Total synthesis of (-)-virginiamycin m2: Application of crotylsilanes accessed by enantioselective Rh(II) or Cu(I) promoted carbenoid Si-H insertion

Article abstract of DOI:10.1021/jo202119p

A stereoselective synthesis of the antibiotic (-)-virginiamycin M ₂ is detailed. A convergent strategy was utilized that proceeded in 10 steps (longest linear sequence) from enantioenriched silane (S)-15. This reagent, which was prepared via a Rh(II)- or Cu(I)-catalyzed carbenoid Si-H insertion, was used to introduce the desired olefin geometry and stereocenters of the C1-C5 propionate subunit. A modified Negishi cross-coupling or an efficient alkoxide-directed titanium-mediated alkyne-alkyne reductive coupling strategy was utilized to assemble the trisubstituted (E,-E)-diene. An underutilized late-stage SmI₂-mediated macrocyclization was employed to construct the 23-membered macrocycle scaffold of the natural product (Figure presented).

Full text of DOI:10.1021/jo202119p

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pubs.acs.org/joc
Total Synthesis of (−)-Virginiamycin M2: Application of
Crotylsilanes Accessed by Enantioselective Rh(II) or Cu(I)
Promoted Carbenoid Si−H Insertion
Jie Wu and James S. Panek*
Department of Chemistry and Center for Chemical Methodology and Library Development, Metcalf Center for Science and
Engineering, 590 Commonwealth Avenue, Boston University, Boston, Massachusetts 02215, United States
S
* Supporting Information
ABSTRACT: A stereoselective synthesis of the antibiotic
(−)-virginiamycin M2 is detailed. A convergent strategy was
utilized that proceeded in 10 steps (longest linear sequence)
from enantioenriched silane (S)-15. This reagent, which was
prepared via a Rh(II)- or Cu(I)-catalyzed carbenoid Si−H
insertion, was used to introduce the desired olefin geometry and
stereocenters of the C1−C5 propionate subunit. A modified Negishi cross-coupling or an efficient alkoxide-directed titanium-
mediated alkyne−alkyne reductive coupling strategy was utilized to assemble the trisubstituted (E,E)-diene. An underutilized
late-stage SmI2-mediated macrocyclization was employed to construct the 23-membered macrocycle scaffold of the natural
product.
derivatives of virginiamycins have exhibited potent antibiotic
activity against methicillin-, erythromycin-, and vancomycin-
resistant S. aureus.2 These important bioactivities led to an
active research area in both academia and industry directed at
their further development.3,4 Efforts toward the semisynthesis
of the virginiamycins culminated with the development of
Synercid, a mixture of two antibiotics dalfopristin 7 (group A)
and quinupristin 8 (group B). This combination of agents was
approved in the United States for the treatment of Gram-
positive bacterial infections in 1999 (Figure 2).5
INTRODUCTION
■
The virginiamycins belong to a class of antibiotics naturally
produced by Streptomyces and consist of two principle groups of
compounds. Group A virginiamycins are 23-membered macro-
lides containing an oxazole subunit, such as virginiamycin M2
(1), virginiamycin M1 (2), madumycin II (3), and griseoviridin
(4); group B virginiamycins are cyclic hexadepsipeptides, such
as virginiamycin S4 (5) and etamycin (6) (Figure 1). They have
Figure 1. Structures associated with the virginiamycin class of natural
products.
Figure 2. Composition of synercid (dalfopristin/quinupristin = 7:3
w/w).
However, semisynthesis of group A compounds has been
limited because of their sensitive functionalities and pH
instability.3 This fact, in addition to its structural complexity,
been used as dietary supplements to accelerate the growth of
animals and to prevent and treat bacterial infections. The
virginiamycins were found to likely bind synergistically to
specific sites on the 23S rRNA of the 50S ribosome, thus
inducing a ribosomal conformational change, interfering with
its peptidyl transferase activity.1 Recently, natural and synthetic
Received: October 14, 2011
Published: November 9, 2011
© 2011 American Chemical Society
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Scheme 1. Retrosynthetic Analysis of Virginiamycin M2
has spurred many efforts toward their total synthesis including
the first total synthesis of a group A natural product
would allow for a high degree of flexibility in our synthetic plan
and thus access to analogues. Accordingly, the convergent
design divided virginiamycin M2 into three fragments of com-
parable complexity. The terminal alkyne 14 would be
assembled with the aid of our crotylation methodology utilizing
the organosilane (S)-15.8a This silane reagent has unique
features as it establishes the C1−C2 syn configuration while
simultaneously creating the C3−C4 (E)-unsaturated ester
subunit, thereby functioning as a formal vinylogous aldol
reagent. The reagent itself will be easily prepared through
Rh(II)- or Cu(I)-catalyzed carbenoid Si−H insertion with an
α-diazoester 19.
virginiamycin M2 from the Schlessinger group.4a
(−)-Virginiamycin M2 is a typical member of group A class of
natural products. Its unique macrolide structure exhibits an
unusual array of structural features, including a 23-membered
lactone accommodating an 2,4-disubstituted oxazole, an (E,E)-
trisubstituted diene, an α,β-unsaturated lactam, an amino acid
residue, a β-hydroxyl ketone subunit, and four stereogenic
centers. This material was originally isolated by Todd and co-
workers in 1966,6 and its structure was confirmed by X-ray
analysis in 1974.7 However, because of the pH sensitivity of the
β-hydroxyl ketone moiety, the total synthesis of group A
compounds had not been achieved until nearly 30 years after
their discovery. The important biological properties of
virginiamycins and the challenging structure of the group A
compounds, together with designing a convergent synthesis
enabling structure−activity relationships (SAR) studies, in-
spired us to develop and excute an efficient synthesis of
(−)-virginiamycin M2. Herein, we provide a detailed account of
our efforts that culminated in an enantioselective synthesis of
(−)-virginiamycin M2.8
RESULTS AND DISCUSSION
■
Preparation of Chiral Silane 15. In a previous inves-
tigation concerning the preparation of the homoallylic ether
linked to an α,β-unsaturated functional group in the total
synthesis of (+)-macbecin I, we took a three-step approach
(crotylation/oxidative cleavage/Horner−Wadsworth−Emmons
reaction) focusing on the use of crotylsilane reagents of type
16.13 In that context, we sought to gain direct access to the
homoaldol products 18 utilizing chiral silane reagents of type
15, as part of our program focused on development of new
chiral silane reagents bearing C-centered chirality capable of
delivering useful levels of asymmetric induction, thereby
complementing our previous work in this area (Scheme 2).
This program was initiated by establishing a reproducible
asymmetric Si−H metal carbenoid insertion into vinyl
diazoesters in order to prepare the chiral silane of type-15. A
convenient, straightforward pathway to prepare enantioen-
riched allylsilanes bearing an ester functional group at the chiral
center was reported by Davies’ group using chiral Rh2(DOSP)4
catalysts,14 wherein they reported a problem of instability when
attempting to purify 15. In our hands, however, we did observe
that pure silane 15 could be obtained by flash chromatography
and stored neat at 4 °C for several months without noticeable
decomposition. The use of excess dimethylphenylsilanes was
crucial to the success of the carbenoid insertion process with
high ee (Table 1, entries 1 and 2). Further experimentation
revealed that increasing catalyst loading afforded silane reagents
with higher ee up to 97% (entries 3 and 4).
RETROSYNTHETIC ANALYSIS OF
(−)-VIRGINIAMYCIN M2
■
Our synthetic plans developed for (−)-virginiamycin M2 were
guided by the structural features of the natural product as well
as our intention to explore and extend the utility of chiral
silane-based bond construction methodology9 (Scheme 1). As a
result of the potential instability of the β-hydroxyl ketone
function, we planned to install it at the final stage of the
synthesis. As such, virginiamycin M2 (1) may be derived
through oxidation and deprotection of the silyl ether 9. We
were encouraged to evaluate the efficiency of a SmI2-mediated
intramolecular Barbier/Reformatsky-type cyclization to con-
struct the 23-membered macrocycle, a strategy that proved to
be effective for macrocyclization in our total synthesis of
kendomycin.10 The acyclic framework 10 could be obtained
by esterification of the homoallylic alcohol 11 and the N-
acyloxazolylproline intermediate 12. To access fragment 11,
metal-mediated cross-coupling strategies were considered to
assemble the conjugated (E,E)-diene, including a modified
Negishi cross-coupling11 and the titanium-mediated reductive
alkyne−alkyne cross-coupling12 between the propargylic
alcohol 13 and terminal alkyne 14. This idea, if successful,
Despite the success with Rh(II) catalysis, a Cu(I)-promoted
reaction was evaluated as an economical alternative. Although
the idea of Cu(I) catalysis had been used to promote Si−H
insertions prior to the application of rhodium catalysis, this area
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Scheme 2. Complementary Crotyl Silane Reagents
Table 1. Optimization of Rh(II)-Catalyzed Carbenoid Si−H Insertion
a
b
entry
catalyst loading (mol %)
equiv of silane
yield (%)
ee (%)
1
2
3
4
1
1
2
3
1.5
5
65
70
68
72
48
88
5
93
5
95−97
a
b
Isolated yields were calculated after purification over silica gel. Based on chiral HPLC analysis (ChiralCel OD 1% IPA) of the primary alcohol,
which was obtained from an LAH reduction of ester 15.
of research remained underdeveloped, and few cases of
asymmetric variants have been reported.15 The C2-symmetric
Cu(I) bis-imine complexes, introduced by Jacobsen’s group,
were affordable and operationally simple to prepare, which
allowed for multigram syntheses of ligands that can be custom
tailored with respect to their electronic and steric properties.16 In
that context, we previously reported useful levels of selectivity in a
Cu(I)-promoted insertion with α-diazophenyl acetates utilizing
C2-symmetric Cu(I) bis-imine complexes (eq 1)17 and anticipated
that we could extend the Cu(I) catalysis to α-diazovinyl acetates
(eq 2).
Our evaluation of Cu(I) C2-symmetric Schiff base complexes
did, in fact, demonstrate that these complexes were viable
options for promoting carbenoid insertion into Si−H bonds
capable of generating crotyl silane 15. In our initial experi-
ments, we observed that treatment of vinyl diazoester 19 with
the chiral Cu(I) complex (MeCN)4CuPF6·(R,R)-20a in the
presence of dimethylphenylsilane at 0 °C, which exhibited good
selectivity with α-diazophenyl acetates (eq 1), afforded the
chiral allylic silane 15 in moderate yield (55%) but with a
negligible level of enantioselectivity (12% ee, eq 2). Efforts to
optimize the reaction focused on a solvent,18 copper source,19
catalyst loading,20 and temperature20 screen with the bis-imine
ligand (R,R)-20a. Indeed, a significant dependence of selectivity
on solvent, copper catalysts, catalyst loading, and tempera-
ture was observed. We observed that 5 mol % of
(CH3CN)4CuBF4·(R,R)-20a with benzene as the solvent
afforded the insertion product (R)-15 with highest selectivity
up to 72% ee.16 Reactions conducted at 0 °C exhibited higher
selectivity than those carried out at room temperature, and
below that temperature, the reaction rate became extremely
slow (taking up to 24 h to reach 20% completion at −20 °C).
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Table 2. 2,6-Disubstituted Ligands in Cu(I)-catalyzed Carbenoid Si−H Insertion
a
b
Isolated yields were calculated after purification over silica gel. Based on chiral HPLC analysis (ChiralCel OD 1% IPA) of the primary alcohol,
which was obtained from an LAH reduction of ester 15.
The carbenoid insertion was also investigated in the absence of
bis-imine ligands, which exhibited no obvious ligand accel-
eration effect since the reaction was completed within 4 h when
catalyzed by (CH3CN)4CuBF4 without the presence of the
bis-imine ligand. Increasing the Cu(I) Schiff base catalyst load-
ing resulted in diminished enantioselectivity (5 mol % catalyst,
72% ee; 15 mol % catalyst, 60% ee; 50 mol % catalyst, 49% ee).
Since we observed that the Cu(I) Schiff base complex was not
sufficiently soluble in benzene solvent, higher catalyst loading
may enhance the background reaction rate, presumably due to
the existence of free (CH3CN)4CuBF4, which promoted the
insertion to afford racemic products, thus resulting in the
formation of silane 15 with decreased optical purity.
In efforts to enhance the level of asymmetric induction, a
series of aryl-substituted bis-imine ligands were synthesized by
condensation of (R,R)-diaminocyclohexane and selected
aromatic aldehydes.21 The derived ligands were evaluated in
the insertion to examine variations of steric and/or electronic
properties of the bis-imine complexes. The 2,6-substituents on
the aryl ligands were crucial for the Si−H insertion, and
reactions became sluggish and almost no selectivity without 2,6-
substituents. In a similar manner as the asymmetric aziridina-
tion, the 2,6-substituents appeared to minimize the formation
of catalytically inactive bimetallic type catalyst (Cu2L2), favoring
the formation of the active monometallic intermediates (CuL)
that went on to afford silane product (R)-15.22 A range of 2,6-
substituted aryl bis-imine ligands ((R,R)-20a to (R,R)-20j)
were screened, and the results are summarized in Table 2.
Not surprisingly, variation of the steric or electronic properties
of ligands (entries 1 to 8) had a marked effect on the
enantioselection of the insertion process. However, none of the
ligands that were evaluated showed a significant improvement
over the 2,6-dichlorobenzaldehyde derived complex Cu-
(I)·(R,R)-20a. Altering the electronic property of (R,R)-20a
by adding an electronegative chloride atom at the para position
(entry 9) resulted in slightly eroded selectivity. In an effort to
enhance the solubility of the Cu(I) bis-imine complex, a long
aliphatic substituent was placed at the para-position to achieve
ligand (R,R)-20j, which was beneficial to the selectivity
(78% ee) while the reactivity was maintained (entry 10).
These studies allowed a comparison of chiral Cu(I) vs Rh(II)
catalysis, with the Rh2(DOSP)4 providing slightly higher levels
of selectivity for the cases examined in this study.
Initial Stages of the Virginiamycin M2 Synthesis:
Preparation of the C1−C13 Fragment. The synthesis
was initiated by carrying out the preparation of the C1−C8
fragment 14a featuring an asymmetric crotylation strategy.8a
Construction of the terminal alkyne 18 began with the
asymmetric crotylation between (S)-15 and isobutyraldehyde
(Table 3). After reaction optimization, the three-component
crotylation promoted by TMSOTf with TMSOBn as the
additive (entry 2) proceeded smoothly to afford vinylogous
product 18b in good yield, moderate syn/anti ratios, and
excellent enantioselectivity. However, when TMSOAc was used
as the additive, only decomposition of starting materials was
observed. In contrast to the three-component process, the two-
component crotylation catalyzed by TiCl4 resulted in the
vinylogous aldol product 18a in good yield and excellent
diastereo- and enantioselectivity (entry 1). To our surprise, a
small amount of α-addition product 18c could be isolated in
15% yield as a single diastereomer. Importantly, products
obtained from this pathway were not observed in the three-
component crotylation process, and exclusive α-addition
product 18c was isolated in good yield by simply switching
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Table 3. Crotylation Using Silane (S)-15
a
b
entry
Lewis acid
additive
solvent
product
dr
yield (%)
1
2
3
TiCl4 (1 equiv)
TMSOTf (1 equiv)
TiCl4 (1 equiv)
none
CH2Cl2
CH2Cl2
18a
18b
>20:1
6.3:1
63
68
80
TMSOBn (2 equiv)
None
MeCN
18c
>20:1
a
b
c
Diastereomeric ratio was based on crude 1H NMR analysis of the reaction mixture. Isolated yield. Both products 18a and 18b were achieved with
95% ee based on chiral HPLC analysis.
Scheme 3. Preparation of Alkyne Subunits
to the more polar solvent from CH2Cl2 to MeCN (entry 3). In
that regard, we proposed that the byproduct 18c was pre-
sumably generated through a titanium mediated addition of
the dienolate intermediate (inset). Esters 18a and 18b were
subjected to Weinreb’s amidation conditions23 with propargyl-
amine in the presence of AlMe3 to afford terminal alkyne
amides 14a and 14b in good yields (Scheme 3A). Notably, a
free hydroxyl group in homoaldol product 18a was compatible
in this amidation to achieve product 14a, which could be
acetylated to provide 14c in excellent yield.
Preparation of the C9−C13 fragment commenced with the
monosilylation of 1,3-propandiol, followed by a Parikh−
Doering oxidation24 to afford aldehyde 21 (Scheme 3B).
Propargylic ether 13 was accessed via Carreira’s protocol25 in a
good yield, with excellent enantioselectivity, which was
subsequently protected as its silyl ether 22 using TBSOTf/
lutidine. The asymmetric addition proceeded efficiently and
without evidence of self-aldol condensation of the starting
aldehyde. Meanwhile, in order to develop an operationally
simpler method that did not require the use of gaseous propyne
at ambient temperature, an alternative pathway was evaluated
by employing an enantioselective ketone reduction using
Corey’s CBS reagent26 to prepare propargylic alcohol 13
(Scheme 3C). The racemic secondary alcohol rac-13 was
introduced by adding aldehyde 21 to the propyne lithium
reagent at −78 °C, followed by MnO2 oxidation to achieve
ynone 23. Asymmetric hydride reduction of 23 using 2-methyl-
(S)-CBS-oxazaborolidine afforded propargylic alcohol 13 in
excellent yield and enantioselectivity (ee = 93%).
Our next challenge was encountered with the assembly to the
conjugated diene 11. While there were several options available
for the construction of branched conjugated dienes, a modified
Negishi cross-coupling established in our laboratory some time
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Scheme 4. Previous Synthesis of (−)-Motuporin Using Regioselective Negishi Cross-Coupling
Scheme 5. Assembly of (E,E)-Diene through Regioselective Negishi Cross-Coupling
ago to assemble the Adda fragment of (−)-motuporin 28 was
selected initially (Scheme 4).11b,27
Pd(0)-catalyzed coupling afforded the (E,E)-diene 32b in high
yield. The one-pot Negishi cross-coupling, which would directly
convert an internal alkyne to coupled product without
generating the intermediate iodide 31, was also examined in
this case. The coupling was initiated with the regioselective
hydrozirconation of the silyl ether internal alkyne derivative
of 13 with Cp2ZrHCl (2 equiv, 50 °C) in THF to afford the
(E)-vinyl zirconate as a single stereoisomer, which was directly
transmetalated with anhydrous ZnCl2 to afford the alkenyl zinc
intermediate, followed by Pd-catalyzed coupling with vinyl
iodide 30b. However, the yield of product 32b was
disappointingly low (approximately 20%) and was most likely
due to the incompatibility of the amide group in the presence
of the hydridic reagent.28
To prepare the N-Boc Adda precursor 27, a modified one-
pot Negishi cross-coupling reaction was conducted to afford
the product in good yield as a single regioisomer, while other
methods such as the hydroboration of internal alkyne 24 with
conventional hydroborating reagents (9-BBN, catecholborane)
resulted in poor regioselectivity. The use of excess Schwartz’s
reagent and an elevated temperature were required to achieve
the thermodynamic adduct 25a with good regioselectivity, most
likely due to the reversible addition of a second equivalent of
Schwartz’s reagent to the initially formed alkenyl zirconocene
25b.11a,b
In regard to our synthetic objective, initial experiments were
focused on the use of terminal alkyne 14b (R1 = Bn), which
was converted to vinyl iodide 30b in a two-step sequence:
(i) stannylcupration afforded exclusively the (E)-terminal
alkenyl stannane 29b;4f (ii) iodination to obtain vinyl iodide
30b (Scheme 5). In order to gain access to vinyl iodide 31, the
propargylic alcohol 13 was protected as its TBDPS ether.
Hydrozirconation of the resulting unsymmetrical acetylene
using Schwartz’s reagent (Cp2ZrHCl, 2 equiv, 50 °C), followed
by trapping the vinyl zirconium intermediate with iodine, led to
the (E)-vinyl iodide 31 as a single olefin-isomer, consistent with
results of our earlier studies on the N-Boc Adda product.27
With sufficient quantities of vinyl iodides 30b and 31 now
available, the execution of the Negishi cross-coupling followed a
protocol of: Li−I exchange, Zn−Li transmetalation, and a
Using a model substrate 18b, deprotection of the benzyl
group utilizing DDQ cleanly afforded product 18a (eq 3);
however, we were unable to achieve the cleavage of benzyl
group of compound 32b to cleanly and reproducibly afford
secondary alcohol 11 (eq 4).29
Since we encountered an unexpected difficulty in the
successful removal of the benzyl protecting group in diene
32b required a change in protecting group strategy, acetate 14c
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was then applied in a Negishi cross-coupling sequence. After
generation of the vinyl iodide 30c through the same process, a
Negishi cross-coupling afforded product 32c in high yield,
which could be cleanly converted to C1−C13 fragment 11
using K2CO3 in methanol (eq 5).
extended by Micalizio and co-workers.12 Although a similar
approach utilizing a homopropargylic ether has been reported
by Micalizio in the synthesis of callystatin A,12b in the present
case, the coupling of propargylic silyl ether 22 with terminal
alkyne did not afford the desired (E,E)-diene 35 (Scheme 6A,
entries 1 and 2), and only the regioisomer 33 and conjugated
allene 34 were isolated and characterized. Since functionaliza-
tion of the terminal alkyne substrate generally occurred at the
terminal carbon of the alkyne,31 we envisioned that the in situ
generated internal alkyne−titanium complex int-132 may
undergo carbometalation with the terminal alkyne presumably
through int-2 and int-3 to afford 33 and 34, respectively
(Scheme 6B). Notably, instead of forming the (E,E)-
trisubstituted diene after hydrolysis, the corresponding allenic
product 34 was isolated and was most likely generated through
β-elimination of int-3 as shown in Scheme 6B.33
Prior to the start of our coupling experiments, Micalizio had
reported an alkoxide-directed reductive cross-coupling.34
However, at this point, the alkoxide-directed alkyne−alkyne
reductive coupling strategy had been underdeveloped in the
context of complex natural product synthesis.35 Further, in
order to overcome the influence of the propargylic ether, we
planned to evaluate the ability of the free secondary hydroxyl
group of propargylic alcohol 13 to direct the reaction. The
experiments were initiated by generating the lithium alkoxide
using n-BuLi, which would then undergo ligand exchange with
the titanium reagent36 to produce lithium isopropoxide, leading
to the presumed metallacyclopropene intermediate int-4
(Scheme 6B).37 If the structure of the tethered alkoxide int-4
was to be retained during the C−C bond formation, it would
preferentially afford the metallacyclopentadiene intermediate
int-6, and not int-5, since this assembly would encounter
significant steric destabilization when forming the bridgehead
alkene.37 Though the coordination of alkoxide with titanium
was expected to exhibit considerable ring strain in the bicyclic
metallacyclopropene intermediate int-4,37a diene 35c was thus
obtained in good yield and excellent regioselectivity (Scheme
6A, entry 3) and without detection of byproduct 33c or 34c.
The free hydroxyl group on the alkyne 14a was compatible for
the reductive coupling as well, since the reaction with alkyne
14a proceeded in a regioselective manner to afford the desired
diol product 35d (entry 4), which was accompanied by small
amounts of allene byproduct 34d.
Alternatively, we investigated an alkyne−alkene reductive
coupling to assemble C1−C8 and C9−C13 fragments, which
enabled a direct comparison with the Negishi cross-coupling
strategy (Scheme 6). The titanium alkoxide based coupling
Scheme 6. Alkyne−Alkyne Reductive Coupling with
Propargylic Ethers and Alcohols
In order to validate the assumption that the reaction was
indeed alkoxide-directed, we conducted control experiments
between internal alkyne 36 and octyne 37 in the absence of an
amide group. As shown in Scheme 7, both reactions (14c and
36, rac-13 and 37) afforded the desired products 35 in good
yield and with small amounts of allene byproduct 34 detected
spectroscopically. Since allene 34 could be easily separated from
the desired product 35, these control experiments supported a
general means of generating (E,E)-trisubstituted dienes through
the alkoxide-directed reductive coupling with propargylic alcohol
bearing internal alkyne as substrates.
Since the alkoxide-directed alkyne−alkyne reductive coupling
product 35d could be protected to afford diene 11 by making
use of the difference in the steric environment of the two
secondary hydroxyl groups (Scheme 6C), the reductive
reactions of differentially functionalized alkynes were initially
introduced by the Sato group30 and have recently been cleverly
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Scheme 7. Control Experiments of Alkoxide-Directed Alkyne−Alkyne Reductive Coupling with Propargylic Alcohol
Scheme 8. Preparation of Acyclic Framework 10
coupling exhibited considerable advantages over the venerable
Negishi cross-coupling sequence: (1) it did not require the
generation of a preactivated and stereodefined vinyl iodide or
vinyl metal species; (2) it was compatible with a free hydroxyl
group in the substrate, thus did not require a redundant
protection and deprotection. In our synthesis of C1−C13
fragment 11, the reductive coupling route required a total of
seven steps compared to 13-steps using the Negishi cross-
coupling strategy, which illustrated its efficiency without
requirements of numerous functional group manipulations.
Preparation of C14−C19 Fragment. Synthesis of the
C14−C19 subunit (Scheme 8) commenced with the pre-
paration of oxazole ester 41 following Hermitage’s protocol.38
Preparation of oxazoline 39 was achieved by the slow addition
of commercial dichloroacetonitrile 38 to a sodium methoxide
methanol solution cooled in an ice bath (0 °C) and subsequent
condensation with serine methyl ester hydrochloride. Treat-
ment of the dichlorooxazoline 39 with sodium methoxide in
methanol, followed by camphorsulfonic acid (CSA) catalyzed
elimination of MeOH afforded oxazole 41. This material was
hydrolyzed to the corresponding carboxylic acid 42, followed
by coupling with D-proline benzyl ester hydrochloride to
achieve the benzyl protected C14−C19 fragment 43 as a 1:1
mixture of rotamers. A subsequent BCl3-promoted cleavage of
benzyl ester provided the C14−C19 carboxylic acid fragment
12 as a 3:1 mixture of rotamers, whereas Pd/C catalyzed
hydrogenation of amide 43 resulted in cleavage of the benzyl
ester protecting group as well as the chloro group.
Final Stages of the Virginiamycin M2 Synthesis. In
contrast to the failed attempts to lactonize at the C1 hydroxyl
using DCC or HOBT coupling reagents, esterification between
11 and 12 proceeded efficiently using Yamaguchi conditions39
to yield ester 44 as a 1:1 mixture of rotamers (Scheme 8). The
use of CSA proved to be more effective when compared to
PPTS and AcOH for the selective monodeprotection of the
primary silyl group, which afforded the desired primary alcohol
with good yield and within a one hour reaction period.
Oxidation of the primary alcohol using IBX in DMSO cleanly
afforded aldehyde 10, which could be further converted to
iodide 45 as a mixture of 1:1 rotamers utilizing NaI in acetone.
However, by switching to an iodination-oxidation sequence, the
IBX reaction of the iodide derivative of 44 resulted in low yield
with a significant amount of uncharacterized byproduct.
The functional group array of the advanced intermediates 10
and 45 represented an interesting synthetic challenge in the
context of macrolide-forming strategies and an opportunity to
evaluate an under-developed Barbier/Reformatsky-type cycliza-
tion approach. We were attracted by the potential of the SmI2-
mediated macrocyclizations, which were reported to have
considerable merits: (1) the large ionic radius of samarium
(approximately 136 pm), and its high oxophilicity, made the
samarium atom effectively chelate with the two reacting
centers; thus, it was efficient for large-ring macrocyclization;
(2) SmI2-mediated reaction occurred in a homogeneous reac-
tion other than with common heterogeneous variants such
as Mg, Zn, and Li, associating with superior reactivity and
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Table 4. Model Study of Barbier/Reformatsky-Type Addition
a
d
entry
reagent
SmI2/THF
T (°C)
time
result
b
b
b
1
2
3
4
5
6
7
8
9
rt
rt
15 min
20 min
1 h
47 (61%), 48 (25%)
47 (80%), 48 (11%)
47 (55%), 48 (30%)
SmI2/Benzene
SmI2/THF
0
e
SmI2/THF
−78
−78
0
2 h
NR
f
SmI2−HMPA (1:4)
Et2Zn/RhCl(PPh3)3
n-BuLi
30 min
40 min
8 h
NA
c
b
c
c
47 (20%), 48 (40%)
47 (48%), 48 (11%)
47 (20%), 48 (10%)
−78
−78
−78
t-BuLi
10 h
i-PrMgCl
30 min
47 (25%), 48 (40%)
a
b
c
d
All reactions were conducted at 0.01 M concentration. Isolated product yield. Results based on 1H NMR analysis of crude product. Product 47
was not detected with heterogeneous catalyst systems (activated Zn and In). Only recovering starting material 46. The amide bond was cleaved.
e
f
selectivity; (3) its reducing ability could be easily enhanced by
additives.40 The intramolecular SmI2-mediated Barbier/
Reformatsky reaction has been used to access medium and
large carbocycles and lactones,41 and we have recently applied
this strategy in our total synthesis of the natural product
kendomycin.10
(Table 5, entry 1). Not surprisingly, exclusively reduced acyclic
aldehyde 49 was obtained, which indicated that the generation
of benzylic-like radical intermediate int-7 may proceed faster
than other transformations. In order to further generate the
desired samarium species int-8, a THF solution of SmI2
(2 equiv) was employed (entry 2). However, a disappointing
yield (approximately 10%) of the desired cyclization product 9
as a mixture of 1:1 diastereomers was obtained, with the major
product as the reduced acyclic aldehyde 49 and acyclic alcohol
50. An even lower yield (<5%) of product 9 was obtained from
highly diluted THF solution (0.002 M) (entry 3), which
indicated that the initially formed radical int-7 may abstract a
hydrogen atom from the solvent (THF) instead of generating
the desired organosamarium species int-8. To prevent
hydrogen atom abstraction from THF, the Tani group has
shown that benzene may be employed as the solvent in SmI2-
promoted intermolecular coupling reactions with aryl and
alkynyl radical intermediates.45 However, this method has not
been extensively applied to other SmI2-promoted reactions,
and, to the best of our knowledge, no reports of using benzene
to suppress the competitive dehalogenation pathway have been
reported in natural product synthesis so far. When the model
experiment (Table 4, entry 2) was carried out in benzene in
place of THF, the coupling product 47 was obtained in higher
yield (80%). Accordingly, the optimized conditions were
applied to the macrocyclization, and resulted in the isolation
of the desired product 9 in much higher yield as a 1:1
diastereomeric mixture (Table 5, entry 4). The less reactive
chloride 10 also participated in the cyclization with similar yield
(Table 5, entry 5).
To demonstrate the feasibility of this strategy in the
virginiamycin M2 case, a model study was conducted to form
the C11−C19 section of the secondary alcohol 9. The
iodoamide 46, which was prepared by displacement of the
chloride 43 using NaI in acetone, was carried forward to
achieve the model product 47. As shown in Table 4, SmI2-
mediated reductive couplings of 46 with 21 were efficient at
room temperature or 0 °C in THF (entries 1 and 3),42 with the
major byproduct as the reduced methyl bearing oxazole 48.
However, no reaction occurred at −78 °C with quantitative
recovery of starting materials (entry 4). Attempts at increasing
the reducing potential of SmI2 by using HMPA as an additive40
led to complete cleavage of the amide bond even at
temperatures as low as −78 °C (entry 5). Other metal
promoters were investigated in the model coupling experiments
and we observed that the homogeneous reagents (Et2Zn/
Wilkinson catalyst,43 n-BuLi, t-BuLi, and i-PrMgCl, entries
6−9) led to alcohol product 47 in moderate yield with lower
efficiency compared to SmI2. However, the heterogeneous
catalysts including activated Zn and In reagents44 afforded only
the reduced byproduct 48.
With the successful demonstration of the SmI2-mediated
Barbier/Reformatsky coupling with a model system, we turned
our efforts to the macrocyclization substrate associated with the
virginiamycin M2 synthesis. There were, however, several
challenges ahead with this late stage macrocyclization: (i) acyclic
substrates 10 or 45 contained several functional groups which
were potentially reactive in an electron-transfer process, includ-
ing the aromatic amide, the α,β-unsaturated amide, the ester
group, and the diene moiety; (ii) to the best of our knowledge,
this would be the largest macrocycle (23-membered) formed
mediated by SmI2 to date; (iii) both precursors 10 and 45
contained a mixture of 1:1 rotamers.
Attempts to oxidize the resulting secondary alcohol 9 using
Dess−Martin reagent or standard Swern conditions were
unsuccessful as these reactions were complicated by varying
amounts of uncharacterized aldehyde byproduct. Ultimately, a
modified TFAA−DMSO Swern procedure46 was used to afford
the desired ketone 51 in good yield. Acetylacetone was adapted
in the procedure and used as a sacrificial enolizable additive to
avoid further enolization and elimination of the β-silyloxy
ketone product 51 (Scheme 9). Final deprotection of the C11
TBDPS ether was accomplished by using Schlessinger’s
protocol4a to reveal (−)-virginiamycin M2 in 70% yield,
which was identical in all analytical and spectroscopic aspects
Initially, the acyclic aldehyde 45 in THF (0.01 M) was
treated with freshly prepared SmI2 THF solution10 dropwise
until the reaction color turned blue, immediately quenching by
carefully bubbling air and adding saturated solution of NH4Cl
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Table 5. SmI2-Mediated Barbier-Type Macrocyclization To Afford Cyclized Product 9
a
b
entry
SM
SmI2 (equiv)
solvent (conc)
reaction time
ratio of products
only 49
yield of 9 (%)
1
2
3
4
5
45
45
45
45
10
1
2
4
4
4
THF (0.01 M)
THF (0.01 M)
THF (0.002 M)
benzene (0.002 M)
2 min
20 min
8 h
0
10
<5
42
40
9/49/50/dimer = 1:5:2:2
trace 9, almost 50
9/49/50 = 4:0:5
8 h
benzene (0.002 M)
8 h
9/49/50 = 4:0:5
a
b
1
Product ratios were based on analysis of the crude H NMR spectra. Product yields were based on chromatography.
Scheme 9. Completion of the Total Synthesis of Virginiamycin M2 (1)
(1H and 13C NMR, IR, HRMS, optical rotation) to the
EXPERIMENTAL SECTION
■
published data.4a
General Information. All reactions were carried out in oven- or
flame-dried glassware under argon atmosphere. Triethylamine and
pyridine were distilled before use. N,N-Dimethylformamide and
dimethyl sulfoxide were distilled over calcium hydride and stored over
4 Å molecular sieves. n-Butyllithium was purchased and standardized by
titration with menthol/2,2′-dipyridyl. All other reagents were used as
supplied. Dichloromethane, toluene, diethyl ether, benzene, tetrahy-
drofuran, and acetonitrile were obtained from a dry solvent system
(alumina) and used without further drying. Unless otherwise noted,
reactions were magnetically stirred and monitored by thin layer
chromatography with 0.20 mm silica gel 60 Å plates. Flash chro-
matography was performed on 32−63 μm 60 Å silica gel. Yields referred
to chromatographically and spectroscopically pure compounds, unless
otherwise noted. 1H and 13C NMR spectra were taken in CDCl3 at 300,
400, or 500 MHz (as indicated), respectively. Chemical shifts are
reported in parts per million relative to CDCl3 (1H, δ 7.24; 13C, δ 77.0).
Data are reported as follows: chemical shift, multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, sept = septuplet, m = multiplet, br =
broad), coupling constant, integration. For spectra which contain
mixtures of amide rotamers, the signals that can be assigned as specific
to a particular rotamer are designated with an asterisk for the major and
a double asterisk for the minor; signals that have contributions from
both rotamers are not denoted with a special character. Diastereomeric
ratios were determined by 1H NMR analysis of crude mixtures,
operating at signal/noise ratio of 200:1. Infrared spectra were recorded
as thin films on NaCl pleates. Optical rotations were recorded on a
CONCLUSION
■
In summary, a highly convergent total synthesis of (−)-virgin-
iamycin M2 (1) was accomplished in 19 steps with the longest
linear sequence of 10-steps from silane (S)-15, or 11-steps from
1,3-propandiol with 6.0% overall yield. On balance, the
successful route compared very favorably with the previous
synthesis reported by Schlessinger and Uguen.4 Notable
synthetic features included an extension on Rh(II) and Cu(I)
promoted carbenoid Si−H insertion to prepare crotylsilane 15
in highly enantioenriched form; the asymmetric crotylation
using the resulting crotyl silane to address stereochemical
features in the preparation of C1−C5 unsaturated amide
subunit; an alkoxide-directed reductive coupling strategy to
assemble the (E,E)-diene, which overcame the reactivity and
regioselectivity problems encountered in the undirected
coupling; a comparison between Negishi cross-coupling and
alkyne−alkyne reductive coupling to prepare the (E,E)-
trisubstituted diene; a SmI2-promoted macrocyclization in the
presence of several potential labile functional groups. The
presented modular synthesis should be instructive and
amenable for the design and synthesis of analogues of group
A pH sensitive virginiamycins, thus enabling further exploration
of the promising biological potential of these macrolide
antibiotics.
digital polarimeter at 589 nm and reported as follows: [α]20
D
(concentration in g/100 mL solvent and solvent). High resolution
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mass-spectra were obtained by electrospray ionization in positive-ion
mode (M + H or M + Na) as indicated.
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 160.1, 138.1, 137.3, 131.2,
129.1, 75.6, 33.5, 24.5, 21.0, 20.6 ppm; IR (thin film) νmax 2923, 2854,
1646, 1436, 846 cm−1; HRMS (CI/NH3) m/z calcd for C26H35N2
[M + H]+ 375.2800, found 375.2789.
General Procedure for Preparation of Diimine Ligands 20.
(R,R)-1,2-Diammonium cyclohexane mono-(+)-tartrate salt47 (2.97 g,
11.2 mmol, 1 equiv) was added to a 200 mL round-bottom flask
equipped with a stir bar, followed by addition of K2CO3 (3.12 g, 22.5
mmol, 2 equiv) and distilled water (15 mL). The mixture was stirred
for 30 min, and EtOH (60 mL) was added. Then a solution of
aldehyde (22.5 mmol, 2 equiv) in EtOH (25 mL) was added dropwise.
The flask was equipped with a reflux condenser, and the resulting
mixture was refluxed for 2 h before being diluted by water (20 mL).
The resulting mixture was cooled in an ice bath for 1 h. The product
was collected by vacuum filtration and washed with EtOH (2 ×
10 mL). The crude solid was redissolved in CH2Cl2 (50 mL) and
washed with water (2 × 30 mL). After drying over MgSO4, the solvent
was removed under reduced pressure to afford product 20 in 80−95%
yield.
(1R,2R,N1E,N2E)-N1,N2-Bis(2,4,6-trichlorobenzylidene)-
cyclohexane-1,2-diamine ((R,R)-20i): [α]20 +16.6 (c = 2.2,
D
CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 8.31 (s, 2H), 7.24 (s,
4H), 3.52 (m, 2H), 1.81 (m, 6H), 1.45 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 155.5, 135.3, 134.9, 131.2, 128.6, 75.0, 32.7, 24.1 ppm; IR
(thin film) νmax 3319, 3263, 2923, 1652, 1224, 1057 cm−1; HRMS(CI/
NH3) m/z calcd for C20H17Cl6N2 [M + H]+ 494.9523, found
494.9535.
(1R,2R,N1E,N2E)-N1,N2-Bis(2,6-dichloro-4-decylbenzylidene)-
cyclohexane-1,2-diamine ((R,R)-20j): [α]20 +29.2 (c = 0.7,
D
CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 2H), 7.06
(s, 4H), 3.54 (m, 2H), 2.50 (t, J = 12.5 Hz, 4H), 1.85 (m, 6H), 1.53
(m, 6H), 1.23 (m, 28H), 0.87 (t, J = 10.5 Hz, 6H); 13C NMR (75
MHz, CDCl3) δ 156.6, 145.7, 134.5, 130.1, 128.6, 74.9, 35.1, 32.9,
31.9, 30.7, 29.6, 29.5, 29.4, 29.3, 29.0, 24.3, 22.7, 14.1 ppm; IR (thin
film) νmax 2926, 2855, 1647, 1465 cm−1; HRMS (CI/NH3) m/z calcd
for C40H59Cl4N2 [M + H]+ 707.3432, found 707.3414.
(1R,2R,N1E,N2E)-N1,N2-Bis(2,6-dichlorobenzylidene)-
cyclohexane-1,2-diamine ((R,R)-20a): [α]20 +18.3 (c = 1.6,
D
1
CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.45 (s, 2H), 7.26 (d, J =
2.0 Hz, 2H), 7.13 (m, 4H), 3.58 (m, 2H), 1.87 (m, 6H), 1.49 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 156.6, 134.8, 132.9, 129.9, 128.6, 74.9,
(R,E)- and (S,E)-Methyl 2-(Dimethyl(phenyl)silyl)pent-3-
enoate ((R)-15 and (S)-15) Using Rh(II) Catalysts. To a stirred
solution of Rh2(S-DOSP)4 (190 mg, 0.1 mmol, 0.02 equiv) in pentane
(5 mL, molecular sieves dried overnight before using) was added
dimethylphenylsilane (3.88 mL, 25 mmol, 5 equiv). The mixture was
cooled to −78 °C, and the diazo ester 19 (700 mg, 5 mmol, 1 equiv)
in pentane (5 mL) was added dropwise over a period of 10 min. The
mixture was stirred at −75 °C for 24 h and concentrated in vacuo.
Chromatography on silica gel (hexane, hexane/ethyl acetate 98:2)
afforded (R)-15 (843 mg, 68% yield) as a yellow oil: 1H NMR
(400 MHz, CDCl3) δ 7.45 (m, 2H), 7.34 (m, 3H), 5.56 (dd, J = 15.6,
10.0 Hz, 1H), 5.19 (dt, J = 15.6, 6.8 Hz, 1H), 3.49 (s, 3H), 3.00 (d, J =
10.0 Hz, 1H), 1.62 (d, J = 6.8 Hz, 3H), 0.35 (s, 6H); 13C NMR
(75 MHz, CDCl3) δ 173.5, 135.7, 133.9, 129.4, 127.6, 124.9,124.7,
32.9, 24.2 ppm; IR (thin film) νmax 2930, 2859, 1646, 1430, 772 cm−1
;
HRMS (CI/NH3) m/z calcd for C20H19Cl4N2 [M + H]+ 427.0302,
found 427.0313.
(1R,2R,N1E,N2E)-N1,N2-Bis(2,6-difluorobenzylidene)-
cyclohexane-1,2-diamine ((R,R)-20b): [α]20 +80.5 (c = 1.4,
D
1
CH2Cl2); H NMR (300 MHz, CDCl3) δ 8.39 (s, 2H), 7.24 (m,
2H), 6.83 (m, 4H), 3.46 (m, 2H), 1.89 (m, 6H), 1.50 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ 163.2, 159.8, 151.6, 130.9, 114.1, 111.8,
111.5, 75.3, 32.5, 24.2 ppm; IR (thin film) νmax 3319, 3267, 1621,
1463, 1220, 1055 cm−1; HRMS (CI/NH3) m/z calcd for C20H19F4N2
[M + H]+ 363.1484, found 363.1473.
(1R,2R,N1E,N2E)-N1,N2-Bis(2-chloro-6-fluorobenzylidene)-
cyclohexane-1,2-diamine ((R,R)-20c): [α]20 +44.0 (c = 1.7,
D
51.0, 43.2, 17.9, −4.6, −4.6 ppm; [α]20 +37.5 (c = 2.2, CH2Cl2); IR
1
CH2Cl2); H NMR (300 MHz, CDCl3) δ 8.41 (s, 2H), 7.16 (m,
D
(thin film) νmax 3071, 2951, 1717, 1428, 1250, 1149, 698 cm−1; HRMS
(CI/NH3) m/z calcd for C14H20O2NaSi [M + Na]+ 271.1130, found
271.1162. Using the racemic versions of 15, the baseline separation by
HPLC could not be achieved. To obtain an accurate ee analysis of the
insertion product, (R)-15 was reduced to the primary alcohol using
LAH in diethyl ether. HPLC analysis was now straightforward using
ChiralCel OD, 1% IPA/hexane, 1 mL/min, tR 15.5 min, tS 11.6 min,
and exhibited 93% ee. Catalyst Rh2(R-DOSP)4 afforded product (S)-
15 with the same yield and ee. (S)-15: [α]20D −22.3 (c = 0.7, CH2Cl2).
(R,E)- and (S,E)-Methyl 2-(Dimethyl(phenyl)silyl)pent-3-
enoate ((R)-15 and (S)-15) Using Cu(I) Catalysts. To a round-
bottom flask charged with a stir bar were added (CH3CN)4Cu(BF4)
(157 mg, 0.5 mmol, 0.05 equiv) and the bis-imine ligand (R,R)-20j
(534 mg, 0.7 mmol, 0.07 equiv). The mixture was dissolved in benzene
(25 mL), and the resulting homogeneous yellow solution was allowed
to stir at room temperature for 30 min. To this solution was added via
syringe neat dimethylphenylsilane (7.76 mL, 50 mmol, 5 equiv), which
was then cooled to 0 °C. To the cooled reaction mixture was slowly
added a solution of diazo ester (1.4 g, 10 mmol, 1 equiv) in benzene
(25 mL) over 1 h by syringe pump. The solution was allowed to stir at
0 °C for another 12 h before being flushed through a thin pad of silica
gel to remove the remaining catalyst. The resulting solution was then
concentrated under vacuum. The crude product was purified by silica
chromatography, hexane eluant recovered dimethylphenylsilane, using
1% ethyl acetate/hexanes as the eluant afforded (R)-15 as a yellow oil
(1.3 g, 5.21 mmol, 52% yield). To obtain an accurate ee analysis of the
insertion product, (R)-15 was reduced to the primary alcohol by LAH
in diethyl ether. HPLC analysis using ChiralCel OD, 1% IPA/hexane,
1 mL/min, tR 15.5 min, tS 11.6 min exhibited 78% ee.
4H), 6.93 (m, 2H), 3.49 (m, 2H), 1.87 (m, 6H), 1.49 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ 162.8, 159.4, 154.4, 135.1, 130.6, 130.5,
125.4, 123.4, 123.3, 115.0, 114.7, 75.1, 32.6, 24.2 ppm; IR (thin film)
νmax 2929, 2859, 1645, 1568, 1448, 1245, 899 cm−1; HRMS (CI/NH3)
m/z calcd for C20H19Cl2F2N2 [M + H]+ 395.0893, found 395.0894.
(1R,2R,N1E,N2E)-N1,N2-Bis(2-bromo-6-chlorobenzylidene)-
cyclohexane-1,2-diamine ((R,R)-20d): [α]20 +24.1 (c = 4.3,
D
1
CH2Cl2); H NMR (300 MHz, CDCl3) δ 8.38 (s, 2H), 7.44 (d, J =
7.8 Hz, 2H), 7.28 (d, J = 7.2 Hz, 2H), 7.05 (t, J = 8.1 Hz, 2H), 3.60
(m, 2H), 1.88 (m, 6H), 1.49 (m, 2H); 13C NMR (75 MHz, CDCl3)
δ 157.9, 134.6, 134.3, 131.7, 130.2, 129.2, 123.9, 74.7, 32.8, 24.2 ppm;
IR (thin film) νmax 2929, 2854, 1652, 1550, 1426, 782 cm−1; HRMS
(CI/NH3) m/z calcd for C20H19Br2Cl2N2 [M + H]+ 514.9292, found
514.9275.
(1R,2R,N1E,N2E)-N1,N2-Bis(2,6-dibromobenzylidene)-
cyclohexane-1,2-diamine ((R,R)-20e): [α]20 +31.2 (c = 4.4,
D
1
CH2Cl2); H NMR (300 MHz, CDCl3) δ 8.33 (s, 2H), 7.48 (d, J =
8.1 Hz, 4H), 6.97 (t, J = 7.8 Hz, 2H), 3.62 (m, 2H), 1.86 (m, 6H),
1.49 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 159.1, 135.6, 132.4,
130.5, 123.6, 74.5, 32.8, 24.2 ppm; IR (thin film) νmax 3319, 3060,
2923, 2848, 1652, 1419, 1223, 1056 cm−1; HRMS(CI/NH3) m/z calcd
for C20H19N2Br4 [M + H]+ 602.8282, found 602.8286.
(1R,2R,N1E,N2E)-N1,N2-Bis(2,6-dimethylbenzylidene)-
cyclohexane-1,2-diamine ((R,R)-20f): [α]20 −30.0 (c = 0.6,
D
1
CH2Cl2); H NMR (300 MHz, CDCl3) δ 8.57 (s, 2H), 7.06 (m,
2H), 6.94 (m, 4H), 3.45 (m, 2H), 2.26 (s, 12H), 1.85 (m, 6H), 1.50
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 160.4, 137.2, 134.1, 128.4,
128.3, 75.5, 33.5, 24.5, 20.5 ppm; IR (thin film) νmax 2921, 2852,
1646, 1463, 1371, 769 cm−1; HRMS (CI/NH3) m/z calcd for
C24H31N2 [M + H]+ 347.2487, found 347.2474.
(4R,5R,E)-Methyl 5-Hydroxy-4,6-dimethylhept-2-enoate
(18a). To a round-bottom flask equipped with a stir bar were
added isobutyraldehyde (720 mg, 10 mmol, 4 equiv) and silane (S)-15
(620 mg, 2.5 mmol, 1 equiv). The flask was capped with a septum.
Anhydrous CH2Cl2 (5 mL) was added to the flask under argon
(1R,2R,N1E,N2E)-N1,N2-Bis(2,4,6-trimethylbenzylidene)-
cyclohexane-1,2-diamine ((R,R)-20h): [α]20 −48.9 (c = 3.0,
D
CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 8.57 (s, 2H), 6.79 (s,
4H), 3.45 (m, 2H), 2.28 (s, 12H), 2.25 (s, 6H), 1.86 (m, 6H), 1.53
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protection, and the solution was cooled to −78 °C. Neat TiCl4
(544 uL, 5 mmol, 2 equiv) was added dropwise, and the resulting
mixture was stirred at −20 °C for 72 h. The reaction was then diluted
with CH2Cl2 (20 mL), quenched with saturated sodium bicarbonate
(20 mL), and warmed to room temperature. The mixture was
extracted with ether (3 × 10 mL), and the combined organic layers
were dried over MgSO4, filtered, and concentrated under reduced
pressure. Purification over silica gel (10% EtOAc/hexane) afforded
CH2Cl2 (20 mL) at 0 °C, under an atmosphere of argon. The mixture
was stirred at rt for 30 min, and the hydroxyl ester 18a (558 mg,
3 mmol, 1 equiv) in CH2Cl2 (5 mL) was added in one portion. The
mixture was heated under reflux for 5 h and then cooled to 0 °C before
carefully quenching with H2O (20 mL). The mixture was extracted
with CH2Cl2 (3 × 20 mL), dried by MgSO4, and concentrated. The
residue was purified by flash chromatography (silica gel, 50% EtOAc/
hexane) to afford product 14a (545 mg, 87% yield) as a white solid:
1
product 18a (292 mg, 63%) as a colorless oil and as a single
[α]20 +33.5 (c = 0.8, CH2Cl2); H NMR (500 MHz, CDCl3) δ 6.82
D
1
diastereomer: [α]20 +33.3 (c = 2.9, CH2Cl2); H NMR (400 MHz,
(dd, J = 15.5, 8.0 Hz, 1H), 5.79 (d, J = 15.5 Hz, 1H), 5.61 (br, 1H),
4.10 (dd, J = 5.5, 2.5 Hz, 2H), 3.24 (m, 1H), 2.47 (m, 1H), 2.23 (t, J =
2.5 Hz, 1H), 1.84 (m, 1H), 1.40 (d, J = 5.0 Hz, 1H), 1.07 (d, J = 6.5
Hz, 3H), 0.90 (d, J = 7.0 Hz, 3H), 0.89 (d, J = 6.5 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 165.6, 148.4, 122.6, 79.5, 79.1, 71.6, 39.6, 30.8,
29.2, 19.7, 16.9, 13.7 ppm; IR (thin film) νmax 3302, 2963, 1669, 1635,
1540, 1032, 987 cm−1; HRMS (CI/NH3) m/z calcd for C12H20NO2
[M + H]+ 210.1494, found 210.1502.
D
CDCl3) 6.91 (dd, J = 16.0, 8.0 Hz, 1H), 5.85 (d, J = 16.0 Hz, 1H), 3.71
(s, 3H), 3.25 (t, J = 5.5 Hz, 1H), 2.49 (m, 1H), 1.70 (m, 1H), 1.36 (br,
1H), 1.07 (d, J = 7.0 Hz, 3H), 0.91 (d, J = 7.0 Hz, 3H), 0.90 (d, J =
7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) 167.0, 152.0, 120.7, 79.2,
51.5, 40.0, 30.9, 19.7, 16.5, 14.0 ppm; IR (thin film) νmax 3457, 2963,
1724, 1437, 1279, 1049, 863 cm−1; HRMS(CI/NH3) m/z calcd for
C10H19O3 [M + H]+ 187.1334, found 187.1328. HPLC analysis using
ChiralCel OD, 1% IPA/hexane, 1 mL/min, tR 11.9 min, tS 24.0 min
exhibited 95% ee.
(4R,5R,E)-Methyl 5-(Benzyloxy)-4,6-dimethylhept-2-enoate
(18b). To a round-bottom flask equipped with a stir bar were added
isobutyraldehyde (360 mg, 5 mmol, 2 equiv), silane (S)-15 (620 mg,
2.5 mmol, 1 equiv), and TMSOBn (900 mg, 5 mmol, 2 equiv). The
flask was capped with a septum. Anhydrous CH2Cl2 (5 mL) was added
to the flask under argon protection. The solution was cooled to −78 °C.
TMSOTf (450 uL, 2.5 mmol, 1 equiv) was added dropwise, and
resulting mixture was stirred at −60 °C for 72 h. Then the reaction was
diluted with CH2Cl2 (20 mL), quenched with saturated sodium
bicarbonate (20 mL), and warmed to room temperature. The mixture
was extracted with ether (3 × 10 mL), and the combined organic layers
were dried over MgSO4, filtered, and concentrated under reduced
pressure. Purification over silica gel (2% EtOAc/hexane) afforded
(3R,4R,E)-2,4-Dimethyl-7-oxo-7-(prop-2-ynylamino)hept-5-
en-3-yl Acetate (14c). Acetyl chloride (44 uL, 0.612 mmol, 1.6
equiv) was added dropwise to a stirred solution of hydroxyamide 14a
(80 mg, 0.383 mmol, 1 equiv) and pyridine (50 μL, 0.612 mmol,
1.6 equiv) in dry CH2Cl2 (3 mL) at 0 °C. DMAP (3 mg, catalytic) was
added in one portion, and the mixture was stirred overnight while
warming to rt. The reaction then was diluted with saturated NH4Cl
solution (2 mL), extracted with CH2Cl2 (2 × 3 mL), washed with
brine (2 mL), dried over MgSO4, and concentrated under reduced
pressure. The residue was purified using flash chromatography (silica
gel, 30% EtOAc/hexane) to afford the acetate product 14c (93 mg,
97% yield) as a white solid: [α]20D +16.4 (c = 1.1, CH2Cl2); 1H NMR
(500 MHz, CDCl3) δ 6.70 (dd, J = 15.5, 8.0 Hz, 1H), 5.84 (br, 1H),
5.80 (d, J = 15.5 Hz, 1H), 4.73 (dd, J = 7.5, 5.0 Hz, 1H), 4.08 (m, 2H),
2.59 (m, 1H), 2.21 (t, J = 2.5 Hz, 1H), 2.04 (s, 3H), 1.83 (m, 1H),
0.99 (d, J = 7.0 Hz, 3H), 0.85 (d, J = 4.5 Hz, 3H), 0.83 (d, J = 4.5 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 170.9, 165.2, 146.3, 123.0, 79.7,
79.4, 71.6, 38.4, 29.7, 29.2, 20.8, 19.6, 16.4, 15.1 ppm; IR (thin film)
νmax 3287, 2969, 1734, 1671, 1542, 1242, 1022 cm−1; HRMS (CI/
NH3) m/z calcd for C14H21NO3Na [M + Na]+ 274.1419, found
274.1409.
product 18b (469 mg, 68%) as a colorless oil and as a 6.3:1 mixture of
1
diastereomers: [α]20 +9.4 (c = 0.4, CH2Cl2); H NMR (400 MHz,
D
CDCl3) δ 7.26 (m, 5H), 6.98 (dd, J = 15.6, 8.0 Hz, 1H), 5.83 (d, J =
15.6 Hz, 1H), 4.53 (s, 2H), 3.71 (s, 3H), 3.07 (t, J = 5.6 Hz, 1H), 2.62
(m, 1H), 1.80 (m, 1H), 1.10 (d, J = 6.8 Hz, 3H), 0.93 (m, 6H); 13C
NMR (75 MHz, CDCl3) δ 167.2, 152.6, 138.6, 128.3, 127.6, 127.5,
120.1, 87.8, 75.2, 51.5, 39.8, 31.3, 20.3, 17.5, 14.7 ppm; IR (thin film)
νmax2963, 1723, 1656, 1275, 1176, 1066 cm−1; HRMS (CI/NH3) m/z
calcd for C17H24O3Na [M + Na]+ 299.1623, found 299.1671. Ee analysis
of product 18b was determined on the alcohol derivative after
deprotection of the benzyl group, which exhibited 95% ee (ChiralCel
OD, 1% IPA/hexane, 1 mL/min, tR 11.9 min, tS 24.0 min).
(E)-Methyl 2-(1-Hydroxy-2-methylpropyl)pent-3-enoate
(18c). To a round-bottom flask equipped with a stirbar were added
freshly distilled isobutyraldehyde (72 mg, 1 mmol, 4 equiv) and silane
(S)-15 (62 mg, 0.25 mmol, 1 equiv). The flask was capped with a
rubber septum. Anhydrous MeCN (0.5 mL) was added to the flask
under argon protection, and the solution was cooled to −30 °C. Next,
neat TiCl4 (27.2 uL, 0.25 mmol, 1 equiv, freshly distilled colorless
liquid) was added dropwise, and the resulting mixture was stirred at
−20 °C for 24 h. Then the reaction was diluted with MeCN (2 mL)
and quenched with saturated sodium bicarbonate (2 mL). After
warming to room temperature, the mixture was extracted with ether
(3 × 1 mL), and the combined organic layers were dried over MgSO4,
filtered, and concentrated. Purification over silica gel (10% EtOAc/
hexane) afforded the α-addition product 18c (37 mg, 80% yield) as a
colorless oil: 1H NMR (500 MHz, CDCl3) δ 5.66 (dq, J = 15.5,
6.5 Hz, 1H), 5.56 (dd, J = 15.5, 9.0 Hz, 1H), 3.69 (s, 3H), 3.54 (t, J =
6.0 Hz, 1H), 3.15 (m, 1H), 2.57 (br, 1H), 1.71 (d, J = 6.0 Hz, 3H),
1.65 (m, 1H), 0.95 (d, J = 6.5 Hz, 3H), 0.87 (d, J = 6.5 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 174.6, 131.4, 124.3, 76.3, 52.3, 52.0, 30.7,
19.1, 18.1, 17.7 ppm; IR (thin film) νmax 3469, 2961, 1720, 1436, 1144,
969 cm−1; HRMS (CI/NH3) m/z calcd for C10H19O3 [M + H]+
187.1334, found 187.1342.
(S)-1-(tert-Butyldimethylsilyloxy)hex-4-yn-3-ol (13) Gener-
ated from Carreira’s Protocol. Zn(OTf)2 (726 mg, 2 mmol,
2 equiv) and (−)-N-methylephedrine (376 mg, 2.1 mmol, 2.1 equiv)
were added to a flame-dried round-bottom flask, which was purged
with argon (three times) and then sealed with a rubber septum.
Toluene (7 mL) and freshly distilled Et3N (212 mg, 2.1 mmol,
2.1 equiv) were added at ambient temperature and the mixture was
stirred vigorously for 2 h (a turbid milky mixture). Then 0.3 mL of
propyne was transferred to the reaction mixture from a cold trap (−78
°C) via cannula. The reaction was stirred under a propyne atmosphere
(propyne-filled balloon). After 5 min, aldehyde 2148 (188 mg, 1 mmol,
1 equiv) in toluene (1 mL) was added over 5 h by the syringe pump
and further stirred for another 12 h. The reaction was diluted with
NH4Cl saturated solution (10 mL), extracted with Et2O (3 × 15 mL),
washed with brine, dried over MgSO4, filtered, and concentrated in
vacuo. Flash chromatography on silica gel (5−10% EtOAc/hexane)
provided 13 (181 mg, 80% yield, 95% ee) as a colorless oil: [α]20
−10.0 (c = 2.9, CH2Cl2); H NMR (400 MHz, CDCl3) δ 4.54 (m,
D
1
1H), 3.98 (m, 1H), 3.79 (m, 1H), 3.31 (d, J = 5.6 Hz, 1H), 1.91 (m,
1H), 1.82 (s, 3H), 1.81 (m, 1H), 0.87 (s, 9H), 0.05 (d, J = 2.8 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ 80.8, 79.8, 62.0, 61.2, 38.9, 25.8,
18.1, 3.5, −5.6 ppm; IR (thin film) νmax 3395, 2955, 2928, 2857, 1514,
1256, 1102, 514 cm−1; HRMS (CI/NH3) m/z calcd for C12H24O2NaSi
[M + Na]+ 251.1443, found 251.1435. Chiral HPLC: since compound
13 was not UV active, and it cannot be detected by HPLC. To check
the product’s % ee, 13 was converted to the benzoate derivative.
(S)-1-(tert-Butyldimethylsilyloxy)hex-4-yn-3-yl Benzoate. Al-
cohol 13 (22.8 mg, 0.1 mmol, 1 equiv) was dissolved in dry CH2Cl2
(0.5 mL, 0.2 M) and treated with BzCl (35 mg, 0.25 mmol, 2.5 equiv),
pyridine (79 mg, 1.0 mmol, 10 equiv), and a catalytic amount DMAP
(∼1 mg). The mixture was stirred overnight under argon atmosphere
and then poured into aqueous saturated NH4Cl (2 mL) and extracted
(4R,5R,E)-5-Hydroxy-4,6-dimethyl-N-(prop-2-ynyl)hept-2-en-
amide (14a). A solution of 2 M trimethylaluminum in CH2Cl2
(6 mL, 12 mmol, 4 equiv) was added dropwise, over 30 min, to a
stirred solution of propargylamine (830 uL, 12 mmol, 4 equiv) in dry
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with Et2O (2 × 2 mL). The combined organic phase was dried by
MgSO4, filtered, and concentrated. The residue was purified by
chromatography (1% EtOAc/hexane) to afford the product (30 mg,
93% yield) as a colorless oil: [α]20D −23.2 (c = 4.1, CH2Cl2); 1H NMR
(400 MHz, CDCl3) δ 8.04 (m, 2H), 7.54 (m, 1H), 7.42 (m, 2H), 5.67
(m, 1H), 3.79 (m, 1H), 2.13 (m, 1H), 2.05 (m, 1H), 1.83 (d, J = 2 Hz,
3H), 0.86 (s, 9H), 0.02 (s, 3H), 0.00 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 165.5, 132.9, 130.1, 129.7, 128.3, 81.9, 76.7, 62.3, 58.9, 38.2,
25.8, 18.2, 3.6, −5.5 ppm; IR (thin film) νmax 3330, 2892, 2811, 1773,
1511, 723 cm−1; HRMS (CI/NH3) m/z calcd for C19H28O3NaSi
[M + Na]+ 355.1705, found 355.1722; HPLC (WhelkO, 1% IPA/
hexane, 1 mL/min, tS 6.2 min, tR 7.0 min) showed 95% ee.
(S)-4,6-Bis(tert-butyldimethylsilyloxy)hex-2-yne (22). Alco-
hol 13 (114 mg, 0.5 mmol, 1 equiv) and 2,6-lutidine (173 μL,
1.5 mmol, 3 equiv) were dissolved in CH2Cl2 (2 mL). TBSOTf
(172 μL, 0.75 mmol, 1.5 equiv) was carefully added at −78 °C by
syringe. Then the cooling bath was removed, and the reaction was
stirred for an additional 4 h at rt. The reaction was quenched by
aqueous saturated NH4Cl (2 mL) and extracted with Et2O (2 ×
5 mL). The combined organic phase was dried by MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
(3R,4R,E)-2,4-Dimethyl-7-oxo-7-((E)-3-(tributylstannyl)-
allylamino)hept-5-en-3-yl Acetate (29c). CuCN (356 mg,
4 mmol, 2 equiv) was suspended in anhydrous THF (20 mL) under
argon protection. The mixture was cooled to −78 °C, a 2.5 M solution
n-BuLi in hexanes (3.2 mL, 8 mmol, 4 equiv) was added dropwise over
5 min, and the reaction was then stirred at −78 °C for 15 min. Bu3SnH
(2.13 mL, 8 mmol, 4 equiv) was added dropwise over 5 min. The
reaction turned yellow, and gas was generated. The mixture was
further stirred 15 min at −78 °C. A solution of the alkyne 14c
(502 mg, 2 mmol, 1 equiv) in anhydrous THF (5 mL) was added
dropwise, and the mixture was stirred for another 3 h at −78 °C before
being quenched with 10% NH3/NH4Cl solution (20 mL). The
mixture was allowed to warm to rt, and the solids were filtered off.
The filtrate was extracted with EtOAc (3 × 15 mL), the extracts were
washed with brine, dried over MgSO4, and concentrated, and the
residue was purified by flash chromatography (silica gel, 15% EtOAc/
hexane) to afford the vinyl stannane 29c (815 mg, 75%) as a colorless
1
oil: [α]20 +2.2 (c = 1.5, CH2Cl2); H NMR (400 MHz, CDCl3) δ =
D
6.69 (dd, J = 15.4,8.2 Hz, 1H), 6.12 (dt, J = 19.0, 1.3 Hz, 1H), 5.95
( dt, J = 19.0, 5.3 Hz, 1H), 5.80 (dd, J = 15.4, 0.8 Hz, 1H), 5.49 (br,
1 H), 4.75 (dd, J = 7.4, 5.0 Hz, 1H), 3.97 (m, 2 H), 2.60 (m, 1 H),
2.05 (s, 3H), 1.86 (m, 1 H), 1.52 (q, J = 7.4 Hz, 6H), 1.28 (sept, J =
7.4 Hz, 6H), 1.03 (d, J = 7.4 Hz, 3H), 0.88 (m,21 H); 13C NMR (75
MHz, CDCl3)170.6, 165.2, 144.8, 143.3, 129.8, 123.8, 79.6, 44.7, 38.2,
29.6, 28.8, 27.0, 20.6, 19.5, 16.1, 15.2, 13.5, 9.2 ppm; IR (thin film)
νmax 3275, 2959, 2927, 2872, 1743, 1630, 1238, 986 cm−1; HRMS(CI/
NH3) m/z calcd for C26H50NO3Sn [M + H]+ 544.2812, found
544.2805.
chromatography (1% EtOAc/hexane) to afford the product 22 (164
1
mg, 96% yield) as a colorless oil: [α]20 −21.1 (c = 6.0, CH2Cl2); H
D
NMR (400 MHz, CDCl3) δ 4.49 (m, 1H), 3.69 (m, 2H), 1.82 (m,
2H), 1.80 (d, J = 2 Hz, 3H), 0.88 (s, 9H), 0.86 (s, 9H), 0.10 (s, 3H),
0.08 (s, 3H), 0.02 (s, 3H), 0.02 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 80.9, 80.0, 60.0, 59.2, 42.0, 25.9, 18.3, 3.5, −4.5, −5.1, −5.3, −5.4
ppm; IR (thin film) νmax 2929, 2857, 1472, 1254, 1096, 835, 775 cm−1
;
(3R,4R,E)-7-((E)-3-Iodoallylamino)-2,4-dimethyl-7-oxohept-
5-en-3-yl Acetate (30c). To a cooled (0 °C), stirred solution of
vinylstannane 29c (543 mg, 1 mmol, 1 equiv) in CH2Cl2 (33 mL) was
added iodine (381 mg, 1.5 mmol, 1.5 equiv). After being stirred for
20 min at 0 °C, the reaction was quenched with saturated Na2S2O3
solution until the reaction mixture turned colorless. The organic layer
was separated, and the water layer was extracted with CH2Cl2 (2 ×
20 mL). The combined organic layer was dried over MgSO4, filtered,
and concentrated under reduced pressure. The residue was purified
by column chromatography on silica gel (15% EtOAc/hexane) to
afford vinyl iodide 30c (367 mg, 97%) as a slightly yellow thick oil:
[α]20D +8.9 (c = 3.6, CH2Cl2); 1H NMR (400 MHz, CDCl3) 6.65 (dd,
J = 15.0, 8.0 Hz, 1H), 6.49 (dt, J = 14.5, 6.0 Hz, 1H), 6.24 (dt, J = 14.5,
1.5 Hz, 1H), 6.19 (br, 1H), 5.80 (dd, J = 15.5, 1.0 Hz, 1H), 4.70 (dd,
J = 7.5, 5.0 Hz, 1H), 3.82 (m, 2 H), 2.56 (m, 1 H), 2.01 (s, 3H), 1.81
(m, 1 H), 0.98 (d, J = 7.0 Hz, 3H), 0.82 (d, J = 6.5 Hz, 3H), 0.81 (d,
J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) 170.9, 165.5, 145.8,
141.4, 123.3, 79.7, 78.4, 43.5, 38.3, 29.7, 20.8, 19.6, 16.4, 15.1 ppm; IR
HRMS (CI/NH3) m/z calcd for C18H38O2NaSi2 [M + Na]+ 365.2308,
found 365.2324.
1-(tert-Butyldimethylsilyloxy)hex-4-yn-3-ol (rac-13). n-BuLi
(5.8 mL, 13 mmol, 1.3 equiv, 2.5 M in hexanes) and THF (10 mL)
were added to a flame-dried round-bottom flask and cooled to
−78 °C. Then propyne (1.5 mL) was transferred to the reaction
mixture from a cold trap (−78 °C) via cannula. The reaction was
stirred at −78 °C for 30 min and then warmed to 0 °C. After 20 min,
the mixture was recooled to −78 °C. Aldehyde 21 (1.88 g, 10 mmol,
1 equiv) in THF (5 mL) was added over 5 min by the syringe and
then warmed to 0 °C to further stir for another 4 h. The reaction was
diluted with saturated NH4Cl solution (10 mL), extracted with Et2O
(3 × 15 mL), washed with brine, dried over MgSO4, filtered, and
concentrated in vacuo. Flash chromatography on silica gel (10%
EtOAc/hexane) provided rac-13 (2.09 g, 92% yield) as a colorless oil.
1-(tert-Butyldimethylsilyloxy)hex-4-yn-3-one (23). To a solu-
tion of rac-13 (2.28 g, 10 mmol, 1 equiv) in CH2Cl2 (50 mL) was
added MnO2 (13 g, 150 mmol, 15 equiv, activated at 150 °C for 12 h)
at rt. After being stirred for 8 h, the mixture was filtered through
Celite. The filtrate was concentrated under reduced pressure and
purified over silica gel with EtOAc/hexanes (5/95) to afford product
(thin film) νmax 3280, 2967, 1739, 1669, 1632, 1240, 1020 cm−1
;
HRMS (CI/NH3) m/z calcd for C14H23INO3 [M + H]+ 380.0723,
found 380.0718.
(S,E)-1-(tert-Butyl(1-(tert-butyldimethylsilyloxy)-5-iodohex-
4-en-3-yloxy)(phenyl)silyl)benzene (31). To a suspension of
Schwartz’s reagent (516 mg, 2 mmol, 2 equiv) in dry THF (3 mL)
was added a solution of the TBDPS ether (466 mg, 1 mmol, 1 equiv) in
dry THF (3 mL) at ambient temperature under an argon atmosphere.
The mixture was warmed to 50 °C and stirred for 1.5 h in the dark. The
mixture was cooled to 0 °C, and a solution of iodine (280 mg, 2.2
mmol, 2.2 equiv) in dry THF (5 mL) was added to the mixture. The
mixture was further stirred at 0 °C for 10 min and was quenched by
saturate Na2S2O3 water solution (15 mL) at rt. The organic layer was
separated, and the water layer was extracted by diethyl ether (2 ×
15 mL). The combined organic extracts were washed with brine and
dried over MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel (1%
1
ketone 23 as a colorless oil (1.92 g, 85% yield): H NMR (400 MHz,
CDCl3) 3.94 (t, J = 6.4 Hz, 2H), 2.70 (t, J = 6.0 Hz, 2H), 1.99 (s, 3H),
0.85 (s, 9H), 0.03 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 186.1,
90.0, 80.1, 58.3, 48.2, 25.6, 18.0, 3.9, −5.6 ppm; IR (thin film) νmax
3482, 2956, 2930, 2857, 2216, 1676, 1255, 1003, 836 cm−1; HRMS
(CI/NH3) m/z calcd for C12H23O2Si [M + H]+ 227.1467, found
227.1497.
(S)-1-(tert-Butyldimethylsilyloxy)hex-4-yn-3-ol (13) Gener-
ated from CBS Asymmetric Reduction. Ketone 23 (1.8 g,
8 mmol) was dissovled in THF (40 mL, 0.2 M) and cooled to
−30 °C. To this solution was added 2-methyl (S)-CBS oxazaboro-
lidine (1.0 M in toluene, 16 mL, 16 mmol, 2 equiv), and borane−
dimethyl sulfide (2.0 M in THF, 20 mL, 40 mmol, 5 equiv) was added
dropwise over 5 min. After the resulting reaction mixture was stirred
for 1 h at −30 °C, the reaction was quenched by addition of ethanol
(10 mL), warmed to room temperature, and diluted with water
(40 mL) and diethyl ether (40 mL). The organic layer was dried over
MgSO4, concentrated under reduced pressure, and purified by flash
column chromatography (SiO2, 10/90 EtOAc/hexanes) to afford
enantioenriched 13 as a colorless oil (1.66 g, 91% yield, 93% ee).
EtOAc/hexane) to afford iodide 31 (551 mg, 93%) as a single
1
regioisomer: [α]20 −52.3 (c = 0.6, CH2Cl2); H NMR (400 MHz,
D
CDCl3) δ7.64 (m, 4H), 7.37 (m, 6H), 6.08 (dq, J = 9.2, 1.2 Hz, 1H),
4.49 (dt, J = 9.2, 6.4 Hz, 1H), 3.59 (m, 2H), 1.84 (m, 1H), 1.78 (d, J =
1.6 Hz, 3H), 1.60 (m, 1H), 1.03 (s, 9H), 0.80 (s, 9H), −0.04 (s, 3H),
−0.05 (s, 3H); 13C NMR (75 MHz, CDCl3) 143.7, 135.9, 135.8, 133.8,
129.6, 129.5, 127.6, 127.5, 96.4, 68.3, 65.8, 59.0, 40.7, 27.8, 27.0,
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25.9, 19.3, 18.1, −5.4 ppm; IR (thin film) νmax3071, 2929, 1471, 1256,
1111, 835, 701 cm−1; HRMS (CI/NH3) m/z calcd for C28H43IO2-
NaSi2 [M + Na]+ 617.1744, found 617.1760.
to −30 °C over 1.5 h. The reaction mixture was stirred at −30 °C for
another 1 h and then cooled to −78 °C at which point terminal alkyne
14c (25 mg, 0.1 mmol, 1 equiv) in toluene (0.5 mL) was added slowly
to the reaction by syringe. After being warmed slowly to −30 °C over
1.5 h, the reaction mixture was further stirred at −30 °C for an
additional 1 h. The reaction was quenched with saturated NH4Cl
solution (3 mL). The mixture was warmed to rt before extracting with
EtOAc (3 × 5 mL). The combined organic layer was dried over
MgSO4, filtered, and concentrated. Purification over silica gel (20%
EtOAc/hexane) afforded diene 33b (29 mg, 49% yield) as a colorless
oil and allene 34b (18 mg, 39% yield) as a colorless oil (single
diastereomer, the absolute configuration was not determined). 33b:
(4R,5R,E)-5-(Benzyloxy)-N-((S,2E,4E)-8-(tert-butyldimethylsi-
lyloxy)-6-(tert-butyldiphenylsilyloxy)-4-methylocta-2,4-dien-
yl)-4,6-dimethylhept-2-enamide (32b) Generated through
Negishi Cross-Coupling. A solution of 31 (594 mg, 1.0 mmol,
1.5 equiv) in dry diethyl ether (2 mL) was treated with t-BuLi
(1.18 mL, 1.7 M in pentane, 2 mmol, 3.0 equiv) at −78 °C for 30 min
and then with a solution of ZnCl2 (1.0 mL, 1 M THF solution,
1.0 mmol, 1.5 equiv) at −78 °C for another 20 min. The reaction
mixture was transferred to 0 °C, treated with a solution of 30b
(286 mg, 0.67 mmol, 1 equiv) and Pd(PPh3)4 (77 mg, 0.067 mmol,
0.1 equiv) in THF (3 mL), and stirred overnight with warming to rt.
The reaction was quenched with saturated NH4Cl solution (3 mL),
extracted with CH2Cl2 (3 × 5 mL), washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. This crude
product was purified by flash chromatography (silica gel, 20% EtOAc/
1
[α]20D −16.2 (c = 2.1, CH2Cl2); H NMR (500 MHz, CDCl3) δ 6.65
(dd, J = 15.0, 8.0 Hz, 1H), 6.02 (d, J = 16.0 Hz, 1H), 5.90 (dt, J = 15.5,
6.0 Hz, 1H), 5.75 (dd, J = 15.5, 1.0 Hz, 1H), 5.52 (q, J = 7.0 Hz, 1H),
5.39 (br, 1H), 4.84 (m, 1H), 4.74 (m, 1H), 3.96 (m, 1H), 3.86 (m,
1H), 3.64 (m, 1H), 3.54 (m, 1H), 2.57 (m, 1H), 2.04 (s, 3H), 1.86 (m,
2H), 1.70 (d, J = 7.0 Hz, 3H), 1.58 (m, 1H), 1.00 (d, J = 7.0 Hz, 3H),
0.86 (m, 24H), 0.02 (s, 6H), 0.01 (s, 3H), −0.06 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 170.8, 165.2, 145.2, 140.5, 132.9, 125.0, 124.1,
123.9, 79.7, 66.1, 59.4, 42.1, 39.9, 38.4, 29.7, 25.9, 25.8, 20.8, 19.7,
18.2, 18.1, 16.2, 15.5, 13.6, −4.9, −5.2, −5.3, −5.4 ppm; IR (thin film)
υmax 3278, 2957, 2930, 2857, 1743, 1240, 1090, 836, 776 cm−1; HRMS
(CI/NH3) m/z calcd for C32H61NO5Si2Na [M + Na]+ 618.3986,
found 618.3967. 34b: [α]20D +23.1 (c = 1.7, CH2Cl2); 1H NMR (500
MHz, CDCl3) δ 6.68 (dd, J = 15.5, 8.5 Hz, 1H), 6.11 (d, J = 15.5 Hz,
1H), 5.78 (dd, J = 15.5, 1.0 Hz, 1H), 5.50 (m, 2H), 5.19 (s, 1H), 4.74
(m, 1H), 3.97 (br, 2H), 3.64 (t, J = 6.5 Hz, 2H), 2.58 (m, 1H), 2.19
(m, 2H), 2.05 (s, 3H), 1.84 (m, 1H), 1.75 (s, 3H), 1.00 (d, J = 6.5 Hz,
3H), 0.86 (m, 15H), 0.02 (s, 6H); 13C NMR (75 MHz, CDCl3) δ
207.5, 170.9, 165.3, 145.4, 132.0, 123.7, 123.4, 99.1, 87.3, 79.8, 62.8,
41.5, 38.4, 32.6, 29.7, 25.9, 20.8, 19.7, 18.3, 16.4, 15.6, 15.3, −5.3 ppm;
IR (thin film) νmax 3289, 2959, 2930, 2857, 1959, 1741, 1670, 1240,
1100, 836 cm−1.
hexane) to afford product 32b (478 mg, 93%) as a colorless oil: [α]20
D
−38.3 (c = 0.8, CH2Cl2); 1H NMR (400 MHz, CDCl3) 7.63 (m, 4H),
7.35 (m, 11H), 6.87 (dd, J = 15.2, 8.0 Hz, 1H), 5.99 (d, J = 15.6 Hz,
1H), 5.76 (d, J = 15.2 Hz, 1H), 5.43 (dt, J = 15.6, 6.4 Hz, 1H), 5.37 (d,
J = 8.8 Hz, 1H), 5.36 (br, 1H), 4.67 (m, 1H), 4.55 (s, 2H), 3.92 (m,
2 H), 3.62 (m, 1H), 3.50 (m, 1H), 3.08 (m, 1H), 2.59 (m, 1H), 1.84
(m, 2H), 1.59 (m, 1H), 1.23 (s, 3H), 1.11 (d, J = 6.8 Hz, 3H), 1.02
(s, 9H), 0.95 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H), 0.81 (s,
9H), −0.05 (s, 3H), −0.06 (s, 3H); 13C NMR (100 MHz,
CDCl3)165.5, 147.9, 138.8, 136.9, 135.9, 135.8, 135.8, 135.3, 134.4,
134.2, 132.3, 129.4, 129.3, 128.3, 127.6, 127.4, 127.3, 123.6, 122.6,
87.9, 75.2, 67.6, 59.3, 41.5, 41.4, 39.7, 31.2, 27.0, 25.8, 20.3, 19.3, 18.1,
17.4, 15.1, 12.4, −5.4 ppm; IR (thin film) υmax 3293, 2955, 2940, 1730,
1629, 1211, 1101, 867 cm−1; HRMS (CI/NH3) m/z calcd for
C47H69NO4Si2Na [M + Na]+ 790.4663, found 790.4634.
(3R,4R,E)-7-((S,2E,4E)-8-(tert-Butyldimethylsilyloxy)-6-(tert-
butyldiphenylsilyloxy)-4-methylocta-2,4-dienylamino)-2,4-di-
methyl-7-oxohept-5-en-3-yl Acetate (32c) Generated through
Negishi Cross-Coupling. A solution of 31 (891 mg, 1.5 mmol,
1.5 equiv) in dry diethyl ether (3 mL) was treated with t-BuLi (1.77
mL, 1.7 M in pentane, 3 mmol, 3.0 equiv) at −78 °C for 30 min and
then with a solution of ZnCl2 (1.5 mL, 1 M THF solution, 1.5 mmol,
1.5 equiv) at −78 °C for another 20 min. The reaction mixture was
transferred to 0 °C, treated with a solution of 30c (380 mg, 1 mmol,
1 equiv) and Pd(PPh3)4 (115 mg, 0.1 mmol, 0.1 equiv) in THF (5 mL),
and stirred overnight with warming to rt. The reaction was quenched
with aqueous NH4Cl (5 mL), extracted with CH2Cl2 (3 × 10 mL),
washed with brine, dried over MgSO4, filtered, and concentrated. This
crude product was purified by flash chromatography (silica gel, 20%
EtOAc/hexane) to afford product 32c (662 mg, 92%) as a colorless oil:
[α]20D −40.2 (c = 0.4, CH2Cl2); 1H NMR (400 MHz, CDCl3) 7.61 (m,
4H), 7.32 (m, 6H), 6.68 (dd, J = 15.2, 8.0 Hz, 1H), 5.98 (d,
J = 15.6 Hz, 1H), 5.78 (d, J = 15.6 Hz, 1H), 5.53 (br, 1H), 5.43 (dt, J =
15.6, 6.4 Hz, 1H), 5.37 (d, J = 8.8 Hz, 1H), 4.75 (m, 1H), 4.66 (m, 1H),
3.92 (m, 2 H), 3.69 (m, 1H), 3.49 (m, 1H), 2.59 (m, 1H), 2.05 (s, 3H),
1.85 (m, 2H), 1.58 (m, 1H), 1.22 (s, 3H), 1.01 (s, 9H), 1.00 (d, J = 5.2
(3R,4R,E)-7-((S,2E,4E)-8-(tert-Butyldimethylsilyloxy)-6-hy-
droxy-4-methylocta-2,4-dienylamino)-2,4-dimethyl-7-oxo-
hept-5-en-3-yl Acetate (35c) through Alkoxide-Directed
Alkyne−alkyne Reductive Coupling. To a −78 °C solution of
alkyne 13 (68 mg, 0.3 mmol, 3 equiv) in Et2O (3 mL) were added
sequentially n-BuLi (2.5 M in hexanes, 112 μL, 0.28 mmol, 2.8 equiv),
ClTi(OiPr)3 (1.0 M in hexanes, 280 μL, 0.28 mmol, 2.8 equiv), and
c-C5H9MgCl (2.0 M in Et2O, 280 μL, 0.56 mmol, 5.6 equiv) dropwise.
The resulting yellow solution turned brown while warming slowly
to −30 °C over 1.5 h. The reaction mixture was stirred at −30 °C for
an additional 1 h and then cooled to −78 °C at which point terminal
alkyne 14c (25 mg, 0.1 mmol, 1 equiv) in Et2O (0.5 mL) was added
slowly by syringe to the reaction flask. After being warmed slowly
to −30 °C over 1.5 h, the mixture was further stirred at −30 °C for
another 10 h. The reaction was quenched with saturated NH4Cl
solution (2 mL). The mixture was warmed to rt before extracting with
EtOAc (3 × 5 mL). The combined organic layers were dried over
MgSO4, filtered, and concentrated. Purification over silica gel (30%
EtOAc/hexane) afforded product 35c (34 mg, 71% yield) as a
colorless oil and as a single regioisomer: [α]20 +15.8 (c = 0.6,
Hz, 3H), 0.86 (m, 6H), 0.80 (s, 9H), −0.05 (s, 3H), −0.06 (s, 3H); 13
C
D
1
CH2Cl2); H NMR (500 MHz, CDCl3) δ 6.68 (dd, J = 15.5, 8.0 Hz,
NMR (75 MHz, CDCl3)170.9, 165.3, 145.3, 136.8, 135.8, 135.8, 135.3,
134.4, 134.1, 132.3, 129.4, 129.3, 127.4, 127.2, 123.7, 123.5, 79.7, 67.6,
59.3, 41.5, 41.4, 38.3, 29.7, 26.9, 25.8, 20.8, 19.7, 19.3, 18.1, 16.3, 15.3,
12.4, −5.5 ppm; IR (thin film) νmax 3277, 2958, 2931, 1742, 1629, 1239,
1105, 702 cm−1; HRMS (CI/NH3) m/z calcd for C42H65NO5Si2Na
[M + Na]+ 742.4299, found 742.4293.
1H), 6.16 (d, J = 15.5 Hz, 1H), 5.78 (dd, J = 15.5, 1.5 Hz, 1H), 5.64
(dt, J = 15.5, 6.5 Hz, 1H), 5.54 (br, 1H), 5.48 (d, J = 8.5 Hz, 1H), 4.74
(m, 1H), 4.68 (m, 1H), 3.96 (m, 2H), 3.86 (m, 1H), 3.77 (m, 1H),
3.13 (br, 1H), 2.58 (m, 1H), 2.05 (s, 3H), 1.83 (m, 2H), 1.75 (s, 3H),
1.63 (m, 1H), 1.00 (d, J = 7.0 Hz, 3H), 0.87 (s, 9H), 0.85 (m, 6H),
−0.06 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 171.0, 165.4, 145.5,
136.7, 134.6, 133.7, 124.3, 123.6, 79.7, 68.3, 61.9, 41.5, 38.7, 38.4, 29.7,
25.8, 20.9, 19.7, 18.1, 16.3, 15.3, 12.8, −5.5; IR (thin film) υmax 3293,
2959, 1741, 1669, 1631, 1540, 1240, 1096, 836 cm−1; HRMS (CI/
NH3) m/z calcd for C26H47NO5SiNa [M + Na]+ 504.3121, found
504.3124.
(3R,4R,E)-7-((S,2E,4Z)-5,7-Bis(tert-butyldimethylsilyloxy)-4-
ethylidenehept-2-enylamino)-2,4-dimethyl-7-oxohept-5-en-3-
yl Acetate (33b) and (3R,4R,E)-7-((E)-8-(tert-Butyldimethylsily-
loxy)-4-methylocta-2,4,5-trienylamino)-2,4-dimethyl-7-oxo-
hept-5-en-3-yl Acetate (34b) Generated through Alkyne−
alkyne Reductive Coupling. To a −78 °C solution of alkyne 22
(68 mg, 0.2 mmol, 2 equiv) in toluene (2 mL) were added sequentially
ClTi(OiPr)3 (1.0 M in hexanes, 0.2 mL, 0.2 mmol, 2 equiv) and
c-C5H9MgCl (2.0 M in Et2O, 0.2 mL, 0.4 mmol, 4 equiv) dropwise.
The resulting yellow solution turned brown while warming slowly
(4R,5R,E)-N-((S,2E,4E)-8-(tert-Butyldimethylsilyloxy)-6-hy-
droxy-4-methylocta-2,4-dienyl)-5-hydroxy-4,6-dimethylhept-
2-enamide (35d) through Alkoxide-Directed Alkyne−alkyne
Reductive Coupling. To a solution of alkyne 13 (136 mg, 0.6 mmol,
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3 equiv) in Et2O (2 mL) at −78 °C were added sequentially n-BuLi
(2.5 M in hexanes, 224 μL, 0.56 mmol, 2.8 equiv), ClTi(O-i-Pr)3 (1.0 M
in hexanes, 560 μL, 0.56 mmol, 2.8 equiv), and c-C5H9MgCl (2.0 M in
Et2O, 560 μL, 1.12 mmol, 5.6 equiv) dropwise. The resulting yellow
solution turned brown while warming slowly to −30 °C over 1.5 h. The
reaction mixture was stirred at −30 °C for an additional 1 h and then
cooled to −78 °C at which point terminal alkyne 14a (42 mg, 0.2 mmol,
1 equiv) in Et2O (1 mL) was added slowly to the reaction by syringe.
After being warmed slowly to −30 °C over 1.5 h, the mixturew was
further stirred at −30 °C for another 24 h. The reaction was quenched
with saturated NH4Cl solution (3 mL). The mixture was warmed to rt
before extracting with EtOAc (3 × 5 mL). The combined organic layer
was dried over MgSO4, filtered, and concentrated under reduced
pressure. Purification over silica gel (50% EtOAc/hexane) afforded
product 35d (42 mg, 48% yield) as a colorless oil with recovered
starting material 14a (8 mg): [α]20D +16.2 (c = 2.4, CH2Cl2); 1H NMR
(400 MHz, CDCl3) δ 6.78 (dd, J = 15.6, 8.0 Hz, 1H), 6.17 (d, J =
15.6 Hz, 1H), 5.81 (d, J = 15.2 Hz, 1H), 5.64 (dt, J = 14.8, 6.0 Hz, 1H),
5.64 (br, 1H), 5.47 (d, J = 8.4 Hz, 1H), 4.68 (m, 1H), 3.98 (m, 2H),
3.85 (m, 1H), 3.76 (m, 1H), 3.23 (t, J = 5.2 Hz, 1H), 3.21 (br, 1H),
2.47 (m, 1H), 1.75 (s, 3H), 1.59−1.80 (m, 3H), 1.06 (d, J = 6.5 Hz,
3H), 0.88 (m, 6H), 0.89 (s, 9H), −0.06 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 165.7, 147.5, 136.7, 134.7, 133.7, 124.4, 123.2, 79.2, 68.2,
61.8, 41.5, 39.6, 38.8, 30.8, 25.8, 19.7, 18.1, 16.7, 14.0, 12.8; IR (thin
film) νmax 3294, 2957, 2929, 2858, 1668, 1628, 1547, 1255, 1096, 836
cm−1; HRMS (CI/NH3) m/z calcd for C24H45NO4NaSi [M + Na]+
462.3016, found 462.3001.
(3R,4R,E)-7-((S,2E,4E)-6-Hydroxy-4-methyl-8-phenylocta-2,4-
dienylamino)-2,4-dimethyl-7-oxohept-5-en-3-yl Acetate (35e)
through Alkoxide-Directed Alkyne−alkyne Reductive Cou-
pling. To a −78 °C solution of alkyne 36 (53 mg, 0.3 mmol, 3 equiv)
in Et2O (3 mL) were added sequentially n-BuLi (2.5 M in hexanes,
112 μL, 0.28 mmol, 2.8 equiv), ClTi(O-i-Pr)3 (1.0 M in hexanes,
280 μL, 0.28 mmol, 2.8 equiv), and c-C5H9MgCl (2.0 M in Et2O,
280 μL, 0.56 mmol, 5.6 equiv) dropwise. The resulting yellow solution
turned brown while warming slowly to −30 °C over 1.5 h. The
reaction mixture was stirred at −30 °C for an additional 1 h and then
cooled to −78 °C at which point terminal alkyne 14c (25 mg,
0.1 mmol, 1 equiv) in Et2O (0.5 mL) was added slowly by syringe to
the reaction flask. After warming slowly to −30 °C over 1.5 h, the
mixture was further stirred at −30 °C for another 12 h. The reaction
was quenched with saturated NH4Cl solution (2 mL). The mixture
was warmed to rt before extracting with EtOAc (3 × 5 mL). The
combined organic layers were dried over MgSO4, filtered, and
concentrated under reduced pressure. Purification over silica gel
(40% EtOAc/hexane) afforded allene 34e (11 mg, 26% yield) and
further stirred at −30 °C for another 12 h. The reaction was quenched
with saturated NH4Cl solution (2 mL). The mixture was warmed to rt
before extracting with EtOAc (3 × 5 mL). The combined organic
layers were dried over MgSO4, filtered, and concentrated under
reduced pressure. Purification over silica gel (2% EtOAc/hexane)
afforded allene 34f (6 mg, 20% yield) and (20% EtOAc/hexane) the
1
desired product 35f (21 mg, 62% yield) as a colorless oil: H NMR
(500 MHz, CDCl3) δ 6.02 (d, J = 15.5 Hz, 1H), 5.64 (dt, J = 15.5, 7.0
Hz, 1H), 5.37 (d, J = 8.5 Hz, 1H), 4.68 (m, 1H), 3.84 (m, 1H), 3.77
(m, 1H), 2.91 (br, 1H), 2.06 (q, J = 6.5 Hz, 2H), 1.78 (m, 1H), 1.76
(s, 3H), 1.64 (m, 1H), 1.33 (m, 2H), 1.23 (m, 6H), 0.89 (m, 12H),
0.05 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 134.9, 134.2, 131.9,
130.1, 68.0, 61.7, 39.1, 32.8, 31.7, 29.5, 28.9, 25.9, 22.6, 18.1, 14.1,
12.9, −5.5, −5.5 ppm; IR (thin film) νmax 3396, 2955, 2928, 2858,
1471, 1255, 1096, 836 cm−1; HRMS (CI/NH3) m/z calcd for
C20H39OSi [M + H − H2O]+ 323.2770, found 323.2782.
(4R,5R,E)-N-((S,2E,4E)-8-(tert-Butyldimethylsilyloxy)-6-(tert-
butyldiphenylsilyloxy)-4-methylocta-2,4-dienyl)-5-hydroxy-
4,6-dimethylhept-2-enamide (11). Diol 35d (137 mg, 0.3 mmol,
1 equiv) and TBDPSCl (83 mg, 0.3 mmol, 1 equiv) were dissolved in
dry CH2Cl2 (3 mL, 0.1 M) and cooled to 0 °C. Imidazole (62 mg,
0.9 mmol, 3 equiv) was added to the solution, and this mixture was
further stirred at 0 °C for another 3 h under an argon atmosphere. The
mixture was poured into saturated NH4Cl solution (2 mL) and
extracted with CH2Cl2 (2 × 5 mL). The combined organic phases
were dried by MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by chromatography (silica gel, 40%
EtOAc/hexane) to afford the product 11 (186 mg, 92% yield) as a
white glassy type solid: [α]20D −30.0 (c = 0.4, CH2Cl2); 1H NMR (400
MHz, CDCl3) δ 7.60 (m, 4H), 7.32 (m, 6H), 6.80 (dd, J = 15.2, 7.6
Hz, 1H), 5.98 (d, J = 16.0 Hz, 1H), 5.78 (d, J = 15.6 Hz, 1H), 5.43 (dt,
J = 15.6, 6.4 Hz, 1H), 5.38 (m, 2H), 4.66 (m, 1H), 3.92 (m, 2 H), 3.60
(m, 1H), 3.49 (m, 1H), 3.26 (m, 1H), 2.48 (m, 1H), 1.83 (m, 1H),
1.72 (m, 1H), 1.58 (m, 1H), 1.22 (d, J = 15.6 Hz, 4.8 Hz, 3H), 1.08 (d,
J = 6.8 Hz, 3H), 1.01 (s, 9H), 0.89 (m, 6H), 0.80 (s, 9H), −0.05 (s,
3H), −0.06 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 165.6, 147.6,
136.8, 135.8, 135.8, 135.3, 134.4, 134.1, 132.3, 129.4, 129.3, 127.4,
127.2, 123.6, 123.2, 79.1, 67.6, 59.3, 41.5, 41.4, 39.6, 30.8, 26.9, 25.8,
19.7, 19.3, 18.1, 16.8, 13.8, 12.4, −5.5 ppm; IR (thin film) νmax 3294,
2957, 2930, 2857, 1668, 1629, 1256, 1106, 702 cm−1; HRMS (CI/
NH3) m/z calcd for C40H63NO4Si2Na [M + Na]+ 700.4193, found
700.4176.
2-(Chloromethyl)oxazole-4-carboxylic Acid (42). Oxazole
ester 41 (1.75 g, 10 mmol, 1 equiv) was dissolved in THF (70 mL)
and H2O (18 mL) cosolvent. LiOH (360 mg, 15 mmol, 1.5 equiv) was
added to this mixture at rt in one portion and stirred for another 12 h.
CH2Cl2 (100 mL) and water (100 mL) were added to this mixture,
and the aqueous phase was adjusted to pH 4 using a KHSO4 (1 M)
solution. The organic phase was separated, and the aqueous phase was
extracted with EtOAc (3 × 80 mL). The combined organic phases
were dried over Na2SO4, filtered, and evaporated under reduced
pressure to afford product 42 (1.53 mg, 95% yield) as a white solid,
(70% EtOAc/hexane) the desired product 35e (23 mg, 55% yield) as a
1
colorless oil: [α]20 −1.0 (c = 1.0, CH2Cl2); H NMR (400 MHz,
D
CDCl3) δ 7.26 (m, 2H), 7.16 (m, 3H), 6.69 (dd, J = 15.2, 8.0 Hz, 1H),
6.18 (d, J = 15.6 Hz, 1H), 5.80 (d, J = 15.2 Hz, 1H), 5.70 (m, 2H),
5.47 (d, J = 8.4 Hz, 1H), 4.76 (dd, J = 7.2, 5.2 Hz, 1H), 4.47 (q, J = 8.0
Hz, 1H), 3.99 (t, J = 6.0 Hz, 2H), 2.64 (m, 3H), 2.06 (s, 3H), 1.85 (m,
2H), 1.79 (m, 1H), 1.73 (s, 3H), 1.01 (d, J = 6.4 Hz, 3H), 0.86 (m,
6H); 13C NMR (100 MHz, CDCl3) δ 170.9, 165.5, 145.5, 141.7,
136.4, 134.6, 134.5, 128.3, 125.8, 124.8, 123.6, 79.8, 67.8, 41.4, 38.9,
38.3, 31.6, 29.7, 20.8, 19.7, 16.4, 15.2, 12.9 ppm; IR (thin film) υmax
3286, 2967, 2936, 1739, 1240, 1121, 700 cm−1; HRMS (CI/NH3) m/z
calcd for C26H37NO4Na [M + Na]+ 450.2620, found 450.2617.
(4E,6E)-1-(tert-Butyldimethylsilyloxy)-5-methyltrideca-4,6-
dien-3-ol (35f) through Alkoxide-Directed Alkyne−alkyne Reduc-
tive Coupling. To a −78 °C solution of alkyne rac-13 (68 mg,
0.3 mmol, 3 equiv) in Et2O (3 mL) were added sequentially
n-BuLi (2.5 M in hexanes, 112 μL, 0.28 mmol, 2.8 equiv), ClTi(OiPr)3
(1.0 M in hexanes, 280 μL, 0.28 mmol, 2.8 equiv), and c-C5H9MgCl
(2.0 M in Et2O, 280 μL, 0.56 mmol, 5.6 equiv) dropwise. The resulting
yellow solution turned brown while warming slowly to −30 °C over
1.5 h. The reaction mixture was stirred at −30 °C for an additional 1 h
then cooled to −78 °C at which point 1-octyne 37 (11 mg, 0.1 mmol,
1 equiv) in Et2O (0.5 mL) was added slowly by syringe to the reaction
flask. After warming slowly to −30 °C over 1.5 h, the mixture was
1
which was pure enough for further use: H NMR (400 MHz, CDCl3)
δ 8.33 (s, 1H), 4.66 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.6,
160.4, 146.1, 133.2, 35.1 ppm; IR (thin film) νmax 3137, 1682, 1589,
1442, 1305, 1114, 988, 880 cm−1; HRMS (CI/NH3) m/z calcd for
C5H5ClNO3 [M + H]+ 161.9958, found 161.9950.
(R)-Benzyl 1-(2-(Chloromethyl)oxazole-4-carbonyl)-
pyrrolidine-2-carboxylate (43). The oxazole acid 42 (730 mg,
4.54 mmol, 1 equiv) was dissolved in CH2Cl2 (60 mL), and EDC·HCl
(870 mg, 4.54 mmol, 1 equiv) was added to the solution. After the
solution was stirred for 30 min, NH(HCl)-Pro-OBn (1.2 g, 5.0 mmol,
1.1 equiv) and TEA (0.63 mL, 45.4 mmol, 1 equiv) were added, and
the mixture was stirred for another 12 h. CH2Cl2 (50 mL) and water
(50 mL) were added, and the aqueous phase was adjusted to pH 4
using a KHSO4 (1 M) solution. The organic phase was separated, and
the aqueous phase was extracted with CH2Cl2 (3 × 50 mL). The
combined organic phase was dried over MgSO4, filtered, and
evaporated under reduced pressure. The residue was purified by
column chromatography on silica gel (20% to 30% EtOAc/hexane) to
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afford product 43 (1.26 g, 80% yield) as a mixture of 1:1 rotamers:
mixture of CH2Cl2 (0.5 mL) and MeOH (0.5 mL) at 0 °C was added
CSA (2.5 mg, 0.01 mmol, 0.2 equiv) in one portion. Stirring was
maintained at 0 °C for an additional 1 h prior to quenching with
saturated NaHCO3 solution (1 mL). The separated aqueous layer was
extracted with EtOAc (3 × 3 mL), and the combined organic layers
were dried over MgSO4, filtered, and evaporated under reduced
pressure. The residue was purified by column chromatography on
silica gel (50% EtOAc/hexane) to afford the alcohol product (38 mg,
62% yield) as a mixture of 1:1 rotamers, with recovering starting
material 44 (25 mg): [α]20D −32.2 (c = 1.3, CH2Cl2); 1H NMR (400
MHz, CDCl3) δ 8.19** (s, 1H), 8.11* (s, 1H), 7.56 (m, 4H), 7.33 (m,
6H), 6.53 (m, 1H), 6.01* (m, 1H), 5.96 (m, 1H), 5.72* (d, J = 16.0
Hz, 1H), 5.66** (d, J = 15.6 Hz, 1H), 5.50** (m, 1H), 5.45 (m, 2H),
5.39** (m, 1H), 4.71 (m, 1H), 4.64 (m, 1H), 4.60** (m, 1H), 4.53*
(s, 2H), 4.46** (s, 2H), 4.03 (m, 1H), 3.95 (m, 1H), 3.83 (m, 1H),
3.68 (m, 2H), 3.55 (m, 1H), 2.52 (m, 1H), 2.20 (m, 1H), 2.17* (m,
1H), 2.02** (m, 1H), 1.79−2.01 (m, 3H),1.70 (m, 2H), 1.48 (s, 3H),
1.19 (s, 9H), 0.99 (s, 9H), 0.82−0.93 (m, 9H); 13C NMR (100 MHz,
CDCl3) δ 172.0**, 171.7*, 166.0*, 165.2**, 159.8, 158.4**, 158.3*,
145.3**, 145.1*, 144.8*, 144.7**, 137.7**, 137.5*, 136.5**, 136.2*,
135.9**, 135.8*, 134.6**, 134.3*, 133.7*, 133.7**, 132.6*, 132.4**,
129.7*, 129.6**, 127.6*, 127.4**, 124.5*, 124.3**, 124.0*, 123.8**,
81.2**, 80.9*, 69.2*, 69.2**, 60.4**, 60.3*, 59.8*, 59.7**, 48.8**,
47.2*, 41.5, 40.0, 38.2**, 37.7*, 35.5**, 35.4*, 31.6**, 30.0**, 29.9*,
28.8*, 27.0, 25.3*, 21.4**, 19.6, 19.4, 19.2, 17.6*, 17.3**, 14.2**,
14.0*, 12.4 ppm; IR (thin film) υmax 3305, 2977, 2325, 1756, 1683, 702
cm−1; HRMS (CI/NH3) m/z calcd for C44H58ClN3O7NaSi [M + Na]+
826.3630, found 826.3613.
[α]20 +35.6 (c = 0.8, CH2Cl2); 1H NMR (400 MHz, CDCl3)
D
δ 8.23** (s, 1H), 8.18* (s, 1H), 7.32 (m, 5H), 5.29* (dd, J = 8.8,
3.2 Hz, 1H), 5.17 (m, 2H), 4.67** (dd, J = 8.8, 4.0 Hz, 1H), 4.60** (s,
2H), 4.24* (q, J = 12.8 Hz, 2H), 4.07** (m, 2H), 3.81* (m, 1H), 3.70*
(m, 1H), 2.07 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 172.4, 171.8,
159.8, 158.3, 158.0, 144.8, 144.7, 137.6, 137.5, 135.7, 135.6, 128.5, 128.4,
128.4, 128.2, 128.1, 128.0, 66.8, 60.5*, 59.9**, 48.8**, 47.6*, 35.6**,
35.3*, 31.6*, 28.5**, 25.2**, 21.9* ppm; IR (thin film) υmax 3471, 3033,
2957, 2882, 1744, 1627, 1427, 1173, 751 cm−1; HRMS (CI/NH3) m/z
calcd for C17H17ClN2O4Na [M + Na]+ 371.0775, found 371.0781.
(R)-1-(2-(Chloromethyl)oxazole-4-carbonyl)pyrrolidine-2-
carboxylic Acid (12). Oxazole benzyl ester 43 (696 mg, 2 mmol,
1 equiv) was dissolved in dry CH2Cl2 (60 mL) and cooled to −20 °C.
BCl3 (6 mL, 1 M solution in hexane, 6 mmol, 3 equiv) was added
dropwise to the reaction. It was further stirred for 3 h while the
temperature was allowed to warm to 0 °C. Then EtOAc (50 mL) and
saturated aqueous NaHCO3 solution (50 mL) were added, and the
aqueous phase was acidified to pH 2 by adding KHSO4 (1 M)
solution. The phase was separated, and the aqueous phase was
extracted with EtOAc (3 × 50 mL). The combined organic layers were
dried over Na2SO4, filtered, and evaporated. The residue was purified
by column chromatography on silica gel (5% MeOH/CH2Cl2) to
afford the acid product 12 (360 mg, 70% yield) as a mixture of 3:1
1
rotamers: [α]20 +128.0 (c = 1.0, CH2Cl2); H NMR (400 MHz,
D
CDCl3) δ 8.30* (s, 1H), 8.27** (s, 1H), 5.28** (dd, J = 4.8, 4.0 Hz,
1H), 4.72* (d, J = 5.2 Hz, 1H), 4.58* (s, 2H), 4.55** (s, 2H), 4.09*
(m, 2H), 3.73** (m, 2H), 1.92−2.37 (m, 4H); 13C NMR (75 MHz,
CDCl3) δ 176.7**, 173.3*, 161.6*, 159.9**, 158.7*, 158.2**, 145.7*,
145.0**, 137.3**, 136.8*, 60.8*, 60.2**, 49.5*, 47.6**, 35.5**, 35.4*,
31.4**, 27.4*, 25.3*, 21.8** ppm; IR (thin film) νmax 3128, 2967,
1733, 1586, 1448, 1180, 1116, 748 cm−1; HRMS (CI/NH3) m/z calcd
for C10H11ClN2O4Na [M + Na]+ 281.0305, found 281.0310.
(R)-((3R,4R,E)-7-((S,2E,4E)-6-(tert-Butyldiphenylsilyloxy)-4-
methyl-8-oxoocta-2,4-dienylamino)-2,4-dimethyl-7-oxohept-
5-en-3-yl) 1-(2-(Chloromethyl)oxazole-4-carbonyl)pyrrolidine-
2-carboxylate (10). IBX (29.5 mg, 0.1 mmol, 2 equiv) was added to
the alcohol (42 mg, 0.05 mmol, 1 equiv) in DMSO (1 mL) at rt. After
stirring 6 h, the reaction was quenched by addition of CH2Cl2 (2 mL)
and water (1 mL). Saturated aqueous NaHCO3 (1 mL) was then
added, and the mixture was further stirred for 10 min. Then the layers
were separated and the aqueous layer was extracted with EtOAc (3 ×
3 mL). The combined organic extracts were dried over MgSO4,
filtered, and evaporated. The residue was purified by column
chromatography on silica gel (40% EtOAc/hexane) to afford the
aldehyde product 10 (38 mg, 92% yield) as a mixture of 1:1 rotamers:
(R)-((3R,4R,E)-7-((S,2E,4E)-8-(tert-Butyldimethylsilyloxy)-6-
(tert-butyldiphenylsilyloxy)-4-methylocta-2,4-dienylamino)-
2,4-dimethyl-7-oxohept-5-en-3-yl) 1-(2-(Chloromethyl)-
oxazole-4-carbonyl)pyrrolidine-2-carboxylate (44). 2,4,6-Tri-
chlorobenzoyl chloride (35 μL, 0.225 mmol, 2.25 equiv) was added
under argon to a suspension of oxazole acid 12 (39 mg, 0.15 mmol,
1.5 equiv) in benzene (0.5 mL), followed by DIPEA (39 μL,
0.225 mmol, 2.25 equiv), and the reaction turned into a clear solution.
A solution of TBDPS ether 11 (66 mg, 0.1 mmol, 1 equiv) in benzene
(0.5 mL) was added to the resulting solution, after which DMAP
(27 mg, 0.225 mmol, 2.25 equiv) was added in one portion. The
mixture was stirred overnight, diluted with EtOAc (2 mL), and washed
with water (2 mL). The water phase was extracted by EtOAc (3 ×
5 mL). The combined organic phase were dried over MgSO4, filtered,
and evaporated. The residue was purified by column chromatography
on silica gel (35% EtOAc/hexane) to afford product 44 (79 mg, 86%
yield) as a mixture of 1:1 rotamers: [α]20D +6.4 (c = 0.8, CH2Cl2); 1H
NMR (400 MHz, CDCl3) δ 8.24** (s, 1H), 8.17* (s, 1H), 7.60 (m,
4H), 7.32 (m, 6H), 6.57 (m, 1H), 5.99 (m, 1H), 5.79* (d, J = 15.6 Hz,
1H), 5.72** (d, J = 15.2 Hz, 1H), 5.54** (m, 1H), 5.47 (m, 2H), 5.37
(d, J = 9.2 Hz, 1H), 4.77 (m, 1H), 4.67* (m, 1H), 4.65 (m, 1H), 4.57*
(s, 2H), 4.51** (s, 2H), 4.09 (m, 1H), 3.93 (m, 2H), 3.72 (m, 1H),
3.52 (m, 2H), 2.57 (m, 1H), 2.28 (m, 1H), 2.04 (m, 1H), 1.91 (m,
3H), 1.60 (m, 2H), 1.22 (s, 3H), 1.01 (s, 9H), 0.99 (m, 3H), 0.94 (m,
6H), 0.80 (s, 9H), −0.06 (s, 3H), −0.07 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 172.0, 171.2, 165.8, 165.1, 159.7, 158.3, 145.3, 145.0,
144.8, 144.7, 137.7, 137.5, 137.0, 136.7, 135.9, 135.9, 135.5, 135.3,
134.4, 134.4, 134.2, 134.2, 132.4, 132.3, 129.4, 129.3, 127.4, 127.3,
124.3, 123.9, 123.8, 123.5, 81.2, 80.8, 67.7, 60.4, 60.3, 59.4, 59.4, 48.8,
47.2, 41.5, 41.4, 38.3, 37.7, 35.5, 35.5, 31.6, 30.0, 29.9, 28.8, 27.0, 25.9,
25.3, 21.5, 19.7, 19.4, 19.3, 18.1, 17.5, 17.1, 14.7, 14.2, 12.4, 12.4, −5.4
ppm; IR (thin film) νmax 3750, 3300, 2931, 2857, 1742, 1671, 1634,
1427, 1110, 702 cm−1; HRMS (CI/NH3) m/z calcd for
C50H72ClN3O7NaSi2 [M + Na]+ 940.4495, found 940.4487.
1
[α]20D −12.0 (c = 0.4, CH2Cl2); H NMR (400 MHz, CDCl3) δ 9.68
(m, 1H), 8.23** (s, 1H), 8.15* (s, 1H), 7.59 (m, 4H), 7.37 (m, 6H),
6.57 (m, 1H), 6.18* (t, J = 5.6 Hz, 1H), 6.00* (d, J = 15.6 Hz, 1H),
5.99** (d, J = 15.6 Hz, 1H), 5.77* (d, J = 15.6 Hz, 1H), 5.72** (d, J =
15.2 Hz, 1H), 5.61** (t, J = 6.0 Hz, 1H), 5.52 (m, 1H), 5.47 (d, J =
9.2 Hz, 1H), 5.43* (m, 1H), 4.92 (m, 1H), 4.75 (m, 1H), 4.63** (m,
1H), 4.57* (s, 2H), 4.51** (s, 2H), 4.08 (m, 2H), 3.92 (m, 1H), 3.72
(m, 1H), 2.48−2.62 (m, 3H), 2.17−2.29 (m, 2H), 1.72−2.12 (m, 5H),
1.25 (s, 3H), 0.99 (s, 9H), 0.84−0.95 (m, 9H); 13C NMR (75 MHz,
CDCl3) δ 201.0, 171.8, 171.5, 165.7, 165.1, 164.9, 159.7, 158.3, 158.2,
144.9, 144.8, 144.5, 144.3, 137.5, 137.2, 135.6, 135.4, 135.3, 133.3,
133.1, 133.0, 132.7, 132.6, 132.5, 129.7, 129.5, 127.5, 127.3, 125.3,
125.2, 125.0, 124.2, 123.7, 81.0, 80.9, 80.6, 66.2, 60.2, 60.1, 51.5, 48.6,
47.0, 47.0, 41.5, 41.1, 38.0, 37.6, 37.5, 35.4, 35.3, 31.4, 29.8, 29.7, 29.1,
28.6, 26.9, 25.1, 24.7, 21.2, 19.4, 19.3, 19.2, 19.0, 17.3, 17.2, 16.9, 14.8,
14.1, 14.0, 12.4 ppm; IR (thin film) νmax 3299, 3071, 2964, 2932, 2857,
1741, 1630, 1428, 1113, 704 cm−1; HRMS (CI/NH3) m/z calcd for
C44H56ClN3O7NaSi [M + Na]+ 824.3474, found 824.3456.
(R)-((3R,4R,E)-7-((S,2E,4E)-6-(tert-Butyldiphenylsilyloxy)-4-
methyl-8-oxoocta-2,4-dienylamino)-2,4-dimethyl-7-oxohept-
5-en-3-yl) 1-(2-(Iodomethyl)oxazole-4-carbonyl)pyrrolidine-2-
carboxylate (45). Chloroaldehyde 10 (90.5 mg, 0.045 mmol, 1 equiv)
and NaI (8 mg, 0.054 mmol, 1.2 equiv) were dissolved in acetone
(1.5 mL) at ambient temperature. After being stirred 6 h in the
absence of light, the solution was diluted with EtOAc (2 mL) and
water (4 mL). After careful evaporation of acetone, additional EtOAc
(2 mL) was added. The organic phase was separated, and the aqueous
phase was extracted with EtOAc (3 × 3 mL). The combined organic
extracts were washed with saturated aqueous Na2S2O3 solution
(R)-((3R,4R,E)-7-((S,2E,4E)-6-(tert-Butyldiphenylsilyloxy)-8-
hydroxy-4-methylocta-2,4-dienylamino)-2,4-dimethyl-7-oxo-
hept-5-en-3-yl) 1-(2-(Chloromethyl)oxazole-4-carbonyl)pyrrolidine-
2-carboxylate. To a solution of 44 (44 mg, 0.048 mmol, 1 equiv) in a
9915
dx.doi.org/10.1021/jo202119p | J. Org. Chem. 2011, 76, 9900−9918

The Journal of Organic Chemistry
Featured Article
(4 mL), dried over Na2SO4, filtered, and evaporated under reduced
pressure. The residue was purified by column chromatography on
silica gel (40% EtOAc/hexane) to afford product 45 (38 mg, 95%
added into the flask. Freshly prepared SmI2 THF solution (0.15 M
solution, 1.33 mL, 0.2 mmol, 4 equiv) was introduced by the syringe
pump within 4 h to the stirred solution. After stirring for another 4 h at
rt, the reaction was quenched by bubbling in air, followed by the
addition of saturated NH4Cl aqueous solution (20 mL), stirring for
15 min. The biphasic mixture was separated, and the aqueous phase
was extracted with EtOAc (3 × 15 mL). The combined organic phases
were dried over Na2SO4, filtered and concentrated under reduced
pressure. The residue was purified by flash chromatography (silica
gel, 40% EtOAc/hexane) to afford 9 (15 mg, 40% yield) as 1:1
diastereomers. (13S)-13-Hydroxy-11-O-(tert-butyldiphenylsilyl)-
yield) as a mixture of 1:1 rotamers: [α]20 −16.0 (c = 1.1, CH2Cl2);
D
1H NMR (400 MHz, CDCl3) δ 9.69 (m, 1H), 8.21** (s, 1H), 8.12*
(s, 1H), 7.61 (m, 4H), 7.37 (m, 6H), 6.58 (m, 1H), 6.13* (t, J = 5.6
Hz, 1H), 6.01* (d, J = 16.0 Hz, 1H), 5.99** (d, J = 16.0 Hz, 1H),
5.77* (d, J = 15.6 Hz, 1H), 5.71** (d, J = 15.6 Hz, 1H), 5.55** (t, J =
6.0 Hz, 1H), 5.50 (m, 2H), 5.48** (m, 1H), 4.92 (m, 1H), 4.75 (m,
1H), 4.64* (m, 1H), 4.34* (s, 2H), 4.28** (s, 2H), 4.06 (m, 2H),
3.66−3.98 (m, 2H), 2.46−2.61 (m, 3H), 2.15−2.29 (m, 2H), 1.80−
2.06 (m, 4H), 1.26 (s, 3H), 1.15 (m,1H), 1.00 (s, 9H), 0.88−0.98 (m,
9H); 13C NMR (125 MHz, CDCl3) δ 201.2, 172.1, 171.7, 166.0,
165.2, 159.9, 159.8, 144.7, 144.5, 144.1, 138.0, 137.8, 136.1, 135.8,
135.8, 133.5, 133.3, 133.2, 133.1, 129.8, 129.7, 127.7, 127.5, 125.4,
81.2, 80.8, 66.5, 60.5, 60.4, 60.3, 51.7, 48.8, 47.2, 41.4, 38.3, 37.7, 33.9,
31.6, 30.0, 28.8, 26.9, 25.3, 24.9, 21.5, 19.8, 19.4, 19.2, 17.7, 13.9, 12.6
ppm; IR (thin film) νmax 3308, 2962, 1734, 1635, 1427, 1111, 702
cm−1; HRMS (CI/NH3) m/z calcd for C44H56IN3O7NaSi [M + Na]+
916.2830, found 916.2800.
virginiamycin M2 (13S)-9: [α]20 −31.5 (c = 0.7, CH2Cl2); 1H
D
NMR (500 MHz, CDCl3) δ 8.09 (s, 1H), 7.63 (m, 4H), 7.33 (m, 6H),
6.38 (dd, J = 16.0, 3.0 Hz, 1H), 6.01 (d, J = 15.0 Hz, 1H), 5.93 (m,
1H), 5.75 (d, J = 9.5 Hz, 1H), 5.71 (d, J = 16.0 Hz, 1H), 5.47 (m, 1H),
4.84 (m, 1H), 4.60−4.67 (m, 2H), 4.54 (m, 1H), 4.47 (m, 1H), 3.62−
3.67 (m, 2H), 3.22 (m, 1H), 3.08 (d, J = 17.5 Hz, 1H), 2.80 (dd, J =
17.0, 10 Hz, 1H), 2.73 (m, 1H), 2.20 (d, J = 13.0 Hz, 1H), 1.93−2.08
(m, 3H), 1.45−1.75 (m, 3H), 1.07 (s, 9H), 1.00−1.04 (m, 9H), 0.95
(d, J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 172.6, 167.1,
161.1, 160.3, 144.3, 143.3, 136.9, 136.6, 135.9, 135.8, 132.9, 132.6,
132.4, 132.3, 130.0, 130.0, 127.8, 127.5, 124.8, 123.8, 81.4, 70.9, 66.8,
59.2, 48.0, 42.7, 41.6, 36.8, 35.0, 29.3, 28.1, 26.9, 25.6, 19.9, 19.1, 18.5,
11.8, 9.0 ppm; IR (thin film) νmax 3312, 3070, 2960, 2928, 2856, 1742,
1670, 1624, 1428, 1183, 1111, 703 cm−1; HRMS (CI/NH3) m/z calcd
for C44H57N3O7NaSi [M + Na]+ 790.3863, found 790.3853. (13R)-
13-Hydroxy-11-O-(tert-butyldiphenylsilyl) virginiamycin M2 (13R)-
(2R)-Benzyl 1-(2-(4-(tert-Butyldimethylsilyloxy)-2-
hydroxybutyl)oxazole-4-carbonyl)pyrrolidine-2-carboxy-
late (47) and (R)-Benzyl 1-(2-Methyloxazole-4-carbonyl)-
pyrrolidine-2-carboxylate (48). Iodide 46 (44 mg, 0.1 mmol,
1 equiv) and aldehyde 21 (19 mg, 0.1 mmol, 1 equiv) were placed into
a flame-dried round-bottom flask. Dry benzene (10 mL, 0.01 M) was
then added into the flask. Freshly prepared SmI2 THF solution
(0.15 M solution, 2.6 mL, 0.4 mmol, 4 equiv) was introduced by the
syringe within 5 min to the stirred solution. After being stirred for
another 20 min at rt, the reaction was quenched by bubbling in air,
followed by the addition of saturated NH4Cl aqueous solution (10 mL),
and stirring for another 15 min. The biphasic mixture was separated,
and the aqueous phase was extracted with diethyl ether (3 × 10 mL).
The combined organic phases were dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography (silica gel, 20−40% EtOAc/hexane) to afford
alcohol 47 (40 mg, 80% yield) as 1:1 diastereomers and the reduced
20
1
9: [α]D −41.0 (c = 0.6, CH2Cl2); H NMR (500 MHz, CDCl3)
δ 8.10 (s, 1H), 7.63 (m, 4H), 7.35 (m, 6H), 6.44 (dd, J = 16.5, 4.0 Hz,
1H), 6.02 (d, J = 15.5 Hz, 1H), 5.86 (d, J = 6.5 Hz, 1H), 5.75 (dd, J =
16.5, 2.0 Hz, 1H), 5.45 (m, 1H), 5.39 (d, J = 9.5 Hz, 1H), 4.72−4.80
(m, 3H), 4.50 (m, 1H), 4.13 (m, 1H), 3.94 (m, 1H), 3.78 (m, 1H),
3.30 (m, 1H), 2.71−2.82 (m, 3H), 2.60 (br, 1H), 1.82−2.08 (m, 5H),
1.61−1.71 (m, 2H), 1.05 (s, 3H), 1.03 (s, 9H), 0.87−0.95 (m, 9H);
13C NMR (75 MHz, CDCl3) δ 171.6, 166.4, 162.3, 160.2, 144.7, 143.8,
143.4, 136.9, 135.9, 135.8, 134.8, 134.0, 133.8, 133.1, 129.7, 129.6,
127.6, 127.4, 124.4, 123.8, 81.1, 68.8, 67.3, 59.2, 48.5, 43.5, 41.5, 36.6,
35.6, 29.3, 28.1, 26.9, 24.8, 19.8, 19.2, 18.6, 12.6, 10.1 ppm; IR (thin
film) νmax 3312, 3070, 2960, 2928, 2856, 1742, 1670, 1624, 1428, 1183,
1111, 703 cm−1; HRMS (CI/NH3) m/z calcd for C44H57N3O7NaSi
[M + Na]+ 790.3863, found 790.3853.
1
byproduct 48 (3.5 mg, 11% yield). 47: H NMR (400 MHz, CDCl3)
δ 8.14* (s, 1H), 8.11** (s, 1H), 7.29 (m, 5H), 5.33* (m, 1H), 5.12
(m, 2H), 4.66** (m, 1H), 4.28* (m, 1H), 4.20** (m, 1H), 4.09 (m,
1H), 3.77 (m, 3H), 2.94 (m, 1H), 2.74 (m, 1H), 2.26 (m, 1H), 2.17
(m, 1H), 1.97 (m, 1H), 1.86 (m, 1H), 1.74 (m, 1H), 1.65 (m, 1H),
0.86 (m, 9H), 0.04 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 173.7,
171.9, 161.9*, 161.9**, 160.3*, 160.3**, 143.4*, 143.3**, 136.8*,
136.8**, 135.7*, 135.5**, 128.5, 128.1, 68.7*, 68.1**, 66.8*, 66.7**,
61.5*, 61.4**, 60.7*, 60.5**, 48.7*, 47.5**, 38.1*, 37.9**, 35.7*,
35.7**, 31.7**, 28.5*, 25.8, 25.2*, 21.8**, 18.1, −5.5, −5.5 ppm; IR
(thin film) νmax 3428, 2954, 2856, 1747, 1617, 1436, 1170, 1093,
836 cm−1; HRMS (CI/NH3) m/z calcd for C26H38N2O6SiNa [M +
11-O-(tert-Butyldiphenylsilyl)virginiamycin M2 (51). In a
flame-dried round-bottom flask, TFAA (14.0 μL, 0.1 mmol, 5 equiv)
in CH2Cl2 (1 mL) was cooled to −78 °C. DMSO (14.2 μL, 0.2 mmol,
10 equiv) was added, and the solution was stirred at −78 °C for 20
min. Alcohol 9 (15 mg, 0.02 mmol, 1 equiv) in CH2Cl2 (0.5 mL) was
added into the solution by the syringe. The reaction was warmed
to −45 °C gradually in 30 min. Then the reaction was cooled to −60
°C. Acetylacetone (10 μL) and Et3N (50 μL, 0.36 mmol, 18 equiv) was
added, and the reaction was stirred at −60 °C for 30 min and warmed
to −35 °C gradually. The reaction was quenched by adding water
(1 mL) and warmed to rt. Saturated aqueous NH4Cl solution was
carefully added to adjust the aqueous phase to neutral. The biphasic
mixture was separated, and the aqueous phase was extracted with
EtOAc (3 × 3 mL). The combined organic phase were dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by preparative thin layer chromatography in the
dark, using 80% EtOAc/hexane as developing solvent. The product
band was eluted with EtOAc (5 × 1 mL), and the EtOAc was
1
Na]+ 525.2397, found 525.2379. 48: H NMR (400 MHz, CDCl3)
δ 8.09** (s, 1H), 8.06* (s, 1H), 7.30 (m, 5H), 5.32* (dd, J = 8.8,
3.2 Hz, 1H), 5.16 (m, 2H), 4.66** (dd, J = 9.2, 4.4 Hz, 1H), 4.07
(m,1H), 3.80* (m, 1H), 3.70** (m, 1H), 2.45** (s, 3H), 2.21 (m,
1H), 2.20* (s, 3H), 1.82−2.06 (m, 3H); 13C NMR (75 MHz, CDCl3)
δ 172.6, 171.9, 160.7**, 160.6*, 160.6*, 160.4**, 143.3*, 143.2**,
136.9*, 136.8**, 135.8**, 135.7*, 128.5, 128.2, 66.9, 59.7*, 59.8**,
48.7*, 47.4**, 31.6**, 28.5*, 25.8*, 21.8**, 13.7*, 13.6** ppm; IR
(thin film) νmax 3447, 2956, 1745, 1628, 1588, 1426, 1174, 1112,
751 cm−1; HRMS (CI/NH3) m/z calcd for C17H18N2O4Na [M + Na]+
337.1164, found 337.1166.
13-Hydroxy-11-O-(tert-butyldiphenylsilyl)virginiamycin M2
(9). Newly made SmI2 in THF solution was prepared as follows:
C2H4I2 (freshly purified white crystal, 564 mg, 2 mmol) and Sm0
powder (330 mg, 2.2 mmol) was placed in a flame-dried round-bottom
flask and purged with argon three times. Degassed, dry THF (10 mL)
was added, and this mixture was stirred in the dark for 8 h to afford
approximate 0.15 M SmI2 THF solution (titrated with 0.05 M iodine
THF solution before using.) Chloride 10 (40 mg, 0.05 mmol, 1 equiv)
was placed into a flame-dried round-bottom flask and purged with
argon three times. Degassed dry benzene (25 mL, 0.002 M) was then
evaporated to obtain product 51 (12 mg, 84% yield) as a glassy solid:
1
[α]20 −22.0 (c = 0.7, CH2Cl2); H NMR (500 MHz, CDCl3) δ 7.88
D
(s, 1H), 7.59 (m, 4H), 7.36 (m, 6H), 6.77 (d, J = 6.0 Hz, 1H), 6.41
(dd, J = 16.5, 5.5 Hz, 1H), 5.94 (d, J = 15.5 Hz, 1H), 5.78 (dd, J =
16.0, 1.5 Hz, 1H), 5.51 (m, 1H), 5.21 (d, J = 9.0 Hz, 1H), 4.90 (m,
1H), 4.74 (dd, J = 15.0, 2.5 Hz, 1H), 4.69 (dd, J = 9.0, 4.0 Hz, 1H),
4.49 (m, 1H), 3.92 (m, 1H), 3.81 (d, J = 15.0 Hz, 1H), 3.69 (m, 1H),
3.58 (d, J = 15.0 Hz, 1H), 3.34 (m, 1H), 2.97 (dd, J = 15.0, 9.0 Hz,
1H), 2.68−2.74 (m, 2H), 2.25 (m, 1H), 1.92 (m, 4H), 1.20 (d, J =
1.0 Hz, 3H), 1.03 (s, 9H), 0.99 (d, J = 7.0 Hz, 3H), 0.95 (d, J = 6.5 Hz,
1H); 13C NMR (75 MHz,CDCl3) δ 199.5, 171.6, 166.8, 160.8, 156.4,
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143.7, 143.6, 137.6, 136.7, 135.8, 135.7, 133.7, 133.6, 133.4, 133.0,
129.7, 129.6, 127.6, 127.5, 124.9, 124.7, 81.3, 66.6, 59.8, 50.2, 48.5,
44.0, 40.8, 36.6, 29.7, 28.4, 26.8, 25.0, 19.7, 19.1, 18.8, 12.3, 11.1 ppm;
IR (thin film) νmax 3308, 3070, 2962, 2930, 2856, 1733, 1672, 1628,
1428, 1183, 1111, 703 cm−1; HRMS (CI/NH3) m/z calcd for
C44H55N3O7NaSi [M + Na]+ 788.3707, found 788.3694.
Uguen, D. Tetrahedron Lett. 1998, 39, 3149−3152. For formal
syntheses of virginiamycin M2, see: (c) Mortensen, M. S.; Osbourn, J. S.;
O’Doherty, G. A. Org. Lett. 2007, 9, 3105−3108. (d) Wang, Y.; Xing, Y.;
Zhang, Q.; O’Doherty, G. A. Chem. Commun. 2011, 47, 8493−8505.
For total syntheses of related type A virginiamycin natural products, see:
(e) Tavares, F.; Lawson, J. P.; Meyers, A. I. J. Am. Chem. Soc. 1996, 118,
3303−3304. (f) Ghosh, A. K.; Liu, W. J. Org. Chem. 1997, 62, 7908−
7909. (g) Entwistle, D. A.; Jordan, S. I.; Montgomery, J.; Pattenden, G.
Synthesis 1998, 603−612. (h) Dvorak, C. A.; Schmitz, W. D.; Poon, D. J.;
Pryde, D. C.; Lawson, J. P.; Amos, R. A.; Meyers, A. I. Angew. Chem., Int.
Ed. 2000, 39, 1664−1666.
(−)-Virginiamycin M2 (1). To ketone 51 (12 mg, 0.016 mmol,
1 equiv) in CH2Cl2 (0.2 mL) at rt was added HF·2pyridine (3.5 N in
CH2Cl2, 90 μL, 20 equiv). The resulting mixture was stirred at rt for
more than 36 h (monitored by TLC). The reaction mixture was
diluted with CH2Cl2 (2 mL), cooled to 0 °C, and then quenched
carefully with 5% aqueous NaHCO3 solution (1 mL). The organic
layer was separated, and the aqueous layer was extracted with EtOAc
(3 × 2 mL). The combined organic layer was dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by preparative thin layer chromatography, using EtOAc as
developing solvent. The product band was removed with EtOAc (5 ×
1 mL), and the EtOAc was evaporated to obtain the natural product
̀
(5) (a) Barriere, J. C.; Paris, J. M. Drugs Future 1993, 18, 833.
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Expert Opin. Invest. Drugs 1994, 3, 115−131.
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(1) (6 mg, 70% yield) as a white glassy solid: [α]20 −35.0 (c = 0.4,
D
(8) Portions of these results have been published in the following
communications: (a) Wu., J.; Chen, Y.; Panek, J. S. Org. Lett. 2010, 12,
2112−2115. (b) Wu, J.; Panek, J. S. Angew. Chem., Int. Ed. 2010, 49,
6165−6168.
1
CH2Cl2); H NMR (500 MHz, CDCl3) δ 8.07 (s, 1H), 6.46 (dd, J =
16.5, 5.0 Hz, 1H), 6.31 (br, 1H), 6.10 (d, J = 15.0 Hz, 1H), 5.76 (dd,
J = 16.5, 2.0 Hz, 1H), 5.66 (m, 1H), 5.39 (d, J = 9.0 Hz, 1H), 4.89 (m,
1H), 4.72 (dd, J = 10.0, 2.0 Hz, 1H), 4.67 (dd, J = 9.0, 3.5 Hz, 1H),
4.43 (m, 1H), 3.97 (m, 1H), 3.81 (s, 2H), 3.71 (m, 1H), 3.38 (m, 1H),
3.03 (dd, J = 17.0, 6.0 Hz, 1H), 2.87 (dd, J = 17.0, 5.5 Hz, 1H), 2.72
(m, 1H), 2.43 (br, 1H), 2.16 (m, 1H), 1.87−1.95 (m, 3H), 1.83 (m,
1H), 1.70 (s, 3H), 1.02 (d, J = 7.0 Hz, 3H), 0.97 (d, J = 6.0 Hz, 3H),
0.93 (d, J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 202.4, 171.7,
166.8, 160.2, 156.8, 144.4, 144.1, 137.1, 136.9, 134.4, 132.5, 125.4,
124.2, 81.5, 65.3, 59.7, 48.8, 48.4, 43.2, 41.0, 36.7, 29.5, 38.4, 25.1,
19.8, 18.7, 12.7, 10.2 ppm; IR (thin film) νmax 3329, 2924, 1736, 1670,
1621, 1441, 1183, 1110, 986 cm−1; HRMS (CI/NH3) m/z calcd for
C28H37N3O7Na [M + Na]+ 550.2529, found 550.2515.
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(18) Screened solvents include THF, MeCN, benzene, toluene,
diethyl ether, fluorobenzene, dioxolane, DME, xylene, hexane, and
dioxane; see the Supporting Information.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: panek@bu.edu.
■
ACKNOWLEDGMENTS
■
Financial support was obtained from NIH CA 53604. We are
grateful to Dr. Baptiste Ronan at Sanofi-Aventis for a
1
comparison of H NMR spectra of compound 9, Professor
Corey R. J. Stephenson at Boston University, Dr. Yu Chen, Dr.
Yun Zhang, and Dr. Jason T. Lowe for helpful discussions, and
Dr. Paul Ralifo and Dr. Norman Lee for assistance with NMR
and HRMS measurements.
REFERENCES
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