Total synthesis of pactamycin and pactamycate: A detailed account

Article abstract of DOI:10.1021/jo301638z

This article describes synthetic studies that culminated in the first total synthesis of pactamycin and pactamycate and, in parallel, the two known congeners, de-6-MSA-pactamycin and de-6-MSA-pactamycate, lacking the 6-methylsalicylyl moiety. Starting with l-threonine as a chiron, a series of stereocontrolled condensations led to a key cyclopentenone harboring a spirocyclic oxazoline. A series of systematic functionalizations led initially to the incorrect cyclopentanone epoxide, which was "inverted" under solvolytic conditions. Installation of the remaining groups and manipulation of the oxazoline eventually led to pactamycin, pactamycate, and their desalicylyl analogues.

Full text of DOI:10.1021/jo301638z

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Total Synthesis of Pactamycin and Pactamycate: A Detailed Account
Stephen Hanessian,* Ramkrishna Reddy Vakiti, Stephane Dorich, Shyamapada Banerjee,
́
and Benoît Deschenes-Simard
̂
́ ́
Department of Chemistry, Universite de Montreal, Montreal, Quebec, Canada H3C 3J7
S
* Supporting Information
ABSTRACT: This article describes synthetic studies that
culminated in the first total synthesis of pactamycin and
pactamycate and, in parallel, the two known congeners, de-6-
MSA-pactamycin and de-6-MSA-pactamycate, lacking the 6-
methylsalicylyl moiety. Starting with L-threonine as a chiron, a
series of stereocontrolled condensations led to a key
cyclopentenone harboring a spirocyclic oxazoline. A series of
systematic functionalizations led initially to the incorrect
cyclopentanone epoxide, which was “inverted” under solvolytic
conditions. Installation of the remaining groups and
manipulation of the oxazoline eventually led to pactamycin,
pactamycate, and their desalicylyl analogues.
INTRODUCTION
■
The plethora of microbial secondary metabolites produced by
the soil bacterium of the Streptomyces family comprise a family
of highly substituted aminocyclopentitol-containing natural
products.1 Among these are pactamycin (1) and pactamycate
(2), two structurally unique and functionally rich metabolites
(Figure 1). Related cyclopentane core structures, albeit with
simpler substitution patterns, are encountered in allosamizoline
(5),2 mannostatin A (6),2 and trehazolamine (7).3 Early studies
on the biosynthesis of pactamycin were reported by Rinehart
and co-workers in 1978.4 More recently, Kudo and co-workers5
cloned the biosynthetic gene cluster involved in the formation
of the cyclopentane ring of pactamycin. Mahmud and co-
workers6 have shown pactamycin (1), pactamycate (2), de-6-
MSA-pactamycin (3), and de-6-MSA-pactamycate (4) are
produced from the same gene cluster.
Pactamycin was isolated in 1961 from a fermentation broth
of Streptomyces pactum var. pactum by scientists at the former
Upjohn Company.7 Although it exhibited in vitro activity
against certain Gram-positive and Gram-negative bacteria, as
well as cytotoxicity toward cancer cell lines, its further
development was curtailed due to its toxicity.8 This can be
attributed to its effect in arresting protein biosynthesis in
eukaryotes as well as in prokaryotes.9 Pioneering X-ray
crystallographic studies by Ramakrishnan and co-workers10
involving pactamycin bound to the 30S site of Thermus
thermophilus showed unique interactions, whereby its two
aromatic moieties are π-stacked against each other like
consecutive RNA bases, while the core aminocyclopentitol
motif mimics the RNA sugar−phosphate backbone. This results
in an intricate network of H-bonded interactions with specific
bases within the 30S site of the ribosome, as well as
intramolecularly.
Figure 1. Structures of pactamycin, pactamycate, de-6-MSA-
pactamycin, de-6-MSA-pactamycate, allosamizoline, mannostatin A,
and trehazolamine.
An initially proposed structure for pactamycin by the Upjohn
scientists in 1970 based on chemical degradation studies11 was
Received: August 6, 2012
Published: October 19, 2012
© 2012 American Chemical Society
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subsequently corrected in 1972 as a result of an X-ray crystal
structure of a derivative.12 To the best of our knowledge,
pactamycin is the most densely functionalized naturally
occurring aminocyclopentitol.13 In spite of its unique
architecture and rich history in the realm of other RNA-
binding natural products, efforts toward its synthesis have been
sparse. Conceptually different approaches toward the con-
struction of the aminocyclopentitol core of pactamycin were
reported by Isobe,14 Knapp,15 and more recently by Johnson,16
Looper,17 Nishikawa,18 and their respective co-workers.
RESULTS AND DISCUSSION
Cyclopentenone Core. A known three-step sequence
■
starting with L-threonine (8) led to the PMP-oxazoline
derivative 9 (Scheme 2a).20 Formation of the enolate with
Scheme 2. (a) Synthesis of the Cyclopentenone Intermediate
13 and (b) Suggested Transition State for the Formation of
10
In a preliminary communication, we reported the first total
synthesis of pactamycin (1) and pactamycate (2).19 Herein, we
provide a detailed account of our efforts, delineating initial
studies that were met with a number of unexpected dead ends
and road blocks, necessitating revisions of synthetic approaches.
Analysis of the structure of pactamycin reveals a number of
challenges, not the least of which are the presence of three
contiguous tertiary centers at C4, C5, and C1 (Scheme 1). We
Scheme 1. Strategic Bond Disconnections to Key
Intermediate Cyclopentenone A
were cognizant that the densely functionalized core motif
would require a judicious choice of carefully orchestrated bond-
forming sequences, in which the order of execution would be
crucial. On the basis of the existing functional groups and
substituents on the cyclopentane core of pactamycin, a series of
bond-forming sequences could be envisaged, as shown in
Scheme 1.
LiHMDS and condensation with O-TBDPS-2-hydroxymethyl
acrolein (B), followed by protection with TESOTf, afforded 10
as a single isomer. The observed stereoselectivity can be
rationalized based on a favored Zimmerman−Traxler transition
state model (Scheme 2b). Reduction of the benzyl ester to the
aldehyde, treatment with MeMgBr, and oxidation of the
resulting alcohol afforded the methyl ketone 11. Ozonolytic
cleavage of the exocyclic methylene group, followed by a highly
stereoselective Mukaiyama-type intramolecular aldol condensa-
tion, proceeding via a presumed Ti-coordinated Si-enol ether or
the corresponding Ti-enolate, afforded 12 as a shelf-stable
crystalline product which was fully characterized by X-ray
crystallography.21 Treatment of 12 with trichloroacetyl chloride
in pyridine led to the corresponding ester, which underwent in
situ β-elimination to give the intended cyclopentenone 13.
Elaboration of the Cyclopentenone Core (Plan A). We
started by exploring a sequence of reactions to introduce
functional groups in a “clockwise manner” commencing with
the carbonyl group at C2 in 13 (Scheme 3). Under a variety of
conditions, reduction led almost exclusively to the (R)-allylic
alcohol 14. This result augured well for the introduction of an
azide group at C2 (and eventually an amine), by an SN2
Straightforward as this plan may have appeared to be at the
outset, we were unaware of the potential difficulties associated
with effecting seemingly routine transformations as new
substituents and appendages were sequentially introduced on
the cyclopentane core. Considering the nature and placement
of the substituents, we chose to secure the aminoalcohol unit
comprising C1 and extending toward C2 (or C5) that could be
further elaborated into the cyclopentane core motif. With this
initial objective in mind, we chose L-threonine as a suitable
chiron that would provide a hydroxyethyl appendage with the
desired absolute configuration and allowed further elaboration
of the α-amino acid segment to introduce C-branching via
enolate or Claisen condensation. Since the aminoalcohol
portion of pactamycin was considered to be an inherent part
of the molecule, we wanted to adopt a modular approach for
the introduction of substituents around the cyclopentane core
to allow for diversification in preparing potentially bioactive
analogues and congeners with diminished toxicity. To this end,
we chose the cyclopentenone core motif A as our initial
objective for synthesis (Scheme 1).
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in 23, followed by deacetylation, led to 24, whose structure was
ascertained by X-ray crystallography of the corresponding p-
bromobenzoate ester.21 It is noteworthy that the direct
epoxidation of 20 gave only trace amounts of 23 and mainly
entailed slow decomposition. Disappointingly, attempts to
prepare the C2 triflate ester of 24 led to a complex mixture of
products.
Scheme 3. Toward the Pactamycin Core, Plan A (Part 1)
Faced with yet another impasse in our attempts to
functionalize C2, we proceeded to study conditions for the
regioselective ring opening of the epoxide 24 with various
anilines.24 Preliminary model studies, to be discussed in a
separate publication, with simple 1-hydroxy-2,3-epoxy-3-methyl
cyclopentanes, with and without protecting groups utilizing
various Lewis acids and anilines, resulted in exclusive opening
at the tertiary carbon atom. Nevertheless, we hoped that the
selectivity could be reversed due to the different topology,
substitution pattern, and steric effects in 24. However,
treatment with 3-isopropenyl aniline in the presence of
Yb(OTf)3 in toluene at 80 °C did not lead to 25 but resulted
in the formation of a complex mixture of products (Scheme
5a).
Scheme 5. Toward the Pactamycin Core, Plan A (Part 3):
Introduction of the Aniline Moiety
reaction to secure the correct stereochemistry as found in
pactamycin. Unfortunately, all attempts to prepare the triflate
ester from 14 led to complex mixtures. Conversion to the
acetate ester 15 and treatment of the latter with Pd(PPh3)4 and
NaN3 or TMSN3 under classical Tsuji−Trost conditions22 was
also unsuccessful, as starting material remained intact and could
be recovered. Selective deprotection of the TES ether in 15
gave 16, which was oxidized under Dess−Martin conditions to
give ketone 17. Deacetylation to 18 with trimethylstannyl
dimethylamine,23 followed by attempted conversion to the
triflate ester led to decomposition. However, treatment of 17
with MeMgBr afforded 19 as a single isomer with the required
orientation as found in pactamycin. Unfortunately, formation of
the corresponding triflate or mesylate esters also failed, giving a
complex mixture of products.
We next decided to postpone the introduction of the azide
group, in favor of the aniline moiety at C3. The acetate 20,
prepared from 19, was transformed to the corresponding allylic
alcohol 21, which was treated with mCPBA to afford epoxide
22 (Scheme 4). Reprotection of the primary hydroxyl group as
Scheme 4. Toward the Pactamycin Core, Plan A (Part 2)
Oxidation of 24 to the corresponding ketone 26 and
reduction with NaBH4 led to the C2 epimeric alcohol 27. Much
to our delight, treatment with 3-isopropenyl aniline in the
presence of Yb(OTf)3 now led to the expected aniline 29.
Definitive confirmation of structure and stereochemistry was
obtained from a single X-ray crystal structure determination of
a p-nitrobenzoate ester derivative.21 The successful regio- and
stereoselective opening of the syn-oriented epoxyalcohol 27 can
be explained by a favorable Yb-coordinated complex (28),24
which presumably was not formed in the case of 24 with an
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anti-orientation of the C2 alcohol compared to 27 (Scheme
5b).
Scheme 7. Toward the Pactamycin Core, Plan B (Part 2):
Introducing the Correct Epoxide
Reassessing our options, it was clear that substantial progress
had been made in reaching the advanced stage of intermediate
29, which possessed all of the required functional appendages
except at C2. Introduction of an azide group would require
reinversion of the C2 hydroxyl group in order to attempt SN2
substitution on the triflate ester. However, our prior negative
experiences along those lines (vide supra) dissuaded us from
continuing this approach.
Elaboration of the Cyclopentenone Core (Plan B). We
returned to the cyclopentenone core motif 13 and considered a
different sequence of funtionalizations. Treatment of 13 with
H2O2 cleanly afforded a product which we believed to be the
“up” epoxide analogue of 30 as observed for 21, due to the
orientation of the bulky O-TES group (Scheme 6). Reduction
Scheme 6. Toward the Pactamycin Core, Plan B (Part 1):
Introducing Azide on the Wrong Epoxide
diastereomer of 31) followed by attempted triflation led to yet
another complex mixture (Scheme 7b).
Inverting the Epoxide (Plan C). From the various attempts
to introduce an azide group at C2 with the correct
stereochemistry, it was clear that a successful triflation and
SN2 azide displacement was possible only with a specific relative
orientation of the epoxy alcohol as found in 31. We were
therefore faced with an “epoxide inversion” issue. Treatment of
the ketone 33 with MeMgBr, then silyl ether deprotection,
cleanly gave 41 (Scheme 8). For the “inversion” of the epoxide,
we would rely on a regioselective solvolytic ring opening,
followed by placing a leaving group at the resulting C3 alcohol,
then treatment with an appropriate base to effect epoxide
formation with the tertiary hydroxyl group at C4, acting as an
internal nucleophile. A variety of conditions were tried to effect
these transformations, but without success.25 We then resorted
to an activation of the epoxide with a Lewis acid in the presence
of acetic acid as a nucleophile in the hope of obtaining the C4-
inverted tertiary alcohol as the acetate ester. In the event,
treatment of 41 with Zn(OTf)2 in acetic acid26 led directly to
the primary acetate ester 44 in excellent yield.
Thus, configurational inversion at C3 and C4 had indeed
been achieved, albeit by an alternative pathway than the one
initially envisaged (vide supra). Presumably, solvolysis
proceeded by initial activation of the epoxide by Zn(OTf)2,
as in 42, followed by formation of a spiroepoxide 43 by
intramolecular attack of the primary hydroxyl group with
inversion of configuration of the tertiary C4 center. Subsequent
regioselective ring opening with acetic acid at the primary
carbon atom of the spiroepoxide, possibly activated by
Zn(OTf)2, led to 44 as the only product in good overall
yield. A two-step sequence restored the TBDPS ether group,
and the resulting triol was converted to the C3,C4-“inverted”
epoxide 46 via the corresponding triflate (71% overall yield
from 33). An X-ray structure of 46 confirmed the structure of
the latter intermediate. Highly regio- and stereoselective
epoxide opening at C3 with 3-isopropenyl aniline in the
of the ketone with NaBH4 in the presence of CeCl3·7H2O gave
a single alcohol at C2, which upon triflation and treatment with
Bu4NN3 afforded a product containing the elusive azide group
for the first time. However, not until the O-TES group was
deprotected, and the resulting alcohol was oxidized, did we
become aware that epoxidation had occurred from the opposite
face of the enone in 13, as evidenced from an X-ray structure.21
Thus, epoxidation had led to 30, which was reduced to 31, and
introduction of azide had led to 32 and 33 after silyl
deprotection and oxidation, rather than the expected 34. We
presume that the combination of the spiro-oxazoline and the
bulky O-TBDPS group may have disfavored the approach of
the hydroperoxide ion from the same side, eventually leading to
the wrong epoxide 30.
We therefore once again changed our order of reactions, now
starting with 15 (Scheme 7a). Deprotection of the silyl ethers
led to 35, which was smoothly epoxidized to 36 with mCPBA
then reprotected to give 37. Oxidation to 38 and X-ray analysis
confirmed the required “up” orientation of the epoxide.
However, deprotection of the acetate ester in 38 and attempted
triflation led to decomposition. Having the ketone 38 in hand,
we also attempted to introduce the methyl group at C5 using a
Grignard reaction. In this case, however, attack occurred from
the side opposite to the epoxide and the spiro-oxazoline to give
the 39, epimeric at C5 with 23. Conversion of 37 to 40 (a
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Scheme 8. Obtaining the Core Structure of Pactamycin
Scheme 9. Toward Pactamycate (First Approach)
presence of Yb(OTf)3 afforded the advanced core structure 47
as the sole product.21 It should be noted that activation of the
epoxide 46 with Yb(OTf)3 occurred in the absence of a
coordinating hydroxyl group, and the regioselective opening
with the aniline could be due to the inductive effect of the
neighboring azido group and to steric effects.
Toward Pactamycate. Having secured the full comple-
ment of substituents directly attached to the cyclopentane core
motif, we set our next objective toward the naturally occurring
congener, pactamycate, previously obtained by acid treatment
of pactamycin.11 Studies by Mahmud and co-workers6 on the
biosynthesis of pactamycin led to the identification and
isolation of pactamycate and its de-6-MSA-counterpart from
the same gene cluster.
Our first steps toward pactamycate consisted of the
conversion of 47 to the N-PMB derivative 48 by treatment
with NaCNBH3 in AcOH20 (Scheme 9). Formation of the
cyclic carbamate 49 using diphosgene in the presence of
activated charcoal27 was followed by an oxidative cleavage of
the exocyclic methylene group to afford 50. Treatment of 50
with ceric ammonium nitrate resulted in decomposition.
However, treatment under strong acidic conditions removed
the N-PMB group, albeit in modest yield, to furnish the 2-azido
analog of de-6-MSA-pactamycate 51. There remained to
esterify the primary hydroxyl group and to reduce the azide
group to reach pactamycate. Thus, treatment of 51 with 6-
methylsalicylic acid in the presence of EDCI under standard
conditions led to the formation of 52 as a mixture of oligomers
containing two or more 6-MSA units as a result of multiple
esterifications of the phenolic hydroxyl group in the initially
formed 2-azido pactamycate. Treatment of 52 with KCN in
MeOH28 effected selective cleavage of the phenolic esters to
afford the desired 2-azido pactamycate 53.
10). The oxazoline group in 47 was cleaved under acidic
conditions to afford the p-methoxybenzoate ester 54. Treat-
ment with DIBAL-H led to 55, which when treated with
diphosgene in the presence of activated charcoal gave the cyclic
carbamate 56. Oxidative cleavage of the exocyclic methylene
group, followed by cleavage of the OTBDPS group in the
presence of TASF29 afforded 51, which had been obtained in
lower yields by the earlier route (see Scheme 9). Esterification
of 51 was successfully achieved using cyanomethyl 2-hydroxy-6-
methylbenzoate (57) according to Porco and co-workers30 to
afford 53. Reductive cleavage of the azido group in presence of
Zn powder in aqueous NH4Cl31 gave crystalline pactamycate
(2) whose structure and absolute stereochemistry was validated
by X-ray crystallography for the first time. De-6-MSA-
pactamycate (4) could be obtained by reductive cleavage of
the azido group in 51, adopting the same methods used for 53.
Onward to Pactamycin. The advanced intermediates 54
and 55 were exquisitely poised for a straightforward completion
of the total synthesis of pactamycin. All that would be required
was the formation of the dimethylurea by suitable functional-
ization of the exposed primary amino group. The availability of
N,N-dimethylcarbonyl chloride as a reagent would practically
ensure access to the desired N,N-dimethylurea from one or
In view of the modest yield of deprotection of the N-PMB
group, coupled with the unwanted double esterification of 51,
we sought an alternative approach to pactamycate (Scheme
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was observed. Instead, the oxazoline 47, formed by an
intramolecular attack of the amino group on the PMBz ester
and elimination of water, was recovered. Under forcing
conditions, using NaH, TBAI, and N,N-dimethylcarbamoyl
chloride, only carbamoylation of 54 was observed. In an effort
to obtain the intended urea via an intermediate isocyanate, we
treated 54 with diphosgene in the presence of activated
charcoal. Surprisingly, this led to the six-membered cyclic
carbamate 58, resulting from an intramolecular attack of the
tertiary alcohol on the isocyanate group. The structure of 58
was ascertained by X-ray analysis. Treatment of the aminotriol
55 with N,N-dimethylcarbamoyl chloride led to the formation
of the carbamate 59, leaving the amino group unperturbed.
We then reasoned that treatment of the cyclic carbamates 47,
56, and 58 with dimethylamine or trimethylstannyl dimethyl-
amine (Me3SnNMe2) could result in the formation of the
elusive N,N-dimethylurea via a direct attack on the carbonyl
group of the carbamate or via a four-center activation mode
with transfer of the dimethylamine group (Scheme 12).
However, in the presence of Me3SnNMe2 in refluxing toluene,
56 was found to be completely stable, while 58 gave the O-
PMBz deprotected carbamate 60.
Scheme 10. Toward Pactamycate (Second Approach)
The unsuccessful attempts to prepare the N,N-dimethylurea
derivative by selective acylation of the seemingly more
nucleophilic primary amino group at C1 underscore the
importance of proximity and steric effects in the densely
functionalized cyclopentane core intermediates such as 54 and
55. The extreme shielding of the amino group was further
demonstrated in a last resort effort to achieve urea formation
(Scheme 13). Thus, benzylation of the aminoester 54 in the
presence of BnBr, NaH, and Bu4NI in THF led unexpectedly to
62, the structure of which was confirmed only after effecting
two additional steps (vide infra). Realizing that benzylation had
not occurred on the amino group from independent analysis,
but as yet unaware of the exact placement of the two benzyl
groups, we treated the product 62 with NaH, TBAI, and N,N-
dimethylcarbamoyl chloride, which resulted in recovery of
starting material. Then, the amine 62 was reduced with DIBAL-
H to cleave the PMB ester, and the resulting amino alcohol 63
was treated with N,N-dimethylcarbamoyl chloride in the
presence of NaH and Bu4NI at rt. The product turned out to
be the carbamate 64, the structure of which was confirmed by
X-ray analysis. Remarkably, and against all predictions,
benzylation had spared the primary amino group and, instead,
had occurred on two adjacent diols, albeit with an internal
functional adjustment. Thus, the alkoxide initially formed from
the tertiary alcohol at C4 of 54 had undergone an
intramolecular silyl transfer reaction33 via 61, transposing the
TBDPS group and exposing a primary alkoxide which was
benzylated to give 62!
more of the aforementioned intermediates.32 However, in
practice, this turned out to be a frustrating experience and a
reflection of the unexpected reactivities of an otherwise
commonly reactive primary amino group in densely function-
alized core motifs, such as 54 and 55 (Scheme 11). When 54
was treated with N,N-dimethylcarbamoyl chloride under a
variety of conditions, none of the desired N,N-dimethylurea
Scheme 11. Attempts To Form the Urea (Part 1)
In an alternative approach, benzylation of intermediate 63
under the same conditions as for 54 gave the tribenzyl ether 65
(Scheme 14). Treatment with diphosgene led to a chromato-
graphically stable isocyanate 66 which was treated with neat
dimethylamine to give the N,N-dimethylurea 67 for the first
time. Oxidative cleavage of the exocyclic methylene group led
to the ketone, which was desilylated to give the crystalline urea
derivative 68. Clearly, without X-ray crystallographic evidence,
it would have been very difficult to interpret the results shown
in Schemes 13 and 14, spectroscopically or otherwise.
Although we became aware of the inertness of the primary
amino group toward acylation and alkylation, we also learned
that in the absence of an interfering hydroxyl at C4, we could
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Scheme 12. Attempts To Form the Urea (Part 2)
Scheme 13. Attempts To Form the Urea (Part 3)
attention instead to “neutralizing” the offending tertiary
hydroxyl group at C4.
Scheme 14. Formation of the Urea via the Isocyanate
Deprotection of the TBDPS ether in 54 led to an aminotriol,
which was converted to the acetonide 69 (Scheme 15).
Formation of the isocyanate, then treatment with neat
dimethylamine, afforded the N,N-dimethylurea derivative 70
in 86% yield. Reductive cleavage of the PMB ester followed by
the oxidative cleavage of the methylene group, and finally,
hydrolysis of the acetonide group gave 71. Esterification as
described for pactamycate (2), followed by reduction of the
azido group, gave pactamycin (1) in excellent yield.21 In
parallel, reduction of the azide group in 71 led to de-6-MSA-
pactamycin (3).
CONCLUSION
■
We described a detailed account of our efforts toward the total
synthesis of pactamycin, pactamycate, and their de-esterified
counterparts. Starting with L-threonine as the chiral corner-
stone, we proceeded to construct the cyclopentenone core
motif A (Scheme 1), which served as the pivotal scaffold upon
which we attempted to introduce the required substituents in a
systematic way. Initial failures and unexpected results forced us
to explore alternative approaches to install functional groups in
regio- and stereocontrolled reactions. At times, the difference
between triumph and disaster hinged upon the judicious choice
of methods and order of execution, such as the solvolytic
nevertheless form isocyanates and even the desired N,N-
dimethylurea, as shown in Scheme 14. Rather than continuing
with the fully protected intermediate 68, we turned our
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(4S,5R,6R,9S)-8-((tert-Butyldiphenylsilyloxy)methyl)-2-(4-
methoxyphenyl)-4-methyl-9-(tripropylsilyloxy)-3-oxa-1-
azaspiro[4.4]nona-1,7-dien-6-ol (14). To a solution of cyclo-
pentenone 13 (3.81 g, 5.81 mmol) in MeOH/CH2Cl2 (30 mL, 1:1)
was added CeCl3·7H2O (4.33 g, 11.63 mmol) at 0 °C under argon
atmosphere, and the mixture was stirred for 10 min. Then, NaBH4
(220 mg, 5.81 mmol) was added portionwise and stirred for 1 h at the
same temperature. The reaction was then quenched with slow addition
of a saturated aqueous NH4Cl solution and extracted three times with
EtOAc. The organic layer was dried over Na2SO4 and concentrated
under reduced pressure. Flash column chromatography using 25%
EtOAc in hexanes eluent afforded the allylic alcohol 14 (3.37 g, 88%)
as a viscous liquid: [α]D20 −6.8 (c 1.00, acetone); IR (neat) νmax 3178
(br, s), 3071, 2957, 2877, 1635, 1610, 1513, 1463, 1427, 1372, 1350,
1307, 1257, 1172, 1144, 1112, 1065, 1039, 1008, 974, 908, 875, 841,
Scheme 15. Completion of the Total Synthesis of
Pactamycin
1
741, 702, 611 cm−1; H NMR (400 MHz, CDCl3) δ 7.86 (2H, d, J =
8.8 Hz), 7.75−7.72 (4H, m), 7.47−7.40 (6H, m), 6.90 (2H, d, J = 8.8
Hz), 6.30 (1H, d, J = 1.9 Hz), 5.10 (1H, q, J = 6.6 Hz), 4.72 (1H, s),
4.37−4.34 (3H, m), 3.86 (3H, s), 2.28 (1H, br s), 1.61 (3H, d, J = 6.6
Hz), 1.11 (9H, s), 0.85 (9H, t, J = 7.9 Hz), 0.56−0.49 (6H, m); 13C
NMR (100 MHz, CDCl3) δ 163.9, 162.0, 147.5, 135.6, 135.4, 133.5,
133.3, 130.1, 129.6, 129.2, 128.5, 127.6, 127.5, 120.4, 113.4, 86.0, 79.8,
78.9, 78.2, 61.3, 55.2, 26.7, 19.2, 16.6, 6.6, 4.7; HRMS-ESI (m/z) calcd
for C38H52NO5Si2 [M + H]+ 658.33785, found 658.33952.
(4S,5S,6R,9S)-8-((tert-Butyldiphenylsilyloxy)methyl)-2-(4-
methoxyphenyl)-4-methyl-9-(tripropylsilyloxy)-3-oxa-1-
azaspiro[4.4]nona-1,7-dien-6-yl acetate (15). To a solution of
allylic alcohol 14 (3.12 g, 4.75 mmol) in CH2Cl2 (20 mL) were added
Et3N (3.31 mL, 23.73 mmol), Ac2O (0.67 mL, 7.12 mmol), and
DMAP (58.6 mg, 0.48 mmol) at 0 °C under argon atmosphere. The
reaction mixture was stirred for 1 h at rt. The reaction was quenched
with aqueous saturated NH4Cl solution and extracted twice with
CH2Cl2. The residue was purified by flash chromatography on silica
gel using 15% EtOAc in hexanes to afford acetate 15 (3.16 g, 95%) as
clear oil: [α]2D0 −22.4 (c 1.00, CHCl3); IR (neat) νmax 3072, 2957,
2935, 2877, 1743, 1640, 1610, 1513, 1462, 1427, 1369, 1306, 1254,
1238, 1169, 1145, 1112, 1071, 1034, 968, 911, 875, 841, 823, 741, 703,
1
613 cm−1; H NMR (400 MHz, CDCl3) δ 7.92 (2H, d, J = 8.9 Hz),
7.73−7.71 (4H, m), 7.47−7.40 (6H, m), 6.93 (2H, d, J = 8.9 Hz), 6.04
(1H, s), 5.73 (1H, s), 5.13 (1H, q, J = 6.8 Hz), 4.65 (1H, s), 4.33 (2H,
q, J = 6.8 Hz), 3.86 (3H, s), 2.07 (3H, s), 1.56 (3H, d, J = 6.8 Hz),
1.12 (9H, s), 0.82 (9H, t, J = 7.9 Hz), 0.54−0.48 (6H, m); 13C NMR
(100 MHz, CDCl3) δ 170.2, 164.0, 162.0, 148.2, 135.5, 135.4, 133.3,
133.2, 129.9, 129.7, 127.7, 127.6, 124.1, 120.5, 113.5, 86.3, 80.7, 79.0,
77.8, 61.2, 55.3, 26.7, 21.2, 19.2, 16.5, 6.6, 4.7; HRMS-ESI (m/z) calcd
for C40H54NO6Si2 [M + H]+ 700.34842, found 700.34801.
“inversion” of the epoxide in presence of Zn(OTf)2 and AcOH.
The capricious SN2 displacement of C2 triflate esters became
cooperative when the substituents in the cyclopentanone ring
provided a favored trajectory of approach for the azide ion.
Epoxide opening with an aniline moiety was possible only when
a neighboring hydroxy group had a syn relationship, favoring a
coordination with the Lewis acid Yb(OTf)3, or when an azide
group was present, exerting an inductive effect. Finally, the
importance of proximity effects and steric shielding became
manifest in the numerous vain attempts to acylate or benzylate
the presumably more basic and nucleophilic primary amino
group in the presence of highly hindered tertiary hydroxyl
groups. In spite of these humbling experiences, logic, deductive
reasoning, and a strong resolve prevailed in the end. Pactamycin
(1) and pactamycate (2) were synthesized in 29 steps (3.1%)
and 26 steps (4.0%), respectively, starting with the known
oxazoline 9. With the recent reports on the antiprotozoal
activities of pactamycin,6 the study of this unique amino
cyclopentitol and its analogues expands their scope as valuable
biological probes to interact with RNAs of diverse sources.
Studies relative to such objectives are in progress and will be
reported in due course.
(4S,5S,6R,9S)-8-((tert-Butyldiphenylsilyloxy)methyl)-9-hy-
droxy-2-(4-methoxyphenyl)-4-methyl-3-oxa-1-azaspiro[4.4]-
nona-1,7-dien-6-yl acetate (16). The disilyl ether 15 (1.72 g, 2.46
mmol) was dissolved in a 1:10:1 mixture of TFA/MeCN/H2O (18
mL) at rt and stirred for 3 h at the same temperature. The
transformation was monitored on ESI-MS, and the reaction mixture
was slowly quenched with a saturated solution of NaHCO3 at 0 °C.
The reaction mixture was extracted three times with EtOAc, dried over
Na2SO4, and concentrated in vacuo. The residue was purified by flash
chromatography on silica gel using 20% EtOAc in hexanes to afford
allylic alcohol 16 (1.21 g, 84%) as a colorless oil: [α]2D0 −65.1 (c 1.00,
CHCl3); IR (neat) νmax 3072, 3014, 2959, 2933, 2857, 1739, 1632,
1610, 1513, 1462, 1427, 1371, 1307, 1255, 1236, 1171, 1112, 1031,
1
840, 823, 744, 703, 612 cm−1; H NMR (400 MHz, CDCl3) δ 7.86
(2H, d, J = 8.9 Hz), 7.75−7.73 (4H, m), 7.47−7.42 (6H, m), 6.92
(2H, d, J = 8.9 Hz), 6.18 (1H, d, J = 1.9 Hz), 5.63 (1H, s), 5.19 (1H, q,
J = 6.7 Hz), 4.50 (2H, s), 4.24 (1H, s), 3.86 (3H, s), 3.02 (1H, br s),
2.07 (3H, s), 1.44 (3H, d, J = 6.7 Hz), 1.12 (9H, s); 13C NMR (100
MHz, CDCl3) δ 169.7, 164.0, 162.2, 150.3, 135.5, 135.4, 133.1, 133.0,
130.1, 129.7, 127.7, 127.6, 126.2, 83.4, 81.0, 80.0, 77.7, 61.6, 55.3, 26.7,
21.2, 19.1, 16.0; HRMS (ESIMS) calcd for C34H40NO6Si [M + H]+
586.26194, found 586.26182.
EXPERIMENTAL SECTION
■
Experimental procedures and characterization data for the preparation
of compounds 1, 2, 8−13, 30−33, 41−47, 51, 53−56, 58, and 69−71
have been reported previously.19
(4S,5S,6R)-8-((tert-Butyldiphenylsilyloxy)methyl)-2-(4-me-
thoxyphenyl)-4-methyl-9-oxo-3-oxa-1-azaspiro[4.4]nona-1,7-
dien-6-yl acetate (17). To a stirred solution of allylic alcohol 16
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(1.13 g, 1.93 mmol) in CH2Cl2 (20 mL) was added Dess−Martin
periodinane (900 mg, 2.12 mmol) at 0 °C under argon atmosphere,
and the reaction mixture was stirred at rt for 2 h. The reaction mixture
was quenched with Na2S2O3/NaHCO3 (7:1) aqueous saturated
solution (20 mL) at 0 °C. The mixture was stirred vigorously until
the two layers were separated at rt. The crude product was extracted
with ether (60 mL × 3). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The residue was purified by flash column
chromatography on silica gel using 15% EtOAc in hexanes afforded
the enone 17 (1.09 g, 97%) as a colorless viscous foam: [α]2D0 −183.5
(c 1.00, CHCl3); IR (neat) νmax 2932, 1733, 1723, 1633, 1609, 1513,
aqueous saturated NH4Cl solution and extracted twice with CH2Cl2.
The residue was purified by flash chromatography on silica gel using
25% EtOAc in hexanes to afford acetate 20 (637 mg, 90%) as clear oil:
[α]2D0 −37.0 (c 1.00, CHCl3); IR (neat) νmax 3220 (br), 2933, 2857,
1739, 1643, 1609, 1513, 1454, 1427, 1370, 1336, 1309, 1254, 1226,
1
1169, 1112, 1086, 1028, 950, 840, 824, 744, 703, 671, 612 cm−1; H
NMR (400 MHz, CDCl3) δ 7.88 (2H, d, J = 8.9 Hz), 7.74−7.70 (4H,
m), 7.48−7.41 (6H, m), 6.92 (2H, d, J = 8.9 Hz), 6.30 (1H, d, J = 2.3
Hz), 5.60 (1H, d, J = 2.3 Hz), 5.23 (1H, q, J = 6.6 Hz), 4.45 (2H, s),
3.87 (3H, s), 2.11 (3H, s), 1.92 (1H, s), 1.43 (3H, d, J = 6.6 Hz), 1.11
(9H, s), 1.08 (3H, s); 13C NMR (100 MHz, CDCl3) δ 169.4, 162.9,
162.2, 154.6, 135.6, 135.5, 133.2, 133.1. 130.1, 129.8, 129.7, 127.7,
127.6, 126.1, 84.9, 83.5, 80.9, 77.4, 60.4, 55.4, 26.8, 21.5, 19.2, 17.2,
17.1; HRMS-ESI (m/z) calcd for C35H42NO6Si [M + H]+ 600.2776,
found 600.2790.
(4S,5S,6R,9S)-9-Hydroxy-8-(hydroxymethyl)-2-(4-methoxy-
phenyl)-4,9-dimethyl-3-oxa-1-azaspiro[4.4]nona-1,7-dien-6-yl
acetate (21). To a solution of silyl ether 20 (624 mg, 1.04 mmol) in
THF (10 mL) were added AcOH (2 drops) and TBAF (1.15 mL, 1.0
M in THF, 1.15 mmol) at 0 °C under argon atmosphere. The reaction
mixture was stirred at rt for 1 h, a saturated aqueous NH4Cl solution
was then added, and the aqueous phase was extracted three times with
EtOAc. The combined organic layers were dried over Na2SO4 and
concentrated in vacuo. The residue was purified by flash
chromatography on silica gel using 60% EtOAc in hexanes to afford
allylic alcohol 21 (320 mg, 85%) as clear oil: [α]2D0 −56.5 (c 1.00,
CHCl3); IR (neat) νmax 3401 (br), 2973, 2936, 2840, 1732, 1634,
1609, 1514, 1454, 1422, 1371, 1338, 1308, 1255, 1172, 1090, 1022,
953, 910, 842, 732 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.88 (2H, d,
J = 8.9 Hz), 6.92 (2H, d, J = 8.9 Hz), 6.26 (1H, d, J = 2.2 Hz), 5.57
(1H, d, J = 2.2 Hz), 5.25 (1H, q, J = 6.6 Hz), 4.37 (2H, d, J = 9.7 Hz),
3.85 (3H, s), 3.21 (1H, br s), 2.08 (3H, s), 1.44 (3H, d, J = 6.6 Hz),
1.18 (3H, s); 13C NMR (100 MHz, CDCl3) δ 169.3, 163.5, 162.4,
155.0, 130.2, 126.4, 119.7, 113.7, 84.7, 83.7, 77.5, 58.6, 55.4, 21.4, 17.2,
17.0; HRMS-ESI (m/z) calcd for C19H24NO6 [M + H]+ 362.15981,
found 362.16011.
1
1427, 1369, 1257, 1226, 1112, 1027, 839, 742, 703, 668 cm−1; H
NMR (400 MHz, CDCl3) δ 7.88 (2H, d, J = 8.9 Hz), 7.69−7.65 (5H,
m), 7.47−7.39 (6H, m), 6.91 (2H, d, J = 8.9 Hz), 5.93 (1H, d, J = 1.9
Hz), 5.06 (1H, q, J = 6.7 Hz), 4.56−4.48 (2H, m), 3.86 (3H, s), 2.13
(3H, s), 1.50 (3H, d, J = 6.7 Hz), 1.12 (9H, s); 13C NMR (100 MHz,
CDCl3) δ 201.9, 169.5, 165.5, 162.5, 150.7, 147.4, 135.5, 135.4, 132.9,
132.7, 130.4, 129.9, 129.8, 127.9, 127.8, 119.4, 113.6, 81.3, 79.4, 59.0,
55.4, 26.8, 21.1, 19.3, 16.1; HRMS-ESI (m/z) calcd for C34H38NO6Si
[M + H]+ 584.2463, found 584.2467.
(4S,5R,9R)-7-((tert-Butyldiphenylsilyloxy)methyl)-9-hydroxy-
2-(4-methoxyphenyl)-4-methyl-3-oxa-1-azaspiro[4.4]nona-
1,7-dien-6-one (18). To a solution of enone 17 (70 mg, 0.12 mmol)
in toluene (3 mL) was added (dimethylamino)trimethyltin (0.1 mL,
0.60 mmol) dropwisely at rt under argon atmosphere and stirred for 3
h. Toluene was removed under reduced pressure, and the residue was
purified by flash column chromatography on silica gel using 25%
EtOAc in hexanes afforded the allylic alcohol 18 (51.4 mg, 79%) as
colorless oil: [α]2D0 −147.9 (c 1.00, CHCl3); IR (neat) νmax 3222 (br s),
3072, 2958, 2932, 2858, 1715, 1626, 1609, 1513, 1462, 1427, 1360,
1307, 1258, 1172, 1113, 1030, 906, 868, 839, 823, 736, 702, 610 cm−1;
1H NMR (400 MHz, CDCl3) δ 7.88 (2H, d, J = 8.9 Hz), 7.71−7.67
(4H, m), 7.65 (1H, d, J = 1.9 Hz), 7.47−7.41 (6H, m), 6.90 (2H, d, J =
8.9 Hz), 4.98 (1H, d, J = 1.9 Hz), 4.94 (1H, q, J = 6.7 Hz), 4.56−4.48
(2H, m), 3.85 (3H, s), 2.24 (1H, br s), 1.60 (3H, d, J = 6.7 Hz), 1.13
(9H, s); 13C NMR (100 MHz, CDCl3) δ 202.8, 165.7, 162.5, 154.4,
145.7, 135.5, 133.0, 132.8, 130.3, 129.9, 129.8, 127.9, 127.8, 119.6,
113.6, 83.2, 80.6, 76.4, 58.9, 55.3, 26.8, 19.2, 16.0; HRMS-ESI (m/z)
calcd for C32H36NO5Si [M + H]+ 542.23573, found 542.23740.
(4S,5R,6S,9R)-7-((tert-Butyldiphenylsilyloxy)methyl)-2-(4-
methoxyphenyl)-4,6-dimethyl-3-oxa-1-azaspiro[4.4]nona-1,7-
diene-6,9-diol (19). To a stirred solution of enone 17 (823 mg, 1.41
mmol) in dry THF (15 mL) was added MeMgBr (2.35 mL, 3.0 M
solution in ether, 7.06 mmol) at −78 °C under argon atmosphere and
stirred for 30 min. Then the temperature was raised to 0 °C and stirred
for 20 min. The reaction mixture was quenched with saturated
aqueous NH4Cl solution and extracted with EtOAc (50 mL × 3). The
combined organic layers were washed with brine, dried over anhydrous
Na2SO4, and concentrated in vacuo. Purification by column
chromatography on silica gel using 35% EtOAc in hexanes afforded
allylic alcohol 19 (676 mg, 86%) as a colorless liquid: [α]2D0 +29.4 (c
1.00, CHCl3); IR (neat) νmax 3402 (br), 3072, 2960, 2932, 2857, 1634,
1610, 1513, 1462, 1427, 1361, 1334, 1308, 1256, 1171, 1112, 1034,
(1R,2R,3S,4S,5R,5′S)-2-Hydroxy-1-(hydroxymethyl)-2′-(4-me-
thoxyphenyl)-2,5′-dimethyl-5′H-6-oxaspiro[bicyclo[3.1.0]-
hexane-3,4′-oxazole]-4-yl acetate (22). To the solution of allylic
alcohol 21 (316 mg, 0.875 mmol) in CH2Cl2 (15 mL) was added
mCPBA (647 mg, 70% in water, 2.63 mmol) at 0 °C under argon
atmosphere. The reaction mixture was stirred for 2 h at the same
temperature. A saturated aqueous Na2SO3 solution was added to the
reaction mixture at 0 °C and stirred for 30 min. The reaction mixture
was then diluted with EtOAc and washed with a saturated aqueous
NaHCO3 solution. The aqueous phase was extracted two times with
EtOAc, and the combined organic layers were dried over Na2SO4 and
concentrated in vacuo. The residue was purified by flash
chromatography on silica gel using 80% EtOAc in hexanes to afford
epoxy alcohol 22 (244 mg, 74%) as a colorless oil: [α]2D0 −15.0 (c 1.00,
CHCl3); IR (neat) νmax 3418 (br), 2937, 1738, 1634, 1610, 1514,
1455, 1422, 1372, 1308, 1255, 1226, 1172, 1092, 1030, 908, 841, 732
1
cm−1; H NMR (400 MHz, CDCl3) δ 7.91 (2H, d, J = 8.9 Hz), 6.92
(2H, d, J = 8.9 Hz), 5.43 (1H, s), 5.24 (1H, q, J = 6.5 Hz), 4.17 (1H, d,
J = 12.7 Hz), 4.07 (1H, d, J = 12.7 Hz), 3.86 (3H, s), 3.75 (1H, s),
2.44 (1H, s), 2.16 (3H, s), 1.33 (3H, d, J = 6.5 Hz), 1.22 (3H, s); 13C
NMR (100 MHz, CDCl3) δ 168.9, 163.0, 162.4, 130.4, 119.8, 113.6,
84.0, 81.0, 77.8, 67.7, 59.6, 58.0, 55.4, 21.2, 17.5, 16.7; HRMS-ESI (m/
z) calcd for C19H24NO7 [M + H]+ 378.1547, found 378.1558.
(1R,2R,3S,4S,5R,5′S)-1-((tert-Butyldiphenylsilyloxy)methyl)-
2-hydroxy-2′-(4-methoxyphenyl)-2,5′-dimethyl-5′H-6-
oxaspiro[bicyclo[3.1.0]hexane-3,4′-oxazole]-4-yl acetate (23).
To a solution of epoxy alcohol 22 (220 mg, 0.583 mmol) in CH2Cl2
(10 mL) were added Et3N (0.2 mL. 1.46 mmol), TBDPSCl (0.16 mL,
0.64 mmol), and DMAP (7 mg, 0.06 mmol) at 0 °C under argon
atmosphere. The reaction mixture was stirred for 4 h at rt, then
quenched with aqueous saturated NH4Cl solution and extracted twice
with CH2Cl2. The combined organic layers were dried over Na2SO4
and concentrated in vacuo. The residue was purified by flash
chromatography on silica gel using 25% EtOAc in hexanes to afford
1
996, 952, 912, 840, 824, 743, 702, 612 cm−1; H NMR (400 MHz,
CDCl3) δ 7.88 (2H, d, J = 8.9 Hz), 7.75−7.70 (4H, m), 7.49−7.43
(6H, m), 6.91 (2H, d, J = 8.9 Hz), 6.22 (1H, br s), 5.25 (1H, q, J = 6.6
Hz), 4.52 (1H, d, J = 8.0 Hz), 4.44 (2H, s), 3.86 (3H, s), 2.90 (1H, s),
2.07 (1H, d, J = 8.0 Hz), 1.63 (3H, d, J = 6.6 Hz), 1.21 (3H, s), 1.11
(9H, s); 13C NMR (100 MHz, CDCl3) δ 163.2, 162.1, 150.6, 135.6,
135.5, 132.8, 132.7, 131.7, 130.1, 130.0, 129.9, 127.8, 120.4, 113.6,
85.1, 83.9, 79.1, 77.7, 61.2, 55.3, 26.8, 19.1, 17.9, 17.2; HRMS-ESI (m/
z) calcd for C33H40NO5Si [M + H]+ 558.26703, found 558.26887.
(4S,5S,6R,9S)-8-((tert-Butyldiphenylsilyloxy)methyl)-9-hy-
droxy-2-(4-methoxyphenyl)-4,9-dimethyl-3-oxa-1-azaspiro-
[4.4]nona-1,7-dien-6-yl acetate (20). To a solution of allylic
alcohol 19 (658 mg, 1.18 mmol) in CH2Cl2 (20 mL) were added Et3N
(0.82 mL. 5.90 mmol), Ac2O (0.17 mL, 1.77 mmol), and DMAP (14
mg, 0.12 mmol) at 0 °C under argon atmosphere. The reaction
mixture was stirred for 1 h at rt. The reaction was quenched with
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silyl ether 23 (323 mg, 90%) as clear oil: [α]2D0 −11.6 (c 1.00, CHCl3);
IR (neat) νmax 3486 (br), 3072, 2960, 2934, 2858, 1746, 1641, 1610,
1513, 1455, 1428, 1372, 1334, 1308, 1254, 1232, 1170, 1113, 1064,
1030, 910, 841, 823, 735, 703, 614 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.93 (2H, d, J = 8.9 Hz), 7.74−7.69 (4H, m), 7.48−7.42
(6H, m), 6.92 (2H, d, J = 8.9 Hz), 5.42 (1H, s), 5.30 (1H, q, J = 6.5
Hz), 4.25 (1H, d, J = 11.6 Hz), 3.90 (1H, d, J = 11.6 Hz), 3.86 (3H, s),
3.58 (1H, s), 3.21 (1H, s), 2.17 (3H, s), 1.35 (3H, d, J = 6.5 Hz), 1.24
(3H, s), 1.09 (9H, s); 13C NMR (100 MHz, CDCl3) δ 168.9, 162.4,
161.9, 135.3, 135.2, 132.0, 131.9, 130.0, 129.7, 129.6, 127.5, 119.7,
113.2, 83.7, 80.6, 77.5, 76.5, 66.3, 61.1, 60.0, 55.0, 26.4, 20.9, 18.8,
17.3, 17.2; HRMS-ESI (m/z) calcd for C35H42NO7Si [M + H]+
616.2725, found 616.2733.
(1R,2R,3R,4S,5R,5′S)-1-((tert-Butyldiphenylsilyloxy)methyl)-
2′-(4-methoxyphenyl)-2,5′-dimethyl-5′H-6-oxaspiro[bicyclo-
[3.1.0]hexane-3,4′-oxazole]-2,4-diol (24). To a solution of acetate
23 (270 mg, 0.44 mmol) in toluene (5 mL) was added
(dimethylamino)trimethyltin (0.36 mL, 2.19 mmol) dropwisely at rt
under argon atmosphere and stirred for 3 h. Toluene was removed
under reduced pressure, and the residue was purified by flash column
chromatography on silica gel using 50% EtOAc in hexanes afforded the
epoxy alcohol 24 (216 mg, 86%) as colorless oil: [α]2D0 +4.4 (c 1.00,
CHCl3); IR (neat) νmax 3326 (br), 2933, 2858, 1632, 1610, 1513,
1454, 1427, 1361, 1332, 1308, 1257, 1174, 1113, 1045, 944, 910, 841,
824, 735, 703, 614 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.92 (2H, d,
J = 8.8 Hz), 7.73−7.70 (4H, m), 7.50−7.42 (6H, m), 6.91 (2H, d, J =
8.8 Hz), 5.27 (1H, q, J = 6.5 Hz), 4.43 (1H, br s), 4.33 (1H, d, J = 11.3
Hz), 4.32 (1H, s), 3.85 (3H, s), 3.80 (1H, d, J = 11.3 Hz), 3.55 (1H,
s), 1.55 (3H, d, J = 6.5 Hz), 1.27 (3H, s), 1.11 (9H, s); 13C NMR (100
MHz, CDCl3) δ 163.4, 162.3, 135.5, 135.4, 131.8, 130.3, 130.2, 128.1,
128.0, 120.2, 113.5, 83.4, 81.7, 77.9, 74.8, 65.3, 63.1, 62.4, 55.3, 26.8,
19.1, 17.5, 17.2; HRMS-ESI (m/z) calcd for C33H40NO6Si [M + H]+
574.26194, found 574.26272.
2931, 1638, 1610, 1513, 1427, 1361, 1256, 1112, 1030, 840, 744, 702,
1
614 cm−1; H NMR (400 MHz, CDCl3) δ 7.96 (2H, d, J = 8.9 Hz),
7.73−7.68 (4H, m), 7.51−7.43 (6H, m), 6.91 (2H, d, J = 8.9 Hz), 5.08
(1H, q, J = 6.5 Hz), 4.46 (1H, d, J = 8.0 Hz), 4.33 (1H, d, J = 11.5
Hz), 4.01 (1H, s), 3.86 (3H, s), 3.66 (1H, d, J = 11.5 Hz), 3.37 (1H,
s), 2.66 (1H, d, J = 8.0 Hz), 1.52 (3H, d, J = 6.5 Hz), 1.30 (3H, s),
1.11 (9H, s); 13C NMR (100 MHz, CDCl3) δ 165.1, 162.3, 135.6,
135.5, 131.9, 131.7, 130.4, 130.3, 130.2, 128.0, 127.9, 120.0, 113.5,
81.5, 80.7, 78.4, 72.3, 64.3, 64.0, 62.8, 55.4, 26.8, 19.0, 18.8, 17.3;
HRMS-ESI (m/z) calcd for C33H40NO6Si [M + H]+ 574.26194, found
574.26343.
(4S,5R,6R,7S,8S,9S)-7-((tert-Butyldiphenylsilyloxy)methyl)-2-
(4-methoxyphenyl)-4,6-dimethyl-8-(3-(prop-1-en-2-yl)-
phenylamino)-3-oxa-1-azaspiro[4.4]non-1-ene-6,7,9-triol (29).
To a stirred solution of epoxy alcohol 27 (56 mg, 0.098 mmol) in
toluene (3 mL) were added the aniline derivative (130 mg, 0.98
mmol) and Yb(OTf)3 (61 mg, 0.049 mmol) at rt under argon
atmosphere. The reaction mixture was heated to 80 °C and stirred for
9 h, then cooled to rt, quenched with water (5 mL), and extracted with
EtOAc (50 mL × 2). The combined organic layers were washed with
0.5 N HCl, saturated aqueous NaHCO3 solution, dried over
anhydrous Na2SO4, and concentrated under reduced pressure. The
residue was purified by flash column chromatography on silica gel
using 40% EtOAc in hexanes to afford the aniline 29 (43 mg, 62%) as
a pale yellow viscous liquid: [α]2D0 +20.5 (c 1.00, CHCl3); IR (neat)
νmax 3421 (br), 2932, 1635, 1604, 1586, 1514, 1427, 1364, 1257, 1171,
1
1105, 1038, 822, 737, 702 cm−1; H NMR (400 MHz, CDCl3) δ
7.92−6.69 (18H, aromatic protons), 5.32 (1H, s), 5.07 (1H, q, J = 6.4
Hz), 5.03 (1H, s), 4.68−4.58 (2H, m), 4.40 (1H, dd, J = 11.2, 4.8 Hz),
4.17−4.12 (2H, m), 3.99 (1H, br s), 3.88 (3H, s), 3.83 (1H, d, J = 10.8
Hz), 2.25 (1H, d, J = 11.6 Hz), 2.10 (3H, s), 1.60 (3H, d, J = 6.4 Hz),
1.19 (3H, s), 1.12 (9H, s); 13C NMR (100 MHz, CDCl3) δ 165.2,
162.9, 147.8, 143.8, 142.3, 135.8, 135.6, 131.4, 131.3, 130.4, 130.2,
130.0, 129.1, 128.0, 127.9, 118.9, 114.9, 113.8, 112.4, 111.9, 111.0,
84.4, 83.6, 80.9, 80.3, 79.4, 72.8, 66.7, 55.5, 27.0, 21.9, 19.0, 17.3, 17.1;
HRMS-ESI (m/z) calcd for C42H51N2O6Si [M + H]+ 707.35235,
found 707.35109.
(4S,5S,6R,9S)-9-Hydroxy-8-(hydroxymethyl)-2-(4-methoxy-
phenyl)-4-methyl-3-oxa-1-azaspiro[4.4]nona-1,7-dien-6-yl ac-
etate (35). To the solution of silyl ether 15 (1.07g, 1.53 mmol) in
THF (10 mL) was added TBAF (3.21 mL, 1.0 M in THF, 3.21 mmol)
at 0 °C under argon atmosphere. The reaction mixture was stirred at rt
for 1.5 h, a saturated aqueous NH4Cl solution was then added, and the
aqueous phase was extracted three times with EtOAc. The combined
organic layers were dried over Na2SO4 and concentrated in vacuo. The
residue was purified by flash chromatography on silica gel using 80%
EtOAc in hexanes to afford diol 35 (489 mg, 92%) as colorless viscous
liquid: [α]2D0 −87.7 (c 1.00, CHCl3); IR (neat) νmax 3351 (br), 1733,
1631, 1514, 1422, 1372, 1308, 1255, 1173, 1028, 914, 841, 746 cm−1;
1H NMR (400 MHz, CDCl3) δ 7.80 (2H, d, J = 8.9 Hz), 6.86 (2H, d, J
(1R,2R,3R,5S,5′S)-1-((tert-Butyldiphenylsilyloxy)methyl)-2-
hydroxy-2′-(4-methoxyphenyl)-2,5′-dimethyl-5′H-6-oxaspiro-
[bicyclo[3.1.0]hexane-3,4′-oxazol]-4-one (26). To a stirred
solution of epoxy alcohol 24 (125 mg, 0.218 mmol) in CH2Cl2 (5
mL) was added Dess−Martin periodinane (102 mg, 0.24 mmol) at 0
°C under argon atmosphere, and the reaction mixture was stirred at rt
for 2 h. The reaction mixture was quenched with Na2S2O3/NaHCO3
(7:1) aqueous saturated solution (10 mL) at 0 °C. The mixture was
stirred vigorously until the two layers were separated at rt. The crude
product was extracted with Et2O (20 mL × 3). The combined organic
layers were washed with brine, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The residue was purified by
flash column chromatography on silica gel using 25% EtOAc in
hexanes afforded the epoxy ketone 26 (115 mg, 92%) as a colorless oil:
[α]2D0 +142.5 (c 1.00, CHCl3); IR (neat) νmax 3478 (br), 3072, 2933,
2858, 1753, 1627, 1610, 1513, 1462, 1427, 1362, 1306, 1257, 1170,
1
1113, 1033, 910, 840, 823, 800, 737, 703, 612 cm−1; H NMR (400
MHz, CDCl3) δ 7.91 (2H, d, J = 9.0 Hz), 7.74−7.69 (4H, m), 7.52−
7.46 (6H, m), 6.89 (2H, d, J = 9.0 Hz), 4.94 (1H, q, J = 6.6 Hz), 4.46
(1H, d, J = 11.8 Hz), 3.85 (3H, s), 3.82 (1H, d, J = 11.8 Hz), 3.20 (1H,
s), 1.68 (3H, d, J = 6.6 Hz), 1.52 (3H, s), 1.11 (9H, s); 13C NMR (100
MHz, CDCl3) δ 204.0, 165.4, 162.3, 135.5, 131.6, 131.4, 130.5, 130.4,
128.1, 128.0, 119.9, 113.4, 82.7, 78.8, 78.5, 67.4, 61.9, 59.7, 55.3, 26.7,
19.4, 19.1, 16.4; HRMS-ESI (m/z) calcd for C33H38NO6Si [M + H]+
572.24629, found 572.24675.
(1R,2R,3R,4R,5R,5′S)-1-((tert-Butyldiphenylsilyloxy)methyl)-
2′-(4-methoxyphenyl)-2,5′-dimethyl-5′H-6-oxaspiro[bicyclo-
[3.1.0]hexane-3,4′-oxazole]-2,4-diol (27). To a solution of epoxy
ketone 26 (78 mg, 0.137 mmol) in MeOH/CH2Cl2 (1:1, 3 mL) was
added NaBH4 (5.2 mg, 0.137 mmol) at −46 °C under argon
atmosphere and stirred for 1 h. The reaction was then quenched with
slow addition of saturated aqueous NH4Cl solution and extracted three
times with EtOAc. The combined organic layers were washed with
brine, dried over Na2SO4, and concentrated under reduced pressure.
Flash column chromatography on silica gel using 35% EtOAc in
hexanes eluent afforded the epoxy alcohol 27 (71 mg, 90%) as a
colorless oil: [α]2D0 +31.0 (c 1.00, CHCl3); IR (neat) νmax 3474 (br),
= 8.9 Hz), 6.06 (1H, s), 5.54 (1H, s), 5.21 (1H, q, J = 6.7 Hz), 4.34
(3H, br s), 4.18 (1H, br s), 3.82 (3H, s), 2.03 (3H, s), 1.43 (3H, d, J =
6.7 Hz); 13C NMR (100 MHz, CDCl3) δ 170.0, 164.7, 162.4, 150.6,
130.2, 126.7, 119.5, 113.6, 83.28, 80.89, 79.38, 78.17, 59.37, 55.32,
21.16, 16.11; HRMS-ESI (m/z) calcd for C18H22NO6 [M + H]+
348.14416, found 348.14499.
(1S,2R,3S,4S,5R,5′S)-2-Hydroxy-1-(hydroxymethyl)-2′-(4-me-
thoxyphenyl)-5′-methyl-5′H-6-oxaspiro[bicyclo[3.1.0]hexane-
3,4′-oxazole]-4-yl acetate (36). To the solution of diol 35 (431 mg,
1.24 mmol) in CH2Cl2 (15 mL) was added mCPBA (918 mg, 70% in
water, 3.73 mmol) at 0 °C under argon atmosphere. The reaction
mixture was stirred for 2 h at the same temperature. A saturated
aqueous Na2SO3 solution was added to the reaction mixture at 0 °C
and stirred for 30 min. The reaction mixture was then diluted with
EtOAc and washed with saturated aqueous NaHCO3 solution. The
aqueous phase was extracted two times with EtOAc, and the combined
organic layers were dried over Na2SO4 and concentrated in vacuo. The
residue was purified by flash chromatography on silica gel using 90%
EtOAc in hexanes to afford epoxy diol 36 (286 mg, 64%) as a colorless
oil: [α]2D0 −41.5 (c 1.00, CHCl3); IR (neat) νmax 3364 (br), 3008, 2937,
9467
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1746, 1633, 1610, 1514, 1455, 1422, 1373, 1334, 1308, 1256, 1230,
mg, 86%) as a colorless liquid: [α]2D0 −56.8 (c 1.00, CHCl3); IR (neat)
νmax 3444 (br), 2957, 2932, 2857, 1745, 1636, 1609, 1513, 1462, 1427,
1373, 1337, 1309, 1255, 1236, 1171, 1113, 1080, 1049, 906, 841, 823,
741, 704, 687, 609 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.87 (2H, d,
J = 8.9 Hz), 7.79−7.75 (4H, m), 7.45−7.41 (6H, m), 6.93 (2H, d, J =
8.9 Hz), 5.12 (1H, s), 5.11 (1H, q, J = 6.5 Hz), 4.49 (1H, d, J = 11.6
Hz), 4.33 (1H, s), 3.87 (3H, s), 3.71 (1H, d, J = 11.6 Hz), 2.15 (3H,
s), 1.37 (3H, d, J = 6.5 Hz), 1.20 (3H, s), 1.09 (9H, s); 13C NMR (100
MHz, CDCl3) δ 169.8, 163.4, 162.8, 135.7, 135.6, 133.2, 133.1, 130.4,
129.7, 129.6, 127.7, 127.6, 118.9, 113.8, 81.7, 78.9, 78.1, 75.3, 69.2,
68.9, 60.5, 55.4, 26.7, 21.3, 19.3, 17.1, 9.9; HRMS-ESI (m/z) calcd for
C35H42NO7Si [M + H]+ 616.27251, found 616.27303.
1
1173, 1088, 1029, 904, 842, 732, 688 cm−1; H NMR (400 MHz,
CDCl3) δ 7.84 (2H, d, J = 8.8 Hz), 6.85 (2H, d, J = 8.8 Hz), 5.30 (1H,
s), 5.20 (1H, q, J = 6.5 Hz), 4.26 (1H, d, J = 12.7 Hz), 4.24 (1H, br s),
3.93 (1H, s), 3.82 (1H, d, J = 12.7 Hz), 3.80 (3H, s), 3.65 (1H, s), 2.11
(3H, s) 1.27 (3H, d, J = 6.5 Hz); 13C NMR (100 MHz, CDCl3) δ
169.7, 163.5, 162.4, 130.4, 119.7, 113.6, 82.3, 78.4, 76.9, 76.3, 67.3,
60.5, 59.7, 55.3, 21.1, 16.4; HRMS-ESI (m/z) calcd for C18H22NO7
[M + H]+ 364.13908, found 364.13963.
(1S,2R,3S,4S,5R,5′S)-1-((tert-Butyldiphenylsilyloxy)methyl)-
2-hydroxy-2′-(4-methoxyphenyl)-5′-methyl-5′H-6-oxaspiro-
[bicyclo[3.1.0]hexane-3,4′-oxazole]-4-yl acetate (37). To a
solution of epoxy alcohol 36 (269 mg, 0.74 mmol) in CH2Cl2 (10
mL) were added Et3N (0.31 mL. 2.22 mmol), TBDPSCl (0.21 mL,
0.82 mmol) and DMAP (9 mg, 0.074 mmol) at 0 °C under argon
atmosphere. The reaction mixture was stirred for 4 h at rt, then
quenched with aqueous saturated NH4Cl solution and extracted twice
with CH2Cl2. The combined organic layers were dried over Na2SO4
and concentrated in vacuo. The residue was purified by flash
chromatography on silica gel using 30% EtOAc in hexanes to afford
silyl ether 37 (392 mg, 88%) as clear oil: [α]2D0 −28.7 (c 1.00, CHCl3);
IR (neat) νmax 3466 (br), 3071, 3011, 2932, 2857, 1747, 1630, 1609,
1512, 1462, 1427, 1373, 1332, 1308, 1254, 1228, 1171, 1113, 1087,
(1R,3R,4S,5R,5′S)-1-((tert-Butyldiphenylsilyloxy)methyl)-4-
hydroxy-2′-(4-methoxyphenyl)-5′-methyl-5′H-6-oxaspiro-
[bicyclo[3.1.0]hexane-3,4′-oxazol]-2-one (Alcohol of 38). To a
solution of epoxy ketone 38 (40 mg, 0.067 mmol) in toluene (3 mL)
was added (dimethylamino)trimethyltin (0.055 mL, 0.33 mmol)
dropwisely at rt under argon atmosphere and stirred for 3 h. Toluene
was removed under reduced pressure, and the residue was purified by
flash column chromatography on silica gel using 35% EtOAc in
hexanes afforded the epoxy alcohol (32.5 mg, 87%) as a colorless oil:
[α]2D0 −93.7 (c 1.00, CHCl3); IR (neat) νmax 3230 (br), 3072, 2932,
2858, 1753, 1614, 1513, 1462, 1427, 1355, 1309, 1259, 1174, 1113,
1
1
1031, 841, 823, 744, 703, 612 cm−1; H NMR (400 MHz, CDCl3) δ
1058, 1030, 996, 863, 841, 823, 798, 743, 702 cm−1; H NMR (400
7.92 (2H, d, J = 8.9 Hz), 7.72−7.68 (4H, m), 7.47−7.41 (6H, m), 6.90
(2H, d, J = 8.9 Hz), 5.39 (1H, s), 5.36 (1H, q, J = 6.5 Hz), 4.21 (1H, d,
J = 11.6 Hz), 4.03 (1H, d, J = 11.6 Hz), 3.96 (1H, d, J = 3.1 Hz), 3.85
(3H, s), 3.58 (1H, s), 3.27 (1H, d, J = 3.1 Hz), 2.15 (3H, s), 1.31 (3H,
d, J = 6.5 Hz), 1.09 (9H, s); 13C NMR (100 MHz, CDCl3) δ 169.5,
163.1, 162.3, 135.5, 135.4, 132.3, 132.2, 130.3, 130.1, 130.0, 127.9,
120.1, 113.5, 82.5, 78.5, 77.9, 76.5, 65.3, 62.8, 60.6, 55.3, 26.7, 21.1,
19.1, 16.4; HRMS-ESI (m/z) calcd for C34H40NO7Si [M + H]+
602.25686, found 602.25821.
MHz, CDCl3) δ 7.90 (2H, d, J = 8.8 Hz), 7.72−7.70 (4H, m), 7.46−
7.39 (6H, m), 6.88 (2H, d, J = 8.8 Hz), 5.12 (1H, q, J = 6.5 Hz), 4.65
(1H, s), 4.35 (1H, d, J = 12.5 Hz), 4.09 (1H, d, J = 12.5 Hz), 4.08 (1H,
s), 3.84 (3H, s), 2.85 (1H, br s), 1.50 (3H, d, J = 6.5 Hz), 1.06 (9H, s);
13C NMR (100 MHz, CDCl3) δ 205.4, 164.9, 162.6, 135.7, 135.6,
133.0, 132.6, 130.6, 129.9, 129.8, 127.8, 119.4, 113.6, 80.7, 79.7, 71.4,
62.4, 61.5, 57.4, 55.3, 26.7, 19.2, 17.0; HRMS-ESI (m/z) calcd for
C32H36NO6Si [M + H]+ 558.23064, found 558.23177.
(1R,2R,3S,4S,5R,5′S)-1-((tert-Butyldiphenylsilyloxy)methyl)-
2′-(4-methoxyphenyl)-5′-methyl-2-(tripropylsilyloxy)-5′H-6-
oxaspiro[bicyclo[3.1.0]hexane-3,4′-oxazole]-4-yl acetate (TES
Ether of 37). To a solution of epoxy alcohol 37 (223 mg, 0.37 mmol)
in CH2Cl2 (10 mL) were added Et3N (0.1 mL. 0.74 mmol), TESCl
(0.075 mL, 0.45 mmol), and DMAP (5 mg, 0.04 mmol) at 0 °C under
argon atmosphere. The reaction mixture was stirred for 4 h at rt, then
quenched with aqueous saturated NH4Cl solution and extracted twice
with CH2Cl2. The combined organic layers were dried over Na2SO4
and concentrated in vacuo. The residue was purified by flash
chromatography on silica gel using 25% EtOAc in hexanes to afford
silyl ether (239 mg, 90%) as clear oil: [α]2D0 −33.8 (c 1.00, CHCl3); IR
(neat) νmax 3071, 3000, 2956, 2935, 2877, 1746, 1637, 1610, 1512,
1460, 1427, 1372, 1323, 1308, 1254, 1228, 1169, 1112, 1075, 1031,
1009, 901, 841, 740, 703, 613 cm−1; 1H NMR (400 MHz, CDCl3) δ =
7.94 (2H, d, J = 8.8 Hz), 7.74−7.72 (4H, m), 7.45−7.40 (6H, m), 6.93
(2H, d, J = 8.8 Hz), 5.31 (1H, s), 5.10 (1H, q, J = 6.5 Hz), 4.21 (1H, d,
J = 12.0 Hz), 3.94 (1H, s), 3.90 (1H, d, J = 12.0 Hz), 3.87 (3H, s),
3.71 (1H, s), 2.09 (3H, s), 1.34 (3H, d, J = 6.5 Hz), 1.08 (9H, s), 0.90
(9H, t, J = 7.9 Hz), 0.65−0.61 (6H, m); 13C NMR (100 MHz, CDCl3)
δ 169.7, 162.9, 162.2, 135.8, 135.7, 133.2, 133.1, 130.3, 129.6, 127.6,
120.3, 113.5, 84.3, 78.5, 78.1, 76.2, 67.7, 60.0, 59.9, 55.3, 26.8, 21.0,
19.3, 16.3, 6.7, 4.8; HRMS-ESI (m/z) calcd for C40H54NO7Si2 [M +
H]+ 716.34333, found 716.34461.
(1R,3S,4S,5R,5′S)-1-((tert-Butyldiphenylsilyloxy)methyl)-2′-
(4-methoxyphenyl)-5′-methyl-2-oxo-5′H-6-oxaspiro[bicyclo-
[3.1.0]hexane-3,4′-oxazole]-4-yl acetate (38). To a stirred
solution of epoxy alcohol 37 (132 mg, 0.22 mmol) in CH2Cl2 (5
mL) was added Dess−Martin periodinane (140 mg, 0.33 mmol) at 0
°C under argon atmosphere, and the reaction mixture was stirred at rt
for 2 h. The reaction mixture was quenched with Na2S2O3/NaHCO3
(7:1) aqueous saturated solution (5 mL) at 0 °C. The mixture was
stirred vigorously until the two layers were separated at rt. The crude
product was extracted with Et2O (30 mL × 3). The combined organic
layers were washed with brine, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The residue was purified by
flash column chromatography on silica gel using 25% EtOAc in
hexanes to afford the epoxy ketone 38 (115 mg, 87%) as colorless
crystals: mp 123−125 °C; [α]2D0 −136.4 (c 1.00, CHCl3); IR (neat)
νmax 3072, 3010, 2959, 2933, 2858, 1754, 1723, 1631, 1609, 1513,
1463, 1427, 1372, 1353, 1309, 1257, 1220, 1170, 1113, 1086, 1058,
1030, 908, 864, 842, 739, 703, 616 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.91 (2H, d, J = 8.9 Hz), 7.71−7.67 (4H, m), 7.47−7.39
(6H, m), 6.90 (2H, d, J = 8.9 Hz), 5.57 (1H, s), 5.16 (1H, q, J = 6.5
Hz), 4.36 (1H, d, J = 12.4 Hz), 4.10 (1H, s), 4.03 (1H, d, J = 12.4 Hz),
3.86 (3H, s), 2.14 (3H, s), 1.37 (3H, d, J = 6.5 Hz), 1.09 (9H, s); 13C
NMR (100 MHz, CDCl3) δ 203.8, 169.3, 164.7, 162.6, 135.6, 135.2,
132.9, 132.6, 130.6, 129.9, 129.8, 127.8, 127.7, 119.2, 113.6, 79.4, 79.1,
73.3, 61.2, 59.6, 57.2, 55.4, 26.7, 20.9, 19.3, 16.8; HRMS-ESI (m/z)
calcd for C34H38NO7Si [M + H]+ 600.24121, found 600.24208.
(1R,2S,3S,4S,5R,5′S)-1-((tert-Butyldiphenylsilyloxy)methyl)-
2-hydroxy-2′-(4-methoxyphenyl)-2,5′-dimethyl-5′H-6-
oxaspiro[bicyclo[3.1.0]hexane-3,4′-oxazole]-4-yl acetate (39).
To a stirred solution of epoxy ketone 38 (66 mg, 0.11 mmol) in dry
THF (3 mL) was added MeMgBr (0.07 mL, 3.0 M solution in ether,
0.22 mmol) at −78 °C under argon atmosphere and stirred for 1 h.
The reaction mixture was quenched with saturated aqueous NH4Cl
solution and extracted with EtOAc (20 mL × 3). The combined
organic layers were washed with brine, dried over anhydrous Na2SO4,
and concentrated in vacuo. Purification by column chromatography on
silica gel using 30% EtOAc in hexanes afforded epoxy alcohol 39 (58
(1R,2R,3R,4S,5R,5′S)-1-((tert-Butyldiphenylsilyloxy)methyl)-
2′-(4-methoxyphenyl)-5′-methyl-2-(tripropylsilyloxy)-5′H-6-
oxaspiro[bicyclo[3.1.0]hexane-3,4′-oxazol]-4-ol (40). To a sol-
ution of disilyl ether (186 mg, 0.26 mmol) in toluene (5 mL) was
added (dimethylamino)trimethyltin (0.21 mL, 1.3 mmol) dropwise at
rt under argon atmosphere and stirred for 3 h. Toluene was removed
under reduced pressure, and the residue was purified by flash column
chromatography on silica gel using 30% EtOAc in hexanes ot afford
the epoxy alcohol 40 (152 mg, 87%) as a colorless oil: [α]2D0 −10.2 (c
1.00, CHCl3); IR (neat) νmax 3256, 2956, 1630, 1513, 1462, 1427,
1
1328, 1307, 1256, 1173, 1112, 841, 741, 702 cm−1; H NMR (400
MHz, CDCl3) δ 7.95 (2H, d, J = 8.9 Hz), 7.76−7.72 (4H, m), 7.45−
7.38 (6H, m), 6.93 (2H, d, J = 8.9 Hz), 5.03 (1H, q, J = 6.5 Hz), 4.30
(1H, d, J = 11.8 Hz), 4.28 (1H, d, J = 11.7 Hz), 3.91 (1H, s), 3.87 (3H,
9468
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Featured Article
s), 3.86 (1H, d, J = 11.8 Hz), 3.73 (1H, s), 1.89 (1H, d, J = 11.8 Hz),
1.52 (3H, d, J = 6.5 Hz), 1.09 (9H, s), 0.92 (9H, t, J = 7.9 Hz), 0.70−
0.63 (6H, m); 13C NMR (100 MHz, CDCl3) δ 163.0, 162.2, 135.8,
135.7, 133.3, 133.0, 130.3, 129.7, 129.6, 127.6, 120.6, 113.5, 83.4, 78.7,
78.4, 74.6, 67.2, 61.0, 60.5, 55.4, 26.8, 19.3, 16.4, 6.8, 4.8; HRMS-ESI
(m/z) calcd for C38H52NO6Si2 [M + H]+ 674.33277, found 674.33367.
(1S,2R,3R,4S,5S)-4-Azido-1-((tert-butyldiphenylsilyloxy)-
methyl)-3-((S)-1-hydroxyethyl)-3-(4-methoxybenzylamino)-2-
methyl-5-(3-(prop-1-en-2-yl)phenylamino)cyclopentane-1,2-
diol (48). To a stirred solution of oxazoline 47 (170 mg, 0.232 mmol)
in dry AcOH (4 mL) was added NaCNBH3 in portions (59 mg, 0.93
mmol) at rt under argon atmosphere. The reaction mixture was heated
to 40 °C and stirred for 12 h. Then, the reaction mixture was
quenched with saturated aqueous NaHCO3 solution and extracted
with EtOAc (50 mL × 3). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, and concentrated in vacuo.
Purification by column chromatography on silica gel using 30% EtOAc
in hexanes afforded N-PMB amino alcohol 48 (132 mg, 77%) as a
colorless liquid: [α]D20 +60.8 (c 1.00, CHCl3); IR (neat) νmax 3413 (br),
2932, 2858, 2106, 1602, 1581, 1513, 1471, 1428, 1373, 1327, 1250,
To the stirred solution of above tetrol in THF (1.5 mL) and H2O (1.5
mL) was added NaIO4 (43 mg, 0.2 mmol) at rt and stirred for 3 h.
The reaction mixture was extracted with EtOAc (50 mL × 3), and the
combined organic layers were washed with brine, dried over anhydrous
Na2SO4, and concentrated in vacuo. Flash column chromatography on
silica gel using 30% EtOAc in hexanes eluted the methyl ketone 50 (81
mg, 78% in 2 steps) as a colorless liquid: [α]2D0 +7.5 (c 1.00, CHCl3);
IR (neat) νmax 3365 (br), 2933, 2106, 1727, 1715, 1673, 1604, 1514,
1
1247, 1179, 1084, 909, 821, 735, 703 cm−1; H NMR (400 MHz,
CDCl3) δ 7.54−7.14 (15H, aromatic protons), 6.80 (1H, d, J = 8.7
Hz), 6.65 (1H, m), 4.85 (1H, d, J = 23.1 Hz), 4.80 (1H, d, J = 23.1
Hz), 4.77 (1H, q, J = 6.4 Hz), 4.15 (1H, d, J = 10.8 Hz), 4.14 (1H, d, J
= 11.0 Hz), 4.02 (1H, d, J = 10.8 Hz), 3.73 (3H, s), 3.70 (1H, s), 3.64
(1H, d, J = 11.0 Hz), 3.05 (1H, br s), 2.82 (1H, br s), 2.53 (3H, s),
1.54 (3H, d, J = 6.4 Hz), 1.44 (3H, s), 1.06 (9H, s); 13C NMR (100
MHz, CDCl3) δ 198.2, 159.2, 158.5, 146.4, 138.0, 135.4, 135.3, 131.6,
131.2, 130.4, 129.8, 129.3, 129.2, 128.1, 128.0, 118.7, 117.9, 113.6,
112.9, 84.5, 81.9, 75.3, 74.5, 66.8, 65.9, 65.7, 55.2, 46.7, 26.9, 26.7,
20.1, 19.1, 17.3; HRMS-ESI (m/z) calcd for C42H50N5O7Si [M + H]+
764.3474, found 764.34611.
1
1175, 1113, 1071, 1035, 890, 822, 738, 702 cm−1; H NMR (400
De-6-MSA-pactamycate (4). To a stirred solution of azide 51 (35
mg, 0.086 mmol) in THF/EtOH/H2O (3:1:1, 2.5 mL) were added
ammonium chloride (14 mg, 0.26 mmol) and zinc powder (8.5 mg,
0.13 mmol) at rt and stirred for 6 h. Then, the reaction mixture was
quenched with aqueous ammonia (10 mL) and extracted with CH2Cl2
(50 mL × 2). The combined organic layers were washed with brine,
dried over anhydrous Na2SO4, and concentrated in vacuo. The residue
was purified by flash column chromatography on silca gel using 8%
MeOH in CHCl3 to afford de-6-MSA-pactamycate 4 (28.5 mg, 87%)
as a pale yellow solid: mp 93−95 °C; [α]2D0 −16.5 (c 1.00, MeOH); IR
(neat) νmax 3372 (br), 2939, 1732, 1674, 1602, 1385, 1359, 1335,
1267, 1063, 894, 777, 690 cm−1; 1H NMR (400 MHz, CD3OD) δ 7.38
(1H, s), 7.21−7.18 (2H, m), 7.00 (1H, m), 4.82 (1H, q, J = 6.6 Hz),
3.91 (1H, d, J = 11.5 Hz), 3.53 (1H, d, J = 11.5 Hz), 3.52 (1H, d, J =
7.9 Hz), 3.49 (1H, d, J = 7.9 Hz), 2.54 (3H, s), 1.53 (3H, d, J = 6.6
Hz), 1.34 (3H, s); 13C NMR (100 MHz, CD3OD) δ 201.6, 161.1,
150.8, 139.1, 130.2, 119.2, 117.9, 113.2, 84.0, 83.0, 78.5, 72.6, 71.2,
63.8, 60.7, 26.9, 17.6, 17.2; HRMS-ESI (m/z) calcd for C18H26N3O6
[M + H]+ 380.18161, found 380.18276.
(S)-1-((1R,2R,3S,4S,5S)-1-Amino-5-azido-3-((tert-
butyldiphenylsilyloxy)methyl)-2,3-dihydroxy-2-methyl-4-(3-
(prop-1-en-2-yl)phenylamino)cyclopentyl)ethyl dimethylcar-
bamate (59). To a solution of amino triol 55 (48 mg, 0.078
mmol) in CH2Cl2 (3 mL) were added Et3N (0.065 mL. 0.47 mmol),
N,N-dimethylcarbamoyl chloride (0.02 mL, 0.23 mmol), and DMAP
(2 mg, 0.016 mmol) at rt under argon atmosphere and stirred for 12 h.
The reaction was then quenched with aqueous saturated NH4Cl
solution and extracted twice with CH2Cl2. The combined organic
layers were washed with brine, dried over anhydrous Na2SO4, and
concentrated in vacuo. The residue was purified by flash
chromatography on silica gel using 40% EtOAc in hexanes afforded
carbamate 59 (45 mg, 84%) as a clear oil: [α]2D0 +86.2 (c 1.00, CHCl3);
IR (neat) νmax 3385 (br), 2931, 2857, 2105, 1687, 1601, 1580, 1488,
1396, 1330, 1268, 1195, 1112, 887, 822, 738, 703 cm−1; 1H NMR (400
MHz, CDCl3) δ 7.63−6.56 (15H, aromatic protons and NH2), 5.36
(1H, q, J = 6.5 Hz), 5.33 (1H, s), 5.04 (2H, s), 4.60 (1H, d, J = 11.2
Hz), 4.18 (1H, dd, J = 11.2, 3.6 Hz), 3.97 (1H, d, J = 10.9 Hz), 3.87
(1H, d, J = 10.9 Hz), 3.74 (1H, d, J = 11.2 Hz), 2.98 (3H, s), 2.96 (3H,
s), 2.11 (3H, s), 1.29 (3H, d, J = 6.5 Hz), 1.26 (3H, s), 1.04 (9H, s);
13C NMR (100 MHz, CDCl3) δ 156.2, 146.4, 143.6, 142.5, 135.8,
MHz, CDCl3) δ 7.64−6.58 (18H, aromatic protons), 5.30 (1H, s),
5.04 (1H, s), 5.01 (1H, s), 4.54 (1H, q, J = 6.7 Hz), 4.36 (1H, d, J =
10.1 Hz), 4.29 (1H, d, J = 6.5 Hz), 4.21 (1H, d, J = 10.1 Hz), 4.14
(1H, m), 4.04 (1H, d, J = 11.1 Hz), 3.98 (1H, d, J = 12.4 Hz), 3.81
(3H, s), 3.76 (1H, d, J = 11.1 Hz), 2.09 (3H, s), 1.62 (3H, s), 1.52
(3H, d, J = 6.7 Hz), 1.11 (9H, s); 13C NMR (100 MHz, CDCl3) δ
158.9, 146.8, 143.6, 142.5, 135.8, 135.6, 132.2, 131.1, 131.0, 130.3,
130.0, 129.3, 129.2, 128.0, 127.9, 115.4, 114.1, 112.2, 112.1, 111.0,
86.0, 80.4, 73.4, 69.7, 69.5, 66.0, 55.3, 47.5, 27.0, 21.9, 20.7, 19.5, 19.0;
HRMS-ESI (m/z) calcd for C42H54N5O5Si [M + H]+ 736.38887,
found 736.38914.
(4S,5R,6R,7S,8S,9S)-9-Azido-7-((tert-butyldiphenylsilyloxy)-
methyl)-6,7-dihydroxy-1-(4-methoxybenzyl)-4,6-dimethyl-8-
(3-(prop-1-en-2-yl)phenylamino)-3-oxa-1-azaspiro[4.4]nonan-
2-one (49). To a stirred solution of N-PMB amino alcohol 48 (125
mg, 0.17 mmol) in dry THF (4 mL) were added activated charcoal
(12 mg), Et3N (0.17 mL, 1.19 mmol) and diphosgene (0.02 mL, 0.17
mmol) added slowly at 0 °C under argon atmosphere and stirred for 1
h. Then, the reaction was quenched by slow addition of a saturated
aqueous NaHCO3 solution and extracted with EtOAc (50 mL × 2).
The combined organic layers were washed with brine, filtered, dried
over anhydrous Na2SO4, and concentrated in vacuo. Flash column
chromatography on silica gel using 25% EtOAc in hexanes eluted the
cyclic carbamate 49 (108 mg, 83%) as a colorless liquid: [α]2D0 +5.8 (c
1.00, CHCl3); IR (neat) νmax 3366 (br), 2932, 2858, 2106, 1725, 1603,
1584, 1514, 1428, 1407, 1362, 1247, 1178, 1113, 1086, 1051, 908, 821,
782, 738, 702 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.54−6.39 (18H,
aromatic protons), 5.33 (1H, s), 5.09 (1H, s), 4.87 (1H, d, J = 15.8
Hz), 4.78 (1H, d, J = 15.8 Hz), 4.77 (1H, d, J = 12.4 Hz), 4.76 (1H, q,
J = 6.2 Hz), 4.15 (1H, d, J = 10.9 Hz), 3.97 (1H, d, J = 10.9 Hz), 3.74
(3H, s), 3.71 (1H, s), 3.40 (1H, br s), 2.86 (1H, s), 2.78 (1H, s), 2.12
(3H, s), 1.54 (3H, d, J = 6.2 Hz), 1.44 (3H, s), 1.07 (9H, s); 13C NMR
(100 MHz, CDCl3) δ 159.3, 158.4, 146.2, 143.4, 142.1, 135.3, 131.8,
131.4, 130.2, 129.8, 129.1, 128.9, 128.0, 127.9, 115.9, 113.6, 112.7,
112.0, 110.8, 84.4, 81.9, 75.4, 74.6, 66.7, 66.2, 65.9, 55.1, 46.7, 26.9,
21.8, 19.8, 19.1, 17.2; HRMS-ESI (m/z) calcd for C43H52N5O6Si [M +
H]+ 762.36814, found 762.36649.
(4S,5R,6R,7S,8S,9S)-8-(3-Acetylphenylamino)-9-azido-7-
((tert-butyldiphenylsilyloxy)methyl)-6,7-dihydroxy-1-(4-me-
thoxybenzyl)-4,6-dimethyl-3-oxa-1-azaspiro[4.4]nonan-2-one
(50). To a stirred solution of olefin 49 (103 mg, 0.135 mmol) in THF
(2 mL), acetone (2 mL), and H2O (0.4 mL) were added NMO (79
mg, 0.677 mmol) and OsO4 (0.1 mL, 4 wt % in H2O) at 0 °C and
stirred for 2 h at rt. A saturated aqueous sodium bisulfite solution was
added to the reaction mixture and stirred for 30 min. The reaction
mixture was extracted with EtOAc (50 mL × 3), and the combined
organic layers were washed with water and brine, dried over anhydrous
Na2SO4, and concentrated in vacuo. Flash column chromatography on
silica gel using 70% EtOAc in hexanes eluted the tetrol as clear oil,
which was directly used for the next reaction without characterization.
135.6, 132.2, 132.0, 129.9, 129.7, 129.3, 127.8, 127.7, 115.3, 112.3,
112.1, 111.0, 83.8, 82.1, 74.2, 72.6, 69.4, 67.9, 64.4, 36.7, 35.9, 26.9,
21.9, 19.1, 17.9, 15.7; HRMS-ESI (m/z) calcd for C37H51N6O5Si [M +
H]+ 687.36847, found 687.37043.
(1S,5R,6S,7S,8R)-6-Azido-1-((tert-butyldiphenylsilyloxy)-
methyl)-8-hydroxy-5-((S)-1-hydroxyethyl)-8-methyl-7-(3-
(prop-1-en-2-yl)phenylamino)-2-oxa-4-azabicyclo[3.2.1]octan-
3-one (60). To a solution of cyclic carbamate 58 (47 mg, 0.06 mmol)
in dry toluene (3 mL) was added (dimethylamino)trimethyltin (0.1
mL, 0.6 mmol) dropwise at rt under argon atmosphere, then the
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Featured Article
reaction mixture was heated to reflux and stirred for 3 h. Toluene was
removed under reduced pressure, and the residue was purified by flash
column chromatography on silica gel using 55% EtOAc in hexanes to
afford diol 60 (33 mg, 86%) as a colorless oil: [α]2D0 +88.4 (c 1.00,
CHCl3); IR (neat) νmax 3398 (br), 2931, 2857, 2107, 1699, 1602,
1582, 1390, 1326, 1263, 1113, 891, 822, 759, 702 cm−1; 1H NMR (400
MHz, CDCl3) δ 7.61−6.74 (15H, aromatic protons and OH), 6.18
(1H, s), 5.30 (1H, s), 5.06 (1H, t, J = 1.5 Hz), 4.85 (1H, s), 4.47 (1H,
d, J = 5.1 Hz), 4.31 (1H, d, J = 11.0 Hz), 4.20 (1H, m), 4.19 (1H, d, J
= 11.2 Hz), 4.01 (1H, m), 3.83 (1H, d, J = 11.2 Hz), 2.10 (3H, s), 1.52
(3H, d, J = 6.6 Hz), 1.30 (3H, s), 1.09 (9H, s); 13C NMR (100 MHz,
CDCl3) δ 150.7, 145.7, 143.3, 143.0, 135.8, 135.5, 130.6, 130.4, 130.2,
129.6, 128.2, 128.0, 116.3, 112.6, 111.8, 110.9, 85.0, 78.5, 74.5, 67.1,
66.8, 65.9, 64.0, 27.0, 21.9, 20.7, 18.9, 16.8; HRMS-ESI (m/z) calcd
for C35H44N5O5Si [M + H]+ 642.31062, found 642.31084.
13.7; HRMS-ESI (m/z) calcd for C48H58N5O4Si [M + H]+ 796.42526,
found 796.42568.
(S)-1-((1R,2R,3S,4S,5S)-1-Amino-5-azido-2-(benzyloxy)-3-
(benzyloxymethyl)-3-(tert-butyldiphenylsilyloxy)-2-methyl-4-
(3-(prop-1-en-2-yl)phenylamino)cyclopentyl)ethyl dimethyl-
carbamate (64). To a solution of amino alcohol 63 (42 mg, 0.053
mmol) in dry THF (2 mL) were added NaH (8.5 mg, 60% dispersion
in mineral oil, 0.21 mmol), N,N-dimethylcarbamoyl chloride (0.01 mL,
0.106 mmol), and TBAI (4 mg, 0.01 mmol) at rt under argon
atmosphere and stirred for 6 h. The reaction was then quenched with
aqueous saturated NH4Cl solution and extracted twice with EtOAc.
The combined organic layers were washed with brine, dried over
anhydrous Na2SO4, and concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel using 20%
EtOAc in hexanes to afford carbamate 64 (37 mg, 81%) as pale yellow
crystals: mp 153−155 °C; [α]2D0 +42.5 (c 1.00, CHCl3); IR (neat) νmax
3416 (br), 2933, 2099, 1698, 1600, 1493, 1393, 1270, 1187, 1109, 909,
(S)-1-((1R,2R,3S,4S,5S)-1-Amino-5-azido-2-(benzyloxy)-3-
(benzyloxymethyl)-3-(tert-butyldiphenylsilyloxy)-2-methyl-4-
(3-(prop-1-en-2-yl)phenylamino)cyclopentyl)ethyl 4-methoxy-
benzoate (62). To a solution of amino diol 54 (330 mg, 0.44 mmol)
in THF (10 mL) were added NaH (88 mg, 60% dispersion in mineral
oil, 2.2 mmol), benzyl bromide (0.13 mL, 1.1 mmol), and TBAI (81
mg, 0.22 mmol) at 0 °C. The reaction mixture was stirred for 2 h at rt,
then quenched with aqueous saturated NH4Cl solution and extracted
with EtOAc (100 mL × 2). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, and concentrated in vacuo.
The residue was purified by flash chromatography on silica gel using
15% EtOAc in hexanes to afford the dibenzyl ether 62 (328 mg, 80%)
as colorless viscous liquid: [α]2D0 +106.7 (c 1.00, CHCl3); IR (neat)
νmax 3416 (br), 2934, 2858, 2098, 1707, 1604, 1580, 1511, 1318, 1276,
1
736, 702 cm−1; H NMR (400 MHz, CDCl3) δ 7.98−6.67 (24H,
aromatic protons), 5.78 (1H, s), 5.42 (1H, d, J = 8.0 Hz), 5.38 (1H, q,
J = 6.4 Hz), 5.16 (1H, s), 4.99 (1H, s), 4.36 (1H, d, J = 8.7 Hz), 4.22
(1H, d, J = 8.7 Hz), 3.98 (1H, d, J = 11.2 Hz), 3.90 (1H, d, J = 11.2
Hz), 3.71 (1H, d, J = 12.3 Hz), 3.56 (1H, s), 3.55 (1H, d, J = 9.9 Hz),
3.42 (1H, d, J = 9.9 Hz), 3.29 (1H, d, J = 12.3 Hz), 3.07 (3H, s), 3.00
(3H, s), 2.00 (3H, s), 1.90 (3H, s), 1.31 (3H, d, J = 6.4 Hz), 1.11 (9H,
s); 13C NMR (100 MHz, CDCl3) δ 155.4, 145.7, 143.4, 141.8, 137.3,
137.0, 136.7, 136.5, 135.7, 135.1, 134.1, 129.6, 129.1, 129.0, 128.9,
128.7, 128.2, 128.1, 128.0, 127.6, 127.3, 127.0, 114.6, 111.8, 111.2,
110.9, 91.7, 90.5, 76.6, 74.5, 71.9, 70.0, 67.7, 67.5, 66.6, 36.6, 36.1,
27.6, 21.8, 20.0, 15.4, 13.2; HRMS-ESI (m/z) calcd for C51H63N6O5Si
[M + H]+ 867.46237, found 867.4628.
1
1257, 1168, 1103, 1029, 771, 738, 702 cm−1; H NMR (400 MHz,
(1S,2S,3R,4R,5S)-2-Azido-4-(benzyloxy)-3-((S)-1-(benzyloxy)-
ethyl)-5-(benzyloxymethyl)-5-(tert-butyldiphenylsilyloxy)-4-
methyl-N1-(3-(prop-1-en-2-yl)phenyl)cyclopentane-1,3-dia-
mine (65). To a solution of amino alcohol 63 (186 mg, 0.234 mmol)
in dry THF (5 mL) were added NaH (38 mg, 60% dispersion in
mineral oil, 0.94 mmol), BnBr (0.04 mL, 0.35 mmol), and TBAI (9
mg, 0.02 mmol) at 0 °C under argon atmosphere and stirred for 3 h.
The reaction was then quenched with aqueous saturated NH4Cl
solution and extracted twice with EtOAc. The combined organic layers
were washed with brine, dried over anhydrous Na2SO4, and
concentrated in vacuo. The residue was purified by flash
chromatography on silica gel using 10% EtOAc in hexanes to afford
amino tribenzyl ether 65 (162 mg, 78%) as clear oil: [α]2D0 +67.5 (c
1.00, CHCl3); IR (neat) νmax 3417 (br), 3029, 2933, 2858, 2098, 1600,
1579, 1494, 1453, 1427, 1329, 1266, 1109, 976, 909, 820, 784, 736,
CDCl3) δ 8.16−6.66 (28H, aromatic protons), 5.78 (1H, s), 5.68 (1H,
q, J = 6.4 Hz), 5.43 (1H, dd, J = 8.0, 1.8 Hz), 5.17(1H, s), 5.00 (1H, t,
J = 1.4 Hz), 4.16 (1H, d, J = 8.9 Hz), 4.11 (1H, d, J = 8.9 Hz), 3.97
(1H, q, J = 11.6 Hz), 3.91 (3H, s), 3.71 (1H, d, J = 12.3 Hz), 3.62 (1H,
d, J = 1.8 Hz), 3.53 (1H, d, J = 9.9 Hz), 3.43 (1H, d, J = 9.9 Hz), 3.26
(1H, d, J = 12.3 Hz), 2.01 (3H, s), 1.92 (3H, s), 1.39 (3H, d, J = 6.4
Hz), 1.13 (9H, s); 13C NMR (100 MHz, CDCl3) δ 165.2, 163.5, 145.7,
143.4, 141.9, 137.2, 136.8, 136.7, 135.7, 135.0, 134.1, 131.7, 129.7,
129.0, 128.9, 128.8, 128.7, 128.2, 128.0, 127.6, 127.3, 127.0, 122.9,
114.7, 113.8, 111.8, 111.3, 110.8, 91.9, 90.6, 76.9, 74.2, 71.9, 70.2, 67.7,
67.6, 66.6, 55.5, 27.6, 21.9, 20.0, 14.7, 13.5; HRMS-ESI (m/z) calcd
for C56H64N5O6Si [M + H]+ 930.46204, found 930.45989.
(S)-1-((1R,2R,3S,4S,5S)-1-Amino-5-azido-2-(benzyloxy)-3-
(benzyloxymethyl)-3-(tert-butyldiphenylsilyloxy)-2-methyl-4-
(3-(prop-1-en-2-yl)phenylamino)cyclopentyl)ethanol (63). To a
stirred solution of p-methoxy benzyl ester 62 (307 mg, 0.33 mmol) in
dry CH2Cl2 (12 mL) was added DIBAL-H (1.65 mL, 1.0 M in toluene,
1.65 mmol) slowly at −78 °C under argon atmosphere and stirred for
1.5 h. The reaction mixture was then quenched with slow addition of
MeOH and warmed to room temperature. A saturated aqueous
potassium sodium tartrate solution was added to the reaction mixture
and stirred for 1 h. The reaction mixture was extracted with CH2Cl2
(100 mL × 2), and the combined organic layers were washed with
brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The
residue was purified by flash column chromatography on silica gel
using 35% EtOAc in hexanes afforded amino alcohol 63 (242 mg,
92%) as colorless liquid: [α]2D0 +27.8 (c 1.00, CHCl3); IR (neat) νmax
3399 (br), 3029, 2933, 2858, 2097, 1600, 1580, 1492, 1453, 1427,
1
701 cm−1; H NMR (400 MHz, CDCl3) δ 8.00−6.68 (29H, aromatic
protons), 5.96 (1H, s), 5.53 (1H, dd, J = 8.0, 2.0 Hz), 5.22 (1H, s),
5.03 (1H, t, J = 1.4 Hz), 4.77 (1H, d, J = 11.4 Hz), 4.47 (1H, d, J = 9.9
Hz), 4.40 (1H, d, J = 11.4 Hz), 4.32 (1H, d, J = 9.9 Hz), 4.16 (1H, q, J
= 6.3 Hz), 4.13 (1H, d, J = 11.7 Hz), 4.01 (1H, d, J = 11.7 Hz), 3.69
(1H, d, J = 12.2 Hz), 3.56 (1H, d, J = 2.1 Hz), 3.53 (1H, d, J = 9.9
Hz), 3.47 (1H, d, J = 9.9 Hz), 3.28 (1H, d, J = 12.2 Hz), 2.05 (3H, s),
1.96 (3H, s), 1.35 (3H, d, J = 6.3 Hz), 1.11 (9H, s); 13C NMR (100
MHz, CDCl3) δ 145.9, 143.4, 141.8, 138.6, 137.8, 137.3, 136.7, 135.6,
135.2, 134.8, 134.2, 129.5, 129.0, 128.9, 128.7, 128.4, 128.1, 127.9,
127.8, 127.7, 127.6, 127.5, 127.4, 127.2, 126.9, 114.5, 111.8, 111.1,
111.0, 92.5, 90.5, 78.4, 71.8, 70.9, 70.0, 67.7, 67.2, 66.3, 27.6, 21.9,
20.0, 13.8, 13.4; HRMS-ESI (m/z) calcd for C55H64N5O4Si [M + H]+
886.47221, found 886.47332.
N-((1S,2S,3R,4R,5S)-5-Azido-3-(benzyloxy)-4-((S)-1-
(benzyloxy)ethyl)-2-(benzyloxymethyl)-2-(tert-butyldiphenyl-
silyloxy)-4-isocyanato-3-methylcyclopentyl)-3-(prop-1-en-2-
yl)aniline (66). To a stirred solution of amine 65 (146 mg, 0.165
mmol) in dry THF (5 mL) were added activated charcoal (15 mg),
Et3N (0.07 mL, 0.49 mmol), and diphosgene (0.04 mL, 0.33 mmol)
slowly at −46 °C under argon and stirred for 20 min. Then, the
reaction was quenched with saturated aqueous NaHCO3 solution and
extracted with EtOAc (50 mL × 2). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, and concentrated in
vacuo. Flash column chromatography on silica gel using 8% EtOAc in
hexanes eluted the stable isocyanate 66 (125 mg, 83%) as a colorless
1
1328, 1258, 1109, 1027, 975, 784, 739, 702 cm−1; H NMR (400
MHz, CDCl3) δ 7.92−6.65 (24H, aromatic protons), 5.93 (1H, t, J =
1.9 Hz), 5.42 (1H, dd, J = 8.0, 2.0 Hz), 5.19 (1H, s), 5.00 (1H, t, J =
1.5 Hz), 4.76 (1H, d, J = 9.7 Hz), 4.41 (1H, d, J = 9.7 Hz), 4.08 (1H,
m), 4.05 (1H, d, J = 11.2 Hz), 3.98 (1H, d, J = 11.2 Hz), 3.61 (1H, d, J
= 12.1 Hz), 3.55 (1H, d, J = 10.0 Hz), 3.47 (1H, d, J = 2.0 Hz), 3.46
(1H, d, J = 10.0 Hz), 2.02 (3H, s), 1.90 (3H, s), 1.12 (3H, d, J = 6.5
Hz), 1.09 (9H, s); 13C NMR (100 MHz, CDCl3) δ 145.8, 143.4, 141.9,
137.8, 137.3, 136.7, 135.6, 135.0, 134.0, 129.6, 129.1, 129.0, 128.4,
128.2, 128.0, 127.9, 127.6, 127.3, 127.0, 114.7, 111.8, 111.2, 111.0,
91.5, 90.7, 78.0, 71.9, 69.7, 69.4, 67.6, 67.3, 66.8, 27.6, 21.8, 20.0, 18.6,
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Featured Article
liquid: [α]2D0 +49.5 (c 1.00, CHCl3); IR (neat) νmax 3417 (br), 3029,
116.7, 112.8, 90.9, 85.8, 73.0, 70.9, 68.9, 67.9, 65.7, 61.7, 36.6, 27.4,
26.8, 19.9.
2933, 2858, 2258, 2098, 1600, 1581, 1454, 1329, 1267, 1110, 909, 821,
1
737, 701 cm−1; H NMR (400 MHz, CDCl3) δ 7.93−6.73 (29H,
3-((1R,2R,3S,4S,5S)-4-(3-Acetylphenylamino)-5-azido-2-
(benzyloxy)-1-((S)-1-(benzyloxy)ethyl)-3-(benzyloxymethyl)-3-
hydroxy-2-methylcyclopentyl)-1,1-dimethylurea (68). To a
stirred solution of silyl ether (44 mg, 0.046 mmol) in dry DMF (2
mL) was added TASF (38 mg, 0.138 mmol) at 0 °C under argon and
allowed to come to room temperature. After being stirred for 1 h at rt,
the reaction mixture was cooled to 0 °C, quenched with a pH 7
phosphate buffer solution, and extracted with EtOAc (50 mL × 3).
The combined organic layers were washed with water (30 mL × 3)
and brine, dried over anhydrous Na2SO4, and concentrated in vacuo.
The residue was purified by flash column chromatography on silica gel
using 50% EtOAc in hexanes to afford the pure keto alcohol 68 (30
mg, 90%) as pale yellow crystals: mp 127−128 °C; [α]2D0 +53.1 (c 1.00,
CHCl3); IR (neat) νmax 3385 (br), 2931, 2102, 1674, 1602, 1538,
aromatic protons), 6.07 (1H, s), 5.65 (1H, dd, J = 8.0, 1.9 Hz), 5.20
(1H, s), 5.02 (1H, s), 4.82 (1H, d, J = 11.5 Hz), 4.44 (1H, d, J = 10.3
Hz), 4.39 (1H, d, J = 11.5 Hz), 4.37 (1H, d, J = 10.3 Hz), 4.28 (1H, q,
J = 6.2 Hz), 4.10 (1H, dd, J = 11.7, 4.0 Hz), 3.83 (1H, d, J = 11.7 Hz),
3.70 (1H, d, J = 12.0 Hz), 3.52 (1H, d, J = 4.0 Hz), 3.50 (1H, d, J = 9.9
Hz), 3.44 (1H, d, J = 12.0 Hz), 3.33 (1H, d, J = 9.9 Hz), 2.04 (3H, s),
1.96 (3H, s), 1.41 (3H, d, J = 6.2 Hz), 1.14 (9H, s); 13C NMR (100
MHz, CDCl3) δ 145.7, 143.3, 142.0, 137.9, 137.6, 137.4, 136.8, 136.0,
135.3, 134.6, 129.4, 129.1, 129.0, 128.7, 128.5, 128.1, 128.0, 127.6,
127.5, 127.4, 127.3, 127.1, 127.0, 125.4, 115.1, 112.0, 111.3, 111.1,
93.0, 88.3, 77.7, 75.6, 73.6, 72.1, 69.6, 68.7, 67.5, 66.8, 27.2, 21.8, 19.9,
14.8, 13.9.
3-((1R,2R,3S,4S,5S)-5-Azido-2-(benzyloxy)-1-((S)-1-
(benzyloxy)ethyl)-3-(benzyloxymethyl)-3-(tert-butyldiphenyl-
silyloxy)-2-methyl-4-(3-(prop-1-en-2-yl)phenylamino)-
cyclopentyl)-1,1-dimethylurea (67). To an isocyanate 66 (96 mg,
0.105 mmol) was added neat 0.2 mL of dimethyl amine (upon
condensing the gas at −46 °C), and the reaction mixture was left
warming to room temperature. It was directly subjected to flash
column chromatography using 20% EtOAc in hexanes to afford urea
67 (89 mg, 88%) as a colorless oil: [α]2D0 +8.6 (c 1.00, CHCl3); IR
(neat) νmax 3400 (br), 3030, 2931, 2857, 2100, 1666, 1602, 1581,
1524, 1496, 1454, 1361, 1334, 1243, 1172, 1108, 1028, 909, 821, 780,
1
1358, 1269, 1173, 1111, 910, 734, 697 cm−1; H NMR (400 MHz,
CDCl3) δ 7.37−7.15 (19H, aromatic protons), 6.92 (1H, d, J = 7.6
Hz), 6.32 (1H, s), 5.64 (1H, s), 4.81 (1H, q, J = 6.3 Hz), 4.68 (1H, d, J
= 11.0 Hz), 4.66 (1H, d, J = 10.8 Hz), 4.59 (1H, d, J = 10.8 Hz), 4.52−
4.49 (2H, m), 4.37 (1H, dd, J = 11.1, 4.3 Hz), 3.94 (1H, d, J = 10.0
Hz), 3.85 (1H, d, J = 7.1 Hz), 3.54 (1H, d, J = 10.0 Hz), 2.97 (6H, s),
2.56 (3H, s), 1.72 (3H, s), 1.40 (3H, d, J = 6.3 Hz); 13C NMR (100
MHz, CDCl3) δ 198.6, 158.4, 147.3, 138.5, 138.1, 138.0, 129.6, 128.6,
128.5, 128.2, 127.8, 127.7, 127.6, 127.5, 127.4, 118.0, 117.4, 113.0,
92.3, 82.4, 76.6, 74.0 72.4, 71.4, 71.2, 70.5, 68.5, 66.8, 36.7, 26.7, 14.9,
14.4; HRMS-ESI (m/z) calcd for C41H49N6O6 [M + H]+ 721.37081,
found 721.37077.
1
733, 701 cm−1; H NMR (400 MHz, CDCl3) δ 7.68−6.41 (29H,
aromatic protons), 5.58 (1H, s), 5.39 (1H, s), 5.08 (1H, s), 4.89 (1H,
d, J = 11.8 Hz), 4.68 (1H, q, J = 6.1 Hz), 4.62 (1H, d, J = 11.8 Hz),
4.50 (1H, d, J = 11.0 Hz), 4.42 (1H, br s), 4.11−3.97 (4H, m), 3.87
(1H, d, J = 10.1 Hz), 3.64 (1H, d, J = 10.1 Hz), 2.90 (6H, s), 2.18 (3H,
s), 1.91 (3H, s), 1.14 (3H, d, J = 6.1 Hz), 0.92 (9H, s); 13C NMR (100
MHz, CDCl3) δ 158.9, 147.2, 143.9, 141.5, 139.2, 139.0, 137.1, 136.2,
135.9, 135.3, 134.7, 129.2, 129.1, 128.6, 128.5, 128.3, 128.1, 128.0,
127.9, 127.2, 127.1, 127.0, 126.8, 126.7, 114.2, 111.7, 111.4, 110.7,
91.0, 86.1, 74.9, 72.9, 70.9, 70.4, 69.2, 67.2, 65.7, 62.3, 36.5, 27.5, 21.9,
19.9; HRMS-ESI (m/z) calcd for C58H69N6O5Si [M + H]+ 957.50932,
found 957.5084.
De-6-MSA-pactamycin (3). To a stirred solution of azide 71 (24
mg, 0.044 mmol) in EtOH/H2O (3:1, 2 mL) were added NH4Cl (7
mg, 0.133 mmol) and zinc powder (4.5 mg, 0.067 mmol) at rt and
stirred for 6 h. Then, the reaction mixture was quenched with aqueous
ammonia (10 mL) and extracted with CH2Cl2 (30 mL × 2). The
combined organic layers were washed with brine, dried over anhydrous
Na2SO4, and concentrated in vacuo. The residue was purified by flash
column chromatography on silca gel using 5% MeOH in CHCl3 to
afford de-6-MSA-pactamycin 3 (19.5 mg, 86%) as a pale yellow oil:
[α]2D0 +32.5 (c 1.00, CHCl3); IR (neat) νmax 3383 (br), 2935, 1678,
1603, 1520, 1440, 1359, 1334, 1269, 1091, 1042, 912, 782, 732, 689
cm−1; 1H NMR (400 MHz, CDCl3) δ 7.86 (1H, br s), 7.29−6.85 (5H,
aromatic protons and NH2), 5.56 (1H, br s), 5.48 (1H, d, J = 9.9 Hz),
4.13 (1H, d, J = 11.7 Hz), 3.93 (1H, m), 3.76 (1H, d, J = 9.9 Hz), 3.75
(1H, d, J = 11.7 Hz), 3.01 (6H, s), 2.97 (1H, s), 2.56 (3H, s), 1.47
(3H, s), 1.06 (3H, d, J = 6.4 Hz); 1H NMR (400 MHz, CDCl3+D2O)
δ = 7.29−6.85 (4H, aromatic protons), 4.14 (1H, d, J = 11.8 Hz), 3.92
(1H, q, J = 6.4 Hz), 3.75 (1H, s), 3.70 (1H, d, J = 11.8 Hz), 3.00 (6H,
s), 2.93 (1H, s), 2.52 (3H, s), 1.45 (3H, s), 1.04 (3H, d, J = 6.4 Hz);
1H NMR (400 MHz, CD3OD) δ = 7.27−7.24 (3H, aromatic protons),
6.93 (1H, m), 4.07 (1H, q, J = 6.5 Hz), 3.94 (1H, d, J = 11.5 Hz), 3.74
(1H, d, J = 2.1 Hz), 3.68 (1H, d, J = 11.5 Hz), 3.01 (1H, d, J = 2.1
Hz), 2.98 (6H, s), 2.56 (3H, s), 1.42 (3H, s), 1.04 (3H, d, J = 6.5 Hz);
13C NMR (100 MHz, CDCl3) δ = 198.8, 159.3, 146.9, 138.1, 129.5,
119.1, 118.4, 110.6, 88.5, 84.9, 73.9, 71.7, 68.1, 62.9, 61.7, 36.9, 26.6,
21.3, 18.2; 13C NMR (100 MHz, CD3OD) δ 201.7, 161.2, 149.4,
139.5, 130.7, 119.7, 118.5, 113.3, 89.6, 85.6, 74.4, 72.9, 69.4, 64.1, 62.3,
37.3, 27.1, 22.0, 18.9; HRMS-ESI (m/z) calcd for C20H33N4O6 [M +
H]+ 425.23946, found 425.23998.
3-((1R,2R,3S,4S,5S)-4-(3-Acetylphenylamino)-5-azido-2-
(benzyloxy)-1-((S)-1-(benzyloxy)ethyl)-3-(benzyloxymethyl)-3-
(tert-butyldiphenylsilyloxy)-2-methylcyclopentyl)-1,1-dime-
thylurea (methylketone of 67). To a stirred solution of olefin 67
(70 mg, 0.073 mmol) in THF (1 mL), acetone (1 mL), and H2O (0.2
mL) were added NMO (60 mg, 0.51 mmol) and OsO4 (0.05 mL, 4 wt
% in H2O) at 0 °C and stirred for 2 h at rt. A saturated aqueous
sodium bisulfite solution was added to the reaction mixture and stirred
for 30 min. The reaction mixture was extracted with EtOAc (30 mL ×
3), and the combined organic layers were washed with water and
brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Flash
column chromatography on silica gel using 70% EtOAc in hexanes
eluted the diol as clear oil, which was directly used for the next
reaction without characterization. To the stirred solution of the above
diol in THF (1 mL) and H2O (1 mL) was added NaIO4 (24 mg, 0.11
mmol) at rt and stirred for 2 h. The reaction mixture was extracted
with EtOAc (30 mL × 3), and the combined organic layers were
washed with brine, dried over anhydrous Na2SO4, and concentrated in
vacuo. Flash column chromatography on silica gel using 30% EtOAc in
hexanes eluted the methyl ketone (55 mg, 78% in 2 steps) as a
colorless liquid: [α]D20 +23.2 (c 1.00, CHCl3); IR (neat) νmax 3434 (br),
2931, 2857, 2099, 1665, 1603, 1585, 1524, 1358, 1272, 1237, 1172,
ASSOCIATED CONTENT
1
1108, 910, 821, 733, 701, 607 cm−1; H NMR (400 MHz, CDCl3) δ
■
7.62−7.08 (29H, aromatic protons), 6.62 (1H, br s), 6.38 (1H, s), 4.84
(1H, d, J = 8.0 Hz), 4.66 (1H, d, J = 12.1 Hz), 4.56 (1H, m), 4.45 (1H,
d, J = 11.1 Hz), 4.19 (1H, m), 4.04−3.98 (2H, m), 3.92 (1H, d, J =
11.3 Hz), 3.86 (1H, d, J = 10.1 Hz), 3.59 (1H, d, J = 10.1 Hz), 2.94
(6H, s), 2.62 (3H, s), 1.89 (3H, s), 1.12 (3H, d, J = 6.4 Hz), 0.91 (9H,
s); 13C NMR (100 MHz, CDCl3) δ 199.3, 158.6, 147.3, 139.3, 138.8,
137.6, 137.0, 136.1, 136.0, 135.1, 134.4, 129.3, 129.2, 128.8, 128.7,
128.4, 128.3, 128.1, 128.0, 127.2, 127.1, 126.9, 126.8, 126.5, 117.2,
S
* Supporting Information
1
Copies of the H and 13C NMR spectra of new compounds
(PDF) and CIF files for compounds 2, 12, 24 (p-
bromobenzoate ester derivative), 29 (p-nitrobenzoate ester
derivative), 33 (phenyloxazoline derivative), 38, 45, 46, 47
(derivative), 58, 64, and 68. This material is available free of
charge via the Internet at http://pubs.acs.org.
9471
dx.doi.org/10.1021/jo301638z | J. Org. Chem. 2012, 77, 9458−9472

The Journal of Organic Chemistry
Featured Article
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2004, 126, 6230−6231. (b) Soukup, M.; Wipf, E. H.; Leuenberger, H.
G. Helv. Chim. Acta 1987, 70, 232−236.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: stephen.hanessian@umontreal.ca.
(21) See the Experimental Section or the Supporting Information.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would like to thank the FQRNT and NSERC for funding.
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