Modular Total Syntheses of Hyperforin, Papuaforins A, B, and C via Gold(I)-Catalyzed Carbocyclization

Article abstract of DOI:10.1021/acs.joc.8b00426

The remarkable biological activities of polyprenylated polycyclic acylphloroglucinols (PPAPs) combined with their highly oxygenated and densely functionalized frameworks have stimulated the interest of synthetic organic chemists over the past decade. Here

Full text of DOI:10.1021/acs.joc.8b00426

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Article
Modular Total Syntheses of Hyperforin, Papuaforins
A, B and C via Gold(I)-Catalyzed Carbocyclization
Gabriel Bellavance, and Louis Barriault
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00426 • Publication Date (Web): 07 May 2018
Downloaded from http://pubs.acs.org on May 7, 2018
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Modular Total Syntheses of Hyperforin, Papuaforins A,
B and C via Gold(I)ꢀCatalyzed Carbocyclization
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Gabriel Bellavance# and Louis Barriault*
Centre for Catalysis, Research and Innovation, Department of Chemistry and Biomolecular Sciences,
University of Ottawa, Ottawa, Canada K1N 6N5.
Louis.Barriault@uottawa.ca
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RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
O
O
R1
OSiR3
R2
LAu+ (5 mol%)
acetone, rt
7 steps
O
R2
OMe
O
R1
Br
Br
(> 10g prepared)
9 steps
O
O
O
O
O
OH
O
O
O
O
O
R
O
Hyperforin
Papuaforin B
R = H, Papuaforin A
R = Me, Papuaforin C
ABSTRACT: The remarkable biological activities of polyprenylated polycyclic acylphloroglucinols
(PPAPs) combined with their highly oxygenated and densely functionalized frameworks have
stimulated the interest of synthetic organic chemists over the last decade. Herein, we report the concise
total syntheses of four natural products PPAPs of which some have antibacterial properties notably
hyperforin and papuaforin A. The salient features of this strategy are the short and gramꢀscalable
synthesis of densely substituted PPAPs scaffolds via a Au(I)ꢀcatalyzed carbocyclization and the lateꢀ
stage functionalization for an unified access to a wide variety of PPAPs
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INTRODUCTION
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Isolated from the Guttiferae plants, polycyclic polyprenylated acylphloroglucinols (PPAPs) are
naturally occurring molecules possessing a distinctive densely substituted and highly oxygenated
bicyclo[3.3.1]nonanone framework. These compounds are mainly classified in three groups; A, B and
C (Figure 1). The compounds in group A are characterized by an acyl moiety at C1 adjacent to an all
quaternary carbon center at C8, while in group C, the acyl moiety on C5 is contiguous a methylene
group. PPAPs belonging in group B are depicted with an acyl group located on C3. More than 200
members of this family have been isolated to date and most of them display a wide range of biological
activities. Isolated from St. John’s wort, hyperforin (1) is probably to most studied natural product of
this family showing promising antidepressant therapeutic properties.1 Through a unique mechanism,
hyperforin (1) prevents the reꢀuptake of various neurotransmitters.2 It was also found that 1 possesses
antimalarial, antimetastatic and antibacterial activities against MRSA bacteria with a minimal inhibitory
concentration of 1.86 ꢀmol.3 Other PPAPs such as papuaforins A, B and C (2ꢀ4) isolated from
Hypericum papuanum found in Papua New Guinea possess modest antibacterial properties activity.4
The structural complexity of PPAPs combined with their therapeutic profiles have stimulated the
genesis of numerous synthetic strategies.5 These strategies culminated in the successful syntheses of
various PPAPs6 including hyperforin (1),7 nemorosone (5),8 and garsubellin A (6).9 In 2014, our group
reported the modular syntheses of hyperforin (1) and papuaforins AꢀC (2ꢀ4) via a gold(I)ꢀcatalyzed
cyclization.10 In this article, a detailed investigation of the synthesis of these molecules is described.11
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Figure 1. Structures of various PPAPs
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RESULTS AND DISCUSSION
Previous work from our group revealed that bicyclic ketone framework 10 can be easily synthesized
through a 6ꢀendo dig gold(I)ꢀcatalyzed carbocyclization of 1,5ꢀenyne 7 using catalyst 8 (Scheme 1).12,13
Taking advantage of this method, we delineated a blueprint in which the bicyclo[3.3.1]nonenone core
11 could serve as a central intermediate for the construction various PPAPs including 1ꢀ4 via lateꢀstage
functionalization at C1 and C3. However, we took early cognizance that the formation of carbonꢀ
carbon at C1 bond adjacent to a quaternary carbon center (C8) might be challenging. From
commercially available enone 15, we devised a modular approach in which the functional groups at C5,
C7 and C8 would be installed through a carefully coordinated sequence of stereoselective alkylation,
allylation and aldol reactions (13→12). To validate our synthetic plan, a model substrate for the gold(I)ꢀ
catalyzed cyclization was thus prepared.
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R2
OTBS
O
O
O
1
2
3
4
TBSO
R1
EtO
EtO
O
8 (2 mol%)
OEt
[AuL1]
acetone, rt
R1
R1
R2
7
10
R2
5
9
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O
1
R1
R2
OSiR3
R2
[Au]
O
8
R3
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R1
Y
O
11
12
Y
2-4
R1
[R3Cu]
O
tBu
tBu
SbF6
P
Au NCMe
O
X
OMe
13
15
8
R2
TMS
O
14
Scheme 1. Retrosynthetic analysis
A oneꢀpot allylation/alkylation on the commercially available ketone 15 using LDA and allylbromide
followed by the addition of MeLi and subsequent addition HCl (1N) provided enone 16 in 83% yield
(Scheme 2). A second alkylation with LiHMDS and MeI afforded ketone 17 in 87% yield. The latter
was then subjected to LDA and proparyl bromide to give 18 in 62% yield as a 3:1 mixture of
diastereomers. Treatment of enone 18 with a catalytic amount of CuI, dimethyl sulfide and MeMgBr
provided ketone 19 in 53% yield which was converted to the corresponding silylenol ether 20 in 46%.
Pleasingly, the exposure of 20 to the phosphino gold catalyst 8 (2 mol%) in dichloromethane afforded
the desired bicyclic ketone 21 in 88% yield. Encouraged by these results, we turned our attention
toward the functionalization of carbon centers C1, C2 and C4. After analyzing various scenarios, we
opted to install the ketone at C4 prior to Au(I)ꢀcyclization and the acyl group at C1 via a direct acylation
on the bicyclo[3.3.1]nonane core. This modular approach would allow the synthesis of hyperforin (1),
papuaforin AꢀC (2ꢀ4) and other PPAPs from common intermediates.
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Scheme 2. Preliminary study
As shown in Scheme 3A, enone 17 was converted to the aldol product 22 in 67% yield which
underwent a organocuprate addition followed by an oxidation to give ketone 23 in 72% yield over two
steps. The replacement of the TMS group by a bromide using AgNO3 and NBS delivered the
bromoethynyl 24 in 93% yield. The latter was then transformed to the corresponding TBSꢀenol 25 using
TBSOTf and 2,6ꢀdiꢀtertꢀbutylꢀ4ꢀmethylpyridine (DTMP) in 78% yield.
Using 5 mol% of
[(JohnPhos)Au(NCMe)][SbF6] (8) in acetone, the enol ether 25 was directly converted into the desired
bicyclic ketone 26 in 93% yield. It is important to notice that the gold(I)ꢀcarbocyclization operated in a
sterically crowded environment and the reaction can be performed on a multiꢀgram scale (>10g).
Finally, the treatment of 26 with a solution of sodium methoxide in methanol led to the formation of
enone 27 in 89% yield having the proper functional groups at C2 and C4.
Drawing inspiration from the work of Danishefsky9b and Simpkins,8b,9c we envisaged the introduction
of the acyl group C1 through a deprotonation/acylation process (Scheme 3B). First, treatment of 27
with LiTMP and freshly distilled TMSCl gave the C3ꢀTMS enone 28 in 94% yield. Preliminary efforts
at direct acylation at C1 using nꢀBuLi, tꢀBuLi and amide lithium bases and various acylating agents
were fruitless. After substantial experimentation, we found that deprotonation using LDA (3.5
equivalents) in the presence of TMSCl (5 equivalents) at ꢀ78 °C in THF followed by the addition of
molecular iodine gave the desired iodoketone 29 in 29% yield along with a significant quantity of byꢀ
product 30 (42% yield). The relative stereochemistry of both structures was confirmed by Xꢀray
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analysis. In an effort to prevent the formation of 30, various conditions for the deprotonation using other
hindered bases such as LiTMP and lithium isopropylꢀtertꢀbutyl amide were examined. Unfortunately,
lower yields ranging from <5% to 15% for the formation of 29 were observed in all cases. Although a
competitive LDAꢀmediated reduction was operative,14,8c we took some solace in the fact that the
formation of iodoketone 29 proved to be reproducible and amenable to gramꢀscale synthesis. In
addition, the reduced product 30 can be easily recycled to 28 in high yields by a selective TMSꢀ
deprotection using K2CO3/MeOH followed by an oxidation. Next, we investigated the metalation
through an iodoꢀlithium exchange followed electrophile addition. A rapid survey of various conditions
rapidly identified tertꢀBuLi as the base of choice. Surprisingly, direct acylation using various acyl
chlorides or cyanides did not lead to the desired product, only deiodonated product 28 was recovered.
However, iodoꢀlithium exchange followed by the addition of isobutyraldehyde led to alcohol 31, which
was oxidized to the corresponding ketone. Finally, the latter was treated with TBAF to deliver 32 in
45% yield over three steps.
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TMS
R
A
1
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O
O
1) MeMgBr, CuI
LDA, 14
TBSOTf, DTMP
CH2Cl2, 78%
17
HO
O
THF, 67%
2) DMP, DCM
72% over 2 steps
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22
23 R = TMS
24 R = Br
AgNO3, NBS
acetone, 93%
8
9
O
O
O
OTBS
8 (5 mol%)
O
MeONa
MeOH, 89%
O
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Br
acetone, r.t.
93%
OMe
Br
25
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B
1) K2CO3, MeOH
2) DMP, DCM
90% over 2 steps
O
O
TMSO
H
LDA (3.5 equiv.)
TMSCl (5 equiv, THF
O
O
O
+
R
OMe
LiTMP
TMS
OMe
TMS
then I2
I
OMe
27 R = H
30 (42%)
29 (29%)
X-ray
TMSCl, 94%
X-ray
28 R = TMS
t-BuLi, i-PrCHO
THF, -78 °C
O
O
O
O
1) DMP, DCM
TMS
OMe
32
2) TBAF, THF
45% (3 steps)
OMe
O
OH
31
Scheme 3. Synthesis of PPAPs core via gold(I)ꢀcarbocyclization and functionalization at C1
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Total Synthesis of Papuaforins A (2), B (3) and C (4)
With conditions to functionalize at C1 in hand, we envisioned the completion of papuaforins AꢀC (2ꢀ
4) by constructing first the pyran moiety and then installing the acyl unit at C1 (Scheme 4). Upon a
cursory inspection of the papuaforin core, one can propose that the pyran ring system could originate
from a 6 ꢀelectrocyclization of dienone 34. Although a Knoevenagel condensation was originally
considered, an approach involving oxidation of the prenyl unit to generate intermediate 34 was the
privileged option. To test this idea, bromoenone 26 was converted to the corresponding allyl ether 35 in
81% yield by treatment with a solution of NaOallyl/allylOH at 50 °C. The latter was then converted to
36 through a Claisen rearrangement in 84% yield. A crossꢀmetathesis followed by oxidation of the
prenyl unit at C3 using PdCl2 and O2 in wet DMSO/H2O (9:1) produced the corresponding dienone 34
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which underwent a spontaneous 6πꢀelectrocyclization to provide pyrans 33 and 37 as a separable
mixture of 2:1 in 33% overall yields.15 To complete the synthesis of 2ꢀ4, installation of the acyl group at
C1 was attempted using the LDA deprotonation/iodination protocol. To our dismay, no desired products
38 and 39 were detected; starting materials 33 and 37 were mostly recovered along with a small quantity
of the corresponding reduced products. In addition, deuteriumꢀlabelling experiments confirmed that no
deprotonation reaction operated at C1 suggesting that pyran ring might be detrimental to reaction.16
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O
O
O
O
O
O
O
O
R = H, Papuaforin A (2)
R = CH3, Papuaforin C (4)
R
O
Papuaforin B (3)
O
O
6eπ
O
O
O
33
O
O
Br
34
26
R
O
O
O
O
O
Na, AllylOH
r.t., 81%
140°C
26
PhMe, 81%
OH
O
35
36
1) Grubbs 2nd (5 mol%)
isoamylene, DCM
2) PdCl2, O2
DMSO/H2O
O
O
O
O
6eπ
+
O
O
34
33
37
LDA, TMSCl
then I2 or D2O
LDA, TMSCl
then I2 or D2O
O
O
O
O
+
Y
Y
O
O
38 Y = I or D
39 Y = I or D
Scheme 4. Formation of the pyran ring of the papuaforins
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Taking into consideration these results, we revised our strategy to include the
1
2
oxidation/electrocyclization as the last synthetic step. Surprisingly, the installation of the allyl chain at
C3 via a Claisen strategy did not follow previous findings (e.g. 35→36). The rearranged product 40
along with a minor isomer was isolated after treatment of 32 with a solution of NaOallyl in allylic
alcohol at 80 °C. One can explain the formation of compounds 40 through retroꢀ
Dieckman/decarboxylation process followed by an aldol reaction. The structure of 41 was determined
by singleꢀcrystal Xꢀray analysis. To connect the prenyl group at C3, enone 32 was exposed to LDA in
the presence of Li(2ꢀTh)CuCN and allyl bromide to produce the allyl 41 in 98% yield followed by
global crossꢀmetathesis to afford 42 in 99% yield. The latter was subjected to a one potꢀ
demethylation/oxidation/electrocyclization with LiCl in DMSO followed by the Pdꢀmediated oxidation
to generate papuaforin A (2) in 24% yield and papuaforin B (3) in 12% yield. Papuaforin C (4) was
prepared using a similar synthetic approach. Intermediate 43 was readily obtained from following the
three steps sequence illustrated in Scheme 5. It is important to outline that only one diastereoisomer
was observed at C12 but the relative stereochemistry was not established. Nevertheless, prenyl 45 was
carried through the final sequence to give papuaforin C (4) in 41% yield which was spectroscopically
identical to the natural product.
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O
HO
O
O
X-Ray
Na, AllylOH
80°C
H
OMe
32
OMe
O
40
LDA, [Li(2-Th)]CuCN
AllylBr, THF 98%
O
O
O
R
O
O
O
LiCl, DMSO
R
+
R
then PdCl2, O2
O
O
OMe
O
O
O
R
Papuaforin B (3)
Papuaforin A (2)
41 R = H
GII, i-amylene
DCM, 99%
(12%)
(24%)
42 R = Me
R
O
O
O
R
R
R
O
O
O
1) t-BuLi,
LiCl, DMSO
LDA, AllylBr
i-BuCHO
29
then PdCl2, O2
41%
[Li(2-Th)]CuCN
THF 82%
2) DMP, DCM
3) TBAF, THF
63% (over 3 steps)
OMe
O
O
12
OMe
12
O
O
43
44 R = H
GII, i-amylene
DCM, 99%
Papuaforin C (4)
45 R = Me
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Scheme 5. Total synthesis of papuaforins A (2), B (3) and C (4)
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4
Total Synthesis of Hyperforin (1)
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8
Having secured the synthesis of 2ꢀ4, we turned our attention to completing the synthesis of hyperforin
(1). At the outset of our retrosynthetic analysis, we imagined that the conjugate addition of the
homoallylic chain on 46 would proceed anti to the allylic chain at C7 to give alcohol 47 (Scheme 6A).
This hypothesis was based on the work of Tostain and Riviere showing that the addition alkyl cuprates
to γꢀsubstituted cyclohexꢀ2ꢀenones 48 gives mainly the anti product 47 presumably through a boat like
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transition state (48→50).17 Alcohol 46 was readily prepared from compound 16 following the same
synthetic route previously described in Scheme 3. The cuprate addition of homoallyl unit to 46 followed
by oxidation with the DessꢀMartin periodinane provided the corresponding ketone with the correct
stereochemistry at C8 (46→47). Although the relative configuration of the major product was not
determined, we continued the synthesis of the hyperforin core following the previous protocols (Scheme
6B). To our surprise, single crystal Xꢀray analysis of the major product 51 revealed that the homoallylic
chain was syn to allyl group which indicated that the cuprate addition did not correlate with Tostain and
Riviere’ findings. These results suggest that the cuprate reaction on enone 46 proceeds via chairꢀlike
transition state (48→49) favoring the synꢀaddition product. In order to obtain the correct
stereochemistry at C8, the homoallyl chain must be installed first on the cyclohexenone framework.
Starting from 15, enone 52 was readily prepared in 83% yield via oneꢀpot allylation/alkylation using
homoallyl magnesium bromide (Scheme 6C). A second allylation followed (52→53) by an aldol
reaction using LDA and aldehyde 14 afforded the desired alcohol 54 as the major diastereomers in 63%
yield (d.r. 5:1:1). The relative stereochemistry of 54 was subsequently established by Xꢀray analysis
(see supporting info for details). Gratifyingly, the addition of dimethyl cuprate addition followed by an
oxidation gave ketone 55 in 73% yield over two steps as the sole diastereomer (d.r. > 20:1). The high
diastereoselectivity of the reaction could be rationalized via the formation of a Mgꢀchelated intermediate
60 in which the axial substituent blocks the top face. Consequently, one can imagine that this
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conformation favors the syn addition of the organocuprate leading to the formation of 47.18,6l Following
the previous established sequence, ketone 55 was efficiently converted the desired bicyclic ketone 59 in
high yields. Silyation at C3 using LiTMP and TMSCl provided the key intermediate 61 in 94% yield.
The relative stereochemistry of 61 was confirmed without ambiguity by single crystal Xꢀray analysis.
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OH
Hypothesis
syn
R2
R4
O
O
R1
O
O
R3
Hyperforin (1)
chair-like
R1
49 Minor
O
+
R4Cu
R3
R2
R3
boat-like
anti
48
R1
HO
OTBS
HO
O
[Cu]
R3
R4
50 Major
TMS
TMS
7
7
46
47
B
O
HO
O
1) LiHMDS, allylBr
THF, 72%
O
6 steps
16
X-Ray
2) LDA, 14, 63%
TMS
OMe
51
46
C
O
O
O
HO
O
LDA, 14
THF -78°C
i) LiHMDS, allylBr
THF
1) MgBr, CuI
THF-DMS
R
15
63% (d.r. = 5:1:1)
TMS
ii)
2) DMP, DCM
73% d.r.> 20:1
TMS
MgBr
then HCl (1N)
83%
55
54
52 R = H
LiHMDS
THF 72%
53 R = allyl
AgNO
3, NBS
acetone, 94%
O
O
O
O
O
OTBS
O
8 (5 mol%),
acetone
O
TBSOTf, DTMP
DCM, 91%
LiTMP, TMSCl
THF 94%
TMS
Br
Br
r.t., 99%
Y
OMe
58 Y = Br
61
MeONa
MeOH, 78%
56
57
59 Y = OMe
X-Ray
R
O
H
R
BrMg
HO
O
H
H
7
7
chair-like
O
60
syn
47
[MeCu]
Scheme 6. Synthesis of intermediate 61
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Ketone 61 was subjected to the deprotonation/iodination conditions to provide 62 in 18% yield along
with 41% yield of reduced product 63 and starting material 61 (35%) (Scheme 7). Iodoꢀ
lithium/alkylation of 63 with isobutyraldehyde to furnish alcohol 64 which was oxidized and then
treated with TBAF to give the desired ketone 65 in 24% overall yield in three steps. Allylation and
crossꢀmetathesis with isobutylene in the presence of Grubbs II (5 mol%) led to tetraprenylated
intermediate 67 in 85% yield.7c Finally, demethylation in hot solution of LiCl in DMSO unveiled
hyperforin (1) in 69% yield concluding this synthetic journey.
1
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17
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60
O
TMSO
H
O
LDA (3.5 equiv.)
TMSCl (5 equiv, THF
O
+
TMS
OMe
TMS
OMe
61
then I2
I
62 (X-Ray)
63
t-BuLi, i-PrCHO
THF, -78 °C
O
O
O
O
GII (5 mol%),
1) DMP, DCM
R
TMS
isobutylene, 120°C
85%
2) TBAF, THF
24% (3 steps)
OMe
OMe
OH
O
65 R = H
64
1) LDA, (Li(2-Th)CuCN
AllylBr, THF 91%
66 R = CH2CH=CH2
O
O
OH
O
LiCl, DMSO
160°C 69%
O
O
OR
O
Hyperforin (1)
67
Scheme 7. Total synthesis of hyperforin (1)
CONCLUSION
The main objective of this study was to establish a short and modular approach allowing the synthesis
of papuaforins AꢀC (2ꢀ4) and hyperforin (1) from common intermediates. Some of the significant
features of the synthesis include: (1) a short synthesis and multigramꢀscale of the
bicyclo[3.3.1]nonanones 11 via an effective gold(I)ꢀcatalyzed carbocyclization; (2) stereoselective
additions and lateꢀstage functionalization of 11 allowing access to a wide variety of PPAPs. This
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The Journal of Organic Chemistry
modular approach can be utilized to rapidly build PPAPs and its derivatives for further biological
investigations.
1
2
3
4
5
6
7
8
EXPERIMENTAL SECTION
9
All reactions were performed under nitrogen or argon atmosphere in flameꢀdried glassware equipped
with a magnetic stir bar and a rubber septum, unless otherwise indicated. All solvents were freshly
distilled prior to use; diethyl ether and THF over sodium and benzophenone; toluene, triethylamine, and
DCM over calcium hydride. All other commercial reagents were used without purification, unless
otherwise noted. Reactions were monitored by thin layer chromatography (TLC) analysis of aliquots
using glass sheets preꢀcoated (0.2 mm layer thickness) with silica gel 60 F254. Thin layer
chromatography plates were viewed under UV light and stained with phosphomolybdic acid or pꢀ
anisaldehyde staining solution. Flash chromatography was carried out with silica gel 60 (230ꢀ400
10
11
12
13
14
15
16
17
18
19
20
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23
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60
1
mesh). H and 13C NMR spectra were recorded on a 400 MHz spectrometer and chemical shifts (δ) are
13
13
reported in parts per million (ppm) with reference to CDCl3 (1H: 7.26; C: 77.1). Assignments of C
signal were made by DEPT experiments. IR spectra were recorded with a FTIR spectrometer. HRMS
were conducted by the John L. Holmes Mass Spectrometry Facility at the University of Ottawa using a
Kratos Concept instrument equipped with magnetic sector electron and electron multiplier detector.
Melting points were measured in capillary tubes and were uncorrected.
rac-4-Allyl-3-methylcyclohex-2-enone (16). A solution of nꢀBuLi (2.4 M in hexanes, 0.233 mL, 8.72
mmol) was added slowly to freshly distilled diisopropylamine (1.30 mL, 9.12 mmol) in THF (30 mL) at
−78 °C and the solution was stirred for 30 min at ꢀ78 °C and 15 min at 0 °C before being cooled to ꢀ78
°C. A solution of 3ꢀmethoxycyclohexꢀ2ꢀenone (15) (1 g, 7.93 mmol) in THF (3 mL) was cannulated at
−78°C and the solution was stirred for 60 min to obtain a slurry. Allyl bromide (0.857 mL, 9.91 mmol)
was added in one portion, the mixture was stirred 60 min at ꢀ78 °C and 3 h at r.t. The solution was then
cooled to ꢀ78 °C and MeLi (1.5 M in Et2O, 13.2 mL, 19.8 mmol) was added in one portion. The
resulting mixture was stirred for 30 min at ꢀ78 °C. It was then warmed to r.t. and stirred for one more
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hour. A solution of 1 M of HCl (30.0 mL) was then added and stirred vigorously for 1 h. Water (30.0
ml) was then added with brine (30.0 mL) and Et2O (30.0 mL), the phases were separated and the
aqueous layer was extracted with ethyl acetate (3x), and the combined organic phases were dried over
MgSO4, filtered and concentrated. The crude oil was purified by chromatography (7ꢀ15%
EtOAc:hexanes) to give 16 (0.785 g, 66%) as a clear yellow oil. Spectral data was in accordance with
reported data and full characterization is available through the literature.19
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rac-4-allyl-3,6-dimethylcyclohex-2-enone (17). LiHMDS (19.5 g, 113 mmol) was charged to 1 L
flame dried flask. THF (500 mL) was added at r.t. and stirred, once all LiHMDS was dissolved the
solution was cooled to −78 °C and 16 (15.5 g, 103 mmol) in THF (30.0 mL) was added via cannula to
the solution. The solution was stirred 1h at ꢀ78 °C, 1h at ꢀ43 °C and iodomethane (7.68 mL, 123 mmol)
was added. The mixture was allowed to warm to r.t. and stirred for 3ꢀ4 h. A saturated solution of NH4Cl
was added and the aqueous layer was extracted with ether (3x). The combined organic phases were
dried over MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography
(3ꢀ7% EtOAc:hexanes) to give 17 (14.8 g, 87%) as a lightly yellow oil. IR (neat film NaCl) 3077, 2964,
2930, 2872, 1673, 1639, 1443, 1378 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 1.09 (d, J = 6.9 Hz, 3H), 1.71ꢀ
1.80 (m, 1H), 1.95 (s, 3H), 1.99 (ddd, J = 13.5, 4.8, 2.8 Hz, 1H), 2.18ꢀ2.33 (m, 2H), 2.37ꢀ2.48 (m, 2H),
13
5.07ꢀ5.12 (m, 2H), 5.79 (s, 1H), 5.74ꢀ5.85 (m, 1H); C NMR (100 MHz, CDCl3) δ ppm 15.4 (CH3),
22.9 (CH3), 34.5 (CH2), 35.6 (CH2), 35.9 (CH), 39.2 (CH), 117.1 (CH2), 126.4 (CH), 136.5 (CH), 164.0
(C), 201.9 (C); HRMS (EI) m/z: [M+] Calcd for C11H16O 164.1201; Found: 164.1205.
rac-4-allyl-3,6-dimethyl-6-(prop-2-ynyl)cyclohex-2-enone (18). A solution of nꢀBuLi (1.60 M in
hexanes, 21.8 mL, 35.0 mmol) was added slowly to diisopropylamine (5.17 mL, 36.6 mmol) in THF
(150 mL) at −78 °C for 45 min. 17 (5.00 g, 33.3 mmol) was added at −78 °C for 60 min and then
propargyl bromide (2.49 mL, 39.9 mmol) was added. The mixture was stirred at r.t. for 3 h. An aqueous
saturated solution of NH4Cl was added and the aqueous layers were extracted with ethyl acetate (3x).
The combined organic phases were dried over anhydrous magnesium sulfate, filtered and the solvent
was evaporated. The crude residue was purified by flash chromatography (10% EtOAc:hexanes) to give
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The Journal of Organic Chemistry
enone 18 (4.92 g, 90%) as a mixture of diastereomer (d.r. = 3:1). Major isomer: IR (neat NaCl):
3305(br.) 3305, 3077, 2976, 2930, 1674 cmꢀ1 1
1
2
3
;
H NMR (400 MHz, CDCl3) δ 5.78 (s, 1H), 5.69 (m, 1H), 5.10
4
5
(m, 2H), 2.49 (m, 2H), 2.35 (m, 1H), 2.15 (m, 3H), 2.01 (t, J = 2.6 Hz, 1H), 1.93 (s, 3H), 1.57 (dd, J = 13.8,
6
7
8
13
10.3 Hz, 1H), 1.16 (s, 3H); C NMR (400 MHz, CDCl3) δ 202.6 (C), 163.0 (C), 135.3(CH), 126.5 (CH),
9
118.1 (CH2), 80.5 (C), 71.4 (CH), 44.0 (C), 38.5 (CH2), 36.9 (CH), 36.7 (CH2), 26.8 (CH2), 22.3 (2 x
10
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60
CH3);
HRMS (EI) m/z: [M+] Calcd for C14H18O 202.1358; Found 202.1379.
rac-4-Allyl-2,5,5-trimethyl-2-(prop-2-ynyl)cyclohexanone (19). To a solution of CuI (63.0 mg, 0.33
mmol) and enone 18 (306 mg, 1.52 mmol) in THF (15.0 mL) and Me2S (1.50 mL) at 0 °C was slowly
added MeMgBr (1.11 mL, 3.0 M in Et2O, 3.33 mmol) over 1 hour. The mixture was then stirred 1 h at 0
°C, then the reaction was stopped by adding NH4Cl aqueous solution, and extracted with Et O. The
2
organic phase was dried over MgSO4 and evaporated in vacuo. The residue was purified by column
chromatography to provide 19 (176 mg, 53%) a dark orange oil. IR (neat NaCl) 3310, 3076, 2965, 2931,
2871, 2124, 1716, 1640, 1436 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 5.76 (m, 1H), 5.02 (m, 2H), 2.49 (m,
0.5H), 2.45 (m, 1H), 2.37 (m, 2H), 2.33 (m, 0.5H), 2.00 (m, 2.5H), 1.70 (m, 2.5H), 1.26 (t, 1H), 1.09 (s,
13
3H), 1.04 (s, 3H), 0.96 (m, 1H), 0.73 (m, 3H); C NMR (400 MHz, CDCl
3
) δ 213.2 (C), 137.6 (CH),
116.3 (CH2), 79.5 (C), 71.5 (CH), 52.9 (CH2), 48.0 (C), 41.5 (CH), 40.0 (CH2), 39.3 (C), 34.2 (CH2),
29.8 (CH3), 27.8 (CH2), 22.2 (CH3), 20.1 (CH3); HRMS (EI) m/z: [M+] Calcd for C15H22O 218.1671;
Found 218.1659.
rac-4-Allyl-2,5,5-trimethyl-2-(prop-2-ynyl)cyclohexanone (20). Ketone 19 (300 mg, 1.37 mmol)
was dissolved in acetonitrile (30.0 mL), and Et3N (0.383 mL, 2.74 mmol) was added. Then flameꢀdried
NaI (0.309 g, 2.04 mmol) and TBSCl (310 mg, 2.04 mmol) were added. The reaction mixture was
allowed to reflux overnight and was then quenched with NaHCO3 saturated solution, and the aqueous
phase was extracted with DCM (3x). The organic phases were then combined, dried and concentrated.
The resulting mixture was filtered through a small silica pad and washed with solution of 7% EtOAc in
hexanes and concentrated again. The crude enol ether 20 (209 mg, 46%) was then directly used for the
next reaction without further purification.
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rac-7-Allyl-5,8,8-trimethylbicyclo[3.3.1]non-2-en-9-one (21). A solution of silyl enol ether 20 (20.0
mg, 0.060 mmol) and (acetonitrile)[(2ꢀbiphenyl)diꢀtertꢀbutylphosphine]gold(I) (0.92 mg, 0.0012 mmol)
in DCM (1 mL) was stirred for 6 h at r.t. The solvent was evaporated and the residue was purified by
flash column chromatography on silica (10% EtOAc:hexanes) to give 21 (11.2 mg, 88%) as a white
solid. IR (neat NaCl) 3081, 3039, 2967, 2921, 1709, 1449, 918 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 5.82
(m, 1H), 5.76 (m, 1H), 5.63 (dddd, J = 9.5 Hz, 6.0 Hz, 1.9 Hz, 1.9 Hz, 1H), 5.03 (m, 1H), 2.41 (m, 3H),
2.25 (m, 1H), 2.03 (m, 1H), 1.82 (dd, J = 13.9 Hz, 4.5 Hz, 1H), 1.59 (ddd, J = 13.7 Hz, 10.8 Hz, 8.6 Hz,
1
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60
13
2H), 1.28 (m, 4H), 1.02 (s, 3H), 0.99 (s, 3H), 0.79 (s, 3H); C NMR (400 MHz, CDCl3) δ 216.5 (C),
138.0 (CH), 129.8 (CH), 126.6 (CH), 116.0 (CH2), 60.3 (CH), 46.0 (CH2), 45.6 (CH2), 42.4 (C), 38.1
(CH), 34.1 (C), 29.7 (CH2), 26.1 (CH3), 23.5 (CH3), 20.8 (CH3); HRMS (EI) m/z: [M+] Calcd for
C15H22O 218.1671; Found 218.1652.
rac-4-Allyl-6-(1-hydroxy-3-(trimethylsilyl)prop-2-ynyl)-3,6-dimethylcyclohex-2-enone (22). A
solution of nꢀBuLi (9.8 M in hexanes, 5.18 mL, 50 mmol) was added slowly to freshly distilled
diisopropylamine (7.57 mL, 53.1 mmol) in THF (250 mL) at −78°C and the solution was stirred for 30
min at ꢀ78°C and 15 min at 0°C. 4ꢀAllylꢀ3,6ꢀdimethylcyclohexꢀ2ꢀenone (17) (7.93 g, 48.3 mmol) was
added via cannula to the solution at ꢀ78 °C. After stirring for 60 min, 3ꢀ(trimethylsilyl)propiolaldehyde
(7) (7.32 g, 58 mmol) was added and the mixture was stirred at ꢀ78 °C for 10 min. The resulting mixture
was quenched with a saturated solution of NH4Cl at ꢀ78 °C. Distilled water was added and the aqueous
layer was extracted with EtOAc:Et2O 1:3 (3x). The combined organic phases were dried over MgSO4,
filtered and concentrated. The crude residue was purified by chromatography (5ꢀ15% EtOAc:hexanes)
to give alcohol enone (22) (9.39 g, 67%) as a mixture of two diastereomer at C4. Major diastereomer
at C4: M.p. 53ꢀ54 °C; IR (neat NaCl) 3421, 2928, 2856, 1657, 1471, 1249, 1060, 838, 811, 776 cmꢀ1;
1H NMR (400 MHz, CDCl3) δ 0.16 (s, 9H), 1.20 (s, 3H), 1.71 (dd, J = 14.3, 8.6 Hz, 1H), 1.96 (s, 3H),
2.13 (m, 2H), 2.51ꢀ2.56 (m, 2H), 2.69 (s, 1H), 4.54 (s, 1 H), 5.10ꢀ5.14 (m, 2H), 5.66ꢀ5.76 (m, 1H), 5.83
(s, 1 H); 13C NMR (100 MHz, CDCl3) δ ꢀ0.2 (3x CH3), 17.2 (CH3), 22.1 (CH3), 36.7 (CH), 36.9 (CH2),
37.4 (CH2), 48.2 (C), 66.8 (CH), 91.2 (C), 102.5 (C), 117.8 (CH2), 126.0 (CH), 135.2 (CH), 163.5 (C),
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202.8 (C); HRMS (EI) m/z: [M+ ꢀMe] Calcd for C16H23O2Si 275.1467; Found: 275.1461. Minor
diastereomer at C4: mp. 68ꢀ70 °C; IR (neat NaCl) 3427, 2962, 1647, 1247, 1053, 1000, 837, 759 cmꢀ1;
1H NMR, (400 MHz, CDCl3) δ 0.14 (s, 9 H) 1.17 (s, 3H) 1.73 (dd, J = 14.3, 6.5 Hz, 1H) 1.97 (s, 3H)
2.16 (dt, J = 14.2, 9.0 Hz, 1H), 2.35 (dd, J =14.3, 5.9 Hz, 1H), 2.48ꢀ2.55 (m, 1H), 2.64 (d, J=6.3 Hz,
1H), 2.65ꢀ2.72 (m, 1H), 4.47 (d, J = 6.3 Hz, 1H), 5.08ꢀ5.13 (m, 2H), 5.77 (dddd, J = 15.7, 11.4, 7.8, 6.2
1
2
3
4
5
6
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13
Hz, 1H), 5.86 (s, 1H); C NMR (100 MHz, CDCl3) δ ꢀ0.2 (3x CH3), 22.2 (CH3), 22.6 (CH3), 33.5
(CH2), 37.3 (CH2), 37.8 (CH), 48.4 (C), 68.6 (CH), 91.5 (C), 103.8 (C), 117.5 (CH2), 127.0 (CH), 135.9
(CH), 164.4 (C), 202.2 (C); HRMS (EI) m/z: [M+] Calcd for C17H26O2Si 290.1702; Found: 290.1656.
rac-4-Allyl-2,5,5-trimethyl-2-(3-(trimethylsilyl)propioloyl)cyclohexanone) (23). To a solution of
purified CuI (9.47 g, 49.7 mmol) and enone (22) (7.83 g, 27 mmol,) in THF (250 mL), Me2S (25 mL)
was added at 0°C and the solution was stirred until the solution becomes homogenous. MeMgBr (41.4
mL, 3.0 M in Et2O, 124 mmol) was added over 90 min with a syringe pump under heavy stirring. After
the addition was completed, the reaction becomes a very dense dark green solution and the solution was
allowed to warm to rt and stirred for 5 h. A saturated solution of NH4Cl was added with equal amount of
distilled water. The mixture was extracted with Et2O (3x). The combined organic phases were dried
over MgSO4 and filtered over a short pad of celite. The crude was concentrated and filtered over celite
one more time using ether to wash the celite pad and concentrated again. The residue was not purified
any further and is use for the next step.
To a solution of crude alcohol in wet DCM (150 mL) was added DessꢀMartin periodinane (13.71 g,
32.3 mmol). The reaction was stirred for 1 h and quenched with a 1:1 mixture of 5% NaHCO3 solution
and saturated solution of Na2S2O3 under heavy stirring for 30 min. The resulting mixture was then
separated and the aqueous phase is extracted 3x with DCM. The organic phases were combined, dried
over MgSO4 and concentrated. The residue was purified by flash chromatography (5% EtOAc:hexane)
to provide diketone (23) (5.90 g, 72 %) as a white solid over 2 steps. M.p. 51ꢀ55 °C; IR (neat NaCl)
1
3074, 2961, 2931, 2855, 1722, 1668, 1454, 1252, 1252, 1047, 848, 762 cmꢀ1; H NMR, (400 MHz,
CDCl3) δ 0.24 (s, 9H), 0.74 (s, 3H), 1.01 (s, 3H), 1.25 (s, 3H), 1.29 (dd, J = 14.70, 12.5 Hz, 1H), 1.59ꢀ
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1.71 (m, 2H), 2.13 (d, J = 13.5 Hz, 1H), 2.36ꢀ2.41 (m, 1H), 2.44 (d, J = 13.5 Hz, 1H), 2.67 (dd, J = 14.6,
1
2
3
13
3.2 Hz, 1H), 5.03ꢀ5.10 (m, 2H), 5.79 (dddd, J = 17.1, 10.0, 8.2, 5.3 Hz, 1H); C NMR (100 MHz,
4
5
6
7
8
9
CDCl3) δ ꢀ0.9 (3x CH3), 19.9 (CH3), 20.4 (CH3), 29.6 (CH3), 34.1 (CH2), 38.7 (CH2), 39.3 (C), 42.7
(CH), 55.5 (CH2), 63.4 (C), 98.8 (C), 101.6 (C), 116.4 (CH2), 137.3 (CH), 188.6 (C), 207.7 (C); HRMS
(EI) m/z: [M+] Calcd for C18H28O2Si 304.1859; Found: 304.1848.
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rac-4-Allyl-2-(3-bromopropioloyl)-2,5,5-trimethylcyclohexanone (24). To a solution of diketone
(23) (1.49 g, 6.41 mmol) in dry acetone (30 mL), was added AgNO3 (0.545 g, 3.21 mmol). The mixture
was stirred for 5 min before the addition of recrystallized NBS (1.25 g, 7.05 mmol). The reaction was
stirred 2h at r.t. then filtered over celite and washed with acetone. The filtrate was concentrated and
purified by flash chromatography (5% EtOAc:hexanes) to afford the corresponding bromide 24 (1.87 g,
93 %) as a white solid. M.p.88ꢀ89 °C; IR (neat NaCl) 2967, 2937, 2864, 1772, 1669, 1447, 1369, 1660
1
cmꢀ1; H NMR (400 MHz, CDCl3) δ 0.75 (s, 3H), 1.02 (s, 3H), 1.26 (s, 3H), 1.31 (dd, 1H), 1.59ꢀ1.73
(m, 2H), 2.15 (d, J = 13.5 Hz, 1H), 2.36ꢀ2.41 (m, 2H), 2.63 (dd, J = 14.6, 3.2 Hz, 1H), 5.06ꢀ5.10 (m,
2H), 5.75ꢀ5.85 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 19.9 (CH3), 20.2 (CH3), 29.6 (CH3), 34.0 (CH2),
38.3 (CH2), 39.3 (C), 42.8 (CH), 55.6 (CH2), 60.3 (C), 63.7 (C), 77.2 (C), 116.5 (CH2), 137.2 (CH),
186.9 (C), 207.0 (C); HRMS (EI) m/z: [M+] Calcd for C15H19BrO2 310.0568; Found: 310.0540.
rac-1-(5-Allyl-2-((tert-butyldimethylsilyl)oxy)-1,4,4-trimethylcyclohex-2-en-1-yl)-3-bromoprop-
2-yn-1-one (25). 2,6ꢀDiꢀtertꢀbutylꢀ4ꢀmethylpyridine (12.64 g, 61.5 mmol) was charged to a flame dried
flask under argon atmosphere. DCM (30 mL) was added followed by the addition of diketone (24) (3.83
g, 12.31 mmol) and the addition of TBSOTf (11.31 mL, 49.2 mmol). The solution was stirred 3 days at
40°C in an oil bath (lower temperature provide lower yields and higher temperature degrades starting
material). The brown solution was quenched slowly with a solution of 5% NaHCO3 and the aqueous
phase was extracted 3x with DCM. The organic phases were combined, dried over MgSO4 and
concentrated. The mixture was purified immediately by flash chromatography (pure hexane to
recuperate 2,6ꢀDiꢀtertꢀbutylꢀ4ꢀmethylpyridine, 30% benzene/hexanes to recuperate the desired silane
enol ether 25 (4.09 g, 78%) a pale yellow oil which becomes a white solid after recrystallization in 5%
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EtOAC:hexanes. M.p. 68ꢀ69 °C; IR (neat NaCl) 2962, 2929, 2856, 2358, 2175, 1670, 1463, 1251, 1155,
1054, 871, 827, 777 cmꢀ1; 1H NMR, (400 MHz, CDCl3) δ 0.17 (d, J = 1.8 Hz, 6H), 0.82 (s, 3H), 0.87 (s,
9H), 1.02 (s, 3H), 1.29 (s, 3H), 1.31ꢀ1.34 (m, 1H), 1.45ꢀ1.68 (m, 2H), 2.03 (dd, J = 14.0, 2.6 Hz, 1H),
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2.24ꢀ2.30 (m, 1H), 4.65 (s, 1H), 4.97ꢀ5.02 (m, 2H), 5.64ꢀ5.75 (m, 1H); C NMR (100 MHz, CDCl3) δ ꢀ
9
5.0 (CH3), ꢀ4.3 (CH3), 18.2 (C), 22.3 (CH3), 23.1 (CH3), 25.7 (3xCH3), 29.3 (CH3), 34.2 (CH2), 35.1
(C), 36.5 (CH2), 40.1 (CH), 54.0 (C), 57.9 (C), 79.2 (C), 116.0 (CH2), 117.6 (CH), 137.8 (CH), 148.4
(C), 190.0 (C); HRMS (EI) m/z: [M+ꢀtꢀBu] Calcd for C21H33BrO2Si 367.0729; Found: 367.0727.
rac-7-allyl-4-bromo-1,6,6-trimethylbicyclo[3.3.1]non-3-ene-2,9-dione (26). To a solution of silane
enol ether 25 (3.31 mmol) in dry acetone (10 mL) was added [JohnPhosAuNCMe][SbF6] (8) (0.128 g,
0.166 mmol). The resulting mixture was left open to air at rt and monitored by TLC until consumption
all the starting material (30 min). The mixture was concentrated and purified by flash chromatography
(3ꢀ5% EtOAc:hexanes) to afford the desired bicyclic ketone 26 (0.98 g, 96%) as a white solid. M.p. 94ꢀ
96 °C; IR (neat NaCl) 3078, 2973, 2937, 1738, 1675, 1594, 1374, 1275, 1143, 993 cmꢀ1; 1H NMR, (400
MHz, CDCl3) δ 0.91 (s, 3H), 1.18 (s, 3H), 1.27 (s, 3H), 1.32 (t, J = 13.4 Hz, 1H), 1.56ꢀ1.66 (m, 1H),
1.72ꢀ1.79 (m, 1H), 1.99 (dd, J = 13.7, 4.3 Hz, 1H), 2.25ꢀ2.30 (m, 1H), 3.28 (s, 1H), 4.96ꢀ5.01 (m, 2H),
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5.56ꢀ5.67 (m, 1H), 6.83 (s, 1H); C NMR (100 MHz, CDCl3) δ 15.3 (CH3), 20.6 (CH3), 27.5 (CH3),
33.9 (CH2), 37.8 (CH), 41.9 (C), 42.2 (CH2), 60.6 (C), 70.6 (CH), 117.1 (CH2), 135.6 (CH), 136.1 (CH),
145.8 (C), 197.4 (C), 205.5 (C); HRMS (ESI) m/z: [M+ HꢀMe] Calcd for C14H17BrO2 296.0412; Found:
296.0351.
rac-7-allyl-4-methoxy-1,6,6-trimethylbicyclo[3.3.1]non-3-ene-2,9-dione (27). Sodium methoxide
(1.17g, 21.69 mmol) was charged to flameꢀdried flask. Methanol (20 mL) was then added slowly. Once
the solution was homogenous, compound 26 (7.23 mmol) was added in one portion. Then the solution
was heated to 45˚C in an oil bath. After 3h, the solvent was evaporated and the crude was purified
directly by flash chromatography (15ꢀ20% EtOAc:hexane) to afford the desired compound 27 (1.68 g,
89%) as a white solid. M.p. 160ꢀ162 °C; IR (neat NaCl) 3085, 2965, 2936, 1730, 1656, 1603, 1443,
1374, 1194, 998 cmꢀ1; 1H NMR, (400 MHz, CDCl3) δ 0.88 (s, 3H), 1.03 (s, 3H), 1.18 (s, 3H), 1.24ꢀ1.31
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(m, 1H), 1.58ꢀ1.66 (m, 1H), 1.72ꢀ1.79 (m, 1H), 2.00 (dd, J = 13.7, 4.5 Hz, 1H), 2.21ꢀ2.27 (m, 1H), 2.85
(s, 1H), 3.74 (s, 3H), 4.95ꢀ4.99 (m, 2H), 5.57ꢀ5.67 (m, 1H), 5.68 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
15.5 (CH3), 20.4 (CH3), 27.0 (CH3), 34.0 (CH2), 38.7 (CH), 41.3 (C), 42.0 (CH2), 56.5 (CH3), 60.1 (C),
65.5 (CH), 105.4 (CH), 116.8 (CH2), 136.5 (CH), 174.6 (C), 197.6 (C), 207.8 (C); HRMS (EI) m/z: [M+]
Calcd for C16H22O3 262.1569; Found: 262.1579.
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rac-7-allyl-4-methoxy-1,6,6-trimethyl-3-(trimethylsilyl)bicyclo[3.3.1]non-3-ene-2,9-dione
(28).
To a solution of 27 (4.76 mmol) in THF (24 mL) at ꢀ78 °C was added a freshly prepared solution of
LiTMP (10.48 mL, 1M in THF, 10.48 mmol). The reaction mixture was stirred for 5 min before the
addition of freshly distilled TMSCl (2.56 mL, 20.0 mmol). The reaction mixture was stirred and allowed
to warm to ꢀ40 °C over 2 h. The reaction was quenched with a saturated solution of NH4Cl, and the
product was extracted with Et2O. The combined organic extracts were dried over MgSO4, and the
solvent was removed under reduced pressure. The crude is purified by flash chromatography (5ꢀ10%
EtOAc:hexanes) to afford 28 (1.49 g, 94%) as a white solid. M.p. 93ꢀ96 °C; IR (neat NaCl) 3077, 2973,
2897, 1732, 1644, 1558, 1333, 1214 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 0.18 (s, 9H), 0.92 (s, 3H), 1.09
(s, 3H), 1.14 (s, 3H), 1.24 (t, J = 13.0 Hz, 1H), 1.56ꢀ1.71 (m, 2H), 1.98 (dd, J = 13.5, 4.3 Hz, 1H), 2.21ꢀ
13
2.26 (m, 1H), 3.27 (s, 1H), 3.74 (s, 3H), 4.95ꢀ5.00 (m, 2H), 5.56ꢀ5.66 (m, 1H); C NMR (100 MHz,
CDCl3) δ 0.5 (3x CH3), 15.8 (CH3), 20.8 (CH3), 25.8 (CH3), 33.7 (CH2), 38.2 (CH), 42.1 (C), 42.2
(CH2), 56.1 (CH3), 60.2 (C), 60.8 (CH), 116.7 (CH2), 123.1 (C), 136.5 (CH), 178.9 (C), 201.5 (C), 208.8
(C); HRMS (ESI) m/z: [M+H ꢀMe] Calcd for C18H28O3Si 320.1808; Found 320.1749.
rac-7-allyl-5-iodo-4-methoxy-1,6,6-trimethyl-3-(trimethylsilyl)bicyclo[3.3.1]non-3-ene-2,9-dione
(29)
and
rac-7-allyl-4-methoxy-1,6,6-trimethyl-3-(trimethylsilyl)-9-(trimethylsilyloxy)bicyclo
[3.3.1]non-3-en-2-one (30). To a solution of 28 (5 mmol) in THF (5 mL) was added freshly distilled
TMSCl (25 mmol) (distilled over CaH2) (mmol) at room temperature and then the solution was transfer
via cannula to a freshly prepared LDA solution (0.58 M in THF, 30 mL, 17.49 mmol) at ꢀ78 °C. After
stirring for 10 min at ꢀ78 °C, the reaction mixture was warmed to 0°C in an ice bath. After stirring for
30 sec at 0 °C, a solution of iodine (3.81g, 15 mmol) in THF (5 mL) was added to mixture via cannula.
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The resulting solution was stirred for 15 min at 0 °C, quenched with saturated aqueous Na2S2O3, diluted
with Et2O, and extracted 3x with Et2O. The organic layer was dried over MgSO4, filtered and
concentrated. The residue was purified by column chromatography (40ꢀ60% benzene:hexanes then 5%
EtOAc:hexanes) to afford iodide 29 (0.666 g, 29%) as a crystalline pale yellow solid along with
compound 30 (0.857 g, 42%) as white solid. Compound 29: M.p. 75ꢀ80 °C; IR (neat NaCl) 2985, 2939,
2358, 1733, 1651, 1650, 1544, 1255 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 0.27 (s, 9H), 0.92 (s, 3H), 1.24
(s, 3H), 1.27 (s, 3H), 1.30ꢀ1.38 (m, 1H), 1.65ꢀ1.74 (m, 1H), 1.90ꢀ1.99 (m, 2H), 2.36ꢀ2.41 (m, 1H), 3.93
(s, 3H), 4.98ꢀ5.03 (m, 2H), 5.60 (dddd, J = 16.7, 10.3, 8.6, 5.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
0.5 (3xCH3), 17.5 (CH3), 20.7 (CH3), 29.0 (CH3), 36.3 (CH2), 39.6 (CH), 41.3 (CH2), 48.0 (C), 62.7 (C),
66.3 (CH3), 85.9 (C), 117.1 (CH2), 125.6 (C), 136.4 (CH), 178.9 (C), 200.2 (C), 200.4 (C); HRMS (EI)
m/z: [M+ꢀMe] Calcd for C18H26IO3Si 445.0696; Found 445.0695. Compound 30: M.p. 90ꢀ94 °C; IR
(neat NaCl) 2985, 2939, 2358, 1733, 1650, 1544, 1255, 1222 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 0.14
(m, 9H), 0.16 (s, 9H), 0.91 (s, 3H), 0.97 (s, 3H), 1.11 (s, 3H), 1.29 (m, 3H), 1.61 (m, 1H), 2.19 (m, 1H),
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2.61 (d, J = 3.1 Hz, 1H), 3.69 (s, 3H), 3.73 (d, J = 3.1 Hz, 1H), 4.94 (m, 2H), 5.60 (m, 1H); C NMR
(100 MHz, CDCl3) δ 0.0 (3x CH3), 0.7 (3x CH3), 20.4 (CH3), 24.0 (CH3), 27.4 (CH3), 32.5 (CH2), 34.4
(C), 34.8 (CH2), 38.6 (CH), 48.7 (C), 49.8 (CH), 55.3 (CH3), 74.4 (CH), 115.8 (CH2), 120.4 (C), 138.0
(CH), 183.0 (C), 206.9 (C); HRMS (EI) m/z: [M+] Calcd for C22H40O3Si2 408.2516; Found: 408.2522.
rac-(7-allyl-5-isobutyryl-4-methoxy-1,6,6-trimethylbicyclo[3.3.1]non-3-ene-2,9-dione (32). Iodide
29 (0.880 mmol) was charged to a flameꢀdried flask and THF (7 mL) was added. The resulting mixture
was cooled to ꢀ78 °C and tꢀBuLi (1.6M solution in pentane, 1.26 mL, 2.02 mmol) was added dropwisely
to obtain a bright yellow solution. After stirring the solution for 5 min at ꢀ78 °C, freshly distilled
isobutyraldehyde (0.16 mL, 1.75 mmol) (distilled over CaSO4) was added dropwise and the reaction
was allowed to stir for 1h at ꢀ78 °C. The reaction was quenched with a saturated solution of NH4Cl. The
aqueous phase was extracted 3x with EtOAc. The organic layers are combined, dried over MgSO4 and
concentrated.
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The crude 31 was used as is and dissolved in wet DCM (7 mL) and DMP (1.87 g, 4.40 mmol) was
added in one portion. After stirring for 3 days, a 1:1 solution of 5% NaHCO3 and saturated solution of
Na2S2O3 was added under heavy stirring for 30 min. The resulting mixture was then separated and the
aqueous phase was extracted 3x with DCM. The organic phases were combined, dried over MgSO4 and
concentrated. The residue was rapidly purified over a pad of silica (5% EtOAc:hexanes).
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The crude mixture was put under an atmosphere of argon and THF (7 mL) was added. The solution
was cooled to 0 °C before adding TBAF (1M solution in THF, 1.05 mL, 1.056 mmol) dropwise. The
mixture was stirred at 0˚C for 1h before adding a saturated solution of NH4Cl. The aqueous phase was
extracted 3x with Et2O and the combined organic phases were dried over MgSO4 and concentrated. The
residue was purified by flash chromatography (15ꢀ30% EtOAc:hexanes) to afford ketone 32 (0.133 g,
45% over 3 steps) as a white solid. M.p. 82ꢀ84 °C; IR (neat NaCl) 2975, 2933, 2360, 1720, 1654, 1601,
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1242 cmꢀ1; H NMR (400 MHz, CDCl3) δ ppm 1.00 (d, J = 6.5 Hz, 3H), 1.03 (s, 3H), 1.17 (d, J = 6.5
Hz, 3H), 1.22 (br s, 6H), 1.32 (dd, J = 13.6, 12.8 Hz, 1H), 1.59ꢀ1.64 (m, 1H), 1.68ꢀ1.76 (m, 1H), 1.96
(dd, J = 13.7, 4.5 Hz, 1H), 2.24ꢀ2.35 (m, 2H), 3.81 (s, 3H), 4.95ꢀ4.99 (m, 2H), 5.54ꢀ5.64 (m, 1H), 5.95
13
(s, 1H); C NMR (100 MHz, CDCl3) δ 15.6 (CH3), 15.9 (CH3), 21.2 (CH3), 21.2 (CH3), 24.0 (CH3),
33.6 (CH2), 40.7 (CH), 41.9 (CH), 42.6 (CH2), 45.2 (C), 56.3 (CH3), 61.0 (C), 75.8 (C), 107.1 (CH),
116.9 (CH2), 136.6 (CH), 173.1 (C), 195.7 (C), 207.4 (C), 208.5 (C); HRMS (EI) m/z: [M+] Calcd for
C20H28O4 332.1988; Found: 332.2006.
rac-7-Allyl-4-(allyloxy)-1,6,6-trimethylbicyclo[3.3.1]non-3-ene-2,9-dione (35). Sodium (0.022 g, 0.961
mmol) was added to allyl alcohol (3.00 mL) and stirred until all sodium is consumed. Compound 26 (0.23 g,
0.739 mmol) was diluted in a minimum of allyl alcohol and added to the solution of sodium allyl alkoxide.
After stirring at 50 °C, the resulting mixture was concentrated and the residue was purified by flash
chromatography (2% EtOAc:hexanes) to provide 35 (0.602 g, 81%). M.p. 72ꢀ74 °C; IR (neat NaCl) 3081,
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2971, 2934, 1733, 1652, 1601, 1340, 1210 cmꢀ1; H NMR (400 MHz, CDCl3) δ 0.88 (s, 3H), 1.05 (s, 3H),
1.17 (s, 3H), 1.27 (m, 1H), 1.61 (m, 1H), 1.76 (m, 1H), 2.00 (m, 1H), 2.24 (m, 1H), 2.87 (s, 1H), 4.42 (m,
2H), 4.96 (m, 2H), 5.32 (dd, J = 10.5, 1.1 Hz, 1H), 5.38 (dd, J = 17.3, 1.3 Hz, 1H), 5.67 (m, 1H), 5.67 (s,
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1H), 5.94 (dddd, J = 16.9, 11.0, 5.7, 5.4 Hz, 1H); C NMR (400 MHz, CDCl3) δ 15.5 (CH3), 20.5 (CH3),
27.1 (CH3), 34.0 (CH2), 38.7 (CH), 41.3 (C), 42.0 (CH2), 60.1 (C), 65.5 (CH), 70.2 (CH2), 106.2 (CH), 116.8
(CH2), 119.5 (CH2), 130.7 (CH), 136.6 (CH), 173.3 (C), 197.7 (C), 207.8 (C); HRMS (EI) m/z: [M+] Calcd
for C18H24O3 288.1725; Found: 288.1734.
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rac-3,7-Diallyl-4-hydroxy-1,6,6-trimethylbicyclo[3.3.1]non-3-ene-2,9-dione (36). A solution of
allyl enol ether 35 (0.100 g, 0.347 mmol) in toluene was placed in a sealed tube and heated at 140 °C for
7 hours. The mixture was cooled down to r.t. and was concentrated. The residue was purified by flash
chromatography (50 % EtOAc:hexanes) to give 36 (0.084 g, 84%) as a lightly yellow oil. 1H NMR (400
MHz, DMSOꢀd6) δ 0.77 (s, 3H), 0.99 (s, 3H), 1.04 (s, 3H), 1.14 (t, J = 7.3 Hz, 1H), 1.21 (t, J = 12.9 Hz,
2H), 1.61 (m, 2H), 1.77 (dd, J = 13.5, 4.3 Hz, 1H), 2.20 (m, 1H), 2.93 (m, 3H), 4.82 (dd, J = 10.1, 2.3
Hz, 1H), 4.88 (dd, J = 17.2, 2.2 Hz, 1H), 4.94 (s, 1H), 4.98 (d, J = 4.7 Hz, 1H), 5.68 (m, 1H); 13C NMR
(400 MHz, DMSOꢀd6) δ 16.4 (CH3), 20.4 (CH3), 26.2 (CH3), 26.9 (CH2), 33.3 (CH2), 38.3 (CH), 40.6
(C), 40.7 (C), 41.23 (CH2), 41.84 (CH2), 58.0 (C), 113.8 (C), 115.2 (CH2), 116.3 (CH2), 136.6 (CH),
137.4 (CH), 208.1 (C); HRMS (EI) m/z: [M+] Calcd for C18H24O3 288.1725; Found: 288.1707.
rac-2,2,6,9,9-Pentamethyl-8-(3-methylbut-2-en-1-yl)-2,6,7,8,9,10-hexahydro-5H-6,10-
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methanocycloocta[b]pyran-5,11-dione (33) and rac-2,2,7,7,10-pentamethyl-8-(3-methylbut-2-en-1-
yl)-2,6,7,8,9,10-hexahydro-5H-6,10-methanocycloocta[b]pyran-5,11-dione (37). Grubb’s 2nd
generation (0.106 g, 0.125 mmol, 15% loading) was added to a solution of 36 (0.24 g, 0.832 mmol) in
DCM (3.00 mL) and the solution was heated at 40 °C for 24h. The solution was thereafter concentrated
and diluted in DMSO: H2O 9:1 (2 mL). PdCl2 (0.166 g, 0.941 mmol) was added and O2 was bubbled
through the solution by means of a balloon for 1h. The crude residue was purified by flash
chromatography (20% EtOAc:hexanes) to give a separable mixture of 33 (62 mg, 22%) and 37 (31 mg,
1
11%) as crystalline solids. Compound 33: IR (neat NaCl) 2979, 2366, 1731, 1654, 1587 cmꢀ1; H
NMR, (400 MHz, CDCl3) δ 0.89 (s, 3H), 1.12 (s, 3H), 1.20 (s, 3H), 1.22ꢀ1.29 (m, 1H), 1.40 (s, 3H),
1.47 (s, 3H), 1.54 (s, 3H), 1.63ꢀ1.65 (m, 2H), 1.65 (s, 3H), 2.01 (dd, J = 13.7, 4.1 Hz, 1H), 2.05ꢀ2.09 (m,
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1H), 2.83 (s, 1H), 4.95ꢀ4.98 (m, 1H), 5.29 (d, J = 10.2 Hz, 1H), 6.39 (d, J = 10.0 Hz, 1H); C NMR
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(400 MHz, CDCl3) δ 16.0 (CH3), 17.9 (CH3), 20.6 (CH3), 25.8 (CH3), 27.3 (CH3), 28.0 (CH2), 28.8
(CH3), 29.4 (CH3), 40.2 (CH), 42.1 (CH2), 42.2 (C), 60.1 (C), 65.3 (CH), 82.4 (C), 112.7 (C), 115.3
(CH), 122.3 (CH), 123.7 (CH), 133.2 (C), 168.2 (C), 193.7 (C), 207.3 (C); HRMS (EI) m/z: [M+] Calcd
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for C22
H30
O3
342.2195; Found: 342.2182. Compound 37: IR (neat NaCl) 2974, 2356, 1733, 1647,
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1575, 1326, 1108 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 0.84 (s, 3H), 1.09 (s, 3H), 1.23 (s, 3H), 1.29ꢀ1.35
(m, 1H), 1.36 (s, 3H), 1.44 (s, 3H), 1.55 (s, 3H), 1.65 (s, 5H), 1.99 (dd, J = 13.8, 3.8 Hz, 1H), 2.07ꢀ2.14
(m, 1H), 2.90 (s, 1H), 4.98ꢀ5.01 (m, 1H), 5.30 (d, J = 10.0 Hz, 1H), 6.40 (d, J = 10.0 Hz, 1H); 13C NMR
(400 MHz, CDCl3) δ 15.1 (CH3), 17.8 (CH3), 20.5 (CH3), 25.7 (CH3), 26.5 (CH3), 27.2 (CH2), 27.9
(CH3), 28.2 (CH3), 39.8 (CH2), 41.3 (CH), 42.3 (C), 52.5 (C), 74.3 (CH), 81.4 (C), 113.5 (C), 115.9
(CH), 122.6 (CH), 123.5 (CH), 133.2 (C), 171.4 (C), 189.7 (C), 206.6 (C); HRMS (EI) m/z: [M+] Calcd
for C22H30O3 342.2195; Found: 342.2182.
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rac-7-Allyl-9-hydroxy-9-isopropyl-4-methoxy-1,6,6-trimethylbicyclo[3.3.1]non-3-en-2-one (40)
Sodium (4.15 mg, 0.180 mmol) was added to allyl alcohol (1.00 mL) in a r.b.f. and stirred until all
sodium has been consumed. Compound 32 (1.2 mg, 0.036 mmol) was diluted in a minimum of allyl
alcohol and added to the solution of sodium allyl alkoxide. The mixture was heated at 80 °C. After
stirring for 18h, the resulting mixture was concentrated and purified by flash chromatography (10%
EtOAc:hexanes) to provide 40 (1 mg, > 90%). Major diastereomer: IR (neat NaCl) 3475, 2948, 2347,
1645, 1610, 1365, 1203 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 0.80 (d, J = 6.9 Hz, 3H), 0.87 (s, 3H), 0.97
(d, J = 6.7 Hz, 3H), 1.15 (s, 3H), 1.27 (s, 3H), 1.47 (dd, J = 14.7, 8.0 Hz, 1H), 1.73 (m, 1H), 1.78 (dd, J
= 14.7, 6.1 Hz, 1H), 1.91 (dt, J = 13.6, 6.7 Hz, 1H), 2.10 (s, 1H), 2.19 (s, 1H), 2.32 (s, 1H), 3.64 (s, 3H),
4.91 (m, 2H), 5.24 (s, 1H), 5.61 (dddd, J = 16.9, 10.2, 8.4, 5.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
18.7 (CH3), 19.2 (CH3), 20.0 (CH3), 24.1 (CH3), 33.9 (CH3), 35.7 (CH), 35.8 (CH), 36.2 (CH2), 36.8
(CH2), 40.5 (CH), 54.4 (CH3), 55.3 (CH), 79.3 (C), 102.7 (CH), 115.9 (CH2), 138.8 (CH), 178.1 (C),
203.5 (C); HRMS (EI) m/z: [M+] Calcd for C19H30O3 306.2195; Found: 306.2217.
rac-3,7-Diallyl-5-isobutyryl-4-methoxy-1,6,6-trimethylbicyclo[3.3.1]non-3-ene-2,9-dione (41). A
solution of nꢀBuLi (2.4 M in hexanes, 0.474 mL, 1.138 mmol) was added slowly to freshly distilled
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diisopropylamine (0.165 mL, 1.156 mmol) in THF (2 mL) at −78°C and the solution was stirred for 30
min at ꢀ78°C and 15 min at 0 °C. A solution of compound 32 (0.373 mmol) in THF (0.5 mL) was added
via cannula at ꢀ78 °C. The solution was stirred for 10 min and a solution of lithium 2ꢀ
thienylcyanocuprate (0.25M in THF, 2.98 mL, 0.746 mmol) was added at ꢀ78 °C. After stirring for 20
min, allyl bromide (0.484 mL, 5.60 mmol) was added dropwisely to the solution and the mixture was
stirred another 20 min. The reaction mixture was quenched with a saturated solution of NH4Cl. The
aqueous phase was extracted 3x with Et2O. The organic phases were combined, dried over MgSO4 and
concentrated. The residue was purified by flash chromatography (3ꢀ5ꢀ10% EtOAc:hexanes) to afford
the desired allyl 41 (138 mg, 0.365 mmol, 98%) as a colorless oil. IR (neat NaCl) 2933, 2362, 1724,
1658, 1598, 1240 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 1.01 (s, 3H), 1.02 (d, J = 6.6 Hz, 3H), 1.16 (d, J
= 6.7 Hz, 3H), 1.21 (s, 3H), 1.26 (s, 3H), 1.28ꢀ1.31 (m, 1H), 1.57ꢀ1.65 (m, 1H), 1.75 (dddd, J = 12.8,
10.5, 4.6, 2.6 Hz, 1H), 1.94 (dd, J = 13.72, 4.51 Hz, 1H), 2.26ꢀ2.32 (m, 1H), 2.37 (sept, J = 6.5 Hz, 1H),
3.40 (m, 2H), 4.10 (s, 3H), 4.95ꢀ5.03 (m, 3H), 5.12 (dq, J = 10.3, 1.60 Hz, 1H), 5.54ꢀ5.64 (m, 1H), 5.87ꢀ
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5.97 (m, 1H); C NMR (100 MHz, CDCl3) δ 16.4 (2xCH3), 21.3 (CH3), 21.5 (CH3), 24.3 (CH3), 28.5
(CH2), 33.5 (CH2), 40.5 (CH), 42.6 (CH2), 42.7 (CH), 45.2 (C), 60.5 (CH3), 60.6 (C), 77.2 (C), 115.7
(CH2), 116.9 (CH2), 120.4 (C), 136.5 (CH), 136.6 (CH), 170.3 (C), 196.3 (C), 208.0 (C), 208.9 (C).
HRMS (EI) m/z: [M+] Calcd for C23H32O4 372.2301; Found: 372.2290.
rac-5-isobutyryl-4-methoxy-1,6,6-trimethyl-3,7-bis(3-methylbut-2-en-1-yl)bicyclo[3.3.1]non-3-
ene-2,9-dione (42). The bisꢀallyl compound 41 (81 mg, 0.217 mmol) was dissolved in DCM (0.75 mL),
to which 2ꢀmethylꢀ2ꢀbutene (4.95 mL, 46.8 mmol) was then added. The resulting mixture was added to
a dried seal tube under argon atmosphere containing Grubbs 2nd generation catalyst (18 mg, 0.022
mmol). The resulting red mixture was heated at 40 °C for 2 hours and the solution was cooled to r.t.
Ethyl vinyl ether (0.2 mL) was added to the mixture and the solution was stirred for 2 min then
concentrated. The residue was purified by flash chromatography (3ꢀ5% EtOAc:hexanes) to afford 42
(92 mg, 0.215 mmol, 99%) as a colorless oil. IR (neat NaCl) 2979, 2933, 1722, 1658, 1596, 1242 cmꢀ1;
1H NMR (400 MHz, CDCl3) δ 1.02 (s, 3H), 1.03 (d, J = 6.5 Hz, 3H), 1.15 (d, J = 6.5 Hz, 3H), 1.20 (s,
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3H), 1.26 (s, 3H), 1.28 (dd, J = 13.5, 12.5 Hz, 1H), 1.54 (s, 3H), 1.57ꢀ1.62 (m, 2H), 1.65 (s, 3H) 1.67ꢀ
1.68 (m, 6H), 1.91 (dd, J = 13.7, 4.1 Hz, 1H), 2.08ꢀ2.12 (m, 1H), 2.36 (sept, J = 6.5 Hz, 1H), 3.19ꢀ3.24
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(m, 1H), 3.36ꢀ3.42 (m, 1H), 4.05 (s, 3H), 4.91ꢀ4.94 (m, 1H), 4.97ꢀ5.00 (m, 1H); C NMR (100 MHz,
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CDCl3) δ 16.5 (CH3), 16.5 (CH3), 17.8 (CH3), 18.1 (CH3), 21.3 (CH3), 21.4 (CH3), 23.5 (CH2), 24.3
(CH3), 25.6 (CH3), 25.8 (CH3), 27.3 (CH2), 40.4 (CH), 42.8 (CH2), 43.7 (CH), 45.2 (C), 60.4 (CH3),
60.6 (C), 77.3 (C), 122.4 (2xCH) ,123.0 (C), 132.9 (C), 133.3 (C), 169.9 (C), 196.6 (C), 208.2 (C),
209.2 (C). HRMS (EI) m/z: [M+] Calcd for C27H40O4 428.2927; Found: 428.2924.
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rac-Papuaforin A (2) and rac-papuaforin B (3). Compound (42) (38 mg, 0.089 mmol) was
dissolved in dry DMSO (1.1 mL) and LiCl (30 mg, 0.709 mmol) was added in one portion. The
resulting mixture was degassed for 10 min and was heated at 120 °C for 120 min. The resulting dark
solution was cooled to r.t. PdCl2 (21 mg, 0.120 mmol) and distilled water (0.11 mL) were added and
oxygen was bubbled through the stirred solution for 90 seconds. Water was added and extracted with
EtOAc (3x). The organic phases were combined, dried over MgSO4 and concentrated. The residue was
first purified by flash chromatography (15% EtOAc:hexanes). The resulting mixture of 2 and 3 was
then purified again by a preparative flash chromatography (5% EtOAc:hexanes) to afford papuaforin A
(2) (8.6 mg, 0.021 mmol, 24%) and papuaforin B (3) (4.3 mg, 0.010 mmol, 12%). Papuaforin A (2): IR
(neat NaCl) 2954, 2362, 1731, 1641, 1579, 1456, 1411, 1328, 1116 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ
1.02 (s, 3H), 1.03 (d, J = 6.5 Hz, 3H), 1.12 (d, J = 6.5 Hz, 3H), 1.24 (s, 3H), 1.28 (s, 3H), 1.38ꢀ1.41 (m,
1H), 1.39 (s, 3H), 1.51ꢀ1.54 (m, 1H), 1.49 (s, 3H), 1.55 (s, 3H), 1.65 (s, 3H), 1.62ꢀ1.72 (m, 1H), 1.95
(dd, J = 13.4, 4.0 Hz, 1H), 2.04ꢀ2.14 (m, 2H), 4.94ꢀ4.98 (m, 1H), 5.37 (d, J = 10.0 Hz, 1H), 6.48 (d, J =
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10.0 Hz, 1H); C NMR (125 MHz, CDCl3)
δ 15.3 (CH3), 15.8 (CH3), 17.8 (CH3), 20.5 (CH3), 21.6
(CH3), 22.8 (CH3), 25.7 (CH3), 26.4 (CH2), 28.1 (CH3), 28.3 (CH3), 40.3 (CH2), 42.3 (CH), 43.2 (CH),
46.3 (C), 52.6 (C), 81.9 (C), 83.4 (C), 113.9 (C), 115.7 (CH), 122.6 (CH), 123.9 (CH), 133.3 (C), 170.8
(C), 188.6 (C), 207.0 (C), 209.2 (C); HRMS (EI) m/z: [M+] Calcd for C26H36O4 412.2614; Found:
412.2605. Papuaforin B (3): IR (neat NaCl) 2954, 2352, 1731, 1654 cmꢀ1; 1H NMR (500 MHz, CDCl3)
δ 1.05 (s, 3H), 1.08 (d, J = 6.6 Hz, 3H), 1.15 (d, J = 6.4 Hz, 3H), 1.24 (s, 3H), 1.32ꢀ1.35 (m, 1H), 1.35
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(s, 3H), 1.50 (s, 3H), 1.54 (s, 6H), 1.63ꢀ1.66 (m, 1H), 1.66 (s, 3H), 1.67ꢀ1.68 (m, 1H), 1.97 (dd, J =
13.8, 4.3 Hz, 1H), 2.10ꢀ2.15 (m, 1H), 2.40 (sept, J = 6.6 Hz, 1H), 4.93ꢀ4.96 (m, 1H), 5.39 (d, J = 10.1
Hz, 1H), 6.51 (d, J = 10.1 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 16.2 (CH3), 16.8 (CH3), 17.8 (CH3),
21.3 (CH3), 21.5 (CH3), 24.0 (CH3), 25.8 (CH3), 27.4 (CH2), 29.0 (CH3), 29.4 (CH3), 40.7 (CH), 42.5
(CH2), 43.7 (CH), 46.2 (C), 61.0 (C), 75.6 (C), 83.8 (C), 115.1 (C), 115.9 (CH), 122.3 (CH), 124.1
(CH), 133.4 (C), 167.3 (C), 191.9 (C), 206.7 (C), 208.9 (C); HRMS (EI) m/z: [M+] Calcd for C26H36O4
412.2614; Found: 412.2539.
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rac-7-Allyl-4-methoxy-1,6,6-trimethyl-5-(2-methylbutanoyl)bicyclo[3.3.1]non-3-ene-2,9-dione
(43). Iodide (29) (0.25 g, 0.543 mmol) was charged to a flame dried flask and THF (4 mL) was added.
The resulting mixture is cooled to ꢀ78 °C and tꢀBuLi (1.6 M solution in pentane, 0.78 mL, 1.25 mmol)
was added dropwise to obtain a bright yellow solution. After stirring the solution for 5 min at ꢀ78˚C, 2ꢀ
methylbutanal (0.116 mL, 1.09 mmol) (distilled over CaSO4) was added dropwise and the reaction was
allowed to stir for 1h at ꢀ78 °C before quenching with a saturated solution of NH4Cl. The aqueous phase
was extracted 3x with EtOAc. The organic layers are combined, dried over MgSO4 and concentrated.
The crude was dissolved in wet DCM (6 mL) and DMP (0.95 g, 2.24 mmol) was added in one
portion. The solution was stirred 3 days at r.t. The resulting reaction mixture was quenched with a 1:1
mixture of 5% NaHCO3 and saturated solution of Na2S2O3 under heavy stirring for 30 min. The
resulting mixture was extracted 3x with DCM. The combined organic phases were dried over MgSO4
and concentrated. The residue was rapidly purified over a pad of silica (5% EtOAc:hexanes).
The resulting residue was put under an atmosphere of argon and THF (6 mL) was added. The
solution was cooled to 0˚C before adding a TBAF (1M solution in THF, 0.537 mL, 0.537 mmol)
dropwise. The mixture was stirred at 0 °C for 1h before quenching the solution with NH4Cl. The
aqueous phase was extracted 3x with Et2O. The organic phases were combined, dried over MgSO4 and
concentrated. The residue was purified by flash chromatography (10ꢀ30% EtOAc:hexanes) to afford
compound 43 (0.115 g, 0.309 mmol, 63% over 3 steps) as a clear oil. IR (neat NaCl) 2958, 1722, 1658,
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Hz, 3H), 1.21 (s, 6H), 1.27ꢀ1.36 (m, 2H), 1.46ꢀ1.53 (m, 1H), 1.55ꢀ1.63 (m, 1H), 1.68ꢀ1.75 (m, 1H), 1.95
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(dd, J = 13.6, 4.6 Hz, 1H), 1.99ꢀ2.07 (m, 1H), 2.24ꢀ2.29 (m, 1H), 3.79 (s, 3H), 4.94ꢀ4.98 (m, 2H), 5.53ꢀ
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5.64 (m, 1H), 5.94 (s, 1H); C NMR (100 MHz, CDCl3) δ 11.6 (CH3), 15.6 (CH3), 16.0 (CH3), 17.4
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(CH3), 24.0 (CH3), 27.5 (CH2), 33.5 (CH2), 42.0 (CH), 42.6 (CH2), 45.2 (C), 47.5 (CH), 56.3 (CH3),
61.0 (C), 75.9 (C), 107.1 (CH), 116.9 (CH2), 136.5 (CH), 173.2 (C), 195.7 (C), 207.2 (C), 208.1 (C);
HRMS (EI) m/z: [M+] Calcd for C21H30O4 346.2144; found: 346.2148.
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rac-3,7-Diallyl-4-methoxy-1,6,6-trimethyl-5-(2-methylbutanoyl)bicyclo[3.3.1]non-3-ene-2,9-
dione (44). A solution of nꢀBuLi (2.4 M in hexanes, 0.474 mL, 1.138 mmol) was added slowly to
freshly distilled diisopropylamine (0.165 mL, 1.156 mmol) in THF (2 mL) at −78 °C and the solution
was stirred for 30 min at ꢀ78 °C and 15 min at 0°C. A solution of 43 (129 mg, 0.373 mmol) in THF (0.5
mL) was added via cannula at ꢀ78 °C. The solution was stirred for 10 min and a solution of lithium 2ꢀ
thienylcyanocuprate (0.25M in THF, 2.98 mL, 0.746 mmol) was added at ꢀ78 °C. After stirring for 20
min, allyl bromide (0.484 mL, 5.60 mmol) was added dropwisely to the solution and the mixture was
stirred another 20 min. The reaction mixture was quenched with a saturated solution of NH4Cl. The
aqueous phase was extracted 3x with Et2O. The organic phases were combined, dried over MgSO4 and
concentrated. The residue was purified by flash chromatography (3ꢀ5ꢀ10% EtOAc:hexanes) to afford 44
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(124 mg, 82%) as a colorless oil. IR (neat,) 2958, 2356, 1722, 1658, 1596, 1242 cmꢀ1; H NMR (400
MHz, CDCl3) δ 0.83 (t, J = 7.5 Hz, 3H), 1.01 (s, 3H), 1.15 (d, J = 6.5 Hz, 3H), 1.21 (s, 3H), 1.25 (s,
3H), 1.27ꢀ1.36 (m, 2H), 1.54ꢀ1.65 (m, 2H), 1.70ꢀ1.78 (m, 1H), 1.93 (dd, J = 13.7, 4.7 Hz, 1H), 2.06ꢀ
2.14 (m, 1H), 2.26ꢀ2.31 (m, 1H), 3.32ꢀ3.48 (m, 2H), 4.09 (s, 3H), 4.95ꢀ5.03 (m, 3H), 5.09 (dq, J = 10.2,
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1.7 Hz, 1H), 5.53ꢀ5.64 (m, 1H), 5.85ꢀ5.95 (m, 1H); C NMR (100 MHz, CDCl3) δ 11.6 (CH3), 16.4
(CH3), 16.5 (CH3), 17.5 (CH3), 24.4 (CH3), 27.7 (CH2), 28.4 (CH2), 33.5 (CH2), 42.6 (CH2), 42.7 (C)
45.2 (CH), 47.4 (CH), 60.5 (CH3), 60.6 (C), 77.4 (C), 115.7 (CH2), 116.8 (CH2), 120.4 (C), 136.4 (CH),
136.6 (CH), 170.5 (C), 196.2 (C), 207.9 (C), 208.5 (C); HRMS (EI) m/z: [M+] Calcd for C24H34O4
386.2457; Found: 386.2472.
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rac-4-Methoxy-1,6,6-trimethyl-3,7-bis(3-methylbut-2-en-1-yl)-5-(2-methylbutanoyl)
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bicyclo[3.3.1] non-3-ene-2,9-dione (45). Compound 44 (113 mg, 0.293 mmol) was dissolved in DCM
(0.75 mL), to which 2ꢀmethylꢀ2ꢀbutene (4.95 mL, 46.8 mmol) was then added. The resulting mixture
was added to a preꢀdried seal tube under argon atmosphere containing Grubbs 2nd generation catalyst
(24 mg, 0.029 mmol). The resulting red mixture was heated at 40 °C for 2 hours and the solution was
cooled to to r.t. Ethyl vinyl ether (0.2 mL) was added to the mixture and the solution was stirred for 2
min then concentrated. The residue was purified by flash chromatography (3ꢀ5% EtOAc:hexanes) to
afford compound the desired prenyl compound 45 (129 mg, 99%) as a colorless oil. IR (neat NaCl)
2933, 2347, 1726, 1660, 1593, 1452, 1245 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 0.85 (t, J = 7.5 Hz, 3H),
1.02 (m, 3H), 1.14 (d, J = 6.5 Hz, 3H), 1.20 (s, 3H), 1.25 (s, 3H), 1.28ꢀ1.36 (m, 2H), 1.53 (s, 3H), 1.57ꢀ
1.62 (m, 3H), 1.65 (s, 3H), 1.68 (m, 6H), 1.90 (dd, J = 13.5, 4.1 Hz, 1H), 2.07ꢀ2.15 (m, 2H), 3.17ꢀ3.23
(m, 1H), 3.41ꢀ3.48 (m, 1H), 4.04 (s, 3H), 4.90ꢀ4.99 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 11.7 (CH3),
16.5 (CH3), 16.6 (CH3), 17.5 (CH3), 17.8 (CH3), 18.1 (CH3), 23.3 (CH2), 24.4 (CH3), 25.6 (CH3), 25.8
(CH3), 27.3 (CH2), 27.6 (CH2), 42.8 (CH2), 43.8 (CH), 45.3 (C), 47.3 (CH), 60.3 (CH3), 60.6 (C), 77.4
(C), 122.3 (CH), 122.4 (CH), 123.0 (C), 132.9 (C), 133.3 (C), 170.1 (C), 196.5 (C), 208.2 (C), 208.8
(C); HRMS (EI) m/z: [M+] Calcd for C28H42O4 442.3083; Found: 442.3083.
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rac-Papuaforin C (4). Compound (29) (120 mg, 0.271 mmol) was dissolved in dry DMSO (3.61 mL)
and LiCl (92mg, 2.169 mmol) was added in one portion. The resulting mixture was degassed for 10 min
before heating at 120 °C for 120 min. The resulting dark solution is then allowed to cool down to r.t. To
this mixture was added PdCl2 (65 mg, 0.366 mmol) and distilled water (0.5 mL). Oxygen was then
bubbled through the stirred solution for 90 seconds. Water was added and extracted with EtOAc (3x).
The organic phases are combined, dried over MgSO4 and concentrated. The residue was purified in a
first time by flash chromatography (15% EtOAc:hexanes) to eliminate most impurities. The resulting
residue was then purified again by preparatory chromatography (1ꢀ5% EtOAc:hexanes) to afford
papuaforin C (4) (48 mg, 0.113 mmol, 41%) along with other isomer (10 mg, 0.023 mmol, 8%). IR
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(neat NaCl) 2954, 2356, 1730, 1637, 1587, 1328 cmꢀ1; H NMR (400 MHz, CDCl3) δ 0.78 (t, J = 7.5
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