Total synthesis of neodolastane diterpenes trichoaurantianolides C and D

Article abstract of DOI:10.1021/acs.joc.5b00355

The first total synthesis of trichoaurantianolides C and D is described. An enantiocontrolled pathway leads to rapid construction of the tricyclic carbon skeleton and establishes the trans-dimethyl geometry of the quaternary bridgehead carbons via a reduc

Full text of DOI:10.1021/acs.joc.5b00355

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Article
Total Synthesis of Neodolastane Diterpenes Trichoaurantianolides C and D
David R. Williams, Paul T Gladen, and Joseph R Pinchman
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00355 • Publication Date (Web): 14 May 2015
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Total Synthesis of Neodolastane Diterpenes Trichoaurantianolides C and D
David R. Williams,* Paul T. Gladen, and Joseph R. Pinchman
Department of Chemistry, Indiana University, Bloomington, Indiana 47405, United
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States
O
OBn
O
H
AcO
O
O
O
CH3
CH3
O
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H C
3
TBSO
H
O
O
R
Trichoaurantianolide C (R = H)
Trichoaurantianolide D (R = Ac)
ABSTRACT: The first total synthesis of trichoaurantianolides C and D is described. An
enantiocontrolled pathway leads to rapid construction of the tricyclic carbon skeleton and
establishes the trans-dimethyl geometry of the quaternary bridgehead carbons via a
reductive cyclization. Application of the π-allyl Stille cross coupling leads to a
nonracemic allylic alcohol as a prerequisite for the introduction of asymmetry in the
cycloheptane system. Two strategies have been examined for elaboration of the
unsaturated tetrahydrofuranyl ring from a common tricyclic intermediate. These efforts
reveal a number of unanticipated issues of reactivity and significant stereochemical
requirements for a novel acyloin rearrangement as well as the elimination and
cyclodehydration of chiral α-hydroxyketones. Key reactions leading to completion of the
synthesis include the stereoselective addition of isopropenyllithium TMEDA complex
and a facile chemoselective oxidation with selenium dioxide.
INTRODUCTION
Trichoaurantianolides A–D were isolated from fruiting bodies of mushrooms of
Tricholoma aurantium and Tricholoma fracticum in 1995, and were independently
1
2
characterized by the studies of Vidari and Steglich. These metabolites were assigned as
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structures 1–4 (Figure 1) on the basis of extensive NMR studies and were presented as a
previously unknown class of diterpenes described as neodolastanes. A confirmation of
2
relative stereochemistry was achieved by an X-ray crystallographic analysis of 2.
0
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O 4
HO
O
O
O
H
1
2
0
12
3
11
10
9
13
14
O
2
7
O
5
15
O
CH
CH3
CH3
6
3
8
16
CH
CH3
3
H C
18 CH
17
H C
3
3
3
19
R
R
1
(Trichoaurantianolide A)
R = OAc)
2 (Trichoaurantianolide B)
(R = OH)
(
5 (Lepistal) (R = H)
6 (Lepistol) (R = H)
O
O
O
O
H
H
O
O
O
CH3
CH3
O
CH3
CH3
CH3
CH3
H C
H C
3
AcO
3
HO
3
(Trichoaurantianolide C)
4 (Trichoaurantianolide D)
Figure 1. Trichoaurantianolides A–D and related metabolites.
2
Steglich and coworkers also assigned the absolute stereochemistry of
trichoaurantianolide B (2) using Hamilton’s applications of linear-hypothesis testing of
crystallographic data, which proved to be in agreement with the proposed configuration
advanced by Vidari’s assessment of the observed Cotton effects. Shortly
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thereafter, Sterner and coworkers reported the isolation of lepistal (5) and lepistol (6),
8
corresponding to the deoxygenated C compounds of 1 and 2, respectively. In 2003, Ohta
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and coworkers characterized the related neodolastanes, tricholomalides A, B, and C, and
concluded that these fungal metabolites had the opposite absolute configuration of the
trichoaurantianolides based on their studies of circular dichroism. The latter claim is
surprising since the body of evidence suggests that related diterpenes from a common
biogenetic pathway in algae, fungi, liverworts, and higher plants are enantiomeric to the
5
metabolites isolated from species of marine invertebrates. Although the carbon
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framework of the trichoaurantianolides and related substances differs substantially from
previously known examples of the tricyclic dolastanes, it was recognized that these
neodolastanes would originate from an enzymatic cyclization of geranylgeranyl
pyrophosphate producing the nonracemic dolabellane cation 8 (Scheme 1). A branch of
this biosynthetic pathway leads to a stereospecific backbone migration to account for
Scheme 1. Biosynthesis of neodolastanes
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CH3
H C
3
CH3
H
CH3
H
H C
3
H C
3
H C
3
CH3
CH3 OPP
CH3
8 (Dolabellane cation)
7 (Geranylgeranyl pyrophosphate)
H C
H C
3
3
CH3
H
CH3
H
H C
H C
3
3
H C
3
H C
3
H
CH3
CH3
1
0 (Neodolastane)
9 (Neodolabellane)
Examples:
O
CH3
CH3
O
O
OAc
HO
AcO
OAc
CH3
O OH
CH3
O
11
12
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translocation of the bridgehead methyl substituent. This event directly forms the
neodolabellanes 9, which are [9.3.0]-bicyclic diterpenes frequently isolated from various
7
species of coral, albeit in the enantiomeric series. The initiation of a transannular
reaction of the neodolabellanes (9) yields the corresponding 5-7-6 tricyclic neodolastanes
8
9
10
(
10). Guanacastepenes, such as 11, and heptemerones, such as 12, are primary
examples of the 5-7-6 neodolastane family. Trichoaurantianolides 1–4 result from
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subsequent oxidations and cleavage of the cyclohexenyl ring of 10 leading to the
formation of novel cis-fused butyrolactones.
Notable biological activity has been reported for these substances. Vidari has
described the antibiotic activity of 1 against Bacillus subtilis and Staphylococcus aureus.
Similarly, antibacterial activity is recorded for lepistal (5) against Streptomyces sp.
ATCC23836 and Bacillus subtilus as well as antifungal activity against Rhodotorula
0
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0
1
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glutinis and Saccharomyces cerevisiae S288c. Initial studies of the guanacastepenes
showed promising antibiotic activity against several drug-resistant strains of
11
Staphylococcus aureus and Enterococcus faecalis, but interest diminished as
subsequent experimentation indicated that these compounds were responsible for lysis of
red blood cells. On the other hand, the tricholomalides A–C were found to induce neurite
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outgrowth in rat pheochromocytoma cells at micromolar concentrations. These
significant biological properties enticed Danishefsky and coworkers to undertake studies
1
2
leading to the total synthesis of racemic tricholomalides A and B. These efforts also led
to a structural revision of these natural products. Herein, a full account of our studies
describe an enantiocontrolled pathway for the first total synthesis of trichoaurantianolides
C and D. Our investigations have explored an intramolecular reductive cyclization
strategy for construction of the central cycloheptane by tethering two nonracemic five-
membered ring components. A notable application of the π-allyl Stille cross coupling
provides for the efficient formation of a tetrasubstituted olefin directly leading to a
Sharpless asymmetric epoxidation for the installation of the critical C-2 stereochemistry.
Efforts to advance these studies have examined two strategies for stereocontrolled
elaboration toward the unsaturated oxacycle of 3 and 4. Unanticipated results are
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described in these investigations, which led us to uncover several notable tactical
solutions with broad implications for synthetic chemistry. Our efforts have revealed
valuable insights of novel reactivity for the synthesis of similarly functionalized
polycyclic systems.
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RETROSYNTHETIC ANALYSIS
The densely functionalized skeleton of trichoaurantianolides C and D presents a
significant challenge for synthesis. The framework contains seven contiguous asymmetric
carbons, six of which are found within the seven-membered ring. In addition, three of
these sites of chirality are fully substituted, and the bridgehead positions at C-7 and C-10
are quaternary carbon centers. We devised an initial strategy for the synthesis of 3 and 4
as illustrated in Scheme 2. Our retrosynthetic analysis presumed that the formation of
trichoaurantianolide B (2) would permit studies of the intramolecular conjugate addition
leading to the bridging furanyl ether in 3. Furthermore, this prospect suggests that the
stereochemistry at C-11 of 3 results by protonation of an intermediate arising from this
1
,4-addition. However, conditions for the thermodynamic interconversion of the natural
metabolites 2 and 3 were undefined. We rationalized that a cross coupling reaction of 13
X = SnBu ; I; or triflate) would permit conversion to the corresponding allylic ether (X =
CH OPMB) for oxidation at C-12 and mild deprotection for studies of the final ring
(
3
2
closure. The C=C double bond of 14 was considered as a reasonable precursor to 13, and
the removal of benzyl protection in 14 would also allow for elaboration to the activated
alkenyl species.
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Scheme 2. Retrosynthetic Analysis
O
4
O
O
OH
1
11
H
3
1
3
O
O
5
2
7
14
O
CH3
CH3
O
10
CH3
CH3 15
CH3
8
CH3
H C
H C
3
3
0
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8
9
0
HO
OH
3
2
OBn
OH
12
1
2
X
11
O
O
O
10
O
7
8
CH3
CH3
CH3
CH3
CH3
CH3
H C
H C
3
3
O
O
R
R
1
4
13
OBn
OBn
1
1
1
1
O
HO
2
O
7
CH3
CH3
CH3
6
CH3
CH3
CH3
CH3
CH3
16
H
O 8
TBSO
15
An important feature of our plan requires the introduction of the desired anti
stereochemistry for the two chiral, fully substituted carbons at C and C10 within the
7
cycloheptane framework of 14. The plan for developing the central seven-membered ring
led us to explore the intramolecular reductive cyclization of 15 to give the cis-fused
butyrolactone. The proposal would use the intact five-membered rings of 15,
incorporating crucial elements of chirality at C-2, C-10, and C-14, and our modeling
predicted a minimization of steric interactions in the cyclization leading to the anti-
dimethyl arrangement. The synthesis of butenolide 15 is envisioned by the formation of
an acrylate ester of the tertiary alcohol in 16, and the application of ring-closing
metathesis (RCM).
An alternative sequence for the installation of the allylic alcohol appendage of 2 is
shown in Scheme 3, and this plan envisions a stereocontrolled nucleophilic addition to
the enone 19. A known Grignard reagent, obtained from (2-bromoallyl)trimethylsilane,
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provides for 1,2-addition to 19 to yield the allylsilane 18 for an oxidation leading to
butyrolactone and enone formation in the penultimate intermediate 17. Subsequent
epoxidation of 17, followed by facile desilylation under basic or acidic conditions, would
then afford a mild conversion to the allylic alcohol of 2. The cycloheptenone 19 is
available by cleavage of the 1,2-diol of 20, which intersected with our analysis of Scheme
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2
2
via straightforward manipulations of the key intermediate 14. By comparison, Scheme
requires careful execution of steps leading to alkene 13 and a challenging cross
coupling reaction to yield 2. Scheme 3 relies on successful stereoselective addition to the
functionalized enone 19. In either case, the stereochemistry of the accessible nonracemic
C-2 alcohol in 16 of Scheme 2 is effectively transferred in the construction of the
quaternary C-7 and C-8 stereogenicity. Thus, our studies initially sought pathways for
convenient preparation of the chiral alcohol 16.
Scheme 3. An Alternative Plan for Formation of 2
HO
O
TMS
O
O
O
O
O
CH3
CH3
CH
CH3
3
CH3
CH
3
H C
3
H C
3
OH
O
R
2
(Trichoaurantianolide B)
17
OH
TMS
OH
O
HO
CH3
CH3
CH3
CH3
1
CH3
R O
CH3
H C
3
1
O
R O
H C
3
O
R2
R2
1
9
1
8
OH
HO
OBn
1
2
11
10
HO
O
CH3
CH3
O
7
8
CH3
CH3
CH3
1
R O
H C
3
H C
3
CH3
O
O
R2
R
2
0
14
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RESULTS AND DISCUSSION
To address the issue of stereocontrol in the formation of the C-2 tertiary alcohol
9b,13
of 16, our efforts developed a noteworthy π-allyl Stille cross coupling
of the
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nonracemic acetate 21 (Scheme 4) with the E-alkenyl stannane 22 to give the
nonconjugated diene 23 (88%). The reaction proceeds in the presence of the unprotected
allylic alcohol and yields the tetrasubstituted alkene with complete retention of olefin
geometry. This protocol provides a general route for the synthesis of configurationally
defined E- and Z-trisubstituted and tetrasubstituted alkenes. In fact, it has proven to be
very useful in the stereocontrolled preparations of skipped 1,4-dienes as shown by
1
3a
additional examples reported in our preliminary studies related to this work. The
15
stannane 22 is readily obtained from ethyl 4-benzyloxy-2-methylacetoacetate (24) in
1
6
three steps by stereocontrolled formation of the triflate 25, reduction, and replacement
1
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of the vinylic triflate of 26 with a higher-order stannylcuprate reagent. The cross
BnO
BnO
1) Me NOH; Tf O (88%)
4 2
O
2) DIBAL at –78 °C (88%)
X
(1)
EtO
3) LDA; THF
CH3
R
CH
3
nBu SnH; CuCN
3
O
25 (X = OTf; R = COOEt)
6 (X = OTf; R = CH OH
add triflate at –78 °C
78 °C → –20 °C
79%)
2
–
(
2
2
4
22 (X = SnBu ; R = CH OH)
3 2
coupling product 23 (Scheme 4) allows for the introduction of the desired C-2
stereochemistry by the application of a Sharpless asymmetric epoxidation (dr 87:13), and
conversion of the resulting primary alcohol to the bromide for reductive elimination using
n-BuLi at –78 °C. Alcohol 16 is purified by silica gel chromatography and alkoxide
formation at 0 °C is followed by dropwise addition of acryloyl chloride. The desired
acrylate (74%) is purified by flash chromatography, with the recovery of a small amount
of starting alcohol (12–18%) which is subsequently resubmitted for acylation. RCM
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using the Grubbs II catalyst in toluene at 70 °C yields butenolide 27 (99%), and the key
aldehyde intermediate 15 is then readily achieved upon TBS deprotection and Dess–
1
9
Martin oxidation.
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a
Scheme 4. Synthesis of the tricyclic skeleton of 2
BnO
OH
SnBu3 BnO
CH3
HO
AcO
CH3
2
2
CH3
CH3
a
b, c, d
CH3
CH3
TBSO
CH3
2
1
TBSO
O
CH3
2
3
OBn
OBn
HO
H C
Cl
O
2
O
CH3
CH3
CH3
CH3
e, f
CH3
CH3
3
CH3
TBSO
1
6
X
2
7 (X = OTBS; H)
g, h
1
5 (X = O) (92%)
BnO
O
H
O
i
H
CH3
CH
3
2
8
O
OBn
OBn
H
O
O
1
0
O
O
7
CH3
CH3
8
CH3
H C
H
3
C
CH3
CH3
H
3
CH3
X
Y
O
2
9 (X = OH; Y = H)
30 (X = H; Y = OH)
2 (X; Y = O) (77%)
33 (X = OAc; Y = H)
3
1
k
j
3
a
i
(
a) 22, Pd(PPh
3
)
4
(cat), LiCl, CuCl, DMSO, 88%; (b) Ti(O Pr)
, PPh , imid, 82%; (d) n-BuLi, –78
, 74%; (f) Grubbs II cat, tol, 70 °C,
99%; g) HF, MeCN, 96%; h) DMP, NaHCO , CH Cl , 92%; i) SmI
HMPA, THF, BuOH, 63% (dr 66:34); j) DMP, NaHCO , CH Cl , 77%;
k) Ac O, pyr, DMAP, CH Cl , 98%.
4
, D-
t
DIPT, BuOOH, 4 Å MS; 75%; (c) CBr
C, 99%; (e) PrMgCl, ClC(O)CHCH
2
4
3
i
°
3
2
2
2
,
t
3
2
2
2
2
2
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3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Studies for the formation of the seven-membered ring have focused on the use of
2
, which has been generally described for intramolecular reductive cyclizations to
SmI
2
0
afford five- and six-membered systems. In our case, preliminary studies have explored
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
conditions for successful cyclizations to occur with HMPA as an additive in THF
solutions of samarium diiodide at 22 °C by the inclusion of small quantities of tert-
13a,21
butanol.
The C-8 diastereomeric alcohols 29 and 30 (dr 67:33) are isolated in 63%
yield and are individually characterized after preparative HPLC. The coordination of
2
2
2
additives with SmI alters the oxidation potential of the in situ reagent and may
dramatically affect the course of the reduction. For example, our reactions produce
substantial amounts of the reduced lactone 31 in the absence of tert-butanol, and no
reaction is observed without the inclusion of HMPA. The tethered arrangement of the
ketyl radical 28 presents a conformational bias for facial selectivity. Thus, both 29 and 30
possess 7,10-anti-dimethyl substitution as a result of a minimization of steric interactions
leading to the cis-fused lactones. In large-scale reactions, the direct conversion of this
mixture to the corresponding acetate or benzoate esters or TBS ethers facilitates the
chromatographic separation of the major isomer 29 as a protected secondary alcohol.
Oxidation of the mixture of alcohols affords a single ketone 32 as a crystalline solid (mp
9
4 °C–95.5 °C), and subsequent X-ray studies have unambiguously confirmed the anti
2
3
7
stereochemistry of the critical quaternary chiral centers (C and C10).
From this point, our retrosynthetic analysis of Scheme 2 incorporates a proposed
oxidation of the C11–C12 double bond for conversion to the allylic alcohol moiety of 13.
A number of strategies were examined to carry out this transformation without success.
For example, epoxidation of the cyclopentene of suitably protected derivatives of 29 (R =
1
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Ac, Bz, or TBS) was followed by typical reagents for isomerization of the epoxide to an
allylic alcohol, and these attempts produced a facile backbone migration of the
bridgehead methyl substituent. Subsequent efforts employed a dihydroxylation of the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
4
4
acetate 33 (Scheme 5) which required DMAP to activate OsO . The procedure gave a
separable mixture of β-diol 34 (75%) and α-diol 35 (25%), and each diastereomer was
separately advanced to simplify our NMR analyses of reaction products. The production
of diol diastereomers seemed to be of no consequence for our planned conversion to the
conjugated enone 2 of Scheme 2, and we arbitrarily selected these diol isomers to
investigate methodology for the elaboration of the bridgehead benzyloxymethylene
substituent into the desired allylic alcohol. For example, the efficient formation of the
19
acetonide 36 was followed by hydrogenation, Dess–Martin oxidation, and reaction with
2
5
the Gilbert–Seyferth reagent to yield the terminal alkyne
a
Scheme 5. Preparation of Stille reaction precursors.
OBn
OAc
Y
OBn
X
O
a, b
O
O
CH3
O
CH3
CH3
H C
3
CH3
CH3
H3C
CH3
OAc
3
3
34 β-diol (X = Y = OH)
35 α-diol (X = Y = OH)
3
6 α-acetonide (O–C(CH ) –O)
3 2
c, d, e
H
O
O
O
X
O
f
O
O
O
g
O
CH3
CH3
CH3
CH3
CH3
H C
H C
3
CH3
3
OAc
OAc
37
3
3
8 (X = SnBu ) (86%)
3
9 (X = I) (50%)
a
t
(a) OsO
4
, DMAP, BuOH, H
2
O, 34 °C, 99% (dr 75:25); (b) Me
, 10% Pd-C (cat), MeOH, 100%; (d) DMP,
, THF, –78 °C, 96%; (f) fac-
2 2
C(OMe) ,
CSA (cat), 0 °C, 95%; (c) H
CH Cl , 99%; (e) HCN
2
2
2
2
P(O)(OMe)
2
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
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5
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5
5
5
5
5
6
t
Mo(CO)
3 3 3 2
(CN Bu) , nBu SnH, THF, hydroquinone, 55 °C, 86%; (g) I ,
CH Cl , 50%.
2
2
3
7. A highly regioselective, molybdenum-catalyzed hydrostannylation of the alkyne 37
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
t
26
3 3
was observed with fac-Mo(CO) (CN Bu) . This noteworthy stannylation proceeded in
high yield, and the preparation of 38 also permitted conversion to the corresponding
27
iodide 39 for subsequent use in Stille carbonylation reactions or with a cross-coupling
2
8
2 3
partner X–CH –OPMB (X = halide or SnBu ).
We utilized the β-acetonide, originating from 34 of Scheme 5, in efforts for
synthesis of the analogous vinyl triflate 42 as summarized in Scheme 6. The sensitive
aldehyde 40, derived from hydrogenolysis and Dess–Martin oxidation of the β-acetonide,
2 2
selectively reacted with trimethylalane in CH Cl to produce a mixture of alcohol
diastereomers (97% (dr 90:10)) for immediate oxidation to the methyl ketone 41. Kinetic
a
Scheme 6. Formation of vinyl triflates 42 and 43.
O
O
R
O
TfO
O
O
b
O
O
O
O
CH3
CH3
CH3
CH3
H C
3
CH3
H C
3
CH3
OAc
OAc
4
4
0 (R = H)
1 (R = CH3)
42
a
O
TfO
c, d, e
O
O
CH3
CH3
CH3
H C
3
OAc
4
3
a
(a) AlMe
3
, CH
2
Cl
2
, 97%, then DMP, NaHCO
, 56%; (c) FeCl , CH Cl
2
; pyr, 50 °C, 90%.
3
, CH
2 2
Cl , 90%; (b) NaHMDS,
THF, –78 °C, PhNTf
0%; (e) SOCl
2
3
2
2
, 0 °C, 63%; (d) IBX, DMSO,
5
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deprotonation at –78 °C led to the unstable triflate 42, and a portion of the material was
also transformed into the enone 43 by hydrolysis of the acetonide, oxidation and
elimination. With considerable efforts, we subsequently attempted cross-coupling and
carbonylation reactions of 38, 39, 42, and 43 using a variety of palladium catalysts in
order to execute the late-stage transformations of Scheme 2. However, these studies
consistently produced rapid decomposition to many polar byproducts which lacked the
presence of the butyrolactone moiety.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To circumvent this difficulty, the strategy outlined in the retrosynthetic analysis of
Scheme 2 was amended to feature the formation of diol 44 of Scheme 7 for a proposed
double elimination to install a cyclic enone as well as the desired terminal alkene. Our
plans for a selective nucleophilic addition to ketone precursors, such as 41, could not be
achieved in the presence of the carbonyl of the butyrolactone. Thus, a reduction of 33
4 2 2 2
(LiAlH ; Et O) followed by TBS protection (TBSOTf; 2,6-lutidine; CH Cl ) yielded the
2
9
tertiary alcohol 45 (Scheme 7). Reductive debenzylation and Swern oxidation gave the
α-hydroxy aldehyde 46 which was converted to ketone 47 in two steps. First, the
formation and addition of the lithium reagent generated by transmetalation of
2 3
PMBOCH SnBu was carried out at –78 °C to avoid the Wittig rearrangement of this
reactive carbanion, and subsequent oxidation uneventfully gave 47. Reactions of the
hindered ketone 47 with excess methylmagnesium bromide (5.0 equiv) proceeded very
slowly at room temperature and led to the isolation of varying amounts of the acyloin
rearrangement product 48 as a single diastereomer along with the desired 49 as well as
3 3
the recovered ketone. The use of methylcerium reagent (CH Li; CeCl ) favored formation
of the eight-membered ketone 48, which is produced by a selective migration of the
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2
2
2
2
2
2
2
2
3
3
3
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3
3
3
4
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4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
neighboring methylene. In principle, the reversible isomerization of the α-ketol of 47 to
the eight-membered cyclooctane 48 should reflect the relative stabilities of these cyclic
systems. In practice, the resubmission of 48 to the reaction conditions led to the recovery
of starting material and no evidence for the formation of 47 or the corresponding alcohol
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
9.
a
Scheme 7. Double elimination approach.
X
H
HO
a
d, e
2
9
CH3
CH3
CH3
TBSO
b, c
OTBS
4
4
5 (X = H; OBn)
6 (X = O)
HO
O
CH3
PMBO
TBSO
PMBO
HO
f
HO
2
CH3
CH3
CH3
CH3
CH3
CH3
OTBS
TBSO
OTBS
47
49
g, h, i
OPMB
HO
HO
CH3
HO
O
PMBO
O
O
O
CH3
CH3
CH3
TBSO
OTBS
OTBS
4
8
4
4
a
(
a) LiAlH
THF, –78 °C, 93%; (c) (COCl)
8%; (d) PMBOCH SnBu , nBuLi, THF, –78 °C, 68% (dr 95:5, 82%
brsm); (e) (COCl ), DMSO, CH Cl , then Et N at –55 °C, 93%; (f) MeLi,
Et O, –78 °C to rt, 40% (83% brsm); (g) OsO
dr 84:16); (h) TBAF, AcOH (2.5:1) in THF, 90%; (i) TEMPO, NaOCl,
KBr, NaHCO , 84%.
4
, Et2O, then TBSOTf, 2,6-lutidine, CH
2
Cl
, then Et
2
(85%); b) Na, NH
3
,
2
, DMSO, CH Cl
2
2
3
N at –55 °C,
9
2
3
2
2
2
3
t
2
4 2
, DMAP, BuOH, H O, 80%
(
3
This result indicates an unexpected thermodynamic preference for the highly substituted
cyclooctane system. Subsequently, we found that the use of newly purchased bottles of
methyllithium in ether (15 equiv) afforded modest yields of the desired diol 49 as a single
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30
diastereomer (40% yield; 83% brsm) without formation of the ketone 48. The three-step
conversion to the desired α-ketol 44 was achieved by the recycling of ketone 47 through
this problematic transformation as well as a noteworthy improvement in the
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29
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31
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34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
stereoselectivity of the dihydroxylation of the C-11/C-12 olefin (dr 84:16). We were
poised to examine the final stages of our total synthesis by the elimination of two
equivalents of water from 44. However, various procedures for effecting dehydration,
3
1
32
including the use of the Martin sulfurane, Burgess reagent, thionyl chloride or mesyl
chloride, led to a multitude of products.
Problems encountered in these elimination attempts led us to investigate the
stereochemistry of the C-11/C-12 diol and its implications in subsequent reactions.
Experiments independently examined β-diol 34 and α-diol 35, as shown in Scheme 8.
a
Scheme 8. Studies leading to ketone 52.
OH
OH
BnO
HO
BnO
HO
O
O
O
O
CH3
CH3
CH3
CH3
CH3
CH3
OAc
OAc
3
4
35
a
b
O
O
BnO
O
O
O
O
O
CH3
CH3
CH3
CH3
CH3
CH3
OAc
OAc
5
0
51
c
OTBS
CH3
OTBS
CH3
RO
HO
O
e
CH3
CH3
CH3
CH3
TBSO
d
OTBS
TBSO
OTBS
5
5
2 (R = Bn)
3 (R = H)
54
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
6
a
(
a) TEMPO, NaOCl, KBr, NaHCO
3
, 90%, then SOCl
2
, pyr, 55 °C, 64%;
, pyr, 55 °C, 50%;
Cl , 2,6-lutidine,
CO , CH Cl , 0 °C,
(
b) TEMPO, NaOCl, KBr, NaHCO
3
, 82%, then SOCl
2
(c) Red-Al, tol –78 °C � +65 °C, then: TBSOTf, CH
8
8
2
2
2%; (d) LiDBB, THF, –78 °C, 77%; (e) Pb(OAc)
9%.
4
, K
2
3
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
3
TEMPO oxidation of 34 led to the syn-elimination of the α-hydroxyketone using
thionyl chloride to afford the enone 50. However, application of these conditions to
diastereomeric 35 resulted in formation of the bridging ether of the trans-fused ketone 51.
Formation of 51 was minimized by adaptation of a published procedure for reaction of
the starting ketol with 1,1'-thiocarbonyldiimidazole followed by syn-elimination in o-
8
a
dichlorobenzene at reflux. The elevated temperature and prolonged reaction time gave
only modest yields of 50 with considerable decomposition using this diastereomer.
Nevertheless, sufficient quantities of the desired enone 50 were available from the major
diol 34, and the enone 50 was advanced using the reduction and protection conditions as
previously described in Scheme 7 to produce 52. Although the Birch conditions for
removal of the benzyl ether of 52 resulted in reductive cleavage of the allylic silyl ether,
3
4
our use of the radical anion of 4,4'-di-tert-butylbiphenyl (LiDBB) gave the desired diol
3. Subsequently, an efficient oxidative cleavage in CH Cl using lead tetraacetate
yielded the seven-membered enone 54 in 89% yield.
5
2
2
In response to the difficulties encountered in our attempts to functionalize three
contiguous, fully-substituted carbons as illustrated in 44 of Scheme 7 (C-2, C-3, and C-7)
we devoted increasing attention to the proposed strategy of Scheme 3. This approach
allowed for direct introduction of a functionalized allylic alcohol equivalent into the C-2
carbonyl of the cycloheptenone precursor. However, the diastereofacial selectivity of the
anticipated nucleophilic addition was our primary concern. In the event, our studies of
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nucleophilic addition using an excess of Grignard reagent (20 equiv) derived from (2-
bromoallyl)trimethylsilane completely failed to produce a reaction with enone 54 at
elevated temperatures (50 °C), whereas the addition of 2-propenyllithium (15 equiv) to
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5
4 at –78 °C provided a mixture of C-2 diastereomers in modest yield (dr 2:1).
Fortunately, significant improvement of this reaction was achieved by precomplexation
35
with tetramethylethylenediamine (TMEDA) in ether at –78 °C leading to the desired C-
2
tertiary alcohol 55 (90% yield (dr 95:5)) (Scheme 9). Deprotection gave an intermediate
triol 56 which afforded the lactone 57 upon oxidation. Thus, a single allylic
a
Scheme 9. Completion of the total synthesis.
X
OR2
O
1
3
HO
a
b,c
O
5
4
14
O
CH3
CH3
H C
3
1
H C
3
R O
OTBS
OTBS
5 (R1 = R2 = TBS)
56 (R1 = R2 = H)
60 (R1 = H; R2 = TBS)
57 (X = H; H and C13–C14
58 (X = H; H and C13=C14
)
)
5
d
e
5
9 (X = O and C13=C14)
f
H
OTBS
O
OH
12
X
g
O
O
O
O
CH3
CH3
H C
3
H C
3
OTBS
OTBS
63
6
6
1 (X = H; H)
2 (X = OH; H)
d
h
3
a
t
(a) isopropenylbromide, BuLi, Et
2
O, TMEDA (1 eqiv) at –78 C, 90% (dr
Cl
, dioxane, 65 °C, 60% (93% brsm); (e) TBAF,
9
8
5:5); (b) TBAF, AcOH (2.5:1), THF, 87%; (c) TPAP, NMO, CH
0%; (d) sublimed SeO
2
2
,
2
AcOH (1:1), THF, 96%; (f) TPAP, NMO, 90%, then, TBAF, AcOH
(2.5:1), 88%; (g) TBSCl, Et
3
N, CH
2
Cl
2
, 62% (84% brsm), then, TPAP,
NMO, 92%; h) TAS-F, DMF, 75%.
36
hydroxylation was required to accomplish our goals. Unfortunately, the completion of
the total synthesis was confounded by a facile SeO
2
reaction of 57 which readily
introduced the cyclopentenone unsaturation of 58. A selective reaction could not be
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2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
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5
5
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5
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5
5
5
5
5
6
achieved since formation of the C13–C14 double bond occurred at a faster rate than the
allylic hydroxylation. The observed dehydrogenation of 57 is particularly effective
because of the ease of enolization of the starting ketone, as well as the resulting
stereochemistry of the intermediate selenoxide that allows for an efficient syn-
elimination. Further oxidation to the C-4 aldehyde 59 also proceeded at a comparable
rate. Alternatively, attempts to effect the desired allylic oxidation using singlet oxygen
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
7
failed. Moreover, reasonable alternatives for elaboration of 54 using the lithium reagent
derived from 3-trimethylsilyl-2-bromo-1-propene with TMEDA complexation did not
proceed.
We overcame these difficulties by the selective cleavage of the primary OTBS
ether of 55 to give 60 of Scheme 9 followed by oxidation to produce the butyrolactone
which was immediately treated with TBAF to yield allylic alcohol 61. The SeO
2
oxidation of 61 gave the desired 62 together with the related aldehyde (X = O). These
reactions were halted prior to the observation of a slower oxidation leading to formation
3
8
of the C-12 ketone. In practice, our reactions were quenched with a Luche reduction,
which provided the diol 62 in 60% yield (93% brsm) after flash column chromatography
with an additional 33% of recovered 61.
Trichoaurantianolide C (3) is cleanly produced by the provisional TBS protection
of the primary allylic alcohol of 62 and oxidation to give the enone 63. Our initial plan to
explore conditions which trigger the internal conjugate addition for interconversions of
trichoaurantianolides B (2) and C (3) did not develop as expected. Indeed, global
3
9
deprotection with TAS-F led exclusively to the ring-closed natural product,
trichoaurantianolide C (3). Trichoaurantiolide D (4) was obtained from synthetic 3 by
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acetylation (Ac
2 2 2
O; DMAP; CH Cl (80%)). The total synthesis of 3 and 4 was confirmed
by comparisons of proton and carbon NMR data and optical rotations with reported
4
0
characterizations of the authentic natural metabolites.
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44
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50
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53
54
55
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58
59
60
CONCLUSION
In summary, the first enantiocontrolled total synthesis of trichoaurantianolides C
and D has been achieved. Trichoaurantianolide C (3) was obtained in 21 steps from the
known allylic acetate 21, and these efforts confirm the original assignment of absolute
configuration by Steglich and Vidari. The stereocontrolled route features a samarium
7
diiodide reductive cyclization to establish the anti-dimethyl configuration at C and C10
quaternary carbons. Studies demonstrate a facile π-allyl Stille coupling for efficient
stereocontrolled preparation of tetrasubstituted alkenes in skipped 1,4-dienes. Our
investigations have also uncovered several aspects of unexpected reactivity in the
formation and reactivity of α-ketols in synthesis, including stereoselective elimination
reactions to yield the corresponding enones, and nucleophilic addition reactions of α-
hydroxy aldehyde and α-hydroxy ketone substrates, as well as a stereoselective acyloin
rearrangement for ring expansion to yield a highly substituted cyclooctanone. Our results
demonstrate improved diastereoselectivity by precomplexation with TMEDA in the
course of nucleophilic addition of an alkenyllithium reagent. Overall, these efforts
provide new insights for the synthesis of polycyclic terpenes.
EXPERIMENTAL SECTION
General Methods. All reactions were performed in flame-dried or oven-dried
glassware under argon atmosphere. All non-volatile samples were pumped to constant
weight at ambient temperature (0.2-0.1 mmHg) following removal of solvents by rotary
1
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evaporation. Non-aqueous reagents were transferred using syringe techniques under
argon atmosphere. Bulk grade hexanes and ethyl acetate for chromatography were
distilled prior to use. Tetrahydrofuran (THF), dimethylformamide (DMF), toluene,
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acetonitrile, diethyl ether (Et
by degassing with argon and then passing through activated alumina columns to remove
water. Triethylamine (Et N) and diisopropylethylamine (DIPEA) were distilled from
CaH under dry argon immediately before use. Commercial reagents were used as
2
O) and dichloromethane (DCM) were obtained anhydrous
3
2
obtained unless otherwise specified. Air-sensitive reagents were handled inside a glove
box under a dry argon atmosphere.
Reactions were monitored by standard thin-layer chromatography (TLC)
techniques using silica gel 60 F254 pre-coated plates (0.25 mm thickness). Following the
run, TLC plates were visualized under UV light and/or by appropriate stains (p-
anisaldehyde or cerric ammonium nitrate or potassium permanganate). Flash column
chromatography was performed with flash silica gel (ultra-pure 40–63 µm)
1
Proton nuclear magnetic resonance ( H NMR) spectra were recorded on 400 MHz
1
3
and 500 MHz instruments. Carbon nuclear magnetic resonance ( C NMR) spectra were
measured using 101 MHz and 125 MHz instruments. NMR coupling constants and signal
1
13
patterns are reported as J values in Hz and δ values in parts per million (ppm). H and C
NMR spectra are internally referenced to residual solvent signals (CDCl referenced to δ
.26 and 77.16 ppm respectively). The following abbreviations were used to indicate the
3
7
multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet. High resolution
mass measurements (HRMS) were obtained using ESI time-of-flight (TOF)
instrumentation. Optical rotation data were obtained on a polarimeter and are reported in
2
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terms of degree of rotation of plane-polarized light. IR spectra were recorded on a FT-
–
1
spectrometer and are reported in terms of frequency of absorption (cm ).
(E)-ethyl-4-(benzyloxy)-2-methyl-3-(tributylstannyl)but-2-enoate (25). To a 3-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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60
1
5
neck round-bottom flask with stir bar, ethyl 4-(benzyloxy)-2-methyl-3-oxobutanoate
(2.05g, 8.19 mmol), hexanes (41 mL), and water (11 mL) were added. The resulting
solution was cooled to 5 °C (internal temp) and tetramethylammonium hydroxide (25 wt
in water, 14.7 mL, 41 mmol) was added dropwise. The reaction was vigorously stirred
%
for 10 min. Triflic anhydride (3.44 mL, 20.48 mmol) was then added dropwise, taking
care to maintain an internal temperature of +5 to +15 °C. After 25 min, water (10 mL)
was added and the reaction was warmed to rt. The organic layer was separated and the
aqueous layer was washed with EtOAc (3 x 20 mL). The combined organic layers were
washed with water (40 mL), brine (30 mL), dried over MgSO
4
, and concentrated in vacuo
to provide a yellow oil. The crude product was purified by flash column chromatography
(
Hexanes/EtOAc (15:1)) to afford 25 (2.85 g, 88%) as a clear colorless oil: R
f
0.26
(
Hexanes/EtOAc (10:1)); IR (film) 3066, 2984, 2872, 1724, 1663, 1455, 1419, 1283,
–
1 1
1213, 1140, 1069, 930, 853, 739 cm ; H NMR (400 MHz, CDCl
3
) δ 7.36–7.30 (m, 5H),
4
3
.58–4.57 (m, 2H), 4.55 (s, 2H), 4.21 (q, J = 7.2 Hz, 2h), 2.05 (s, 3H), 1.27 (t, J = 7.2 Hz,
1
3
H); C NMR (100 MHz, CDCl
3
) δ 165.8, 152.4, 137.1, 128.4, 127.9, 125.9, 118.4 (q, J
+
=
3.2 Hz), 72.7, 66.2, 61.9, 14.0, 13.9; HRMS (ESI-TOF) m/z [M+Na] calcd for
C
15
H
17
O
6
SF
E)-4-(benzyloxy)-2-methyl-3-(tributylstannyl)but-2-en-1-ol (26). A solution of 25
9.70 g, 25.4 mmol) in THF (508 mL) was cooled to –78 °C and was treated with a
dropwise addition of DIBAL-H (1M in hexanes, 63.4 mL, 63.4 mmol). After 90 min, the
3
Na 405.0596; found, 405.0581.
(
(
2
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reaction was allowed to warm to 0 °C. The reaction was then recooled to –78 °C and an
additional portion of DIBAL-H (1M in hexanes, 15.2 mL, 15.2 mmol) was introduced.
After 30 min, the reaction was allowed to warm to 0 °C, quenched with saturated aqueous
Rochelle’s salt (100 mL) and warmed to rt. After stirring for 2 h, the organic layer was
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separated and the aqueous layer was washed with CH
mL). The organic extracts were then combined, washed with brine (50 mL), dried over
MgSO , filtered and concentrated in vacuo to provide a yellow oil. The crude product
was purified by flash column chromatography (gradient elution Hexanes/EtOAc (7:3 to
:1)) to afford 26 (7.63 g, 88%) as a clear colorless oil: R 0.20 (Hexanes/EtOAc (4:1));
IR (film) 3413, 2929, 2873, 1689, 1410, 1211, 1141, 1068, 918, 821 cm ; H NMR (500
2 2 2
Cl (100 mL), and Et O (3 x 100
4
1
f
–
1 1
MHz, CDCl
3
) δ 7.38–7.32 (m, 5H), 4.54 (s, 2H), 4.26 (s, 2H), 4.15 (d, J = 6.4 Hz, 2H),
13
1
3
.95 (s, 3H), 1.82 (t, J = 6.4 Hz, 1H); C NMR (126 MHz, CDCl ) δ 143.1, 136.8, 134.6,
128.6, 128.2, 128.0, 118.4 (q,–CF
3
), 72.7, 65.9, 62.2, 15.1; HRMS (ESI-TOF) m/z
+
[
M+Na] calcd for C13
H
15
O
5
SF
3
Na 363.0490; found, 363.0480.
(E)-4-(benzyloxy)-2-methyl-3-(tributylstannyl)but-2-en-1-ol (22). A solution of
diisopropylamine (8.55 mL, 60.8 mmol) in THF (168 mL) was cooled to –78 °C and
treated with dropwise addition of nBuLi (2.46M in hexanes, 24.7 mL, 60.8 mmol). After
1
3
h, nBu SnH (13.7 mL, 51.48 mmol) was added dropwise via syringe. After 30 min,
anhydrous CuCN (2.31 g, 25.9 mmol) was added in one portion and the cold bath was
removed. Within ten min, the cloudy yellow suspension became a clear orange solution,
and the reaction was cooled back to –78 °C. Vinyl triflate 26 (4.00 g, 11.7 mmol) in THF
(8 mL) was added dropwise over 15 min, and the reaction was allowed to warm slowly to
–
20 °C over 1.5 h. The reaction was quenched at –20 °C with a solution of 90% saturated
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aqueous NH
for 30 min. Et
extract was washed with Et
washed with brine (75 mL), dried over MgSO
provide a yellow oil. The crude product was purified by flash column chromatography
gradient elution Hexanes/EtOAc (8:1 to 5:1)) to afford 22 (4.45 g, 79%) as a clear
colorless oil: R 0.5 (Hexanes/EtOAc (4:1); IR (film) 3374, 2954, 2870, 2853, 1615,
1454, 1376, 1100, 1070, 1028 cm ; H NMR (500 MHz, CDCl
4
Cl/10% NH
4
OH (200 mL), and the reaction was warmed to rt, and stirred
2
O (100 mL) was added and the organic layer was separated. The aqueous
O (3 x 100 mL), and the organic extracts were combined,
, filtered and concentrated in vacuo to
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4
(
f
–
1 1
3
) δ 7.35–7.26 (m, 5H),
4
1
.49 (s, 2H), 4.17 (t, JSn-H = 23.5 Hz, 2H), 4.11 (d, J = 6.1 Hz, 2H), 2.02 (t, J = 6.1 Hz,
1
3
H), 1.94–1.91 (m, 3H), 1.52–1.28 (m, 12H), 0.99–0.86 (m, 15H); C NMR (126 MHz,
CDCl
3
) δ 149.0, 138.8, 138.1, 128.3, 127.8, 127.6, 72.4, 71.1, 62.7, 29.1, 27.4, 24.3, 13.7,
+
1
0.8; HRMS (ESI-TOF) m/z [M+Na] calcd for C24
H
42
O
2
SnNa 505.2104; found,
505.2101.
(2R,3S)-3-((benzyloxy)methyl)-3-(((4R,5R)-5-(2-((tert-
(
butyldimethylsilyl)oxy)ethyl)-4-isopropyl-5-methylcyclopent-1-en-1-yl)methyl)-2-
methyloxiran-2-yl)methanol (23). To a 200 mL round-bottom flask, LiCl (511 mg, 12.1
mmol) was added and flame-dried under vacuum. Once cooled the flask was charged
3 4
with Pd(PPh ) (232 mg, 0.2 mmol) and CuCl (671 mg, 10.1 mmol). After flushing the
1
4
flask with argon for five min, a solution of allylic acetate 21 (712 mg, 2.61 mmol) in
dry DMSO (20.2 mL) was added followed by vinyl stannane 22 (1.26 g, 2.61 mmol) in
DMSO (20 mL). The resulting reaction mixture was degassed (3x) by the freeze-pump-
thaw method. The reaction was stirred for one h at rt, and then heated at 50 °C for 36 h.
2
After cooling to rt, water (400 mL) and Et O (200 mL) were added, and the organic
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extracts were separated. The aqueous layer was extracted with Et
combined organic layers were washed with brine (40 mL) and dried over Na
Concentration in vacuo provided a brown oil. The crude product was purified by flash
column chromatography (Hexanes/EtOAc/Et N (85:10:5)) to afford 23 (861 mg, 88%) as
a clear colorless oil: R 0.37 (Hexanes/EtOAc (4:1)); [α] –1.4 (c 0.4, CHCl
421, 2955, 2857, 1472, 1255, 1092, 1006, 935, 775 cm ; H NMR (500 MHz, CDCl
7.40–7.28 (m, 5H), 5.11 (s, 1H), 4.51 (d, J = 12.5 Hz, 1H), 4.47 (d, J = 12.5 Hz, 1H),
2
O (2 x 200 mL) and the
2
SO4.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
2
0
f
D
3
); IR (film)
) δ
–
1 1
3
3
4
6
.16–4.06 (m, 2H), 4.00 (d, J = 10.0 Hz, 1H), 3.91 (d, J = 10.0 Hz, 1H), 3.71 (td, J = 9.7,
.5 Hz, 1H), 3.47 (td, J = 10.0, 4.7 Hz, 1H), 2.73 (d, J = 17.0 Hz, 1H), 2.66 (d, J = 16.5
Hz, 1H), 2.25–2.16 (m, 1H), 2.04 (t, J = 6.2 Hz, 1H), 1.87–1.62 (m, 5H), 1.78 (s, 3H),
.01 (d, J = 6.0 Hz, 3H), 0.89 (s, 9H), 0.88 (s, 3H), 0.86 (d, J = 6.1 Hz, 3H), 0.04 (s, 6H);
1
1
3
3
C NMR (101 MHz, CDCl ) δ 147.3, 138.0, 137.0, 132.1, 128.4, 127.9, 127.7, 123.3,
7
–
2.7, 69.7, 64.0, 61.0, 51.4, 50.0, 40.6, 34.5, 30.2, 29.4, 26.0, 22.6, 22.3, 19.8, 18.4, 17.6,
+
5.1, –5.2; HRMS (ESI-TOF) m/z [M+Na] calcd for C30
H
50
O
3
SiNa 509.3427; found,
509.3412.
Z)-4-(benzyloxy)-3-(((4R,5R)-5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-
isopropyl-5-methylcyclopent-1-en-1-yl)methyl)-2-methylbut-2-en-1-ol (23a). A
(
heterogeneous solution of D–DIPT (231 mg, 0.986 mmol), CH
2
Cl
2
(16 mL) and 4Ǻ
i
powdered molecular sieves (400 mg) was cooled to –20 °C and treated with Ti(O Pr)
4
t
(
243 µl, 0.822 mmol) dropwise. After 1 h, BuOOH (457 µl, 3.6M in toluene, 1.64 mmol)
was added dropwise. After 1 h, the reaction was cooled to –40 °C and a solution of 23
400 mg, 0.822 mmol) in CH Cl (3 mL) was introduced via syringe followed by a
CH Cl (3 mL) syringe wash. The reaction was allowed to stir for 40 h, then warmed to –
(
2
2
2
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5 °C, and quenched with a 30% aqueous NaOH solution saturated with NaCl (1.3 mL)
followed by H
The mixture was then filtered through Celite, and the filtrate was diluted with H
mL) and CH Cl (50 mL). The organic layer was then separated and the aqueous layer
was washed with CH Cl (2 x 50 mL). The organic extracts were combined, washed with
brine (20 mL), dried over MgSO , filtered and concentrated in vacuo to provide a cloudy
2
O (10 mL). The reaction mixture was warmed to rt, with stirring for 1.5 h.
2
O (50
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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33
34
35
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37
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47
48
49
50
51
52
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60
2
2
2
2
4
yellow oil. The product was purified by flash column chromatography (Hexanes/EtOAc
(5:1)) to provide 23a (331 mg, 75%) as a 87:13 mixture of inseparable epoxy alcohol
20
diasteromers. R
f 3
0.30 (Hexanes/EtOAc (4:1)); [α] –0.6 (c 3.62, CHCl ); IR (film) 3454,
D
–
1
2
955, 2896, 1472, 1256, 1090, 835, 775 cm . The major diastereomer was characterized
1
as follows: H NMR (500 MHz, CDCl
3
) δ 7.38–7.29 (m, 5H), 5.41 (s, 1H), 4.53 (d, J =
12.0 Hz, 1H), 4.43 (d, J = 12.0 Hz, 1H), 3.80–3.54 (m, 6H), 3.43 (td, J =9.7, 4.8, 1H),
2
1
.49 (d, J = 17.9 Hz, 1H), 2.42 (d, J = 8.9, 4.5 Hz, 1H), 2.13 (dd, 17.1, 1.9 Hz, 1H), 1.95–
.90 (m, 1H), 1.83–1.60 (m, 4H), 1.45 (s, 3H), 1.02 (d, J = 6.1 Hz, 3H), 0.89–0.86 (m,
1
3
15H), 0.03 (s, 6H); C (126 MHz, CDCl
3
) δ 145.3, 137.3, 128.5, 128.0, 127.9, 124.9,
7
1
3.7, 72.0, 66.6, 65.5, 64.2, 60.5, 50.8, 49.9, 40.5, 35.0, 29.9, 29.3, 26.0, 22.6, 22.4, 19.5,
+
50 4
8.3, 17.0, –5.2; HRMS (ESI-TOF) m/z [M+Na] calcd for C30H O SiNa 525.3376;
found, 525.3370.
2-((1R,5R)-2-(((2S,3S)-2-((benzyloxy)methyl)-3-(bromomethyl)-3-methyloxiran-
-yl)methyl)-5-isopropyl-1-methylcyclopent-2-en-1-yl)ethoxy)(tert-butyl)dimethylsilane
23b). To a solution of epoxyalcohol 23a (1.18 g, 2.35 mmol) in CH Cl (47 mL) at 0 °C
(2.34 g, 7.05 mmol) followed by
(
2
(
2
2
was added imidazole (959 mg, 14.1 mmol), and PPh
3
4
CBr (2.34 g, 7.05 mmol). The reaction flask was protected from light and stirred for 30
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2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
min at which time the solvent was then removed in vacuo to provide a white solid. The
crude product was purified by flash column chromatography (Hexanes/EtOAc (20:1))
affording bromide 23b (1.06 g, 82%) as a 87:13 mixture of inseparable diastereomers as a
0
1
2
3
4
5
6
7
8
9
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1
2
3
4
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8
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4
5
6
7
8
9
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1
2
3
4
5
6
7
8
9
0
2
0
clear, yellow oil. R
f
0.41 (Hexanes/EtOAc (10:1)); [α] –18.7 (c 2.97, CHCl
3
); IR (film)
D
–1
2
955, 2857, 1470, 1373, 1255, 1092 cm ; The major diastereomer was characterized as
1
3
follows: H NMR (500 MHz, CDCl ) δ 7.35–7.28 (m, 5H), 5.57 (s, 1H), 4.59 (d, J = 12.0
Hz, 1H), 4.48 (d, J = 12.0 Hz, 1H), 3.91 (d, J = 11.0 Hz, 1H), 3.71–3.63 (m, 1H), 3.56 (d,
J = 10.4 Hz, 1H), 3.48 (d, J = 11.0 Hz, 1H), 3.44–3.37 (m, 1H), 3.39 (d, J = 10.5 Hz,
1
H), 2.82 (d, J = 17.4 Hz, 1H), 2.36–2.25 (m, 1H), 1.95–1.90 (m, 1H), 1.86 (d, J = 17.5
Hz, 1H), 1.84–1.58 (m, 4H), 1.52 (s, 3H), 1.02 (d, J = 5.9 Hz, 3H), 0.89–0.88 (m, 15H),
13
0
3
.03 (s, 6H); C NMR (126 MHz, CDCl ) δ 145.2, 137.8, 128.3, 127.7, 127.6, 124.0,
73.3, 69.0, 67.8, 62.6, 60.6, 50.7, 50.1, 40.6, 36.4, 35.1, 29.3, 28.7, 26.0, 22.5, 22.4, 19.5,
+
1
5
8.3, 17.3, –5.2, –5.3; HRMS (ESI-TOF) m/z [M+Na] calcd for C30
H
49
O
3
SiBrNa
87.2532; found, 587.2533.
(R)-1-(benzyloxy)-2-(((4R,5R)-5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-
isopropyl-5-methylcyclopent-1-en-1-yl)methyl)-3-methylbut-3-en-2-ol (16). A solution of
bromide 23b (2.66 g, 4.71 mmol) in THF (79 mL) was cooled to –100 °C in a hexanes/N
2
(l) bath and treated by the dropwise addition of nBuLi (2.86 mL, 2.47 M in hexanes, 7.05
mmol). The reaction was stirred for 25 min with a cooling bath temperature no higher
than –85 °C. The reaction was then allowed to warm to –78 °C and then was quenched
with pH 7 buffer (22 mL) and warmed to rt. The organic layer was separated and the
2 2
aqueous layer was extracted with CH Cl (3 x 20 mL). The combined organic extracts
were dried with Na SO , and concentrated in vacuo to provide a clear, colorless oil.
2
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Purification by flash column chromatography (Hexanes/EtOAc (10:1)) provided 16 (1.85
g) and a second fraction of 16 and epi-16 (406 mg) as a 1:1 mixture of C-2 alcohol
diastereomers as clear colorless oils which were resubjected to chromatography to obtain
additional quantities of pure 16. Overall yield of 16 and epi-16: 99%. This purification
also afforded a small amount of pure epi-16 for characterization purposes. Data for
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
0
characterization of 16: R
(film) 2953, 3928, 2856, 1462, 1255, 1091 cm ; H NMR (500 MHz, CDCl
.26 (m, 5H), 5.67 (s, 1H), 5.15 (s, 1H), 4.97 (s, 1H), 4.57 (s, 2H), 3.67 (td, J = 9.8, 6.2
Hz, 1H), 3.50–3.45 (m, 1H), 3.47 (d, J = 9.0 Hz, 1H), 3.42 (d, J = 9.0 Hz, 1H), 2.62 (s,
H), 2.29–2.20 (m, 2H), 2.18–2.14 (d, J = 16.2 Hz, 1H), 1.91–1.83 (m, 1H), 1.82–1.74
m, 1H), 1.72 (s, 3H), 1.71–1.58 (m, 3H), 1.00 (d, J = 5.9 Hz, 3H), 0.88 (s, 9H), 0.87–
f
0.44 (Hexanes/EtOAc (10:1)); [α] –18.7 (c 0.34, CHCl
3
); IR
D
–
1 1
3
) δ 7.36–
7
1
(
1
3
0.83 (m, 6H), 0.03 (s, 6H); C NMR (126 MHz, CDCl
3
) δ 147.4, 144.3, 138.1,128.4,
1
2
27.7, 124.1, 112.3, 76.9, 76.5, 73.5, 60.5, 50.5, 50.3, 40.7, 35.0, 32.4, 29.2, 26.0, 22.7,
+
2.2, 20.0, 19.9, 18, –5.2; HRMS (ESI-TOF) m/z [M+Na] calcd for C30
0.40 (Hexanes/EtOAc
); IR (film) 2953, 2929, 2857, 1462, 1365, 1255, 1091
) δ 7.37 – 7.27 (m, 5H), 5.65 (s, 1H), 5.18 (s, 1H), 4.98
s, 1H), 4.58 (s, 2H), 3.67 (td, J = 9.7, 6.3 Hz, 1H), 3.45 – 3.40 (m, 1H), 3.46 (d, J = 9.2
Hz, 1H), 3.41 (d, J = 9.2 Hz, 1H), 2.51 (s, 1H), 2.30–2.19 (m, 2H), 1.96–1.85 (m, 1H),
50 3
H O SiNa
509.3427; found, 509.3404. Data for characterization of epi-16: R
f
20
(10:1)); [α] +12.9 (c 0.35, CHCl
3
D
–
1 1
cm ; H NMR (400 MHz, CDCl
3
(
1
6
.83–1.55 (m, 5H), 1.77 (s, 3H), 1.00 (d, J = 6.0 Hz, 3H), 0.92–0.82 (m, 15H), 0.03 (s,
13
3
H); C NMR (101 MHz, CDCl ) δ 147.9, 144.7, 138.2, 128.4, 127.6, 124.0, 112.3, 76.8,
76.5, 73.5,60.7, 50.7, 50.3, 40.7,35.1, 32.4, 29.3, 26.0,22.7, 22.3, 20.1, 19.9, 18.4, –5.2 (2
+
C); HRMS (ESI-TOF) m/z [M+Na] calcd for C30
H
50
O
3
SiNa 509.3427; found, 509.3422.
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(
R)-1-(benzyloxy)-2-(((4R,5R)-5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-
isopropyl-5-methylcyclopent-1-en-1-yl)methyl)-3-methylbut-3-en-2-yl acrylate (16a). A
solution of alcohol 16 (643 mg, 1.32 mmol) in THF (13 mL) was cooled to 0 °C and was
0
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8
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treated by dropwise addition of isopropylmagnesium chloride (1.5M in Et
1.59 mmol) over five min and then allowed to warm to rt. After 1 h, acryloyl chloride
644 µl, 7.92 mmol) was added dropwise which turned the solution from colorless to a
clear yellow color, and this mixture was stirred for an additional 16 h at rt. The reaction
was cooled to 0 °C and quenched with saturated aqueous NaHCO (10 mL). After
warming to rt, CH Cl (10 mL) and water (10 mL) were added and the layers were
separated. The aqueous layer was washed with CH Cl (2 x 15 mL), and the organic
layers were combined. The combined organic extracts were washed with brine (10 mL),
dried over Na SO , filtered and concentrated in vacuo to provide a clear yellow oil.
2
O, 1.06 mL,
(
3
2
2
2
2
2
4
Purification by flash column chromatography (Hexanes/EtOAc (30:1)) provided the
corresponding acrylate 16a (526 mg, 74%, 90% brsm) as a clear colorless oil and the
recovered allyl alcohol 16 (117 mg, 18%)). Data for characterization of the ester 16a: R
f
20
0.45 (Hexanes/EtOAc (10:1)); [α] –6.9 (c 0.29, CHCl
3
); IR (film) 2955, 2855, 1725,
) δ 7.34–7.24 (m, 5H), 6.34 (m, 1H),
6.10 (m, 1H), 5.77 (m, 1H), 5.52 (s, 1H), 5.10 (s, 1H), 5.06 (s, 1H), 4.55 (d, J = 12.0 Hz,
H), 4.50 (d, J = 12.0 Hz, 1H), 3.98 (d, J = 10.0 Hz, 1H), 3.93 (d, J = 9.6 Hz, 1H), 3.66
td, J = 9.8, 6.4, 1H), 3.44 (td, J = 9.7, 5.1, 1H), 2.79 (dd, J = 17.5, 2.2 Hz, 1H), 2.52 (d,
D
–
1 1
1
472, 1195, 1090 cm ; H NMR (400 MHz, CDCl
3
1
(
J = 17.6 Hz, 1H), 2.24–2.18 (m, 1H), 1.88–1.56 (m, 8H), 0.99 (d, J = 6.0 Hz, 3H), 0.88
13
(
s, 9H), 0.86 (s, 3H), 0.83 (d, J = 6.0 Hz, 3H), 0.04 (s, 3H), 0.03 (s, 3H); C NMR (101
3
MHz, CDCl ) δ 164.5, 144.4, 143.5, 138.3, 130.0, 129.6, 128.2, 127.5, 127.5, 123.9,
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13.1, 85.9, 73.3, 71.6, 60.5, 50.9, 50.1, 40.8, 35.0, 29.9, 29.2, 26.0, 22.7, 22.1, 19.8,
+
19.7, 18.3, –5.2; HRMS (ESI-TOF) m/z [M+Na] calcd for C33
H
52
O
4
SiNa 563.3533;
found, 563.3511.
R)-5-((benzyloxy)methyl)-5-(((4R,5R)-5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-
10
11
12
13
14
15
16
17
18
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(
isopropyl-5-methylcyclopent-1-en-1-yl)methyl)-4-methylfuran-2(5H)-one (27). A solution
of acrylate ester 16a (660 mg, 1.22 mmol) in toluene (61 mL) was heated to 70 °C and a
solution of Grubbs II catalyst (103.5 mg, 0.122 mmol) was introduced in toluene (12.2
mL) via a syringe pump over 6 h. After an additional 90 min of stirring, the reaction was
cooled to rt, and the solvent was removed in vacuo to provide a tan oil. The product was
purified by flash column chromatography (Hexanes/EtOAc (10:1)) to provide the
butenolide 27 (622 mg, 99%) as a light brown solid: R
f
0.63 (Hexanes/EtOAc (2:1));
); IR (film) 2955, 2859, 1759, 1650, 1471, 1364, 1292, 1255,
094, 954 cm ; H NMR (500 MHz, CDCl ) δ 7.36–7.26 (m, 5H), 5.83 (d, J = 1.4 Hz,
H), 5.48 (s, 1H), 4.57 (d, J = 12.5 Hz, 1H), 4.48 (d, J = 12.5 Hz, 1H) 3.67–3.62 (m, 3H),
2
0
[
α] +2.4 (c 0.83, CHCl
3
D
–
1 1
1
1
3
3.45 (td, J = 9.8, 5.1 Hz, 1H), 2.52 (dd, J = 16.9, 1.7 Hz, 1H), 2.26–2.21 (m, 1H), 2.17 (d,
J = 16.9 Hz, 1H), 2.00 (d, J = 1.4 Hz, 3H), 1.91–1.85 (m, 1H), 1.81–1.74 (m, 1H), 1.72–
1
.63 (m, 2H), 1.61–1.54 (m, 1H), 0.98 (d, J = 6.0 Hz, 3H), 0.88 (s, 9H), 0.86 (s, 3H), 0.84
1
3
(d, J = 6.0 Hz, 3H), 0.03 (s, 6H); C NMR (126 MHz, CDCl
3
) δ 137.5, 128.4, 127.8,
1
2
27.6, 126.2, 118.4, 90.4, 73.8, 72.3, 60.3, 50.6, 50.3, 40.8, 34.7, 29.5, 29.1, 26.0, 22.7,
+
2.0, 20.2, 18.3, 13.9, –5.2 (2 C); HRMS (ESI-TOF) m/z [M+Na] calcd for
SiNa 535.3220; found, 535.3247.
R)-5-((benzyloxy)methyl)-5-(((4R,5R)-5-(2-hydroxyethyl)-4-isopropyl-5-
methylcyclopent-1-en-1-yl)methyl)-4-methylfuran-2(5H)-one (27a). To a solution of
31 48 4
C H O
(
2
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