Enantioselective approach to quinolizidines: Total synthesis of cermizine D and formal syntheses of senepodine G and cermizine C

Article abstract of DOI:10.1021/jo400324t

The formal syntheses of C₅-epi-senepodine G and C ₅-epi-cermizine C have been accomplished through a novel diastereoselective, intramolecular amide Michael addition process. The total synthesis of cermizine D has been achieved throug

Full text of DOI:10.1021/jo400324t

Article
pubs.acs.org/joc
Enantioselective Approach to Quinolizidines: Total Synthesis of
Cermizine D and Formal Syntheses of Senepodine G and Cermizine C
Nagarathanam Veerasamy, Erik C. Carlson, Nathan D. Collett, Mrinmoy Saha, and Rich G. Carter*
Department of Chemistry, Oregon State University, 153 Gilbert Hall, Corvallis, Oregon 97331, United States
S
* Supporting Information
ABSTRACT: The formal syntheses of C5-epi-senepodine G and C5-
epi-cermizine C have been accomplished through a novel diaster-
eoselective, intramolecular amide Michael addition process. The total
synthesis of cermizine D has been achieved through use of an
organocatalyzed, heteroatom Michael addition to access a common
intermediate. Additional key steps of this sequence include a matched,
diastereoselective alkylation with an iodomethylphenyl sulfide and
sulfone-aldehyde coupling/reductive desulfurization sequence to
combine the major subunits. The utility of a Hartwig-style C−N
coupling has been explored on functionally dense coupling partners.
Diastereoselective conjugate additions to α,β-unsaturated sulfones
have been investigated, which provided the key sulfone intermediate
in just six steps from commercially available starting materials. The
formal syntheses of senepodine G and cermizine C have been
accomplished through an intramolecular cyclization process of a N-Boc-protected piperidine sulfone.
INTRODUCTION
■
Since the initial isolation of lycopodine from Lycopodium
complanatum in Germany by von Karl Bodeker in 1881,1 a
̈
diverse collection of alkaloid natural products has been
discovered in the lycopdium club mosses. These plants have
been used for millennia as treatments for a wide range of
ailments, from controlling fever to schizophrenia to memory
loss. The first systematic study of the lycopodium club mosses
was spearheaded by Professor William A. Ayer from the
University of Alberta, leading to numerous advances in the field
of structural determination, biogenesis, and natural product
synthesis.2 More recently, Professor Jun’ichi Kobayashi’s
laboratory at the University of Hokkaido has continued to
mine these plants for additional alkaloid constituents, providing
multiple new compounds and new chemical scaffolds.3 Several
other laboratories have probed these plants for medicinally
useful alkaloids.4
Pelletierine (1) was first isolated from pomegranate by
Tanret in 1878 and serves as a common building block in the
biosynthesis of many of the lycopodium alkaloids (Figure 1).5
Despite its deceptively simple structure,6 this compound has
Figure 1. Piperidine- and quinolizidine-based natural products.
been the target of considerable synthetic attention and
numerous total syntheses.7,8 Many of the quinolizidine-natural
quinolizidine natural products 2−8 have garnered considerable
synthetic attention14−16 including total syntheses of the more
complicated members cernuine (8)14c,17 and cermizine D
(7).14c,17,18 This quinolizidine scaffold is also present in other
products identified by Ayer, Kobayashi, and others are derived
from pelletierine through the pelletierine condensation.9
Representative members of these quinolizidine natural products
include cermizine C10 (and its biosynthetic precursor
senepodine G), myrtine,11 and lasbines I−II.12 More complex
versions include the incorporation of a second formal unit of
pelletierine such as cermizine D10 and cernuine.13 These
Received: February 11, 2013
Published: April 29, 2013
© 2013 American Chemical Society
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members of the lycopodium alkaloids such as himeradine A.19
Our interest in these compounds was initially stimulated by
himeradine A and has expanded into developing general
approaches to access significant cross sections of the lycopodium
alkaloid family.8b,18,19b,20 Herein, we disclose a full account of
our total synthesis of cermizine D (7).18 In addition, we report
the formal syntheses of both cermizine C (2) and senepodine
G (3) as well as their C5 epimers.
Scheme 2. Retrosynthetic Analysis of Cermizine C and
Senepodine G
RESULTS AND DISCUSSION
■
Our efforts started with the observation that a core piperidine
ring was present in each of these natural products. We
envisioned that this piperidine scaffold could be constructed via
an organocatalyzed, intramolecular heteroatom Michael
addition of a suitably constructed enal precursor 9 (Scheme
1).8b To our surprise, this transformation had not been
Scheme 1. Organocatalyzed Intramolecular Heteroatom
Michael Addition and Total Synthesis of Pelletierine
guide the outcome of the transformation. The resultant product
14 from this cyclization could be readily converted to the
[4.4.0] bicyclic lactam 12, which Snider and co-workers have
previously converted onto senepodine G (3) and cermizine C
(2).14a,29
The necessary cyclization precursor 15 was constructed in
two steps from the previously prepared methyl ester 1620
(Scheme 3). Treatment of methyl ester 16 with the
Scheme 3. Synthesis of the Amide Cyclization Precursor
explored at the time we initiated this project.15h,21 Prior work in
the area had focused on an intermolecular version using highly
nucleophilic nitrogen sources;22 however, it is important to
note the pioneering intramolecular contributions from Hsung
and co-workers using vinylogous amides.23 We were pleased to
find that a general enantioselective approach could be
developed using the Jørgensen catalyst 1024 to provide the
resultant cyclized product 11 in good yield and high
eneantioselectivity.8b This approach was used for an efficient
enantioselective total synthesis of (−)-pelletierine (1).8b
Inspired by our initial successes with carbamate nitrogen
nucleophiles in the intramolecular heteroatom Michael
addition,8b we were intrigued by the possibility that alternate
nitrogen nucleophiles could be utilized. We were particularly
interested in the possibility that amides could serve as a
nucleophile for this transformation, specifically on substrates
containing additional stereochemistry in the resultant piper-
idine ring (e.g., 14) (Scheme 2). Interestingly, only limited
examples of simple primary amide nucleophiles25 have been
exploited in γ- or Δ-lactam formation via a heteroatom Michael
manifold.26 Hirama and co-workers explored a silyloxy
substituent within the carbon backbone of intramolecular
heteroatom Michael addition of an amide in their synthesis of
swainsonine.27 Shultz’s laboratory posthumously reported an
intramolecular heteroatom Michael addition onto a fused α,β-
unsaturated lactone to generate a [4.3.0] bicyclic scaffold.28 We
sought to probe the inherent stereoselectivity of the process
and exploit the possibility that catalyst control could be used to
dimethylaluminum-amide complex produced the amide 17.
Cross metathesis with crotonaldehyde (18) using the
Hoveyda−Grubbs second generation catalyst 19 produced
the enal 15 in good yield. This product 15 proved stable for
prolonged periods when stored frozen in benzene.
With the cyclization precursor in hand, we set out to explore
the possibility of expanding the organocatalyzed intramolecular
Michael addition to include amide nucleophiles (Table 1).
Using an achiral Lewis acid (BF3·Et2O) we observed slow
cyclization with essentially no diastereoselectivity (entry 1).
Interestingly, we have exploited a related BF3·Et2O-catalyzed,
intramolecular heteroatom Michael addition in our himeradine
A work for the construction of a piperidine ring with high
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Table 1. Exploration of Intramolecular Heteroatom Michael
Addition with Amide
Scheme 4. Formal Synthesis of C5-epi-Senepodine G and C5-
epi-Cermizine C
yield
entry
catalyst
conditions
CH3CN, rt
time
(14:C5-epi-14)
1
2
3
4
5
6
7
8
9
BF3·Et2O
10
1 d
5 d
40% (1:1.3)
n/d (1:1)
50% (1:10)
45% (1:1)
45%(1:2)
DCE/MeOH (1:1), rt
DCE/MeOH (1:1), rt
DCE/MeOH (1:1), rt
DCE/MeOH (1:1), rt
DCE/MeOH (1:1), rt
DCE/MeOH (9:1), rt
DCE, rt
ent-10
20
6 d
epi-senepodine G (27) and C5-epi-cermizine C (28) by Snider
and co-workers, thereby confirming the stereochemical assign-
ment of the heteroatom Michael addition.14a
Next, we turned out attention toward cermizine D (7)
(Scheme 5). Our initial retrosynthesis toward 7 exploited a
4 d
21
3 d
22
14 h
19 h
1 d
70% (1:4)
69% (1:4)
60% (1:4)
67% (1:4)
22
22
22
DCE, H2O (1 equiv), rt
19 h
Scheme 5. Retrosynthetic Analysis of Cermizine D
diastereocontrol.19b Use of our previous Jørgensen catalyst
conditions8b at low temperatures did not induce any
cyclization; however, warming of the reaction mixture to
room temperature provided the cyclized product as a 1:1
diastereomeric mixture at C5 (entry 2). Use of the enantiomeric
catalyst ent-10 resulted in clean formation of C5-epi-14 in
reasonable yield [entry 3, 50% yield, 1:10 dr (14:C5-epi-14)].
We also screened alternative monofunctional catalysts (e.g.,
MacMillan’s catalyst 20); however, this catalyst proved
unselective (entry 4). Our laboratory has extensively exploited
the use of proline sulfonamides for a range of trans-
formations.30 Consequently, we screened catalyst 21 in the
transformation, but poor diastereoselectivity was observed
(entry 5, 1:2 dr). Use of the alternate sulfonamide 2230g
provided a significant rate acceleration but with continued
modest levels of selectivity (entry 6, 14 h, 70% yield, 1:4 dr).
The reaction did not proceed at any appreciable rate at
temperatures below rt. Variation of the solvent mixture had
little impact on the transformation (entries 7−9).
The formal synthesis of C5-epi-senepodine G from aldehyde
C5-epi-14 is shown in Scheme 4. Treatment of aldehyde C5-epi-
14 with the known phosphonate 2331 under Masamune−
Roush conditions followed by hydrogenation yielded the
thioester 24. Reduction using NaBH4 in MeOH/THF followed
by treatment with MsCl provided the primary mesylate 25. The
lactam 26 was constructed by treatment of 25 with NaHMDS.
This intermediate 2632 has been previously converted onto C5-
common intermediate strategy to access the A and C rings. The
B ring would be incorporated through a reductive ring closing
metathesis (RCM) approach.33 The key C−N bond-forming
event between allylic carbonate 31 and amine 30 would be
facilitated through allylic amination chemistry developed by
Hartwig and co-workers.34 While we are unaware of an example
using α-branched secondary amines for this transformation
(e.g., 30), Helmchen and co-workers demonstrated some
promising examples of utilizing this amination chemistry for the
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synthesis of a series of piperidine-containing natural products.35
Both of the proposed coupling partners for this reaction could
be derived from a common intermediate 32. This aldehyde 32
is readily accessible from our intramolecular, heteroatom
Michael addition chemistry.8b
Scheme 7. Attempted Hartwig Coupling of Major Subunits
Synthesis of both of the key subunits from the common
intermediate 32 is shown in Scheme 6. Starting from the known
Scheme 6. Synthesis of Major Subunits through a Common
Intermediate
Boc-protected amine 3315h,21 (accessible in one step from
commercially available hex-5-en-1-amine or two steps from 1-
bromo-5-hexene), cross metathesis with crotonaldehyde (18)
provided the Michael addition precursor 34. Using a modified
version of our originally developed conditions,8b organo-
catalyzed, intramolecular heteroatom Michael addition pro-
duced the desired common intermediate 32 in excellent yield
and enantioselectivity. Conversion of 32 into the allylic
carbonate 31 was accomplished through Wittig olefination
followed by reduction and carbonate formation. Similarly,
addition of MeMgBr to aldehyde 32 followed by DMP
oxidation yielded ketone 35. Wittig olefination and Boc
deprotection using TFA gave the target secondary amine as
its TFA salt (30·TFA).
Our revised approach is shown in Scheme 8. We envisioned a
reductive amination strategy to couple the two subunits and our
previous reductive RCM approach to form the central B ring.
The A ring enone 45 could be derived from previously
Scheme 8. Revised Retrosynthetic Approach
With the two subunits in hand, we turned our attention to
the critical C−N bond-forming event (Scheme 7). Given the
challenging steric nature of the transformation, we first tested
the individual subunits with less demanding coupling partners.
While C−N bond formation could be accomplished in both
cases, the regioselectivity was disappointing. With the allyl
carbonate 31 and pyrrolidine, the undesired linear coupling
product 37 was observed in high yield (19:1 rr). The secondary
amine 30 proved slightly more compatible with the coupling
process, providing a branched to linear product ratio of 3:2 by
1H NMR. Undeterred, we screened the desired combination of
31 and 30; however, no C−N coupled material was observed.
On the basis of these results, it became clear that a revised
approach toward cermizine D was necessary.
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prepared piperidine intermediate 32. The amine 44 could be
accessed through Ellman tert-butyl sulfinamide chemistry.36
Both the primary amine 44 and the enone 45 could be
readily accessed from known intermediates (Scheme 9). The
Scheme 10. Successful Retrosynthetic Approach to
Cermizine D
Scheme 9. Synthesis of Primary Amine and Enone Subunits
reductive amination process would likely need to be circum-
vented. Finally, we desired to return to the common
intermediate approach found in our original strategy toward
cermizine D. Based on these requirements, our ultimately
successful retrosynthetic approach exploited the key common
intermediate 32 to access both the A and C rings of the natural
product. The two subunits would be joined through a sulfone-
aldehyde coupling/reductive desulfurization sequence. The
necessary sulfone 56 would be accessible from the same key
aldehyde 32.
In order to incorporate the C15 methyl stereocenter, we
envisioned using a diastereoselective Evans alkylation (Scheme
11). This historically reliable method has been routinely
Scheme 11. Synthesis of the Evans Oxazolidinones
requisite primary amine 44 was available in three steps from the
known aldehyde 4637 via imine formation with (R)-tert-butyl
sulfinamide (47) followed by addition of methallyl Grignard
and treatment with concentrated HCl. The diastereoselectivity
1
in the key C−C bond-forming event was 6:1 based on H
NMR analysis. The enone 45 was available via Grignard
addition to the aldehyde 32 followed by DMP oxidation. Enone
45 provided us with an alternative method to gauge
enantioselectivity after nucleophilic addition to the aldehyde
32. The resultant enantioselectivity was established by chiral
HPLC analysis to be 90% ee; however, this enantioselectivity
could be increased through a single recrystallization to 99%.
Imine formation between enone 45 and amine 44 appeared to
be feasible under forcing [Ti(Oi-Pr)4, neat, overnight]
conditions; however, reductive amination of the intermediate
imine proved unselective. More troubling was the observation
that the C5 stereocenter appeared to have epimerized under the
reaction conditions. One possible manifold for this epimeriza-
tion at C5 could be through β-elimination of the intermediate
imine followed by reclosure.
employed to circumvent mismatched stereochemical combina-
tion in synthesis.38 Based on the Evans model, we required the
(S)-benzyl oxazolidinone 60, which was readily accessed from
the aldehyde 32 through homologation followed by Pinnick
oxidation and acyl oxazolidinone formation. The analogous
(R)-oxazolidinone series was also prepared through the same
process.
The exploration of the diasteroselectivity in the key
alkylation yielded unexpected results (Table 2). In contrast to
what is normally seen in Evans alkylations, a pronounced
matched/mismatched effect was observed. Treatment of
oxazolidinone 60 with LiHMDS led to poor conversion
Given the roadblocks encountered in both of our approaches
involving C−N bond-forming strategies to couple the two
subunits of cermizine D, we sought an alternate approach that
incorporated the carbon backbone first (Scheme 10). In
addition, the β-elimination phenomenon observed in the
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Table 2. Exploration of Evans Alkylation
Scheme 12. Synthesis of the Sulfone Moiety
a
entry
conditions
yield (%)
dr
13). Using aldehyde 58, Eschenmoser methylenation provided
the enal 70, which was reduced to the corresponding alcohol
71. While compelling precedent existed for diastereoselective
hydrogenation of 1,1-disubstituted alkenes similar to 71,41
attempted reduction using 10 mol % (S)-Ru(OAc)2(T-BINAP)
(74) gave low yield (40%) and no diastereoselectivity. We also
explored a reductive protonation strategy through the α,β-
unsaturated oxazolidinone 73. This strategy proved similarly
unsuccessful, as L-Selectride reduction showed a slight
preference for the undesired C15 stereochemistry after
protonation with methanol. It should be noted that this
reduction strategy is dependent on controlling the s-cis/s-trans
ratio between the 1,1-disubstituted alkene and the C8 carbonyl
moiety.
While our original alkylation sequence did provide an
effective way to access the sulfone 56, we were intrigued by
the possibility of exploiting to our advantage the pronounced
mismatched/matched relationship of the diastereoselective
alkylation (Scheme 14). One possibility would involve using
the matched oxazolidinone 61 with an electrophile such as
thiophenylmethyl iodide (PhSCH2I) or phenyl iodomethyl
sulfone (PhSO2CH2I). We were only aware of a single example
for utilizing one of those electrophiles with an oxazolidinone-
based nucleophile. Baker and co-workers reported the
alkylation of 75 with PhSCH2I in low yield upon extended
reaction times (5 d, −20 °C, 30% yield).42 Alternatively, we
considered the possibility of a diastereoselective thio-Michael
addition based on some compelling literature precedent;43
however, our preliminary examples exploring conjugate
reduction and hydrogenations as described previously in
Scheme 13 made this approach seem less attractive.
1
2
3
4
60, LiHMDS (1.1 equiv)
60, NaHMDS (1.6 equiv)
60, KHMDS (2.0 equiv)
61, NaHMDS (2.0 equiv)
29
92
87
77
1:1 (66:64)
1.5:1 (66:64)
1:1.4 (66:64)
1:20 (67:65)
a
10 equiv of MeI was used in each case.
(entry 1) and essentially no diastereoselectivity. Use of
alternate bases (and at slightly higher equivalencies) led to
improved levels of reactivity. NaHMDS (entry 2) gave a slight
preference for the desired stereochemistry (92% yield, 1.5:1 dr
66:64)]. The major isomer 66 generated crystals suitable for X-
ray crystallographic analysis,39 thereby establishing both the
absolute configuration of the newly created stereocenter as well
as confirming the stereochemical assignment of the heteroatom
Michael reaction. Despite this low selectivity, a 55% isolated
yield of the major isomer could be obtained, providing
reasonable material throughput. KHMDS (entry 3) gave
continued high chemical yields but now with a slight preference
for the undesired stereoisomer [87% yield, 1:1.4 dr (66:64)].
Use of the alternate (R)-oxazolidinone 61 led to a highly
diastereoselective process, favoring the undesired stereoisomer
65 [77% yield, 20:1 dr (65:67), entry 4]. Confirmation of the
stereochemistry was obtained by reduction of the acyl
oxazolidinone and comparison with the products derived
from the (S)-oxazolidinone series. One possible explanation
for this pronounced difference in diastereoselectivity could be a
chelation between the enolate derived from oxazolidinone and
the Boc moiety (e.g., intermediates 62 and 63). While this
would create a typically unfavorable nine-membered cyclic
structure, the presence of multiple sp2-hybridized atoms would
reduce the number of disruptive transannular interactions.
Please note that the Boc-protected nitrogen likely forces the
C13 substituent to adopt an axial conformation.40
Our second generation approach to the synthesis of sulfone
56 is shown in Scheme 15. We were pleased to find that
alkylation of oxazolidinone 61 with the PhSCH2I proceeded
smoothly to provide the desired product 82 in 70% yield and
10:1 dr. It was key that the electrophile was prepared
immediately prior to use as storage for even 3 h resulted in
dramatically reduced yields. We attribute the efficiency of this
process to the matched relationship of the oxazolidinone and
piperidine stereochemistries as shown in intermediate 63.
Reduction of 82 under standard conditions produced the
alcohol 83. Next, oxidation of the sulfide using ammonium
molybdate followed by iodide incorporation yielded 84. Finally,
With the C15 alkylated material in hand, we constructed the
needed sulfone 56 in three steps (Scheme 12). Borohydride
reduction of the C8 carbonyl provided the alcohol 68.
Conversion to the sulfide was accomplished using diphenyl
disulfide and PBu3 in excellent yield. Subsequent oxidation
using ammonium molybdate gave the target sulfone 56 in high
yield.
Given the poor diastereoselectivity in the key C15 alkylation,
we explored alternate approaches to its construction (Scheme
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Scheme 13. Attempted Approaches To Improve
Stereoselectivity
Scheme 14. Prior Work in Diastereoselective (and
Enantioselective) Construction of β-Thio Carbonyl
Compounds
monodentate phosphoramidite ligands; however, they specifi-
cally commented in the manuscript that “...with the less reactive
dimethyl zinc no conversion was obtained...”45
In order to explore a substrate-controlled conjugate addition
process, we synthesized the required α,β-unsaturated sulfones
and silyl sulfones (Scheme 16). Olefination of aldehyde 32 with
the HWE reagent 85 produced the target alkene in modest E/Z
selectivity (4:1, 86:87). No attempt was made to improve this
selectivity of this process at this time. In order to study the
possible influence of the Boc moiety, we replaced the nitrogen
protecting group with a benzyl moiety via TFA deprotection
and nitrogen alkylation. The vinyl silyl sulfones 92 and 93 were
constructed via Isobe’s two-step protocol of Peterson
olefination followed by sulfide oxidation in again modest, but
unoptimized E/Z selectivity.
With these Michael acceptors in hand, we first explored the
potential of the vinyl silyl sulfones (Table 3). Use of methyl
lithium resulted in preferential desilylation followed by olefin
isomerization to produce 95 (entry 1). We are unsure of the
enantiomeric purity of this product as a viable epimerization
mechanism can be envisioned involving a β-elimination process
to form a dienyl sulfone intermediate. Using lower order
cuprates, we were successful in facilitating the desired conjugate
addition (entries 3 and 4); however, these transformations
produced primarily the undesired C15 epimer after desilylation.
Use of the alternate olefin isomer 93 (entry 5) continued to
dehalogenation using Pd/C and hydrogen gas provided the
previously prepared sulfone 56 in 99% yield.
While the second generation route provided noticeable
improvements in stereoselectivity and material through-put, the
lingering issue of the overall step-count for the process
remained. In principle, the conversion of aldehyde 32 into
sulfone 56 should be a two-step process: olefination to make
the α,β-unsaturated sulfone and diastereoselective conjugate
addition of a methyl nucleophile to make the target
intermediate 56. While tempting, serious hurdles remained
for implementing such an approach, particularly in the
diastereoselective conjugate addition step. We had hoped that
substrate control could be exploited to direct the newly formed
stereochemistry. While only limited examples of such trans-
formations are known,44 Isobe’s work using 1-TMS, 1-
phenylsulfonyl alkenes was compelling.44b Regarding reagent-
controlled conjugate additions, we were unaware of compelling
precedent for conjugate addition of methyl nucleophiles to α,β-
unsaturated sulfones. Feringa and co-workers have reported an
elegant catalytic process using pyridinyl sulfones and
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available reagents. Attempts to improve the stereoselectivity
and chemical yield of this process through use of alternate
electrophile 87 resulted in decomposition (entry 4). In
addition, use of the benzyl protected series 88 proved similarly
ineffective. It is clear from these experiments that a delicate
balance exists in controlling the reactivity of these α,β-
unsaturated sulfones.
Scheme 15. Second Generation Synthesis of Sulfone Subunit
With multiple viable routes to the key intermediate 56, we
embarked on our key coupling strategy (Scheme 17).
Treatment of sulfone 56 with LDA followed by the addition
of aldehyde 32 produced both the expected product 96/97 and
the unexpected cyclic product 98 as a single diastereomer with
undetermined stereochemistry at C8. Fortunately, the undesired
product 98 could be completely suppressed by reducing the
reaction time for deprotonation from 15 to 1 min, resulting in a
93% yield of the desired C7−C8 coupled material as a
stereochemical mixture. This mixture could be interconverted
through an oxidation/reduction process. Interestingly, for-
mation of the unexpected product 98 could be optimized to
87% yield through variation in the reaction time and
temperature. Subsequent desulfurization produced the known
lactam intermediate 12.14 This lactam 12 constitutes a formal
synthesis of both senepodine G (3) and cermizine C (2) based
on work by Snider and co-workers.14
The total synthesis of cermizine D is shown in Scheme 18.
Using hydroxyl sulfone 97, Raney Ni desulfurization yielded the
free alcohol, which proved unstable to purification. Con-
sequently, direct Boc deprotection of the crude material
revealed the intermediate 99 as its bis HCl salt. While
desulfurizations of keto sulfones are well-precedented, propor-
tionally less work has focused on the desulfurization of hydroxy
sulfones,46 likely due to the competitive elimination pathway
commonly seen in Julia couplings.47 Treatment of the salt 99
with triphenyl phosphine and carbon tetrabromide in the
presence of triethyl amine generated the natural product 7 in
60% yield over three steps. We were pleased to find that upon
favor the undesired stereochemistry in the conjugate addition,
albiet in reduced selectivity (55% yield, 1.9:1 dr (94:56).
We also explored the possibility for conjugate addition to the
vinyl sulfone 86 with more success (Table 4). Initial attempts
with MeLi or high order cuprates resulted in extensive
decomposition of the starting material (entries 1 and 2). We
attribute this decomposition pathway to a competitive
deprotonation process of γ-hydrogens of the vinyl sulfone via
a similar pathway to the product 95 seen in the previous table.
Fortunately, use of lower order cuprate nucleophiles under
carefully controlled conditions did produce the desired
conjugate addition product, albeit in modest yield and no
diastereoselectivity (entry 3). Despite these shortcomings, this
conjugate addition process provides an exceedingly short
approach to sulfone 56 − just six steps from commercially
1
comparison of our H/13C NMR and optical rotation data for
7·TFA that it was in good agreement with the data reported by
Takayama and co-workers.14c,17 While not directly stated in the
original isolation paper, the spectroscopic data reported by
Hirasawa and co-workers were collected on the TFA salt of
cermizine D.18
Scheme 16. Second-Generation Synthesis of Sulfone Subunit
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Table 3. Exploration of Conjugate Addition to Vinyl Silyl Sulfones
entry
electrophile
conditions
result (yield, dr)
1
2
3
4
5
92
92
92
92
93
MeLi (1.5 equiv), Et2O, −78 to −50 °C
95 (85%)
CuI (3 equiv), MeLi (5.9 equiv), Et2O, −78 °C to rt
CuI (10 equiv), MeLi (19.6 equiv), Et2O, −78 to 0 °C
CuI (6 equiv), MeLi (11.8 equiv), Et2O, 0 °C
CuI (10 equiv), MeLi (19.7 equiv), Et2O, −78 °C to rt
decomp
94 (60%, 10:1 dr)
94 (93%, 8:1 dr)
94 (55%, 1.9:1 dr)
Table 4. Exploration of Conjugate Addition to Vinyl Sulfones
entry
sulfone
conditions
result (yield, dr)
1
2
3
4
86
86
86
87
MeLi (1.5 equiv), Et2O, −78 °C
decomp
CuCN (3 equiv), MeLi (5.9 equiv), Et2O, −78 °C to rt
CuI (3 equiv), MeLi (5.9 equiv), Et2O, −78 °C
CuI (3 equiv), MeLi (5.9 equiv), Et2O, −78 °C
decomp
56:94 (55%, 1:1.2 dr)
decomp
Scheme 17. Coupling of Major Subunits and Formal
Synthesis of Senepodine G and Cermizine C
Scheme 18. Total Synthesis of Cermizine D
was accessed via an organocatalyzed, heteroatom Michael
addition. This common intermediate 32 is exploited to
construct two of the three piperidine rings found in cermizine
D as well as the vast majority of the carbon framework.
Additional key steps of this sequence include a matched,
diastereoselective alkylation with an iodomethylphenyl sulfide
and sulfone-aldehyde coupling/reductive desulfurization se-
quence to combine the major subunits. The longest linear
sequence of the synthesis (just nine steps using the cuprate
addition strategy in Table 4 or 16 steps via the sulfide alkylation
strategy described in Scheme 15) compares favorably to prior
work in the field. Through the cermizine D work, the possible
CONCLUSION
■
In summary, a novel diastereoselecetive, intramolecular amide
Michael addition process has been developed and applied to
the formal synthesis of C5-epi-senepodine G and C5-epi-
cermizine C. In addition, the total synthesis of cermizine D
has been accomplished using a common intermediate 32, which
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1H), 6.87−6.77 (m, 1H), 6.14−6.07 (m, 2H), 5.88 (brs, 1H), 2.44−
2.39 (m, 1H), 2.30−2.17 (m, 3H), 2.12−2.06 (m, 1H) 1.00 (d, J = 6
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 193.9, 173.9, 156.2, 134.6,
42.5, 39.6, 29.9, 19.8; HRMS (EI+) calcd for C8H13NO2 (M+)
155.0946, found 155.0944.
utility of Hartwig-style C−N couplings have been explored on
functionally dense coupling partners, providing important
limitations to the methodology. Finally, the serendipitous
discovery of an intramolecular cyclization process48 with
sulfone 56 provided a rapid route to the formal synthesis of
senepodine G and cermizine C. Subsequent application to
additional lycopodium alkaloids will be reported in due course.
EXPERIMENTAL SECTION
■
General. Infrared spectra were recorded neat unless otherwise
indicated and are reported in cm−1. 1H NMR spectra were recorded in
deuterated solvents and are reported in ppm relative to tetramethylsi-
lane and referenced internally to the residually protonated solvent. 13C
NMR spectra were recorded in deuterated solvents and are reported in
ppm relative to tetramethylsilane and referenced internally to the
residually protonated solvent. HRMS data was collected using a TOF
mass spectrometer.
Aldehyde 14. To a solution of 15 (0.0574 g, 0.401 mmol) in
MeOH (2 mL) was added 10 (0.0479 g, 0.080 mmol) in DCE (1.9
mL). After 4 d, the reaction was concentrated in vacuo and loaded
directly silica gel, purified by chromatography eluting in 100% EtOAc
to give a crude mixture of three compounds that were concentrated in
vacuo. The crude mixture was dissolved in CH2Cl2 (2 mL) and stirred
with 10% aq HCl (3 mL). After 2 h, the reaction was extracted with
CH2Cl2 (10 mL × 2). The dried (MgSO4) extract was concentrated in
vacuo to give 14 (10:1 dr) (0.031 mg, 0.200 mmol, 50%) as a greenish
Routine monitoring of reactions was performed using EM Science
DC-Alufolien silica gel, aluminum-backed TLC plates. Flash
chromatography was performed with the indicated eluents on EM
Science Gedurian 230−400 mesh silica gel.
Air- and/or moisture-sensitive reactions were performed under
usual inert atmosphere conditions. Reactions requiring anhydrous
conditions were performed under a blanket of argon, in glassware
dried in an oven at 120 °C or by flame and then cooled under argon.
Dry THF and DCM were obtained via a solvent purification system.
All other solvents and commercially available reagents were either
purified via literature procedures or used without further purification.
oil: [α]23 = +10.43° (c 1.63, CHCl3); IR (neat) 3213, 2955, 1722,
D
1
1660, 1457, 1408, 1338, 1280, cm−1; H NMR (300 MHz, CDCl3) δ
9.80 (s, 1H), 6.14 (brs, 1H), 3.97−3.90 (m, 1H), 2.82−2.75 (dd, J =
18.6, 3.9 Hz, 1H), 2.65−2.56 (dd, J = 18.6, 8.7 Hz, 1H), 2.49−2.44
(dd, J = 13.2, 2.4 Hz, 1H), 2.01−1.86 (m, 4H), 1.06 (d, J = 12.6 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 200.0, 172.4, 50.5, 47.5, 39.6,
37.1, 27.4, 21.3; HRMS (EI+) calcd for C8H13NO2 (M+) 155.0946,
found 155.0921.
Amide 17. To a solution of 16 (0.140 g, 0.986 mmol) in CH2Cl2
(5 mL) at rt was added dimethylaluminumamide (0.733 mL, 1.13
mmol, 1.5 M in CH2Cl2), and the reaction was warmed to 33 °C. After
stirring for 16 h, dimethylaluminumamide (0.30 mL, 0.45 mmol, 1.5 M
in CH2Cl2) was added. After stirring for 24 h, the reaction was cooled
to rt, quenched with MeOH (0.5 mL), and allowed to stir for 10 min,
and satd aq Rochel’s salt (5 mL) was added and stirred 10 min to form
two clear layers. The reaction was extracted with CH2Cl2 (3 × 15 mL).
The dried (MgSO4) extract was concentrated in vacuo and purified by
chromatography over silica gel, eluting with 10−50% EtOAc/hexanes,
to give 17 (0.105 g, 0.83 mmol, 85%) as a white solid. Mp 93.2−91.7
Thioester SI-1. To a solution of 14 (0.280 g, 1.16 mmol) in
CH3CN (5.8 mL) were added sequentially LiCl (0.059 g, 1.39 mmol)
and DIPEA (0.150 g, 1.16 mmol). After 10 min, the solution was
cooled to 0 °C. After 5 min, a precooled (0 °C) solution of 23 (0.18 g,
1.16 mmol) in CH3CN (6 mL) was cannulated into the reaction (2 ×
0.5 mL MeCN rinse). The reaction was allowed to warm to rt over 10
min. After 30 min, the reaction was quenched with aq HCl (2 mL 1.22
M) and extracted with EtOAc (3 × 20 mL). The dried extract
(MgSO4) was concentrated in vacuo and purified by chromatography
over silica gel, eluting with 95% EtOAc/hexanes to give SI-1 (0.160 g,
0.66 mmol, 57%) as a white solid. Mp 76.5−75.0 °C; [α]23D = −34.3°
°C; [α]23 = +5.98° (c 1.07, CHCl3); IR (neat) 3352, 3183, 2954,
D
1
2911, 1664, 1631, 1413, 1152 cm−1; H NMR (400 MHz, CDCl3) δ
5.83−5.48 (m, 3H), 5.05 (d, J = 12.4 Hz, 2H), 2.28 (dd, J = 13.6, 5.2
Hz, 1H), 2.13−1.97 (m, 4H), 1.00 (d, J = 6 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 174.9, 136.5, 116.6, 42.8, 41.0, 30.4, 19.5; HRMS (EI
+) calcd for C7H13NO (M+) 127.0997, found 127.0993.
1
(c 0.525, CHCl3); IR (neat) 2954, 2927, 2862, 1662 cm−1; H NMR
(400 MHz, CDCl3) δ 6.76 (m, 1H), 6.20 (d, J = 18.8 Hz, 1H), 5.97
(bs, 1H), 3.56 (m, 1H), 2.97 (m, 2H), 2.50−2.25 (m, 3H), 2.00−1.80
(m, 3H) 1.30 (t, 3H), 1.05 (m, 4H); 13C NMR (100 MHz, CDCl3) δ
189.4, 172.9, 138.8, 131.7, 51.6, 39.5, 39.0, 36.8, 27.4, 23.1, 21.4, 14.7;
HRMS (EI+) calcd for C12H20O2SN (M+) 242.1215, found 242.1214.
Enal 15. To a solution of 17 (178 mg, 1.41 mmol) in CH2Cl2 (13
mL) at rt were added sequentially crotonaldehyde (0.59 mL, 495 mg,
7.06 mmol) and second generation Hoveyda−Grubbs catalyst (6.7 mg,
0.010 mmol). After 1 h, another portion of the second generation
Hoveyda−Grubbs catalyst (2.2, 0.003 mmol) was added. After stirring
for 2 h, the reaction was concentrated in vacuo, loaded directly onto
silica gel, and purified by chromatography, eluting with 10−100%
EtOAc/hexanes and 5−10% MeOH/CH2Cl2, to give 15 (184 mg, 1.19
mmol, 84%) as a brown oil and recovered alkene 17 (29 mg, 0.22
mmol): [α]23D = −7.93° (c 1.35, CHCl3); IR (neat) 3350, 3198, 2960,
1684, 1405, cm−1; 1H NMR (300 MHz, CDCl3) δ 9.48 (d, J = 7.8 Hz,
Thioester 24. To a solution of SI-1 (0.615 g, 2.54 mmol) in
EtOAc (60 mL) at rt under an inert argon atmosphere was added Pd/
C (10 wt %, 0.490 g), and the reaction flask was purged with a balloon
of H2 gas and allowed to stir under a balloon of H2 gas. After 2 d, the
H2 atmosphere was purged with argon for 5 min. The reaction was
then filtered through Celite (EtOAc 200 mL wash), concentrated in
vacuo, and purified by chromatography over silica gel, eluting with 10%
MeOH/EtOAc, to give 24 (0.615 g, 2.54 mmol, 99%) as a white wax:
[α]23 = −2.46° (c 0.65, CHCl3); IR (neat) 3215, 2954, 2927, 1684,
D
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1
1653 cm−1; H NMR (400 MHz, CDCl3) δ 5.7 (bs, 1H), 3.39 (m,
extracted with ether (3 × 40 mL). The dried (MgSO4) extract was
concentrated in vacuo at 0 °C to give crude azide. The crude azide was
then redissolved in THF/H2O (5:1, 50 mL) and PPh3 (4.00 g, 15.2
mmol) was added. After 15 h, Et3N (5.14 g, 7.05 mL, 50.83 mmol)
and Boc-anhydride (8.33 g, 8.77 mL, 38.13 mmol) were added. After
12 h, THF was removed in vacuo, and brine (100 mL) was added and
extracted with ether (3 × 100 mL). The dried (MgSO4) extract was
concentrated in vacuo and purified by chromatography over silica gel,
eluting with 1−20% EtOAc/hexanes to give 3321a (2.43 g, 12.23
mmol, 96% over 3 steps) as a colorless oil. IR (neat) 3364, 3075, 2975,
1H), 2.88 (m, 2H), 2.57 (m, 2H), 2.43 (bd, 1H), 1.50 (m, 2H), 1.27
(t, 3H) 1.05 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 199.0, 172.4,
52.6, 43.5, 39.7, 37.1, 36.1, 27.6, 23.3, 21.5, 21.0, 14.8; HRMS (EI+)
calcd for C12H21NO2S (M+) 243.1293, found 243.1290.
1
2931, 1700, 1642, 1365, 1172 cm−1; H NMR (400 MHz, CDCl3) δ
Alcohol SI-2. To a solution of 24 (0.082 g, 0.34 mmol) in MeOH/
THF 1:1 (4 mL) at rt was added NaBH4 (0.100 g, 2.63 mmol) in small
portions to maintain continuous hydrogen evolution. After 1 h, the
reaction was quenched with satd aq NaHCO3 (6 mL) and extracted
with EtOAc (3 × 10 mL). The dried extract (MgSO4) was
concentrated in vacuo and purified by chromatography over silica
gel, eluting with 20% MeoH/EtOAc to give SI-2 (0.061 g, 0.328
5.80 (ddt, J = 13.3, 10.1, 6.6 Hz, 1H), 5.02 (dq, J = 17.2, 1.7 Hz, 2H),
4.52 (br s, 1 H), 3.12−3.15 (m, 2H), 2.07−2.12 (m, 2H), 1.48−1.55
(m, 3H), 1.47 (s, 9H), 1.43−1.45 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 156.0, 138.5, 114.6, 79.0, 40.4, 33.3, 29.5, 28.4, 26.0; HRMS
(EI+) calcd for C11H22NO2 (M + H) 200.1651, found 200.1648.
mmol, 98%) as a white wax: [α]23 = −21.6° (c 0.37, CHCl3); IR
D
(neat) 3286, 2933, 1653 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.8 (bs,
1H), 3.67 (m, 2H), 3.39 (m, 1H), 2.44 (bd, 2H), 1.95−1.84 (m, 4H),
1.66−1.55 (m, 7H), 1.28 (m, 2H), 1.06 (m, 4H); 13C NMR (100
MHz, CDCl3) δ 173.1, 61.9, 52.9, 39.5, 37.5, 36.2, 32.2, 27.6, 21.5,
21.2; HRMS (EI+) calcd for C10H19NO2 (M+) 185.14158, found
185.14196.
Enal 34. To a solution of 33 (1.5 g, 7.52 mmol) in dry DCM (85
mL) were added crotonaldehyde 18 (0.266 g, 3.12 mL, 37.5 mmol)
and second generation Hoveyda−Grubbs catalyst (71 mg, 0.113
mmol), and the mixture was stirred at room temperature. After 5 h, the
solvent was removed in vacuo, and the crude was purified by
chromatography over silica gel, eluting with 25−40% EtOAc/hexanes
to give 3421a (1.59 g, 7.01 mmol, 94%) as a dark colored oil. IR (neat)
3357, 2976, 2934, 2865, 1693, 1521, 1366, 1169 cm−1; 1H NMR (700
MHz, CDCl3) δ 9.51 (d, J = 7.7 Hz, 1H), 6.85 (dt, J = 15.4, 6.3 Hz,
1H), 6.13 (dd, J = 15.4, 7.7 Hz, 1H), 4.62 (br s, 1H), 3.15−3.16 (m,
2H), 2.36−2.39 (m, 2H), 1.51−1.57 (m, 4H), 1.45 (s, 9H); 13C NMR
(175 MHz, CDCl3) δ 194.1, 158.2, 156.0, 133.2, 79.3, 40.1, 32.3, 29.7,
28.4, 25.0; HRMS (EI+) calcd for C12H22NO3 (M + H) 228.1600,
found 228.1608.
Mesylate 25. To a solution of SI-2 (0.120 g, 0.648 mmol) in THF
(30 mL) at 0 °C were added sequentially Et3N (0.131 g, 1.296 mmol)
and MsCl (0.118 g, 1.038 mmol). After 15 min, the ice bath was
removed, and the reaction was allowed to warm to rt. After 45 min, the
reaction was quenched with H2O (15 mL) and extracted with EtOAc
(3 × 15 mL). The dried extract (MgSO4) was concentrated in vacuo
and purified by chromatography over silica gel, eluting with 10%
MeOH/EtOAc, to give 25 (0.150 g, 0.570 mmol, 88%) as a white
solid. Mp 91.5−90.0 °C; [α]23D 1= −33.41° (c 0.82, CHCl3); IR (neat)
3177, 2943, 2916, 1653 cm−1; H NMR (400 MHz, CDCl3) δ 6.45
(bs, 1H), 4.24 (t, 2H), 3.39 (m, 1H), 3.02 (s, 3H), 3.57−3.54 (m,
1H), 2.41 (m, 2H), 1.92−1.84 (m, 3H), 1.83−1.73 (m, 2H), 1.60−
1.49 (m, 4H), 1.02 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 172.7,
69.5, 52.7, 39.7, 37.4, 37.1, 36.3, 29.0, 27.6, 21.5, 21.1; HRMS (EI+)
calcd for C11H21NO4S (M+) 263.1191, found 263.1197.
Aldehyde 32. To a solution of 34 (970 mg, 4.27 mmol) in MeOH
(30.6 mL) was added a solution of the catalyst 10 (254 mg, 0.43
mmol) in DCE (10.2 mL) via syringe, and the mixture was placed in
the freezer unstirred (−25 °C). After 10 d, water (50 mL) was added
and extracted with DCM (3 × 60 mL). The dried (MgSO4) extract
was concentrated in vacuo and purified by chromatography over silica
gel, eluting with 0−25% EtOAc/hexanes to give known 3221a (825 mg,
3.63 mmol, 85%) as a colorless oil. [α]20D = −36.0 (c 1.0, CHCl3); IR
(neat) 2935, 2864, 2727, 1693, 1521, 1416, 1167, 867 cm−1; 1H NMR
(400 MHz, CDCl3) δ 9.60−9.61 (m, 1H), 4.70−4.71 (m, 1H), 3.86
(d, J = 12.4 Hz, 1H), 2.58−2.70 (m, 2H), 2.42 (ddd, J = 15.2, 6.4, 2.0
Hz, 1H), 1.36−1.60 (m, 5H), 1.32 (s, 9H), 1.25−1.27 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 200.5, 154.5, 79.7, 45.8, 44.5, 39.1, 28.8,
28.2, 25.1, 18.8; HRMS (EI+) calcd for C12H21NO3 (M+) 227.1522,
found 227.1513.
Lactam 26. To a solution of 25 (11 mg, 0.042 mmol) in THF (2
mL) at 0 °C was added NaHMDS (0.045 mmol, 4.5 μL, 1 M in THF).
After 5 min, the ice bath was removed, and the reaction was allowed to
warm to rt. After 55 min, the reaction was quenched with H2O (15
mL) and extracted with CH2Cl2 (3 × 15 mL). The dried extract
(MgSO4) was concentrated in vacuo to give 26 (6 mg, 0.038 mmol,
90%) as a clear oil. [α]23D = −29.7° (c 0.93, CHCl3); IR (neat) 2928,
2854, 1647 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.78 (bd, 1H), 3.19
(m, 1H), 2.49−2.40 (m, 2H), 1.99−1.69 (m, 6H), 1.44−1.36 (m, 2H),
1.39−1.36 (m, 2H), 0.98 (d, 3H); 13C NMR (100 MHz, CDCl3) δ
169.5, 56.7, 41.8, 41.2, 39.7, 34.6, 26.5, 25.4, 24.3, 21.3. The spectral
data match those previously reported for 26.14a
Benzoate SI-5. To a solution of aldehyde 32 (89.5 mg, 0.394
mmol) in MeOH (3 mL) at 0 °C was added NaBH4 (44.7 mg, 1.183
mmol). After 30 min, the reaction was quenched with aq NH4Cl (5
mL) solution and extracted with ether (3 × 10 mL). The dried
(MgSO4) extract was concentrated in vacuo to give the crude alcohol
32, which was carried to the next step.
Boc-Protected Amine 33. To a solution 6-bromo-1-hexene (SI-
3) (2.08 g, 12.70 mmol) in DMF/H2O (9:1, 50 mL) was added NaN3
(2.07 g, 31.83 mmol). After 12 h, brine was added, and the azide was
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To a solution of crude alcohol SI-4 (∼0.39 mmol) in DCM (1.97
mL) at 0 °C was added DMAP (144.4 mg, 1.18 mmol) followed by p-
chlorobenzoyl chloride (103.4 mg, 75.5 μL, 0.591 mmol). After 15
min, the reaction mixture was warmed to rt over a period of 30 min.
After 12 h, water (5 mL) was added and extracted with ether (3 × 10
mL). The dried (MgSO4) extract was concentrated in vacuo and
purified by chromatography over silica gel, eluting with 15−30%
EtOAc/hexanes to obtain known SI-521a (121.6 mg, 0.33 mmol, 84%
over 2 steps) as a colorless oil. The enantiomeric excess was
determined with the aid of HPLC analysis Chiralcel IC (25 cm × 0.46
Carbonate 31. To a solution of SI-7 (158 mg, 0.62 mmol) in
CH2Cl2 (10.0 mL) at 0 °C were added sequentially pyridine (147 mg,
0.150 mL, 1.86 mmol) and ClCO2Me (64.4 mg, 0.054 mL, 0.68
mmol). After 1 h, the solution was then diluted with water (15 mL)
and sequentially extracted with EtOAc (3 × 20 mL). The combined
organic layers were washed sequentially with brine (20 mL) and satd
aq NH4Cl (20 mL). The dried (MgSO4) extract was concentrated in
vacuo and purified by chromatography over silica gel, eluting with 10−
25% EtOAc/hexanes to give 31 (158 mg, 0.502 mmol, 81%) as a
colorless oil. [α]23 = −27.4° (c 1.0, CHCl3); IR (neat) 2934, 2857,
D
1750, 1688, 1266 cm−1; 1H NMR (300 MHz, CDCl3) δ 5.69−5.76 (m,
1H), 5.60−5.68 (m, 1H), 4.56 (d, J = 6 Hz, 2H), 4.28 (bs, 1H), 3.95
(d, J = 12.4 Hz, 1H), 3.78 (s, 3H), 2.75 (t, J = 12.8 Hz, 1H), 2.41−
2.49 (m, 1H), 2.20−2.30 (m, 1H), 1.50−1.70 (m, 5H), 1.40−1.50 (m,
1H), 1.39 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 155.6, 155.0,
133.6, 125.3, 79.2, 68.3, 54.7, 49.9, 38.9, 32.9, 28.4, 27.7, 25.4, 18.8;
HRMS (EI+) calcd for C16H28NO5 (M+) 314.1967, found 314.1961.
cm column), hexane/isopropanol 90:10, flow = 1.0 mL/min, tR,minor
=
11.5 min, tR,major = 10.2 min. [α]20 = −11.0° (c 1.0, CHCl3); IR
D
(neat) 2934, 2861, 1721, 1688, 1595, 1448, 1415, 1365, 1307, 1275,
1
1169, 1145, 1091, 760 cm−1; H NMR (400 MHz, 40 °C, CDCl3) δ
7.98 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 4.47 (br s, 1H),
4.29−4.47 (m, 2H), 4.04 (d, J = 13.2 Hz, 1H), 2.82 (t, J = 13.2 Hz,
1H), 2.18−2.25 (m, 1H), 1.81−1.90 (m, 1H), 1.55−1.72 (m, 5H),
1.38−1.49 (m, 10H); 13C NMR (100 MHz, 40 °C, CDCl3) δ 165.7,
154.9, 139.3, 131.0, 128.9, 128.6, 79.4, 63.0, 48.0, 38.8, 29.0, 28.8, 28.4,
25.5, 19.0; HRMS (ES+) calcd for C19H27NO4Cl (M + H) 368.1629,
found 368.1618.
Ketone 35. To a solution of 32 (410 mg, 1.80 mmol) in Et2O (15
mL) at rt was slowly added a solution of MeMgBr (1.8 mL, 5.4 mmol,
3.0 M in Et2O). The mixture was allowed to stir at rt for 2 h. The
reaction was quenched with satd aqueous NH4Cl (5 mL). Then the
solution was extracted with Et2O (3 × 30 mL), and the combined
organic layers were dried over MgSO4 and concentrated in vacuo to
give SI-8.
To a solution of crude SI-8 (1.8 mmol) in CH2Cl2 (20 mL) was
added sodium bicarbonate (756 mg, 9 mmol) followed by Dess
Martin’s reagent (1.56 g, 3.6 mmol). After 2 h the reaction was
quenched with 10% aqueous sodium bicarbonate (10 mL) and
extracted with Et2O (3 × 30 mL). The combined organic layers were
dried over MgSO4, concentrated in vacuo, and purified by
chromatography over silica gel, eluting with 0−25% EtOAc/hexanes
to give known 35 (315 mg, 1.3 mmol, 73% over 2 steps) as a colorless
oil. 1H NMR (300 MHz, CDCl3) δ 4.74 (d, J = 4.5 Hz, 1H), 3.98 (d, J
= 12, 1H), 2.79 (t, J = 12.9 Hz, 1H), 2.66 (dd, J = 7.8, 1.8 Hz, 2H),
2.20 (s, 3H), 1.50−1.75 (m, 5H), 1.40−1.55 (m, 2H), 1.47 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 207.1, 154.7, 79.6, 47.3, 44.3, 39.4,
30.1, 29.7, 28.4, 25.3, 18.9.
Ester SI-6. To a solution of 32 (450 mg, 1.97 mmol) in CH2Cl2
was added Ph3PCHCO2Me (522 mg, 2.96 mmol). After 16 h, the
resulting solution was concentrated in vacuo, suspended in a 3:1
mixture of hexanes/ether (60 mL), filtered over Celite, and then rinsed
with a 3:1 mixture of hexanes/ether (30 mL). The resulting solution
was concentrated in vacuo and purified by chromatography over silica
gel, eluting with 10−30% EtOAc/hexanes to give SI-6 (445 mg, 1.58
mmol, 80%) as a colorless oil. [α]23 = −16.5° (c 1.0, CHCl3); IR
D
(neat) 2975, 2936, 2858, 1725, 1689, 1412, 1272 cm−1; 1H NMR (400
MHz, CDCl3) δ 6.86 (dt, J = 15.6 Hz, J = 7.6 Hz, 1H), 5.80 (d, J =
15.6, 1H), 4.34 (bs, 1H), 3.96 (d, J = 12 Hz, 1H), 3.66 (s, 3H), 2.71 (t,
J = 12.9 Hz, 1H), 2.52−2.61 (m, 1H), 2.25−2.32 (m, 1H), 1.50−1.70
(m, 5H), 1.30−1.46 (m, 1H), 1.39 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 166.6, 154.8, 146.0, 122.6, 79.4, 51.3, 49.6, 38.7, 32.9, 28.3,
25.3, 18.8; HRMS (EI+) calcd for C15H26NO4 (M+) 284.1862, found
284.1868.
Alcohol SI-7. To a solution of SI-6 (356 mg, 1.258 mmol) in
CH2Cl2 (12 mL) at −78 °C was added DIBAL-H (3.77 mL, 3.77
mmol, 1.0 M in CH2Cl2). After 2 h, the mixture was warmed to room
temp and quenched with satd aq sodium tartrate (150 mL). After
vigorous stirring for 1 h, the mixture was extracted with CH2Cl2 (3 ×
50 mL) and washed with brine (30 mL). The dried (MgSO4) extract
was concentrated in vacuo and purified by chromatography over silica
gel, eluting with 20−40% EtOAc/hexanes to give SI-7 (298 mg, 1.17
Alkene SI-9. To a solution of 35 (315 mg, 1.3 mmol) in THF (8
mL) was added a premade solution of methyl triphenylphosphonium
bromide (932.7 mg, 2.61 mmol) with n-BuLi (1.55 mL, 2.48 mmol,
1.6 M in hexanes) in THF (5 mL) at 0 °C. After 2 h, the reaction was
quenched with water (5 mL) and extracted with EtOAc (3 × 25 mL),
the combined organic layers were dried over MgSO4, concentrated in
vacuo, and purified by chromatography over silica gel, eluting with 0−
25% EtOAc/hexanes to give SI-9 (242 mg, 1.01 mmol, 78%) as a
mmol, 93%) as a colorless oil. [α]23 = −33.3° (c 2.0, CHCl3); IR
colorless oil. [α]23 = −26.1° (c 1.0, CHCl3); IR (neat) 3073, 2974,
D
D
(neat) 3446, 2933, 2859, 1685, 1418, 1364, 1162 cm−1; 1H NMR (400
MHz, CDCl3) δ 5.54−5.66 (m, 2H), 4.22 (bs, 1H), 3.99−4.02 (m,
2H), 3.91 (d, J = 12.4 Hz, 1H), 2.72 (t, J = 12.8 Hz, 1H), 2.40 (bs,
1H), 2.33−2.38 (m, 1H), 2.12−2.19 (m, 1H), 1.50−1.70 (m, 5H),
1.40−1.50 (m, 1H), 1.39 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
155.2, 131.4, 129.0, 79.2, 63.2, 50.2, 38.9, 32.8, 28.4, 27.7, 25.4, 18.8;
HRMS (EI+) calcd for C14H26NO3 (M+) 256.1913, found 256.1918.
2934, 2856, 1693, 1647, 1413, 1364, 1266, 1161 cm−1; 1H NMR (400
MHz, CDCl3) δ 4.74 (d, J = 15.9 Hz, 2H), 4.38 (bs, 1H), 3.98 (d, J =
11.1 Hz, 1H), 2.81 (t, J = 12.9 Hz, 1H), 2.30−2.37 (m, 1H), 2.18−
2.26 (m, 1H), 1.79 (s, 3H), 1.50−1.66 (m, 5H), 1.47 (s, 9H), 1.25−
1.50 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 155.0, 142.8, 112.6,
79.0, 48.5, 38.8, 38.1, 28.2, 27.3, 25.5, 22.1, 18.8; HRMS (EI+) calcd
for C14H26NO2 (M + H) 240.1964, found 240.1960.
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Alkene 30·TFA. To a solution of SI-9 (120 mg, 0.50 mmol) in
CH2Cl2 (2.3 mL) was added TFA (2.3 mL). The solution was allowed
to stir for 2 h. The solution was concentrated in vacuo to give 30·TFA
isomer), 4.81 (bs, 1.2 H, mixed isomers), 4.05 (bs, 1.20 H, mixed
isomers), 2.68−2.92 (m, 3.7 H, mixed isomers), 1.44−1.68 (m, 8.8 H,
mixed isomers), 1.44 (s, 10.8 H, mixed isomers); 13C NMR (400
MHz, CDCl3) δ 200.9, 198.4, 154.8, 154.7, 143.0, 140.3, 135.2, 134.5,
133.1, 130.5, 129.6, 129.3, 128.9, 128.6, 128.4, 128.3, 126.1, 79.6, 47.9,
44.2, 41.7, 39.4, 28.4, 28.2, 25.3, 18.9; HRMS (CI+) calcd for
C20H27NO3 (M+) 329.1991, found 329.1978.
(127 mg, 0.50 mmol, 99%) as a colorless glassy solid. [α]23 = −9.8°
D
(c 1.0, CHCl3); IR (neat) 2950, 2865, 2545, 1780, 1674, 1437, 1202
cm−1; 1H NMR (400 MHz, CDCl3) δ 8.46 (bs, 1H), 4.84 (d, J = 36.8
Hz, 2H), 3.39 (bs, 1H), 3.12 (bs, 1H), 2.90 (bs, 1H), 2.43 (bs, 1H),
2.26 (m, 1H), 1.70−1.90 (m, 3H), 1.60−1.70 (m, 4H), 1.40−1.55 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 138.9, 115.5, 55.2, 45.1, 42.0,
28.4, 22.2, 21.7; HRMS (EI+) calcd for C11H18F3NO2 (M+) 253.1290,
found 253.1287.
Aldehyde 46. To a solution of oxalyl chloride (980.7 mg, 7.726
mmol, 0.663 mL) in DCM (15 mL) at −78 °C was added a solution of
DMSO (644 mg, 8.24 mmol, 0.585 mL) in DCM (4 mL). After 10
min, SI-10 (1.0 g, 5.15 mmol) in DCM (5 mL) was added dropwise at
−78 °C. After 1.5 h, Et3N (2.34 g, 3.23 mL, 23.18 mmol) was added,
and the mixture was warmed to 0 °C. Once the mixture reached 0 °C,
the reaction was quenched with water (25 mL) and extracted with
DCM (3 × 25 mL). The combined organic layers were washed with
brine (25 mL), and the dried (MgSO4) extract was concentrated in
vacuo and purified by chromatography over silica gel, eluting with 8−
15% EtOAc/hexanes to obtain 4637 (881 mg, 4.60 mmol, 89%) as a
1
colorless oil. H NMR (400 MHz, CDCl3) δ 9.78 (s, 1H), 7.25−7.40
(m, 5H), 4.52 (s, 2H), 3.51 (t, J = 6 Hz, 2H), 2.46−2.50 (m, 2H),
1.73−1.80 (m, 2H), 1.64−1.71 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 202.5, 138.5, 128.4, 127.7, 127.6, 73.0, 69.8, 43.6, 29.2, 19.0.
Amines 37/38. To a solution of 31 (25 mg, 0.08 mmol) and
pyrrolidine (7.4 mg, 0.10 mmol) in THF (0.5 mL) was added a
premade solution of 36 (2.7 mg, 0.004 mmol) and [Ir(COD)Cl]2 (4.3
mg, 0.008 mmol) in THF (0.25 mL) at rt. After 16 h, the solution was
concentrated in vacuo and purified by chromatography over basic
alumina, eluting with 10−30% EtOAc/hexanes to give a 19:1 mixture
of 37 (19 mg, 0.062 mmol, 77%) and 38 (1 mg, 0.003 mmol, 4%) as
colorless oils. [α]23D = −28.5°, (c 0.85, CHCl3); IR (neat) 2930, 2850,
2778, 1694, 1164 cm−1; 1H NMR (300 MHz, CDCl3) δ 5.48−5.68 (m,
2H), 4.25 (bs, 1H), 3.95 (d, J = 12.4 Hz, 1H), 3.01 (d, J = 6 Hz, 2H),
2.75 (t, J = 12.8 Hz, 1H), 2.48 (s, 3H), 2.20−2.45 (m, 2H), 1.77 (s,
4H), 1.50−1.60 (m, 6H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 155.0, 129.8, 79.0, 58.2, 53.9, 39.0, 33.0, 30.3, 29.7, 28.5, 27.5, 25.5,
23.4, 18.8; HRMS (EI+) calcd for C18H33N2O2 (M + H) 309.2542,
found 309.2543.
Imine 48. To a solution of 46 (881 mg, 4.58 mmol) and 47 (610
mg, 5.04 mmol) in DCM (8 mL) was added anhydrous CuSO4 (1.827
g, 11.45 mmol), and the mixture was stirred at rt. After 12 h, the
mixture was filtered through a pad of Celite, concentrated in vacuo, and
purified by chromatography over silica gel, eluting with 10−25%
EtOAc/hexanes to obtain 48 (1339 mg, 4.53 mmol, 99%) as a pale
yellow oil. [α]20 = −188.50° (c 1.00, CHCl3); IR (neat) 3083, 3061,
D
1
3027, 2928, 2864, 1621, 1454, 1362, 1083, 737, 698 cm−1; H NMR
(700 MHz, CDCl3) δ 8.08 (t, J = 4.9 Hz, 1H), 7.28−7.31 (m, 1H),
7.33−7.36 (m, 4H), 4.51 (s, 2H), 3.51 (t, J = 6.3 Hz, 2H), 2.54−2.56
(m, 2H), 1.73−1.78 (m, 2H), 1.68−1.72 (m, 2H), 1.20 (s, 9H); 13C
NMR (175 MHz, CDCl3) δ 169.4, 138.5, 128.4, 127.62, 127.58, 72.9,
69.8, 56.5, 35.9, 29.3, 22.4, 22.3; HRMS (EI+) calcd for C16H26NO2S
(M + H) 296.1684, found 296.1690.
Ketone 45. To a solution of 32 (530 mg, 2.09 mmol) in THF (15
mL) at −78 °C was added a premade solution of 51 (8 mL, 4.0 mmol,
0.2 M in THF) at rt. After 30 min, the temperature was raised to −50
°C and stirred at this temperature for the next 3 h. Then, the reaction
was quenched with satd aq NH4Cl (5 mL), extracted with Et2O (3 ×
30 mL), and washed with brine (15 mL). The dried (MgSO4) extract
was concentrated in vacuo to provide crude alcohol 53. The crude
alcohol 53 was then redissolved in DCM (45 mL), and NaHCO3
(877.8 mg, 10.45 mmol) was added followed by Dess Martin’s reagent
(1.77 g, 4.18 mmol) at rt. After 3 h, the reaction was quenched with
satd aq NaHCO3 (15 mL). Then the solution was extracted with Et2O
(3 × 30 mL). The dried (MgSO4) extract was concentrated in vacuo
and purified by chromatography over silica gel, eluting with 5−20%
EtOAc/hexanes to give 45 (trans:cis = 1:0.14), (477 mg, 1.46 mmol,
Sulfonamide 50. To a solution of 48 (1.40 g, 4.74 mmol) in
PhMe (24 mL) at −78 °C was added a premade solution of 49 (7.10
mmol, 14.22 mL, 0.2 M in THF) slowly. After 2 h the reaction mixture
was quenched with satd aq NH4Cl (30 mL) and warmed to rt. The
dried (MgSO4) mixture was filtered through Celite, concentrated in
vacuo, and purified by chromatography over silica gel, eluting with 20−
50% EtOAc/hexanes to obtain 50 (1.37 g, 3.87 mmol, 82%) as a
colorless oil. [α]20 = −74.2° (c 1.00, CHCl3); IR (neat) 3268, 3225,
D
3069, 3030, 2937, 2861, 1652, 1455, 1363, 1069 cm−1; 1H NMR (700
MHz, CDCl3) δ 7.34−7.37 (m, 4H), 7.29−7.32 (m, 1H), 4.81 (m,
1H), 4.90 (t, J = 2.1 Hz, 1H), 4.53 (s, 2H), 3.49 (t, J = 6.3 Hz, 2H),
3.38−3.43 (m, 1H), 3.26 (d, J = 4.2 Hz, 1H), 2.32 (dd, J = 14.0, 5.6
Hz, 1H), 2.22 (dd, J = 14.0, 8.4 Hz, 1H), 1.76 (s, 3H), 1.62−1.66 (m,
2H), 1.51−1.60 (m, 2H), 1.43−1.50 (m, 2H), 1.20 (s, 9H); 13C NMR
(175 MHz, CDCl3) δ 142.5, 138.6, 128.4, 127.6, 127.5, 114.2, 72.9,
70.2, 55.6, 51.5, 44.4, 35.1, 29.7, 22.6, 22.0, 21.9; HRMS (EI+) calcd
for C20H34O2NS (M + H) 352.2310, found 352.2310.
70% over 2 steps) as pale yellow oil. [α]20 = +16.5 (c 1.05, CHCl3);
D
1
IR (neat) 2974, 2934, 2862, 1689, 1609, 1164 cm−1; H NMR (400
MHz, CDCl3) δ 7.54−7.63 (m, 3.5 H, mixed isomers), 7.34−7.41 (m,
3.7 H, mixed isomers), 6.86 (d, J = 12.8 Hz, 0.2 H, cis isomer), 6.79
(d, J = 16 Hz, 1H, major isomer), 6.24 (d, J = 12.8 Hz, 0.2 H, minor
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was concentrated in vacuo to obtain crude 58.50 The crude aldehyde
58 is taken to the next step.
To a solution of crude aldehyde 58 (∼8.1 mmol) in a 1:1 mixture
t
(200 mL) of BuOH and H2O was added 2-methyl-2-butene (19.94
mL, 186.3 mmol) followed by NaH2PO4·H2O (11.18 g, 81.0 mmol)
and NaOCl2 (3.68 g, 40.5 mmol). After 2.5 h, the reaction mixture was
quenched with satd aq NaCl (50 mL) and extracted with ether (3 ×
100 mL). The dried (MgSO4) extract was concentrated in vacuo to
obtain the crude acid SI-12. The crude acid SI-12 was taken to the
next step.
Amine 44. To a solution of 50 (1.140 g, 3.24 mmol) in MeOH (21
mL) was added conc HCl (12.8 M, 6.48 mmol, 0.504 mL). The
resulting solution was allowed to stir for 1 h before being concentrated
in vacuo and purified by chromatography over silica gel, eluting with
50% EtOAc/hexanes to 10% MeOH/DCM to obtain 44 (930 mg,
3.24 mmol, 99%) as the HCl salt, which was then dissolved in satd aq
Na2CO3 (50 mL) and extracted with DCM (3 × 30 mL) to obtain 44
To a solution of crude acid SI-12 (∼8.1 mmol) in dry THF (66
mL) was added triethylamine (1.64 g, 2.6 mL, 18.3 mmol) followed by
pivaloyl chloride (977 mg, 1.0 mL, 8.1 mmol) at −20 °C. After 3 h,
LiCl (364 mg, 8.61 mmol) and (4S)-benzyloxazolidin-2-one (59)
(1.21 g, 6.82 mmol) were added sequentially, and the mixture was
warmed to rt over a period of 3 h. After 30 min, the reaction was
quenched with water (50 mL) and extracted with ether (3 × 100 mL).
The dried (MgSO4) extract was concentrated in vacuo and purified by
chromatography over silica gel, eluting with 38−50% ether/pentane to
obtain 6051 (2.49 g, 5.98 mmol, 73% over 3 steps) as a colorless oil.
as the free amine. [α]20 = +5.6° (c 1.00, CHCl3); IR (neat) 3077,
D
3026, 2933, 2847, 1656, 1454, 1360, 1095 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.28−7.36 (m, 5H), 4.84 (s, 1H), 4.76 (s, 1H), 4.52 (s, 2H),
3.50 (t, J = 6.4 Hz, 2H), 2.91 (br s, 1H), 2.16−2.19 (m, 1H), 1.92 (dd,
J = 13.6, 9.2 Hz, 1H), 1.73 (s, 3H), 1.62−1.66 (m, 2H), 1.44−1.59 (m,
6H); 13C NMR (100 MHz, CDCl3) δ 143.3, 138.6, 128.4, 127.7,
127.5, 112.8, 72.9, 70.3, 48.4, 47.0, 37.8, 29.9, 23.0, 22.3; HRMS (EI+)
calcd for C16H26NO (M + H) 248.2014, found 248.2015.
[α]20 = +14.87° (c 1.58, CHCl3); IR (neat) 2926, 2852, 1783, 1687,
D
1416, 1389, 1364, 1161, 701 cm−1; 1H NMR (400 MHz, 40 °C,
CDCl3) δ 7.26−7.34 (m, 3H), 7.20−7.22 (m, 2H), 4.67−4.70 (m,
1H), 4.31−4.32 (m, 1H), 4.13−4.22 (m, 2H), 4.00 (d, J = 12.0 Hz,
1H), 3.30 (dd, J = 13.2, 2.8 Hz, 1H), 2.94−3.00 (m, 1H), 2.74−2.86
(m, 3H), 2.13−2.15 (m, 1H), 1.77−1.80 (m, 1H), 1.59−1.67 (m, 5H),
1.45 (s, 9H), 1.27−1.40 (m, 1H); 13C NMR (100 MHz, 40 °C,
CDCl3) δ 173.0, 155.1, 153.4, 135.5, 129.4, 128.9, 127.2, 79.2, 66.2,
55.2, 49.6, 38.7, 38.0, 32.3, 29.0, 28.4, 25.6, 24.3, 19.1; HRMS (EI+)
calcd for C23H33N2O5 (M + H) 417.2390, found 417.2382.
Enol Ether SI-11. To a suspension of methoxymethyl-triphenyl-
phosphonium chloride 57 (15.09 g, 44.01 mmol) in ether (371 mL)
was added PhLi (20.7 mL, 41.4 mmol, 2.0 M in Bu2O) at −78 °C
dropwise over 10 min period. The resulting solution was then warmed
to rt over a period of 15 min. After 20 min, the reaction mixture was
cooled back to 0 °C, and a solution of aldehyde 32 (23.79 mmol) in
ether (247 mL) was added. After 2 h, the reaction was quenched with
satd aq NH4Cl (100 mL), and the precipitate was dissolved, extracted
with ether (3 × 150 mL), and washed with satd aq NaHCO3. The
dried (MgSO4) extract was concentrated in vacuo and purified by
column chromatography over silica gel, eluting with 0−20% EtOAc/
hexanes to obtain the enol ether SI-1149 (4.0 g, 15.4 mmol, 65%) as a
Oxazolidinone 66. To a solution of oxazolidinone 60 (708 mg,
1.70 mmol) in dry THF (9.4 mL) at −78 °C was added NaHMDS
(1.36 mL, 2.72 mmol, 2.0 M in THF). After 30 min, MeI (2.4 g, 1.06
mL, 17 mmol) was added. After 2 h, the reaction was quenched with
satd aq NH4Cl (20 mL) and extracted with ether (3 × 50 mL). The
dried (MgSO4) extracted was concentrated in vacuo and purified by
chromatography over silica gel, eluting with 25−45% ether/pentane to
obtain 6652 (396 mg, 0.92 mmol, 54%) as a colorless solid. Mp 135−
137 °C; [α]20D = +23.2° (c 1.00, CHCl3); IR (neat) 2933, 2863, 1783,
1681, 1475, 1417, 1392, 1163, 741 cm−1; 1H NMR (700 MHz,
CDCl3) δ 7.32−7.34 (m, 2H), 7.26−7.29 (m, 1H), 7.23−7.24 (m,
2H), 4.77 (br s, 1H), 4.24−4.28 (m, 2H), 4.14 (s, 1H), 3.92 (s, 1H),
3.28 (s, 1H), 3.26 (dd, J = 13.3, 2.8 Hz, 1H), 2.81 (dd, J = 12.6, 9.8
Hz, 1H), 2.75 (t, J = 12.6 Hz, 1H), 1.83−1.89 (m, 2H), 1.59 (m, 5H),
1.41 (s, 9H), 1.39−1.42 (m, 1H), 1.26 (d, J = 6.3 Hz, 3H); 13C NMR
(175 MHz, CDCl3) δ 176.9, 155.2, 153.2, 135.7, 129.5, 128.8, 127.2,
79.1, 66.3, 55.4, 47.6, 39.2, 38.3, 34.6, 33.4, 29.5, 28.4, 25.7, 19.2, 18.7;
HRMS (EI+) calcd for C24H34N2O5 (M+) 430.2468, found 430.2460.
colorless oil of 1:1.27 (Z/E) diastereomeric mixture. [α]20 = −43.5°
D
(c 1.0, CHCl3); IR (neat) 2932, 2855, 1693, 1448, 1415, 1270, 1108,
1
934 cm−1; H NMR (700 MHz, CDCl3) δ 6.32 (d, J = 12.6 Hz, 1H),
5.93 (dt, J = 6.3, 1.4 Hz, 1H), 4.67 (dt, J = 12.6, 7.7 Hz, 1H), 4.33 (q, J
= 7.0 Hz, 1H), 4.21 (br s, 2H), 3.97 (br, s, 2H), 3.59 (s, 3H), 3.51 (s,
3H), 2.84 (t, J = 12.6 Hz, 1H), 2.76 (td, J = 13.3, 2.1 Hz, 1H), 2.42 (m,
1H), 2.27−2.25 (m, 2H), 2.13−2.09 (m, 1H), 1.6−1.51 (m, 9H), 1.47
(s, 18H), 1.43−1.38 (m, 3H); 13C NMR (175 MHz, CDCl3) δ 155.2,
148.1, 147.5, 103.4, 99.6, 79.0, 78.9, 59.5, 55.8, 50.7, 38.9, 28.5, 28.2,
27.8, 27.2, 25.6, 25.5, 24.4, 18.9, 18.8; HRMS (EI+) calcd for
C14H25NO3 (M+) 255.1835, found 255.1828.
Oxazolidinone 61. To a solution of crude acid SI-12 (∼7.17
mmol) in dry THF (58 mL) was added triethylamine (1.45 g, 2.02
mL, 14.34 mmol) followed by pivaloyl chloride (865 mg, 0.883 mL,
7.17 mmol) at −20 °C. After 3 h, LiCl (364 mg, 8.61 mmol) and
(4R)-benzyloxazolidin-2-one (ent-59) (1.21 g, 6.82 mmol) were added
sequentially, and the mixture was warmed to rt over a period of 3 h.
After 30 min, the reaction was quenched with water (50 mL) and
extracted with ether (3 × 100 mL). The dried (MgSO4) extract was
concentrated in vacuo and purified by chromatography over silica gel,
Oxazolidinone 60. To a stirred solution of enol ether SI-11 (8.1
mmol) in acetone (97 mL) was added PTSA·H2O (771 mg, 4.05
mmol). After 20 min, the reaction was quenched with water (20 mL)
and extracted with DCM (3 × 50 mL). The dried (MgSO4) extract
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eluting with 38−50% ether/pentane to obtain 61 (2.34 g, 5.62 mmol,
78% over 3 steps) as a colorless oil. [α]20D = −46.4° (c 1.12, CHCl3);
IR (neat) 2931, 2857, 1783, 1682, 1477, 1416, 1391, 1271, 1162, 762,
702 cm−1; 1H NMR (700 MHz, CDCl3) δ 7.35−7.37 (m, 2H), 7.29−
7.31 (m, 1H), 7.24 (d, J = 7.0 Hz, 2H), 4.66−4.69 (m, 1H), 4.36 (br s,
1H), 4.17−4.22 (m, 2H), 4.02 (br s, 1H), 3.38 (d, J = 10.5, 1H), 3.01−
3.06 (m, 1H), 2.75−2.86 (m, 3H), 2.17 (br s, 1H), 1.80 (br s, 1H),
1.60−1.70 (m, 5H), 1.49 (s, 9H), 1.39−1.47 (m, 1H); 13C NMR (175
MHz, CDCl3) δ 175.0, 155.1, 153.4, 135.5, 129.4, 128.9, 127.3, 79.4,
66.2, 55.3, 50.0, 38.9, 38.0, 32.7, 28.9, 28.5, 25.6, 24.4, 19.1; HRMS
(CI+) calcd for C23H33N2O5 (M + H) 417.2390, found 417.2378.
7.27 (t, J = 7.6 Hz, 2H), 7.18 (t, J = 7.6 Hz, 1H), 4.29 (br s, 1H), 3.98
(d, J = 12.8 Hz, 1H), 2.94 (m, 2H), 2.78 (t, J = 12.8 Hz, 1H), 1.69−
1.82 (m, 2H), 1.47−1.62 (m, 6H), 1.46 (s, 9H), 1.36−1.45 (m, 1H),
1.08 (d, J = 6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 154.9, 137.4,
129.1, 128.8, 125.6, 79.2, 48.4, 41.2, 38.9, 35.7, 30.4, 28.5, 27.9, 25.6,
19.6, 18.9; HRMS (EI+) calcd for C20H31NO2S (M+) 349.2076, found
349.2076.
Sulfone 56. To a solution of sulfide 69 (114 mg, 0.327 mmol) in
dry EtOH (3.35 mL) was added (NH4)6Mo7O24·4H2O (81.6 mg,
0.066 mmol) followed by H2O2 (1.7 mL, 16.5 mmol, 30% aqueous).
After 12 h, water (10 mL) was added and extracted with DCM (3 × 20
mL). The dried (MgSO4) extract was concentrated in vacuo and
purified by chromatography over silica gel, eluting with 20−30%
EtOAc/hexanes to obtain 56 (123.4 mg, 0.32 mmol, 99%) as a
colorless oil. [α]20D = −23.48° (c 1.15, CHCl3); IR (neat) 2929, 1733,
1683, 1653, 1635, 1418, 1364, 1306, 1148, 1086, 1025 cm−1; 1H NMR
(400 MHz, CDCl3) δ 7.93 (d, J = 7.6 Hz, 2H), 7.64 (t, J = 7.2 Hz,
1H), 7.56 (t, J = 7.2 Hz, 2H), 4.26 (br s, 1H), 3.94 (d, J = 12.8 Hz,
1H), 3.29 (br s, 1H), 2.93−2.98 (m, 1H), 2.72 (t, J = 12.8 Hz, 1H),
2.13−2.17 (m, 1H), 1.72−1.76 (m, 1H), 1.44−1.60 (m, 6H), 1.45 (s,
9H), 1.25−1.44 (m, 1H), 1.16 (d, J = 6.4 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 154.8, 140.8, 133.3, 129.1, 127.6, 79.3, 62.0, 47.7,
39.1, 36.3, 28.4, 27.8, 26.1, 25.4, 19.9, 18.8; HRMS (EI+) calcd for
C20H31NO4S (M+) 381.1974, found 381.1962.
Oxazolidinone 65. To a solution of oxazolidinone 61 (66 mg,
0.158 mmol) in dry THF (0.49 mL) at −78 °C was added NaHMDS
(0.127 mL, 0.253 mmol, 2.0 M in THF). After 30 min, MeI (224 mg,
0.1 mL, 1.58 mmol) was added. After 2 h, the reaction was quenched
with satd aq NH4Cl (5 mL) and extracted with ether (3 × 10 mL).
The dried (MgSO4) extract was concentrated in vacuo and purified by
chromatography over silica gel, eluting with 25−45% ether/pentane to
obtain 65 (53 mg, 0.122 mmol, 77%) as a colorless oil. [α]20
=
D
−77.2° (c 1.00, CHCl3); IR (neat) 2930, 2855, 1782, 1686, 1454,
1
1415, 1389, 1168, 730 cm−1; H NMR (400 MHz, 40 °C, CDCl3) δ
7.27−7.36 (m, 4H), 7.22 (d, J = 6.8 Hz, 1H), 4.63 (m, 1H), 4.35 (br s,
1H), 4.23 (d, J = 8.0 Hz, 1H), 4.15 (dd, J = 8.8, 2.0 Hz, 1H) 3.93 (d, J
= 12.8, 1H), 3.72−3.81 (m, 1H), 3.27 (dd, J = 13.2, 3.2 Hz, 1H),
2.78−2.85 (m, 2H), 2.48 (br s, 1H), 1.50−1.62 (m, 5H), 1.48 (s, 9H),
1.34−1.43 (m, 2H), 1.31 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, 40
°C, CDCl3) δ 176.9, 155.2, 152.9, 135.4, 129.4, 128.9, 127.3, 79.5,
66.1, 55.4, 49.6, 38.7, 37.9, 35.6, 33.8, 29.7, 28.4, 25.6, 19.4, 18.2;
HRMS (EI+) calcd for C24H34N2O5 (M+) 430.2468, found 430.2470.
Alcohol 68. To a solution of the oxazolidinone 66 (151 mg, 0.351
mmol) in dry THF (14.6 mL) at 0 °C was added MeOH (56.1 mg,
0.71 mL, 1.75 mmol) followed by LiBH4 (36.7 mg, 1.68 mmol). After
30 min, the reaction mixture was warmed to rt over a period of 10 min.
After 2 h, the reaction mixture was quenched with satd aq NH4Cl (25
mL) and extracted with ether (3 × 30 mL). The dried (MgSO4)
extract was concentrated in vacuo and purified by chromatography over
silica gel, eluting with 20−30% EtOAc/hexanes to obtain the alcohol
6853 (88.5 mg, 0.344 mmol, 98%) as a colorless oil. [α]20D = −44.7° (c
1.00, CHCl3); IR (neat) 3438, 2929, 1682, 1417, 1365, 1317, 1270,
1167, 1026, 991, 877, 768 cm−1; 1H NMR (400 MHz, 40 °C, CDCl3)
δ 4.38 (br s, 1H), 3.97 (d, J = 12.8 Hz, 1H), 3.51 (d, J = 4.8 Hz, 2H),
2.75−2.82 (m, 1H), 1.57−1.60 (m, 8H), 1.47 (s, 9H), 1.32−1.40 (m,
1H), 0.95 (d, J = 6.0 Hz, 3H); 13C NMR (100 MHz, 40 °C, CDCl3) δ
155.2, 79.3, 68.4, 48.5, 38.9, 33.7, 32.7, 28.5, 25.6, 18.8, 17.4; HRMS
(EI+) calcd for C14H27NO3 (M+) 257.1991, found 257.1992.
Oxazolidinone 73. To a solution of aldehyde 58 (26 mg, 0.107
mmol) in DCM (0.8 mL) were sequentially added N,N-dimethylme-
thyleneiminium iodide (49.8 mg, 0.27 mmol) and Et3N (21.8 mg, 30.3
μL, 0.215 mmol). After 24 h, satd NaHCO3 (1 mL) was added and
extracted with DCM (3 × 10 mL). The dried (MgSO4) extract was
concentrated in vacuo to obtain the crude 70. The crude 70 is taken to
the next step.
To a solution of crude enal 70 (∼0.107 mmol) in a 1:1 mixture (2.6
t
mL) of BuOH and H2O was added 2-methyl-2-butene (0.26 mL, 2.4
mmol) followed by NaH2PO4·H2O (146.6 mg, 1.06 mmol) and
NaOCl2 (48.3 mg, 0.53 mmol). After 2.5 h, the reaction mixture was
quenched with satd aq NaCl (5 mL) and extracted with ether (3 × 10
mL). The dried (MgSO4) extract was concentrated in vacuo to obtain
the crude acid SI-13. The crude acid SI-13 was taken to the next step.
To a solution of crude acid SI-13 (∼0.107 mmol) in dry THF
(0.856 mL) was added triethylamine (21.7 mg, 30.1 μL, 0.214 mmol)
followed by pivaloyl chloride (12.9 mg, 13.2 μL, 0.107 mmol) at −20
°C. After 3 h, LiCl (5.4 mg, 0.128 mmol) and (4R)-benzyloxazolidin-
2-one (ent-59) (18 mg, 0.102 mmol) were added sequentially, and the
mixture was warmed to rt over a period of 3 h. After 30 min, the
reaction was quenched with water (5 mL) and extracted with ether (3
× 10 mL). The dried (MgSO4) extract was concentrated in vacuo and
purified by chromatography over silica gel, eluting with 38−50%
ether/pentane to obtain 73 (19.7 mg, 0.046 mmol, 43% over 3 steps)
Sulfide 69. To a solution of alcohol 68 (85 mg, 0.33 mmol) in dry
THF (0.78 mL) at 0 °C were added PhSSPh (144 mg, 0.66 mmol)
and Bu3P (153.4 mg, 0.187 mL, 0.76 mmol). After 10 min, the
reaction was warmed to rt over a period of 20 min. After 12 h, the
solvent was removed in vacuo and purified by chromatography over
silica gel, eluting with 15−30% ether/pentane to obtain the sulfide 69
(114 mg, 0.327 mmol, 99%) as a colorless oil. [α]20D = −33.1° (c 0.96,
CHCl3); IR (neat) 2920, 2845, 1733, 1683, 1652, 1635, 1540, 1558,
1506, 1457 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.34−7.36 (m, 2H),
as a colorless oil. [α]20 = −38.8° (c 1.43, CHCl3); IR (neat) 2934,
D
1
1788, 1684, 1413, 1364, 1160, 1042, 918, 735, 703 cm−1; H NMR
(700 MHz, CDCl3) δ 7.36 (t, J = 7.0 Hz, 2H), 7.29−7.31 (m, 1H),
7.24 (d, J = 7.0 Hz, 2H), 5.60 (s, 1H), 5.57 (s, 1H), 4.72−4.76 (m,
1H), 4.40−4.41 (m, 1H), 4.26 (t, J = 8.4 Hz, 1H), 4.20 (dd, J = 8.4, 4.2
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Hz, 1H), 4.00 (br s, 1H), 3.45−3.47 (m, 1H), 2.81−2.86 (m, 2H),
2.77 (dd, J = 14.0, 7.0 Hz, 1H), 2.65−2.67 (m, 1H), 1.74−1.75 (m,
1H), 1.57−1.64 (m, 5H), 1.48 (s, 9H); 13C NMR (175 MHz, CDCl3)
δ 170.2, 154.9, 153.1, 141.0, 135.3, 129.4, 129.0, 127.4, 123.3, 79.4,
66.6, 55.6, 49.0, 39.4, 37.6, 33.5, 28.5, 27.1, 25.5, 18.8; HRMS (ES+)
calcd for C24H32N2O5Na (M + Na) 451.2209, found 451.2190.
40 °C, CDCl3) δ 7.42−7.44 (m, 2H), 7.19−7.34 (m, 8H), 4.64 (br s,
1H), 4.34 (br s, 1H), 4.11−4.27 (m, 3H), 3.92 (d, J = 13.2 Hz, 1H),
3.27−3.41 (m, 3H), 2.72−2.85 (m, 2H), 2.44 (br s, 1H), 1.70−1.77
(m, 1H), 1.48−1.61 (m, 5H), 1.46 (s, 9H), 1.34−1.42 (m, 1H); 13C
NMR (100 MHz, 40 °C, CDCl3) δ 174.4, 155.2, 152.9, 136.3, 135.5,
129.8, 129.4, 128.90, 128.86, 127.2, 126.3, 79.7, 66.1, 55.6, 49.2, 40.9,
38.9, 37.8, 36.5, 31.9, 29.4, 28.4, 25.5, 19.3; HRMS (ES+) calcd for
C30H39N2O5S (M + H) 539.2580, found 539.2593.
Alcohol 71. To a solution of crude enal 70 (∼0.103 mmol) in
MeOH (0.78 mL) and Et2O (0.22 mL) at 0 °C was added NaBH4 (3.9
mg, 0.103 mmol, 3 portions) portionwise over a period of 20 min.
After an additional 30 min, the reaction was quenched with H2O (2
mL) and extracted with ether (3 × 10 mL). The dried (MgSO4)
extract was concentrated in vacuo and purified by column
chromatography over silica gel, eluting with 10−30% Et2O/pentane
to obtain a alcohol 71 (17.5 mg, 0.069 mmol, ∼40% over 2 steps).
Alcohol 83. To a solution of 82 (42 mg, 0.078 mmol) in THF (3.3
mL) at 0 °C was added MeOH (12.4 mg, 0.017 mL, 0.39 mmol)
followed by LiBH4 (8.2 mg, 0.374 mmol). After 30 min, the reaction
mixture was warmed to rt over a period of 10 min. After 2 h, the
reaction mixture was quenched with satd aq NH4Cl (5 mL) and
extracted with ether (3 × 10 mL). The dried (MgSO4) extract was
concentrated in vacuo and purified by chromatography over silica gel,
eluting with 35−45% EtOAc/hexanes to obtain 83 (27.6 mg, 0.076
[α]20 = −35.5° (c 0.96, CHCl3); IR (neat) 3423, 2934, 2860, 1674,
D
1
1418, 1366, 1321, 1265, 1162, 1041, 898, 802, 767 cm−1; H NMR
mmol, 97%) as a colorless oil. [α]20 = −40.8° (c 1.30, CHCl3); IR
D
(700 MHz, CDCl3) δ 5.03 (br s, 1H), 4.82 (br s, 1H), 4.52 (br s, 1H),
4.14 (d, J = 6.3 Hz, 2H), 3.90−3.95 (m, 2H), 2.85 (t, J = 12.6 Hz, 1H),
2.61 (br s, 1H), 2.12 (br s, 1H), 1.57−1.66 (m, 6H), 1.45 (s, 9H); 13C
NMR (175 MHz, CDCl3) δ 156.1, 146.4, 113.8, 79.7, 67.4, 49.1, 39.6,
35.1, 28.4, 25.5, 18.8; HRMS (ES+) calcd for C14H25NO3Na (M +
Na) 278.1732, found 278.1736.
(neat) 3419, 2927, 2856, 1689, 1665, 1419, 1365, 1272, 1068, 738, 691
1
cm−1; H NMR (400 MHz, 40 °C, CDCl3) δ 7.37−7.39 (m, 2H),
7.27−7.31 (m, 2H), 7.18 (t, J = 7.2 Hz, 1H), 4.29 (br s, 1H), 3.95 (d, J
= 10.4 Hz, 1H), 3.72−3.77 (m, 2H), 3.16 (dd, J = 12.8, 6.4 Hz, 1H),
3.03 (dd, J = 12.4, 5.2 Hz, 1H), 2.76−2.83 (m, 1H), 1.75 (br s, 2H),
1.59−1.64 (m, 5H), 1.42−1.50 (m, 11H); 13C NMR (100 MHz, 40
°C, CDCl3) δ 155.5, 137.0, 129.2, 128.9, 125.9, 79.6, 64.3, 48.0, 39.4,
37.8, 36.2, 30.8, 28.5, 28.0, 25.4, 18.8; HRMS (EI+) calcd for
C20H32NO3S (M + H) 366.2103, found 366.2108.
Oxazolidinone 65. To a solution of 73 (16.5 mg, 0.039 mmol) in
THF (0.53 mL) at −78 °C was added L-Selectride (42.4 μL, 42.4
μmol, 1.0 M solution in THF). After 15 min, the reaction was
quenched with satd aq NH4Cl solution (1 mL) and extracted with
Et2O (3 × 5 mL). The dried (MgSO4) extract was concentrated in
vacuo to obtain 65 and its C15-epimer (14.1 mg, 0.033 mmol, 85%) as
a (2:1) diastereomeric mixture.
Sulfone SI-14. To a solution of sulfide 83 (12.5 mg, 0.034 mmol)
in EtOH (0.36 mL) was added (NH4)6Mo7O24·4H2O (8.5 mg, 0.007
mmol) followed by H2O2 (0.163 mL, 1.7 mmol, 30% aqueous). After
12 h, water (2 mL) was added and extracted with DCM (3 × 5 mL).
The dried (MgSO4) extract was concentrated in vacuo and purified by
chromatography over silica gel, eluting with 50−85% EtOAc/hexanes
to obtain the sulfone SI-14 (12.7 mg, 0.032 mmol, 94%) as a colorless
oil. [α]20 = −21.9° (c 0.48, CHCl3); IR (neat) 3434, 2926, 2854,
D
1
1681, 1447, 1420, 1366, 1305, 1146, 740 cm−1; H NMR (400 MHz,
Alcohol 72. To a solution of allylic alcohol 71 (9.3 mg, 0.036
mmol) in MeOH (0.5 mL) at rt was added (S)-Ru(OAc)2(T-BINAP)
(5.5 mg, 10 mol %), and the argon was then removed by flushing with
H2 gas. After 5 min, the reaction was sealed under 1 atm of H2
(balloon). After 3 d, the hydrogen was removed by flushing with
argon, and the reaction mixture was filtered through Celite washing
with EtOH (5 mL). The filtered extract was concentrated in vacuo to
give alcohol 72 (3.7 mg, 0.014 mmol, ∼40%) as a 1:1 diastereomeric
mixture.
40 °C, CDCl3) δ 7.95−7.97 (m, 2H), 7.64−7.68 (m, 1H), 7.57−7.60
(m, 2H), 4.25 (br s, 1H), 3.93 (d, J = 12.8 Hz, 1H), 3.84 (br s, 2H),
3.31 (br s, 2H), 2.76 (t, J = 13.2 Hz, 1H), 2.17−2.19 (m, 1H), 1.73−
1.87 (m, 2H), 1.53−1.63 (m, 5H), 1.47 (s, 10H); 13C NMR (100
MHz, 40 °C, CDCl3) δ 155.0, 140.5, 133.5, 129.3, 127.7, 79.8, 63.8,
57.5, 47.3, 39.5, 33.7, 31.5, 28.5, 27.9, 25.3, 18.8; HRMS (EI+) calcd
for C20H31NO5SNa (M + Na) 420.1821, found 420.1816.
Iodide 84. To a solution of sulfone SI-14 (14.0 mg, 0.036 mmol)
in THF (1.24 mL) at 0 °C were sequentially added imidazole (7.4 mg,
0.108 mmol), PPh3 (18.4 mg, 0.07 mmol), and I2 (17.7 mg, 0.07
mmol). After 20 min, the reaction mixture was warmed to rt over a
period of 5 min. After 3 h, the reaction was quenched with satd aq
sodium thiosulfate (5 mL) and extracted with ether (3 × 5 mL). The
dried (MgSO4) extract was concentrated in vacuo and purified by
chromatography over silica gel, eluting with 20−35% EtOAc/hexanes
to obtain the iodide 84 (15.3 mg, 0.03 mmol, 84%) as a colorless oil.
Oxazolidinone 82. To a solution of 61 (40 mg, 0.14 mmol) in
THF (0.58 mL) at −78 °C was added NaHMDS (0.115 mL, 0.23
mmol, 2.0 M in THF). After 30 min, neat PhSCH2I54 (350 mg, 1.4
mmol) was added. After 1 h, the reaction was quenched with satd aq
NH4Cl (5 mL) and extracted with ether (3 × 10 mL). The dried
(MgSO4) extract was concentrated in vacuo and purified by
chromatography over silica gel, eluting with 20−40% ether/pentane
[α]20 = −14.6° (c 1.0, CHCl3); IR (neat) 2930, 2856, 1681, 1447,
D
to obtain 8242 (48 mg, 0.088 mmol, 63%) as a colorless oil. [α]20
=
1417, 1365, 1307, 1152, 1086, 738 cm−1; 1H NMR (400 MHz, 40 °C,
CDCl3) δ 7.97−7.99 (m, 2H), 7.65−7.69 (m, 1H), 7.57−7.61 (m,
2H), 4.31 (br s, 1H), 3.99 (d, J = 14.0 Hz, 1H), 3.53−3.61 (m, 2H),
D
−28.2° (c 1.05, CHCl3); IR (neat) 2974, 2929, 1782, 1684, 1482,
1
1414, 1389, 1364, 1273, 1159, 1107, 739 cm−1; H NMR (400 MHz,
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3.21−3.37 (m, 2H), 2.79 (t, J = 13.2 Hz, 1H), 1.96−2.06 (m, 2H),
1.51−1.71 (m, 6H), 1.49 (s, 9H), 1.32−1.46 (m, 1H); 13C NMR (100
MHz, 40 °C, CDCl3) δ 154.9, 140.4, 133.6, 129.3, 127.8, 79.7, 59.4,
47.5, 39.2, 34.8, 32.7, 28.8, 28.5, 25.5, 19.1, 13.7; HRMS (ES+) calcd
for C20H30INO4SNa (M + Na) 530.0838, found 530.0833.
Vinyl Sulfone 88. To a solution of 86 (105 mg, 0.287 mmol) in
DCM (0.66 mL) at 0 °C was added TFA (1.21 g, 0.814 mL, 10.63
mmol). After 30 min, the reaction mixture was warmed to rt. After 10
min, the solvent was removed under reduced pressure, and the crude
TFA salt SI-15 was taken to next step.
Sulfone 56. To a stirred solution of iodide 84 (10 mg, 0.0197
mmol) in EtOH (0.48 mL) under argon was added Pd/C (20 mg, 20
wt %), and the argon was then removed by flushing with H2 gas. After
5 min, the reaction was sealed under 1 atm of H2 (balloon). After 18 h,
the hydrogen was removed by flushing with argon, and the reaction
mixture was filtered through Celite washing with EtOH (5 mL). The
filtered extract was concentrated in vacuo and purified by
chromatography over silica gel, eluting with 20−30% EtOAc/hexanes
to give sulfone 3 (7.4 mg, 0.0195 mmol, 99%) as a colorless oil.
To a solution of crude TFA salt SI-15 (∼0.287 mmol) in
acetonitrile (0.8 mL) were added K2CO3 (79.4 mg, 0.575 mmol) and
TBAI (105.3 mg, 0.287 mmol) followed by benzyl bromide (54.1 mg,
37.6 μL, 0.316 mmol). After 1.5 h, the reaction mixture was directly
purified by chromatography over silica gel, eluting with 70−100%
EtOAc/hexanes to obtain 88 (86 mg, 0.242 mmol, 84% over 2 steps).
[α]20 = −17.1° (c 2.20, CHCl3); IR (neat) 3060, 3028, 2932, 2854,
D
2794, 2756, 1629, 1446, 1318, 1307,1291, 1146, 1086, 1069, 749, 688
cm−1; 1H NMR (700 MHz, CDCl3) δ 7.9 (d, J = 7.0 Hz, 2H), 7.63 (tt,
J = 7.0, 1.4 Hz, 1H), 7.54 (t, J = 7.7 Hz, 2H), 7.24−7.31 (m, 5H),
7.10−7.14 (m, 1H) 6.42 (d, J = 15.4 Hz, 1H), 3.93 (d, J = 14.0 Hz,
1H), 3.24 (d, J = 13.3 Hz, 1H), 2.71−2.74 (m, 1H), 2.52−2.63 (m,
3H), 2.08 (t, J = 9.1 Hz, 1H), 1.64−1.67 (m, 2H), 1.52−1.53 (m, 1H),
1.44−1.48 (m, 2H), 1.32−1.38 (m, 1H); 13C NMR (175 MHz,
CDCl3) δ 144.9, 140.7, 139.1, 133.3, 131.6, 129.3, 128.7, 128.3, 127.6,
126.9, 59.4, 58.2, 51.3, 33.5, 30.4, 25.1, 23.1; HRMS (ES+) calcd for
C21H26NO2S (M + H) 356.1684, found 356.1667.
Vinyl Sulfones 86 and 87. To a solution of PhSO2Me (1.08 g,
6.94 mmol) in THF (61.2 mL) at 0 °C was added nBuLi (6.1 mL, 15.3
mmol, 2.5 M solution in hexanes). After 20 min, ClP(O)(OEt)2 (1.19
g, 0.99 mL, 6.88 mmol) was added. After 30 min, the reaction mixture
was cooled to −78 °C, and a solution of aldehyde 32 (1.16 g, 5.1
mmol) in THF (16.1 mL) was added. After 15 min, the reaction
mixture was warmed to 0 °C over a period of 10 min. After 2 h, the
reaction was quenched with aq NH4Cl (100 mL) solution and
extracted with ether (3 × 100 mL). The dried (MgSO4) extract was
concentrated in vacuo and purified by chromatography over silica gel,
eluting with 10−30% EtOAc/hexanes to obtain sequentially 86 (1.22
g, 3.4 mmol, 66%) followed by 87 (305 mg, 0.85 mmol, 17%).
Sulfides 90 and 91. To a solution of 89 (0.639 g, 2.38 mmol) in
THF (12.9 mL) at −78 °C was added nBuLi (1.5 mL, 2.38 mmol, 1.6
M solution in hexanes). After 5 min, the reaction mixture was warmed
to −45 °C over a period of 3 h. After 10 min, it was warmed to −25
°C over a period of 1 h. After 5 min, it was cooled back to −78 °C, and
a solution of aldehyde 32 (250 mg, 1.1 mmol) in THF (1.0 mL) was
added. After 5 min, the reaction mixture was warmed to −10 °C over a
period of 20 min. After 15 min, the reaction was quenched with aq
NH4Cl (30 mL) solution and extracted with ether (3 × 30 mL). The
dried (MgSO4) extract was concentrated in vacuo and purified by
chromatography over silica gel, eluting with 5−20% EtOAc/hexanes to
obtain a (3:1) diastereomeric mixture of vinyl sulfides 90 and 91 (134
mg, 0.33 mmol, 30%). IR (neat) 2971, 2936, 2860, 1690, 1583, 1476,
(E)-Vinyl Sulfone 86: [α]20 = −15.9° (c 1.10, CHCl3); IR (neat)
D
3059, 2975, 2934, 2859, 1693, 1681, 1633, 1476, 1416, 1319, 1147,
1
1086, 752, 688 cm−1; H NMR (700 MHz, 40 °C, CDCl3) δ 7.86−
7.88 (m, 2H), 7.60−7.62 (m, 1H), 7.53 (t, J = 7.7 Hz, 2H), 6.90−6.95
(m, 1H), 6.39 (d, J = 15.4 Hz, 1H), 4.41 (br s, 1H), 3.98 (br s, 1H),
2.60−2.69 (m, 2H), 2.37−2.41 (m, 1H), 1.49−1.64 (m, 5H), 1.47 (s,
9H), 1.40−1.43 (m, 1H); 13C NMR (175 MHz, 40 °C, CDCl3) δ
154.7, 143.7, 140.6, 133.2, 132.0, 129.2, 127.6, 79.8, 49.3, 39.0, 32.1,
28.4, 28.1, 25.2, 18.8; HRMS (ES+) calcd for C19H27NO4NaS (M +
Na) 388.1559, found 388.1545.
1
1413, 1364, 1248, 1164, 1054, 839, 741 cm−1; H NMR (400 MHz,
CDCl3) δ 7.19−7.28 (m, 5.2 H, mixed isomers), 7.10−7.14 (m, 1.3H,
mixed isomers), 6.58 (t, J = 6.8 Hz, 1H, major isomer), 6.46 (t, J = 7.2
Hz, 0.3H, minor isomer), 4.46 (br s, 1H, major isomer), 4.33 (br s,
0.3H, minor isomer), 4.05 (br d, J = 12.4 Hz, 0.3H, minor isomer),
3.96 (br d, J = 10.0 Hz, 1H, major isomer), 2.89 (ddd, J = 15.2, 8.8, 6.8
Hz, 1H, major isomer), 2.74−2.82 (m, 1.3 H, mixed isomers), 2.47−
2.64 (m, 1.6 H, mixed isomers), 1.53−1.65 (m, 7H, mixed isomers),
1.49 (s, 9H, major isomer), 1.45 (s, 2.7H, minor isomer), 1.32−1.40
(m, 0.8H, mixed isomers), 0.18 (s, 2.7H, minor isomer), 0.02 (s, 9H,
major isomer); 13C NMR (100 MHz, 40 °C, CDCl3) δ 154.9, 149.5,
137.7, 137.6, 135.7, 134.3, 129.7, 128.7, 128.6, 128.2, 125.9, 125.2,
79.4, 79.1, 50.7, 50.0, 39.1, 33.0, 31.7, 28.54, 28.45, 27.8, 25.5, 25.4,
19.1, 0.5, −1.1; HRMS (ES+) calcd for C22H36NO2SiS (M + H)
406.2236, found 406.2224.
(Z)-Vinyl Sulfone 87: [α]20 = −9.0° (c 1.0, CHCl3); IR (neat)
D
3060, 2974, 2934, 2864, 1688, 1681, 1626, 1476, 1447, 1414, 1365,
1317, 1149, 1086, 750, 688 cm−1; 1H NMR (400 MHz, 40 °C, CDCl3)
δ 7.92 (d, J = 7.2 Hz, 2H), 7.61−7.65 (m, 1H), 7.54−7.58 (m, 2H),
6.30 (br s, 2H), 4.42 (br s, 1H), 3.97 (d, J = 12.0 Hz, 1H), 3.17−3.22
(m, 1H), 2.83−2.86 (m, 2H), 1.57−1.70 (m, 5H), 1.36−1.47 (m,
10H); 13C NMR (100 MHz, 40 °C, CDCl3) δ 155.0, 143.9, 141.7,
133.3, 131.3, 129.2, 127.2, 79.5, 50.0, 39.1, 28.7, 28.6, 28.4, 25.4, 19.0;
HRMS (ES+) calcd for C19H27NO4NaS (M + Na) 388.1559, found
388.1555.
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Sulfones 92 and 93. To a solution of mixture of sulfides 90 and
91 (64 mg, 0.158 mmol) in EtOH (1.6 mL) was added
(NH4)6Mo7O24·4H2O (39 mg, 0.032 mmol) followed by H2O2
(0.82 mL, 7.9 mmol, 30% aqueous). After 4 h, water (10 mL) was
added and extracted with DCM (3 × 15 mL). The dried (MgSO4)
extract was concentrated in vacuo and purified by chromatography over
silica gel, eluting with 30−50% ether/pentane to obtain 92 (48.2 mg,
0.11 mmol, 70%) and 93 (16.1 mg, 0.037 mmol, 23%).
(Z)-Vinyl Sulfone 92: IR (neat) 2974, 2937, 2863, 1685, 1593,
1476, 1446, 1414, 1299, 1249, 1165, 1141, 1085, 884, 843, 760, 590
cm−1; 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 7.2 Hz, 2H), 7.52−
7.61 (m, 3H), 6.59 (br s, 1H), 4.35 (br s, 1H), 3.86 (br d, J = 12.4 Hz,
1H), 2.91 (br s, 1H), 2.51−2.55 (m, 2H), 1.52−1.66 (m, 3H), 1.45 (s,
9H), 1.27−1.40 (m, 3H), 0.29 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 155.3, 154.8, 147.9, 143.4, 132.7, 129.0, 127.0, 79.5, 49.8, 38.9, 31.4,
28.7, 28.5, 25.3, 18.9, −0.4; HRMS (ES+) calcd for C22H36NO4SiS (M
+ H) 438.2134, found 438.2136.
Sulfone 56. To a stirred suspension of CuI (28.8 mg, 0.151 mmol)
in ether (0.88 mL) at 0 °C was added MeLi (0.185 mL, 0.296 mmol,
1.6 M solution in ether). After 5 min, the reaction was cooled to −78
°C. After 5 min, a solution of vinyl sulfone 86 (18 mg, 50 μmol) in
ether (0.13 mL) was added. After 5 min, the reaction mixture was
slowly warmed to −20 °C over a period of 45 min. After 5 h, the
reaction was quenched with aq NH4Cl (5 mL) and extracted with
ether (3 × 10 mL). The dried (MgSO4) extract was concentrated in
vacuo and purified by column chromatography over silica gel, eluting
with 10−30% EtOAc/hexanes to obtain a 1.0:1.2 mixture of sulfones
(56 and 94, respectively) (10.8 mg, 28.3 μmol, 55%).
(E)-Vinyl Sulfone 93: IR (neat) 2974, 2933, 2857, 1686, 1588,
1475, 1446, 1414, 1365, 1295, 1164, 1143, 1086, 847, 761, 721, 691
cm−1; 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 7.2 Hz, 2H), 7.45−
7.57 (m, 4H), 4.48−4.51 (m, 1H), 4.08 (br d, J = 13.6 Hz, 1H), 2.72−
2.81 (m, 2H), 2.58 (ddd, J = 14.8, 8.0, 6.8 Hz, 1H), 1.52−1.72 (m,
5H), 1.50 (s, 9H), 1.45−1.47 (m, 1H), 0.18 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 155.3, 154.8, 143.9, 141.8, 132.6, 128.8, 127.3, 80.0,
50.1, 39.2, 31.7, 28.5, 28.3, 25.3, 19.1, 0.5; HRMS (ES+) calcd for
C22H36NO4SiS (M + H) 438.2134, found 438.2137.
Hydroxy Sulfones 96 and 97. To a solution of sulfone 56 (60
mg, 0.157 mmol) in dry THF (0.253 mL) at −78 °C was added
LDA55 (0.236 mL, 0.236 mmol, 1.0 M in THF/hexanes). After 1 min,
a solution of aldehyde 32 (89.1 mg, 0.392 mmol) in THF (0.147 mL)
was added. After 20 min, the reaction was quenched with satd aq
NH4Cl (5 mL) and extracted with ether (3 × 10 mL). The dried
(MgSO4) extract was concentrated in vacuo and purified by
chromatography over silica gel, eluting with 20−80% ether/pentane
to obtain a 1.0:1.5 mixture of 97 and 96, respectively (84.9 mg, 0.146
mmol, 93%), as a colorless oil.
Hydroxy Sulfone 97: [α]20 = −45.0° (c 1.00, CHCl3); IR (neat)
D
3391, 2929, 2851, 1683, 1652, 1418, 1366, 1273, 1166, 1145, 868, 723,
613 cm−1; 1H NMR (400 MHz, 40 °C, CDCl3) δ 7.88 (d, J = 7.6 Hz,
4H), 7.50−7.56 (m, 6H), 4.30−4.38 (m, 4H), 3.94−3.96 (m, 4H),
3.82 (br s, 2H), 3.38 (br s, 2H), 2.74−2.80 (m, 4H), 2.26 (br s, 4H),
1.67−1.73 (m, 4H), 1.47−1.59 (m, 24H), 1.41−1.42 (m, 40 H), 1.26−
1.28 (6H); 13C NMR (100 MHz, 40 °C, CDCl3) δ 156.5, 155.0, 142.7,
133.5, 132.8, 129.2, 129.0, 128.7, 128.3, 128.2, 128.1, 128.0, 80.2, 79.4,
79.3, 72.8, 66.1, 49.0, 46.4, 39.2, 34.7, 34.4, 29.6, 29.5, 29.2, 28.6, 28.5,
28.4, 28.3, 28.1, 28.0, 25.6, 25.4, 19.3, 19.0, 18.9, 18.0; HRMS (ES+)
calcd for C32H53N2O7S (M + H) 609.3573, found 609.3569.
Sulfone 94. To a stirred suspension of CuI (24.0 mg, 0.126 mmol)
in ether (0.32 mL) at 0 °C was added MeLi (0.155 mL, 0.248 mmol,
1.6 M solution in ether). After 25 min, a solution of vinyl sulfone 92
(9.2 mg) in ether (0.05 mL) was added. After 35 min, the reaction
mixture was quenched with aq NH4Cl (5 mL) and extracted with ether
(3 × 10 mL). The dried (MgSO4) extract was concentrated in vacuo,
and the crude was taken to the next step.
To a solution of crude sulfone (∼21 μmol) in MeOH (0.26 mL)
was added KF (6.3 mg, 0.109 mmol) at rt. Aft 1 h, the reaction mixture
was quenched with aq NaHSO3 solution (5 mL) and extracted with
DCM (3 × 10 mL). The dried (MgSO4) extract was concentrated in
vacuo and purified by column chromatography over silica gel, eluting
with 10−30% EtOAc/hexanes to obtain a 1:8 diastereomeric mixture
of sulfones (3 and epi-C15 3, respectively) (7.5 mg, 20 μmol, 93%, 2
steps). [α]20D = −21.67° (c 0.48, CHCl3); IR (neat) 2926, 2852, 1682,
1447, 1416, 1365, 1305, 1271, 1149, 1070 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.93 (d, J = 7.6 Hz, 2H), 7.67 (t, J = 7.2 Hz, 1H), 7.59 (t, J =
7.2 Hz, 2H), 4.29 (br s, 1H), 3.97 (br s, 1H), 3.16 (dd, J = 14.0, 5.6
Hz, 1H), 3.01 (dd, J = 14.4, 6.0 Hz, 1H), 2.81 (t, J = 12.8 Hz, 1H),
2.15−2.22 (m, 1H), 2.01 (br s, 1H), 1.58 (m, 5H), 1.45 (s, 9H), 1.18−
1.30 (m, 2H) 1.13 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 154.8, 140.2, 133.4, 129.3, 127.9, 79.2, 62.6, 47.7, 38.8, 36.8, 29.2,
28.5, 25.9, 25.6, 20.3, 19.1; HRMS (EI+) calcd for C20H31NO4S (M+)
381.1974, found 381.1964.
Hydroxy Sulfone 96: [α]20 = −37.7° (c 0.98, CHCl3); IR (neat)
D
3420, 2929, 2854, 1683, 1652, 1473, 1456, 1418, 1365, 1271, 1165,
1
1145, 1083 cm−1; H NMR (400 MHz, 40 °C, CDCl3) δ 7.88−7.96
(m, 4H), 7.50−7.60 (m, 6H), 4.18−4.25 (m, 4H), 4.04 (br s, 2H),
3.80−3.90 (m, 4H), 3.45−3.52 (m, 2H), 3.28 (br s, 2H), 2.69−2.78
(m, 4H), 2.13−2.29 (m, 4H), 1.71−1.80 (m, 8H), 1.32−1.54 (m, 58
H), 1.23−1.25 (6H); 13C NMR (100 MHz, 40 °C, CDCl3) δ 155.3,
155.2, 155.1, 154.9, 141.9, 141.6, 140.5, 133.5, 133.3, 129.14, 129.07,
129.0, 128.1, 128.0, 128.0, 79.5, 79.3, 79.2, 71.1, 68.0, 48.4, 39.5, 39.3,
39.1, 37.0, 35.4, 35.1, 34.9, 29.6, 29.1, 28.53, 28.47, 28.46, 28.43, 28.33,
28.30, 28.0, 27.8, 25.5, 25.4, 25.3, 25.2, 19.1, 19.0, 18.9, 18.5, 17.4;
HRMS (ES+) calcd for C32H53N2O7S (M + H) 609.3573, found
609.3562.
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Keto Sulfone SI-16. To a solution of alcohol 96 (15 mg, 24.6
μmol) in DCM (0.71 mL) at 0 °C was added solid NaHCO3 (10.35
mg, 0.123 mmol) followed by DMP (20.87 mg, 0.049 mmol). After 30
min, the reaction mixture was warmed to rt over a period of 15 min.
After 1.5 h, the reaction was quenched with satd aq Na2S2O3 (5 mL)
solution and extracted with DCM (3 × 10 mL). The dried (MgSO4)
extract was concentrated in vacuo and purified by chromatography over
silica gel, eluting with 20−30% EtOAc/hexanes to obtain the keto
Amide 12. To a solution of sulfone 98 (8.5 mg, 28 μmol) in dry
MeOH (0.55 mL) at 0 °C was added Na2HPO4 (199 mg, 1.4 mmol)
followed by 5% Na/Hg (318 mg, 0.69 mmol). After 20 min, the
reaction was quenched with satd aq NH4Cl (2 mL), diluted with
EtOAc (5 mL) and filtered through Celite and extracted with EtOAc
(3 × 5 mL). The dried (MgSO4) extract was concentrated in vacuo and
purified by chromatography over silica gel, eluting with 40−60%
EtOAc/hexanes to obtain the known amide 1214a (4.0 mg, 23.9 μmol,
sulfone SI-16 (13.9 mg, 23.0 μmol, 93%) as a colorless oil. [α]20
=
86%) as a colorless oil. [α]20 = −24.4° (c 0.32, CHCl3); IR (neat)
D
D
2929, 2855, 1636, 1463, 1447, 1279, 1258, 1103 cm−1; 1H NMR (700
MHz, CDCl3) δ 4.79 (dq, J = 12.6, 2.1 Hz, 1H), 3.34−3.38 (m, 1H),
2.47 (ddd, J = 16.8, 4.2, 2.1 Hz, 1H), 2.43 (td, J = 12.6, 2.8 Hz, 1H),
2.06−2.10 (m, 1H), 2.02 (dd, J = 16.8, 9.1 Hz, 1H), 1.89−1.92 (m,
1H), 1.61−1.69 (m, 4H), 1.51−1.58 (m, 1H), 1.45−1.49 (m, 1H),
1.37−1.45 (m, 1H), 1.00 (t, J = 6.3 Hz, 3H); 13C NMR (175 MHz,
CDCl3) δ 168.5, 55.6, 43.0, 40.6, 36.9, 33.6, 25.4, 25.1, 24.5, 20.5;
HRMS (ES+) calcd for C10H18NO (M + H) 168.1388, found
168.1394.
−13.3° (c 0.70, CHCl3); IR (neat) 2929, 2855, 1717, 1684, 1447,
1
1417, 1365, 1271, 1165, 1083, 1083, 872 cm−1; H NMR (400 MHz,
40 °C, CDCl3) δ 7.79−7.84 (m, 4H), 7.56−7.61 (m, 2H), 7.47−7.51
(m, 4H), 4.56 (m, 2H), 4.21−4.37 (m, 4H), 3.84−3.86 (m, 4H),
2.84−2.91 (m, 2H), 2.40−2.65 (m, 6H), 2.24 (br s, 1H), 2.09 (br s,
1H), 1.76−1.80 (m, 2H), 1.49 (m, 10 H), 1.35−1.40 (m, 44H), 1.20−
1.31 (m, 8H), 1.16 (d, J = 6.8 Hz, 3H), 1.03−1.04 (m, 3H); 13C NMR
(100 MHz, 40 °C, CDCl3) δ 200.8, 200.7, 200.5, 200.4, 154.8, 154.7,
154.5, 139.0, 133.94, 133.90, 129.1, 129.0, 128.9, 128.8, 79.42, 79.38,
79.2, 78.4, 48.0, 47.1, 46.8, 46.0, 45.9, 45.7, 40.0, 39.7, 39.2, 34.5, 33.7,
31.1, 30.5, 28.5, 28.42, 28.35, 27.7, 27.3, 25.3, 25.14, 25.11, 18.9, 18.84,
18.76, 18.67, 17.5, 17.0, 16.8; HRMS (ES+) calcd for C32H50N2O7NaS
(M + Na) 629.3236, found 629.3194.
Cermizine D (7). To a solution of sulfone 97 (44.2 mg, 73.0 μmol)
in EtOH (1.46 mL) at 80 °C was added skeletal Raney Ni (1.77 g, 3
portions) portionwise over a period of 7 h. After an additional 8 h, the
reaction mixture was cooled down to rt and filtered through Celite.
The solvent was removed in vacuo to obtain the crude alcohol SI-17,
which was unstable to purification and carried on as crude.
To a solution of the crude alcohol SI-17 (∼73 μmol) in MeOH
(1.53 mL) was added TMSCl (133.3 mg, 0.156 mL, 1.23 mmol). After
4 h, the solvent was removed in vacuo to obtain the crude 99. The
crude 99 is taken to the next step.
Hydroxy Sulfones 97 and 96. To a solution of keto sulfone SI-
16 (4.0 mg, 6.6 μmol) in MeOH (0.12 mL) at rt was added NaBH4
(2.5 mg, 6.6 μmol). After 1 h, the reaction was quenched with aq
NH4Cl (5 mL) and extracted with DCM (3 × 5 mL). The dried
(MgSO4) extract was concentrated in vacuo and purified by
chromatography over silica gel, eluting with 30−80% ether/pentane
to obtain a 1.0:1.5 mixture (4.0 mg, 6.5 μmol, 99%) of 97 and 96
respectively as colorless oil.
To a solution of crude alcohol 99 (∼73 μmol) in DCM (2.1 mL) at
0 °C were added sequentially PPh3 (28.8 mg, 0.11 mmol), CBr4 (36.3
mg, 0.11 mmol), and Et3N (44.3 mg, 0.06 mL, 0.438 mmol). The
solution was slowly warmed to rt over a period of 15 min. After 3 h,
the solvent was removed in vacuo and purified by chromatography over
silica gel, by eluting with (2:4:94) to (2:10:88) ratio of NH4OH/
MeOH/CHCl3 to afford cermizine D (7)10 (11.0 mg, 0.044 mmol,
Cyclic Sulfone 98. To a solution of sulfone 56 (20 mg, 52.4 μmol)
in THF (0.39 mL) at −78 °C was added LDA9 (0.131 mL, 0.131
mmol, 1.0 M in THF/hexanes). After 20 min, the reaction mixture was
warmed to 0 °C. After 15 min, the reaction was quenched with satd aq
NH4Cl (5 mL) and extracted with ether (3 × 10 mL). The dried
(MgSO4) extract was concentrated in vacuo and purified by
chromatography over silica gel, eluting with 70−80% EtOAc/hexane
60% over 3 steps) as a pale yellow oil. [α]20 = +40.8° (c 0.90,
D
MeOH); IR (neat) 3360, 3294, 2926, 2853, 1639, 1455, 1442, 1373,
1121 cm−1; 1H NMR (700 MHz, MeOH-d4) δ 3.39 (br d, J = 15.4 Hz,
1H), 3.15−3.19 (m, 1H), 3.03−3.07 (m, 2H), 2.59−2.68 (m, 3H),
2.01 (qd, J = 12.6, 4.2, 1H), 1.78−1.90 (m, 5H), 1.62−1.74 (m, 3H),
1.53−1.60 (m, 2H), 1.43−1.49 (m, 2H), 1.40 (td, J = 12.6, 5.6 Hz,
1H), 1.19−1.24 (m, 3H), 1.12 (ddd, J = 14.0, 9.8, 4.2 Hz, 1H), 0.93
(d, J = 7.0 Hz, 3H), 0.83 (q, J = 11.9 Hz, 1H); 13C NMR (175 MHz,
MeOH-d4) δ 57.7, 53.5, 48.6, 46.2, 39.9, 39.8, 39.0, 33.2, 25.3, 25.1,
24.3, 24.0, 21.3, 18.2; HRMS (EI+) calcd for C16H30N2 (M+)
250.2409, found 250.2414.
to obtain 98 (14 mg, 45.5 μmol, 87%) as a colorless oil. [α]20
=
D
+55.0° (c 0.2, CHCl3); IR (neat) 3064, 2926, 2854, 1645, 1447, 1308,
1148, 1083, 688.6, 525.7, 458.0 cm−1; 1H NMR (700 MHz, CDCl3) δ
7.94 (dd, J = 8.4, 0.7 Hz, 2H), 7.67 (tt, J = 7.0, 1.4 Hz, 1H), 7.58 (t, J =
7.7 Hz, 2H), 4.72−4.74 (m, 1H), 3.75 (t, J = 1.4 Hz, 1H), 3.32−3.35
(m, 1H), 3.06−3.07 (m, 1H), 2.44 (td, J = 13.3, 2.8 Hz, 1H), 2.32
(ddd, J = 14.7, 11.2, 4.2 Hz, 1H), 1.86−1.88 (m, 1H), 1.74−1.80 (m,
3H), 1.42−1.50 (m, 3H), 1.13 (d, J = 7.7 Hz, 3H); 13C NMR (175
MHz, CDCl3) δ 160.3, 139.9, 133.7, 128.93, 128.85, 72.3, 53.3, 42.8,
33.8, 32.2, 25.5, 25.3, 24.2, 18.9; HRMS (ES+) calcd for C16H22NO3S
(M + H) 308.1320, found 308.1309.
TFA Salt of Cermizine-D (7·TFA). To a solution of cermizine D
(7) (2.0 mg, 8.0 μmol) in dry DCM (0.1 mL) was added TFA (3
drops) at 0 °C. After 10 min, the solvent was removed in vacuo to
afford the cermizine D bis-TFA salt (7·TFA)14c (3.8 mg, 8.0 μmol,
99%) as pale yellow oil. [α]20D = +16.8° (c 0.41, MeOH) {lit.11 [α]20
D
= +24.2° (c 0.50, MeOH)}; IR (neat) 3390, 2960, 2925, 2853, 1674,
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1455, 1430, 1202, 1139, 799, 721 cm−1; 1H NMR (700 MHz, MeOH-
d4) δ 3.96 (br t, J = 11.2 Hz, 1H), 3.71−3.74 (m, 2H), 3.45 (br d, J =
6.3 Hz, 1H), 3.35−3.37 (m, 1H), 3.18 (td, J = 13.3, 3.5 Hz, 1H), 3.08
(td, J = 14.2, 2.8 Hz, 1H), 2.33 (ddd, J = 11.2, 9.1, 3.5 Hz, 1H), 2.16−
2.25 (m, 2H), 1.93−2.06 (m, 5H), 1.55−1.85 (m, 10H), 1.02 (m, 1H),
1.02 (d, J = 6.3 Hz, 3H); 13C NMR (175 MHz, MeOH-d4) δ 62.5,
54.2, 51.5, 50.0, 46.0, 39.1, 38.1, 36.4, 31.0, 25.0, 24.7, 23.7, 23.2, 23.1,
21.6, 18.6; HRMS (EI+) calcd for C16H31N2 (M + H) 251.2487, found
251.2478.
(7) Early total syntheses: (a) Beyerman, H. C.; Maat, L. Recl. Trav.
Chim. Pays-Bas 1963, 82, 1033−39. (b) Beyerman, H. C.; Maat, L.
Recl. Trav. Chim. Pays-Bas 1965, 84, 385−88. (c) Beyerman, H. C.;
Maat, L.; van Veen, A.; Zweistra, A. Recl. Trav. Chim. Pays-Bas 1965,
84, 1367−79.
(8) Total syntheses since 2005: (a) Turcaud, S.; Martens, T.;
Sierecki, E.; Perard-Viret, J.; Royer, J. Tetrahedron Lett. 2005, 46,
5131−5134. (b) Carlson, E. C.; Rathbone, L. K.; Yang, H.; Collett, N.
D.; Carter, R. G. J. Org. Chem. 2008, 73, 5155−5158. (c) Cheng, G.;
Wang, X.; Su, D.; Liu, H.; Liu, F.; Hu, Y. J. Org. Chem. 2010, 75,
1911−1916. (d) Beng, T. K.; Gawley, R. E. J. Am. Chem. Soc. 2010,
132, 12216−12217. (e) Liu, J. D.; Chen, Y. C.; Zhang, G. B.; Li, Z. Q.;
Chen, P.; Du, J. Y.; Tu, Y. Q.; Fana, C. A. Adv. Synth. Catal. 2011, 353,
2721−2730. (f) Monaco, M. R.; Renzi, P.; Schietroma, D. M. S.; Bella,
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C spectra for all new compounds; X-ray
crystallographic data (in CIF format ) for compound 66. This
material is available free of charge via the Internet at http://
pubs.acs.org.
́
́
M. Org. Lett. 2011, 13, 4546−4549. (g) Bosque, I.; Gonzalez-Gomez,
J. C.; Foubelo, F.; Yus, M. J. Org. Chem. 2012, 77, 780−784.
(h) Chiou, W. H.; Chen, G. T.; Kao, C. L.; Gao, Y. K. Org. Biomol.
Chem. 2012, 10, 2518−2520.
AUTHOR INFORMATION
Corresponding Author
*E-mail: rich.carter@oregonstate.edu.
(9) (a) Matsunaga, T.; Kawasaki, I.; Kaneko, T. Tetrahedron Lett.
1967, 8, 2471−2473. (b) Quick, J.; Meltz, C. J. Org. Chem. 1979, 44,
573−578.
■
(10) Morita, H.; Hirasawa, Y.; Shinzato, T.; Kobayashi, J. Tetrahedron
2004, 60, 7015−7023.
Notes
The authors declare no competing financial interest.
(11) (a) Slosse, P.; Hootele, C. Tetrahedron Lett. 1978, 397−398.
(b) Slosse, P.; Hootele, C. Tetrahedron Lett. 1979, 4587−4588.
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ACKNOWLEDGMENTS
■
Financial support was provided by the National Institutes of
Health (NIH) (GM63723) and Oregon State University). The
authors are grateful to Professor Claudia Maier and Jeff Morre
(OSU) for mass spectra data and Dr. Lev Zakharov (OSU) for
X-ray crystallographic analysis of 66. Finally, the authors thank
Professor James D. White (OSU) and Dr. Roger Hanselmann
(Rib-X Pharmaceuticals) for their helpful discussions.
(13) Marion, L.; Manske, R. H. F. Can. J. Res. 1948, 26, 1−2.
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with satd aq sodium thiosulfate solution (15 mL), satd aq NaHCO3
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min, the white slurry was warmed to −10 °C. After 15 min, the LDA
solution (1.0 M in THF/hexanes) was used for the reaction.
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