Total syntheses of several iridolactones and the putative structure of noriridoid scholarein A: An intramolecular Pauson-Khand reaction based one-stop synthetic solution

Article abstract of DOI:10.1039/c9ob00855a

A simple and general approach towards the total syntheses of several iridolactones such as (±)-boschnialactone, (±)-7-epi-boschnialactone, (±)-teucriumlactone, (±)-iridomyrmecin, (±)-isoboonein, (±)-7-epi-argyol, (±)-scabrol A, (±)-7-epi-scabrol A, and (±)-patriscabrol as well as the putative structure of scholarein A is delineated. The synthetic strategy features a diastereoselective intramolecular Pauson-Khand reaction (IPKR) to construct the iridoid framework followed by some strategic synthetic manipulations to access the targeted monoterpenes including those having diverse oxy-functionalization patterns and with 3-5 contiguous stereogenic centres in a highly stereocontrolled manner. Also, the present endeavour includes the first total synthesis of scabrol A.

Full text of DOI:10.1039/c9ob00855a

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DOI: 10.1039/C9OB00855A
ARTICLE
Total Syntheses of several Iridolactones and the Putative Structure
of Noriridoid Scholarein A: An Intramolecular Pauson-Khand
Reaction based One-stop Synthetic Solution
Received 00th January 20xx,
Accepted 00th January 20xx
Abdus Salam, Sayan Ray, Md. Abu Zaid, Dileep Kumar and Tabrez Khan*
DOI: 10.1039/x0xx00000x
A simple and general approach towards the total syntheses of several iridolactones such as (±)-boschnialactone, (±)-7-epi-
boschnialactone, (±)-teucriumlactone, (±)-iridomyrmecin, (±)-isoboonein, (±)-7-epi-argyol, (±)-scabrol A, (±)-7-epi-scabrol A,
(±)-patriscabrol as well as the putative structure of scholarein A is delineated. The synthetic strategy features a
diastereoselective intramolecular Pauson-Khand reaction (IPKR) to construct the iridoid framework followed by some
strategic synthetic manipulations to access the targeted monoterpenes including those having diverse oxy-functionalization
pattern and with 3-5 contiguous stereogenic centre in a highly stereocontrolled manner. Also, the present endeavour
constitutes the first total synthesis of scabrol A.
Me
H
H
H
H
H
O
O
O
O
Introduction
HO
O
O
O
O
H
H
H
Me
Me
Me
Me
Iridoids represents one of the most prevalent family of
monoterpenoids with more than 300 members already
inventoried1 ever since the report of the first member,
iridomyrmecin in the late 1940’s.2 Existing either in the
glycosidic or non-glycosidic form, these natural products are the
vital components of the medicinal plants used in traditional
medicinal practice exhibiting wide array of bioactivities ranging
from antiviral, antibacterial, anti-inflammatory, antitumor and
cardiovascular activity among others.3,4 Also, iridoids have been
found to be attractants of butterflies and cats as well as exhibit
defensive function against their predators.5,6 Their commercial
importance in agricultural pest management is further
augmented by their ability to act as sex pheromones against
agricultural significant species of aphids.7 While, from structural
perspective iridoids manifest a confined cyclopenta[c]pyran
scaffold as exemplified through some distinct members of this
family captured in Figure 1. However, it is the attendant
stereochemical intricacies and the varied oxygenation pattern
generally in the cis-fused confined bicyclic framework that
renders them as attractive targets for total synthesis.
Iridomyrmecin (1)
Isoboonein (2)
Boschnialactone (3) Teucriumlactone (4)
Me
H
Me
Me
H
O
H
H
O
O
O
HO
HO
HO
HO
O
O
O
O
HO
H
HO
H
H
H
Me
Me
Me
Me
Argyol (5)
Scabrol A (6)
Patriscabrol (7)
Isopatriscabrol (8)
H
H
H
H
HO
HO
HO
HO
O
O
O
O
H
H
Me
H
H
Me
Scholarein C (11)
Me
OMe
Me
Scholarein B (10)
OH
Scholarein D (12)
Scholarein A (9)
Figure 1. Representative examples of iridoid monoterpenes.
recently disclosed approach towards the synthesis of iridoid
framework.9 There are few synthesis which deserve special
mention and the list includes, Suh et al. synthesis of a natural
iridoid via an intramolecular Pd(0) catalyzed allylic-alkylation
and transesterification sequence,10 Lupton and co-workers
strategy to access the iridoid framework via NHC catalyzed
rearrangement of α, β-unsaturated enol ester,11 and the very
recent Chakraborty et al. reported Ti(III)-mediated reductive
epoxide opening-cyclization sequence for accessing
iridolactones.12
Despite several strategies reported in the literature we
comprehended there are very few synthesis which addresses
the diverse oxy-functionality pattern manifested on the
cyclopentane ring of the iridoid framework.8f,10,13 Henceforth,
there still exists the necessity to develop more efficient and cost
economical synthetic approach to access iridoids with relatively
higher degree of oxygenation through a unified strategy. And
therefore, in view of our ongoing interest9 in the synthesis of
iridoids we were motivated to demonstrate the adaptation of
Owing to their interesting biological and structural
attributes iridoids have garnered immense worldwide attention
both from biologists and chemists.3,4,8 Numerous synthetic
approaches for elegant access to the iridolactones has been
reported, a majority of which were highlighted by us in our
* Organic Synthesis Laboratory,
School of Basic Sciences,
Indian Institute of Technology Bhubaneswar,
Khurdha-752050, Odisha, India
E-mail: tabrez@iitbbs.ac.in.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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DOI: 10.1039/C9OB00855A
ARTICLE
H
O
O
Me
H
H
H
H
HO
H
O
O
Me
argyol (5)
O
O
HO
Me
Me
boschnialactone (3)
scabrol A (6)
OTs
H
OTBS
OTBS
O
H
H
H
H
IPKR
O
O
O
O
O
O
H
13
O
C
O
O
Me
H
14
15
Me
O
Me
Me
teucriumlactone (4)
7-epi-boschnialactone (3')
Me
Me
Me
H
H
O
OH
H
O
HO
HO
O
O
Me
16
HO
H
H
H
H
O
O
Me
H
HO
Me
isoboonein (2)
patriscabrol (7)
O
O
Me
Me
iridomyrmecin (1)
scholarein A (9)
Scheme 1. Retrosynthetic strategy for accessing iridoids 1-9.
our recently disclosed de novo approach utilizing an
intramolecular Pauson-Khand reaction (IPKR) as the key step to
access ten iridoids in a stereocontrolled manner, emanating
from a very cheap and readily accessible starting material like
solketal.
to serve as a potential intermediate. Exploitation of the C6
carbonyl group in 13 as the functional group handle was
anticipated to offer the other desired functionalization of the
cyclopentane ring in context of the targeted natural products
(1-9) while the C4 tosylate in the tetrahydropyran ring was
planned to be manipulated to the δ-lactone ring or simply
jettisoned in context of scholarein A (9). Moreover, entry to one
iridoid could serve as the key for accessing other natural
products, for instance synthesis of 7-epi-boschnialactone (3ʹ)
could serve as a precursor to furnish first teucriumlactone (4)
and subsequently iridomyrmecin (1). While entry to the crucial
intermediate 13 was planned through our recently reported9
diastereoselective IPKR on silyl protected enyne ether (15) to
initially arrive at 14 and subsequently 13 through a couple of
synthetic intervention. Whereas, the synthesis of 15 could be
traced down from the very cheap and commercially available
solketal (16).9
Results and discussion
Adoption of a divergent approach from a common
intermediate for accessing the targeted monoterpenoids we
believed would be ideal in terms of demonstrating the
generality and flexibility of the synthesis. Therefore in this
context, the retrosynthetic plan we envisaged for the synthesis
of iridoids (1-9) is as captured in Scheme 1. The bicyclic ether 13
embodying the iridoid framework and having carbonyl
functionality at the C6 and tosylate at C4 position was expected
Scheme 2. Total synthesis of isoboonein 2
OTs
OTBS
OTBS
OH
H
H
H
LiHMDS
i) 10% HCl, THF
rt, 12 h
-78 C to -40
C


TsCl, Et3N,
O
O
O
O
O
DMAP, DCM,
rt, 4 h, 92%
O
O
O
ii) H2, Pd/C,
EtOAc, 4 h, 73%
over 2 steps
then MeI, HMPA
THF, 8 h, 75%
H
13
H
14
H
17
Me
Me
Me
18
Co2(CO)8, TMNO
DCM, -15 C -rt, 8 h,
68%, cis:trans = 9:1

(i) NaBH4, MeOH, 0 oC, 1 h
Me
Me
(ii) DIAD, PPh3, 0 oC -rt, p-NO2C6H4CO2H, dry THF, 8 h
OTBS
ref. 9
O
72 % over 2 steps
OH
O
O2N
O
16
15
H
OTs
OTs
O
H
H
i) tBuOK, tBuOH,
reflux, 1 h,
H
H
(i) K2CO3, MeOH
O
O
10% HCl, THF
rt, 12 h, 80%
1 h, rt
HO
TIPSO
TIPSO
O
O
O
O
O
ii) PCC, DCM
(ii) TIPSOTf, Et3N,
DMAP, DCM,
0 oC -rt, 2 h,
H
H
H
Me
rt, 2 h, 55%
over 2 steps
Me
Me
Me
21
20
isoboonein
19
83% over 2 steps
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ARTICLE
OTs
O
OTs
O
OTs
i) tBuOK, tBuOH,
reflux, 1 h,
H
H
H
H
H
O
O
i) NaBH4, MeOH, 0 °C, 1 h;
Zn, TMSCl
O
O
ii) PCC, DCM
rt, 2 h, 57%
ii) (CF3SO2)2O, py, -78 °C, 2 h;
iii) K2CO3, -78 °C- rt, 1 h
MeOH:DCM,
0 °C, 2 h, 70%
H
H
H
Me
Me
Me
Me
over 2 steps
23
22
13
71% over 3 steps
7-epi-boschnialactone (3')
(i) LiHMDS, - 78 °C
CH2=NMe2 I, 16 h;
i) tBuOK, tBuOH, reflux, 1 h;
ii) PCC, DCM, rt, 2 h, 54%
over 2 steps
(ii) MeI, DCM:THF(1:1), 2 h;
(iii) sat. aq. NaHCO3 , 46%
over 3 steps
Me
H
H
H
H
H
H
O
O
O
O
H2, PtO2
H2, PtO2
O
EtOH, rt, 5 h,
54%
O
O
O
MeOH, rt, 12 h,
74%
H
H
Me
Me
Me
teucriumlactone (4)
Me
boschnialactone (3)
iridomyrmecin (1)
24
Scheme 3. Synthesis of iridoids 1, 3, 4 and epimeric iridoid 3ʹ.
For operationalization of the proposed retrosynthetic plan NMR spectral data of the synthetic 2 was found to identical with
outlined in Scheme 1, we first choose isoboonein as the target that reported for the natural isoboonein,15 thereby confirming
for total synthesis. In this context, the enyne ether 15 was the accomplishment of its total synthesis.
subjected to our standardized IPKR condition9 to arrive at 17
After accomplishing the synthesis of natural product 2
with excellent diastereoselectivity (cis:trans = 9:1). Elaboration attention was then turned toward demonstrating the
of 17 to 14 via stereoselective methylation and then subsequent accessibility of iridoids 1, 3 and 4 from the key intermediate 13
silyl deprotection followed by highly stereoselective enone (Scheme 3) to magnify the divergent nature of the proposed
double bond reduction using 10% Pd/C smoothly furnished the synthetic plan. Therefore, to accomplish the synthesis of iridoid
bicyclic hydroxy ketone 18. Further, tosylation of 18 under 1 and 4, the intermediate 13 as delineated in Scheme 3 was first
routine condition readily delivered the key intermediate 13 in subjected to a Zn/TMSCl mediated Clemmensen reduction16 to
excellent yield. With access to 13, it was matter of reducing the arrive at 22. Then, repetition of our 2-step synthetic
C6 carbonyl group and manipulating the tosylate group in the manipulation of the C4-tosylate group in 22 to the δ-lactone as
tetrahydropyran ring to the δ-lactone. To accomplish this task, described in Scheme 2, offered C7-epimer of boschnialactone
13 was subjected to borohydride reduction and to our delight (3ʹ) in satisfactory yield having spectroscopic data similar to
the reaction ended up delivering a single diastereomer but reported by others.17 Next, from this epimeric natural product
deviant from the desired stereochemistry at the C6 hydroxyl (3’) it was just a matter of introducing the exocyclic methylene
group in consonance with our earlier observation and by others at C4 position for acquisition of natural product 4 and
on similar substrates.9 Therefore, Mitsonubu protocol14 was subsequently 1 through stereoselective exocyclic double bond
adopted to invert the C6 -hydroxy group resulting from the reduction from the exo face. For this task, among the various
borohydride reduction of 13, from α to β face through options for doing the C4 methylenation we indeed prefer to
formation of p-nitrobenzoate derivative 19. Hydrolysis of 19 choose the Eschenmoser18 protocol to access teucriumlactone
with K2CO3 in MeOH delivered the alcohol with desired (4) through three step process in a single pot operation.
stereochemistry of the C6 -hydroxy group in good yield which Thereafter, subsequent reduction of 4 using Adam’s catalyst in
we opted to protect as the TIPS ether to arrive at 20. With 20 in presence of H2 gas19 effortlessly delivered iridomyrmecin (1) in
hand, the next task was to eliminate the C4-tosylate group in the a stereoselective fashion. The NMR spectral data of the
tetrahydropyran ring and oxidize the resultant dihydropyran to synthetic 1 and 4 were found to exhibit close resemblance to
access the δ-lactone. Towards this goal, subjection of 20 initially that reported for the natural products,2,20 thereby confirming
t
t
to BuOK in refluxing BuOH facilitated the desired elimination the accomplishment of their total synthesis.
and then exposure of the crude eliminated product to PCC
Further, in context of boschnialactone (3) the synthetic
smoothly delivered the desired TIPS protected bicyclic lactone demand was to epimerize the C7-Me group in the key
21. Eventually, TIPS deprotection in 21 using 10% HCl in THF led intermediate 13 and in view of the presence of adjacent C7
to the natural iridolactone isoboonein (2) in good yield. The carbonyl group the task was anticipated to be easily achievable.
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ARTICLE
Me
H
Me
Me
H
H
H
H
O
LiHMDS
-78 °C to -40 °C
O
O
O
mCPBA
+
O
O
DCM, 0 °C - rt, 4 h
87%;
27:28 = 1.8:1
O
O
O
O
then MeI, HMPA
THF, 8 h, 61%
H
Me
H
26
Me
H
24
Me
Me
27
28
15% H2SO4
(i) Hg(OAc)2, aq. THF, 80 °C, 12 h;
(ii) NaBH4, 0 °C - rt, 15 min., 78%
(i) Hg(OAc)2, aq. THF, 80 °C, 12 h;
(ii) NaBH4, 0 °C - rt, 15 min., 76%
THF, rt, 1 h,
73%
Me
O
Me
H
Me
H
H
H
H
O
O
O
O
+
HO
HO
+
O
O
O
O
O
HO
H
OH
H
HO
H
HO
H
Me
Me
Me
patriscabrol (7)
Me
7-epi-scabrol A (6') [18%]
Me
scabrol A (6) [60%]
7-epi-argyol (5') [30%]
25 (46%)
Scheme 4. Synthesis of 5ʹ, 6, 6ʹ and 7.
However, all our efforts to do the desired epimerization under Scheme 4, first to access natural iridoid 5 and 6, the task of
several base catalyzed conditions proved to be non-rewarding, olefinic double bond hydration in 24 and 24 derived 26 in a
thereby forcing us to adopt an alternate approach as Markownikov’s fashion was undertaken.22 Initially, 24 was
highlighted in Scheme 3. The problem was circumvented subjected to oxymercuration using Hg(OAc)2 in refluxing aq.
through a stereoselective borohydride reduction of the C6 THF and then demercurated to surprisingly arrive at an easily
carbonyl group and subsequent elimination of the resultant separable mixture of unexpected 25 as the major product and
alcohol in a regioselective fashion to arrive at bicyclic olefin 23. the C7 epimer of natural iridoid argyol (5ʹ) instead of 5, as the
Then the elaboration of 23 via a 2 step synthetic intervention minor product of the reaction. The formation of 25 could be
to the bicyclic lactone 24 followed by stereoselective olefin rationalized through a tentative mechanism as highlighted in
double bond reduction in 24 employing Adam’s catalyst in Scheme 5. Mercuration of of the double bond in 24 from the
presence of H2 gas furnished the desired synthetic natural endo face is presumed to offer first the mercurinium ion 24'a
product boschnialactone (3) with NMR spectral signature which then undergoes a 1,2-hydride shift to form the
similar to that of the isolated natural product21 thereby carbocation 24’b. Thereafter, a spontaneous E2 elimination in
confirming its total synthesis.
24'b could be accounted for the formation of a more stable
In our synthetic journey, we next planned to embark on the allylic carbocation at C7a position in 24'c. Eventually the
synthesis of iridoids 5-7 in view of accessibility to bicyclic nucleophilic attack of H2O in 24'c at C7a position from the exo
lactone intermediate 24. Towards this goal as delineated in
face could be attributed for formation of 25. On the other hand,
Scheme 5. A plausible mechanism for the formation of 25 and 5ʹ from 24.
H
H
H
H
O
O
O
O
[1,2]
Hg(OAc)2
-Hg
Hg
O
O
O
O
hydride
shift
-AcOH
OAc
Hg
Me
OAc
H
24
H
H
Me AcO
24'c
Me
Me
AcO
24'b
AcO
24'a
Hg(OAc)2
H2O
-AcOH
H
H
H
H
H
O
O
O
O
O
H2O
-AcOH
NaBH4
Hg
AcO
O
-Hg
-AcOH
O
O
Hg
Me
OAc
HO
H
HO
H
OH
25
Me
Me
24b
Me
AcO
24a
7-epi-argyol (5')
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OH OH
(i) p-TSA (cat.)
benzene, reflux, 5 h
OTs
O
OTs
O
H
H
H
H
(i) H2, Pd/C,dry EtOAc,
3 h, 85%
refer
Scheme 2
60% over 4
steps
O
O
O
TIPSO
HO
O
O
(ii) NaBH4, MeOH
1 h, 98%
H
H
H
30
H
31
Me
Me
Me
Me
13
20
DIAD, PPh3, 0 o
C
p-NO2C6H4CO2H
dry THF, 8 h, 75 %
H
H
H
H
H
O
O
K2CO3, MeOH
1 h, rt, 90%
10% HCl, THF
rt, 12 h, 80%
TIPSO
HO
O
O
O
H
32
Me
Me
Me
29
scholarein A (9)
Scheme 6. Synthesis of the proposed structure of scholarein A (9).
O2N
X-ray crystal structure of 32
the oxymercuration on 24 (Scheme 5) from a completely good yield which on TIPS deprotection of the C6 hydroxy group
opposite face and then borohydride mediated demercuration smoothly furnished the targeted natural product.
could be attributed for formation of 5ʹ. Interestingly, exposure
Alternatively, the natural product was also accessed via 30
of 26 (derived via a kinetically controlled methylation on 24) to which resulted from the cyclic ketal protection on 13 followed
similar oxymercuration-demercuration reaction condition by base mediated tosyl elimination (Scheme 6). Thereafter, the
milieu to our delight offered the desired natural product scabrol catalytic hydrogenation of the dihydropyran ring in 30 over
A (6) as the predominant product along with its C7 epimer (6ʹ) as extended duration not only reduced the dihydropyran ring but
the minor product (Scheme 4). The NMR spectral data of the also deprotected the C6 ketal to offer the unmasked carbonyl
synthetic scabrol A (6) was found to exhibit close resemblance group which on borohydride reduction offered 31 in excellent
to that reported for the natural product23 thereby culminating yield albeit with undesired stereochemistry of the C6-OH group.
in the first total synthesis of scabrol A.
Nevertheless, exposure of 31 to the typical Mitsonubu reaction
On the other hand to access iridoid natural product 7, the condition14 using p-nitrobenzoic acid as the nucleophile offered
intermediate 26 was subjected to an mCPBA mediated the crystalline p-nitrobenzoate derivate 32 in good yield. Single
epoxidation to arrive at an easily separable mixture of α and β crystal X-ray diffraction studies of 3224 unambiguously secured
epoxide, 27 and 28 respectively, albeit with the desired the desired stereochemistry of all its stereogenic centres. Then,
diastereomer 28 as the minor product. Nevertheless, with 28 in it was just a matter of hydrolyzing 32 to accomplish the
hand it was just a matter of acid catalyzed hydrolysis of the synthesis of 9. However, we were taken by surprise when the
epoxide13c to arrive at the synthetic patriscabrol 7 in good yield. comparison of the NMR spectral data of our synthetic
The NMR spectral data of our synthetic sample was in close scholarein A (9) indicated significant mismatch with that
agreement with that reported earlier13c thereby confirming the reported for the natural product.25 However, on the contrary
accomplishment of its total synthesis.
our NMR data was in close agreement with that of another
Lastly, the task of synthesizing noriridoid scholarein A (9) synthetic scholarein A, reported by others (refer Supp.
was taken in hand and to accomplish its synthesis again the Information for spectral comparison).26 While the earlier
intermediate 13 proved to be the ideal starting material. reports hasn’t commented anything about this mismatch,26 but
However, in context of 9 the expulsion of the C4 tosylate group on the basis of our unambigous synthetic exercise involving X-
in 13 turned out to be a tricky proposition in the presence of C6 ray crystal structure analysis of the precusor (32) leading to the
carbonyl group therefore two alternative routes as depicted in natural product we suggest that there has been error in the
Scheme 6 were explored to access 9. Through the first route, reported structure of scholarein A (9) and hence there lies the
the already synthesized intermediate 20 in context of need for structural revision of scholarein A (9).27 Efforts are
isoboonein was exploited to access scholarein A (9). Base underway in our laboratory to synthesize the other possible
mediated elimination of the tosylate group in 20 followed by diastereomer of the proposed structure of the natural product
reduction of the resultant dihydropyran ring afforded 29 in and come up with the revised structure.
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Journal Name
found to be pure enough through NMR spectral analysis to be
used in the next step.
Conclusions
View Article Online
DOI: 10.1039/C9OB00855A
In summary, we have successfully demonstrated though in
racemic fashion, a general and simple route to access quite a
few iridoids including those having higher oxygenation pattern
commencing from very cheap starting material like solketal. A
quick entry to the iridoid framework via a diastereoselective
IPKR followed by some strategic synthetic interventions
enabled access to isoboonein, boschnialactone, 7-epi-
boschnialactone, teucriumlactone, iridomyrmecin, 7-epi-argyol,
scabrol A, 7-epi- scabrol A, patriscabrol and the proposed
structure of scholarein A in a stereocontrolled and divergent
fashion. Also, the present synthesis of scabrol A happens to be
the first total synthesis in the literature for the natural product.
Further, efforts are underway to demystify the structure of
scholarein A and expand the scope of the approach for
accomplishing the synthesis of more complex iridoids. Also,
development of an asymmetric version of the approach is under
exploration which shall be disclosed soon.
To an ice cold solution of DIAD (1.08 mL, 5.52 mmol, 4
equiv.) at 0 °C in dry THF (5 mL), PPh3 (2.89 g, 11.03 mmol, 8
equiv.) was added and stirred for 10 min. thereafter a solution
of the crude alcohol (450 mg, 1.38 mmol) in dry THF (1.5 mL)
obtained from the above step was added at same temperature.
Subsequently, after another 10 min. p-nitrobenzoic acid (4.61 g,
27.57 mmol, 20 equiv.) was added and the mixture was allowed
to warm to rt and continued stirring for another 8 h until
complete consumption of starting material and formation of a
new spot was indicated by the TLC analysis. The reaction was
quenched with sat. aq. NH4Cl solution followed by extraction
with EtOAc (3 × 25 mL). Drying of the organic phase over Na2SO4
and then solvent removal under reduced pressure gave a solid
residue which was subjected to SiO2-gel column
chromatography using hexanes/EtOAc (8:2) as the eluent to
access the p-nitrobenzoate derivative 19 (525 mg, 72% yield
over 2 steps) as white solid. IR (neat): νmax 2917, 2850, 1721,
1599, 1349, 1274, 1176, 772 cm-1; 1H NMR (400 MHz, CDCl3) δ
8.27 (d, J = 9.0 Hz, 2H), 8.14 (d, J = 9.0 Hz, 2H), 7.80 (d, J = 8.0
Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 5.40 (td, J1 = 7.0 Hz; J2 = 3.0 Hz,
1H), 4.24 (td, J1 = 9.0 Hz; J2 = 5.0 Hz, 1H), 3.88 (dd, J1 = 11.0 Hz;
J2 = 5.0 Hz, 1H), 3.80 (dd, J1 = 12.0 Hz; J2 = 1.0 Hz, 1H), 3.62 (dd,
J1 = 12.0 Hz; J2 = 4 Hz, 1H), 3.17 (dd, J1 = 11.0 Hz; J2 = 10.0 Hz,
1H), 2.46 (s, 3H), 2.37-2.31 (m, 1H), 2.26-2.16 (m, 1H), 2.08-1.98
(m, 2H), 1.85 (ddd, J1 = 15.0 Hz; J2 = 8.0 Hz; J3 = 3.0 Hz, 1H), 0.99
(d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 163.93, 150.51,
145.33, 135.66, 133.41, 130.56 (2C), 130.02 (2C), 127.79 (2C),
123.57 (2C), 78.30, 78.23, 68.72, 66.10, 45.45, 40.74, 38.14,
35.80, 21.69, 12.19.
rel-(4R,4aS,6R,7R,7aR)-7-methyl-6-(triisopropylsilyl)oxy)octa-
hydrocyclopenta[c]pyran-4-yl-4-methylbenzenesulfonate (20):
To a stirred solution of p-nitrobenzoate derivative 19 (500 mg,
1.05 mmol) was added K2CO3 ( 720 mg, 5.25 mmol, 5 equiv.) in
MeOH (10 mL)and the mixture was allowed to stir at rt for 1 h
until complete consumption of starting material was indicated
by TLC analysis. The reaction was quenched with sat. aq. NH4Cl
solution followed by extraction with EtOAc (3 × 15 mL). Drying
of the organic phase over Na2SO4 and then solvent removal
under reduced pressure gave an oily residue which was
subjected to SiO2-gel column chromatography using
hexanes/EtOAc (7:3) as the eluent to access the crude alcohol
which was directly used in the next step.
Experimental Section
General Information: All the reagents were purchased from
Sigma-Aldrich and other commercial suppliers and used without
further purification. While most of the desired solvents supplied
by commercial suppliers were dried using the standard drying
procedures.28 All non-aqueous reactions were executed under
nitrogen atmosphere. The 1H and 13C NMR spectra were
recorded on 400 and 100 MHz Bruker spectrometer
respectively using TMS as an internal standard. The following
abbreviations are used for spin multiplicity: s = singlet, d =
doublet, t = triplet, q = quartet, p = quintet/pentet, dd = doublet
of doublet, ddd = doublet of doublet of doublet, dt = doublet of
triplet, td = triplet of doublet, dqd = doublet of quartet of
doublet and m = multiplet. The chemical shifts are reported as
δ values (ppm) and the coupling constants (J) values are
reported in Hz. High Resolution Mass Spectra (HRMS) were
obtained using electron spray ionization (ESI) technique and
TOF as mass analyzer. IR spectra were recorded on a Bruker
FT/IR-460 Plus spectrometer. Reactions monitoring were done
using precoated SiO2-gel GF254 glass TLC plates while spot
visualizations were done under UV light and spot developing
stains like p-anisaldehyde or KMnO4. Purifications were done
using column chromatography with 100-200 mesh size SiO2-gel
as the stationary phase. Compounds 13-15, 17, 18 and 30 were
synthesized as per our earlier reported procedure.9
rel-(4R,4aS,6R,7R,7aR)-7-methyl-4-(tosyloxy)octahydrocyclo-
penta[c]pyran-6-yl 4-nitrobenzoate (19): To stirred solution of
13 (500 mg, 1.54 mmol) in dry MeOH (5 mL) at 0 °C, NaBH4 (88
mg, 2.32 mmol) was added. The reaction mixture was then
allowed to warm to room temperature and stirred for another
1 h until complete consumption of starting material and
formation of a new spot was indicated by the TLC analysis. After
aqueous work-up followed by extraction with EtOAc (3 × 15 mL),
the organic phase was dried over Na2SO4 and then subjected to
removal of solvent under reduced pressure to arrive at the
crude reduced product (450 mg) as a colourless oil, which was
To the cold solution of crude alcohol obtained after
hydrolysis of benzoate 19 at 0 °C in dry DCM (5 mL) was added
Et3N (1.4 mL, 10.05 mmol, 10 equiv.) followed by sequential
addition of TIPSOTf (0.42 mL, 1.58 mmol, 1.5 equiv.) and DMAP
( 1 mg, 0.01 mmol, 0.01 equiv.). The reaction mixture was then
allowed to warm to rt and continued stirring for another 2 h
until complete consumption of starting material and formation
of a new spot was indicated by the TLC analysis. The reaction
was worked up by removing the solvent under reduced pressure
and then subjecting the resultant residue to SiO2-gel column
chromatography using hexanes/EtOAc (8:2) as the eluent to
arrive at pure TIPS protected bicyclic alcohol 20 (421 mg, 83%
yield over 2 steps) as colorless oil. IR (neat): νmax 2943, 1598,
6 | J. Name., 2012, 00, 1-3
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1
1464, 1367, 1177, 947, 682 cm-1; H NMR (400 MHz, CDCl3) δ 1H), 3.00-2.90 ( m, 1H)), 2.64 (dd, J1 = 15 Hz, J2 = 7VHiezw,A1rtHicl)e,O2n.l3in8e
DOI: 10.1039/C9OB00855A
7.80 (d, J= 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.23-4.15 (m, 2H), (dd, J1 = 15 Hz, J2 = 4 Hz, 1H), 2.16 (tt, J1 = 10 Hz, J2 = 4 Hz, 1H),
3.84 (dd, J1 = 11.0 Hz; J2 = 5.0 Hz, 1H), 3.73 (dd, J1 = 12.0 Hz; J2 = 2.06 (dd, J1 = 14 Hz, J2 = 8 Hz, 1H), 1.92 (dqd, J1 = 10 Hz, J2 = 7 Hz,
1.0 Hz, 1H), 3.58 (dd, J1 = 12.0 Hz; J2 = 4 Hz, 1H), 3.16 (dd, J1 = J3 = 3 Hz, 1H), 1.46 (br s, 1H), 1.42 (ddd, J1 = 14 Hz, J2 = 10 Hz, J3
11.0 Hz; J2 = 10.0 Hz, 1H), 2.43 (s, 3H), 2.25-2.18 (m, 1H), 1.94- = 4 Hz, 1H), 1.08 (d, = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
1.80 (m, 2H), 1.74-1.61 (m, 2H), 1.02 (br s, 21H), 0.96 (d, J = 6.0 173.50, 75.61, 68.52, 41.63, 41.54, 41.42, 34.47, 32.62, 12.64.
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 144.88, 133.77, 129.82 HRMS (ESI) m/z calcd for C9H15O3 (M+H)+ : 171.1016; found:
(2C), 127.77 (2C), 79.51, 74.32, 68.62, 66.71, 44.55, 40.35, 171.1015.
39.77, 39.38, 21.60, 18.05 (3C), 17.99 (3C), 12.65, 12.28 (3C). rel-(4R,4aS,7R,7aS)-7-methyl-6-oxooctahydrocyclopenta[c]
HRMS (ESI) m/z calcd for C25H43O5SSi (M+H)+ : 483.2595; found: pyran-4-yl-4-methylbenzene-sulfonate (22): To
483.2597.
rel-(4aR,6R,7R,7aS)-7-methyl-6-(triisopropylsilyl)oxy)-
a
stirred
solution of 13 (400 mg, 1.23 mmol) in 4 ml of MeOH and DCM
(ratio of 3:1 respectively) containing activated Zn powder (2.4 g,
hexahydrocyclopenta[c]pyran-3(1H)-one (21): To a stirred 37 mmol, 30 equiv.) was added TMSCl (4.7 mL, 37 mmol, 30
solution of TIPS protected bicyclic alcohol 20 (400 mg, 0.83 equiv.) at 0 °C. The reaction was continued stirring for an
mmol) in tBuOH (4 mL) was added tBuOK (465 mg, 4.15 mmol, additional 1.5
h at same temperature until complete
5 equiv.) at rt. The reaction mixture was then allowed to reflux consumption of starting material and formation of a new spot
for 1 h until complete consumption of starting material and was indicated by TLC analysis. The reaction was quenched with
formation of a new spot was indicated by the TLC analysis. The NaHCO3 (3.1 g, 37 mmol, 30 equiv.) and allowed to warm to rt
reaction was quenched with sat. aq. NH4Cl solution followed by over 10 min. followed by addition of sat. aq. NH4Cl and then
extraction with EtOAc (3 × 15 mL). Drying of the organic phase extraction in EtOAc (3 × 15 mL). Drying of the organic phase over
over Na2SO4 and then removal of solvent under reduced Na2SO4 and then removal of solvent under reduced pressure
pressure gave a crude oily residue which was directly used in gave a crude oily residue which was subjected to SiO2-gel
the next step.
column chromatographic purification using hexanes/EtOAc
To the cold solution of crude residue obtained from the (8:2) as the eluent to arrive at pure 22 ( 267 mg, 70% yield) as
°
above reaction in dry DCM (5 mL) at 0 C, PCC (535 mg, 2.49 colorless oil. IR (neat): νmax 2952, 2870, 1598, 1463, 1363, 1176,
1
mmol, 3 equiv.) was added. The reaction mixture was then 1099, 957 cm-1; H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8 Hz,
allowed to warm to rt and stirred for another 2 h until complete 2H), 7.34 (d, J = 8 Hz, 2H), 4.28 (td, J1 = 9 Hz, J2 = 4 Hz, 1H), 3.83
consumption of starting material and formation of a new spot (dd J1 = 11 Hz, J2 = 4 Hz, 1H), 3.64 (dd J1 = 12 Hz, J2 = 3 Hz, 1H),
was indicated by the TLC analysis. The reaction was worked up 3.54 (dd J1 = 12 Hz, J2 = 4 Hz, 1H), 3.20 (dd J1 = 12 Hz, J2 = 9 Hz,
by removing the solvent under reduced pressure and then 1H), 2.45 (s, 3H), 2.14 (ddd, J1 = 15 Hz, J2 = 7 Hz, J3 = 3 Hz, 1H),
subjecting the resultant residue to SiO2-gel column 1.94-1.78 (m, 2H), 1.68-1.56 (m, 2H), 1.42-1.35 (m, 1H), 1.22-
chromatographic purification using hexanes/EtOAc (9:1) as the 1.10 (m, 1H), 0.93 (d, J = 6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
eluent to arrive at lactone 21 (148 mg, 55% yield over 2 steps). 144.85, 133.87, 129.83 (2C), 127.81 (2C), 77.97, 68.46, 66.69,
IR (neat): νmax 2943, 1752, 1462, 1079, 1040, 882, 676 cm-1; 1H 47.82, 43.14, 33.40, 31.35, 26.47, 21.64, 19.71. HRMS (ESI) m/z
NMR (400 MHz, CDCl3) δ 4.31 (dd, J1 = 12 Hz, J2 = 4 Hz, 1H), 4.24 calcd for C16H23O4S (M+H)+ : 311.1312; found: 311.1315.
(t, J = 3 Hz, 1H), 4.13 (dd, J1 = 12 Hz, J2 = 4 Hz, 1H), 2.94-2.84 (m, (±) 7-epi-boschnialactone (3ʹ): To a stirred solution of tosylate
t
t
1H), 2.63 (dd, J1 = 15 Hz, J2 = 7 Hz, 1H), 2.35 (dd, J1 = 15 Hz, J2 = 22 (200 mg, 0.64 mmol.) in BuOH (2.5 mL) was added BuOK
4 Hz, 1H), 2.15 (tt, J1 = 10 Hz, J2 = 4 Hz, 1H), 2.03 (dd, J1 = 13 Hz, (358 mg, 3.20 mmol, 5 equiv.) at rt. The reaction mixture was
J2 = 8 Hz, 1H), 1.89-1.81 (m, 1H), 1.35 (ddd, J1 = 14 Hz, J2 = 10 Hz, then allowed to reflux for 1h until complete consumption of
J3 = 3 Hz, 1H), 1.06 (br s, 24H); 13C NMR (100 MHz, CDCl3) δ starting material and formation of a new spot was indicated by
173.67, 76.23, 68.74, 42.44, 42.35, 41.89, 34.57, 32.55, the TLC analysis. The reaction was quenched with sat. aq. NH4Cl
18.14(3C), 18.11(3C), 13.42, 12.48 (3C). HRMS (ESI) m/z calcd solution followed by extraction with EtOAc (3 × 15 mL). Drying
for C18H35O3Si (M+H)+ : 327.2350; found: 327.2359.
of the organic phase over Na2SO4 and then removal of solvent
(±) isoboonein (2): To a stirred solution of lactone 21 (125 mg, under reduced pressure gave a crude oily residue which was
0.38 mmol) in THF (2.5 mL), 10% HCl (2.5 mL) was added at rt directly used in the next step.
and the reaction was allowed to stir for 12 h until complete
To the cold solution of crude residue obtained from the
consumption of starting material and formation of a new spot above step in dry DCM (2.5 mL) at 0 °C, PCC (413 mg, 1.92 mmol,
was indicated by the TLC analysis. The reaction was worked up 3 equiv.) was added. The reaction mixture was then allowed to
by quenching it with sat. aq. NaHCO3 solution followed by warm to rt and stirred for another 2 h until complete
extraction with EtOAc (3 × 15 mL). Drying of the organic phase consumption of starting material and formation of a new spot
over Na2SO4 and then removal of solvent under reduced was indicated by the TLC analysis. The reaction was worked up
pressure gave a crude oily residue which was subjected to SiO2- by removing the solvent under reduced pressure and then
gel column chromatography using hexanes/EtOAc (2:8) as the subjecting the resultant residue to SiO2-gel column
eluent to arrive at the synthetic natural product isoboonein 2 chromatographic purification using hexanes/EtOAc (8:2) as the
(52 mg, 80% yield) as colorless oil. IR (neat): νmax 2971, 2931, eluent to arrive at 7-epi-boschnialactone 3ʹ (57 mg, 57% yield
1
1734, 1248 cm-1; H NMR (400 MHz, CDCl3) δ 4.32 (dd, J1 = 12 over 2 steps). IR (neat): νmax 2952, 1746, 1479, 1387, 1275, 1166,
1
Hz, J2 =4 Hz, 1H), 4.15 (dd, J1 = 12 Hz, J2 = 3 Hz, 1H), 4.14-4.13 (m, 1037, 969, 748 cm-1; H NMR (400 MHz, CDCl3) δ 4.25 (dd, J1 =
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12 Hz, J2 = 4 Hz, 1H), 4.07 (dd J1 = 12 Hz, J2 = 5 Hz, 1H), 2.63-2.53 45.44, 41.13, 37.9, 37.30, 34.16, 29.82, 18.39, 12.74. HRMS (ESI)
View Article Online
+
DOI: 10.1039/C9OB00855A
(m, 2H), 2.34-2.28 (m, 1H), 2.02-1.98 (m, 1H), 1.89-1.73 (m, 3H), m/z calcd for C10H16NaO2 (M+Na) : 191.1043; found: 191.1045.
1.26-1.08 (m, 2H), 1.03 (d, J2 = 6 Hz, 3H); 13C NMR (100 MHz, rel-(4R,4aS,7aS)-7-methyl-1,3,4,4a,5,7a-hexahydrocyclo-
CDCl3) δ 173.62, 68.89, 44.53, 37.43, 34.76, 34.73, 34.54, 33.33, penta[c]pyran-4-yl-4-methyl- benzenesulfonate (23): To the
18.63. HRMS (ESI) m/z calcd for C9H15O2 (M+H)+ : 155.1067; solution of the reduced product (800 mg, 2.45 mmol) in dry
found: 155.1074.
DCM (15 mL) obtained from the borohydride reduction of 13 as
(±) teucriumlactone (4): To a stirred solution of 7-epi- per the already described procedure, was added pyridine (2.97
boschnialactone 3ʹ (50 mg, 0.32 mmol.) in 2.5 mL of dry THF was mL, 36.75 mmol, 15 equiv.) followed by Tf2O (3.3 mL, 19.60
added LiHMDS (1.0 M in THF, 0.7 mL, 0.65 mmol, 2 equiv.) at - mmol, 8 equiv.) at -78 °C. The reaction was further stirred for an
78 °C and the resulting mixture was stirred for 2 h at same additional 1 h at the same temperature. Then after 1 h, K2CO3
temperature. After 2 h, Eschenmoser salt (180 mg, 0.975 mmol, (6.76 g, 49.0 mmol, 20 equiv.) was added and the reaction was
3 equiv.) was added and the reaction was subsequently allowed allowed to warm to rt over 1 h, until complete consumption of
to warm to rt over 10 h until complete consumption of starting starting material and formation of a new spot was indicated by
material and formation of new spot was indicated by TLC the TLC analysis. The reaction was worked up by pouring it into
analysis. The reaction was quenched with sat. aq. NH4Cl solution chilled water followed by extraction with Et2O. The organic
followed by extraction with EtOAc (3 × 15 mL). Drying of the phase was washed with aq. CuSO4, H2O and brine, dried over
organic phase over Na2SO4 and subsequent removal of solvent Na2SO4 and concentrated in vacuum to arrive at a crude residue
under reduced pressure gave a crude residue which was directly which was subjected to SiO2-gel column chromatography using
used in the next step.
hexanes/EtOAc (7:3) as the eluent to arrive at the bicyclic olefin
To the cold solution of crude residue obtained from the 23 (597 mg, 79% yield over 2 steps) as a colorless oil. IR (neat):
above step in 2 mL of DCM:THF (1:1) was added MeI (0.1 mL, νmax 2923, 1597, 1445, 1362, 1175, 1095, 959 cm-1; 1H NMR (400
1.62 mmol, 5 equiv.) at 0 °C and the resulting mixture was MHz, CDCl3) δ 7.79 (d, J = 8 Hz, 2H), 7.34 (d, J = 8 Hz, 2H), 5.31
continued stirring for another 2 h at same temperature. After (br s , 1H), 4.37-4.32 (m, 1H), 3.74-3.65 (m, 3H), 3.33 (dd, J1 = 12
addition of sat. aq. NaHCO3 solution (3 mL) the reaction mixture Hz, J2 = 8 Hz, 1H), 2.59 (br s, 1H), 2.45 ( s, 3H)), 2.38 (ddd, J1 = 13
was allowed to warm to room temperature over 2 h. The Hz, J2 = 6 Hz, J3 = 4 Hz, 1H), 2.28-2.20 (m, 1H), 1.98-1.88 (m, 1H),
reaction was then diluted with water followed by extraction 1.67 (br s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.80, 140.97,
with EtOAc (3 × 15 mL). Drying of the organic phase over Na2SO4 133.78, 129.80 (2C), 127.73 (2C), 124.60, 78.07, 67.73, 66.93,
and subsequent removal of solvent under reduced pressure 46.14, 41.87, 33.50, 21.60, 14.61. HRMS (ESI) m/z calcd for
gave a crude residue which was subjected to SiO2-gel column C16H20NaO4S (M+Na)+ : 331.0975; found: 331.0982.
chromatographic purification using hexanes/EtOAc (8:2) as the rel-(4aR,7aS)-7-methyl-1,4a,5,7a-tetrahydrocyclopenta[c]
eluent to arrive at the synthetic natural product pyran-3(4H)-one (24): To a stirred solution of tosylate 23 (600
teucriumlactone 4 (25 mg, 46% over 2 steps). IR (neat): νmax mg, 1.95 mmol) in tBuOH (5 mL) was added tBuOK (1.09 g, 9.75
1
2953, 1733, 1638, 1460, 1303, 1139, 1083, 935 cm-1; H NMR mmol, 5 equiv.) at rt. The reaction mixture was then allowed to
(400 MHz, CDCl3) δ 6.04 (t, J = 1 Hz, 1H), 5.46 (t, J = 1 Hz, 1H), reflux for 1 h until complete consumption of starting material
4.18 (dd, J1 = 11 Hz, J2 = 4 Hz, 1H), 4.04 (dd, J1 = 11 Hz, J2 = 5 Hz, and formation of a new spot was indicated by the TLC analysis.
1H), 3.14 (dd, J1 = 18 Hz, J2 = 10 Hz, 1H), 2.17−2.04 (m, 1H), The reaction was quenched with sat. aq. NH4Cl solution
1.99−1.80 (m, 3H), 1.48−1.38 (m, 1H), 1.29− 1.16 (m, 1H), 1.08 followed by extraction with EtOAc (3 × 20 mL). Drying of the
(d, J = 6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.40, 140.41, organic phase over Na2SO4 and then removal of solvent under
124.64, 68.23, 45.37, 41.86, 36.86, 34.92, 33.90, 18.90. HRMS reduced pressure gave a crude oily residue which was directly
(ESI) m/z calcd for C10H15O2 (M+H)+ : 167.1067; found: 167.1067. used in the next step.
(±) iridomyrmecin (1): A solution of teucriumlactone 4 (20 mg,
To the cold solution of crude residue obtained from the
°
0.120 mmol.) in MeOH (1.5 mL) was subjected to catalytic above reaction in dry DCM (5 mL) at 0 C, PCC (1.26 g, 5.85
hydrogenation using PtO2 (1.5 mg) under 1 atmosphere H2 mmol, 3 equiv.) was added. The reaction mixture was then
pressure at rt for 12 h until complete consumption of starting allowed to warm to room temperature and stirred for another
material was indicated by TLC analysis. The reaction was worked 2 h until complete consumption of starting material and
up by passing it through a short celite bed followed by washing formation of a new spot was indicated by the TLC analysis. The
of the celite bed with EtOAc. The combined organic phase were reaction was worked up by removing the solvent under reduced
evaporated under vacuum and the resultant crude residue was pressure and then subjecting the resultant residue to SiO2-gel
subjected to SiO2-gel column chromatographic purification column chromatographic purification using hexanes/EtOAc
using hexanes/EtOAc (9:1) as the eluent to arrive at the (7:3) as the eluent to arrive at lactone 24 (159 mg, 54% yield
synthetic natural product iridomyrmecin 1 (15 mg, 74% yield).29 over 2 steps). IR (neat): νmax 2923, 1743, 1632, 1451, 1301, 1239,
1
IR (neat): νmax 2925, 1747, 1639, 1455, 1378, 1107, 985 cm-1; 1H 1142, 1074, 981 cm-1; H NMR (400 MHz, CDCl3) δ 5.42 (br s,
NMR (400 MHz, CDCl3) δ 4.26 (dd, J1 = 12 Hz, J2 = 3 Hz, 1H), 4.18 1H), 4.32 (dd, J1 = 12 Hz, J2 = 4 Hz, 1H), 4.25 (dd J1 = 12 Hz, J2 = 4
(d, J = 12 Hz, 1H), 2.74−2.67 (m, 1H), 2.64-2.55 (m, 1H), Hz, 1H), 3.00-2.91 (m, 2H), 2.76-2.68 (m, 1H), 2.64 (dd, J1 = 15
1.91−1.74 (m, 4H), 1.15 (d, J = 7 Hz, 3H), 1.05 (d, J = 6.0 Hz, 3H), Hz, J2 = 7 Hz, 1H), 2.38 (dd, J1 = 15 Hz, J2 = 4 Hz, 1H), 2.13-2.06
1.11−0.97 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 176.24, 67.90, (m, 1H), 1.69 (d, J = 2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
173.37, 136.72, 126.78, 67.50, 47.37, 39.63, 35.80, 32.70, 14.51.
8 | J. Name., 2012, 00, 1-3
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HRMS (ESI) m/z calcd for C9H13O2 (M+H)+ : 153.0910; found: mmol) in 1 mL THF was added LiHMDS (1.0 M in THF, 0.80 mL,
View Article Online
153.0918.
0.78 mmol, 2 equiv.) at –78 °C and theDrOesI:u1l0t.i1n0g39m/Ci9xOtuBr0e08w55aAs
(±) boschnialactone (3): The lactone 24 (25 mg, 0.164 mmol) in stirred for 4 h at same temperature. After 4 h, MeI (0.12 mL,
EtOH ( 1 mL) was subjected to catalytic hydrogenation using 1.95 mmol, 5 equiv.), HMPA (0.2 mL) dissolved in 1 mL of dry
PtO2 (2 mg) under 1 atmosphere H2 pressure at rt for 5 h until THF were added and the mixture was subsequently stirred at -
complete consumption of starting material was indicated by TLC 78 °C for another 1 h and then allowed to warm to -50 °C and
analysis. The reaction was worked up by passing it through a continued stirring for another 1 h until significant formation of
short celite bed followed by washing of the celite bed with a new spot was indicated by the TLC analysis. The reaction was
EtOAc. The combined organic phase was evaporated under quenched with sat. aq. NH4Cl solution followed by extraction
vacuum and the resultant crude residue was subjected to SiO2- with EtOAc (3 × 10 mL). Drying of the organic phase over Na2SO4
gel column chromatographic purification using hexanes/EtOAc and then removal of solvent under reduced pressure gave a
(9:1) as the eluent to arrive at the synthetic natural product crude residue which was subjected to SiO2-gel column
boschnialactone 3 (18 mg, 70% yield). IR (neat): νmax 2924, 1737, chromatography to access first marginal amount of
1
1641, 1461, 1379, 1241, 1188, 1056, 919 cm-1; H NMR (400 dimethylated product (9 mg, 14%) followed by the predominant
MHz, CDCl3) δ 4.22 (dd, J1 = 12 Hz, J2 = 6 Hz, 1H), 4.12 (dd J1 = 12 monomethylated bicyclic lactone 26 (40 mg, 61% yield and 73%
Hz, J2 = 9 Hz, 1H), 2.64-2.56 (m, 2H), 2.42 (dq, J1 = 9 Hz, J2 = 6 brsm) and then recovery of slightly unreacted 24 (10 mg). IR
1
Hz, 1H), 2.28 (dd, J1 = 17 Hz, J2 = 11 Hz, 1H), 2.20-2.12 (m, 1H), (neat): νmax 2924, 1745, 1640, 1546, 1257 cm-1; H NMR (400
1.94-1.85 (m, 1H), 1.77-1.69 (m, 1H), 1.53-1.47 (m, 1H), 1.35 MHz, CDCl3) δ 5.39 (br s, 1H), 4.40 (dd, J1 = 11 Hz, J2 = 6 Hz, 1H),
(dq, J1 = 12 Hz, J2 = 7 Hz, 1H), 1.03 (d, J = 7 Hz, 3H); 13C NMR 3.93 (t, J = 12 Hz, 1H), 3.02 (br s, 1H), 2.73 (dd, J1 = 16 Hz, J2 = 8
(100 MHz, CDCl3) δ 173.88, 67.52, 39.63, 37.33, 35.06, 34.83, Hz, 1H), 2.44-2.32 (m, 2H), 2.16 (d, J = 17 Hz, 1H), 1.63 (s, 3H),
32.82, 32.79, 14.64. HRMS (ESI) m/z calcd for C9H15O2 (M+H)+ : 1.19 (d, J = 6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.83,
155.1067; found: 155.1074.
rel-(4aR,7aR)-7a-hydroxy-7-methyl-1,4a,5,7a-
136.73, 126.19, 68.77, 48.07, 40.91, 38.92, 38.81, 14.68, 14.03.
HRMS (ESI) m/z calcd for C10H15O2 (M+H)+: 167.1067; found:
tetrahydrocyclopenta [c]pyran-3(4H)-one (25): To a solution of 167.1068.
24 (40 mg, 0.26 mmol) in 2 ml of THF:H2O (3:1) was added (±) scabrol A (6): To a stirred solution of 26 (40 mg, 0.24 mmol)
Hg(OAc)2 (248 mg, 0.78 mmol, 3 equiv.) at rt and then in 2 ml of THF:H2O (3:1) was added Hg(OAc)2 (223 mg, 0.72
subsequently stirred at 80 °C for another 12 h until complete mmol, 3 equiv.) at rt and then subsequently stirred at 80 °C for
consumption of starting material and formation of a new spot another 12 h until complete consumption of starting material
was indicated by TLC analysis. Thereafter, the reaction was and formation of a new spot was indicated by TLC analysis.
cooled to ambient temperature before adding NaBH4 (59 mg, Thereafter, the reaction was cooled to ambient temperature
1.56 mmol, 6 equiv.) and stirred for 15 min. until completion of before adding NaBH4 (54 mg, 1.44 mmol, 6 equiv.) and stirred
the reaction was indicated by TLC analysis. The reaction was for 15 min until completion of the reaction was indicated by TLC
quenched with sat. aq. NH4Cl, diluted with H2O followed by analysis. The reaction was quenched with sat. aq. NH4Cl, diluted
extraction with EtOAc (3 × 10 mL). Drying of the organic phase with H2O followed by extraction with EtOAc (3 × 10 mL). Drying
over Na2SO4 and then removal of solvent under reduced of the organic phase over Na2SO4 and then removal of solvent
pressure gave a crude residue which was subjected to SiO2-gel under reduced pressure gave a crude residue which was
column chromatography to access first 25 (20 mg, 46% yield) as subjected to SiO2-gel column chromatography to access first
colorless oil and then 7-epi-argyol (5ʹ) (13 mg, 30%). Spectral scabrol A, 6 (27 mg, 60% yield) as colorless oil and then 7-epi-
data for 25, IR (neat): νmax 3022, 2923, 1732, 1598, 1360, 1065 scabrol A (6ʹ) (8 mg, 18%). Data for (±) scabrol A, 6: IR (neat):
1
cm-1; 1H NMR (400 MHz, CDCl3) δ 5.64-5.62 (m, 1H), 3.98 (d, J = νmax 3437, 2966, 1726, 1380, 1250, 1176 cm-1; H NMR (400
12 Hz, 1H), 3.54 (d, J = 12 Hz, 1H), 3.12-3.05 (m, 1H), 2.95 (dd, J1 MHz, CDCl3) 4.42 (t, J = 12 Hz, 1H), 4.33 (dd, J1 = 12 Hz, J2 = 7 Hz,
= 18 Hz, J2 = 10 Hz, 1H), 2.73-2.64 (m, 1H), 2.35 (dd, J1 = 18 Hz, 1H), 2.48 (dq, J1 = 11 Hz, J2 = 7 Hz, 1H), 2.29 (td, 3.93 (t, J1 = 11
J2 = 6 Hz, 1H), 2.15 (ddd, J1 = 17 Hz, J2 = 4 Hz, J3 = 2 Hz, 1H), 1.74 Hz, J2 = 7 Hz, 1H), 2.08-1.94 (m, 2H), 1.83-1.78 (m, 1H), 1.73-
(dd, J1 = 4 Hz, J2 = 2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 1.67 (m, 2H), 1.37 (s, 3H), 1.18 (d, J = 6 Hz, 3H); 13C NMR (100
177.12, 137.55, 130.34, 100.78, 64.08, 37.86, 37.67, 37.52, MHz, CDCl3) δ 176.63, 79.58, 65.77, 46.70, 42.56, 42.46, 38.98,
12.42. HRMS (ESI) m/z calcd for C9H12O3Na (M+Na)+ : 191.0679; 30.08, 27.73, 13.58. HRMS (ESI) m/z calcd for C10H17O3 (M+H)+:
found: 191.0667.
185.1172; found: 185.1173.
(±)7-epi-argyol (5ʹ): IR (neat): νmax 2924, 1730, 1546, 1198, 965 (±) 7-epi-scabrol A (6ʹ): IR (neat): νmax 3421, 2972, 1726, 1641,
cm-1; 1H NMR (400 MHz, CDCl3) δ 4.47 (dd, J1 = 12 Hz, J2 = 8 Hz, 1179, 1056 cm-1; 1H NMR (400 MHz, CDCl3) 4.27 (dd, J1 = 11 Hz,
1H), 4.32 (dd, J1 = 12 Hz, J2 = 6 Hz,, 1H), 2.66-2.52 (m, 2H), 2.48 J2 = 6 Hz, 1H), 3.86 (t, J = 12 Hz, 1H), 2.41-2.25 (m, 4H), 1.76-
– 2.42 (m, 1H), 2.26 – 2.20 (m, 1H), 2.02 – 1.94 (m, 1H), 1.83 – 1.72 (m, 2H), 1.59-1.53 (m, 2H), 1.28 (s, 3H), 1.24 (d, 6 Hz, 3H);
1.77 (m, 1H), 1.72 – 1.56 (m, 2H), 1.37 (s, 3H); 13C NMR (100 13C NMR (100 MHz, CDCl3) δ 175.58, 80.54, 66.75, 49.16, 41.69,
MHz, CDCl3) δ 173.68, 79.92, 66.56, 46.03, 41.91, 35.17, 34.92, 39.11, 37.71, 29.79, 23.61, 14.34. HRMS (ESI) m/z calcd for
30.79, 28.00. HRMS (ESI) m/z calcd for C9H15O3 (M+H)+: C10H17O3 (M+H)+: 185.1172; found: 185.1174.
171.1016; found: 171.1017.
rel-(1aS,1bR,5R,5aS,6aS)-1a,5-dimethylhexahydrooxireno-
rel-(4R,4aS,7aS)-4,7-dimethyl-1,4a,5,7a-tetrahydrocyclopenta [2',3':4,5]cyclopenta[1,2-c] pyran-4(1aH)-one (27): To a stirred
[c] pyran-3(4H)-one (26): To a solution of 24 (60 mg, 0.39 solution of 26 (60 mg, 0.36 mmol) in dry DCM (4 mL) was added
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mCPBA (86 mg, 0.5 mmol, 1.4 equiv.) at 0 °C and stirred for 4 h solvent under reduced pressure gave a crude oily residue which
View Article Online
DOI: 10.1039/C9OB00855A
until the consumption of starting material and formation of a was directly used in the next step.
new spot was indicated by TLC analysis. The reaction was
To the crude residue from above step in EtOAc (1 mL) was
worked up by quenching it with sat. aq. NaHCO3 followed by added 10% Pd/C (10 mg) and the reaction was allowed to stir at
extraction with DCM (3× 10 mL). Drying of the organic phase rt under H2 balloon pressure for 4 h until complete consumption
over Na2SO4 and then removal of solvent under reduced of starting material was indicated by TLC analysis. The reaction
pressure gave a crude residue which was subjected to SiO2-gel mixture was worked up by filtering it through a short celite bed
column chromatography using hexanes/EtOAc (1:1) as the followed by washing of the celite bed with EtOAc (4 × 5 mL). The
eluent to access first the α-epoxide 27 (36 mg, 55% yield) as the combined organic phase were evaporated under reduced
predominant product and β-epoxide 28 (20 mg, 31% yield) as pressure to arrive at a crude residue which was subjected to
the minor product. Data for 27: IR (neat): νmax 2971, 1732, 1456, SiO2-gel column chromatography using hexanes/EtOAc (19:1) as
1384, 1167, 1017 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.51 (dd, J1 the eluent to access pure 29 (33 mg, 62% yield over 2 steps) as
= 11 Hz, J2 = 7 Hz, 1H), 4.36 (t, J = 11 Hz, 1H), 3.43 (d, J = 1 Hz, colorless oil. IR (neat): νmax 2942, 2866, 1463, 1383, 1147, 883
1H), 2.66 (ddd, J1 = 11 Hz, J2 = 10 Hz, J3 = 7 Hz, 1H), 2.56 – 2.42 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.40 (dd, J1 = 10 Hz, J2 = 5 Hz,
(m, 1H), 2.23 – 2.07 (m, 2H), 1.97 (d, J = 13.3 Hz, 1H), 1.41 (s, 1H), 3.82-3.76 (m, 2H), 3.65 (dd, J1 = 12 Hz, J2 = 4 Hz, 1H), 3.33
3H), 1.13 (d, J = 7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 176.26, (td, J1 = 11 Hz, J2 = 3 Hz, 1H), 2.22 – 2.13 (m, 1H), 2.09-1.99 (m,
67.66, 67.05, 65.51, 41.77, 41.52, 39.01, 31.56, 16.59, 13.33. 1H), 1.80-1.77 (m, 2H), 1.65 (ddd, J1 = 10 Hz, J2 = 6 Hz, J3 = 3 Hz,
HRMS (ESI) m/z calcd for C10H15O3 (M+H)+ : 183.1016; found: 1H), 1.54 – 1.46 (m, 1H), 1.41 – 1.29 (m, 1H), 1.08 (br s, 21H),
183.1017.
0.99 (d, J = 7 Hz, 3H).; 13C NMR (100 MHz, CDCl3) δ 74.84, 67.31,
rel-(1aR,1bR,5R,5aS,6aR)-1a,5-dimethylhexahydrooxireno
67.01, 43.82, 42.75, 38.38, 33.49, 29.90, 18.14 (3C), 18.09 (3C),
[2',3':4,5] cyclopenta[1,2-c] pyran-4(1aH)-one ((28) : Minor 12.97, 12.40 (3C). HRMS (ESI) m/z calcd for C18H37O2Si (M+H)+ :
product of epoxidation on 26. IR (neat): νmax 2984, 1732, 1456, 313.2557; found: 313.2558.
1385, 1261, 1044 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.30 (dd, J1 rel-(4aS,6S,7R,7aS)-7-methyloctahydrocyclopenta[c]pyran-6-
= 11 Hz, J2 = 5.0 Hz, 1H), 4.06 (dd, J1 = 12 Hz, J2 =11 Hz, 1H), ol (31): To a stirred solution of 309 (250 mg, 1.05 mmol) in dry
3.41 (s, 1H), 2.61-2.57 (m, 1H), 2.55 (dd, J1 = 14 Hz, J2 =8 Hz, EtOAc (3 mL) was added 10% Pd/C (50 mg). The mixture was
1H), 2.28 (dq, J1 = 10 Hz, J2 = 7 Hz, 1H), 2.00 (dt, J1 = 18, J2 =9 then allowed to stir at rt under H2 balloon pressure for 3 h until
Hz, 1H), 1.63 (ddd, J1 = 14 Hz, J2 = 7 Hz, J3 = 1 Hz, 1H), 1.40 (s, complete consumption of starting material was indicated by TLC
3H), 1.20 (d, J = 7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 174.77, analysis. The reaction mixture was worked up by filtering it
65.90 , 64.77, 64.54, 43.51, 39.56, 39.50, 35.85, 15.31, 14.39. through a short celite bed followed by washing of the celite bed
HRMS (ESI) m/z calcd for C10H15O3 (M+H)+ : 183.1016; found: with EtOAc (4 × 5 mL). The combined organic phase were
183.1016.
evaporated under reduced pressure to arrive at a crude residue
(±) patriscabrol (7): To a stirred solution of epoxide 28 (15 mg, directly used in the next step.
0.08 mmol) in 2 mL of THF was added 2.5 mL of 1.5 M H2SO4 at
To the solution of crude residue resulting from the above
0 °C and the reaction was allowed to warm to rt over 2 h. On step in 2.5 mL MeOH was added NaBH4 (40 mg, 1.05 mmol) at 0
completion of the reaction, it was quenched with sat. aq. °C. The mixture was then allowed to stir at rt for 1 h until
NaHCO3 followed by extraction with EtOAc (3× 10 mL). Drying of complete consumption of starting material was indicated by TLC
the organic phase over Na2SO4 and then removal of solvent analysis. The reaction mixture was quenched with H2O followed
under reduced pressure gave a crude residue which was by extraction with EtOAc (3 × 10 mL). Drying of the organic
subjected to SiO2-gel column chromatography using phase over Na2SO4 and then removal of solvent under reduced
hexanes/EtOAc (1:2) to access synthetic patriscabrol, 7 (16 mg, pressure gave a crude residue which was subjected to SiO2-gel
73%) IR (neat): νmax 2986, 1721, 1461, 1384, 1256, 1183, 1039 column chromatography using hexanes/EtOAc (1: 1) as the
cm-1; 1H NMR (400 MHz, CDCl3) δ 4.43 (t, J = 12 Hz, 1H), 4.36 eluent to access the pure alcohol 31 (136 mg, 83% yield over 2
(dd, J1 = 12 Hz, J2 = 7 Hz, 1H), 3.98 (t, J = 4 Hz, 1H), 2.60 – 2.39 steps) as colourless oil. IR (neat): νmax 3442, 2924, 1455, 1210,
1
(m, 2H), 2.28 – 2.14 (m, 1H), 1.98-1.95 (m, 2H), 1.37 (s, 3H), 1.18 1108, 913, 745 cm-1; H NMR (400 MHz, CDCl3) δ 3.90 – 3.84 (m,
(d, J = 6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ176.71 , 81.21 , 2H), 3.81 (dd, J1 = 12, J2 = 3 Hz, 1H), 3.63 (dd, J1 = 12, J2 = 4 Hz,
80.66, 65.61, 44.04, 39.53, 38.96, 37.68, 22.35, 13.60. HRMS 1H), 3.41 (td, J1 = 11 Hz, J2 = 3 Hz, 1H), 2.28 – 2.20 (m, 1H), 2.14-
(ESI) m/z calcd for C10H17O4 (M+H)+ : 201.1121; found: 201.1123. 2.05 (m, 1H), 2.03-1.96 (m, 1H), 1.77 – 1.58 (m, 3H), 1.45-1.38
rel-triisopropyl((4aS,6R,7R,7aS)-7-methyloctahydrocyclo-
(m, 2H), 1.08 (d, J = 7 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 80.78,
penta[c]pyran-6-yl)oxy)silane (29): To a stirred solution of 67.14, 66.79, 45.10, 42.04, 40.00, 33.96, 29.88, 16.67. HRMS
t
tosylate 20 (80 mg, 0.16 mmol.) in BuOH (2 mL) was added (ESI) m/z calcd for C9H17O2 (M+H)+ : 157.1223; found: 157.1229.
tBuOK (90 mg, 0.80 mmol, 5 equiv.) at rt. The reaction mixture rel-(4aS,6R,7R,7aS)-7-methyloctahydrocyclopenta[c]pyran-6-
was then allowed to reflux for 1 h until complete consumption yl 4-nitrobenzoate (32): To an ice cold solution of DIAD (0.5 mL,
of starting material and formation of a new spot was indicated 2.56 mmol, 4 equiv.) at 0 °C in dry THF (2 mL), PPh3 (1.34 g, 5.12
by the TLC analysis. The reaction was quenched with sat. aq. mmol, 8 equiv.) was added and allowed to stir for 10 min.,
NH4Cl solution followed by extraction with Et2O (3 × 10 mL). thereafter a solution of alcohol 31 (100 mg, 0.64 mmol) in dry
Drying of the organic phase over Na2SO4 and then removal of THF (2 mL) was added at same temperature. Subsequently,
after another 10 min. p-nitrobenzoic acid (2.13 g, 12.80 mmol,
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20 equiv.) was added and the mixture was allowed to warm to 2928, 1275, 1260, 1107, 1039, 977 cm-1; H NMR (400 MHz,
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DOI: 10.1039/C9OB00855A
rt and continued stirring for another 8 h until complete CDCl3) δ 4.29-4.25 (m, 1H), 3.85 – 3.80 (m, 2H), 3.68 (dd, J1 = 12
consumption of starting material and formation of a new spot Hz, J2 = 4 Hz, 1H), 3.33 (td, J1 = 11 Hz, J2 = 2 Hz, 1H), 2.26 – 2.17
was indicated by the TLC analysis. The reaction was quenched (m, 1H), 2.15 – 2.04 (m, 1H), 1.85 (ddd, J1 = 14 Hz, J2 = 6 Hz, J3 =
with sat. aq. NH4Cl solution followed by extraction with EtOAc 3 Hz, 1H), 1.77 (ddd, J1 = 14 Hz, J2 = 8 Hz, J3 = 3.0 Hz, 1H), 1.65 –
(3 × 15 mL). Drying of the organic phase over Na2SO4 and then 1.59 (m, 1H), 1.56 – 1.49 (m, 1H), 1.43 – 1.32 (m, 2H), 1.01 (d, J
solvent removal under reduced pressure gave a solid residue = 7 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 74.65, 67.24, 66.86,
which was subjected to SiO2-gel column chromatography using 43.13, 41.54, 37.58, 33.83, 30.16, 11.70. HRMS (ESI) m/z calcd
hexanes/EtOAc (8:2) as the eluent to access the p- for C9H17O2 (M+H)+ : 157.1223; found: 157.1227.
nitrobenzoate derivative 32 (146 mg, 75% yield) as white solid.
IR (neat): νmax 2954, 1720, 1606, 1527, 1348, 1275, 1103, 937,
764 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 9.0 Hz, 2H),
8.18 (d, J = 9.0 Hz, 2H), 5.56 (td, J1 = 6 Hz , J2 = 3 Hz, 1H), 3.90-
3.85 (m, 2H), 3.71 (dd, J1 = 12 Hz , J2 = 4 Hz, 1H), 3.37 (td, J1 = 12
Hz, J2 = 2 Hz, 1H), 2.48 – 2.38 (m, 1H), 2.35 – 2.27 (m, 1H), 2.08
(ddd, J1 = 15 Hz, J2 = 7 Hz, J3 = 3 Hz, 1H), 1.96 (ddd, J1 = 15 Hz, J2
= 8 Hz, J3 = 3 Hz, 1H), 1.78 – 1.73 (m, 1H), 1.63 – 1.57 (m, 1H),
1.46 (dtd, J1 = 14 Hz, J2 = 11 Hz, J3 = 4 Hz, 1H), 1.05 (d, J = 7 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ 164.23, 150.48, 136.08, 130.57
(2C), 123.54 (2C), 79.27, 67.15, 66.50, 44.32, 39.26, 36.62,
34.04, 29.75, 12.26. HRMS (ESI) m/z calcd for C16H20NO5 (M+H)+
: 306.1336; found: 306.1342.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
T. K. gratefully acknowledges the financial support from the
Science and Engineering Research Board (SERB), DST, India
(Sanction No. EMR/2014/000826) towards the iridoid project as
well as the Council of Scientific and Industrial Research (CSIR),
India (Sanction No. 02(0320)/17/EMR-II) for funding the lab.
A.S. and D. K. are thankful to SERB, DST and CSIR for JRF and SRF
respectively. All the authors also thank IIT Bhubaneswar for the
financial and infrastructural support.
rel-(4aS,6R,7R,7aS)-7-methyloctahydrocyclopenta[c]pyran-6-
ol [Proposed structure of scholarein A] (9) via 29: To a stirred
solution of 29 (33 mg, 0.11 mmol) in THF (1 mL), 10% HCl (1 mL)
was added at rt and the reaction was allowed to stir for 12 h
until complete consumption of starting material and formation
of a new spot was indicated by the TLC analysis. The reaction
was worked up by quenching it with sat. aq. NaHCO3 solution
followed by extraction with EtOAc (3 × 10 mL). Drying of the
organic phase over Na2SO4 and then removal of solvent under
reduced pressure gave an oily residue which was subjected to
SiO2-gel column chromatography using hexanes/EtOAc (7: 3) as
the eluent to access the synthetic version of proposed
scholarein A (13 mg, 80%) as colourless oil. IR (neat): νmax 3454,
Notes and references
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1
2928, 1275, 1260, 1107, 1039, 977 cm-1; H NMR (400 MHz,
CDCl3) δ 4.29-4.25 (m, 1H), 3.85 – 3.80 (m, 2H), 3.68 (dd, J1 = 12
Hz, J2 = 4 Hz, 1H), 3.33 (td, J1 = 11 Hz, J2 = 2 Hz, 1H), 2.26 – 2.17
(m, 1H), 2.15 – 2.04 (m, 1H), 1.85 (ddd, J1 = 14 Hz, J2 = 6 Hz, J3 =
3 Hz, 1H), 1.77 (ddd, J1 = 14 Hz, J2 = 8 Hz, J3 = 3.0 Hz, 1H), 1.65 –
1.59 (m, 1H), 1.56 – 1.49 (m, 1H), 1.43 – 1.32 (m, 2H), 1.01 (d, J
= 7 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 74.65, 67.24, 66.86,
43.13, 41.54, 37.58, 33.83, 30.16, 11.70. HRMS (ESI) m/z calcd
for C9H17O2 (M+H)+ : 157.1223; found: 157.1227.
rel-(4aS,6R,7R,7aS)-7-methyloctahydrocyclopenta[c]pyran-6-
ol [Proposed structure of scholarein A] (9) via 32: To a stirred
solution of p-nitrobenzoate derivative 32 (100 mg, 0.33 mmol)
in MeOH (2 mL) was added K2CO3 (228 mg, 1.65 mmol, 5 equiv.)
and the mixture was allowed to stir at rt for 1 h until complete
consumption of starting material was indicated by TLC analysis.
The reaction was quenched with sat. aq. NH4Cl solution
followed by extraction with EtOAc (3 × 15 mL). Drying of the
organic phase over Na2SO4 and then removal of solvent under
reduced pressure gave an oily residue which was subjected to
SiO2-gel column chromatography using hexanes/EtOAc (7: 3) as
the eluent to access the synthetic version of proposed
scholarein A (46 mg, 90%) as colourless oil. IR (neat): νmax 3454,
4
5
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a) For a synthetic review on iridoids please refer: A. Nangia, G.
Prasuna, B. Rao, Tetrahedron, 1997, 53, 14507-45 and ref.
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Organic & Biomolecular Chemistry
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ARTICLE
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24 CCDC 1898028 contain the crystallographic information for
the crystal 32. This data can be obtained free of charge from
the Cambridge Crystallographic Data Centre by emailing at
deposit@ccdc.cam.ac.uk or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
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of NMR spectral data of the natural scholarein A remains
unanswered since 05th Aug. 2018.
28 D. L. F. Armarego, D. D. Perrin, Purification of Laboratory
chemicals, IV Ed., 1996, pp. 110-349.
12 | J. Name., 2012, 00, 1-3
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Page 13 of 13
Organic & Biomolecular Chemistry
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DOI: 10.1039/C9OB00855A
Total Syntheses of several Iridolactones and the Putative Structure of Noriridoid Scholarein A: An
Intramolecular Pauson-Khand Reaction based One-stop Synthetic Solution
Abdus Salam, Sayan Ray, Md. Abu Zaid Dileep Kumar and Tabrez Khan*
Me
H
O
HO
HO
O
H
H
H
H
H
Me
patriscabrol
O
O
HO
O
O
HO
Me
Me
7-epi-argyol
isoboonein
Me
H
H
H
O
O
O
O
OR
H
HO
Me
Me
scabrol A
boschnialactone
O
C
O
Me
H
H
O
O
O
O
H
Me
HO
H
Me
7-epi-boschnialactone
7-epi-scabrol A
H
H
H
H
O
HO
Me
H
O
O
O
Me
Me
teucriumlactone
scholarein A
O
H
Me
iridomyrmecin
A general synthetic strategy featuring a diastereoslective intramolecular Pauson-Khand reaction
(IPKR) to construct the iridoid framework followed by some strategic synthetic manipulations to access
ten iridoids in a stereocontrolled manner is delineated.