Enantioselective syntheses of tremulenediol A and tremulenolide A

Article abstract of DOI:10.1016/j.tet.2006.05.087

A concise entry to the skeleton of the tremulane sesquiterpenes is described that culminated in the first enantioselective syntheses of tremulenediol A and tremulenolide A. The approach features a series of efficient transition metal-catalyzed reactions c

Full text of DOI:10.1016/j.tet.2006.05.087

Tetrahedron 62 (2006) 10497–10506
Enantioselective syntheses of tremulenediol A and tremulenolide A
*
Brandon L. Ashfeld and Stephen F. Martin
Department of Chemistry and Biochemistry, The University of Texas at Austin, 1 University Station A5300,
Austin, TX 78712-0165, USA
Received 11 January 2006; revised 2 May 2006; accepted 8 May 2006
Available online 17 August 2006
Abstract—A concise entry to the skeleton of the tremulane sesquiterpenes is described that culminated in the first enantioselective syntheses
of tremulenediol A and tremulenolide A. The approach features a series of efficient transition metal-catalyzed reactions commencing with an
enantioselective rhodium(II)-catalyzed intramolecular cyclopropanation followed by a regioselective allylic alkylation and a diastereoselec-
tive rhodium(I)-catalyzed [5+2] cycloaddition.
Ó 2006 Elsevier Ltd. All rights reserved.
11
1. Introduction
12
4
11
10
9
15
14
3
3
1
10
9
2
15
14
1
2
The tremulanes constitute a novel class of sesquiterpene
natural metabolites that is characterized by an unusual car-
boskeletal array 1 isomeric to the lactarane skeleton (2).1
Tremulenolide A (3) and tremulenediol A (4) are two repre-
sentative tremulanes that were isolated in 1993 from the
fungal pathogen Phellinus tremulae during the course of
a project to develop tactics to control fungal decay and stain-
ing in trembling or quaking aspen (Populus tremuloides).1
Aspen represents 11% of the entire Canadian timber re-
source and 54% of the net merchantable hardwood timber.
P. tremulae, the most serious wood rotting pathogen of aspen
in Canada, greatly reduces the potential economic value of
this timber reserve (Fig. 1).
12
7
4
7
6
5
8
5
8
13
6
13
Lactarane Carbon
Tremulane Carbon
Skeleton (2)
Skeleton (1)
OH
O
O
OH
H
H
Tremulenolide A (3)
Tremulenediol A (4)
Although the commercial advantages associated with the
potential biological activity of these two natural products
are of considerable interest in itself, the structural features
of the skeletal core of 3 and 4 present an even greater stimulus
to their selection as synthetic targets. For example, in 1998
Davies and Doan reported the syntheses of racemic 3 and 4
in overall yields of 0.8 and 0.9%, respectively.2 His strategy
featured the cyclopropanation of an appropriately functional-
ized diene with the requisite vinylcarbenoid followed by
a Cope rearrangement of the intermediate divinylcyclopro-
pane generated in situ to assemble the seven-membered
ring of the hydroazulene core with a high level of relative
stereoselectivity.3,4 However, efforts to apply this plan to
an efficient enantioselective synthesis using a chiral dirho-
dium(II) catalyst were unsuccessful.
Figure 1.
We have long been interested in developing methods for the
enantioselective synthesis of biologically relevant natural
products. In this context, the 2,3,6,9-substitution pattern on
the bicyclo[5.3.0]decane skeleton and the relative configura-
tions of the three stereogenic centers on the seven-membered
ring captured our attention as being well suited for applica-
tion of synthetic methodology that was being contemporane-
ously developed by our group.
The initial stimulus for our general approach to the tremu-
lane skeleton 5, which is outlined in Scheme 1, was a report
by Wender that vinylcyclopropanes with tethered alkyne
functional groups could undergo diastereoselective intramo-
lecular rhodium(I)-catalyzed [5+2] cycloadditions to give
hydroazulenes.5 Based upon this account, we reasoned that
an intermediate such as 6 might be accessible by allylic
* Corresponding author. Tel.: +1 512 471 3915; fax: +1 512 471 4180;
e-mail: sfmartin@mail.utexas.edu
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.05.087

10498
B. L. Ashfeld, S. F. Martin / Tetrahedron 62 (2006) 10497–10506
OH
alkylation of the vinylcyclopropyl lactone 8 that would in
turn arise from an intramolecular cyclopropanation of the di-
vinyl diazoacetate 9. We had previously demonstrated that
vinylcyclopropanes related to 8 underwent several kinds of
regioselective allylic alkylations via a SN20-like manifold.6
Because the stereochemistry at C(3) and C(7) of 5 is estab-
lished in the cyclopropanation step, it occurred to us that 8
should be accessible via an enantioselective cyclopropana-
tion using the chiral carboxamide dirhodium(II)-catalysts
we had developed in collaboration with Doyle.7 Our recent
total synthesis of ambruticin establishes a benchmark for
the application of this method to the construction of complex
natural products.8,9 This methodology has also been used for
the synthesis of conformationally constrained peptide ana-
logs to study protein–ligand interactions.10
O
O
OH
H
6
H
3
4
HO2C
H
H
OR
CO2H
OR
6
H
10
11
O
O
R
H
H
H
O
O
R
N2
H
Intramolecular
Allylic
3
Me
7
[5+2] Cycloaddition
Alkylation
8
9
H
+
5
6
X
O
O
OR
O
H
O
HO
Asymmetric
E
+
N2
12
13
E
Cyclopropanation
H
Scheme 2.
9
7
8
The opening move in the synthesis was the enantioselective
construction of cyclopropyl lactone 8 via a straightforward
four-step sequence of reactions beginningwith commercially
available 2-methyl-2-vinyl oxirane (14) (Scheme 3). Thus,
treatment of oxirane 14 with the sulfur ylide of trimethylsul-
fonium iodide followed by spontaneous b-elimination of
dimethylsulfide provided the known divinyl carbinol 15 in
84% yield.13 Subsequent acylation of 15 with diketene in
the presence of 4-dimethylaminopyridine (DMAP) and
sodium acetate provided acetoacetate 16 in 93% yield. A
one-pot diazo transfer reaction of 16 with p-toluenesulfonyl
azide (p-TsN3) and Et3N, followed by hydrolytic cleavage of
the ketone functionality with LiOH$H2O provideddiazoester
9 in 97% overall yield. The use of the Corey–Myers diazo-
esterification protocol to prepare 9 directly from 15 was
also explored,14 but the sterically hindered tertiary alcohol
proved resistant to acylation under these conditions.
Scheme 1.
Having thus formulated our overall strategy, we set to the task
of synthesizing tremulenolide A (3) and tremulenediol A (4).
These efforts recently culminated in the first enantioselective
entry to this class of sesquiterpene natural products.11 We
were also intrigued by the possibility of conducting one or
more of the transition metal-catalyzed transformations in
one pot to streamline the overall operation, and this hypo-
thesis led to the development of some novel tandem reac-
tions.12 We now report some details of these investigations.
2. Results and discussion
2.1. First generation strategy
Our first generation approach toward the tremulane sesqui-
terpenes is illustrated in Scheme 2. We envisioned that trem-
ulenolide A (3) would arise from an allylic oxidation of the
diol moiety in tremulenolide A (4), which would be readily
accessible via refunctionalization of 10. The selective hydro-
genation of the trisubstituted D5,6-double bond in 10 was
anticipated to proceed preferentially from the less hindered
face. The hydroazulene 10 would then in turn be derived
from enyne 11 via a diastereoselective rhodium(I)-catalyzed
intramolecular [5+2] cycloaddition. An organocopper medi-
ated SN20 ring opening of lactone 8 with alkyl halide 12
would lead to the vinylcyclopropane 11, which comprises
all the carbon atoms present in 3 and 4. As noted previously,
8 would be prepared from the enantioselective, intramolec-
ular rhodium(II)-catalyzed cyclopropanation of diazoester
9, whereas propargyl alcohol (13) was viewed as a suitable
precursor of 12.
O
O
O
O
OH
O
O
Me2S=CH2
84%
DMAP, NaOAc, THF
93%
14
15
16
O
O
H
H
p-TsN3, Et3N, CH3CN;
Rh2[5(R)-MEPY]4
O
O
then LiOH•H2O
97%
CH2Cl2
99% (dr = 1:1, 94% ee)
N2
Me
9
8
Scheme 3.
When diazoester 9 was exposed to 0.1 mol % of Rh2[5(R)-
MEPY]4, intramolecular cyclopropanation proceeded

B. L. Ashfeld, S. F. Martin / Tetrahedron 62 (2006) 10497–10506
10499
smoothly to yield the desired cyclopropyl lactone 8 as a
mixture (1:1) of products epimeric at C(4) in 99% yield
and 94% ee for each diastereomer.7 The enantioselectivity
of the cyclopropanation reaction was determined by treating
the diastereomeric mixture of cyclopropyl lactones 8 with
1 equiv of phenyllithium to yield the corresponding dia-
stereomeric ketones. Subsequent analytical chiral HPLC
analysis of each ketoalcohol showed that the cyclopropana-
tion of diazoester 9 proceeded in 94% ee and that a diastereo-
meric mixture of cyclopropyl lactones obtained in the
cyclization is inconsequential because the epimeric center
was slated for destruction in the next step of the synthesis.
The optimized sequence provided the requisite cyclopropyl
lactone 8 in 71% overall yield from 14.
A number of conditions were screened, including, but not
limited to, PBr3, PBr3 and pyridine, and TMSCl and LiBr;
none of these procedures gave any better results. The instabil-
ity of 20 no doubt contributed to the problem.
With limited quantities of bromide 20 in hand, we turned our
attention toward coupling the derived organocuprate with
cyclopropyl lactone 8. However, perhaps not surprisingly,
metallation of the tertiary homopropargylic halide 20 proved
exceedingly difficult. Several attempts to effect metal–halo-
gen exchange to give the derived organolithium or Grignard
reagent were universally unsuccessful. It thus became appar-
ent that introducing the gem-dimethyl moiety directly at an
early stage would not be feasible, and a change in tactics
was indicated.
In order to examine the underlying feasibility of the proposed
organocuprate-mediated SN20 ring opening reaction, cyclo-
propyl lactone 8 was treated with the tertiary organocuprate
reagent derived from t-BuLi and CuCN (Scheme 4).15 Grat-
ifyingly, the desired vinylcyclopropane 17 was obtained in
80% yield as a mixture (2.3:1) of E/Z-olefinic isomers.
Thus, our strategy for preparing a vinylcyclopropane related
to 11 appeared soundly based.
2.2. Second generation approach: some initial studies
The difficulties that had been encountered in generating an
unstabilized tertiary carbanion led us to consider a more tra-
ditional means of effecting the allylic alkylation of the cyclo-
propyl lactone 8 to provide a vinyl cyclopropane that would
participate in the proposed [5+2] cycloaddition. We thus for-
mulated the modified plan as summarized in Scheme 6 in
which a conventional transition metal-catalyzed allylic
alkylation of 8 served as a pivotal step. Indeed, we had previ-
ously shown that such lactones underwent highly regioselec-
tive, Pd(0)-catalyzed alkylations with stabilized carbanions
to give the expected products in high yields.6 The slight
drawback of this approach relative to the original plan was
the necessity of reducing the malonate moiety in an interme-
diate derived from 21 into a gem-dimethyl group. Neverthe-
less, the strategy was still concise and merited examination.
HO2C
H
H
H
Me
H
t-BuLi, CuCN, THF
–78 C to rt, 3 h
80% (E/Z = 2.3:1)
O
°
O
8
17
Scheme 4.
Buoyed with confidence that the more complex organocup-
rate reagent derived from alkyne 12 would behave similarly,
we turned our attention toward the task of synthesizing the
homopropargylic tertiary bromide 20 (Scheme 5). Toward
this end, the alcohol 19was first prepared in high overall yield
by a simple two-step sequence of reactions. Propargyl alco-
hol (13) was first treated with BnBr and NaH in the presence
of TBAI to yield 18 in 98% yield. The benzyl protecting
group was selected in anticipation that it could be removed
concomitantly with the catalytic hydrogenation that would
reduce the D5,6-olefin later in the synthesis (vide supra). The
homopropargyl alcohol 18 was converted into the alcohol 19
in nearly quantitative yield by sequential deprotonation with
n-BuLi and reaction of the resultant acetylide anion with iso-
butylene oxide in the presence of BF3$OEt2. Unfortunately,
conversion of alcohol 19 into the corresponding bromide
20 proved troublesome. After considerable experimentation,
the conversion was effected using TMSBr in CH2Cl2,16 but
the reaction was inefficient, proceeding in a mere 23% yield.
HO2C
H
OBn
CO2H
H
E
E
3 or 4
OBn
E
H
E
21
22
O
H
H
+
MeO2C
OBn
O
CO2Me
Me
23
8
Scheme 6.
Because the cyclopropanation and the [5+2] cycloaddition
steps in our synthetic plan were both rhodium catalyzed, we
were intrigued by the notion that the allylic alkylation step
mightalsoberhodiumcatalyzed. Hence, Evans’useofamod-
ified Wilkinson’s catalyst to promote allylic alkylations cap-
tured our attention.17,18 We were of course cognizant of the
fact that such reactions typically proceeded to give products
in which the nucleophile attacked the more substituted termi-
nus of the allylic moiety, irrespective of the structure of the
starting material. Such a regiochemical outcome was oppo-
site to that which was required for the problem at hand. Nev-
ertheless, if RhCl(PPh3)3/P(OMe)3 or another rhodium
catalyst were capable of catalyzing the allylic alkylation of
cyclopropyl lactone 8 to give 22, the possibility of inducing
O
BnBr, NaH, TBAI
OH
OBn
DMF, 0 °C
→
rt
n-BuLi, BF3•OEt2
98%
THF, –78 °C
∼100%
→ rt
13
18
OH
Br
TMSBr, CH2Cl2
BnO
BnO
rt
→
50 °C, 6 h
23%
19
20
Scheme 5.

10500
B. L. Ashfeld, S. F. Martin / Tetrahedron 62 (2006) 10497–10506
HO2C
H
H
the subsequentintramolecular [5+2]cycloadditionin situ was
too attractive to ignore. Such a tandem rhodium(I)-catalyzed
allylic alkylation and [5+2] cycloaddition sequence would
represent a novel and rapid entry to hydroazulenes in general
and the tremulane bicyclic core in particular.
[Rh(CO)2Cl]2, NaH, THF
+
8
23
20% (E/Z = 1:1)
OBn
MeO2C
MeO2C
The malonate 23 was prepared in good overall yield from
commercially available 2-butyn-1,4-diol (24) by a relatively
straightforward sequence of reactions, although the mono-
protection of 24 was somewhat problematic (Scheme 7). Ini-
tial experiments to monobenzylate 24 relied upon a report
that showed symmetrical diols could be selectively mono-
benzylated with Ag2O and benzyl bromide.19 When diol 24
was treated with Ag2O and BnBr, 25 was obtained, albeit
in 51% yield. Given the modest yield and high cost of a sil-
ver-mediated monoalkylation procedure, more conventional
benzylation methods were explored. In a preliminary experi-
ment, the diol 24 was treated with BnBr and NaH, but 25 was
obtained in only 17% yield. Changing the solvent from THF
to DMF led to a slight increase in the yield to 24%. Finally, it
was found that reaction of diol 24 with benzyl bromide, NaH,
and tetrabutylammonium iodide (TBAI) in DMF, provided
25 in 53% yield. Subsequent treatment of propargyl alcohol
25 with methanesulfonyl chloride (MsCl) and Et3N in
CH2Cl2 provided the known mesylate 26 in 92% yield.20
Treatment of mesylate 26 with sodiodimethyl malonate
gave 23 in 97% yield. This three-step sequence enabled the
production of multigram quantities of 23 in an overall yield
of 48%.
27
Scheme 8.
alkylations.22 In exploring the scope of these processes, we
showed that the reactions proceeded with good to excellent
regioselectivity for a variety of allylic carbonates. The pre-
ferred product was generally the one in which the nucleophile
became attached to the carbon bearing the carbonate leaving
group, irrespective of the structure of the starting carbonate
(Scheme 9). The structure of the starting material generally
maps directly on the product, an unusual phenomenon in
transition metal-catalyzed allylic alkylations. Ignoring the
considerable body of literature on the regiochemistry of
Rh-catalyzed allylic alkylations thus paid considerable
dividends.
R5
CO2Me
R2
3
CO2Me
R2
R3
R4
R2
R1
R3
R
R4
R5
R5
CO2Me
Na
R1
OCO2Me
R4
R1
+
[Rh(CO)2Cl]2
MeO2C
CO2Me
30
MeO2C
29
28
Major
Minor
Scheme 9.
MsCl, Et3N,
BnBr, TBAI
NaH, DMF
53%
HO
OH
HO
OBn
CH2Cl2
92%
Encouraged by the formation of cyclopropyl enyne 27 from
the [Rh(CO)2Cl]2-catalyzed reaction of 8 and the sodium
salt of 23, the feasibility of conducting a domino allylic alkyl-
ation/[5+2] cycloaddition sequencewas examined. However,
these exploratory experiments were unsuccessful, and none
of the desired cycloadduct was obtained. It should be noted
that there are no examples in the literature of rhodium-
catalyzed [5+2] cycloadditions of cis-cyclopropyl enyne
carboxylates like 27.5 In order to assess whether such com-
pounds were suitable substrates for these carbocyclizations,
a number of experiments were conducted in which the cata-
lyst, additive, solvent, and temperature were varied to see
whether 27 would cyclize as expected. In one of the experi-
ment, a solution of 27 containing [Rh(CO)2Cl]2 in toluene
was heated to 55 ꢀC for 12 h to give a compound that has
not been unequivocally identified, but the NMR spectral
data are consistent with the tentatively assigned structure
31 (Scheme 10).
24
25
CH2(CO2Me)2, NaH
MeO2C
OBn
MsO
OBn
THF
97%
CO2Me
26
23
Scheme 7.
The stage was thus set to explore the transition metal-
catalyzed allylic alkylation of 8 with the anion derived from
23. Because of our penchant to develop novel rhodium-
catalyzed domino reactions, we ignored the ample literature
precedent that strongly suggested such a reaction involving
8 would proceed with the incorrect regiochemistry. In initial
experiments we found that treating the cyclopropyl lactone 8
with the sodium enolate of malonate 23 in the presence of
RhCl(PPh3)3/P(OMe)3 gave no isolable alkylation product,
even after extended reaction times and elevated tempera-
tures. Because the dimeric rhodium(I) catalyst [Rh(CO)2Cl]2
was known to catalyze the intramolecular [5+2] cycloaddi-
tions,21 we queried if perchance it might also catalyze allylic
alkylations. In the event, reaction of 8 with the sodium salt of
23 in the presence of [Rh(CO)2Cl]2 afforded an E/Z-mixture
(1:1) of 27 as the only isolable product, albeit in only about
20% (unoptimized) yield (Scheme 8).
HO2C
H
CO2H
BnO
H
MeO2C
MeO2C
[Rh(CO)2Cl]2, PhMe
55 °C, 12 h
OBn
37%
MeO2C
MeO2C
H
31
Tentatively Proposed
Structure
27
Not only did we thus discover that [Rh(CO)2Cl]2 could
catalyze allylic alkylations, but we also found that the regio-
chemistry of such reactions was opposite to that expected.
This unexpected yet felicitous result led us to develop
[Rh(CO)2Cl]2 as a novel catalyst for promoting allylic
Scheme 10.
Although we were unsuccessful in developing a domino
[Rh(CO)2Cl]2-catalyzed allylic alkylation and [5+2] cyclo-
addition route to 3 and 4, wewere able to apply such reactions

B. L. Ashfeld, S. F. Martin / Tetrahedron 62 (2006) 10497–10506
10501
to simpler, yet closely related, substrates.12 For example, re-
action of 32 with the malonate anion 33 in the presence of
[Rh(CO)2Cl]2 (5 mol %) led to the cycloadduct 34 in excel-
lent overall yield (Scheme 11). The regio- and diastereoselec-
tivity in this domino process was the same as that observed by
Wender.21
protection of the intermediate primary hydroxyl as its TBS–
ether provided 37 in 67% overall yield (Scheme 13). It was
now necessary to reduce the diester moiety to install the req-
uisite gem-dimethyl moiety. Although treatment of 37 with
DIBALH in toluene did reduce the methyl esters to generate
the expected 1,3-diol, some silyl deprotection also occurred.
However, reduction of 37 with LiAlH4 gave the desired 1,3-
diol in 91% yield. Subsequent treatment with methanesul-
fonyl chloride (MsCl) and Et3N provided bismesylate 38 in
79% yield.
H
TBSO
+
OTBS
H
[Rh(CO)2Cl]2
E
E
MeCN, rt → 80 °C
E
E
OBn
83%
Regioselectivity = 1:0
H
OCOCF3
OTBS
1) NaBH4, THF
32
33
34
MeO2C
MeO2C
1) LiAlH4, THF
36
E = CO2Me
2) TBSCl, ImH, DMF
67%
2) MsCl, Et3N, CH2Cl2
72%
H
Scheme 11.
37
2.3. Second generation approach: successful endgame
OBn
OBn
OH
OMs
OMs
OTBS
Given the poor efficiency with which [Rh(CO)2Cl]2 cata-
lyzed the allylic alkylation of cyclopropyl lactone 8 with
malonate 23, we decided to examine the use of the more
traditional Pd(0) catalysts. After brief experimentation to
optimize conditions, we found that the reaction of 8 with
the sodium enolate of 22 in the presence of 10 mol %
Pd(PPh3)4 and additional PPh3 (70 mol %) provided enyne
27 in 71% yield (Scheme 12). The next stage of the sequence
involved a [5+2] cycloaddition in which cleavage of the
more substituted cyclopropane bond was needed to construct
the requisite bicyclo[5.3.0]decane. Based upon results
reported by Wender,21 we reasoned that such cleavage would
require that the carboxylic acid moiety in 27 be first reduced
to the corresponding aldehyde. Thus, treatment of 27 with
oxalyl chloride and DMF followed by reduction of the crude
acid chloride with LiAlH(OiBu)3 provided aldehyde 35 in
84% yield.23 The primary alcohol resulting from over-reduc-
tion was also obtained in 12% yield, butsubsequent oxidation
with Dess–Martin periodinane proceeded quantitatively to
provide 35 in 96% overall yield. Heating 35 in the presence
of [Rh(CO)2Cl]2 proceeded with high regioselectivity to fur-
nish the desired cycloadduct 36 in 85% yield. The structure of
36 was assigned based upon analysis of the HMQC and
HMBC NMR data, together with comparisons to Wender’s
reported spectral data for similar compounds.21
1) LiBHEt3, THF
2) TBAF, THF
70%
H
H
38
39
OH
O
H
O
OH
H2, Pd/C
82%
MnO2, CH2Cl2
86%
H
4
3
Scheme 13.
Initial attempts to reduce the bismesylate functionality in 38
to providethegem-dimethyl moiety were performed utilizing
LiAlH4. Unfortunately, the reaction was somewhat recalci-
trant and failed to proceed to completion. Partially reduced
monomesylate was recovered, even after extended reaction
times (>24 h). Ultimately, 38 was cleanly reduced using
LiBHEt3 to give the desired gem-dimethyl intermediate
that was treated with TBAF in THF to deliver 39 in 70%
overall yield for the two steps. When 39 was subjected to
heterogeneous catalytic hydrogenation in the presence of
base-washed palladium on carbon under H2 (1 atm), stereo-
and chemoselective reduction of the trisubstituted olefin
ensued with concomitant removal of the benzyl protecting
group to provide tremulenediol A (4) in 82% yield as the
HO2C
H
H
1) (COCl)2, DMF, CH2Cl2
Pd(PPh3)4, PPh3
8 + 23
t
NaH, THF
71%(E/Z = 1:0)
2) LiAlH(O Bu)3, THF, –78 °C
1
OBn
only isolable product. The spectral data (e.g., 500 MHz H
MeO2C
MeO2C
84% ( 96% after cycling)
and 125 MHz 13C NMR and IR) and optical rotation for
synthetic 4 were consistent with those reported in the litera-
ture.1 Subsequent treatment of 4 with MnO2 provided
tremulenolide A (3), which also exhibited spectral character-
istics (e.g., 500 MHz 1H and 125 MHz 13C NMR) and optical
rotation consistent with those reported in the literature.1
27
H
H
OHC
OBn
CHO
[Rh(CO)2Cl]2
MeO2C
PhMe,110°C
MeO2C
H
OBn
MeO2C
MeO2C
85%
35
36
3. Conclusions
Scheme 12.
In summary, concise, enantioselective syntheses of tremul-
enediol A (4) and tremulenolide A (3), two representative
sesquiterpene metabolites of the tremulane class, have
been achieved. The synthetic route is highlighted by a chiral
With cycloadduct 36 in hand, completion of the syntheses
of 3 and 4 required a series of refunctionalizations. Thus, re-
duction of the aldehyde group in 36 with NaBH4 followed by

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B. L. Ashfeld, S. F. Martin / Tetrahedron 62 (2006) 10497–10506
rhodium(II)-catalyzed cyclopropanation to establish the req-
uisite absolute stereochemistry. A transition metal-catalyzed
allylic alkylation is then utilized to assemble the complete
carbon ensemble present in the natural products and set
the stage for a diastereoselective rhodium(I)-catalyzed
[5+2] intramolecular cycloaddition. These studies led to
the discovery and development of a novel [Rh(CO)2Cl]2-
catalyzed allylic alkylation reaction that generally proceeds
with a unique regioselective outcome for structurally differ-
ent substrates. This allylic alkylation has been coupled in
tandem with a number of different [Rh(CO)2Cl]2-catalyzed
carbocyclizations, including [5+2] cycloadditions, to enable
rapid access to complex cyclic carboskeletal frameworks.
The trio of transition metal-catalyzed operations described
herein results in a convergent and highly efficient enantio-
selective entry to 3 and 4 as evidenced by their synthesis
in 6% (16 steps) and 5.2% (17 steps) overall yields, respec-
tively. Other applications of these and other sequential and
domino transition metal-catalyzed reactions are in progress
and will be reported in due course.
(610 mg, 6.23 mmol) in THF (18 mL) at ꢁ10 ꢀC. The reac-
tion mixture was allowed to warm to room temperature by re-
moval of the cooling bath and stirred for 5.5 h. Satd aq NaCl
(20 mL) and Et2O (20 mL) were added, and the layers were
separated. The aqueous phase was extracted with Et2O
(2ꢂ20 mL), and the combined organic fractions were dried
(MgSO4) and concentrated under reduced pressure. The
crude residue was purified by Kugelrohr distillation (55–
57 ꢀC, 0.1 mmHg) to yield 1.052 g (93%) of 16 as a colorless
oil: 1H NMR (300 MHz) d 6.08 (dd, J¼17.4, 10.8 Hz, 2H),
5.20 (m, 4H), 3.38 (s, 2H), 2.23 (s, 3H), 1.61 (s, 3H); 13C
NMR (65 MHz) d 200.7, 165.6, 139.7, 114.7, 83.3, 51.0,
30.1, 23.9; IR (CHCl3) 2987, 1744, 1720, 1642, 1410,
1361, 1318, 1269, 1149, 997, 932 cmꢁ1; mass spectrum
(CI) m/z 183.1028 [C10H15O3 (M+1) requires 183.1021],
165, 161, 159, 139, 135, 121, 103 (base).
4.1.2. 3-Methylpenta-1,4-dien-3-yl diazoacetate (9). A so-
lution of p-toluenesulfonyl azide (826 mg, 4.28 mmol) (syn-
thesized from p-toluenesulfonyl chloride and sodium azide)
in CH3CN (6 mL) was added to a stirred solution of 16
(648 mg, 3.57 mmol) and Et3N (0.75 mL, 5.35 mmol) in
CH3CN (30 mL) at room temperature. The reaction mixture
was stirred for 4 h, whereupon a solution of LiOH$H2O
(449 mg, 10.7 mmol) in H2O (3.5 mL) was added, and the
reaction mixture was stirred for an additional 4 h. The mix-
ture was diluted with water (30 mL) and extracted with Et2O
(3ꢂ30 mL). The combined organic fractions were washed
with satd aq NaCl (100 mL), dried (MgSO4), and concen-
trated under reduced pressure. The crude residue was puri-
fied by flash chromatography eluting with pentane/Et2O
(10:1) to give 573 mg (97%) of 9 as a yellow oil: 1H NMR
(300 MHz) d 6.08 (dd, J¼17.5, 10.7 Hz, 2H), 5.23 (d,
J¼17.5 Hz, 2H), 5.18 (d, J¼10.7 Hz, 2H), 4.69 (br s, 1H),
1.65 (s, 3H); 13C NMR (65 MHz) d 171.0, 140.2, 131.8,
114.1, 82.6, 20.8; IR (CHCl3) 3033, 2985, 2109, 1694,
1371, 1248, 1186, 1092, 992, 924, 740 cmꢁ1; mass spectrum
(CI) m/z 167.0821 [C8H11N2O2 (M+1) requires 167.0821],
166 (base), 143, 142.
4. Experimental
4.1. General
Solvents and reagents were reagent-grade and used without
purification unless otherwise noted. Dichloromethane
(CH2Cl2), triethylamine (Et3N), and diisopropylamine were
distilled from calcium hydride and stored under nitrogen.
Tetrahydrofuran (THF) and diethyl ether (Et2O) were passed
through a column of neutral alumina and stored under argon.
Methanol (MeOH) and dimethylformamide (DMF) were
passed through a column of molecular sieves and stored
under argon. Toluene was passed through a column of Q5
reactant and stored under argon. All reactions were done in
flame-dried glassware under nitrogen unless otherwise indi-
1
cated. H nuclear magnetic resonance (NMR) spectra were
obtained at either 500, 400 or 300 MHz as solutions in
CDCl3. 13C NMRwere obtained at either 125, 100 or 75 MHz
as solutions in CDCl3. Chemical shifts are reported in parts
per million (ppm, d), and referenced from tetramethylsilane.
Coupling constants are reported in hertz (Hz). Spectral split-
ting patterns are designated as s, singlet; d, doublet; t, triplet;
q, quartet; m, multiplet; comp, complex; and br, broad. Infra-
red (IR) spectra were obtained using a Perkin–Elmer FTIR
1600 spectrophotometer using sodium chloride plates as
indicated, and reported as wave numbers. Low-resolution
chemical ionization mass spectra were obtained with a
Finnigan TSQ-70 instrument. High-resolution measure-
ments were made with a VG Analytical ZAB2-E instrument.
Analytical thin layer chromatography was performed using
Merck 250 micron 60F-254 silica gel plates. The plates
were visualized with UV light, ninhydrin, phosphomolybdic
acid, p-anisaldehyde, and potassium permanganate. Flash
column chromatography was performed according to Still’s
procedure24 using ICN Silitech 32-63 D 60A silica gel.
4.1.3. [1S-(1b,5a)]-4-Methyl-4-vinyl-3-oxabicyclo[3.1.0]-
hexan-2-one (8). A solution of 9 (23 mg, 0.137 mmol) in
CH2Cl2 (7 mL) was added to a refluxing solution of
Rh2[5(R)-MEPY]4 (13 mg, 13.7 mmol) in CH2Cl2 (114 mL)
over 17 h using a syringe pump. The resulting mixture was
heated under reflux for 4 h and then allowed to cool to room
temperature. The mixture was concentrated under reduced
1
pressure and a crude H NMR spectra indicated a mixture
(1:1) of endo and exo isomers. The crude residue was purified
by flash chromatography eluting with pentane/Et2O (1:1) to
give 19 mg (99%) of 8 as a clear, colorless oil (combined
mass of both isomers isolated). Isomer A: 1H NMR
(300 MHz) d 5.98 (dd, J¼17.2, 10.7 Hz, 1H), 5.37 (d, J¼
17.2 Hz, 1H), 5.18 (d, J¼10.7 Hz, 1H), 2.16–2.04 (m, 2H),
1.44 (s, 3H), 1.17 (ddd, J¼8.8, 7.6, 5.0 Hz, 1H), 1.00 (dt, J¼
5.0, 3.2 Hz, 1H); 13C NMR (65 MHz) d 174.3, 133.0, 119.0,
66.7, 31.6, 29.8, 28.3, 21.5; IR (CHCl3) 2987, 1769, 1453,
1413,1313, 1248,1196, 1044,959,838 cmꢁ1;massspectrum
(CI) m/z 139.0764 [C8H11O2 (M+1) requires 139.0759], 139
4.1.1. 3-Methylpenta-1,4-dien-3-yl acetoacetate (16).
A
1
solution of freshly distilled diketene (1.048 g,
(base). Isomer B: H NMR (300 MHz) d 5.85 (dd, J¼17.3,
12.5 mmol) in THF (2 mL) was added dropwise to a stirred
mixture of N,N-dimethylaminopyridine (DMAP) (152 mg,
1.25 mmol), sodium acetate (102 mg, 1.25 mmol), and 1513
10.9 Hz, 1H), 5.27 (dd, J¼17.3, 1.0 Hz, 1H), 5.15 (dd,
J¼10.9, 1.0 Hz, 1H), 2.21–2.04 (m, 2H), 1.55 (s, 3H), 1.14
(ddd, J¼8.8, 7.6, 4.9 Hz, 1H), 0.88 (dt, J¼4.9, 3.4 Hz, 1H).

B. L. Ashfeld, S. F. Martin / Tetrahedron 62 (2006) 10497–10506
10503
4.1.4. 2-((1R,2S)-2-(Hydroxydiphenylmethyl)cyclopro-
pyl)but-3-en-2-ol. A 1.0 M solution of PhLi in THF
(0.58 mL, 0.58 mmol) was added to a stirred solution of 8
(20 mg, 0.14 mmol) in THF (1.5 mL) at 0 ꢀC, the cooling
bath was removed, and the mixture was stirred for 1.5 h. It
was then cooled to 0 ꢀC, and satd aq NaHCO3 (2 mL) was
added. The layers were separated, and the aqueous phase
was extracted with Et2O (3ꢂ2 mL). The organic fractions
were dried (MgSO4) and concentrated under reduced pres-
sure. The crude residuewas purified by flash chromatography
eluting with hexanes/EtOAc (2:1) to give 38 mg (92%) of the
target ketone as a mixture (1:1) of diastereomers as a clear,
colorless oil: 1H NMR (500 MHz) d 7.69–7.66 (comp, 2H),
7.42–7.39 (comp, 2H), 7.38–7.31 (comp, 2H), 7.28–7.23
(comp, 3H), 7.17 (app tt, J¼7.5, 1.5 Hz, 1H), 6.02 (dd,
J¼17.5, 11.0 Hz, 1H), 5.19 (dd, J¼17.5, 1.0 Hz, 1H), 5.02
(dd, J¼11.0, 1.0 Hz, 1H), 1.98 (ddd, J¼16.5, 9.0, 7.0 Hz,
1H), 1.23 (ddd, J¼12.5, 7.5, 5.0 Hz, 1H), 1.11 (ddd,
J¼16.5, 9.0, 7.5 Hz, 1H), 0.95 (s, 3H), 0.80 (ddd, J¼14.0,
9.0, 5.0 Hz, 1H); 13C NMR (125 MHz) d 149.3, 149.0,
145.5, 127.8, 127.8, 126.8, 126.7, 126.6, 126.2, 111.3,
75.2, 72.0, 30.8, 28.7, 28.4, 3.11; IR (CH2Cl2) 3585, 3366,
3003, 1598, 1491, 1448, 1185, 1062, 924 cmꢁ1; mass spec-
trum (CI) m/z 239.1499 [C20H21O2 (M+1) requires
239.1541], 277 (base), 259, 199, 193; HPLC (Chiralcel AD
column, hexanes/isopropanol 98:2, flow¼0.5 mL/min,
tR¼60.8, 62.7, 73.1, 78.1 min).
temperature by removal of the cooling bath and stirred for
an additional 40 min. Satd aq NaHCO3 (5 mL) was added,
and the layers were separated. The aqueous phase was
extracted with Et2O (3ꢂ5 mL), and the combined organic
fractions were washed with satd aq NaCl (5 mL), dried
(MgSO4), and concentrated under reduced pressure. The
crude residue was purified by flash chromatography eluting
with hexanes/EtOAc (3:1) to give 218 mg (w100%) of 19
1
as a clear, yellow oil: H NMR (400 MHz) d 7.34–7.25
(m, 5H), 4.58 (s, 2H), 4.18 (t, J¼2.0 Hz, 2H), 2.42 (t,
J¼2.0 Hz, 2H), 2.29 (br s, 1H), 1.31 (s, 6H); 13C NMR
(100 MHz) d 137.2, 128.2, 127.8, 127.6, 83.5, 78.7, 71.4,
69.9, 57.5, 34.4, 28.7; IR (Neat) 3416, 3031, 2973, 2930,
2858, 2282, 2220, 1496, 1454 cmꢁ1; mass spectrum (CI)
m/z 219.1374 [C14H19O2 (M+1) requires 219.1385], 237,
219, 183, 171 (base), 161, 143.
4.1.7. 6-Benzyloxy-2-bromo-2-methyl-4-hexyne (20). Tri-
methylsilyl bromide (0.12 mL, 0.916 mmol) was added to
a solution of 19 (50 mg, 0.229 mmol) in CH2Cl2 (3 mL) at
room temperature, and the reaction mixture was stirred for
4 h. The mixture was warmed to 50 ꢀC (bath temperature),
stirred for an additional 2 h, and allowed to cool to room tem-
perature by removal of the cooling bath. The reaction mixture
was diluted with satd aq NaHCO3 (3 mL), and the layers were
separated. The aqueous phase was extracted with Et2O
(3ꢂ12 mL). The combined organic fractions were dried
(Na2SO4) and concentrated under reduced pressure. The
crude residue was purified by flash chromatography eluting
with hexanes/EtOAc (20:1) to give 15 mg (23%) of 20 as
4.1.5. (2S,3S)-(2-(1,4,4-Trimethylpent-1-enyl)cyclopro-
panecarboxylic acid (17). A 1.40 M solution of t-BuLi in
pentane (0.31 mL, 0.43 mmol) was added to a solution of
CuCN (20 mg, 0.22 mmol) in degassed THF (1 mL) at
ꢁ78 ꢀC, and the resulting slurry was allowed to warm slowly
to 0 ꢀC with stirring (app 10 min). This yellow solution was
then transferred via cannula to a solution of 8 (20 mg,
0.14 mmol) in degassed THF (0.5 mL) at 0 ꢀC, the solution
was allowed to warm to room temperature by removal of
the cooling bath and stirred for 4 h. The mixture was then
cooled to 0 ꢀC and satd aq NH4Cl/NH4OH (9:1, 2 mL) was
added. The layers were separated, and the aqueous phase
was extracted with CH2Cl2 (3ꢂ2 mL), the combined organic
fractions were dried (Na2SO4) and concentrated under re-
duced pressure. The crude residue was purified by flash chro-
matography eluting with hexanes/EtOAc (2:1) to give 22 mg
(80%) of 17 as a mixture (2.3:1) of trans and cis isomers as
1
a clear, colorless oil: H NMR (400 MHz) d 7.38–7.26 (m,
5H), 4.61 (s, 2H), 4.19 (t, J¼2.0 Hz, 2H), 2.86 (t,
J¼2.0 Hz, 2H), 1.85 (s, 6H); 13C NMR (100 MHz) d 137.2,
128.3, 128.0, 127.7, 83.1, 78.9, 71.3, 62.4, 57.4, 38.3, 33.6;
IR (CDCl3) 2969, 2926, 2859, 2259, 1721, 1453, 1371,
1264, 1107, 1070, 707 cmꢁ1; mass spectrum (CI) m/z
279.0378 [C14H16O1Br (Mꢁ1) requires 279.0384], 281,
279, 265, 263, 201, 183, 171 (base).
4.1.8. 4-Benzyloxy-2-butyn-1-ol (25). NaH (2.326 g of a
60% mineral oil suspension, 58.0 mmol) was added portion
wise to a solution of 2-butyn-1,4-diol (24) (10.0 g,
116.3 mmol) in DMF (250 mL) at 0 ꢀC. The resulting mix-
ture was stirred for 30 min, whereupon TBAI (2.148 g,
5.8 mmol) and benzyl bromide (6.9 mL, 58.0 mmol) were
added and the reaction mixture allowed towarm to room tem-
perature by removal of the cooling bath and stirred for an
additional 2 h. H2O (200 mL) and 10% HCl (200 mL) were
added, and the layers separated. The aqueous phase was ex-
tracted with Et2O (3ꢂ200 mL), and the combined organic
fractions were dried (MgSO4), and concentrated under
reduced pressure. The crude residue was purified by flash
chromatography eluting with hexanes/EtOAc (3:1) to give
5.460 g (53%) of 25 as a clear, yellow oil. 1H NMR
(500 MHz) d 7.35–7.27 (comp, 5H), 4.57 (s, 2H), 4.30
(t, J¼1.8 Hz, 2H), 4.19 (t, J¼1.8 Hz, 2H), 1.82 (br s, 1H);
13C NMR (65 MHz) d 137.1, 128.4, 128.0, 127.8, 84.7,
81.6, 71.7, 57.3, 51.0; mass spectrum (CI) m/z 176 (base),
154, 146.
1
a clear, colorless oil: trans isomer: H NMR (400 MHz)
d 5.43–5.40 (m, 1H), 2.06–1.79 (m, 4H), 1.62 (d, J¼
0.7 Hz, 3H), 1.43 (app dt, J¼7.8, 5.2 Hz, 1H), 1.11 (ddd,
J¼12.4, 7.6, 4.8 Hz, 1H), 0.86 (s, 9H); 13C NMR
(100 MHz) d 177.9, 130.1, 126.0, 41.8, 31.7, 30.7, 29.2,
19.6, 17.1, 12.0; IR (CHCl3) 3689, 3022, 1602, 1226 cmꢁ1
;
mass spectrum (CI) m/z 197.1543 [C12H21O2 (M+1) requires
197.1542], 393, 197 (base), 179, 151, 141, 125.
4.1.6. 6-Benzyloxy-2-methyl-4-hexyn-2-ol (19). A 1.9 M
solution of n-BuLi in hexanes (1.1 mL, 2.0 mmol) was added
toastirredsolutionofprotectedpropargyl alcohol18(292 mg,
2.0 mmol) in THF (2.5 mL) at ꢁ78 ꢀC, and the resulting
yellow solution was stirred for 1 h. To a solution of iso-
butylene oxide (72.1 mg, 0.089 mL, 1 mmol) in THF
(2.5 mL), freshly distilled BF3$OEt2 (283 mg, 0.25 mL,
2 mmol) was added and the reaction mixture was stirred for
7 h at ꢁ78 ꢀC. The solution was allowed to warm to room
4.1.9. 2-(4-Benzyloxy-2-butynyl)malonic acid dimethyl
ester (23). Dimethyl malonate (2.58 mL, 22.6 mmol) was
added to a suspension of NaH (542 mg of a 60% mineral

10504
B. L. Ashfeld, S. F. Martin / Tetrahedron 62 (2006) 10497–10506
oil suspension, 13.5 mmol) in THF (15 mL) at 0 ꢀC, and the
mixture was stirred for 25 min. A solution of 26 (1.147 g,
4.51 mmol) in THF (5 mL) was then added via syringe, and
the reaction mixture was allowed to warm to room tempera-
ture and stirred for an additional 2.5 h. The mixture was
cooled to 0 ꢀC, H2O (20 mL) was added, and the layers were
separated. The aqueous phase was extracted with Et2O
(3ꢂ20 mL), and the combined organic fractions were dried
(Na2SO4), and concentrated under reduced pressure. The
crude residue was purified by flash chromatography eluting
with hexanes/EtOAc (2:1) to give 1.269 g (97%) of 23 as a
clear, colorless oil: 1H NMR (500 MHz) d 7.33–7.25 (comp,
5H), 4.53 (s, 2H), 4.10 (t, J¼2.1 Hz, 2H), 3.74 (s, 6H), 3.60
(t, J¼7.6 Hz, 1H), 2.84 (dt, J¼7.5, 2.1 Hz, 2H); 13C NMR
(65 MHz) d 168.3, 137.3, 128.3, 128.0, 127.7, 82.4, 79.4,
71.1, 57.2, 52.7, 23.9; IR (Neat) 3031, 2954, 2853, 1738,
1454, 1345, 1071 cmꢁ1; mass spectrum (CI) m/z 291.1232
[C16H19O5 (M+1) requires 291.1230], 261, 183.
mixture was stirred at ꢁ78 ꢀC for 1 h. Aq 1 M HCl (2 mL)
was added, and the mixture allowed to warm to room temper-
ature by removal of the cooling bath, and then the layers were
separated. The aqueous phase was extracted with EtOAc
(3ꢂ2 mL), and the combined organic fractions were then
dried (Na2SO4), and concentrated under reduced pressure.
The crude residue was purified by flash chromatography elut-
ing with hexanes/EtOAc (3:1) to give 84 mg (84%) of 35 as
a clear, colorless oil: 1H NMR (300 MHz) d 8.74 (d,
J¼6.9 Hz, 1H), 7.36–7.28 (comp, 5H), 5.31 (t, J¼7.8 Hz,
1H), 4.55 (s, 2H), 4.13 (t, J¼2.1 Hz, 2H), 3.74 (s, 3H), 3.73
(s, 3H), 2.91–2.83 (comp, 4H), 2.11 (app dt, J¼15.9,
8.1 Hz, 1H), 1.86 (app ddt, J¼12.0, 7.8, 4.8 Hz, 1H), 1.72
(s, 3H), 1.59 (app dt, J¼7.2, 5.1 Hz, 1H), 1.33 (app dt,
J¼7.8, 5.4 Hz, 1H); 13C NMR (75 MHz) d 201.7, 170.3,
137.5, 134.9, 128.1, 127.8, 121.1, 81.3, 79.3, 71.2, 57.3,
56.9, 52.8, 30.6, 30.2, 28.3, 23.2, 17.8, 11.8; IR (CDCl3)
2953, 2853, 2256, 1736, 1697, 1437, 1292, 1208,
1069 cmꢁ1; mass spectrum (CI) m/z 413.1959 [C24H29O6
(M+1) requires 413.1964], 413 (base), 305, 245.
4.1.10. 2-(4-Benzyloxybut-2-ynyl)-2-[3-(2S,3S)-(2-car-
boxycyclopropyl)but-2-enyl]malonic acid dimethyl ester
(27). Pd(PPh3)4 (81 mg, 73 mmol) and PPh3 (190 mg,
0.725 mmol) were added sequentially to a solution of 8
(100 mg, 0.725 mmol) in degassed THF (4 mL) at room tem-
perature, and the resulting solution was stirred for 20 min. In
a separate flask, 23 (462 mg, 1.59 mmol) was added to
a slurry of NaH (58 mg of a 60% mineral oil suspension,
1.45 mmol) in degassed THF (4 mL) at room temperature.
After stirring for 20 min at room temperature, the resulting
homogeneous solution was transferred via cannula to the
flask containing the catalyst and substrate. The mixture was
heated under reflux for 4 h. The resulting dark brown solution
was allowed to cool to room temperature byremoval of the oil
bath and then cooled to 0 ꢀC. Aq 1 M NaHSO4 (8 mL) was
added, and the layers were separated. The aqueous phase
was extracted with CH2Cl2 (3ꢂ10 mL). The combined or-
ganic fractions were washed with satd aq NaCl (10 mL),
dried (Na2SO4), and concentrated under reduced pressure.
The crude residue was purified by flash chromatography elut-
ing with hexanes/EtOAc (2:1–1:1) to give 220 mg (71%) of
4.1.12. (3aS,7S)-8-Benzyloxymethyl-7-formyl-4-methyl-
3,3a,6,7-tetrahydro-1H-azulene-2,2-dicarboxylic acid
dimethyl ester (36). [Rh(CO)2Cl]2 (2 mg, 4.8 mmol) was
dissolved in degassed toluene (2 mL), and a solution of 35
(20 mg, 0.048 mmol) in degassed toluene (5 mL) was added.
The resulting mixture was heated for 30 min at 110 ꢀC (bath
temperature). The mixture was allowed to cool to room tem-
perature by removal of the oil bath, and then filtered through
a short plug of neutral alumina. The filtrate was concentrated
under reduced pressure, and the crude residue was purified
by flash chromatography eluting with hexanes/EtOAc (3:1)
to give 17 mg (85%) of 36 as a clear, colorless oil:
1H NMR (500 MHz) d 9.59 (s, 1H), 7.36–7.27 (comp, 5H),
5.51–5.49 (m, 1H), 4.51 (d, J¼11.6 Hz, 1H), 4.46 (d,
J¼11.8 Hz, 1H), 4.01 (app dt, J¼12.1, 1.2 Hz, 1H), 3.76
(s, 3H), 3.74 (s, 3H), 3.37 (br s, 1H), 3.23 (dd, J¼17.3,
2.0 Hz, 1H), 3.20 (t, J¼6.0 Hz, 1H), 2.89 (dd, J¼16.7,
1.4 Hz, 1H), 2.73 (ddd, J¼12.4, 7.4, 2.0 Hz, 1H), 2.68–
2.59 (m, 1H), 2.35–2.29 (m, 1H), 2.07 (t, J¼12.7 Hz, 1H),
1.68 (d, J¼0.6 Hz, 1H); 13C NMR (125 MHz) d 200.4,
171.7, 171.4, 142.5, 138.2, 134.3, 128.4, 127.7, 127.6,
122.8, 71.9, 71.2, 57.3, 52.9, 52.8, 51.7, 44.5, 39.3, 39.3,
26.4, 24.2; IR (CDCl3) 3022, 2954, 1732, 1698, 1436,
1374, 1291, 1211, 1071 cmꢁ1; mass spectrum (CI) m/z
413.1956 [C24H29O6 (M+1)], 413, 305 (base), 273, 245.
1
27 as a clear, yellow oil: H NMR (500 MHz) d 7.35–7.27
(comp, 5H), 5.13 (t, J¼7.4, 1.5 Hz, 1H), 4.57 (s, 2H), 4.07
(t, J¼1.0 Hz, 6H), 3.68 (s, 3H), 3.66 (s, 3H), 2.83 (br s, 2H,
C9-H), 2.81 (br s, 2H, C7-H), 1.95 (br q, J¼16.2, 8.1 Hz,
1H), 1.81 (m, 1H), 1.70 (s, 3H), 1.36 (m, 1H), 1.10 (m,
1H); 13C NMR (125 MHz) d 175.9, 170.5, 137.5, 128.4,
128.2, 127.8, 127.8, 121.1, 82.0, 78.8, 71.2, 57.1, 52.7,
30.7, 29.7, 22.8, 19.6, 17.3, 17.3; IR (CDCl3) 2952, 2259,
1735, 1698, 1436, 1291, 1211, 1070 cmꢁ1; mass spectrum
(CI) m/z 429.1907 [C16H19O5 (M+1) requires 429.1913],
399, 321, 279.
4.1.13. [2S,3S]-8-Benzyloxymethyl-7-hydroxymethyl-4-
methyl-3,3a,6,7-tetrahydro-1H-azulene-2,2-dicarboxylic
acid dimethyl ester. NaBH4 (2 mg, 0.029 mmol) was added
in one portion to a solution of 36 (6 mg, 0.014 mmol) in THF
(1 mL) at 0 ꢀC, and the mixture was stirred for 1 h 15 min.
Satd aq NH4Cl (1 mL) was added and the layers were sepa-
rated. The aqueous phase was extracted with EtOAc
(3ꢂ1 mL), and the combined organic fractions were dried
(Na2SO4), and concentrated under reduced pressure. The
crude residue was purified by flash chromatography eluting
with hexanes/EtOAc (3:1) to give 5 mg (83%) of the primary
alcohol as a clear, colorless oil: 1H NMR (500 MHz) d 7.35–
7.27 (comp, 5H), 5.50–5.48 (m, 1H), 4.53 (s, 2H), 4.03 (d,
J¼10.0 Hz, 1H), 3.79 (d, J¼10.0 Hz, 1H), 3.74 (s, 3H),
3.73 (s, 3H), 3.69 (dd, J¼13.9, 5.2 Hz, 1H), 3.64 (dd,
J¼10.6, 6.0 Hz, 1H), 3.60–3.55 (m, 1H), 3.17 (br d,
4.1.11. 2-(4-Benzyloxybut-2-ynyl)-2-[3-(2S,4S)-(2-form-
ylcyclopropyl)but-2-enyl]malonic acid dimethyl ester
(35). Oxalyl chloride (50 mL, 0.485 mmol) was added drop-
wise to a solution of 27 (104 mg, 0.242 mmol) and DMF (five
drops) in CH2Cl2 (2.5 mL) at 0 ꢀC. The reaction mixture
was allowed to warm to room temperature by removal of
the cooling bath and then stirred for 3 h. The mixture was
concentrated under reduced pressure, and the crude acid
chloride was dissolved in THF (2 mL). The solution was
cooled to ꢁ78 ꢀC, and a slurry of LiAlH(OtBu)3 (124 mg,
0.485 mmol) in THF (0.5 mL) was added. The reaction

B. L. Ashfeld, S. F. Martin / Tetrahedron 62 (2006) 10497–10506
10505
J¼16.7 Hz, 1H), 2.95–2.92 (m, 1H), 2.75 (ddd, J¼12.4, 7.4,
2.0 Hz, 1H), 2.42–2.35 (m, 2H), 2.28–2.20 (comp, 2H), 2.04
(t, J¼12.6 Hz, 1H), 1.71 (s, 3H); 13C NMR (125 MHz)
d 171.9, 171.7, 141.8, 137.9, 135.2, 130.7, 128.4, 127.8,
127.7, 123.2, 72.7, 72.2, 64.1, 57.0, 52.9, 52.8, 45.2, 42.9,
39.4, 39.2, 29.0, 23.8; IR (CHCl3) 3468, 3015, 2954, 1731,
1436, 1273, 1201, 1060 cmꢁ1; mass spectrum (CI) m/z
415.2124 [C25H31O6 (M+1) requires 415.2121], 415, 307
(base), 207, 247.
4.1.16. ((3aS,4Z,7S,8E)-8-(Benzyloxymethyl)-7-((tert-bu-
tyldimethylsilyloxy)methyl)-2-methanesulfonyloxy-
methyl-4-methyl-1,2,3,3a,6,7-hexahydroazulen-2-yl)-
methyl methanesulfonate (38). Methanesulfonyl chloride
(291 mg, 0.20 mL, 2.50 mmol) was added dropwise to a
stirred solution of the diol from the preceding experiment
(120 mg, 0.25 mmol) and Et3N (257 mg, 0.35 mL,
2.50 mmol) in CH2Cl2 (5 mL) at 0 ꢀC, and the resultant
mixture was stirred for 3 h. Satd aq NaHCO3 (5 mL) was
added, and the layers were separated. The aqueous phase
was extracted with Et2O (3ꢂ5 mL), and the combined
organic fractions were dried (Na2SO4), and concentrated
under reduced pressure. The crude residue was purified by
flash chromatography eluting with hexanes/EtOAc (2:1) to
provide 137 mg (79%) of 38 as a clear, colorless oil:
1H NMR (500 MHz) d 7.37–7.28 (comp, 5H), 5.48–5.44
(m, 1H), 4.49 (d, J¼11.6 Hz, 1H), 4.44 (d, J¼11.6 Hz, 1H),
4.21–4.06 (comp, 2H), 4.16 (d, J¼9.6 Hz, 1H), 4.08 (d,
J¼9.6 Hz, 1H), 3.92 (br s, 1H), 3.70–3.62 (comp, 2H),
3.51–3.44 (m, 1H), 3.03 (s, 3H), 3.03 (s, 3H), 2.54–2.53
(m, 1H), 2.42–2.25 (comp, 3H), 2.17 (dd, J¼13.2, 8.0 Hz,
1H), 1.70 (s, 3H), 0.88 (s, 9H), 0.01 (s, 6H); 13C NMR
(125 MHz) d 138.8, 138.2, 133.9, 133.1, 128.2, 127.6,
127.5, 123.4, 72.5, 72.3, 72.3, 72.1, 69.1, 62.7, 42.8, 37.2,
37.1, 36.6, 36.6, 31.4, 25.8, 24.3, 18.1, ꢁ5.1, ꢁ5.2; IR
(CDCl3) 3100, 3031, 2929, 2856, 2260, 1730, 1469, 1362,
1255, 1178, 1094, 978, 850, 778, 527; mass spectrum (CI)
m/z 629.2627 [C30H49O8SiS2 (M+1) requires 629.2638],
629, 557, 555 (base).
4.1.14. (3aS,4Z,7S,8E)-Dimethyl 8-((benzyloxy)methyl)-
3,3a,6,7-tetrahydro-7-[(t-butyldimethylsiloxy)methyl]-4-
methylazulene-2,2(1H)-dicarboxylate (37). TBSCl (24 mg,
0.16 mmol) was added in one portion to a solution of
imidazole (11 mg, 0.16 mmol) and the alcohol from the pre-
ceding experiment (32 mg, 78.0 mmol) in DMF (2 mL) at
room temperature, and the reaction mixture was stirred for
4 h. Satd aq NaCl (1 mL) was added, and the layers were
separated. The aqueous phase was extracted with Et2O
(3ꢂ1 mL), and the combined organic fractions were dried
(Na2SO4), and concentrated under reduced pressure. The
crude residue was purified by flash chromatography eluting
with hexane/EtOAc (2:1) to provide 33 mg (81%) of 37 as
a clear, colorless oil: 1H NMR (500 MHz) d 7.32–7.31
(comp, 5H), 5.42–5.41 (m, 1H), 4.47 (d, J¼12.0 Hz, 1H),
4.42 (d, J¼12.0 Hz, 1H), 3.96 (d, J¼10.0 Hz, 1H), 3.95 (d,
J¼10.0 Hz, 1H), 3.72 (s, 3H), 3.71 (s, 3H), 3.64 (app t,
J¼9.5 Hz, 1H), 3.59 (dd, J¼9.5, 5.5 Hz, 1H), 3.37–3.36
(m, 1H), 3.10 (d, J¼17.0 Hz, 1H), 2.96 (dd, J¼17.5,
2.5 Hz, 1H), 2.54 (m, 1H), 2.35–2.31 (m, 1H), 2.27–2.23
(m, 1H), 1.96 (app t, J¼13.0 Hz, 1H), 1.70 (d, J¼1.0 Hz,
3H), 0.84 (s, 9H), 0.03 (s, 6H); 13C NMR (125 MHz)
d 171.9, 171.9, 138.8, 138.4, 133.2, 131.9, 128.3, 127.6,
127.4, 123.4, 72.4, 71.8, 62.6, 57.4, 56.7, 52.7, 46.5, 41.7,
39.1, 25.8, 25.6, 17.9, ꢁ3.7; mass spectrum (CI) m/z
529.2957 [C30H45O6Si (M+1) requires 529.2985], 529,
421, 289 (base), 275.
4.1.17. [(3aE,5S,7Z,8aS)-4-(Benzyloxymethyl)-2,2,8-tri-
methyl-1,2,3,5,6,8a-hexahydroazulen-5-yl]methanol
(39). A 1.0 M solution of LiBHEt3 (0.71 mL, 0.71 mmol) in
THF was added to a solution of 38 (56 mg, 0.08 mmol) in
THF (2 mL) at room temperature, and the mixturewas stirred
for 8 h. The reaction mixture was then cooled to 0 ꢀC, 1 M
HCl (2 mL) was added, and the mixture was allowed to
warm to room temperature. The layers were separated, and
the aqueous phase was extracted with EtOAc (5ꢂ5 mL).
The combined organic fractions were washed with satd aq
NaCl (mL), dried (Na2SO4), and concentrated under reduced
pressure. The crude residue was then dissolved in THF
(1.7 mL), and a solution of TBAF (85 mg, 0.27 mmol) in
THF (0.3 mL) was added at room temperature. The reaction
was stirred for 3 h and then satd aq NaCl (5 mL) was added,
and the layers were separated. The aqueous phase was ex-
tracted with EtOAc (5ꢂ5 mL), the combined organic frac-
tions were dried (Na2SO4), and concentrated under reduced
pressure. The crude residue was purified by flash chromato-
graphy eluting with hexanes/EtOAc (2:1) to provide 20 mg
4.1.15. (3aS,4Z,7S,8E)-Dimethyl 8-((benzyloxy)methyl)-
3,3a,6,7-tetrahydro-7-[(t-butyldimethylsiloxy)methyl]-4-
methylazulene-2,2(1H)-diol. LiAlH4 (21 mg, 0.55 mmol)
was added to a stirred solution of diester 20 (145 mg,
0.27 mmol) in THF (3 mL) at 0 ꢀC. The reaction mixture
was allowed to warm slowly to room temperature and stirred
for 4 h. The mixture was then cooled to 0 ꢀC, and satd aq
potassium sodium tartrate (3 mL) was added, and the mix-
ture was stirred for 30 min at room temperature. The layers
were separated, and the aqueous phase was extracted with
EtOAc (5ꢂ5 mL). The combined organic fractions were
washed with satd aq NaCl (5 mL), dried (Na2SO4), and con-
centrated under reduced pressure to yield 120 mg (91%) of
diol as an opaque, colorless oil: 1H NMR (500 MHz)
d 7.34–7.28 (comp, 5H), 5.42–5.40 (m, 1H), 4.49 (d, J¼
11.6 Hz, 1H), 4.44 (d, J¼11.6 Hz, 1H), 3.97 (d, J¼10.4 Hz,
1H), 3.95 (d, J¼10.4 Hz, 1H), 3.71 (d, J¼9.2 Hz, 1H), 3.65
(d, J¼9.2 Hz, 1H), 3.74–3.57 (comp, 4H), 3.43–3.38 (m,
1H), 2.55–2.52 (m, 1H), 2.41–2.16 (comp, 6H), 1.71 (s,
3H), 0.88 (s, 9H), 0.01 (s, 6H); 13C NMR (125 MHz)
d 141.8, 138.5, 134.8, 131.5, 128.3, 127.8, 127.6, 122.7,
72.8, 72.1, 71.1, 67.4, 62.9, 45.7, 45.3, 44.5, 42.4, 42.2,
37.6, 37.5, 35.9, 18.3, ꢁ5.4, ꢁ5.4; mass spectrum (CI) m/z
473.3063 [C28H45O4Si (M+1) requires 473.3087], 473,
365, 233, 215 (base).
1
(70%) of 39 as a clear, colorless oil: H NMR (500 MHz)
d 7.38–7.27 (comp, 5H), 5.49–5.44 (m, 1H), 4.52 (s, 1H),
4.01 (d, J¼9.6 Hz, 1H), 3.75–3.68 (comp, 3H), 2.51 (app t,
J¼6.0 Hz, 1H), 2.47–2.78 (comp, 2H), 2.25 (dd, J¼16.0,
2.0 Hz, 1H), 2.20–2.18 (m, 1H), 2.13 (d, J¼16.0 Hz, 1H),
1.76 (ddd, J¼11.6, 7.6, 2.0 Hz, 1H), 1.68 (s, 3H), 1.51 (app
t, J¼12.0 Hz, 1H), 1.07 (s, 3H), 0.96 (s, 3H); 13C NMR
(125 MHz) d 147.2, 138.1, 137.2, 129.2, 128.4, 127.8,
127.7, 122.5, 72.7, 72.5, 64.3, 47.0, 46.0, 44.8, 43.3, 35.4,
29.4, 29.3, 26.8, 23.9; IR (CDCl3) 2955, 2247, 1602, 1454,
1365, 1307, 1058; mass spectrum (CI) m/z 325.2171
[C22H29O2 (M+1) requires 325.2168], 327, 323, 295, 247,
219 (base).

10506
B. L. Ashfeld, S. F. Martin / Tetrahedron 62 (2006) 10497–10506
4.1.18. Tremulenediol A (4). Palladium on carbon (10 wt %,
1 mg) was added to a solution of 39 (5 mg, 15.3 mmol) in
MeOH (0.1 mL) at room temperature. The atmosphere in
the flask was then replaced with H2 (1 atm) and the mixture
was stirred under an atmosphere of H2 (balloon) for 3 d.
The reaction mixture was then filtered through a pad of Cel-
ite, and the filtrate was concentrated under reduced pressure.
The crude residue was purified by flash chromatography elut-
ing with hexanes/EtOAc (1:1) to provide 3 mg (82%) of 4 as
a clear, colorless oil; [a]2D5 +40.0 (c 0.24, MeOH) [lit.1 [a]D
+41.7 (c 0.24, MeOH)]. Spectra were consistent with lit-
erature data:1 1H NMR (500 MHz) d 4.25 (d, J¼11.0 Hz,
1H), 4.02 (app t, J¼9.5 Hz, 1H), 3.84 (dt, J¼11.0, 1.5 Hz,
1H), 3.62 (dd, J¼9.5, 5.0 Hz, 1H), 3.10 (br t, J¼8.5 Hz, 1H),
2.57–2.54 (m, 1H), 2.29 (dd, J¼15.5, 2.5 Hz, 1H), 1.93 (br d,
J¼15.0 Hz, 1H), 1.84–1.81 (m, 1H), 1.80 (br d, J¼11.5 Hz,
1H), 1.79–1.74 (m, 1H), 1.61 (dd, J¼12.5, 3.0 Hz, 1H),
1.59–1.58 (m, 1H), 1.54–1.51 (m, 1H), 1.38 (br d,
J¼12.0 Hz, 1H), 1.07 (s, 3H), 0.87 (s, 3H), 0.82 (d,
J¼7.0 Hz, 3H); 13C NMR (125 MHz) d 145.8, 132.4, 65.8,
63.3, 48.0, 46.0, 45.5, 45.4, 37.0, 32.6, 31.6, 28.5, 26.9,
22.5, 11.6.
References and notes
1. Ayer, W. A.; Cruz, E. R. J. Org. Chem. 1993, 58, 7529–7534.
2. Davies, H. M. L.; Doan, B. D. J. Org. Chem. 1998, 63, 657–660.
3. Davies, H. M. L.; McAfee, M. J.; Oldenburg, C. E. M. J. Org.
Chem. 1989, 54, 930–936.
4. Davies, H. M. L. Tetrahedron 1993, 49, 5203–5223.
5. Wender, P. A.; Dyckman, A. J.; Husfield, C. O.; Kadereit, D.;
Love, J. A.; Rieck, H. J. Am. Chem. Soc. 1999, 121, 10442–10443.
6. Martin, S. F.; Hom, R. K.; Dwyer, M. P. Tetrahedron 1999, 40,
6721–6724.
7. Doyle, M. P.; Austin, R. E.; Bailey, A. S.; Dwyer, M. P.;
Dyatkin, A. B.; Kalinin, A. V.; Kwan, M. M. Y.; Liras, S.;
Oalmann, C. J.; Pieters, R. J.; Protopopova, M. N.; Raab,
C. E.; Roos, G. H. P.; Zhou, Q.-L.; Martin, S. F. J. Am.
Chem. Soc. 1995, 117, 5763–5775.
8. Berberich, S. M.; Cherney, R. J.; Colucci, J.; Courillon, C.;
Geraci, L. S.; Kirkland, T. A.; Marx, M. A.; Schneider, M.;
Martin, S. F. Tetrahedron 2003, 59, 6819–6832.
9. Kirkland, T. A.; Colucci, J.; Geraci, L. S.; Marx, M. A.;
Schneider, M.; Kaelin, D. E., Jr.; Martin, S. F. J. Am. Chem.
Soc. 2001, 123, 12432–12433.
10. Davidson, J. P.; Lubman, O.; Rose, T.; Waksman, G.; Martin,
S. F. J. Am. Chem. Soc. 2002, 124, 205–215.
11. Ashfeld, B. L.; Martin, S. F. Org. Lett. 2005, 7, 4535–4537.
12. Ashfeld, B. L.; Miller, K. A.; Smith, A. J.; Tran, K.; Martin,
S. F. Org. Lett. 2005, 7, 1661–1663.
13. Alcaraz, L.; Harnett, J. J.; Mioskowski, C.; Martel, J. P.; Le
Gall, T.; Shin, D.; Falck, J. R. Tetrahedron Lett. 1994, 35,
5449–5452.
14. Corey, E. J.;Myers,A.G.Tetrahedron Lett. 1984, 25, 3559–3562.
15. Neipp, C. E.; Humphrey, J. M.; Martin, S. F. J. Org. Chem.
2001, 66, 531–537.
16. Nakada, Y.; Yura, Y.; Murayama, K. Bull. Chem. Soc. Jpn.
1976, 49, 1072–1074.
17. Evans, P. A.; Nelson, J. D. Tetrahedron Lett. 1998, 39, 1725–
1728.
18. Evans, P. A.; Nelson, J. D. J. Am. Chem. Soc. 1998, 120, 5581–
5582.
19. Bouzide, A.; Sauve, G. Tetrahedron Lett. 1997, 38, 5945–5948.
20. Wipf, P.; Rahman, L. T.; Rector, S. R. J. Org. Chem. 1998, 63,
7132–7133.
4.1.19. Tremulenolide A (3). MnO2 (3.0 mg, 33.0 mmol)
was added to a solution of 4 (4.0 mg, 16.0 mmol) in CH2Cl2
(1 mL) at room temperature. The resulting mixture was
stirred for 24 h, filtered through a short plug of silica gel,
and concentrated under reduced pressure. The crude residue
was purified by flash chromatography eluting with hexanes/
EtOAc (5:1) to provide 3.4 mg (86%) of 3 as a clear, colorless
oil; [a]2D5 +99.6 (c 0.24, MeOH) [lit.1 [a]D +110.7 (c 0.14,
MeOH)]. Spectra results were consistent with literature
data:1 1H NMR (500 MHz) d 4.35 (app t, J¼8.5 Hz, 1H),
3.63 (dd, J¼10.5, 8.0 Hz, 1H), 3.23–3.20 (m, 1H), 3.12–
3.07 (m, 1H), 2.88 (dd, J¼19.0, 3.0 Hz, 1H), 2.47 (ddd,
J¼19.0, 4.5, 3.0 Hz, 1H), 2.17–2.11 (m, 1H), 2.08–2.02
(m, 1H), 1.86–1.80 (m, 1H), 1.78–1.71 (m, 1H), 1.50 (d,
J¼10.0 Hz, 1H), 1.50–1.43 (comp, 2H), 1.13 (s, 3H), 0.99
(s, 3H), 0.95 (d, J¼7.5 Hz, 3H); 13C NMR (125 MHz)
d 172.2, 161.7, 121.0, 70.8, 48.4, 45.5, 44.9, 41.0, 37.3,
32.9, 32.7, 29.1, 28.2, 27.4, 17.8.
21. Wender, P. A.; Dyckman, A. J. Org. Lett. 1999, 1, 2089–2092.
22. Ashfeld, B. L.; Miller, K. A.; Martin, S. F. Org. Lett. 2004, 6,
1321–1324.
Acknowledgements
Acknowledgement is made to the National Institute of
General Medical Sciences (GM 31077), the Robert A. Welch
Foundation, Pfizer, Inc., and Merck Research Laboratories
for their generous support of this research.
23. Morohashi, A.; Satake, M.; Nagai, N.; Oshima, Y.; Yasumoto,
T. Tetrahedron 2000, 56, 8995–9001.
24. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923–
2925.