An approach toward the total synthesis of subergorgic acid

Article abstract of DOI:10.1016/j.tet.2008.04.005

Ireland-Claisen rearrangement of a substituted alkenyl cyclopentanecarboxylate provided a monocyclic isomer containing the proper stereochemistry for four of the five stereogenic centers in subergorgic acid. Efforts to construct the additional rings in the molecule were thwarted as a result of steric and other factors. The results provide insights regarding the Ireland-Claisen rearrangement in five-membered ring systems. The formation of spiro-compounds from sterically and stereoelectronically demanding systems as reported herein has the potential to serve as a general strategy for the synthesis of such sub-units in both natural and unnatural products.

Full text of DOI:10.1016/j.tet.2008.04.005

Tetrahedron 64 (2008) 5482–5490
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An approach toward the total synthesis of subergorgic acid
,
John C. Gilbert y, Jiandong Yin z
*
Department of Chemistry and Biochemistry, 1 University Station MC A5300, The University of Texas at Austin, Austin, TX 78712, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Ireland–Claisen rearrangement of a substituted alkenyl cyclopentanecarboxylate provided a monocyclic
isomer containing the proper stereochemistry for four of the five stereogenic centers in subergorgic acid.
Efforts to construct the additional rings in the molecule were thwarted as a result of steric and other
factors. The results provide insights regarding the Ireland–Claisen rearrangement in five-membered ring
systems. The formation of spiro-compounds from sterically and stereoelectronically demanding systems
as reported herein has the potential to serve as a general strategy for the synthesis of such sub-units in
both natural and unnatural products.
Received 15 February 2008
Received in revised form 31 March 2008
Accepted 1 April 2008
Available online 8 April 2008
Dedicated to Professor William von E.
Doering on the occasion of his 90th birthday
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Subergorgic acid
Ireland–Claisen rearrangement
Facial selectivity
Diastereoselectivity
1. Introduction1
A major challenge in synthesizing subergorgic acid lies in de-
fining the relative stereochemistry of its three methyl groups, which
Over the past 35 years, organic chemists have been interested in
developing synthetic methodologies for the rapid and efficient acqui-
sition of triquinane natural products.2 More than 80 such compounds
from sources including plants, marine organisms, and microbes have
been reported.3 Many have beenpopular targets for total synthesis. The
high level of interest in their synthesis is also attributable to the con-
tinuing disclosure of many new and unusual assemblies of the rings
and the significant biological activities of this class of compounds.
Subergorgic acid (1) is a member of the angular triquinanes.
Initially isolated from the gorgonian coral Subergorgia suberosa,4,5 it
is believed to be the first terpene having the triquinane framework
to be obtained from marine sources.4 Its structure was assigned
using spectral, chemical, and X-ray crystallographic methods.5
sets it apart relative to the other known angular triquinane ses-
quiterpenes.6 To date, five studies directed toward the total syn-
thesis of subergorgic acid6 and four successful total syntheses have
been reported, with two of the latter being of the racemic7 and two
of the enantioselective category.8 In our approach, we envisioned
that a single Ireland–Claisen rearrangement9 could be profitably
applied to establish the critical cis relationship of the two methyl
substituents at C8 and C11, as portrayed in the retrosynthetic
analysis for a stereoselective approach to 1 shown in Scheme 1.
CO2CH3
CO2CH3
CH3
CO2H
CH3
CH3
O
O
H3C
A
O
H3C
A
H3C
A
14
CO2H
B
C
B
B
C
OH
15
10
CH3
H
2
11
9
13
H3C
H
1
CH3
O
2
A
1
3
8
3
B
C
4
5
6
CO2CH3
O
12
CH3
H3C
H3C
CO2CH3
CH3
CO2CH3
1
CH3
H3C
O
O
O
H3C
B
B
C
OH
* Corresponding author. Tel.: þ1 4085544780; fax: þ1 8665729825.
E-mail address: jgilbert@scu.edu (J.C. Gilbert).
B
H
4
y
Current address: Department of Chemistry, Santa Clara University, Santa Clara,
5
6
CA 95053, USA.
z
Scheme 1.
Current address: Tyger Scientific Inc., 324 Stokes Avenue, Ewing, NJ 08638, USA.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.005

J.C. Gilbert, J. Yin / Tetrahedron 64 (2008) 5482–5490
5483
O
CH2
O
H3C
HO
CH2
OCH3
H3C
CH2OR
OCH3
CH2OC
OCH3
9
NO2
H3C
i
ii
iii
OCH3
O
O
O
10: R =H
11: R = TIPS
8
iv
vi
v
H3C
H3C
O
O
CH2OR1
CH2OR2
H3C
CH2OC
H3C
12
CH3
H3C
CH2OC
CH3
H3C
vii
ix
O
H3C
H3CO
RO
viii
(Z)-7: R1 = TIPS, R2 = H
(E)-7: R1 = H, R2 = TIPS
13: R = H
14: R = TIPS
Scheme 2. Reagents: (i) CH3CHO, DABCO, 90%; (ii) PPh3, DEAD, p-nitrobenzoic acid, THF, ꢀ42 ꢁC, 86%; (iii) K2CO3, MeOH, THF, 82%; (iv) TIPSOTf, 2,6-lutidine, CH2Cl2, 80%; (v) DIBAL-
H, CH2Cl2, ꢀ23 ꢁC; H2O, 92%; (vi) PPh3, DEAD, mesitoic acid, THF, ꢀ42 ꢁC, 75%; (vii) DIBAL-H, CH2Cl2, ꢀ23 ꢁC; H2O, 92%; (viii) TIPSOTf, 2,6-lutidine, CH2Cl2, 91%; (ix) MeLi, Et2O,
ꢀ78 ꢁC, 96%.
Subergorgic acid can potentially be derived from the precursor 2
through a stereocontrolled Michael addition of a methyl group fol-
lowed by hydrolysis of the methyl ester. Ring C in 2 could be con-
structed from 3 via Dreiding’s method,10 i.e., transforming the
(Z)- and (E)-7, which were synthesized using conditions analogous
to those established for similar compounds.15 Methyl acrylate was
first transformed to hydroxyester 8 (Scheme 2),16 which afforded
9 via the modified Mitsunobu reaction17 and transesterification
gave 10. Protecting the hydroxyl group using triisopropylsilyl
trifluoromethanesulfonate (TIPSOTf)18 furnished 11, which was
reduced to diol (Z)-7.19 The overall yield was 47%.
For various reasons (vide infra), synthesis of (E)-7 was also
required and was accomplished using conditions similar to those of
Charrette and Cote.15 Analogous to the formation of 9, an SN20
reaction between 8 and mesitoic acid was used to form 12, which
was transformed to 14 by chemoselective reduction of 12 to 1319
and silylation;18 cleavage of the mesitoate function afforded (E)-7.20
The overall yield was 54%.
carboxylic acid function into an a-alkynone, followed by flash vac-
uum pyrolysis (FVP) to form an alkylidenecarbene, which would
undergo 1,5-C–H insertion leading specifically to the cyclo-
pentenone ring. Ring A in 3 could be constructed from 5 through
ozonolysis of the alkene to form a ketone, followed by a C–H
insertion of the alkylidenecarbene intermediate, which could be
generated from the ketone via a previously reported strategy.11 The
acid 5 should be available from the Ireland–Claisen rearrangement
reaction of 6. This key step was expected to provide the
proper relative stereochemistry at C1, C8, and C11, based on the
Ireland–Claisen rearrangement of crotyl or prenyl 2-methyl-
cyclopentanecarboxylates as reported by Gilbert et al.12 Alterna-
tively, the sequence for the construction of rings A and C could be
reversed, i.e., ring C in 4 could be formed before the formation of ring
A in 2.
Our approach, if successful, would give 1 by means of a novel
and efficient strategy that potentially features high facial selectivity
and diastereoselectivity and is more straightforward than previous
approaches. Moreover, we envisioned that this diastereoselective
total synthesis could readily be turned to an asymmetric total
synthesis. This could be accomplished by starting with the desired
enantiomer of 6 prepared from esterification involving the appro-
priate allylic alcohol and enantiomer of the carboxylic acid.
2-Methylcyclopentanecarboxylic acid (15),x the carboxylic acid
component of ester (Z)-16a, was prepared as a mixture from
2-methyl-1-cyclopentene-1-carboxylic acid21 by the Freifelder
method (Scheme 3).22 The acids were transformed to their acid
chlorides,24 which were esterified with (Z)-7 to produce a 1:1.5
mixture of (Z)-16a.25 Separating the isomers was unnecessary
because the stereochemistry at C1 of the ring is destroyed upon
forming the ester enolate.
Subjecting esters (Z)-16a to the modified26 Ireland–Claisen
rearrangement provided diastereomers 18a, 18b,{ and 18c in a ratio
of 4.3:4.5:1 in 78% yield (Scheme 3). This result was encouraging
because the reaction provided a high facial selectivity of 8.8:1, the
ratio of 18ab:18c, in favor of the desired cis relationship between
the methyl group of the ring and the carboxylic acid function. The
facial selectivity in this rearrangement confirmed the previous
supposition that the methyl substituent on the ring is sufficiently
sterically demanding to bias the transfer of the allylic fragment of
ketene silylacetal 17 to the re-face.12
2. Results and discussion
An earlier model study showed that presence of the methoxy-
carbonyl group in ester (E)-6 fostered fragmentation rather than
rearrangement under the conditions of the Ireland–Claisen re-
action.13 To circumvent this, we planned to prepare an analog of (E)-
6 in which a protected alcohol would serve as a surrogate for the
methoxycarbonyl group. It was also of interest to investigate
whether the facial or diastereoselectivity would be affected by the
substituents on the double bond. There were prior instances where
both yield and diastereoselectivity of Ireland–Claisen rearrange-
ments were strongly dependent on the protecting groups for the
hydroxymethyl moiety.14 Therefore, steric factors associated with
the alkene might play an important role on the diastereoselectivity
of the rearrangement.
Assigning the relative configuration in 18a initially involved
500 MHz NMR spectroscopic techniques, viz., 1H–1H COSY, 13C–1H
x
Carboxylic acid 15 obtained by hydrogenation was a mixture of trans- and cis-
isomer in a 1:1.5 ratio. When the reaction was repeated, a 1:1 mixture of isomers
was observed. A previous preparation by our group afforded a 2:1 mixture of the
trans- and cis-isomer. To account for these variations, we found that the ratio of the
isomeric carboxylic acids was dependent on the conditions of hydrogenation,
a phenomenon that has been observed in the hydrogenation of other systems.23
{
Crystallographic data for the structures in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supplementary publication nos.
CCDC 675696–675699. Copies of the data can be obtained, free of charge, on ap-
plication to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: þ44 (0) 1223
336033 or e-mail: deposit@ccdc.cam.ac.uk].
Experimentally, the reduction of the methoxycarbonyl group in
(E)-6 was conducted before the esterification of allylic alcohols

5484
J.C. Gilbert, J. Yin / Tetrahedron 64 (2008) 5482–5490
H2C
R
H2C
R
R
R
H2C
OTMS
O
R
R
R
O
O
R
O
OTIPS
+
OTIPS
+
OTIPS
R
R
H
R
H
1'
i
R
ii, iii
iv
OH
O
OH
1
CO2H
CO2H
CO2H
18a
18b
18c/d
OTIPS
OTIPS
R = CH3
15a trans:cis = 1:1.5 (Z)-16a trans:cis = 1:1.5 (E,Z)- or (Z,Z)-17
15b trans:cis = 13:1 (Z)-16b trans:cis = 13:1
18a:18b:18c = 4.3:4.5:1.0 78% yield
18a:18b:18d = 1.0:8.0:2.0 99% yield
Scheme 3. Reagents: (i) H2/5% Pd(C)/NaOH/H2O/EtOH/rt, 96 h, 94%; (ii) (COCl)2, C6H6, DMF, rt, 3 h, 94%; (iii) (Z)-7, Py, rt, 16 h, 95% (two steps); (iv) LDA, TMSCl, TEA, THF, ꢀ78 ꢁC;
ꢀ78 ꢁC to rt, 24 h; satd NH4Cl, 3 h, 99%.
COSY, NOESY, and DEPT, and these techniques were applied to 18b
as well. X-ray crystallography of three advanced intermediates
derived from 18a confirmed its relative stereochemistry and that of
crystalline 18b was proven directly by this technique. The stereo-
chemistry of 18c in terms of the relative configuration of the newly
formed C1–C10 bond was not determined.
The drawback of the rearrangement of (Z)-16a is that there is
little diastereoselectivity at the newly formed chiral center C10, the
ratio of 18a and 18b being almost 1:1. Isomer 18a is desired because
it embodies the proper stereochemistry for C1, C8, and C11 of 1.
Moreover, because the stereochemistry of C1 ultimately defines
that of C5, accomplishing a diastereoselective synthesis of 18a
results in stereochemical control for four out of the total of five
asymmetric centers present in 1.
through a chair-like TS would afford the undesired 18b. This
diastereoselectivity is reversed with (E)-16.
Consequently, we proposed to effect the Ireland–Claisen
rearrangement using pure trans- or cis-(Z)-16. The mixture of acids
15 or esters (Z)-16 was inseparable, but the approach of Nenitzescu
and Ionescu29a,b gave 15 as a 13:1 mixture of trans-/cis-isomer.k
Esterifying this mixture with (Z)-7 afforded a 13:1 mixture of
isomers (Z)-16b, rearrangement of which produced 99% yield of
three diastereomers, 18a, 18b, and 18d, in a ratio of 1:8:2 (Scheme
3). The relative stereochemistry of 18d was not determined but was
different from 18c, as shown by 1H NMR spectroscopy.
This result was encouraging because the reasonably high re-
facial selectivity (9:2) was analogous to that observed with (Z)-16a,
where the substrate was a 1:1.5 mixture of two isomers. Ad-
ditionally, the rearrangement of (Z)-16b featured acceptable
diastereoselectivity, given the 1:8 ratio of 18a/18b.
The results of the rearrangements of (Z)-16ab with different
ratios of isomers suggested that the diastereoselectivity of the
overall process was mainly defined by the stereochemistry of
the starting esters, which in turn determines the geometry of the
ketene silylacetals formed from them. This supports our previous
hypothesis that the geometry of the intermediate ketene silyl-
acetals plays a critical role in the diastereochemical outcome of
the rearrangement of esters.12 There was no diastereoselectivity
with (Z)-16a because (E,Z)- and (Z,Z)-17 were formed in nearly
equal quantities; their rearrangements are destined to form 18a
and 18b, respectively, in almost equal amounts (Scheme 4). With
(Z)-16b (trans/cis¼13:1), the diastereoselectivity of 1:8 arises
because (E,Z)-17 is the acetal predominantly formed from the
trans-isomer (vide infra); its rearrangement gives 18b as the major
product.
To circumvent the formation of 18b, we envisioned that
inverting the diastereoselectivity by starting with (E)-16 would
afford (E,E)-17, which would preferentially rearrange to the desired
18a. In a manner analogous to the synthesis of (Z)-16, a 13:1 trans/
cis mixture of (E)-16 was prepared by esterification of (E)-7 with
15b. Subjecting this ester to Ireland–Claisen rearrangement26
gave a mixture comprising only 18a and 18b in a 10:1 ratio
with complete re-facial selectivity and high diastereoselectivity
(Scheme 5).
As postulated by Gilbert et al.,12 the diastereoselectivity associ-
ated with generating the new chiral center C10 can be ascribed to
two factors: the geometry of the intermediate ketene silylacetal 17,
(E,Z) versus (Z,Z), and the actual transition state of the [3,3]-sig-
matropic rearrangement, chair-like versus boat-like. Analogous to
an earlier analysis,12 Scheme 4 portrays the formation of the de-
sired 18a and undesired 18b from the two possible ketene silyl-
acetals. We assume that the ratio of (E,Z)- versus (Z,Z)-17 mirrors
the 1:1.5 ratio of esters (Z)-16a. [3,3]-Sigmatropic rearrangement of
(E,Z)-17 via a chair-like transition state (TS) gives 18b, whereas it
provides the desired 18a via a boat-like TS. The nature of the TSs
is reversed for the formation of these two products through
rearrangement of (Z,Z)-17.
Given that a chair-like TS is preferred in a [3,3]-sigmatropic
rearrangement in the absence of unusual steric constraints, we felt
that the geometry of the ketene silylacetal 17 played a critical role
in the diastereochemical outcome of the rearrangement of (Z)-16a.
In this context, it would be informative if either (E,Z)- or (Z,Z)-17
could be produced preferentially from deprotonation of a pure
trans- or cis-isomer of (Z)-16. Thus, formation of (Z,Z)-17 followed
by rearrangement would form the desired 18a via the favored chair-
like TS (Scheme 4), whereas generating (E,Z)-17 and rearrangement
TIPSOCH2
R
CH2OTIPS
OTMS
TIPSOCH2
R
S
R R
H
CH2
H
O
O
H
R
R
H
H
OTMS
CO2H
18b
(E,Z)-17
Chair
(Z,Z)-17
Boat
Undesired
R = CH3
k
Attempts to prepare the pure trans- or cis-isomer of (Z)-16 directly via esteri-
fication of (Z)-7 with a pure isomer of acid 15 were challenging. Although most
previous preparations of 15 by several different routes gave the trans-isomer as the
major product or a mixture of both isomers in similar amounts,22,27 there were
reports claiming formation of either mainly or pure cis-15.28 There were also re-
ports claiming formation of pure trans-15.29 For practical reasons, we adopted the
method of Nenitzescu and Ionescu, which afforded the 13:1 mixture of the desired
isomer by way of a haloform reaction on the corresponding mixture of isomeric
1-(2-methylcyclopentyl)ethanones (19). Although this route does not provide only
trans-15 as claimed,29a,b the approach is highly stereoselective and more so than the
method reported by Jorgenson et al., who reported that pure trans-15 could be
obtained via selective basic hydrolysis of a trans/cis mixture of ethyl 2-methyl-
cyclopentanecarboxylate;29c this was not the case in our hands.
TIPSOCH2
H
R
OTMS
R
R
CH2
H
R
O
H
O
R
H
R
H
R
CH2
CO2H
18a
TIPSO
OTMS
TIPSOCH2
(Z,Z)-17
Chair
(E,Z)-17
Desired
Boat
Scheme 4.

J.C. Gilbert, J. Yin / Tetrahedron 64 (2008) 5482–5490
5485
importance of these determines the preference for different tran-
sition states in the deprotonation.
CH3
O
CH3
For the trans-ester, SIB in the trans-syn TS (20b) is assumed to be
stronger than SIA in the trans-anti analog 20a, based on Ireland’s
chair-like TS model.30 The kinetic enolization of the trans-ester
occurs mainly through 20a to form (Z)-21, which leads to (E,Z)- or
(E,E)-ketene silylacetal 17. From this point, the identity of the final
products is determined by the rearrangement itself. Whether it
gives the desired 18a or undesired 18b via a chair- or boat-like TS is
solely a matter of the geometry of the allylic fragment of the
starting ester. In another words, the stereochemical outcome after
this stage would be governed by routes as shown in Scheme 4 for
acetals (E,Z)- and (Z,Z)-17. A comparable analysis can be applied to
(E,E)- and (Z,E)-17.
19
R
R
OTMS
O
O
i
O
R
R
TIPSO
(E,E)- or (Z,E)-17
TIPSO
(E)-16
trans:cis = 13:1
R = CH3
For the cis-isomer, SIA in cis-anti TS (20c) is speculated to be
more important than SIB in cis-syn TS (20d). Consequently,
deprotonation of the cis-ester would be expected to proceed largely
via 20d, generating an (E)-enolate that yields (Z)-ketene silylacetal.
The identity of the final products is again defined by the rear-
rangement itself.
OTIPS
H2C
OTIPS
H2C
R
R
R
R
H
H
+
CO2H
CO2H
18a
18b
In summary, the relative importance of SIA versus SIB nicely
rationalizes the diastereoselectivity of the Ireland–Claisen rear-
rangement of (Z)- and (E)-16. With (Z)-16a as a 1:1.5 mixture of
trans- and cis-isomer, enolization proceeds almost equally through
20a and 20d to form the (E)-acetal for the trans-ester and the (Z)-
acetal for the cis-ester, respectively. The two intermediates rear-
range through chair-like/boat-like TSs to afford products 18a and
18b in a 1:1 ratio (Scheme 4).
As for (E)-16 (trans/cis¼13:1), enolization of the trans-ester
occurs mainly through 20a to form (E,E)-17, and predominantly via
20d for the cis-ester to generate (Z,E)-17. The ratio of (E,E)-17/(Z,E)-
17 should be approximately 13:1, so 18a is obtained as the major
diastereomer from (E,E)-17, whereas 18b is furnished as the minor
isomer from (Z,E)-17 (Scheme 4). The decline from 13:1 to 10:1 in
the diastereoselectivity for the rearrangement of (E)-16 might be
18a:18b = 10:1
92% yield
Scheme 5. Reagents: (i) LDA, TMSCl, TEA, THF, ꢀ78 ꢁC; ꢀ78 ꢁC to rt, 24 h; satd NH4Cl,
3 h, 92%.
The diastereoselectivity of forming the ketenesilyl acetals
clearly is a key factor in defining the stereochemical outcome of the
Ireland–Claisen rearrangement of (E)- and (Z)-16. Based on Ire-
land’s model for deprotonation in acyclic systems,30 four types of
chair-like TSs merit consideration for the kinetic enolization step
that leads to the enolates serving as precursors to the acetals
(Scheme 6). There are two competing steric interactions, one being
an alkyl–alkoxy interaction (SIA), i.e., interaction between the ring
methyl group and the alkoxy fragment of the ester (A1,3-in-
teraction), and the other being an interaction between the ring
methyl group and the isopropyl fragment of LDA (SIB). The relative
due to the result of
a combination of three factors: (1)
inhomogeneity of the starting trans-ester; (2) preferred but not
R1
O
R2
O
(E)- or (Z)-16
R1 = CH3
R2 = CH2C(CH2OTIPS)CHCH3
trans-Ester
cis-Ester
trans-anti
cis-anti
cis-syn
OR2
trans-syn
OR2
OR2
OR2
SIA
SIA
SIA
SIA
Li
O
Li
H
Li
O
Li
H
R1
O
O
H
H
R1
i
H
i
i
H
i
H
Pr
H
Pr
Pr
H
H
Pr
N
N
Pr
N
Pr
N
Pr
i
i
i
i
R1
Pr
H
H
H
R1
20d
H
20a
H
20b
H
20c
SIB
SIB
SIB
SIB
Syn/anti refers to relationship
between carbonyl oxygen and
methyl group in the transition
state for deprotonation
R1
R1
R1
R1
OR2
OLi
OR2
OTMS
OR2
OLi
OR2
OTMS
(Z)-21
(E,Z)- or (E,E)-17 (Z,Z)- or (Z,E)-17
(E)-21
Scheme 6.

5486
J.C. Gilbert, J. Yin / Tetrahedron 64 (2008) 5482–5490
exclusive formation of the (E,E)-17; (3) preferred but not exclusive
chair-like TS for (E,E)-17.
OTIPS
OTIPS
H2C
R
H2C
R
The second factor seems to be the most important, however. As
discussed previously, the creation of diastereomeric rearrangement
products was a result of poor selectivity in acetal formation rather
than competition between chair- and boat-like TSs for the rear-
rangement.12 Nevertheless, the diastereoselectivity of the rear-
rangement of (E)-16 was substantially improved compared to that
of the simpler systems,12 though the role of the triisopropylsiloxy-
methyl group in the deprotonation of (E)-16 is not clearly
understood.
With the key intermediate 18a in hand, efforts to construct rings
A and C of 1 were pursued. An immediate problem was encoun-
tered in a model reaction where subjecting 18b to ozonolysis31
resulted in spirolactols 22a{ and 22b rather than ketone 22c, in
a 5.3:1 ratio (Scheme 7). The relative configuration in 22a was
determined by X-ray crystallographic analysis.
i, ii
iii
R
R
R
CO2H
CO2CH3
18a
23
R = CH3
OTIPS
OTIPS
O
OTIPS
R
H
R
iv
R
R
O
R
CO2CH3
CO2CH3
25
O
26
24
v
Scheme 8. Reagents: (i) (COCl)2, C6H6, DMF; (ii) MeOH, Py, 85%; (iii) O3, CH2Cl2,
ꢀ78 ꢁC; Ph3P, ꢀ78 ꢁC to rt, 12 h, 96%; (iv) (EtO)2P(O)CHN2 (DAMP), t-BuOK, THF,
ꢀ78 ꢁC; 24 in THF, ꢀ78 ꢁC to rt, 12 h; (v) TMSCHN2, n-BuLi, THF, ꢀ78 ꢁC, 30 min; 24 in
THF, ꢀ78 ꢁC to rt, 12 h, 50%.
H2C
OTIPS
R
R
R
OH
O
R
R
OTIPS
R
H
i
+
O
CO2H
OH
OTIPS
OTIPS
TMS
N2
R
OTIPS
O
O
N2
O
LiO
C
18b
R = CH3
22a
22b
OTIPS
R
R
R
-
TMSCN2 Li+
CO2CH3
O
-TMSOLi
OTIPS
R
R
R
R
H
CO2CH3
CO2CH3
CO2H
24
R = CH3
27
28
-N2
22c
OTIPS
(Not formed)
TIPSOCH2
R
OTIPS
- Li+
Scheme 7. Reagents: (i) O3, CH2Cl2, ꢀ78 ꢁC; Ph3P, ꢀ78 ꢁC to rt, 91%.
R
R
R
H
R
C
R
OCH3
O
C
O
+
CO2CH3
R
O
CH3
B-
Esterifying the carboxylic acid group circumvented this prob-
lem, as ozonolysis of the methyl ester of 18a afforded ketoester
24 in excellent yield. Attempts to convert 24 to 25 via the Wittig
Horner type reaction32 following known procedures11 were
unsuccessful, providing either recovered ketoester or a mixture of
unidentifiable products; 1H NMR of the mixture gave no evidence
for 25.
29
25
30a
and/or
OTIPS
- Li+
OTIPS
H
OTIPS
- Li+
R
R
H
H
H
BH
O
O
O
+
R
R
R
O
O
O
B-
CH3
Use of (trimethylsilyl)diazomethane (TMSCHN2),33a a more
nucleophilic reagent33b in place of DAMP, caused complete dis-
appearance of 24. However, the isolated product was 26 (Scheme
8), as evidenced by 1H NMR analysis of the purified product,
which showed a pair of methyl doublets but no downfield singlet
for an ester methyl group. Further spectroscopic analyses, viz.,
1H–1H COSY, 13C–1H COSY, NOESY, and DEPT, confirmed this
assignment.
A possible mechanism for forming 26 is provided in Scheme 9.
Nucleophilic attack by the (trimethylsilyl)diazomethane anion on
the carbonyl group of 24 gives 27, which eliminates TMSOLi to
produce 28. Loss of dinitrogen provides carbene 29, which is con-
verted to ylide 30a and/or 30b rather than undergoing C–H in-
sertion to yield the desired 25. Removing the ester methyl group
leaves anion 31, which furnishes 26. The diversion of 29 to 30ab in
principle should be reversible, but the ensuing nucleophilic attack
on 30ab would drive the process irreversibly to 31.
This outcome, although disappointing with regard to our pres-
ent goal, results in the formation of unsaturated spirolactone 26
under extremely mild conditions and represents a novel synthetic
method for preparing such lactones.34 This approach has the po-
tential to serve as a general methodology in organic synthesis if
optimization, which we did not pursue, affords yields higher than
the moderate one obtained.
30b
31
26
Scheme 9.
In the context of the proposed mechanism, lactol formation
might be the consequence of the minimal steric hindrance associ-
ated with nucleophilic attack on the methyl group in ylides 30a and
b. Alternatively, if attack on 29 involves the oxygen atom of the
methoxy group, the minimal steric bulk of this group optimizes the
potential for attacking the carbenic center. Thus, an ester having
a sterically bulkier alkoxy moiety might be less prone to such
intramolecular nucleophilic attack, thereby favoring the desired
C–H insertion.
To test this, a model study was undertaken. As seen in Scheme
10, 32 was synthesized and rearranged to afford cis- and trans-
33ab. The cis relationship of the methyl and carboxylic acid groups
in 33a was assumed based on previous results. tert-Butyldime-
thylsilyl esters 34ab were then produced,35a but their ozonolysis
resulted in the formation of an unidentifiable mixture containing
none of the desired 35ab, despite reports that such esters survive
ozonolysis conditions.35b
The tert-butyl, neopentyl, and isopropyl esters 36 were syn-
thesized and subjected to ozonolysis (Scheme 11). The first two

J.C. Gilbert, J. Yin / Tetrahedron 64 (2008) 5482–5490
OTIPS
5487
CH3
CH3
O
OTIPS
O
H2C
R
H2C
R
i, ii
O
OH
CH3
CH2
i, ii
R
R
CO2H
CO2R1
iii
32
15
36
18a
trans:cis 13:1
trans:cis 13:1
a. R1 = t-butyl, 45%
R = CH3
b. R1 = neopentyl, 28%
c. R1 = isopropyl, 84%
CH3 OTMS
O
H2C
CH3
H2C
CH3
CH3
CH3
[3,3]
iii
+
CH3
CO2H
CO2H
CH2
OTIPS
OTIPS
33b
33a
O
R
R
33a:33b = 5.5:1
A
B
iv
R
R
iv
CO2CHR2
CO2CHR2
38
37
H2C
CH3
H2C
CH3
O
CH3
CH3
CH3
CH3
Scheme 11. Reagents: (i) (COCl)2, C6H6, DMF; (ii) R1OH, Py, rt, 16–20 h, or 120 ꢁC,
20 h, 45%, 28%, 84%, respectively (two steps); (iii) O3, CH2Cl2, ꢀ78 ꢁC; Ph3P, ꢀ78 ꢁC to
v
+
rt, 93%; (iv) TMSCHN2, n-BuLi, THF, ꢀ78 ꢁC; 38 in THF, with or without HMPA, ꢀ78 ꢁ
C
CO2R
35ab
CO2R
CO2R
to rt.
34b
R = (CH3)3CSi(CH3)2
34a
Carbonyl oxide 45 is apparently also attacked by the oxygen atom of
the trimethylsilyl group to give 47, as shown in route b. The silyl
group then migrates to produce 48, silylation–desilylation of which
provides 43a, possibly via 49.
Scheme 10. Reagents: (i) (COCl)2, C6H6, DMF; (ii) 2-methyl-2-propen-1-ol, Py, 71%
(two steps); (iii) LDA, TMSCl, TEA, THF, ꢀ78 ꢁC; ꢀ78 ꢁC to rt; satd NH4Cl, 96%; (iv) C6H6,
TBDMSCl, DBU, 75%; (v) O3, CH2Cl2, ꢀ78 ꢁC; Ph3P, ꢀ78 ꢁC to rt.
Increasing the steric hindrance at the oxygen atom of the silyl
ether group represented a strategy for circumventing this problem,
so triethylsilyl and tert-butyldimethylsilyl ethers 41b and c were
synthesized. However, ozonolysis of 41b resulted in the formation
of a 1:3.1 mixture of 42b and 43b, in which 42b remained the
minor component. This was also true for the tert-butyldime-
thylsilyl ether 41c, although the ratio of 42c/43c increased to 1:2.
Our hypothesis that increasing the steric bulk of substituents on
the silicon atom would suppress spirolactolization appears to
be validated, but this undesired process remains dominant
nonetheless.
Attempts to oxidize the double bond in 41c using osmium
tetroxide and sodium periodate in ether/H2O provided only
recovered starting material (Scheme 12), whereas these reagents
gave a mixture of unidentifiable products in 1,4-dioxane/H2O. Us-
ing non-migratory protecting groups, viz., benzyl and p-methoxy-
benzyl, for the alcohol function in 41 proved fruitless; starting
material was quantitatively recovered each time.
afforded unidentifiable mixtures, but 36c gave ketone 37. Treating
37 with TMSCHN2 anion, either with or without added HMPA, led
to an intractable mixture in which no vinylic proton peaks attrib-
utable to 38 were detected via 1H NMR analysis. This analysis also
excluded the formation of spirolactone 26.
These results prompted exploration of a route to ring A of 1 in
which the offending neopentyl-like carbonyl functional group was
absent. Acid 18a was reduced to form diol 39, which was
monoprotected to give 40 (Scheme 12). To preclude possible cy-
clization problems upon ozonolysis as with 18b, 40 was converted
to silyl ether 41a, ozonolysis of which produced a mixture (1:6.2)
in which the desired 42a was the minor component. The major
isomer was 43a,{ the structure and relative configuration of which
were unambiguously determined by X-ray crystallographic
analysis.
The formation of 42a and 43a is explicable by the accepted
mechanism of ozonolysis.36 As portrayed in Scheme 13, zwitterion
45, derived from 44, reacts with formaldehyde in route a to form
a secondary ozonide 46, which is ultimately reduced to afford 42a.
Modifying the ozonolysis conditions themselves proved suc-
cessful for our purposes. Knowing that 45 could either react with
an aldehyde or a ketone or be trapped by nucleophilic solvents,37
OH
OTIPS
OTIPS
OTIPS
H2C
R
H2C
R
H2C
R
H2C
R
O
OTIPS
R
R
H
OTIPS
ii
i
v
iv
+
R
R
R
R
R
O
CH2OR1
CH2OR1
OR1
CO2H
CH2OH
CH2OH
R
40
41
42
43
18a
R = CH3
39
a. R1 = TMS
b. R1 = TES
93%
91%
a. R1 = H
42:43 = 1.0:6.2 88%
42:43 = 1.0:3.1 85%
b. R1 = TES
iii or vii
No reaction
c. R1 = TBDMS 91%
c. R1 = TBDMS 42:43 = 1.0:2.0 92%
vi
Recovered 41c or
intractable mixture
Scheme 12. Reagents: (i) LiAlH4, Et2O, 45 ꢁC, 96%; (ii) TIPSCl, imidazole, DMF, 85%; (iii) TMSCl, TEA, THF, with or without HMDS and Py; (iv) R1OTf, 2,6-lutidine, CH2Cl2, 93%, 91%,
91%, respectively; (v) O3, CH2Cl2, Py, ꢀ78 ꢁC; Me2S, ꢀ78 ꢁC to 0 ꢁC, 88%, 85%, 92%, respectively; (vi) OsO4, NaIO4, H2O, Et2O or 1,4-dioxane; (vii) KH or NaH, PhCH2Br or
p-MeOC6H4CH2Cl, with or without Bu4NI or HMPA, THF.

5488
J.C. Gilbert, J. Yin / Tetrahedron 64 (2008) 5482–5490
OTIPS
OTIPS
OTIPS
OTIPS
H2C
R
H2C
O
H
R
O
R
R
R
O
O
O3, CH2Cl2
pyr, -78 °C
i
ii or
iii
R
R
R
No reaction
CH2OTMS
CH2OTBDMS
CH2OTBDMS
CH2OTMS
41c
42c
44
41a
R = CH3
R = CH3
iv
-CH2O
OTIPS
TIPSO
R
H
R
R
OTIPS
C:
CH2OTBDMS
50
OTIPS
R1
R2
H
H
R
R
R
R
O
-
O
-
O
O
a
+
b
R
b
+
+
O
TMS
O=CH2
CH2OTMS
CH2
52 (a:b = 2.7:1)
a. R1 = H, R2 = OTBDMS
b. R1 = OTBDMS, R2 = H
47
45
a
OTIPS
R
OTIPS
R
H
OTIPS
OTMS
H
R
R
O
R
O
CH2OTBDMS
51
O
O
O
R
R
H
OTIPS
CH2OTMS
46
Scheme 14. Reagents: (i) O3, CH3CHO, Py, ꢀ78 ꢁC; Me2S, K2CO3, H2O, ꢀ78 ꢁC to 0 ꢁC,
99%; (ii) TMSCHN2, n-BuLi, THF or DME, ꢀ78 ꢁC; 42c in THF or DME, ꢀ78 ꢁC to rt; (iii)
(EtO)2P(O)CHN2, t-BuOK, THF, ꢀ78 ꢁC; 42c in THF, ꢀ78 ꢁC to rt; (iv) TMSCHN2, n-BuLi,
THF, ꢀ78 ꢁC; 42c in THF, HMPA, ꢀ78 ꢁC to rt, 52%.
48
(CH3)2S
O
R
OH
(CH3)2S
OTIPS
43a
R
H
OTIPS
O
as solvent, but was consumed when the reaction was run in a 1:50
mixture of HMPA and THF (step vi or vii in Scheme 15). Un-
fortunately, no vinylic protons were seen in the 1H NMR spectrum of
the crude reaction mixture. The reaction did yield spiroketone 58,{
whose structure was confirmed by X-ray crystallographic analysis.
As expected, the relative configuration of 58 is consistent with
that of 18a and spiro-compounds 26, 43a, and 52. Rationalizing the
formation of 58 could involve TMSCHN2 anion first deprotonating
55 to form 57, followed by intramolecular aldol condensation. An
attempted solution for this problem that involved trapping 57 as its
O
-
R
O
R
+
R
(CH3)3Si OS(CH3)2
CH2OTMS
42a
49
Scheme 13.
added formaldehyde could capture 45 and yield 46, followed by
the normal reduction to afford the desired ketone. As shown in
Scheme 14, ozonolysis of 41c in acetaldehyde instead of
dichloromethane afforded 42c as the sole product and in excellent
yield.
With 42c in hand, construction of ring A of subergorgic acid was
attempted. Subjecting 42c to reaction with TMSCHN2 anion or
DAMP anion in THF gave only recovered starting material (Scheme
14). When treated with a solution of TMSCHN2 anion in HMPA/THF,
42c was consumed but failed to produce 51. Rather, NMR data
suggested formation of a mixture of 52a and b in a 2.7:1 ratio, and
further spectroscopic analysis, viz., 1H–1H COSY, 13C–1H COSY,
NOESY, and DEPT, confirmed the assignments.
The isolation of 52 is consistent with the formation of carbene
50, which selectively inserts into the siloxy C–H bond rather than
the methine C–H bond. This problem seemed solvable by making
the siloxy C–H bond unavailable for carbene insertion. This
strategy could be realized by transforming acid 18a into ketone
53, followed by protection of the ketone moiety as the ethylene
acetal 54 (Scheme 15). In practice, attempts to produce 53
by directly treating 18a with methyllithium in ether or THF
all resulted in recovery of starting material. The inability for
CH3Li to add to 18a and for ethylene glycol to convert 53 to 54
reflects the steric hindrance at the carbonyl function of 18a.
Fortunately, a two-step sequence was successful for the conver-
sion of 18a to 53, ozonolysis of which afforded diketone 55 in
good yield.
OTIPS
OTIPS
R
OTIPS
H2C
R
H2C
R
H2C
R
R
O
ii,iii
iv
R
CO2H
COCH3
R
54
O
18a
53
R = CH3
i
v
OTIPS
OTIPS
R
No reaction
O
R
O
R
viii
R
CH2
COCH3
TBDMSO
59
55
vi or vii
vi or vii
OTIPS
OTIPS
OH
H
OTIPS
R
R R
-
R
H
A
O
B
R
R
COCH3
56
O
58
O
57
Scheme 15. Reagents: (i) MeLi, ether or THF, with or without HMPA, rt or reflux; NH4Cl;
(ii) (COCl)2, C6H6, DMF; (iii) MeLi, THF, ꢀ78 ꢁC to rt, 72% (two steps); (iv) (CH2OH)2, p-TSA,
C6H6, 4 Å molecular sieves, 85 ꢁC; (v) O3, CH2Cl2, ꢀ78 ꢁC; Ph3P, ꢀ78 ꢁC to rt, 86%; (vi)
TMSCHN2, n-BuLi, THF, ꢀ78 ꢁC, 55 in THF, HMPA, ꢀ78 ꢁC to rt, 60%; (vii) (EtO)2P(O)CHN2,
t-BuOK, THF, ꢀ78 ꢁC; 55 in THF, HMPA, ꢀ78 ꢁC to rt, 60%; (viii) various conditions.
Expecting that nucleophilic attack would occur regioselectively
on the less-hindered carbonyl, 55 was treated with TMSCHN2 anion
to produce 56. Starting diketone was recovered when THF was used

J.C. Gilbert, J. Yin / Tetrahedron 64 (2008) 5482–5490
5489
silyl enol ether failed. Experiments using various conditions
resulted in recovery of 55 or formation of 58 and/or unidentifiable
products.
by the oxygen atom of the OTBDMS group in 42c (Scheme 14)
resulted in carbene insertion at that position rather than at the
tertiary C–H bond of the cyclopentane ring to form ring A of 51,
a promising precursor to subergorgic acid.
The general strategy of using a-elimination of vinyl halide to
generate alkylidenecarbenes failed in this case.38 Dibromide 61, the
precursor to the necessary 62, was not formed using a variety of
conditions nor were dibromides 63 and 64.
The recalcitrance toward nucleophilic attack of a carbonyl group
adjacent to a quaternary center and the undesired intramolecular
nucleophilic trapping of an alkylidenecarbene prevented comple-
tion of the proposed expeditious route to subergorgic acid (1).
Nonetheless, the Ireland–Claisen rearrangement of substituted
alkenyl 2-methylcyclopentanecarboxylates has been demonstrated
to be highly stereoselective in establishing four of the five stereo-
centers present in it. This is thus a powerful methodology for the
synthesis of triquinanes and other five-membered ring-containing
natural products if the challenges associated with steric hindrance
and chemoselectivity encountered here can be solved.
Br
OTIPS
OTIPS
Br
OTIPS
Br
R
R
R
R
R
R
R
CONEt2
CONEt2
CONEt2
60
R = CH3
61
62
Br
Br
OTIPS
OTIPS
R
3. Experimental
R
R
CH2OR1
CH2OR1
63
3.1. General procedure for the preparation of lithium
diisopropylamide (LDA)
41
c. R1 = TBDMS
d. R1 = TIPS
c. R1 = TBDMS
d. R1 = TIPS
R = CH3
Following a standard procedure developed by Rathke et al.,40
a solution of LDA (2.2 mmol) in THF was prepared as follows. To
a 25-mL round-bottomed flask (rbf) was added THF (3 mL) at 0 ꢁC
under N2 atmosphere. Diisopropylamine (0.3 mL, 2.2 mmol) was
added, followed by the dropwise addition of n-BuLi (1.5 mL,1.6 M in
hexane) via syringe. The resulting mixture was stirred at 0 ꢁC for
10 min, then cooled to ꢀ78 ꢁC, at which time the solution was ready
for use.
Br
Br
OTIPS
OTIPS
R
R
R
R
CO2CH3
CO2CH3
R = CH3
64
23
3.2. General procedures for the Ireland–Claisen
rearrangement
Applying
a-elimination of a 1,1-dihaloalkene to produce an
alkylidenecarbene39 was also attempted. As a model for our goal,
alcohol 65 was converted to 66 in good yield,39 and this provided
67 upon treatment with LDA (Scheme 16). Carbene 68 should be
accessible based on known procedures,39b although this was not
tested. However, applying the addition reaction to 42c (Scheme 17)
gave only quantitative recovery of the starting ketone under vari-
ous conditions.
All rearrangements were carried out under strictly anhydrous
conditions according to the known procedures.26 A solution of
LDA40 (2.2 mmol) in THF (3 mL) was prepared in a 25-mL rbf and
cooled to ꢀ78 ꢁC under a N2 atmosphere. A 15-mL centrifuge tube
was charged with TMSCl/TEA/THF (2.0:0.5:3.7, volume ratio),
centrifuged for 10 min, then cooled to ꢀ78 ꢁC, and kept under N2.
Three milliliters of the supernatant of the centrifugate was trans-
ferred via cannula to the LDA solution. The resulting mixture was
stirred at ꢀ78 ꢁC for 5 min. To this mixture was added, dropwise via
cannula, a solution of the allyl ester in THF (1 mL), which had been
prepared in a 5-mL rbf and precooled to ꢀ78 ꢁC under a positive
pressure of N2. This mixture was stirred at ꢀ78 ꢁC for 30 min before
the cooling bath was removed. The mixture was then allowed to
warm to rt and stirred at this temp for 18–48 h before the aqueous
(aq) workup to effect hydrolysis. The resulting biphasic mixture
(top org. phase with brown color, bottom aq phase with cream
color) was transferred to a separatory funnel, the org. phase was
separated, and the aq phase was extracted with Et2O (3ꢂ10 mL).
The combined org. phases were washed with brine (3ꢂ10 mL),
dried, and concentrated. The resulting brown oil residue was
subjected to flash chromatography to furnish the pure rearrange-
ment products, e.g., (1S*,2R*,10R*)-1-(1-methyl-2-triisopropylsiloxy-
methyl-2-propenyl)-2-methylcyclopentanecarboxylic acid (18a).
In summary, steric and stereoelectronic factors thwarted for-
mation of ring A in subergorgic acid. The nucleophilic oxygen atoms
such as those in 24 presented a problem by trapping the carbene
intermediate (Scheme 8). Inability to protect the neopentyl-like
carbonyl group of 53 (Scheme 15) precluded ozonolysis of the al-
kene moiety to form a ketone that could possibly have been con-
verted to the desired bicyclic compound according to the known
procedures.31,33 Finally, the activation of the secondary C–H bond
C
O
CBr2
HO CHBr2
TMSO CHBr2
i
ii
iii
iv
65
66
67
68
Scheme 16. Reagents: (i) [(CH2)5CH]2NH, n-BuLi, THF; CH2Br2, cyclohexanone, ꢀ78 ꢁC;
10% HCl; (ii) HMDS, TMSCl, Py, 50 ꢁC, 52% (two steps); (iii) LDA, THF, ꢀ78 ꢁC to rt; (iv)
n-BuLi or MeLi, hexanes, low temperatures.
1H NMR (300 MHz, CDCl3):
d
5.14 (d, J¼1.8 Hz, 1H, vinylic), 4.90 (d,
J¼1.2 Hz, 1H, vinylic), 4.05–4.25 (m, 2H, CH2O), 2.50 (q, J¼7.2 Hz,
OTIPS
OTIPS
CHBr2
1H, allylic), 2.40–1.20 (m, 31H, ring Hs, homoallylic CH3, and TIPS),
O
HO
R
0.93 (d, J¼6.9 Hz, 3H, ring CH3); 13C NMR (75 MHz, CDCl3):
d
181.7,
R
i
152.9, 107.9, 66.0, 60.1, 42.1, 38.1, 32.8, 29.6, 23.1, 18.0, 15.9, 15.3,
R
R
12.0; 1H NMR (500 MHz, DMSO-d6):
d 11.96 (s, 1H, COOH), 5.04 (d,
CH2OTBDMS
CH2OTBDMS
J¼2.0 Hz, 1H, vinylic), 4.83 (d, J¼1.7 Hz, 1H, vinylic), 4.07–4.17 (m,
2H, CH2O), 2.47 (q, J¼7.2 Hz, 1H, allylic), 0.98–2.09 (m, 28H, ring Hs
and TIPS), 0.98 (d, J¼7.2 Hz, 3H, homoallylic CH3), 0.88 (d, J¼6.9 Hz,
42c
R = CH3
69
Scheme 17. Reagents: (i) [(CH2)5CH]2NH, n-BuLi, THF; CH2Br2, ꢀ78 ꢁC, 2 h; satd NH4Cl
and acidified to pH 3 with 10% aq HCl.
3H, ring CH3); 13C NMR (125 MHz, DMSO-d6):
d 176.3, 153.2, 106.9,

5490
J.C. Gilbert, J. Yin / Tetrahedron 64 (2008) 5482–5490
13. Fakhreddine, F. H. M. A. Thesis; Univ. of Texas: Austin, 1996.
14. (a) Mulzer, J.; Mohr, J.-T. J. Org. Chem. 1994, 59, 1160–1165; (b) Ishizaki, M.;
Niimi, Y.; Hoshino, O. Chem. Lett. 2001, 546–547.
15. Charrette, A. B.; Cote, B. Tetrahedron Lett. 1993, 34, 6833–6836.
16. Hoffmann, M. R. Angew. Chem., Int. Ed. Engl. 1983, 22, 795–796.
17. Hughes, D. L. Org. React. 1992, 2, 386–387.
65.4, 59.0, 40.8, 37.6, 32.4, 29.1, 22.4, 17.8, 15.7, 15.2, 11.4; HRMS for
C
21H41O3Si (MþH)þ calcd 369.2825, found 369.2826.
Acknowledgements
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We thank the Robert A. Welch Foundation (Grant F-815) for
partial financial support of this work; Professor Stephen F. Martin
for providing access to an ozonator; Dr. Ben A. Shoulders for his
invaluable dedication to and assistance in operating NMR spec-
trometers and helpful discussions with the results; Dr. Vincent
Lynch for obtaining X-ray crystallographic data.
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Supplementary data
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General experimental methods, full experimental and charac-
terization details, and copies of 1H, 13C, and 2D NMR spectra of the
reported compounds. Supplementary data associated with this
article can be found in the online version, at doi:10.1016/
j.tet.2008.04.005.
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