Evolution of a protecting-group-free total synthesis: Studies en route to the neuroactive marine macrolide (-)-palmyrolide A

Article abstract of DOI:10.1021/jo301121f

A full account of our synthetic work toward the first total synthesis of the neuroactive marine macrolide (-)-palmyrolide A is described. Our first-generation approach aimed to unlock the unknown C(5)-C(7) stereochemical relationship via the synthesis of

Full text of DOI:10.1021/jo301121f

Article
pubs.acs.org/joc
Evolution of a Protecting-Group-Free Total Synthesis: Studies en
Route to the Neuroactive Marine Macrolide (−)-Palmyrolide A
Rodolfo Tello-Aburto, Tara D. Newar, and William A. Maio*
Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, New Mexico 88003, United States
S
* Supporting Information
ABSTRACT: A full account of our synthetic work toward the first
total synthesis of the neuroactive marine macrolide (−)-palmyrolide A
is described. Our first-generation approach aimed to unlock the
unknown C(5)−C(7) stereochemical relationship via the synthesis of
four diastereomers of palmyrolide A aldehyde, a known degradation
product. When these efforts provided inconclusive results, recourse to
synthesizing all possible stereocombinations of the 15-membered
macrolide was undertaken. These studies were critical in confirming
the absolute stereochemistry, yielding the first total synthesis of
(+)-ent-palmyrolide A. Subsequent to this work, the first protecting-
group-free total synthesis of natural (−)-palmyrolide A is also
reported.
confirmed by total synthesis.4 It should be noted that, for
INTRODUCTION
In 2010, Gerwick and co-workers reported the isolation and
■
apratoxin, (1) the relative stereochemistry between its C(37)
5
a
structural elucidation of palmyrolide A [(−)-1],1 a neuroactive
macrolide found in a cyanobacterial assemblage composed of
Leptolyngbya and Oscillatoria species collected in the Northern
Pacific at Palmyra Atoll. Initial biological studies revealed 1 to be
a potent inhibitor of calcium ion oscillations in murine
cerebrocortical neurons and to possess a sodium ion channel
blocking ability in neuroblastoma cells.1 Importantly, (−)-pal-
myrolide A displays no appreciable cytotoxicity when screened
against human lung adenocarcinoma cells.1
methyl and C(39) tert-butyl is anti, and (2) this stereochemical
relationship was first proposed employing the Murata J-based
configurational analysis on the macrocycle, and later confirmed
by total synthesis.
N-Methyl enamide macrocycles3b−d are exceedingly rare in the
natural product literature, with few reported examples; until
recently,6 none have been confirmed by total synthesis. Of note,
these compounds all contain a tert-butyl group α to the lactone
ester within their molecular framework and are likely derived
from the same genus of cyanobacteria. A related family of
macrolides possesses an N-H enamide,7 although with cis-olefin
geometry. Several other compounds have side chains decorated
with N-H enamides;8 however, to the best of our knowledge,
only one class features an N-methyl enamide subunit.8f
The connectivity of (−)-palmyrolide A was determined by
detailed NMR studies.1 However, as a result of the increased
hydrolytic stability imparted to the lactone due to the
neighboring tert-butyl group, the authors were unable to degrade
the macrolide into acyclic fragments that would prove useful in
determining the absolute stereochemistry. As a result, the Murata
J-based configurational analysis2 was applied to the 15-
membered macrocycle in order to determine the relative
stereochemistry between the C(5) methyl and the C(7) tert-
butyl centers. This data, in conjunction with NOE correlations,
suggested that the relationship between C(5) and C(7) was syn.
An important detail to emerge from these degradation/
hydrolysis studies is that the authors were able to induce ring-
opening of the macrolide to yield palmyrolide A aldehyde (cf. 2
or 3, Scheme 1).1
We became interested in (−)-palmyrolide A as a synthetic
target not only because of its interesting biological profile but
also due to the presence of two unique structural elements: the
rare tert-butyl moiety and the trans-N-methyl enamide. A search
of the literature reveals few examples of isolated natural products
that contain a sterically encumbered tert-butyl group α to the
lactone ester,3 with (−)-apratoxin A3a being the sole example
Because of the uncertainty regarding the absolute config-
uration of palmyrolide A, at the outset of our synthetic campaign,
we decided to target all possible C(5)−C(7) diastereomeric
combinations. While Gerwick identified the relative config-
uration between the C(5) methyl and the C(7) tert-butyl to be
syn, based on the apratoxin A literature,3a,4 we believed that the
relationship between these two groups could also be anti. During
the design of our first-generation synthetic route, and after noting
the scant literature references regarding the formation of
enamide-containing macrocycles,9 we sought to first determine
the unknown absolute stereochemistry of 1 by synthesizing all
possible diastereocombinations of palmyrolide A aldehyde, a
compound we believed to be an easier to achieve subgoal, and
whose three stereocenters were anticipated to be identical to the
Received: May 31, 2012
Published: June 21, 2012
© 2012 American Chemical Society
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Scheme 1. Stereochemical Combinations of Natural Palmyrolide A Aldehyde
Scheme 2. Retrosynthetic Analysis
Scheme 3. Divergent Syntheses of Fragments 4 and 5
macrolide. Once the correct stereochemistry had been assigned,
our plan was to then target only the N-methyl enamide
macrocycle that would correspond to the correct structure of
palmyrolide A.
we used it to our advantage in planning a unique synthetic
strategy aimed to target the different stereocombinations
concurrently. Rather than design our synthesis around the
known C(14) center, we thought that a more economical
approach would be to target only one C(5)−C(7) syn
enantiomer and one C(5)−C(7) anti enantiomer, and then
pair each of these with the two stereochemical combinations of
the C(14) methyl. In this way, we would utilize a common
fragment for each series (cf. 4 and 5) to gain access to all four
RESULTS AND DISCUSSION
■
Aldehyde Studies. In the isolation report, the absolute
stereochemistry of the C(14)5b methyl group was unequivocally
assigned to be in the R configuration.1 This is a critical point, and
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Scheme 4. Synthesis of Acids 6a and 6b
possible diastereomeric combinations of palmyrolide A aldehyde
(cf. 2a, ent-2b, 3a, ent-3b, Scheme 2), representing one seco-
aldehyde from each enantiomeric set. We chose to set C(7) in
the (S) arrangement to coincide with the absolute stereo-
chemistry found in an analogous position in apratoxin A.
For the syntheses of fragments 4 and 5, we relied on elegant
chemistry developed by Cavelier and co-workers10 during their
recent synthesis of oxoapratoxin, an oxazoline analogue of
apratoxin A. The syntheses of fragments 4 and 5 commenced
with a D-proline-catalyzed asymmetric aldol union between
pivaldehyde and acetone to furnish β-hydroxy ketone (−)-7,
following the known literature account (Scheme 3).10 This
reaction was critical in establishing the C(7) tert-butyl stereo-
center and is the point at which the synthesis of the syn
diastereomer diverged from the anti.
the benzoyl ester, followed by sulfite formation and oxidation,
provided anti-cyclic sulfate (+)-10 in comparable yield to (−)-8
(Scheme 3).
Nucleophilic ring-opening of the syn-cyclic sulfate using a
mixed organometallic reagent derived from allylmagnesium
chloride and copper(I) iodide has already been documented to
occur at the least-hindered site,10 resulting in complete inversion
of configuration at that center. During our first-generation
synthesis, we found that a Grignard derived from commercially
available benzyl-4-bromobutyl ether, using copper(I) iodide as
catalyst, could also serve as an efficient nucleophile in this
process. Pleasingly, ring-opening and subsequent hydrogenolysis
of syn-(−)-8 occurred in good overall yield and provided anti-diol
(−)-9 as a single diastereomer (Scheme 3).
We believed that nucleophilic ring-opening of anti-(+)-10
using the same mixed organometallic species would likewise
produce the analogous syn-alcohol; however, there have been no
literature reports of such a reaction. In the event, ring-opening,
followed by hydrogenolysis, led to the formation of syn-diol
(−)-11 as a single regioisomer and in >99% diastereoselectivity
(Scheme 3). We believe this to be the first example of the
nucleophilic ring-opening of an anti-1,3-cyclic sulfate.
At this stage, the chemistry employed for the construction of
either amide 4 or 5 was the same for both the syn and the anti
series. Chemoselective oxidation of the primary alcohol with
TEMPO/PhI(OAc)2,17 followed by Pinnick (Lindgren−
Kraus)18 oxidation, obviated the need for excessive protecting
group manipulations, and afforded both carboxylic acids in good
yield (Scheme 3). In the final step, each acid was separately
transformed into the respective secondary amide [cf. (−)-5 and
(−)-4, Scheme 3] via treatment with methylamine and EDCI/
HOBt. Amide formation proceeded smoothly and occurred with
no lactone byproduct formation resulting from the undesired
nucleophilic attack of the pendant alcohol on the activated
carbonyl eight atoms away. We believe this to be due to (1)
sterics surrounding the alcohol as a result of the neighboring tert-
butyl group and (2) the enhanced nucleophilicity of methyl-
amine compared to the secondary alcohol. Of note, the only
protecting group employed during the synthesis of fragments
In the Cavelier studies,10 stereoselective syn reduction of
(−)-7 was affected using diethylmethoxyborane/NaBH4,11
which provided an acceptable mixture of syn and anti
diastereomers (95:5). Unfortunately, in our hands, this reduction
strategy did not yield a synthetically workable mixture of isomers.
Chromatographic separation also proved difficult. Pleasingly,
recourse to the stereoselective Kiyooka reduction using 2.5 equiv
of DIBAl-H12 provided the requisite diol in excellent yield and
high diastereoselectivity (Scheme 3). This modification also
obviated the need for a challenging silica gel purification step.
Next, in two synthetic operations involving (1) treatment with
thionyl chloride in pyridine and (2) oxidation using RuO4,13 the
syn-diol was easily converted into syn-cyclic sulfate (−)-8 in good
overall yield.
To synthesize anti-cyclic sulfate (+)-10, we relied on the
Evans−Tishchenko reduction14 using freshly prepared
samarium(II) iodide in THF,15 which provided the requisite
anti-diol stereochemistry in greater than 99% diastereoselectivity.
Unfortunately, the one-step Evans tetramethylammonium
triacetoxyborohydride [Me4NHB(OAc)3] method16 produced
diastereomeric mixtures that were difficult to separate (vide
supra). The Evans−Tishchenko reduction, while necessitating an
extra synthetic operation (i.e., hydrolysis), was useful in
providing high yields of the anti-diol precursor. Hydrolysis of
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Scheme 5. Synthesis of All Four Diastereomeric Combinations of Palmyrolide A Aldehyde
(−)-4 and (−)-5 was the benzyl ether required during the ring-
opening operation.
separately with acid (−)-6a and then with acid (+)-6b (Scheme
5). We found this to be readily achieved by first forming
anhydrides via premixing each acid with 2,4,6-trichlorobenzoyl
chloride (the Yamaguchi reagent),21 and then adding these to
their respective alcohol coupling partners (Scheme 5). In this
way, we were able to manufacture amides (−)-16a/(−)-ent-16b
and (−)-17a/(−)-ent-17b (Scheme 5). For the conversion to
seco-aldehydes, each amide was separately treated with DDQ/
H2O, followed by alcohol oxidation with the Dess−Martin
periodinane22 (Scheme 5). Using this route, we were able to
synthesize the two C(5)−C(7) syn combinations [cf. (−)-2a and
(−)-ent-2b], and the two C(5)−C(7) anti [cf. (−)-3a and
(−)-ent-3b], representing one aldehyde from each enantiomeric
set.
We next turned our attention to the synthesis of enantiomer
acids 6a and 6b (Scheme 4); each could be easily prepared
relying on the Myers pseudoephedrine method19 to install the
requisite stereochemistry at what will become the C(14) site.
Commercially available alcohol 12 was first protected as a p-
methoxybenzyl ether20 and then saponified to yield acid 1320b
(Scheme 4). Treatment with oxalyl chloride, followed by (R,R)-
pseudoephedrine, led to amide (−)-14, which could be
selectively alkylated with iodomethane and hydrolyzed to
produce acid (−)-6a in good yield and in high enantioselectivity.
In a similar manner, 13 could be converted to the acid chloride,
reacted with (S,S)-pseudoephedrine and the resultant amide
[(+)-15] subjected to the same alkylation/hydrolysis protocol to
produce acid (+)-6b (Scheme 4). It is also possible to synthesize
amide (−)-14 directly from the PMB-protected ethyl ester.
Direct displacement using the disodium salt of (R,R)-
pseudoephedrine gave the desired product in 73% yield. While
this yield is higher, it required the use of 2 equiv of the PMB-
protected version of 12, a compound that was difficult to
manufacture in pure form. The two-step method [(1)
saponification, (2) i. acid chloride formation, ii. addition of
(R,R)-pseudoephedrine], while time-consuming, allowed us to
conserve precious starting material with only a modest loss in
yield (∼25% overall).
As each aldehyde was synthesized, we compared its 1H NMR
spectrum with the authentic palmyrolide A aldehyde spectrum
reported by Gerwick.1 An examination of the spectra showed that
the synthetic C(5)−C(7) syn-aldehydes had major discrepancies
with the reported aldehyde spectrum; the C(5)−C(7) anti series
were a closer match. On the basis of this data, we believed that the
relative stereochemistry between C(5) and C(7) could, in fact,
be anti, contrary to the studies documented in the isolation
report.1 To distinguish between the two anti-aldehydes, which
were very similar by 1H NMR, we considered the J-coupling data
for the C(7)−H. In the Gerwick report, this proton is split into a
doublet of doublets with coupling constants of 2.2 and 9.8 Hz.
The J values of aldehyde (−)-3a are 2.7 and 9.3 Hz; (−)-ent-3b
has coupling constants of 3.6 and 8.4 Hz.
We now had the necessary fragments in hand to assemble the
four diastereomeric combinations of palmyrolide A aldehyde.
This required the combination of alcohols (−)-4 and (−)-5
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The chemical shift information, in conjunction with the
coupling data, seemed to suggest that aldehyde (−)-3a was the
best fit to the literature values. However, we were not confident
that it was a close enough match to claim we had solved the
stereochemical issue.23 We were encouraged that, for (−)-3a, the
C(14)-methyl was in the R configuration, matching what
Gerwick determined in the isolation report,1 and the stereo-
chemistry at C(5) and C(7) matched the absolute stereo-
chemistry found in apratoxin A.3a,4 However, rather than risk
assigning the absolute stereochemistry of palmyrolide A based on
these data, we decided it would be in our best interest to
unambiguously determine the stereochemistry via synthesis of
the macrolide corresponding to aldehyde (−)-3a.
Cyclization Studies 1. After attempts at a dehydrative
cyclization of (−)-3a,24 we next sought to transform the aldehyde
into a trans-vinyl triflate, which we believed would be an optimal
coupling partner with the pendant secondary amide. Unfortu-
nately, efforts to form the vinyl triflate, using known methods,25
only resulted in the complete decomposition of starting material.
When these studies did not prove feasible, a redesign of the ring-
closing strategy was undertaken.
ruthenium−vinylidene species before migration of the amide
occurs, followed by reductive elimination. We believe that
formation of the vinyl ruthenium or the vinylidene intermediate
in our cyclic system may require too high a strain barrier. This
may be the reason we observed no desired macrolide product.
We then turned our attention to the possible union of the
secondary amide with a pendant vinyl iodide coupling partner
(cf. 20, Scheme 6). This strategy would call upon a metal-
catalyzed process to unite the vinyl iodide with the amide.
Unfortunately, when we treated vinyl iodide 20 under palladium-
catalyzed conditions,27 using Pd(dba)3/t-bu-XPhos,27b no
cyclization occurred. The failure in this process may be due to
the methyl substituent on the reacting nitrogen of the amide.
While N-methyl amides have been documented to be competent
coupling partners for Pd-catalyzed C−N bond forming
processes,27 primary amides are superior when using copper
catalysis. Therefore, we decided to synthesize the corresponding
vinyl iodide/primary amide macrocyclization precursor and
attempt a copper-promoted strategy, similar to a method
recently reported by Evano and co-workers.9c This route proved
successful (vide infra).
Our first thought was that cyclization to form the trans-N-
methyl enamide could be affected exploiting an intramolecular
version of the well-studied Goossen ruthenium-catalyzed
conditions26 to unite a secondary amide with a terminal alkyne.
Unfortunately, when we synthesized alkyne 19, and treated it
with the optimized reaction conditions, using [Ru-
(methallyl)2(COD)] as catalyst,26a no macrolide product was
observed (Scheme 6). According to Goossen, the mechanism for
Cyclization Studies 2. After the disappointing attempts at
enamide formation, we turned our attention to the production of
a primary amide-containing macrocyclization precursor (cf. 21a,
Scheme 7). This strategy would require the synthesis of amide
24, a compound similar to (−)-5, differing only in substitution at
the amide nitrogen (Scheme 8). The synthesis of this fragment
was straightforward and made use of the Cavelier precedent10 for
the construction of TES-protected alcohol (−)-23 from syn-
cyclic sulfate (−)-8. We chose to switch from 4-benzyloxybu-
tylmagnesium bromide (Scheme 3) to allylmagnesium bromide
(Scheme 8) because this approach would potentially shave off
one linear operation from the overall synthetic route
(deprotection). Cross metathesis of (−)-23 with freshly distilled
acryloyl chloride employing the Hoveyda−Grubbs II precata-
lyst,28 followed by in situ addition of ammonium hydroxide,
allowed access to the α,β-unsaturated primary amide in 58%
yield.29 This product was easily converted to amide alcohol
(−)-24 via hydrogenation, which occurred, due to solvent effects,
with concomitant loss of the labile triethylsilyl group30 (Scheme
8).
Scheme 6. Retrosynthetic Analysis of Our First-Generation
Cyclization Studies
With the necessary fragment in hand [(−)-24], we turned our
attention to the construction of vinyl iodide 28 (Scheme 9). The
synthesis began employing known alcohol 25, produced in three
literature operations from commercially available 3-butyn-1-ol.31
Alcohol-to-iodide interconversion proceeded in high yield, and
the resultant diiodide (26) was used in the Myers alkylation19
the amide/alkyne union is proposed to involve the oxidative
addition of the amide nitrogen onto the metal, followed by
insertion of the alkyne and subsequent formation of a vinyl−
ruthenium complex. This intermediate rearranges into a
Scheme 7. Retrosynthetic Analysis of Our Second-Generation Cyclization Studies
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Scheme 8. Synthesis of the C(5)−C(7) anti Primary Amide
Scheme 9. Synthesis of Vinyl Iodide 28
with (S,S)-propionamide (27a), which produced the desired
product in good yield and high diastereoselectivity (>20:1 by 1H
NMR). Subsequent hydrolysis with NaOH provided acid
(−)-28a with negligible loss of stereopurity, and complete
preservation of the trans-vinyl iodide unit.32
workers during their recent synthesis of the 13-membered
cyclopeptide paliurine F.9c Even though paliurine F features a cis-
N-H enamide, we believed that these optimized conditions could
also be used for the construction of a trans-N-H enamide within
the larger macrocycle of palmyrolide A. Formation of the 15-
membered macrocycle, using a high-dilution modification (0.01
M) to coupling conditions developed by Buchwald,36 afforded
the trans-N-H enamide product in modest yield and as a mixture
of rotational isomers. In the final step, treatment with sodium
hydride, followed by N-alkylation with iodomethane,26c provided
trans-N-methyl enamide (+)-21a in excellent yield (Scheme 11).
A comparison with the reported spectra of palmyrolide A was
made. Compound (+)-21a, featuring the natural C(14)-R
stereochemistry, did not match the literature values reported
by Gerwick for the 15-membered macrolide.1 This was a
suprising result, especially since this macrolide stereochemistry
corresponded directly with aldehyde (−)-3a, which seemed to be
the best fit of the Gerwick aldehyde data (vide supra).
Undeterred, we decided to quickly invert the stereochemistry
at C(14) and manufactured the macrolide that would correspond
to aldehyde (−)-ent-3b. This was accomplished via (1) synthesis
of vinyl iodide (+)-28b exploiting the Myers alkylation, (2)
joining this fragment with anti-(−)-24, and then subjecting the
resultant amide [(−)-32] to the same end game protocol as was
employed for (+)-21a (Scheme 12). Pleasingly, there was a
complete 1H and 13C NMR match with macrolide (+)-ent-21b,
where the C(14) methyl group is inverted relative to the natural
macrolide. On the basis of the known configuration at this center,
this would mean that our palmyrolide should be enantiomeric to
the natural product: optical rotation comparison confirmed that
we had indeed synthesized the enantiomer of (−)-palmyrolide A,
Earlier attempts to manufacture iodide (−)-28a employed the
Evans oxazolidinone33 as a chiral auxiliary (cf. 29, Scheme 10).
Scheme 10. Unsuccessful Alkylation Attempts
Unfortunately, when 29 was treated with NaHMDS, followed by
diiodide 26, no reaction was observed (Scheme 10). When 26
was replaced by triflate 30,34 we did observe alkylation;35
however, the yield was low and the product obtained was
contaminated with a significant amount of starting material,
which could not be separated by silica gel chromatography
(Scheme 10).
Similar to our aldehyde studies (vide supra), union of amide
alcohol (−)-24 with (−)-28a, employing 2,4,6-trichlorobenzoyl
chloride as a coupling agent, provided vinyl iodide (−)-31 in
good yield (Scheme 11). For the critical macrocyclization step,
we relied on the intramolecular copper(I) iodide/Cs2CO3/N,N′-
dimethylethylenediamine conditions exploited by Evano and co-
Scheme 11. Synthesis of anti-Macrolide 21a
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Scheme 12. Synthesis of anti-Macrolide ent-21b
Scheme 13. Synthesis of the C(5)−C(7) syn Primary Amide
Scheme 14. Synthesis of Both C(5)−C(7) syn-Macrolides
(+)-ent-palmyrolide A {[α]D = +23 (c = 0.65, CHCl3), lit. [α]D =
−29 (c = 0.9, CHCl3)}.
These data reveal that the relative stereochemistry between the
C(5) methyl and C(7) tert-butyl centers is anti, and not syn, as
originally proposed by Gerwick.1,6 Also of interest, the absolute
stereochemistry between these two sites is enantiomeric to the
absolute stereochemistry found in an analogous location in
apratoxin A.3a,4
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While working on the C(5)−C(7) anti-macrolides, we were
also simultaneously synthesizing the C(5)−C(7) syn series (vide
infra). At the time, we were still uncertain if our aldehyde studies
had been correct in allowing us to assign the relative
stereochemistry as anti, especially in light of the Gerwick NOE
and J-based coupling analysis, which suggested a syn relationship.
The synthesis of the requisite C(5)−C(7) syn-amide (cf. 34) was
accomplished, utilizing similar chemistry as before (Scheme 13).
Once in hand, amide (−)-34 was separately joined with acids
(−)-28a and (+)-28b, and subjected to macrocyclization/N-
methyl formation, producing (−)-22a and (−)-ent-22b,
respectively (Scheme 14).
macrolide series. To test this hypothesis, a simple epimerization
experiment with concentrated HCl in methanol would
demonstrate how palmyrolide A aldehyde could invert the
stereochemistry at C(14). Unfortunately, after replicating the
same conditions found in the Gerwick account (6N HCl/
MeOH),1 we were not able to observe any evidence to suggest
that aldehyde ent-(−)-3b could convert into (−)-3a.
We now speculate that there may be a concentration
dependence giving rise to the minor anomalies observed via
NMR. Another explanation may be that some unknown impurity
in the authentic sample could produce a hydrogen-bonding effect
that would cause the molecule to twist in such a way as to alter the
chemical shift and coupling values slightly relative to our pure,
synthetic compounds.23 Unfortunately, at this stage, we do not
have strong evidence to support either argument. However, we
do know the absolute stereoidentities of the aldehydes prepared
via synthesis, and those formed via ring-opening at the enamide
site; neither are a perfect match to the Gerwick aldehyde data.
Second-Generation Synthesis. After the successful com-
pletion of the first phase of our work, namely, the determination
of the relative stereochemistry of palmyrolide A, we set out to
confirm the absolute stereochemistry via total synthesis of the
natural (−)-enantiomer. We also took this opportunity to
address two shortcomings of our initial route: the overall number
of steps and the low-yielding cross-metathesis processes.37
To manufacture the (−)-enantiomer of palmyrolide A, our
second-generation approach would exploit L-proline in the initial
organo-catalyzed asymmetric aldol union to set the stereo-
chemistry at the C(7) tert-butyl site as R (Scheme 16). Similar to
our earlier studies, stereoselective Kiyooka syn reduction of
(+)-ent-7 was affected using 2.5 equiv of DIBAl-H, which
provided the requisite diol in good yield and high diaster-
eoselectivity (Scheme16). The syn-cyclic sulfate [(+)-ent-8]
could be made in a similar fashion as (−)-8, and nucleophilic
ring-opening using the mixed organometallic reagent derived
from allylmagnesium chloride and copper(I) iodide was critical
in allowing access to the natural C(5)−C(7) anti-stereochemical
combination [cf. (+)-37, Scheme 16].
As anticipated, the C(5)−C(7) syn-macrolides did not match
the NMR data provided in the isolation report. The most
diagnostic peak was the C(7) methine proton: for natural
(−)-palmyrolide A, the chemical shift is δ 4.88 ppm and the
signal is split into a doublet of doublets with coupling constants
of 1.5 and 11.0 Hz. For (−)-22a, the value we observed was δ
4.79 ppm (J = 0.3, 9.9 Hz), and for the all-syn diastereomer,
(−)-ent-22b, the value was δ 4.86 ppm (J = 0.9, 10.2 Hz).
Stability Studies. After unambiguously determining the
relative and absolute stereochemistry of palmyrolide A, we were
still intrigued that our aldehyde spectra did not perfectly
correlate with the degradation spectrum reported by Gerwick.
Our studies seemed to suggest that the best match to the
macrolide would be the relative stereochemistry contained in
aldehyde (+)-3a; however, through total synthesis, we learned
that this did not map onto the natural macrolide stereochemistry.
Our initial thought was that the synthetic experiments employed
to set the absolute stereochemistry in our aldehyde series were
incorrect; this line of reasoning was quickly ruled out. Upon
sitting in aged chloroform overnight, the trans-N-methyl
enamide moiety rapidly hydrolyzes to the corresponding
aldehyde. A comparison of (−)-3a and ent-(−)-3b formed in
this manner (Scheme 15) to the corresponding aldehydes
prepared via synthesis (Scheme 5) revealed a perfect match in
each case, meaning our stereochemical assignments had been
sound.
We next decided to study the isolation report in greater detail.1
After close examination of the conditions used to degrade
palmyrolide A into palmyrolide A aldehyde, we reasoned that
ring-opening of natural palmyrolide A could also be accompanied
by epimerization at the C(14) site. In this way, we might be able
to argue the discrepancy observed between our aldehyde and
In our first-generation synthesis, the alcohol was protected as a
triethylsilyl-ether before cross-metathesis with acryloyl chloride
(Scheme 8). Wanting to obviate the need for any protecting
groups in our second-generation approach, we decided to
attempt cross-metathesis directly on alcohol (+)-37. This
strategy would be extremely difficult using acryloyl chloride, as
we anticipated that the free alcohol at C(7) would readily react
with the acid chloride that is employed in an excess amount. By
substituting acryloyl chloride with acrylamide, we would avoid
the possibility of alcohol protection and directly arrive at the
requisite amide product (cf. 38) in a single synthetic operation.
In the event, cross-metathesis between (+)-37 and acrylamide,
using the Grubbs II precatalyst (5 mol %) in dichloroethane at 70
°C, gave smooth conversion to the desired amide after 18 h;
however, the yield for this process was moderate (52%).
Regardless, this modification had allowed us to operate directly
on free alcohol (+)-37. Encouraged by this result, we decided to
employ copper(I) iodide as cocatalyst (2 mol % Grubbs II, 3 mol
% CuI, Scheme 16), calling upon the recently reported studies of
Lipshutz and co-workers.38 This modification was critical in
allowing us to lower the catalyst loading using a moderately
unreactive coupling partner (acrylamide) and achieve a high
yield of the desired amide product [cf. (+)-38, 83% isolated, 92%
Scheme 15. Trace-Acid-Catalyzed Ring-Opening
39
1
by H NMR] in only 3 h. To the best of our knowledge, we
believe this to be the first reported example of a cross-metathesis
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Scheme 16. Second-Generation Synthesis Applied to (−)-Palmyrolide A
raphy (TLC) was performed using plates precoated with silica gel 60 Å
F-254 (250 μm) and visualized by UV light, KMnO4, or anisaldehyde
stains, followed by heating. Silica gel (particle size = 40−63 μm) was
used for flash chromatography. 1H and 13C NMR spectra were recorded
at 300 and 75 MHz or at 400 and 100 MHz, respectively, and are
reported relative to residual solvent peak (δ 7.26 and δ 77.0 for 1H and
reaction using acrylamide under the modified Lipshutz CuI
conditions.40,41
Hydrogenation of (+)-38, followed by union of (+)-ent-24
with acid (−)-28a, led to the formation of macrocyclization
precursor (+)-ent-32, which was smoothly closed to the N-H
enamide using the modified Buchwald conditions.42 In the final
step, N-alkylation using sodium hydride/iodomethane allowed
access to the natural enantiomer, (−)-palmyrolide A {[α]D =
−27 (c = 0.86, CHCl3), lit. [α]D = −29 (c = 0.9, CHCl3)}. Of
signifigant note, this second-generation synthesis employs no
protecting groups43 and allows access to the desired macrolide in
only 10 linear steps, with 7% overall yield.
1
13C in CDCl3). Data for H NMR spectra are reported as follows:
chemical shift (δ ppm) (multiplicity, coupling constant (Hz),
integration). Spectra obtained are described using the following
abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet. IR samples were prepared by evaporation from CHCl3 or
CH2Cl2 on NaCl plates. High-resolution mass spectra were obtained
using positive electrospray ionization.
(S)-4-Hydroxy-5,5-dimethylhexan-2-one [(−)-7)]. (−)-7 was
prepared following the literature procedure of Cavelier and co-workers.
A screw-top flask was charged with pivaldehyde (5.89 mL, 54.3 mmol)
and D-proline (2.50 g, 21.7 mmol) dissolved in DMSO (183.0 mL) and
reagent grade acetone (51.0 mL). The reaction flask was then sealed, and
the mixture was allowed to stir for 5 days at room temperature before
being quenching with a half-saturated NH4Cl solution (100 mL). The
reaction mixture was then extracted with EtOAc, dried over MgSO4,
filtered, and concentrated to afford crude aldol product (−)-4, which
was purified by flash column chromatography (4:1 hexanes/EtOAc) to
afford 5.28 g (68%) of a slightly yellow oil. 1H, 13C, and optical rotation
data were in agreement with literature values.10
In summary, we have described efficient total syntheses for
both natural (−)-palmyrolide A and its optical enantiomer,
(+)-ent-palmyrolide A, the former being accomplished for the
first time. En route to this structurally interesting, biologically
active molecule, we have also revealed the syntheses of all four
possible stereocombinations of palmyrolide A aldehyde and
three additional diastereocombinations of the palmyrolide A
macrolide. Critical to the success of this work was the first
reported application of the Buchwald CuI/Cs2CO3/N,N′-
dimethylethylenediamine strategy to form a 15-membered
macrocycle at the trans-N-H enamide junction. Also of note,
the first use of acrylamide as a competent cross-metathesis
partner, using the CuI/Grubbs II precatalyst conditions of
Lipshutz, allowed us to achieve an efficient, protecting-group-
free synthesis in only 10 linear operations. Future work from our
laboratory will focus on analogue development, as well as the
synthesis of a related family of enamide-containing natural
products.
(2S,4S)-5,5-Dimethylhexane-2,4-diol [(−)-S1]. A solution of
(−)-7 (1.63 g, 11.3 mmol) in dry THF (220.0 mL) was cooled to
−78 °C and treated with a solution of DIBAl-H (1.0 M in heptane, 28.36
mL, 28.4 mmol) slowly, allowing each drop to run down the side of the
flask. The reaction mixture was allowed to stir at −78 °C for 3.5 h before
being quenched by the addition of a 10% HCl aqueous solution (30
mL). After the cooling bath was removed, the contents of the flask were
warmed to room temperature and allowed to stir for an additional 3 h.
The crude reaction mixture was then partitioned between ether (50 mL)
and brine (50 mL), and the aqueous phase was re-extracted with
additional ether washes. The combined organic phases were then dried
over MgSO4, filtered, and concentrated to afford crude diol as a 10:1
mixture of diastereomers, which were purified by flash column
chromatography (9:1 → 8:2 hexanes/EtOAc) to afford 1.38 g (83%)
EXPERIMENTAL SECTION
■
General Remarks. Unless otherwise noted, reactions were
performed in flame-dried glassware under an atmosphere of dry
nitrogen. Reaction solvents (CH2Cl2, THF, and Et2O) were purified
before use in a solvent purification system under a flow of dry nitrogen.
Dimethylsulfoxide (DMSO) and toluene were distilled from CaH2. All
other solvents and reagents were purchased from commercial suppliers
and used as received, unless otherwise specified. Thin-layer chromatog-
1
of clean syn-diol (−)-S1 as an amorphous white solid. H, 13C, and
optical rotation data were in agreement with literature values.10
(4S,6S)-4-(tert-Butyl)-6-methyl-1,3,2-dioxathiane 2,2-dioxide
[(−)-8]. (−)-8 was prepared following the literature procedure of
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Cavelier and co-workers. A solution of diol (−)-S1 (0.403 g, 2.76 mmol)
in dry pyridine (12.5 mL) was cooled to 0 °C and treated with SOCl2
(1.00 mL, 13.8 mmol). The reaction mixture was allowed to stir at 0 °C
for 45 min before being quenched by the addition of water. The contents
of the flask were then extracted with CH2Cl2 and washed with a
saturated aqueous KHSO4 solution, followed by a saturated aqueous
NaHCO3 solution. The combined organic layers were then dried over
MgSO4, filtered, and concentrated to afford the crude sulfite, which was
taken on to the next step without further purification. The crude sulfite
was then dissolved a 2:1:1 mixture of water/MeCN/CCl4 (22 mL:22
mL:11 mL) and treated with RuCl3·xH2O (0.030 g) and NaIO4 (0.884
g, 4.14 mmol). The biphasic reaction mixture was then vigorously stirred
at room temperature for 2 h before being diluted with Et2O and
extracted from a saturated aqueous NaHCO3 solution. The crude sulfate
was purified by flash column chromatography (8:2 hexanes/EtOAc) to
afford 0.491 g (85% over two steps) of syn-cyclic sulfate (−)-8 as an
and concentrated. The crude aldehyde was purified by flash column
chromatography (85:15 hexanes/EtOAc) to afford 0.154 g (93%) of the
purified material, which was taken directly on to the next step without
characterization. In a separate flask, a mixture of sodium chlorite
(NaClO2, 0.122 g) and sodium phosphate (NaH2PO4, 0.086 g) was
dissolved in water (2 mL), and this solution was added to a mixture of
aldehyde in t-BuOH (1 mL) and 2-methyl-2-butene (0.5 mL). The
reaction mixture was allowed to stir at room temperature for 45 min
before being quenched with water and extracted using ethyl acetate. The
combined organic layers were dried over MgSO4, filtered, and
concentrated to provide the crude acid, which was taken directly on
to the next step without characterization. The acid (ca. 0.76 mmol) was
dissolved in dry CH2Cl2 (15.2 mL) and sequentially treated with (in this
order) methylamine hydrochloride (0.051 g, 0.760 mmol), HOBt
(0.103 g, 0.760 mmol), DMAP (0.093 g, 2.28 mmol), and EDCI (0.146
g, 0.760 mmol). The reaction mixture was allowed to stir at room
temperature for 12 h before being diluted with CH2Cl2 and washed with
a half-saturated aqueous solution of citric acid. The combined organic
layers were dried over MgSO4, filtered, and concentrated. The crude
product was purified by flash column chromatography (100:1 EtOAc/
Et3N) to afford 0.130 g (74% over two steps) of amide (−)-5 as an
amorphous white solid. [α]2D1.6 = −50.8 (c = 1.04, CHCl3); 1H NMR (δ,
ppm, CDCl3, 300 MHz) 5.68 (bs, 1H), 3.26 (dd, J = 1.9, 10.2 Hz, 1H),
2.79 (d, J = 4.8 Hz, 3H), 2.16 (dd, J = 7.0, 7.8 Hz, 2H), 1.61−1.80 (m,
3H), 1.40−1.61 (m, 2H), 1.34 (ddd, J = 1.9, 9.2, 14.0 Hz, 1H), 1.20 (td, J
= 1.0, 4.0, 14.0 Hz, 1H), 1.05 (ddd, 4.4, 8.8, 17.7 Hz, 1H), 0.93 (d, J = 6.7
Hz, 3H), 0.87 (s, 9H); 13C NMR (δ, CDCl3, 75 MHz) 173.8, 77.2, 39.0,
36.6, 34.9, 34.6, 29.3, 26.2, 25.7, 23.0, 20.9; IR (thin film) ν 3305, 2952,
1651, 1562, 1411, 1363 cm−1; HRMS m/z calcd for C13H27NO2Na [M +
Na]+, 252.1934; found, 252.1931.
(3S,5R)-5-Hydroxy-2,2-dimethylhexan-3-yl Benzoate
[(+)-S3]. A solution of (−)-7 (0.500 g, 3.50 mmol) in dry THF (14
mL) was cooled to −10 °C (ice/brine) and treated with freshly distilled
benzaldehyde (1.06 mL, 10.5 mmol), followed by a freshly prepared
solution of SmI2 in THF (17.3 mL, ca. 0.1 M). The reaction mixture was
allowed to stir at −10 °C for 2 h before being quenched with a saturated
aqueous solution of sodium bicarbonate (NaHCO3), and extracted
using ether. The combined organic layers were dried over MgSO4,
filtered, and concentrated. The crude product was purified by flash
column chromatography (7:3 hexanes/EtOAc) to afford 0.989 g (99%)
of benzoate (+)-S3 as a colorless oil. [α]2D3.0 = +2.3 (c = 1.25, CHCl3); 1H
NMR (δ, ppm, CDCl3, 300 MHz) 8.04−8.10 (m, 2H), 7.54−7.62 (m,
1H), 7.41−7.50 (m, 2H), 5.07 (m, 1H), 3.49−3.64 (m, 1H), 3.30 (d, J =
3.5 Hz, 1H), 1.54−1.67 (m, 2H), 1.11 (d, J = 6.2 Hz, 3H), 0.94 (s, 9H);
13C NMR (δ, ppm, CDCl3, 75 MHz) 167.8, 133.2, 129.8, 129.7, 128.4,
1
amorphous white solid. H, 13C, and optical rotation data were in
agreement with literature values.10
(3S,5S)-9-(Benzyloxy)-2,2,5-trimethylnonan-3-ol [(−)-S2].
Freshly ground magnesium turnings (0.030 g, 1.24 mmol) were
flame-dried under vacuum and, upon cooling, were suspended in dry
THF (2 mL). A small piece of iodine was added, and the flask was cooled
to 0 °C before 4-bromobutyl benzyl ether (2.20 mL, 1.04 mmol, 90%)
was added dropwise via syringe. The reaction mixture was allowed to
warm to room temperature and then warmed by hand until it reached a
gentle reflux. The yellow/gray suspension was allowed to stir for 1 h
before being added, via cannula, to a flask containing a solution of cyclic
sulfate (−)-8 (0.064 g, 0.300 mmol) and CuI (0.060 g, 0.310 mmol) in
dry THF (4.0 mL) at −25 °C. Upon addition, the reaction mixture
immediately turned purple and was allowed to stir at −25 °C for 5 h
before being warmed to room temperature and concentrated in vacuo.
The solid residue was dissolved in ether (30 mL) and treated with a 20%
aqueous H2SO4 solution (10 mL). The contents of the flask were then
stirred vigorously for 12 h before the phases were separated and the
aqueous layer extracted with ether, dried over MgSO4, filtered, and
concentrated. The crude product was purified by flash column
chromatography (9:1 hexanes/EtOAc) to afford 0.060 g (66%) of
alcohol (−)-S2 as a colorless oil. [α]2D2.6 = −38.5 (c = 1.06, CHCl3); 1H
NMR (δ, ppm, CDCl3, 300 MHz) 7.15−7.28 (m, 5H), 4.43 (s, 2H),
3.40 (t, J = 6.6 Hz, 2H), 3.19 (d, J = 9.9 Hz, 1H), 1.45−1.68 (m, 4H),
1.31−1.44 (m, 2H), 1.17−1.30 (m, 2H), 1.09 (ddd, J = 4.2, 10.2, 14.2
Hz, 1H), 0.90−1.03 (m, 1H), 0.86 (d, J = 6.6 Hz, 3H), 0.80 (s, 9H); 13C
NMR (δ, ppm, CDCl3, 75 MHz) 138.6, 128.3, 127.6, 127.4, 77.6, 72.8,
70.4, 39.3, 35.3, 34.9, 30.0, 29.9, 25.6, 23.4, 21.0; IR (neat, thin film) ν
3469, 2950, 2866, 1454, 1363, 1101 cm−1; HRMS m/z calcd for
C19H32O2Na [M + Na]+, 315.2294; found, 315.2293.
79.1, 63.2, 39.1, 34.4, 26.1, 22.8; IR (neat, thin film) ν 3494, 2965, 1700,
1284, 1273, 1125, cm−1; HRMS m/z calcd for C15H22O3Na [M + Na]+,
273.1461; found, 273.1457.
(5S,7S)-5,8,8-Trimethylnonane-1,7-diol [(−)-9]. Benzyl ether
(−)-S2 (0.239 g, 0.810 mmol) was dissolved in a 1:1 EtOAc/EtOH
mixture (20 mL) and treated with 10% Pd/C (0.080 g). The reaction
mixture was then flushed with hydrogen gas and allowed to stir under an
atmosphere of hydrogen (using a balloon). After TLC showed the
complete consumption of starting material (24 h), the reaction mixture
was diluted with EtOAc and filtered through a short plug of Celite,
rinsing several times with fresh EtOAc. The filtrate was concentrated in
vacuo and purified by flash column chromatography (1:1 EtOAc/
(2R,4S)-5,5-Dimethylhexane-2,4-diol [(+)-S4]. To a solution of
benzoate (+)-S3 (0.876 g, 3.50 mmol) in MeOH (20 mL) was added
K2CO3 (5.50 g, 39.7 mmol) in a single portion at room temperature.
After TLC showed the complete consumption of starting material, the
reaction was quenched by the addition of water and concentrated in
vacuo. The residue was then extracted using ethyl acetate, and the
combined organic layers were dried over MgSO4, filtered, and
concentrated. The crude product was purified by flash column
chromatography (1:1 hexanes/EtOAc) to afford 0.532 g (93%) of diol
(+)-S4 as an amorphous white solid. 1H, 13C, and optical rotation data
were in agreement with literature values.10
(4S,6R)-4-(tert-butyl)-6-methyl-1,3,2-dioxathiane-2,2-diox-
ide [(+)-10]. (+)-10 was prepared in a similar manner as syn-cyclic
sulfate (−)-8. The crude product was purified by flash column
chromatography (8:2 hexanes/EtOAc) to afford 0.309 g (89% over
two steps) of anti-cyclic sulfate (+)-10 as an amorphous white solid.
[α]2D3.0 = +0.19 (c = 0.93, CHCl3); 1H NMR (δ, ppm, CDCl3, 300 MHz)
4.94 (ddq, J = 4.6, 6.6, 13.0 Hz, 1H), 4.60 (dd, J = 3.6, 11.3 Hz, 1H), 2.30
(ddd, J = 6.0, 11.3, 14.1 Hz, 1H), 1.75 (ddd, J = 3.7, 4.5, 14.1 Hz, 1H),
1.64 (d, J = 6.6 Hz, 3H), 1.02 (s, 9H); 13C NMR (δ, ppm, CDCl3, 75
MHz) 88.4, 81.0, 34.2, 29.9, 25.0, 19.5; IR (neat, thin film) ν 2972, 1469,
hexanes) to afford 0.166 g (99%) of diol (−)-9 as a colorless oil. [α]D21.8
=
−55.6 (c = 1.09, CHCl3); 1H NMR (δ, ppm, CDCl3, 300 MHz) 3.62 (t, J
= 6.4 Hz, 2H), 3.27 (dd, J = 1.8, 10.2 Hz, 1H), 0.97−1.73 (m, 11H), 0.92
(d, J = 6.6 Hz, 3H), 0.86 (s, 9H); 13C NMR (δ, ppm, CDCl3, 75 MHz)
77.5, 62.8, 39.2, 35.1, 34.9, 32.9, 29.9, 25.6, 23.0, 20.9; IR (neat, thin
film) ν 3351, 2950, 2868, 1463, 1364, 1074, 985 cm−1; HRMS m/z calcd
for C12H26O2Na [M + Na]+, 225.1825; found, 225.1823.
(5S,7S)-7-Hydroxy-5,8,8-trimethylnonanamide [(−)-5]. Diol
(−)-9 (0.166 g, 0.810 mmol) was dissolved in dry CH2Cl2 (12 mL)
and treated with TEMPO (0.013 g, 0.081 mmol), followed by
iodobenzene diacetate (0.313 g, 0.970 mmol). The reaction mixture
was allowed to stir at room temperature for 6 h before being quenched
by the addition of a saturated aqueous solution of sodium thiosulfate
(Na2S2O3). The contents of the flask were then extracted with CH2Cl2,
and the combined organic layers were then dried over MgSO4, filtered,
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Article
1369, 1194, 1051, 1041, 950, 916, 856 cm−1; HRMS m/z calcd for
C8H16O4SNa [M + Na], 231.0661; found, 231.0659.
N-((1R,2R)-1-Hydroxy-1-phenylpropan-2-yl)-6-((4-
methoxybenzyl)oxy)-N-methylhexanamide [(−)-14]. To a sol-
ution of acid 13 (0.300 g, 1.18 mmol) in dry CH2Cl2 (12 mL) was added
oxalyl chloride (0.11 mL, 1.30 mmol) dropwise, followed by a single
drop of DMF; gas evolution immediately occurred. The reaction
mixture was allowed to stir at room temperature overnight before being
concentrated in vacuo. In a separate flask, (−)-pseudoephedrine (0.196
g, 1.18 mmol) was dissolved in dry THF (3 mL), treated with
triethylamine (0.21 mL, 1.54 mmol), and cooled to 0 °C. To this was
added the recently prepared acid chloride in dry THF (3 mL) via canula.
The reaction mixture was allowed to stir at 0 °C for 1 h before being
quenched with brine and extracted using EtOAc. The combined organic
layers were dried over MgSO4, filtered, and concentrated. The crude
product was purified by flash column chromatography (1:1 hexanes/
EtOAc) to afford 0.335 g (70%) of amide (−)-14 as an amorphous white
solid. [α]2D4.0 = −56.2 (c = 2.26, CHCl3); 1H NMR (δ, ppm, CDCl3, 300
MHz, mixture of rotamers) 7.17−7.41 (m, 7H), 6.80−6.91 (m, 2H),
4.50−4.35 (m, 5H), 4.42−4.60 (m, 0.6H), 4.39−4.41 (s, 2H), 3.96 (m,
0.3H), 3.77 (s, 3H), 3.42 (t, J = 6.5 Hz, 2H), 2.87 (s, 0.8H), 2.76 (s, 2H),
2.32−2.43 (m, 0.4H), 2.20−2.29 (m, 1H), 1.50−1.68 (m, 4H), 1.30−
1.45 (m, 2H), 1.07 (d, J = 6.8, 2H), 0.95 (d, J = 6.8, 2H); 13C NMR (δ,
ppm, CDCl3, 75 MHz, mixture of rotamers) 175.5, 174.3, 159.3, 142.8,
141.9, 130.9, 129.5, 128.8, 128.5, 127.8, 127.1, 126.6, 114.0, 77.8, 77.7,
75.6, 72.8, 70.3, 70.2, 58.5, 55.5, 34.5, 33.8, 33.0, 29.8, 27.0, 26.4, 26.2,
25.4, 25.0, 15.7, 14.6; IR (neat, thin film) ν 3391, 2935, 1614, 1513,
1454, 1247, 1094, 1034 cm−1; HRMS m/z calcd for C24H33NO4Na [M +
Na]+, 422.2301; found, 422.2295.
(3S,5R)-9-(Benzyloxy)-2,2,5-trimethylnonan-3-ol [(−)-S5].
(−)-S5 was prepared in a similar manner as benzyl ether (−)-S2. The
crude product was purified by flash column chromatography (8:2
hexanes/EtOAc) to afford 0.309 g (94%) of benzyl ether (−)-S5 as a
colorless oil. [α]2D2.8 = −23.1 (c = 2.4, CHCl3); 1H NMR (δ, ppm, CDCl3,
300 MHz) 7.25−7.36 (m, 5H), 4.50 (s, 2H), 3.47 (t, J = 6.6 Hz, 2H),
3.29 (dd, J = 1.7, 10.4 Hz, 1H), 1.55−1.72 (m, 3H), 1.09−1.49 (m, 7H),
0.89 (d, J = 6.4 Hz, 3H), 0.88 (s, 9H); 13C NMR (δ, ppm, CDCl3, 75
MHz) 138.6, 128.3, 127.6, 127.4, 77.2, 78.8, 70.4, 38.9, 38.2, 34.8, 30.0,
29.5, 25.6, 23.6, 18.9; IR (neat, thin film) ν 2956, 2875, 1455, 1362,
1093, 1029, 1011, 895 cm−1; HRMS m/z calcd for C19H32O2Na [M +
Na]+, 315.2294; found, 315.2291.
(5R,7S)-5,8,8-Trimethylnonane-1,7-diol [(−)-11]. (−)-11 was
prepared in a similar manner as diol (−)-9. The crude product was
purified by flash column chromatography (1:1 hexanes/EtOAc) to
afford 0.101 g (90%) of diol (−)-11 as a colorless oil. [α]2D2.7 = −39.8 (c =
0.92, CHCl3); 1H NMR (δ, ppm, CDCl3, 300 MHz) 3.64 (t, J = 6.5 Hz,
2H), 3.28 (d, J = 10.3 Hz, 1H), 1.50−1.75 (m, 3H), 1.11−1.48 (m, 8H),
0.88 (δ, J = 6.4 Hz, 3H), 0.88, (s, 9H); 13C NMR (CDCl3, 75 MHz) 77.4,
63.0, 38.8, 38.0, 34.8, 33.0, 29.6, 25.7, 23.2, 19.0; IR (neat, thin film) ν
3351, 2934, 2869, 1460, 1364, 1073, 979 cm−1; HRMS m/z calcd for
C12H26O2Na [M + Na]+, 225.1825; found, 225.1823.
(5R,7S)-7-Hydroxy-N,5,8,8-tetramethylnonanamide [(−)-4].
(−)-4 was prepared in a similar manner as amide (−)-5. The crude
product was purified by flash column chromatography (100:1 EtOAc/
Et3N) to afford 0.020 g (74% over three steps) of amide (−)-4 as an
amorphous white solid. [α]2D2.9 = −32.9 (c = 1.64, CHCl3); 1H NMR (δ,
ppm, CDCl3, 300 MHz) 5.68 (bs, 1H), 3.25 (dd, J = 1.7, 10.4 Hz, 1H),
2.78 (d, J = 4.7 Hz, 3H), 2.15 (t, J = 7.8 Hz, 2H), 1.51−1.78 (m, 4H),
1.06−1.39 (m, 4H), 0.87 (d, overlapped, 3H), 0.87 (s, 9H); 13C NMR
(δ, ppm, CDCl3, 75 MHz) 173.9, 77.3, 38.6, 37.8, 36.7, 34.8, 29.3, 26.2,
25.7, 23.1, 19.0; IR (neat, thin film) ν 3304, 2952, 1652, 1562, 1410,
1075 cm−1; HRMS m/z calcd for C13H27NO2Na [M + Na]+, 252.1934;
found, 252.1931.
Ethyl 6-((4-Methoxybenzyl)oxy)hexanoate (S7). A suspension
of NaH (0.037 g, 0.920 mmol, 60% dispersion in mineral oil) in dry
ether (18 mL) was treated with p-methoxybenzyl alcohol (1.14 mL, 9.22
mmol) dropwise. The reaction mixture was allowed to stir at room
temperature for 30 min before being cooled to 0 °C. Trichloroacetoni-
trile (0.92 mL, 9.22 mmol) was added dropwise, and the reaction flask
was allowed to gradually warm to room temperature. After 5 h, the
contents of the flask were concentrated, and the resultant orange oil was
suspended in hexanes (25 mL) and MeOH (0.1 mL). The solid
precipitate was then filtered through a short plug of Celite, rinsing
several times with fresh hexanes, and the filtrate was concentrated. The
crude trichloroacetimidate was dissolved in dry CH2Cl2 (30 mL) and
cooled to 0 °C. To this was added ethyl-6-hydroxyhexanoate (1.00 mL,
6.14 mmoL), followed by camphor sulfonic acid (CSA, 0.143 g, 0.610
mmol). The contents of the flask were allowed to gradually warm to
room temperature and stir for 12 h. A saturated aqueous solution of
sodium bicarbonate (NaHCO3) was then added, and the mixture was
extracted using CH2Cl2. The combined organic layers were dried over
Na2SO4, filtered, and concentrated. The crude product was purified by
flash column chromatography (95:5 hexanes/EtOAc) to afford 1.35 g
(78%) of ester S7 as a colorless oil. 1H and 13C were in agreement with
literature values.20
(R)-N-((1R,2R)-1-Hydroxy-1-phenylpropan-2-yl)-6-((4-
methoxybenzyl)oxy)-N,2-dimethylhexanamide [(−)-S8]. Lith-
ium chloride (0.2133 g, 5.03 mmol) was placed in a round-bottom
flask under vacuum and flame-dried before use. Once cooled, the flask
was placed under an atmosphere of nitrogen and charged with
diisopropylamide (0.26 mL, 1.88 mmol) and dry THF (4 mL). The
contents of the flask were cooled to 0 °C and treated with nBuLi (2.5 M
in hexanes, 0.75 mL, 1.89 mmol) dropwise. After 20 min, the LDA
solution was cooled to −78 °C before a solution of amide (−)-14 (0.335
g, 0.83 mmol) in dry THF (3 mL) was added dropwise via cannula. After
1 h at −78 °C, the flask was allowed to warm to 0 °C for 15 min, and then
room temperature for 5 min. The flask was then cooled back down to 0
°C, and iodomethane (78 μL, 1.82 mmol) was added neat. The reaction
mixture was allowed to stir at 0 °C for 20 min before being quenched by
the addition of a saturated aqueous solution of NH4Cl (10 mL). The
phases were separated, and the aqueous phase was extracted with
EtOAc. The combined organic layers were then dried over MgSO4,
filtered, and concentrated. The crude product was purified by flash
column chromatography (1:1 hexanes/EtOAc) to afford 0.280 g (80%)
of amide (−)-S8 as an amorphous white solid. [α]2D3.3 = −74.2 (c = 1.46,
1
CHCl3); H NMR (δ, ppm, CDCl3, 300 MHz, mixture of rotamers)
7.16−7.40 (m, 7H), 6.80−6.89 (m, 2H), 4.86 (bs, 0.4H), 4.59 (t, J = 7.0
Hz, 0.7H), 4.51 (dd, J = 8.3, 2.4 Hz, 0.3H), 4.40 (s, 1.3H), 4.37 (s, 0.5H),
4.32 (t, J = 6.8 Hz, 0.3H), 4.00−4.11 (m, 0.2H), 3.40 (t, J = 6.4 Hz,
1.8H), 2.53 (s, 3H), 2.87 (s, 0.6H), 2.75 (s, 2H), 2.48−2.60 (m, 0.6H),
1.47−1.71 (m, 2.5H), 1.21−1.39 (m, 2H), 1.15 (d, J = 6.9 Hz, 2H), 1.09
(d, J = 6.6 Hz, 1H), 98 (d, J = 6.7 Hz, 2H); 13C NMR (δ, ppm, CDCl3, 75
MHz, mixture of rotamers) 178.5, 177.5, 158.9, 142.4, 141.6, 130.4,
129.0, 128.4, 128.0, 127.2, 126.7, 113.5, 76.0, 75.1, 72.3, 69.7, 59.2, 57.8,
55.0, 36.2, 35.4, 34.2, 33.5, 29.5, 26.9, 23.9, 23.8, 17.5, 17.1, 15.5, 14.2; IR
(neat, thin film) ν 3389, 2935, 2860, 1613, 1513, 1453, 1247, 1097, 1035
cm−1; HRMS m/z calcd for C25H35NO4Na [M + Na]+, 436.2458; found,
436.2456.
(R)-6-((4-Methoxybenzyl)oxy)-2-methylhexanoic Acid
[(−)-6a]. To a solution of amide (−)-S8 (0.280 g, 0.670 mmol) in t-
BuOH (6 mL) and MeOH (6 mL) was added an aqueous solution of
NaOH (3.22 N, 12 mL). A condenser was attached, and the reaction
mixture was heated to 85 °C overnight. The flask was allowed to cool
before the contents were partitioned between water (30.0 mL) and
CH2Cl2 (30.0 mL). The phases were separated, and the organic layer
containing recovered pseudoephedrine was set aside. The aqueous layer
was acidified using concentrated HCl to pH ∼3 before being extracted
using CH2Cl2. The combined organic layers were dried over MgSO4,
6-((4-Methoxybenzyl)oxy)hexanoic Acid (13). Ester S7 was
dissolved a 2:2:1 mixture of THF/MeOH/H2O (30 mL) and treated
with NaOH (0.902 g, 22.6 mmol). A condenser was attached, and the
reaction mixture was heated to 60 °C overnight. The flask was allowed to
cool before the contents were concentrated in vacuo. The aqueous
residue was acidified using concentrated HCl to pH ∼3 and then
saturated with solid NaCl before being extracted using EtOAc. The
combined organic layers were dried over MgSO4, filtered, and
concentrated. The crude product was purified by flash column
chromatography (7:3 hexanes/EtOAc) to afford 1.41 g (70%) of acid
13 as a thick colorless oil. 1H and 13C were in agreement with literature
values.20b
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filtered, and concentrated. The crude product [0.168 g (93%)], as a thick
colorless oil, was sufficiently clean to use in the next step without further
purification. [α]2D2.2 = −7.9 (c = 1.27, CHCl3); 1H NMR (δ, ppm, CDCl3,
300 MHz) 10.50 (bs, 1H), 7.26 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.6 Hz,
2H), 4.43 (s, 2H), 3.80 (s, 3H), 3.44 (t, J = 6.5 Hz, 2H), 2.46 (ddq, J =
7.0, 7.0, 13.0 Hz, 1H), 1.55−1.77 (m, 3H), 1.34−1.5 (m, 3H), 1.18 (d, J
= 7.0 Hz, 3H); 13C NMR (δ, CDCl3, 100 MHz) 183.0, 159.1, 130.6,
129.2, 113.7, 72.5, 69.7, 55.2, 39.3, 33.2, 29.5, 23.8, 16.8; IR (neat, thin
film) ν 2937, 2862, 1700, 1612, 1513, 1247, 1097, 1035 cm−1; HRMS
m/z calcd for C15H22O4Na [M + Na]+, 289.1410; found, 289.1409.
N-((1S,2S)-1-Hydroxy-1-phenylpropan-2-yl)-6-((4-
methoxybenzyl)oxy)-N-methylhexanamide [(+)-15]. (+)-15 was
prepared in a similar manner as amide (−)-14. The crude product was
purified by flash column chromatography (1:1 EtOAc/hexanes) to
afford 0.350 g (73%) of amide (+)-15 as an amorphous white solid.
[α]2D3.2 = +66.9 (c = 1.27, CHCl3); 1H NMR (δ, ppm, CDCl3, 300 MHz,
mixture of rotamers) 7.17−7.41 (m, 7H), 6.80−6.91 (m, 2H), 4.42−
4.60 (m, 0.6H), 4.39−4.41 (s, 2H), 3.96 (m, 0.3H), 3.77 (s, 3H), 3.42 (t,
J = 6.5 Hz, 2H), 2.87 (s, 0.8H), 2.76 (s, 2H), 2.32−2.43 (m, 0.4H),
2.20−2.29 (m, 1H), 1.50−1.68 (m, 4H), 1.30−1.45 (m, 2H), 1.07 (d, J =
6.8, 2H), 0.95 (d, J = 6.8, 2H); 13C NMR (δ, CDCl3, 75 MHz, mixture of
rotamers) 175.5, 174.3, 159.3, 142.8, 141.9, 130.9, 129.5, 128.8, 128.5,
127.8, 127.1, 126.6, 114.0, 77.8, 77.7, 75.6, 72.8, 70.3, 70.2, 58.5, 55.5,
34.5, 33.8, 33.0, 29.8, 27.0, 26.4, 26.2, 25.4, 25.0, 15.7, 14.6; IR (neat,
thin film) ν 3391, 2935, 1614, 1513, 1454, 1247, 1094, 1034 cm−1;
HRMS m/z calcd for C24H33NO4Na [M + Na]+, 422.2301; found,
422.2292.
(S)-N-((1S,2S)-1-Hydroxy-1-phenylpropan-2-yl)-6-((4-
methoxybenzyl)oxy)-N,2-dimethylhexanamide [(+)-S9]. (+)-S9
was prepared in a similar manner as amide (−)-S8. The crude product
was purified by flash column chromatography (1:1 EtOAc/hexanes) to
afford 0.263 g (72%) of amide (+)-S9 as an amorphous white solid.
[α]2D3.8 = +77.1 (c = 1.0, CHCl3); 1H NMR (δ, ppm, CDCl3, 300 MHz,
mixture of rotamers) 7.16−7.40 (m, 7H), 6.80−6.89 (m, 2H), 4.86 (bs,
0.4H), 4.59 (t, J = 7.0 Hz, 0.7H), 4.51 (dd, J = 2.4, 8.3 Hz, 0.3H), 4.40 (s,
1.3H), 4.37 (s, 0.5H), 4.32 (t, J = 6.8 Hz, 0.3H), 4.00−4.11 (m, 0.2H),
3.40 (t, J = 6.4 Hz, 1.8H), 2.53 (s, 3H), 2.87 (s, 0.6H), 2.75 (s, 2H),
2.48−2.60 (m, 0.6H), 1.47−1.71 (m, 2.5H), 1.21−1.39 (m, 2H), 1.15
(d, J = 6.9 Hz, 2H), 1.09 (d, J = 6.6 Hz, 1H), 0.98 (d, J = 6.7 Hz, 2H); 13C
NMR (δ, ppm, CDCl3, 75 MHz, mixture of rotamers) 178.5, 177.5,
158.9, 142.4, 141.6, 130.4, 129.0, 128.4, 128.0, 127.2, 126.7, 113.5, 76.0,
75.1, 72.3, 69.7, 59.2, 57.8, 55.0, 36.2, 35.4, 34.2, 33.5, 29.5, 26.9, 23.9,
23.8, 17.5, 17.1, 15.5, 14.2; IR (neat, thin film) ν 3389, 2935, 2860, 1613,
1513, 1453, 1247, 1097, 1035 cm−1; HRMS m/z calcd for
C25H35NO4Na [M + Na]+, 436.24583; found, 436.24583.
with additional CH2Cl2. The combined organic layers were then dried
over MgSO4, filtered, and concentrated. The crude product was purified
by flash column chromatography (1:1 EtOAc/hexanes) to afford 0.069 g
(91%) of amide (−)-16a as a colorless oil. [α]2D3.0 = −14.3 (c = 2.31,
CHCl3); 1H NMR (δ, ppm, CDCl3, 300 MHz) 7.25 (d, J = 8.5 Hz, 2H),
6.87 (d, J = 8.5 Hz, 2H), 5.68 (bs, 1H), 4.83 (d, J = 10.6 Hz, 1H), 4.42 (s,
2H), 3.80 (s, 3H), 3.44 (t, J = 6.5 Hz, 2H), 2.74 (d, J = 4.8 Hz, 3H),
2.36−2.49 (m, 1H), 2.08 (t, J = 7.6 Hz, 2H), 1.48−1.72 (m, 6H), 1.30−
1.48 (m, 4H), 1.19−1.30 (m, 3H), 1.16 (d, J = 7.0 Hz, 3H), 0.88 (d,
overlapped, 3H), 0.87 (s, 9H); 13C NMR (δ, ppm, CDCl3, 75 MHz)
176.5, 173.6, 159.1, 130.5, 129.2, 113.7, 78.0, 74.4, 69.9, 55.2, 39.9, 37.7,
36.9, 36.7, 34.6, 33.5, 29.6, 29.2, 26.2, 25.9, 24.0, 23.2, 19.0, 17.5; IR
(neat, thin film) ν 3307, 2937, 2868, 1727, 1651, 1513, 1248, 1171,
1098, 1036, 821 cm−1; HRMS m/z calcd for C28H47NO5Na [M + Na]+,
500.3346; found, 500.3336.
(R)-(3S,5R)-2,2,5-Trimethyl-9-(methylamino)-9-oxononan-3-
yl-6-hydroxy-2-methylhexanoate [(−)-S10]. To a solution of
amide (−)-16a (0.069 g, 0.017 mmol) in CH2Cl2/water (20:1, 2.0
mL) at room temperature was added DDQ (0.050 g, 0.210 mmol). The
reaction mixture was allowed to vigorously stir for 1 h before being
diluted with CH2Cl2 and washed with a saturated aqueous solution of
sodium bicarbonate (NaHCO3) and brine. The combined organic layers
were dried over MgSO4, filtered, and concentrated.The crude product
was purified by flash column chromatography (1:1 EtOAc/hexanes →
100:1 EtOAc/Et3N) to afford 0.043 g (82%) of alcohol (−)-S10 as a
colorless oil. [α]2D3.6 = −28.7 (c = 2.15, CHCl3); H NMR (δ, ppm,
1
CDCl3, 300 MHz) 5.88 (bs, 1H), 4.80 (d, J = 10.6 Hz, 1H), 3.61 (t, J =
6.1 Hz, 2H), 2.77 (d, J = 4.7 Hz, 3H), 2.77 (s, overlapped, 1H), 2.38−
2.52 (m, 1H), 2.11 (t, J = 7.6 Hz, 2H), 1.46−1.77 (m, 6H), 1.30−1.44
(m, 3H), 1.17−1.29 (m, 4H), 1.14 (d, J = 7.0 Hz, 3H), 0.88 (d, J = 6.1
Hz, 3H), 0.85 (s, 9H); 13C NMR (δ, ppm, CDCl3, 75 MHz) 176.8,
173.9, 78.1, 62.4, 39.8, 37.7, 37.0, 36.6, 34.5, 33.7, 32.6, 29.5, 26.2, 25.9,
23.7, 23.5, 19.1, 17.7; IR (neat, thin film) ν 3306, 2956, 2936, 1729,
1649, 1562, 1461, 1381, 1161 cm−1; HRMS m/z calcd for
C20H39NO4Na [M + Na]+, 380.2771; found, 380.2764.
(R)-(3S,5R)-2,2,5-Trimethyl-9-(methylamino)-9-oxononan-3-
yl-2-methyl-6-oxohexanoate [(−)-2a]. A solution of alcohol
(−)-S10 (0.026 g, 0.072 mmol) in dry CH2Cl2 (2 mL) was treated
with NaHCO3 (0.061 g, 0.72 mmol), followed by the Dess−Martin
periodinane (0.154 g, 0.360 mmol). The resulting suspension was
allowed to stir at room temperature for 1 h before being quenched with a
saturated aqueous solution of sodium thiosulfate (Na2S2O3). The
contents of the flask were then stirred vigorously for 1 h, and then the
layers were separated. The aqueous layer was extracted using CH2Cl2,
and the combined organic layers were dried over MgSO4, filtered, and
concentrated. The crude product was purified by flash column
chromatography (1:1 EtOAc/hexanes → 9:1 EtOAc/hexanes) to afford
0.023 g (89%) of aldehyde (−)-2a as a colorless oil. [α]2D3.2 = −19.5 (c =
1.15, CHCl3); 1H NMR (δ, ppm, CDCl3, 300 MHz) 9.76 (t, J = 1.2 Hz,
1H), 5.77 (bs, 1H), 4.82 (dd, J = 1.0, 11.3 Hz, 1H), 2.79 (d, J = 4.7 Hz,
3H), 2.38−2.51 (m, 3H), 2.13 (t, J = 7.6 Hz, 2H), 1.34- 1.79 (m, 7H),
1.13−1.29 (m, 4H), 1.17 (d, J = 7.0 Hz, 3H), 0.88 (d, J = 5.8 Hz, 3H),
0.86 (s, 9H); 13C NMR (δ, ppm, CDCl3, 75 MHz) 202.4, 176.2 (2C),
78.3, 43.8, 39.8, 37.7, 36.9, 36.7, 34.6, 33.0, 29.3, 26.2, 25.9, 23.3, 19.9,
19.0, 17.6; IR (neat, thin film) ν 3305, 2960, 1727, 1650, 1551, 1366,
1163, 1075 cm−1; HRMS m/z calcd for C20H37NO4Na [M + Na]+,
378.26148; found, 378.26145.
(S)-6-((4-Methoxybenzyl)oxy)-2-methylhexanoic acid
[(+)-6b]. (+)-6b was prepared in a similar manner as acid (−)-6a.
The crude product [0.127 g (75%)], as a thick colorless oil, was
sufficiently clean to use in the next step without further purification.
[α]2D4.7 = +9.4 (c = 1.80, CHCl3); 1H NMR (δ, ppm, CDCl3, 300 MHz)
11.24 (bs, 1H), 7.26 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 4.43 (s,
2H), 3.80 (s, 3H), 3.44 (t, J = 6.5 Hz, 2H), 2.46 (ddq, J = 7.0, 7.0, 13.0
Hz, 1H), 1.55−1.77 (m, 3H), 1.34−1.5 (m, 3H), 1.18 (d, J = 7.0 Hz,
3H); 13C NMR (δ, CDCl3, 75 MHz) 183.0, 159.0, 130.5, 129.2, 113.7,
72.4, 69.7, 55.2, 39.3, 33.2, 29.5, 23.8, 16.7; IR (neat, thin film) ν 2937,
2862, 1700, 1612, 1513, 1247, 1097, 1035 cm−1; HRMS m/z calcd for
C15H22O4Na [M + Na]+, 289.1410; found, 289.1407.
(R)-(3S,5R)-2,2,5-Trimethyl-9-(methylamino)-9-oxononan-3-
yl-6-((4-methoxy benzyl)oxy)-2-methylhexanoate [(−)-16a]. A
solution of acid (−)-3a (0.070 g, 0.260 mmol) in dry THF (2.6 mL) was
treated with freshly distilled DIPEA (64.1 μL, 0.36 mmol), followed by
2,4,6-trichlorobenzoyl chloride (72.7 μL, 0.41 mmol). The mixture was
stirred at room temperature for 3 h, and the resulting mixed anhydride
was then concentrated in vacuo. The residue was dissolved in dry
toluene (5.2 mL) and was added, via cannula, to a separate flask
containing amide (−)-4 (0.037 g, 0.150 mmol) and DMAP (0.032 g,
0.260 mmol). The reaction mixture was allowed to stir at room
temperature for 12 h before CH2Cl2 (20 mL) was added, and the
mixture was washed with a saturated aqueous solution of NaHCO3 (20
mL). The phases were separated, and the aqueous layer was extracted
(S)-(3S,5R)-2,2,5-Trimethyl-9-(methylamino)-9-oxononan-3-
yl-6-((4-methoxy benzyl)oxy)-2-methylhexanoate [(−)-ent-
16b]. (−)-ent-16b was prepared in a similar manner as amide
(−)-16a, using acid (+)-6b and amide (−)-4. The crude product was
purified by flash column chromatography (1:1 EtOAc/hexanes) to
afford 0.072 g (99%) of amide (−)-ent-16b as an amorphous white solid.
[α]D24.1 = −8.8 (c = 1.0, CHCl3); 1H NMR (δ, ppm, CDCl3, 300 MHz)
7.24 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 5.60 (bs, 1H), 4.81 (dd,
J = 10.9, 1.3 Hz, 1H), 4.41 (s, 2H), 3.79 (s, 3H), 3.42 (t, J = 6.5 Hz, 2H),
2.76 (d, J = 4.8 Hz, 3H), 2.35−2.48 (m, 1H), 2.09 (t, J = 7.6 Hz, 2H),
1.47−1.75 (m, 6H), 1.3−1.46 (m, 3H), 1.14−1.29 (m, 4H), 1.14 (d, J =
6.9 Hz, 3H), 0.88 (d, J = 6.0 Hz, 3H), 0.86 (s, 9H); 13C NMR (δ, ppm,
CDCl3, 75 MHz) 176.4, 173.6, 159.1, 130.6, 129.2, 113.7, 77.9, 72.5,
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69.9, 55.2, 40.1, 37.8, 36.9, 36.8, 34.5, 33.5, 29.6, 29.3, 26.2, 26.0, 24.0,
23.3, 19.0, 17.5; IR (neat, thin film) ν 3306, 2936, 1727, 1650, 1513,
1462, 1366, 1247, 1171, 1098, 1036, 821 cm−1; HRMS m/z calcd for
C28H47NO5Na [M + Na]+, 500.3346; found, 500.3336.
(−)-3a as a colorless oil. [α]2D3.6 = −51.2 (c = 0.92, CHCl3); 1H NMR (δ,
ppm, CDCl3, 300 MHz) 9.75 (t, J = 1.3 Hz, 1H), 6.11 (bs, 1H), 4.75 (dd,
J = 2.7, 9.3 Hz, 1H), 2.78 (d, J = 4.7 Hz, 3H), 2.38−2.50 (m, 2H), 1.94−
2.22 (m, 2H), 1.55−1.83 (m, 4H), 1.32−1.53 (m, 4H), 1.20−1.32 (m,
3H), 1.17 (d, J = 7.0 Hz, 3H), 0.93−1.07 (m, 1H), 0.86 (d, overlapped,
3H), 0.85 (s, 9H); 13C NMR (δ, ppm, CDCl3, 100 MHz) 202.0, 176.4,
173.8, 78.8, 43.7, 39.8, 37.6, 36.2, 34.6, 34.6, 32.9, 29.0, 26.1, 25.9, 22.9,
20.7, 19.8, 17.4; IR (neat, thin film) ν 3305, 2957, 1722, 1648, 1552,
1462, 1366, 1164 cm−1; HRMS m/z calcd for C20H37NO4Na [M + Na]+,
378.2614; found, 378.2615.
(S)-(3S,5S)-2,2,5-Trimethyl-9-(methylamino)-9-oxononan-3-
yl-6-((4-methoxy benzyl)oxy)-2-methylhexanoate [(−)-ent-
17b]. (−)-ent-17b was prepared in a similar manner as amide
(−)-16a, using acid (+)-6b and amide (−)-5. The crude product was
purified by flash column chromatography (1:1 EtOAc/hexanes) to
afford 0.039 g (93%) of amide (−)-ent-17b as an amorphous white solid.
[α]2D2.0 = −29.4 (c = 1.82, CHCl3); 1H NMR (δ, ppm, CDCl3, 300 MHz)
7.24 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 6.08 (bs, 1H), 4.74 (dd,
J = 8.3, 3.5 Hz, 1H), 4.41 (s, 2H), 3.79 (s, 3H), 3.41 (t, J = 6.5 Hz, 2H),
2.79 (d, J = 4.8 Hz, 3H), 2.36−2.50 (m, 1H), 1.98−2.21 (m, 2H), 1.52−
1.82 (m, 4H), 1.19−1.50 (m, 7H), 1.15 (d, J = 7.0 Hz, 3H), 0.93−1.07
(m, 2H), 0.86 (d, overlapped, 3H), 0.85 (s, 9H); 13C NMR (δ, ppm,
CDCl3, 75 MHz) 176.9, 173.8, 159.1, 130.6, 129.2, 113.7, 78.6, 72.5,
69.8, 55.2, 40.1, 37.6, 36.1, 34.48, 34.45, 33.5, 29.6, 28.8, 26.1, 25.9, 24.0,
22.8, 20.8, 17.4; IR (neat, thin film) ν 3292, 2954, 1727, 1650, 1513,
1462, 1245, 1171, 1098 cm−1; HRMS m/z calcd for C28H47NO5Na [M +
Na]+, 500.3346; found, 500.3340.
(S)-(3S,5R)-2,2,5-Trimethyl-9-(methylamino)-9-oxononan-3-
yl-6-hydroxy-2-methylhexanoate [(−)-S11]. (−)-S11 was pre-
pared in a similar manner as alcohol (−)-S10, using amide (−)-ent-
16b. The crude product was purified by flash column chromatography
(1:1 EtOAc/hexanes → 100:1 EtOAc/Et3N) to afford 0.034 g (64%) of
alcohol (−)-S11 as a colorless oil. [α]2D4.1 = −18.0 (c = 1.70, CHCl3); 1H
NMR (δ, ppm, CDCl3, 300 MHz) 5.85 (bs, 1H), 4.80 (d, J = 10.6 Hz,
1H), 3.59 (t, J = 6.5 Hz, 2H), 2.76 (d, 4.8 Hz, 3H), 2.36−2.48 (m, 1H),
2.10 (t, J = 7.5 Hz, 2H), 1.46−1.76 (m, 7H), 1.29−1.45 (m, 3H), 1.09−
1.29 (m, 4H), 1.14 (d, J = 7.0 Hz, 3H), 0.87 (d, J = 6.2 Hz, 3H), 0.85 (s,
9H); 13C NMR (δ, ppm, CDCl3, 75 MHz) 176.3, 173.9, 78.0, 62.4, 40.5,
37.8, 37.0, 36.7, 34.5, 33.6, 32.7, 29.5, 26.2, 25.9, 23.7, 23.5, 19.0, 17.7; IR
(neat, thin film) ν 3305, 2936, 1729, 1651, 1563, 1462, 1366, 1163, 1074
cm−1; HRMS m/z calcd for C20H39NO4Na [M + Na]+, 380.2771; found,
380.2767.
(S)-(3S,5R)-2,2,5-Trimethyl-9-(methylamino)-9-oxononan-3-
yl-2-methyl-6-oxohexanoate [(−)-ent-2b]. (−)-ent-2b was pre-
pared in a similar manner as aldehyde (−)-2a, using alcohol (−)-S11.
The crude product was purified by flash column chromatography (1:1
EtOAc/hexanes → 9:1 EtOAc/hexanes) to afford 0.022 g (68%) of
aldehyde (−)-ent-2b as a colorless oil. [α]2D4.1 = −16.7 (c = 1.08, CHCl3);
1H NMR (δ, ppm, CDCl3, 300 MHz) 9.74 (t, J = 1.5 Hz, 1H), 5.67 (bs,
1H), 4.81 (dd, J = 1.2, 11.2 Hz, 1H), 2.78 (d, J = 4.8 Hz, 3H), 2.39−2.49
(m, 3H), 2.11 (d, J = 7.5 Hz, 2H), 1.34−1.78 (m, 7H), 1.13−1.29 (m,
4H), 1.16 (d, J = 7.0 Hz, 3H), 0.87 (d, J = 5.8 Hz, 3H), 0.85 (s, 9H); 13C
NMR (δ, CDCl3, 75 MHz) 202.2, 175.9, 173.6, 78.2, 43.7, 40.0, 37.8,
36.9, 36.8, 34.5, 33.0, 29.4, 26.2, 25.9, 23.4, 19.9, 19.0, 17.5; IR (neat,
thin film) ν 3305, 2960, 1727, 1651, 1552, 1366, 1257, 1164, 1076 cm−1;
HRMS m/z calcd for C20H37NO4Na [M + Na]+, 378.2615; found,
378.2614.
(S)-(3S,5S)-2,2,5-Trimethyl-9-(methylamino)-9-oxononan-3-
yl-6-hydroxy-2-methylhexanoate [(−)-S13]. (−)-S13 was pre-
pared in a similar manner as alcohol (−)-S10, using amide (−)-ent-
17b. The crude product was purified by flash column chromatography
(1:1 EtOAc/hexanes → 100:1 EtOAc/Et3N) to afford 0.028 g (98%) of
alcohol (−)-S13 as a colorless oil. [α]2D1.6 = −34.82 (c = 1.37, CHCl3);
1H NMR (δ, ppm CDCl3, 300 MHz) 6.10 (bs, 1H), 4.76 (dd, J = 2.2, 9.5
Hz, 1H), 3.63 (t, J = 6.4 Hz, 2H), 2.79 (d, J = 4.8 Hz, 3H), 2.39−2.51 (m,
1H), 2.00−2.23 (m, 2H), 1.91 (bs, 1H), 1.63−1.80 (m, 2H), 1.22−1.60
(m, 10H), 1.16 (d, J = 7.0 Hz, 3H), 0.87 (d, overlapped, 3H), 0.86 (s,
9H); 13C NMR (δ, ppm, CDCl3, 75 MHz) 176.8, 174.0, 78.6, 62.5, 40.2,
37.6, 36.2, 34.5, 33.3, 32.5, 28.8, 26.2, 25.9, 25.9, 23.5, 23.0, 20.8, 17.4; IR
(neat, thin film) ν 3296, 2956, 1728, 1651, 1562, 1462, 1366, 1164 cm−1;
HRMS m/z calcd for C20H39NO4Na [M + Na]+, 380.2771; found,
380.2764.
(S)-(3S,5S)-2,2,5-Trimethyl-9-(methylamino)-9-oxononan-3-
yl-2-methyl-6-oxohexanoate [(−)-ent-3b]. (−)-ent-3b was pre-
pared in a similar manner as aldehyde (−)-2a, using alcohol (−)-S13.
The crude product was purified by flash column chromatography (1:1
EtOAc/hexanes → 9:1 EtOAc/hexanes) to afford 0.019 g (83%) of
aldehyde (−)-ent-3b as a colorless oil. [α]2D3.6 = −40.6 (c = 1.01, CHCl3);
1H NMR (δ, ppm, CDCl3, 300 MHz) 9.76 (s, 1H), 6.03 (bs, 1H), 4.76
(dd, J = 3.6, 8.4 Hz, 1H), 2.80 (d, J = 4.9 Hz, 3H), 2.45 (t, J = 6.5 Hz,
3H), 2.00−2.23 (m, 2H), 1.55−1.83 (m, 5H), 1.21−1.54 (m, 5H), 1.17
(d, J = 7.0 Hz, 3H), 0.94−1.10 (m, 1H), 0.87 (d, overlapped, 3H), 0.86
(s, 9H); 13C NMR (δ, ppm, CDCl3, 75 MHz) 202.0, 176.4, 173.8, 78.9,
78.8, 43.7, 40.0, 37.6, 36.2, 34.5, 34.5, 33.0, 28.8, 25.9, 22.9, 22.9, 19.8,
17.4; IR (neat, thin film) ν 3305, 2957, 1726, 1649, 1552, 1366, 1195,
1164 cm−1; HRMS m/z calcd for C20H37NO4Na [M + Na]+, 378.2615;
found, 378.2614.
(3S,5S)-2,2,5-Trimethyloct-7-en-3-ol [(−)-S14]. (−)-S14 was
prepared following the literature procedure of Cavelier and co-workers.
To a flask containing a solution of cyclic sulfate (−)-8 (0.057 g, 0.27
mmol) and CuI (0.063 g, 0.32 mmol) in dry THF (0.5 mL) at −25 °C
was added allylmagnesium bromide (1.0 M in ether, 1.36 mL, 1.36
mmol). The purple-colored reaction mixture was allowed to stir at −25
°C for 5 h before being warmed to room temperature and then
concentrated in vacuo. The solid residue was dissolved in ether (10 mL)
and treated with a 20% aqueous H2SO4 solution (2 mL). The contents
of the flask were then stirred vigorously for 12 h before the phases were
separated and the aqueous layer extracted with ether, dried over MgSO4,
filtered, and concentrated. The crude product was purified by flash
column chromatography (8:2 hexanes/EtOAc) to afford 0.036 g (76%
(R)-(3S,5S)-2,2,5-Trimethyl-9-(methylamino)-9-oxononan-3-
yl-6-((4-methoxy benzyl)oxy)-2-methylhexanoate [(−)-17a].
Was prepared in a similar manner as amide (−)-16a, using acid
(−)-6a and amide (−)-5. The crude product was purified by flash
column chromatography (1:1 EtOAc/hexanes) to afford 0.078 g (81%)
of amide (−)-17a as an amorphous white solid. [α]2D2.0 = −40.1 (c = 1.90,
CHCl3); 1HNMR (δ, ppm, CDCl3, 300 MHz) 7.24 (d, J = 8.7 Hz, 2H),
6.86 (d, J = 8.7 Hz, 2H), 6.11 (bs, 1H), 4.75, (dd, J = 1.1, 8.8 Hz, 1H),
4.41 (s, 2H), 3.79 (s, 3H), 3.42 (t, J = 6.5 Hz, 2H), 2.78 (d, J = 4.7 Hz,
3H), 2.35−2.50 (m, 1H), 1.97−2.20 (m, 2H), 1.20−1.85 (m, 12H), 1.15
(d, J = 7.0 Hz, 3H), 0.91−1.08 (m, 1H), 0.86 (d, J = 6.0 Hz, 3H), 0.86 (s,
9H); 13CNMR (δ, ppm, CDCl3, 75 MHz) 176.9, 173.9, 159.1, 130.6,
129.2, 113.7, 78.6, 72.5, 69.8, 55.2, 39.9, 37.6, 36.1, 34.5, 34.4, 33.4, 29.6,
28.8, 26.1, 25.9, 24.0, 22.8, 20.8, 17.5; IR (neat, thin film) ν 3306, 2955,
1727, 1651, 1513, 1248, 1171, 1099 cm−1; HRMS m/z calcd for
C28H47NO5Na [M + Na]+, 500.3346; found, 500.3350.
(R)-(3S,5S)-2,2,5-Trimethyl-9-(methylamino)-9-oxononan-3-
yl-6-hydroxy-2-methylhexanoate [(−)-S12]. (−)-S12 was pre-
pared in a similar manner as alcohol (−)-S10, using amide (−)-17a.
The crude product was purified by flash column chromatography (1:1
EtOAc/hexanes → 100:1 EtOAc/Et3N) to afford 0.048 g (82%) of
alcohol (−)-S12 as a colorless oil. [α]2D1.6 = −54.8 (c = 1.2, CHCl3); 1H
NMR (δ, ppm, CDCl3, 300 MHz) 6.25 (bs, 1H), 4.76 (dd, J = 9.9, 1.6
Hz, 1H), 3.55−3.70 (m, 2H), 2.77 (d, J = 4.8 Hz, 3H), 2.37−2.50 (m,
1H), 2.27 (bs, 1H), 2.00−2.20 (m, 2H), 1.63−1.83 (m, 2H), 1.21−1.60
(m, 10H), 1.16 (d, 7.0 Hz, 3H), 0.92−1.04 (m, 1H), 0.86 (d, overlapped,
3H), 0.85 (s, 9H); 13C NMR (δ, ppm, CDCl3, 75 MHz) 177.0, 174.1,
78.4, 62.2, 40.0, 37.5, 36.2, 34.6, 34.5, 33.1, 32.4, 28.8, 26.1, 25.9, 23.6,
23.1, 20.7, 17.7; IR (neat, thin film) ν 3304, 2950, 1729, 1649, 1560,
1462, 1366, 1163, 1074 cm−1; HRMS m/z calcd for C20H39NO4Na [M +
Na]+, 380.2771; found, 380.2764.
(R)-(3S,5S)-2,2,5-Trimethyl-9-(methylamino)-9-oxononan-3-
yl-2-methyl-6-oxohexanoate [(−)-3a]. (−)-3a was prepared in a
similar manner as aldehyde (−)-2a, using alcohol (−)-S12. The crude
product was purified by flash column chromatography (1:1 EtOAc/
hexanes → 9:1 EtOAc/hexanes) to afford 0.008 g (95%) of aldehyde
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yield) of alcohol (−)-S14 as a colorless oil. 1H, 13C, and optical rotation
1602, 1419, 1246, 1199, 1167, 1117, 945. Because of volatility, we were
not able to obtain an HRMS for diiodide 26.
data were in agreement with literature values.10
Triethyl(((3S,5S)-2,2,5-trimethyloct-7-en-3-yl)oxy)silane
[(−)-23]. Alcohol (−)-S14 (0.713 g, 4.18 mmol) was dissolved in dry
CH2Cl2 (40 mL) and treated with imidazole (1.14 g, 16.7 mmol),
DMAP (0.051 g, 0.4 mmol), and triethylsilyl chloride (0.84 mL, 5.02
mmol). The reaction mixture was allowed to stir overnight at room
temperature before being diluted with CH2Cl2 and washed with a
saturated aqueous NaHCO3 solution and brine. The combined organic
layers were then dried over MgSO4, filtered, and concentrated. The
crude product was purified by flash column chromatography (95:5
hexanes/EtOAc) to afford 1.16 g (98% yield) of silyl ether (−)-23 as a
colorless oil. 1H, 13C, and optical rotation data were in agreement with
literature values.10
(5S,7S,E)-5,8,8-Trimethyl-7-((triethylsilyl)oxy)non-2-enamide
[(−)-S15]. To a solution of silyl ether (−)-23 (0.049 g, 0.17 mmol) in
dry CH2Cl2 (1 mL) was added freshly distilled acryloyl chloride (0.021
mL, 0.25 mmol), followed by the Hoveyda−Grubbs II precatalyst
(0.0054 g, 0.0086 mmol). The flask was flushed with nitrogen, and the
reaction mixture was allowed to stir overnight at room temperature.
After the disappearance of starting material was noted by TLC, NH4OH
(1 mL) was added in a single portion. The contents of the flask were
stirred vigorously for 1 h before the phases were separated and the
aqueous phase extracted with CH2Cl2. The combined organic layers
were then dried over MgSO4, filtered, and concentrated. The crude
product was purified by flash column chromatography (1:1 → 2:1
EtOAc/hexanes) to afford 0.033 g (58% yield) of amide (−)-S15 as a
pale yellow foam. [α]2D1.5 = −118.9 (c = 1.12, CHCl3); 1H NMR (δ, ppm,
CDCl3, 300 MHz) 6.88−6.78 (m, 1H), 5.83 (d, J = 15 Hz, 1H), 3.33
(dd, J = 2.1, 8.1 Hz, 1H), 2.39−2.30 (m, 1H), 1.93−1.69 (m, 2H), 1.42−
1.21 (m, 2H), 0.96 (t, J = 8.1 Hz, 9 H), 0.91 (d, J = 6.8 Hz, 3H), 0.84 (s,
9H), 0.60 (q, J = 7.6 Hz, 6H); 13C NMR (δ, ppm, CDCl3, 75 MHz)
167.6, 144.9, 124.1, 78.6, 40.7, 38.4, 35.6, 29.5, 26.2, 21.0, 7.2, 5.8; IR
(neat, thin film) ν 3348, 3183, 2956, 2913, 2876, 1674, 1646, 1617,
1414, 1107, 1086, 977, 737 cm−1; HRMS m/z calcd for C18H37NO2SiNa
[M + Na]+, 350.2486; found, 350.2485.
(5S,7S)-7-Hydroxy-5,8,8-trimethylnonanamide [(−)-24].
Amide (−)-S15 (0.026 g, 0.074 mmol) was dissolved in a 1:1 mixture
of EtOH/EtOAc (2 mL) and treated with Pd/C (0.025 g). The reaction
mixture was then flushed with hydrogen gas and allowed to stir
overnight under an atmosphere of hydrogen (using a balloon). After
TLC showed the complete consumption of starting material, the
reaction mixture was diluted with EtOAc and filtered through a short
plug of Celite, rinsing several times with fresh EtOAc. The filtrate was
concentrated in vacuo and purified by flash column chromatography
(100:1 EtOAc/Et3N) to afford 0.014 g (89% yield) of amide (−)-24 as
an amorphous white solid. [α]2D4.1 = −54.9 (c = 1.01, CHCl3); 1H NMR
(δ, ppm, CDCl3, 400 MHz) 5.64 (bs, 2H), 3.28 (dd, J = 2.0, 10.4 Hz,
1H), 2.22 (t, J = 7.2 Hz, 2H), 1.87−1.48 (m, 5H), 1.39−1.32 (m, 1H),
1.26−1.19 (m, 1H), 1.11−1.02 (m, 1H), 0.94 (d, J = 6.4 Hz, 3H), 0.88
(s, 9H); 13C NMR (δ, ppm, CDCl3, 100 MHz) 175.7, 77.2, 39.0, 35.9,
34.9, 34.6, 29.4, 25.7, 22.8, 20.9; IR (neat, thin film) ν 3352, 3195, 2953,
2870, 1667, 1615, 1479, 1463, 1394, 1364, 1072 cm−1; HRMS m/z calcd
for C12H25NO2Na [M + Na]+, 238.1778; found, 238.1776.
(E)-1,4-Diiodobut-1-ene (26). Triphenylphosphine (2.15 g, 8.21
mmol) and imidazole (0.559 g, 8.21 mmol) were dissolved in dry
CH2Cl2 (25 mL) and cooled to 0 °C. To this was added iodine crystals
(2.08 g, 8.21 mmol), and the contents of the flask were allowed to stir at
0 °C for 15 min before a solution of alcohol 2531 (1.55 g, 7.82 mmol) in
dry CH2Cl2 (15 mL) was added via cannula. The cooling bath was
removed, and the reaction mixture was allowed to stir at room
temperature for 4 h. The mixture was concentrated in vacuo and
redissolved in ether. The triphenylphosphine oxide, which precipitated,
was filtered over Celite, and the filtrate was washed several times with
ether. The combined ether layers were again concentrated in vacuo and
purified directly by flash column chromatography (100% hexanes) to
afford 2.18 g (90% yield) of diiodide 26 as a slightly yellow oil. 1H NMR
(δ, ppm, CDCl3, 300 MHz) 6.52−6.43 (m, 1H), 6.21 (d, J = 14.4, 1H),
3.15 (t, J = 6.0 Hz, 2H), 2.62 (q, J = 6.9 Hz, 2H); 13C NMR (δ, ppm,
CDCl3, 75 MHz) 143.9, 78.0, 39.5, 2.9; IR (neat, thin film) ν 3045, 2956,
(R,E)-N-((1S,2S)-1-Hydroxy-1-phenylpropan-2-yl)-6-iodo-
N,2-dimethylhex-5-enamide [(+)-S16]. Lithium chloride (0.147 g,
3.47 mmol) was placed in a round-bottom flask under vacuum and
flame-dried before use. Once cooled, the flask was placed under an
atmosphere of nitrogen and charged with diisopropylamide (0.18 mL,
1.30 mmol) and dry THF (1 mL). The contents of the flask were cooled
to 0 °C and treated with nBuLi (2.5 M in hexanes, 0.52 mL, 1.30 mmol)
dropwise. After 20 min, the LDA solution was cooled to −78 °C before a
solution of amide 27a (0.128 g, 0.57 mmol) in dry THF (2 mL) was
added dropwise via cannula. After 1 h at −78 °C, the flask was allowed to
warm to 0 °C for 15 min, and then room temperature for 5 min. The
flask was then cooled back down to 0 °C, and a solution of diiodide 26
(0.446 g, 1.44 mmol) in dry THF (1 mL) was added slowly via cannula.
The reaction mixture was allowed to stir at 0 °C for 30 min before being
quenched by the addition of a saturated aqueous solution of NH4Cl (10
mL). The phases were separated, and the aqueous phase was extracted
with CH2Cl2, followed by EtOAc. The combined organic layers were
then dried over MgSO4, filtered, and concentrated. The crude product
was purified by flash column chromatography (1:1 EtOAc/hexanes) to
afford 0.127 g [54% (83% borsm)] of vinyl amide (+)-S16 as an
amorphous white solid and as a pair of rotamers (∼3:1 ratio). [α]D23.8
=
1
+39.3 (c = 1.90, CHCl3); H NMR (mixture of rotamers, δ, ppm,
CDCl3, 400 MHz) 7.40−7.24 (m, 8H), 6.51 (minor, quintet, J = 6.8 Hz,
0.3H), 6.40 (major, quintet, J = 7.6 Hz, 1H), 6.02 (minor, d, J = 14.8 Hz,
0.3H), 5.8 (major, d, J = 14.4 Hz, 1H), 4.63−4.55 (m, 2H), 4.42 (bs,
1H), 4.07−4.00 (minor, m, 0.3H), 2.90 (minor, s, 1H), 2.84 (major, s,
3H), 2.67−2.53 (m, 1.4H), 2.07−1.85 (m, 3.3H), 1.80−1.72 (m, 1H),
1.45−1.33 (m, 1.5H), 1.14 (d, J = 6.8 Hz, 3H), 1.05 (d, J = 6.8 Hz, 4H),
1.01 (d, J = 6.8 Hz, 1.3H); 13C NMR (mixture of rotamers, δ, ppm,
CDCl3, 100 MHz) 177.9, 176.9, 146.4, 145.8, 142.5, 141.4, 128.7, 128.3,
127.5, 126.9, 126.1, 76.1, 75.4, 75.0, 57.7, 35.5, 34.7, 33.7, 32.2, 27.1,
18.0, 17.4, 15.6, 14.3; IR (neat, thin film) ν 3377, 3061, 3029, 2968,
2933, 2873, 1616, 1453, 1409, 1374, 1108. 1082, 1050, 1027, 701 cm−1;
HRMS m/z calcd for C17H24INO2Na [M + Na]+, 424.0744; found,
424.0738.
(R,E)-6-Iodo-2-methylhex-5-enoic acid [(−)-28a]. A solution of
amide (+)-S16 (0.095 g, 0.230 mmol) in t-BuOH (2 mL) and MeOH (2
mL) was treated with an aqueous NaOH solution (3.22 N, 4 mL). A
condenser was attached, and the mixture was heated to 85 °C for 24 h.
The flask was allowed to cool before the contents were concentrated in
vacuo. The aqueous residue was diluted with water and washed with
CH2Cl2. The aqueous layer was acidified with concentrated HCl
solution and again extracted with CH2Cl2. The combined organic layers
were then dried over MgSO4, filtered, and concentrated to afford 0.058 g
(95%) of vinyl iodide (−)-28a as a colorless oil that would be used
directly in the next step without further purification. [α]2D1.9 = −18.8 (c =
1
0.82, CHCl3); H NMR (δ, ppm, CDCl3, 400 MHz) 6.54−6.44 (m,
1H), 6.06 (td, J = 1.2, 14.4 Hz, 1H), 2.48 (sextet, J = 6.9 Hz, 1H), 2.12
(dq, J = 1.2, 7.5 Hz, 2H), 1.87−1.75 (m, 1H), 1.62−1.48 (m, 1H), 1.20
(d, J = 7.2 Hz, 3H); 13C NMR (δ, ppm, CDCl3, 100 MHz) 182.3, 145.2,
75.6, 38.4, 33.6, 31.9, 16.8; IR (neat, thin film) ν 3049, 2967, 2930, 1702
cm−1; HRMS m/z calcd for C7H11IO2Na [M + Na]+, 276.9696; found,
276.9694.
(R,E)-(3S,5S)-9-Amino-2,2,5-trimethyl-9-oxononan-3-yl-6-
iodo-2-methylhex-5-enoate [(−)-31]. A solution of vinyl iodide
(−)-28a (0.044 g, 0.17 mmol) in dry THF (1.7 mL) was treated with
freshly distilled DIPEA (47.3 mL, 0.27 mmol), followed by 2,4,6-
trichlorobenzoyl chloride (26.5 mL, 0.17 mmol). The mixture was
stirred at room temperature for 3 h, and the resulting mixed anhydride
was then concentrated in vacuo. The residue was dissolved in dry
toluene (4.0 mL) and was added, via cannula, to a separate flask
containing amide (−)-24 (0.0157 g, 0.072 mmol) and DMAP (0.0142 g,
0.11 mmol). The reaction mixture was allowed to stir at room
temperature for 18 h before CH2Cl2 (20 mL) was added, and the
mixture was washed with a saturated aqueous solution of NaHCO3 (20
mL). The phases were separated, and the aqueous layer was extracted
with additional CH2Cl2. The combined organic layers were then dried
over MgSO4, filtered, and concentrated. The crude product was purified
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by flash column chromatography (1:1 EtOAc/hexanes) to afford 0.027 g
(−)-S18. The crude product [0.012 g (65%)], as an amorphous white
solid, was sufficiently clean to use in the next step without further
(81% yield) of amide (−)-31 as an amorphous white solid. [α]D21.4
=
−42.1 (c = 1.08, CHCl3); 1H NMR (δ, ppm, CDCl3, 300 MHz) 6.49 (dt,
J = 7.2, 14.4 Hz, 1H), 6.02 (d, J = 14.4 Hz, 1H), 5.88 (bs, 1H), 5.46 (bs,
1H), 4.79 (dd, J = 4.5, 6.3 Hz, 1H), 2.45 (sextet, J = 6.9 Hz, 1H), 2.23−
2.15 (m, 2H), 2.12−2.05 (m, 2H), 1.86−1.69 (m, 2H), 1.61−1.25 (m,
6H), 1.17 (d, J = 7.2 Hz, 3H), 1.11−0.99 (m, 1H), 0.91−0.87 (doublet/
singlet overlapping, 12H); 13C NMR (δ, ppm, CDCl3, 75 MHz) 176.5,
175.8, 145.6, 79.0, 75.5, 39.3, 37.7, 35.7, 34.79, 34.77, 33.9, 32.3, 29.2,
26.1, 22.8, 21.1, 17.5; IR (neat, thin film) ν 3429, 3351, 3203, 2962,
2934, 2868, 1725, 1665, 1607, 1461, 1380, 1366, 1259, 1181, 1119,
1067, 957, 935 cm−1; HRMS m/z calcd for C19H34INO3Na [M + Na]+,
474.1476; found, 474.1471.
purification. [α]2D5.1 = +21.0 (c = 1.06, CHCl3); H NMR (δ, ppm,
1
CDCl3, 400 MHz) 6.54−6.44 (m, 1H), 6.06 (td, J = 1.2, 14.4 Hz, 1H),
2.48 (sextet, J = 6.9 Hz, 1H), 2.12 (dq, J = 1.2, 7.5 Hz, 2H), 1.87−1.75
(m, 1H), 1.62−1.48 (m, 1H), 1.20 (d, J = 7.2 Hz, 3H); 13C NMR (δ,
ppm, CDCl3, 100 MHz) 182.3, 145.2, 75.6, 38.4, 33.6, 31.9, 16.8; IR
(neat, thin film) ν 3049, 2967, 2930, 1702 cm−1; HRMS m/z calcd for
C7H11IO2Na [M + Na]+, 276.9696; found, 276.9699.
(S,E)-(3S,5S)-9-Amino-2,2,5-trimethyl-9-oxononan-3-yl-6-
iodo-2-methylhex-5-enoate [(−)-32]. (−)-32 was prepared in a
similar manner as amide (−)-31, using vinyl iodide (+)-28b. The crude
product was purified by flash column chromatography (1:1 EtOAc/
hexanes) to afford 0.098 g (74%) of amide (−)-32 as an amorphous
(3R,13S,15S,E)-15-(tert-Butyl)-3,8,13-trimethyl-1-oxa-8-aza-
cyclopentadec-6-ene-2,9-dione [(+)-21a]. A mixture of amide
(−)-31 (0.022 g, 0.048 mmol), copper iodide (0.005 g, 0.026 mmol),
and cesium carbonate (0.030 g, 0.092 mmol) was suspended in dry THF
(5 mL). N,N′-Dimethylethylenediamine (20 μL, 0.026 mmol) was
added, and the reaction flask was degassed by bubbling dry nitrogen gas
for 10 min. The septum was quickly removed and replaced with a glass
stopper. The contents of the flask were then heated at 60 °C overnight.
The flask was allowed to cool to room temperature before being diluted
with EtOAc and filtered through a short plug of silica gel. The crude N-H
macrolide was then concentrated in vacuo and purified by flash column
chromatography (8:2 hexanes/EtOAc) to afford 0.005 g (32%) of
enamide S17, which was used in the next step without extensive
characterization. Enamide S17 (0.005 g, 0.015 mmol) was dissolved in
dry THF (0.5 mL), cooled to 0 °C, and treated with sodium hydride
(60% dispersion, 0.003 g, 0.077 mmol). The cooling bath was removed,
and the flask was allowed to warm to room temperature and stir for 20
min. Iodomethane (0.1 mL, 1.61 mmol) was then added. After 20 min,
the reaction mixture was diluted with EtOAc and quenched with water.
The phases were separated, and the aqueous phase was extracted with
additional EtOAc. The combined organic layers were then dried over
MgSO4, filtered, and concentrated. The crude product was purified by
flash column chromatography (8:2 hexanes/EtOAc) to afford 0.005 g
(90%) of (+)-21a as a colorless oil. [α]2D1.4 = +2.7 (c = 0.39, CHCl3); 1H
NMR (δ, ppm, CDCl3, 400 MHz) 6.63 (d, J = 13.6 Hz, 1H), 4.92 (ddd, J
= 5.2, 8.8, 13.6 Hz, 1H), 4.85 (dd, J = 2.0, 9.6 Hz, 1H), 3.05 (s, 3H),
2.60−2.42 (m, 3H), 2.32 (dt, J = 7.2, 13.6 Hz, 1H), 2.24−2.17 (m, 1H),
2.03−1.95 (m, 1H), 1.84−1.74 (m, 1H), 1.68−1.54 (m, 2H), 1.49−1.30
(m, 4H), 1.26 (d, J = 7.2 Hz, 3H), 1.03−0.93 (m, 1H), 0.89 (d, J = 6.4
Hz, 3H), 0.86 (s, 9H); 13C NMR (δ, ppm, CDCl3, 100 MHz) 175.4,
172.8, 129.8, 110.2, 76.5, 37.2, 36.6, 35.4, 34.3, 33.6, 31.0, 29.8, 29.5,
27.3, 25.9, 24.9, 20.0, 19.2; IR (neat, thin film) ν 2959, 2927, 2873, 1728,
1675, 1646, 1466, 1413, 1384, 1366, 1333, 1298, 1240, 1205, 1193,
1171, 1121, 933 cm−1; HRMS m/z calcd for C20H35NO3Na [M + Na]+,
360.2509; found, 360.2503.
1
white solid. [α]2D3.2 = −20.5 (c = 1.01, CHCl3); H NMR (δ, ppm,
CDCl3, 400 MHz) 6.52−6.44 (m, 1H), 6.02 (d on top of a bs, J = 14.4
Hz, 3H), 4.78 (dd, J = 3.6, 8.4 Hz, 1H), 2.49−2.42 (m, 1H), 2.23−2.05
(m, 4H), 1.85−1.71 (m, 2H), 1.55−1.43 (m, 3H), 1.41−1.37 (m, 1H),
1.31−1.20 (m, 1H), 1.16 (d, J = 6.8 Hz, 3H), 1.10−0.99 (m, 1H), 0.98
(d, J = 6.8 Hz, 3H), 0.87 (s, 9H); 13C NMR (δ, ppm, CDCl3, 100 MHz)
176.3 (2C), 145.4, 78.8, 75.3, 39.2, 37.5, 34.6, 34.5, 33.7, 33.6, 32.1, 28.9,
25.9, 22.6, 20.8, 17.4; IR (neat, thin film) ν 3423, 3350, 3200, 2964,
2872, 1724, 1667, 1607, 1462, 1397, 1379, 1366, 1222, 1186, 1123,
1065, 957 cm−1; HRMS m/z calcd for C19H34INO3Na [M + Na]+,
474.1476; found, 474.1463.
(3S,13S,15S,E)-15-(tert-Butyl)-3,8,13-trimethyl-1-oxa-8-aza-
cyclopentadec-6-ene-2,9-dione [(+)-ent-21b]. (+)-ent-21b was
prepared in a similar manner as macrolide (−)-21a, using amide
(−)-32. The crude product was purified by flash column chromatog-
raphy (8:2 hexanes/EtOAc) to afford 0.013 g (40% over two steps) of
macrolide (+)-ent-21b as a colorless oil. [α]2D2.9 = +23.4 (c = 0.65,
CHCl3); 1H NMR (δ, ppm, CDCl3, 400 MHz) 6.47 (d, J = 14 Hz, 1H),
5.27 (dt, J = 7.2, 14 Hz, 1H), 4.88 (dd, J = 2.0, 10.8 Hz, 1H), 3.04 (s, 3H),
2.52−2.43 (m, 1H), 2.42−2.34 (m, 2H), 2.33−2.24 (m, 2H), 1.86−1.71
(m, 3H), 1.70−1.45 (m, 3H), 1.41−1.31 (m, 2H), 1.21 (d, J = 7.2 Hz,
3H), 1.11−1.02 (m, 1H), 0.90 (d, J = 6.4 Hz, 3H), 0.87 (s, 9H); 13C
NMR (δ, ppm, CDCl3, 100 MHz) 175.3, 172.9, 130.7, 117.3, 38.9, 35.8,
35.2, 34.5, 32.8, 31.7, 29.3, 27.0, 26.1, 24.3, 20.6, 16.8 [Note: At 100
MHz, we did not observe the C(7) CH signal at δ 76.9 ppm. At this
frequency, the peak is buried under the CDCl3 peak. Pleasingly, the peak
is visible in the HMQC spectra]; IR (neat, thin film) ν 2963, 2873, 1725,
1676, 1649, 1465, 1366, 1250, 1180, 1127, 1072, 936 cm−1; HRMS m/z
calcd for C20H35NO3Na [M + Na]+, 360.2509; found, 360.2503.
(3S,5R)-2,2,5-Trimethyloct-7-en-3-ol [(−)-S19]. (−)-S19 was
prepared in a similar manner as alcohol (−)-S14, using (+)-10. The
crude product was purified by flash column chromatography (95:5
hexanes/EtOAc) to afford 0.170 g (67%) of alcohol (−)-S19 as a
colorless oil. [α]2D2.1 = −51.1 (c = 1.19, CHCl3); H NMR (δ, ppm,
1
(S,E)-N-((1R,2R)-1-Hydroxy-1-phenylpropan-2-yl)-6-iodo-
N,2-dimethylhex-5-enamide [(−)-S18]. (−)-S18 was prepared in a
similar manner as vinyl iodide (+)-S16, using amide 27b. The crude
product was purified by flash column chromatography (1:1 EtOAc/
hexanes) to afford 0.969 g [50% (77% borsm)] of vinyl iodide (−)-S18
as an amorphous white solid and as a pair of rotamers (∼3:1 ratio).
CDCl3, 300 MHz) 5.79 (dddd, J = 7.0, 7.0, 10.9, 16.3 Hz, 1H), 5.02
(dddd, J = 1.5, 2.3, 3.7, 5.2 Hz, 1H), 4.98 (t, J = 1.5 Hz, 1H), 3.29 (dd, J =
1.9, 10.5 Hz, 1H), 1.90−2.12 (m, 2H), 1.76 (m, 1H), 1.36 (ddd, J = 3.3,
10.5, 13.9 Hz, 1H), 1.34 (bs, 1H), 1.19 (ddd, 1.8, 10.5, 13.9 Hz, 1H),
0.90 (d, J = 6.7 Hz, 3H), 0.88 (s, 9H); 13C NMR (δ, ppm, CDCl3, 75
MHz) 137.5, 115.8, 77.4, 42.7, 38.4, 34.8, 29.6, 25.6, 18.7; IR (neat, thin
film) ν 3398, 2957, 1824, 1639, 1477, 1465, 1377, 1305, 1073, 993, 909
cm−1; HRMS m/z calcd for C11H22ONa [M + Na]+, 193.1563; found,
193.1562.
[α]2D3.8 = −35.1 (c = 1.23, CHCl3); H NMR (mixture of rotamers, δ,
1
ppm, CDCl3, 400 MHz) 7.40−7.24 (m, 8H), 6.51 (minor, quintet, J =
6.8 Hz, 0.3H), 6.40 (major, quintet, J = 7.6 Hz, 1H), 6.02 (minor, d, J =
14.8 Hz, 0.3H), 5.8 (major, d, J = 14.4 Hz, 1H), 4.63−4.55 (m, 2H), 4.42
(bs, 1H), 4.07−4.00 (minor, m, 0.3H), 2.90 (minor, s, 1H), 2.84 (major,
s, 3H), 2.67−2.53 (m, 1.4H), 2.07−1.85 (m, 3.3H), 1.80−1.72 (m, 1H),
1.45−1.33 (m, 1.5H), 1.14 (d, J = 6.8 Hz, 3H), 1.05 (d, J = 6.8 Hz, 4H),
1.01 (d, J = 6.8 Hz, 1.3H); 13C NMR (mixture of rotamers, δ, ppm,
CDCl3, 100 MHz) 177.9, 176.9, 146.4, 145.8, 142.5, 141.4, 128.7, 128.3,
127.5, 126.9, 126.1, 76.1, 75.4, 75.0, 57.7, 35.5, 34.7, 33.7, 32.2, 27.1,
18.0, 17.4, 15.6, 14.3; IR (neat, thin film) ν 3377, 3061, 3029, 2968,
2933, 2873, 1616, 1453, 1409, 1374, 1108. 1082, 1050, 1027, 701 cm−1;
HRMS m/z calc’d for C17H24INO2Na [M + Na]+, 424.0744; found,
424.0738.
Triethyl(((3S,5R)-2,2,5-trimethyloct-7-en-3-yl)oxy)silane
[(−)-33]. (−)-33 was prepared in a similar manner as silyl ether (−)-23,
using alcohol (−)-S19. The crude product was purified by flash column
chromatography (95:5 hexanes/EtOAc) to afford 0.261 g (92%) of silyl
ether (−)-33 as a colorless oil. [α]2D3.4 = −32.9 (c = 1.13, CHCl3); 1H
NMR (δ, ppm, CDCl3, 300 MHz) 5.78 (dddd, J = 7.0, 7.0, 11.4, 16.0 Hz,
1H), 5.01 (bd, J = 5.9 Hz, 1H), 4.97 (s, 1H), 3.34 (dd, J = 1.5, 9.1 Hz,
1H), 1.86−2.07 (m, 2H), 1.55−1.71 (m, 1H), 1.38 (ddd, J = 2.6, 9.1,
13.6 Hz, 1H), 1.15 (ddd, J = 1.5, 10.9, 13.6 Hz, 1H), 0.97 (t, J = 7.8 Hz,
6H), 0.86 (d, J = 6.5 Hz, 3H), 0.84 (s, 9H), 0.61 (q, J = 7.8 Hz, 9H); 13C
NMR (δ, ppm, CDCl3, 75 MHz) 137.5, 115.6, 78.8, 43.0, 40.2, 35.5,
29.6, 26.2, 19.0, 7.2, 5.8; IR (neat, thin film) ν 2955, 2876, 1640, 1460,
(S,E)-6-Iodo-2-methylhex-5-enoic Acid [(+)-28b]. (+)-28b was
prepared in a similar manner as vinyl iodide (−)-28a, using vinyl iodide
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1238, 1092, 1029, 910, 737 cm−1; HRMS m/z calcd for (C17H36OSi)2Na
[2M + Na]+, 591.4963; found, 591.4957.
1.80 (ddd, J = 7.6, 13.6, 15.5 Hz, 1H), 1.37−1.68 (m, 5H), 1.13−1.33
(m, 3H), 1.15 (d, J = 7.1 Hz, 3H), 0.89 (d, J = 5.5 Hz, 3H), 0.86 (s, 9H);
13C NMR (δ, ppm, CDCl3, 75 MHz) 175.9, 175.6, 145.5, 78.2, 75.2,
39.2, 37.7, 36.9, 36.1, 34.5, 33.7, 32.1, 29.4, 26.0, 23.1, 19.0, 17.4; IR
(neat, thin film) ν 3351, 2964, 1726, 1666, 1461, 1366, 1183, 1066 cm−1;
HRMS m/z calcd for C19H34INO3Na [M + Na]+, 474.1475; found,
474.1462.
(5S,7S,E)-5,8,8-Trimethyl-7-((triethylsilyl)oxy)non-2-enamide
[(−)-S20]. (−)-S20 was prepared in a similar manner as amide (−)-S15,
using silyl ether (−)-33. The crude product was purified by flash column
chromatography (1:1 hexanes/EtOAc) to afford 0.135 g (82%) of amide
(−)-S20 as a pale yellow foam and as a ca. 25:1 mixture of E/Z olefin
isomers that could not be separated by column chromatography. [α]D22.8
= −23.6 (c = 2.33, CHCl3); 1H NMR (δ, ppm, CDCl3, 300 MHz) 6.82
(dt, J = 7.5, 15.2 Hz, 1H), 6.01 (bs, 1H), 5.82 (d, J = 15.2 Hz, 1H), 5.56
(bs, 1H), 3.32 (dd, J = 1.1, 9.0 Hz, 1H), 2.18 (ddd, J = 6.1, 6.1, 13.5 Hz,
1H), 2.04 (ddd, J = 8.0, 8.0, 14.5 Hz, 1H), 1.65−1.83 (m, 1H), 1.36
(ddd, J = 2.1, 9.0, 13.7 Hz, 1H), 1.13−1.25 (m, 1H), 0.95 (t, J = 7.8 Hz,
6H), 0.86 (d, J = 6.5 Hz, 3H), 0.82 (s, 9H), 0.59 (q, J = 7.8 Hz, 9H); 13C
NMR (δ, ppm, CDCl3, 75 MHz) 168.0, 144.9, 123.9, 78.6, 41.1, 40.4,
35.5, 29.4, 26.2, 18.9, 7.2, 5.8; IR (neat, thin film) ν 3335, 3169, 2955,
1673, 1616, 1415, 1085, 739 cm−1; HRMS m/z calcd for
C18H37NO2SiNa [M + Na]+, 350.2485; found, 350.2478.
(5R,7S)-7-Hydroxy-5,8,8-trimethylnonanamide [(−)-34].
(−)-34 was prepared in a similar manner as amide (−)-24, using
amide (−)-S20. The crude product was purified by flash column
chromatography (100:1 EtOAc/Et3N) to afford 0.074 g (87%) of amide
(−)-34 as an amorphous white solid. [α]2D2.0 = −13.7 (c = 0.43, CHCl3);
1H NMR (δ, ppm, CDCl3, 300 MHz) 5.40 (bs, 2H), 3.28 (dd, J = 1.7,
10.4 Hz, 1H), 2.22 (t, J = 7.6 Hz, 2H), 1.58−1.78 (m, 3H), 1.12−1.42
(m, 5H), 0.90 (d, J = 6.8 Hz, 3H), 0.88 (s, 9H); 13C NMR (δ, ppm,
CDCl3, 75 MHz) 175.7, 77.3, 38.6, 37.7, 36.0, 34.8, 29.3, 25.7, 22.8, 19.0;
IR (neat, thin film) ν 3351, 2953, 1666, 1462, 1394, 1075, 1007 cm−1;
HRMS m/z calcd for C12H25NO2Na [M + Na]+, 238.1777; found,
238.1775.
(R,E)-(3S,5R)-9-Amino-2,2,5-trimethyl-9-oxononan-3-yl-6-
iodo-2-methylhex-5-enoate [(−)-35]. (−)-35 was prepared in a
similar manner as amide (−)-31, using amide (−)-34 and acid (−)-28a.
The crude product was purified by flash column chromatography (1:1
hexanes/EtOAc) to afford 0.033 g (45%) of amide (−)-35 as an
amorphous white solid. [α]2D1.7 = −16.9 (c = 1.63, CHCl3); 1H NMR (δ,
ppm, CDCl3, 300 MHz) 6.48 (dt, J = 7.0, 14.4 Hz, 1H), 6.01 (d, J = 14.4
Hz, 1H), 5.75 (bs, 1H), 5.46 (bs, 1H), 4.82 (d, J = 10.6 Hz, 1H), 2.36−
2.51 (m, 1H), 2.18 (t, J = 7.6 Hz, 2H), 2.08 (q, J = 7.5 Hz, 2H), 1.71−
1.87 (m, 1H), 1.38−1.70 (m, 4H), 1.18−1.36 (m, 4H), 1.16 (d, J = 7.0
Hz, 3H), 0.90 (d, J = 7.0 Hz, 3H), 0.87 (s, 9H); 13C NMR (δ, ppm,
CDCl3, 75 MHz) 175.9, 175.6, 145.5, 78.2, 75.2, 39.0, 37.7, 36.8, 36.1,
34.6, 33.7, 32.1, 29.5, 26.0, 23.1, 19.0, 17.3; IR (neat, thin film) ν 3351,
2964, 1726, 1667, 1462, 1380, 1183, 1067, 935 cm−1; HRMS m/z calcd
for C19H34INO3Na [M + Na]+, 474.1475; found, 474.1463.
(3S,13R,15S,E)-15-(tert-Butyl)-3,8,13-trimethyl-1-oxa-8-aza-
cyclopentadec-6-ene-2,9-dione [(−)-ent-22b]. (−)-ent-22b was
prepared in a similar manner as macrolide (−)-21a, using amide (−)-36.
The crude product was purified by flash column chromatography (9:1
hexanes/EtOAc) to afford 0.010 g (29% over two steps) of macrolide
(−)-ent-22b as a colorless oil. [α]2D3.2 = −45.5 (c = 0.5, CHCl3); 1H NMR
(δ, ppm, CDCl3, 300 MHz) 6.66 (d, J = 13.9 Hz, 1H), 5.13 (dt, J = 13.9,
6.8 Hz, 1H), 4.86 (dd, J = 0.9, 10.2 Hz, 1H), 3.06 (s, 3H), 2.36−2.66 (m,
3H), 2.03−2.36 (m, 2H), 1.50−1.97 (m, 5H), 1.23−1.40 (m, 3H), 1.19
(d, J = 6.9 Hz, 3H), 1.10−1.20 (m, 1H), 0.94 (d, J = 6.0 Hz, 3H), 0.90 (s,
9H); 13C NMR (δ, ppm, CDCl3, 75 MHz) 175.6, 172.6, 131.0, 112.9,
79.0, 38.0, 36.5, 36.4, 34.9, 33.9, 33.0, 30.8, 27.7, 27.2, 26.1, 22.7, 20.6,
17.5; IR (neat, thin film) ν 2964, 1725, 1675, 1647, 1463, 1382, 1260,
1178, 1082, 935 cm−1; HRMS m/z calcd for C20H35NO3Na [M + Na]+,
360.2509; found, 360.2506.
(R)-4-Hydroxy-5,5-dimethylhexan-2-one [(+)-ent-7]. (+)-ent-7
was prepared in a similar manner as alcohol (−)-7, using L-proline as
organocatalyst. The crude product was purified by flash column
chromatography (4:1 hexanes/EtOAc) to afford 2.16 g (51%) of alcohol
(+)-ent-7 as a slightly yellow oil. [α]2D3.6 = +71.1 (c = 1.11, CHCl3); 1H
NMR (δ, ppm, CDCl3, 300 MHz) 3.68 (dd, J = 2.2, 10.1 Hz, 1H), 2.93
(bs, 1H), 2.59 (dd, J = 2.1, 17.1 Hz, 1H), 2.44 (dd, J = 10.1, 17.2 Hz,
1H), 2.16 (s, 3H), 0.87 (s, 9H); 13C NMR (δ, ppm, CDCl3, 75 MHz)
210.4, 74.8, 45.0, 34.1, 30.8, 25.5; IR (neat, thin film) ν 3468, 2956,
2872, 1710, 1480, 1365, 1288, 1245, 1163, 1076 cm−1; HRMS m/z calcd
for (C8H16O2)2Na [2M + Na]+, 311.2193; found, 311.2193.
(2R,4R)-5,5-Dimethylhexane-2,4-diol [(+)-ent-S1]. (+)-ent-S1
was prepared in a similar manner as diol (−)-S1, using alcohol
(+)-ent-7. The crude product was purified by flash column
chromatography (1:1 hexanes/EtOAc) to afford 0.626 g (65%) of diol
(+)-ent-S1 as an amorphous white solid. [α]2D3.5 = +1.9 (c = 1.15,
CHCl3); 1H NMR (δ, ppm, CDCl3, 300 MHz) 4.04−3.92 (m, 1H), 3.46
(dd, J = 1.9, 10.6 Hz, 1H), 3.13 (bs, 1H), 2.67 (bs, 1H), 1.58 (ddd, J =
2.2, 2.2, 14.4 Hz, 1H), 1.39 (ddd, J = 9.7, 10.4, 14.4 Hz, 1H), 1.20 (d, J =
6.2 Hz, 3H), 0.33 (s, 9H); 13C NMR (δ, ppm, CDCl3, 75 MHz) 81.0,
69.3, 38.6, 34.8, 25.5, 24.5; IR (neat, thin film) ν 3351, 2961, 2871, 1127,
1079 cm−1; HRMS m/z calcd for C8H18O2Na [M + Na]+, 169.1199;
found, 169.1198.
(4R,6R)-4-(tert-Butyl)-6-methyl-1,3,2-dioxathiane 2,2-dioxide
[(+)-ent-8]. (+)-ent-8 was prepared in a similar manner as sulfate (−)-8,
using diol (+)-ent-S1. The crude product was purified by flash column
chromatography (8:1 hexanes/EtOAc) to afford 0.822 g (92% over two
steps) of syn-cyclic sulfate (+)-ent-8 as an amorphous white solid. [α]D23.0
= +4.2 (c = 1.65, CHCl3); 1H NMR (δ, ppm, CDCl3, 300 MHz) 5.00−
4.86 (m, 1H), 4.52 (dd, J = 5.6, 8.8 Hz, 1H), 1.85 (t, J = 5.5 Hz, 1H), 1.85
(t, J = 8.6 Hz, 1H), 1.47 (dd, J = 6.3, 8.8 Hz, 3H), 1.00 (s, 9H); 13C NMR
(δ, ppm, CDCl3, 75 MHz) 91.8, 81.0, 34.3, 31.6, 25.2, 20.8; IR (neat,
thin film) ν 2966, 2877, 1386, 1370, 1187, 1045, 892, 876 cm−1; HRMS
m/z calcd for C8H16O4SNa [M + Na]+, 231.0662; found, 231.0661.
(3R,5R)-2,2,5-Trimethyloct-7-en-3-ol [(+)-37]. (+)-37 was pre-
pared in a similar manner as alcohol (−)-S14, using sulfate (+)-ent-8.
The crude product was purified by flash column chromatography (9:1
hexanes/EtOAc) to afford 0.80 g (88%) of alcohol (+)-37 as a colorless
oil. [α]2D3.0 = +37.3 (c = 1.07, CHCl3); 1H NMR (δ, ppm, CDCl3, 300
MHz) 5.86−5.86 (m, 1H), 5.05−4.97 (m, 2H), 3.31 (dd, J = 1.8, 10.2
Hz, 1H), 1.93−1.70 (m, 2H), 1.42 (ddd, J = 1.8, 9.2, 14.3 Hz, 1H), 1.36
(bs, 1H), 1.19 (ddd, J = 5.1, 9.2, 19.4 Hz, 1H), 0.95 (d, J = 6.6, 3H), 0.88
(s, 9H); 13C NMR (δ, ppm, CDCl3, 75 MHz) 137.1, 116.0, 77.5, 39.8,
38.5, 35.0, 29.8, 25.6, 20.9; IR (neat, thin film) ν 3391, 3076, 2956, 2870,
1478, 1459 1364 1069, 992, 910 cm−1; HRMS m/z calcd for
(C11H22O)2Na [2M + Na]+, 363.3233; found, 363.3234.
(3R,13R,15S,E)-15-(tert-Butyl)-3,8,13-trimethyl-1-oxa-8-aza-
cyclopentadec-6-ene-2,9-dione [(−)-22a]. (−)-22a was prepared
in a similar manner as macrolide (−)-21a, using amide (−)-35. The
crude product was purified by flash column chromatography (85:15
hexanes/EtOAc) to afford 0.005 g (18% over two steps) of macrolide
(−)-22a as a colorless oil. [α]2D4.0 = −44.0 (c = 0.16, CHCl3); 1H NMR
(δ, ppm, CDCl3, 300 MHz) 6.68 (d, J = 13.8 Hz, 1H), 4.86 (ddd, J = 4.3,
10.2, 4.7 Hz, 1H), 4.78 (dd, J = 0.3, 9.9 Hz, 1H), 3.07 (s, 3H), 2.64 (dt, J
= 8.1, 13.6 Hz, 1H), 2.44−2.58 (m, 1H), 2.02−2.39 (m, 3H), 1.84−2.01
(m, 2H), 1.30−1.46 (m, 5H), 1.23 (d, J = 7.2 Hz, 3H), 1.03−1.13 (m,
2H), 0.94 (d, J = 4.8 Hz, 3H), 0.87 (s, 9H); 13C NMR (δ, ppm, CDCl3,
75 MHz) 175.8, 172.1, 129.9, 110.2, 78.6, 38.4, 37.0, 35.3, 34.9, 31.8,
31.7, 29.7, 29.1, 28.0, 25.9, 23.3, 19.6, 19.4; IR (neat, thin film) ν 2962,
1729, 1675, 1646, 1464, 1384, 1199, 1165, 1125, 1084, 930 cm−1;
HRMS m/z calcd for C20H35NO3Na [M + Na]+, 360.2509; found,
360.2504.
(S,E)-(3S,5R)-9-Amino-2,2,5-trimethyl-9-oxononan-3-yl-6-
iodo-2-methylhex-5-enoate [(−)-36]. (−)-36 was prepared in a
similar manner as amide (−)-31, using amide (−)-34 and acid (+)-28b.
The crude product was purified by flash column chromatography (1:1
hexanes/EtOAc) to afford 0.052 g (65%) of amide (−)-36 as an
amorphous white solid. [α]2D2.2 = −4.1 (c = 0.26, CHCl3); 1H NMR (δ,
ppm, CDCl3, 300 MHz) 6.48 (dt, J = 7.0, 14.4 Hz, 1H), 6.01 (d, J = 14.4
Hz, 1H), 5.79 (bs, 1H), 5.48 (bs, 1H), 4.82 (dd, J = 1.2, 10.7 Hz, 1H),
2.36−2.50 (m, 1H), 2.18 (t, J = 6.7 Hz, 2H), 2.07 (q, J = 7.4 Hz, 2H),
(5R,7R,E)-7-Hydroxy-5,8,8-trimethylnon-2-enamide [(+)-38].
To a solution of alcohol (+)-37 (0.050 g, 0.29 mmol) in dry CH2Cl2 (4
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Article
mL) was added acrylamide (0.031 g, 0.44 mmol), CuI (0.002 g, 0.009
mmol), and the Grubbs II precatalyst (0.005 g, 0.006 mmol). The
reaction mixture was first degassed by bubbling in dry nitrogen for 10
min before being heated to 40 °C for 3 h. The flask was then cooled to
room temperature, and the solvent was removed under vacuum. The
crude residue was diluted with EtOAc, transferred to a separatory funnel,
and washed three times with water. The combined organic layers were
then dried over MgSO4, filtered, and concentrated. The crude product
was purified by flash column chromatography (8:2 EtOAc/hexanes) to
afford 0.052 g (83%) of amide (+)-38 as a colorless oil. [α]2D4.9 = +40.2 (c
= 1.01, CHCl3); 1H NMR (δ, ppm, CDCl3, 400 MHz) 6.84 (dt, J = 7.1,
15.3 Hz, 1H), 5.84 (d, 15.3 Hz, 1H), 5.63 (bs, 2H), 3.28 (d, 9.8 Hz, 1H),
2.39−2.31 (m, 1H), 2.05−1.92 (m, 2H), 1.90 (bs, 1H), 1.39 (ddd, J =
1.7, 9.3, 14.3 Hz, 1H), 1.25 (ddd, J = 3.9, 10.3, 14.4 Hz, 1H), 0.95 (d, 6.6
Hz, 3H), 0.87 (s, 9H); 13C NMR (δ, ppm, CDCl3, 100 MHz) 157.5,
145.1, 124.0, 77.3, 38.5, 38.0, 34.9, 29.7, 25.6, 21.0; IR (neat, thin film) ν
3342, 3193, 2955, 2870, 1675, 1641, 1607, 1396, 1365, 1069 cm−1;
HRMS m/z calcd for C12H23NO2Na [M + Na]+, 236.1621; found,
236.1620.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H and 13C NMR spectra of all new compounds and
1
copies of H NMR spectra of all known compounds. This
material is available free of charge via the Internet at http://pubs.
acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wmaio@nmsu.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would like to thank New Mexico State University for
providing financial assistance in terms of a startup package, as
well as Professor William Gerwick (UCSD) and Dr. Alban
Pereira (UCSD) for helpful discussions and for providing FIDs
of their Palmyrolide A work. We would also like to acknowledge
Ms. Emily M. Johnson and Ms. Cheyenne K. Valdez for their
technical assistance, and the COSMIC Laboratory facility at Old
Dominion University, VA, for providing high-resolution mass
spectrometry services. This article is dedicated to Professor Gary
H. Posner with admiration and respect on the happy occasion of
his 69th birthday in 2012.
(5R,7R)-7-Hydroxy-5,8,8-trimethylnonanamide [(+)-ent-24].
Amide (+)-38 (0.052 g, 0.244 mmol) was dissolved in a 1:1 mixture
of EtOH/EtOAc (2.4 mL) and treated with Pd/C (0.052 g). The
reaction mixture was then flushed with hydrogen gas and allowed to stir
overnight under an atmosphere of hydrogen (using a balloon). After 16
h, the reaction mixture was diluted with EtOAc and filtered through a
short plug of Celite, rinsing several times with fresh EtOAc. The filtrate
was concentrated in vacuo and purified by flash column chromatography
(100:1 EtOAc/Et3N) to afford 0.041 g (78%) of amide (+)-ent-24 as a
colorless oil. [α]2D3.4 = +40.5 (c = 1.01, CHCl3); H NMR (δ, ppm,
1
CDCl3, 300 MHz) 5.85 (bs, 1H), 5.76 (bs, 1H), 3.26 (dd, J = 2.1, 10.3
Hz, 1H), 2.20 (t, J = 7.2 Hz, 2H), 1.86 (bs, 1H), 1.79−1.44 (m, 4H),
1.34 (ddd, J = 1.9, 9.2, 14.0 Hz, 1H), 1.27−1.14 (m, 1H), 1.13−0.97 (m,
1H), 0.93 (d, J = 6.7 Hz, 3H), 0.86 (s, 9H); 13C NMR (δ, ppm, CDCl3,
75 MHz) 175.8, 77.2, 39.0, 35.9, 34.9, 34.5, 29.3, 25.7, 22.8, 20.9; IR
(neat, thin film) ν 3351, 2953, 1663, 1385 cm−1; HRMS m/z calcd for
C12H25NO2Na [M + Na]+, 238.1778; found, 238.1776.
REFERENCES
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colorless oil. [α]2D3.6 = −26.7 (c = 0.86, CHCl3); H NMR (δ, ppm,
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(40) We have observed faithful reproducibility for this union over
several successful attempts.
(41) Acrylamide has been previously used in cross-metathesis
processes employing the Grubbs II precatalyst alone (see ref 29);
however, to obtain high yields, the olefin partner (typically Type 1) is
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where olefin (+)-37 is a precious metathesis partner.
(42) We also attempted macrocyclization using the CuTc [copper(I)
thiophene-2-carboxylate] conditions developed by Porco. Unfortu-
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6289
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