron Letters 53 (2012) 2730–2732
2731
MOMO
MOMO
O
O
O
O
O
O
O
LiAlH4
ethylene glycol
OMOM
O
O
OCH3
OCH3
OH
THF, 0 oC, 4 h, 85%
HEW
base
MOMO
HC(OMe)3, TBABr3, 12 h, 92%
(EtO)2P
8
+
9
10
TBDPSCl, imidazole
O
DMF, 4 h, rt, 95%
O
7
6
5
O
HO
O
O
vinylmagnesium bromide
THF, -78 oC, 6 h, 86%
PPTS
OTBDPS
OTBDPS
OTBDPS
Scheme 4. Attempted HEW reaction.
acetone:H2O (5:1)
55 oC, 87%
13
11
12
MOMCl, DIPEA,, TBAI
THF, 80 oC, 3 h, 90%
OH
MOMO
MOMO
OsO4, NaIO4
2,6-lutidine
,
MOMO
MOMO
MOMO
MOMO
O
allylmagnesium bromide
THF, -78 oC, 3 h, 86%
OTBDPS
OTBDPS
OTBDPS
O
Proton abstraction
dioxane:H2O (3:1),
rt, 16h, 87%
H
O
16
14
15
MOMCl, DIPEA,, TBAI
THF, 80 oC, 3 h, 97%
27
6
Scheme 5. Rationale for the failure of the key HEW reaction.
OMOM
OMOM
MOMO
OMOM
MOMO
MOMO
TPAP, NMO, 4Å MS
rt, 2 h,CH2Cl2, 78%
TBAF
THF, rt, 6 h, 90%
OH
OTBDPS
O
Table 1
18
17
6
Reactions conditions applied for HEW reaction
Scheme 2. Synthesis of aldehyde 6.
Base
Temperature
Solvent
Result
n-BuLi
Ba(OH)2
K2CO3
NaH
À78 °C
rt to reflux
rt
THF
THF
THF
DME
Elimination
No reaction
No reaction
Elimination
Our retrosynthesis involves forming the C11–C12 olefinic double
bond by employing the ring-closing metathesis (RCM)6 from
bis-MOM-triene 5, which might be synthesized from Horner–Em-
25–35 °C
mons–Wadsworth olefination (HEW)7 using aldehyde
6 and
phosphonate 7 (Scheme 1).8
and inconsistent. Deketalization11 of compound 11 under acidic
condition afforded us cyclopentanone 12 in 87% yield, which upon
treatment with vinylmagnesium bromide gave the tertiary alcohol
as a single isomer and the relative stereochemistry was confirmed
by NOE as 13. The tertiary alcohol subsequently was protected as
the MOM ether to obtain 14 in 87% yield.12 The one-pot oxidative
cleavage of olefin resulted in aldehyde 15.13 Allylation of com-
pound 15 using allylmagnesium bromide produced homoallylic
alcohol 16 as a mixture of diastereomers in the ratio of 1:1. The
resultant secondary alcohol was protected as a MOM ether to yield
bis-MOM ether 17. TBAF-mediated desilylation was achieved at
room temperature to yield primary alcohol 18.14
Synthesis of racemic aldehyde 6 commenced with cyclopenta-
none methylcarboxylate 8 (Scheme 2). First, we protected the ke-
tone as the ketal with ethylene glycol and trimethyl
orthoformate.9 The primary alcohol was obtained by the reduction
of ester 9 with LiAlH4 and was protected as the TBDPS ether.10 We
chose TBDPS as the protecting group because we wanted it to serve
two purposes: (1) the bulky nature of this group should assist in a
stereoselective vinyl addition on an adjacent ketone, which is rel-
evant to the synthesis of our target; and (2) the Si-protecting group
would give us the flexibility of late stage deprotection and would
avoid undesirable deprotection of other protected alcohols. In the
initial phase of our research, we used a p-methoxyphenyl group
(PMP) for protecting this hydroxyl group. While stereoselective vi-
nyl addition worked well, the ceric ammonium nitrate-mediated
deprotection of the PMP group in a later stage was low yielding
We employed three different oxidation methods for the synthe-
sis of aldehyde 6. Pyridinium dichromate (PDC)15 resulted in
modest yield of aldehyde and required long reaction time and
the workups were often very capricious given the amount of
TBSCl, Et3N,
(COCl)2, DMSO); Et3
N
HO
OH
OTBS
HO
OTBS
O
CH2Cl2, rt, 95%
CH2Cl2, -78 oC, 95%
20
19
21
O
O
(EtO)2P
LiCl, DBU
CH3CN, rt, 88%
OEt
O
O
O
HCl
(COCl)2, DMSO; Et3
N
EtO
OTBS
EtO
EtO
OH
O
ethanol, rt, 92%
CH2Cl2, -78 oC, 92%
22
23
24
O
Ph3PCH3Br, n-BuLi
THF, 0 oC, 86%
O
P
O
EtO
(EtO)2
25
7
wilkinson's catalyst, Et3
THF, reflux SiH X
O
(EtO)2P
O
, n-BuLi
O
Ph3PCH3Br, KOtBu
THF, 0 oC, 2 h, 72%
H2, Pd/C
EtO
EtOAC, 60 psi, 60 o
6h, 100%
C
EtO
O
THF, 65%
26
27
Scheme 3. Synthesis of phosphonate 7.

2732
P. Mohan et al. / Tetrahedron Letters 53 (2012) 2730–2732
reagent used. Swern conditions proved to be harsh on our sub-
strate as we encountered an elimination of one of the MOM group
in low yield.16 Given the sensitive nature of substrate, we opted for
a milder oxidation. TPAP/NMO condition was found to be ideal for
this transformation and gave the requisite aldehyde 6 in 78%
yield.17
Acknowledgement
We would like to thank the Texas Tech University for providing
financial support to this research.
Supplementary data
The synthesis of phosphonate 7 began with mono-TBS protec-
tion of neo-pentyl glycol. Subsequent Swern oxidation gave alde-
hyde 21. Ester 22 was generated in a good yield upon subjection
of aldehyde to Horner–Emmons–Wadsworth olefination.18 Alcohol
23 was obtained after TBS-deprotection under acidic conditions;
after which Swern oxidation afforded aldehyde 24 in 92% yield. A
Wittig olefination was employed to convert aldehyde into diene
25 (Scheme 3).19 After repeated failures in performing the desired
regioselective reduction of a double bond utilizing Wilkinson’s cat-
alyst along with triethylsilane, we modified our synthetic scheme.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.03.
080.
References and notes
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a
,b-Unsaturated ester 24 was hydrogenated under 60 psi
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Bryan, R. F. J. Am. Chem. Soc. 1970, 92, 4476; (b) Kupchan, S. M.; Sigel, C. W.;
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hydrogen atmosphere using Pd/C (Scheme 4). Saturated ester 26
was obtained and subjected to Wittig olefination to yield ester
27, which upon treatment with lithiated ethylphosphonate fur-
nished the target phosphonate 7.
We were now set for the key HEW olefination between bis-
MOM aldehyde 6 and phosphonate 7 to provide triene 5. Unfortu-
nately, the two fragments did not couple under various conditions.
Frequently, we observed that one of the MOMOÀ groups of alde-
hyde 6 was being eliminated (Scheme 5). We rationalized the elim-
ination of MOMOÀ group was made possible through the
deprotonation of
mechanism.
a-carbon hydrogen, followed by an E1cb
Apparently, aldehyde 6 is sensitive and prone to b-elimination
even under the mildest basic conditions. Nevertheless we at-
tempted to couple the two fragments under various conditions
employing different bases but to our disappointment none of these
methods afforded the desired product 5 (Table 1).
Generally, we observed the b-eliminated product 27 when we
employed strong bases such as n-BuLi and NaH, and the use of
milder bases resulted in no reaction. Another reason which might
be hindering the formation of the desired enone 5 is the fact that
aldehyde 6 is sterically congested, thereby slowing down the
nucleophilic addition step. An alternative pathway to furnish en-
one with inducing minimal structural changes in the existing syn-
thetic scheme is under investigation and is subjected for future
communication.
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