Total Synthesis of Δ12-Prostaglandin J3: Evolution of Synthetic Strategies to a Streamlined Process

Article abstract of DOI:10.1002/chem.201601449

The total synthesis of Δ¹²-prostaglandin J₃(Δ¹²-PGJ₃, 1), a reported leukemia stem cell ablator, through a number of strategies and tactics is described. The signature cross-conjugated dienone structural motif of 1 was forged by an aldol reaction/dehydration sequence from key building blocks enone 13 and aldehyde 14, whose lone stereocenters were generated by an asymmetric Tsuji–Trost reaction and an asymmetric Mukaiyama aldol reaction, respectively. During this program, a substituent-governed regioselectivity pattern for the Rh-catalyzed C?H functionalization of cyclopentenes and related olefins was discovered. The evolution of the synthesis of 1 from the original strategy to the final streamlined process proceeded through improvements in the construction of both fragments 13 and 14, exploration of the chemistry of the hitherto underutilized chiral lactone synthon 57, and a diastereoselective alkylation of a cyclopentenone intermediate. The described chemistry sets the stage for large-scale production of Δ¹²-PGJ₃and designed analogues for further biological and pharmacological studies.

Full text of DOI:10.1002/chem.201601449

DOI: 10.1002/chem.201601449
Full Paper
&
Total Synthesis |Hot Paper|
Total Synthesis of D12-Prostaglandin J3:
Evolution of Synthetic Strategies to a Streamlined Process
K. C. Nicolaou,*[a] Kiran Kumar Pulukuri+,[a] Ruocheng Yu+,[a] Stephan Rigol,[a]
Philipp Heretsch,[a] Charles I. Grove,[a] Christopher R. H. Hale,[a, b] and Abdelatif ElMarrouni[a]
Abstract: The total synthesis of D12-prostaglandin J3 (D12-
PGJ3, 1), a reported leukemia stem cell ablator, through
a number of strategies and tactics is described. The signa-
ture cross-conjugated dienone structural motif of 1 was
forged by an aldol reaction/dehydration sequence from key
building blocks enone 13 and aldehyde 14, whose lone ste-
reocenters were generated by an asymmetric Tsuji–Trost re-
action and an asymmetric Mukaiyama aldol reaction, respec-
tively. During this program, a substituent-governed regiose-
lectivity pattern for the Rh-catalyzed CÀH functionalization
of cyclopentenes and related olefins was discovered. The
evolution of the synthesis of 1 from the original strategy to
the final streamlined process proceeded through improve-
ments in the construction of both fragments 13 and 14, ex-
ploration of the chemistry of the hitherto underutilized
chiral lactone synthon 57, and a diastereoselective alkylation
of a cyclopentenone intermediate. The described chemistry
sets the stage for large-scale production of D12-PGJ3 and de-
signed analogues for further biological and pharmacological
studies.
Introduction
The search for cytotoxic agents against cancer stem cells
(CSCs) has received increasing attention from the scientific
community.[1] Although they represent only a small subpopula-
tion of cancer cells, CSCs are notoriously resistant toward con-
ventional therapies driving growth, proliferation, and relapse.[2]
In 2011, Paulson and Prabhu reported the isolation of D12-pros-
taglandin J3 (D12-PGJ3, 1, Figure 1) and 15-deoxy-D12,14-prosta-
glandin J3 (15d-PGJ3, 2, Figure 1)[3] from endogenous metabo-
lites of eicosapentaenoic acid (EPA, 5, Figure 2), the dietary fish
oil w-3 polyunsaturated fatty acid. D12-PGJ3 was claimed to se-
lectively induce apoptosis in leukemia stem cells (LSCs) in in
vitro studies (IC50 value ~12 nm) with no significant effects on
normal hematopoietic stem cells.[3] In addition, intraperitoneal
administration of D12-PGJ3 to two infected murine models suc-
cessfully eradicated LSCs and restored normal physiological pa-
rameters.[3] Other favorable properties attributed to D12-PGJ3
include reasonable stability and bioavailability and minimal hy-
persensitivity.[4] These results elevate D12-PGJ3 (1) to a lead
compound warranting further investigation in search of new
Figure 1. Molecular structures of D12-prostaglandin J3 (D12-PGJ3) and related
natural products.
therapies for the treatment of acute and chronic myelogenous
leukemia (AML and CML).[3–5]
The structure of D12-PGJ3 (1), isolated in only microgram
quantities, was proposed based on mass spectrometric and UV
spectroscopic measurements and biosynthetic analogy consid-
erations to the known J2 series prostaglandins [D12-PGJ2 (3)
and 15d-PGJ2 (4) (Figure 1)].[3,6,7] Specifically, it was surmised
that the J3 series of PGJs [PGJ3 (7), D12-PGJ3 (1) and 15d-PGJ3
(2), see Figure 2a] are the biosynthetic downstream products
of EPA (5)-derived prostaglandin D3 [PGD3 (6), Figure 2a]
formed through dehydration, isomerization, and further dehy-
dration (Figure 2).[3] A similar biosynthetic pathway was known
to account for the formation of 15d-PGJ2 (4) from arachidonic
acid (ARA, 8, see Figure 2b).[6] Despite their structural resem-
blance, the ARA- and EPA-derived PGJs might act differently on
the p53 tumor suppression protein.[3] Whereas 15d-PGJ2 (4) is
known to functionally inactivate p53, the proapoptotic effect
[a] Prof. Dr. K. C. Nicolaou, Dr. K. K. Pulukuri,+ R. Yu,+ Dr. S. Rigol,
Dr. P. Heretsch, Dr. C. I. Grove, C. R. H. Hale, Dr. A. ElMarrouni
Department of Chemistry, BioScience Research Collaborative
Rice University, 6100 Main Street, Houston, TX 77005 (USA)
E-mail: kcn@rice.edu
[b] C. R. H. Hale
Department of Chemistry, The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201601449.
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readily available. Some of these studies were also accompanied
by developments in synthetic methodologies, such as the
Corey–Bakshi–Shibata asymmetric reduction[14] and catalytic
asymmetric Diels–Alder reaction,[15] that desirably impacted or-
ganic synthesis in general.
Intrigued by the remarkable antileukemic properties report-
ed for D12-PGJ3, we initiated a program directed toward its
total synthesis. In 2014, we reported the first total synthesis of
this molecule, which allowed its structural confirmation.[16]
Herein, we provide a detailed account of our work, including
the development of several distinct strategies to access and as-
semble the various building blocks employed, culminating into
a short and efficient process for the synthesis of this target
molecule [D12-PGJ3 (1)] that could provide it in large amounts
and be applicable to the construction of its analogues as well
as other related prostanoids.[17]
Results and Discussion
Figure 2. Biosynthesis of the a) J3 and b) J2 series of prostaglandins.[3,6]
First-generation synthesis: Application of asymmetric Tsuji–
Trost alkylation and asymmetric Mukaiyama aldol reaction
In light of the reactive nature of the 2-alkylidene cyclopente-
none moiety, some of the previous approaches toward these
types of prostaglandins involved masked forms of this structur-
al unit, which were unmasked in the final step of the syntheses
(e.g., via retro-Diels–Alder reaction,[18] Saegusa–Ito oxida-
tion,[17g] bis-allylic alcohol oxidation[17b]). We decided to pursue
a more straightforward approach involving the convergent
union of cyclopentenone 13 and b-siloxyaldehyde 14 via aldol
reaction/dehydration as indicated retrosynthetically in Figure 4.
Although such a sequence would generate the cross-conjugat-
ed dienone directly, the stability of the C15 bis-homoallylic al-
cohol [as opposed to the homoallylic alcohol in D12-PGJ2 (3,
Figure 1)] under the proposed reaction conditions could not
be assumed a priori. Both fragments, 13 and 14, contain
a lone stereocenter that was to be introduced asymmetrically.
In contrast to the strategies employed in Kobayashi’s synthesis
of D12-PGJ3 (1) has been suggested to arise from activation of
the same protein.[3]
The most prominent structural feature of prostaglandins 1–4
(Figure 1) is the cross-conjugated dienone structural motif,
which is also shared by other natural and designed prosta-
noids, such as 9–12 (Figure 3).[8–11] Some of these have been
shown to react with endogenous nucleophiles (e.g., gluta-
thione, protein cysteine residues) selectively at the endocyclic
double bond (rather than the exocyclic double bond).[12] Com-
putational studies attributed this selectivity to a higher LUMO
coefficient and greater distribution of positive charge at the
endocyclic b-carbon of the enone system.[12]
Due to their natural scarcity and important biological prop-
erties, the prostaglandins have been the target of numerous
total syntheses,[13] with one of the challenges being the install-
ment of substituents on the conformationally flexible five-
membered ring. Such endeavors not only enabled the structur-
al elucidation of these often labile secondary metabolites, but
also facilitated their biological investigation by rendering them
Figure 3. Selected prostanoids with cross-conjugated dienone structural
motifs.
Figure 4. First-generation retrosynthetic analysis of D12-PGJ3 (1). PMB=para-
methoxybenzyl; TBS=tert-butyldimethylsilyl.
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of D12-PGJ2 (3),[17d,e] we envisioned derivation of enone 13 from
cyclopentene 15 through Wittig olefination and regioselective
CÀH functionalization (Figure 4). The latter intermediate could
be obtained by catalytic asymmetric Tsuji–Trost alkylation of
racemic acetate 16. The C15 stereocenter (PGJ numbering) of
the b-siloxyaldehyde fragment 14 was expected to arise from
an asymmetric Mukaiyama aldol reaction of hex-3-ynal (17,
Figure 4). Subsequent (Z)-selective alkyne hydrogenation
would then install the C17–C18 olefinic bond, a distinctive
structural feature of the J3 series prostaglandins.
The synthesis of cyclopentenone fragment 13 began with
the preparation of racemic acetate 16 following a modified lit-
erature procedure,[19] as outlined in Scheme 1a. Thus, reduction
of commercially available 2-cyclopentenone (18) (DIBAL-H) fol-
lowed by acetylation (Ac2O, Et3N, DMAP) gave volatile acetate
16 in 62% overall yield. Asymmetric Tsuji–Trost allylic alkyla-
tion[20] of racemic 16 with the enolate of dimethyl malonate
(generated through in situ deprotonation with Cs2CO3) pro-
ceeded smoothly in the presence of [(h3-C3H5)PdCl]2 (0.5 mol%)
and (S,S)-DACH-phenyl Trost ligand (1.5 mol%), furnishing di-
methyl ester 19 in 71% yield and 97% ee. The absolute config-
uration and ee were deduced from comparison of the optical
rotation with that of the known enantiomer (i.e., antipode of
19).[20b] Heating a mixture of diester 19 and KI in wet DMI at
1308C resulted in mono decarboxylation, affording ester 15 in
excellent yield (94%).
With ester 15 in hand, we proceeded to examine the CÀH
functionalization/oxidation step with the hope that the C11
methylene could be oxidized in preference to the C8 methine
(PGJ numbering). It was found after systematic experimenta-
tion (see Table 1) that the combination of tBuOOH and catalyt-
ic amounts of [Rh2(cap)4], a catalyst introduced by Doyle
et al.,[21] produced the desired regioisomer 20 in 48% yield.
Other common conditions [e.g., SeO2, tBuOOH–PDC,[22]
tBuOOH–bleach,[23] Mn(OAc)3 with or without O2 atmos-
phere[24]] proved to be inferior. During our earlier investiga-
tions,[16] we had also studied the CÀH oxidation on alternative
substrates with either a TBS-protected primary alcohol (15b,
entry 3, Table 1) or a dimethyl acetal (15c, entry 4, Table 1),
both of which could be converted, in principle, to the C6 alde-
hyde for the upcoming Wittig olefination (vide infra). However,
under identical conditions, these substrates provided the tri-
substituted enones 20b and 20c, respectively (entries 3 and 4,
Table 1), in which the CÀH oxidation occurred with concomi-
tant olefin transposition.[25] Intrigued by this observation, we
prepared a series of substrates with different ring sizes and
side-chain functionalities (15, 15a–j, Table 1) and subjected
them to the action of tBuOOH in the presence of catalytic
amounts of [Rh2(cap)4] (conditions A[21a]) or Mn(OAc)3 (condi-
tions B[24a]). As it turned out, most of the substituted cyclopen-
tenes examined (15b–j, entries 3–11, Table 1) afforded the
transposed enones (20b–j) as the major or exclusive product.
On the other hand, substrates 15 and 15a (entries 1 and 2), in
which a side-chain electron-withdrawing group is connected
to the five-membered ring through a single methylene bridge,
underwent direct allylic oxidation without migration of the
double bond.
Scheme 1. Synthesis of cyclopentenone fragment 13. Reagents and condi-
tions: a) DIBAL-H (1.2 equiv), CH2Cl2, 08C, 30 min; b) Ac2O (2.0 equiv), Et3N
(2.5 equiv), DMAP (0.1 equiv), CH2Cl2, 0 to 258C, 18 h, 62% for the two
steps; c) dimethyl malonate (3.0 equiv), [(h3-C3H5)PdCl]2 (0.005 equiv), (S,S)-
DACH-phenyl Trost ligand (0.015 equiv), Cs2CO3 (3.0 equiv), CH2Cl2, 258C, 3 h,
71% (97% ee); d) KI (8.0 equiv), DMI/H2O (10:1), 1308C, 12 h, 94%;
e) [Rh2(cap)4] (0.005 equiv), tBuOOH (5.0 equiv), K2CO3 (0.5 equiv), CH2Cl2,
258C, 1.5 h; then [Rh2(cap)4] (0.005 equiv), tBuOOH (5.0 equiv), 258C, 1.5 h,
48%; f) CeCl3·7H2O (1.0 equiv), NaBH4 (1.0 equiv), À308C, 10 min, 95%;
g) DIBAL-H (2.2 equiv), CH2Cl2, À788C, 45 min; h) IPh3P(CH2)5OPMB (26)
(2.5 equiv), NaHMDS (3.0 equiv), THF, À78 to 258C, 18 h, 75% for the two
steps; i) TBSCl (1.5 equiv), imid. (3.0 equiv), CH2Cl2, 0 to 258C, 15 min, 92%;
j) DIBAL-H (1.1 equiv), CH2Cl2, À788C, 45 min; k) IPh3P(CH2)5OPMB (26)
(1.5 equiv), NaHMDS (2.0 equiv), THF, À78 to 258C, 6 h, 92% for the two
steps; l) TBAF (1.2 equiv), THF, 0 to 258C, 5 h, 91%; m) PCC (2.0 equiv),
CH2Cl2, 258C, 3 h, 93%; n) PPh3 (5.0 equiv), toluene, reflux, 18 h, 95%. DACH-
phenyl Trost ligand=N,N’-(1S,2S)-cyclohexane-1,2-diylbis[2-(diphenylphos-
phino)benzamide]; DIBAL-H=diisobutylaluminum hydride; DMAP=4-dime-
thylaminopyridine; DMI=1,3-dimethyl-2-imidazolidinone; imid.=1H-imida-
zole; NaHMDS=sodium bis(trimethylsilyl)amide; PCC=pyridinium chloro-
chromate; [Rh2(cap)4]=dirhodium tetracaprolactamate; TBAF=tetra-n-buty-
lammonium fluoride.
A mechanistic rationale was proposed to account for the
above heterogeneity in regioselectivity as shown in Figure 5.
C
Thus, tBuOO , the species responsible for hydrogen atom ab-
straction, is generated through the reaction of tBuOOH with
[Rh2(cap)4] (Figure 5a).[21a] Due to its moderate reactivity, reac-
C
tions of tBuOO with aliphatic CÀH bonds are known to be
highly selective, resulting in generation of the most stable radi-
cals.[26] In the case of 3-substituted cyclopentenes (A, Fig-
ure 5b), abstraction of the tertiary allylic hydrogen leads to al-
lylic radical B, whose reaction with another equivalent of
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Table 1. Regioselective allylic oxidation of substituted cyclopentenes and
related cycloalkenes with [Rh2(cap)4] (cat.) and tBuOOH (A) or Mn(OAc)3
(cat.) and tBuOOH (B).[a]
Entry
1
Substrate
Product(s)
Yield [%][b]
A: 48
B: 35
A: 41
B: 37
2
A: 63
B: 61
3
4
5
6
A: 45
B: 39
A: 38
B: 47
A: 26/13
B: 20/0
A: 20/14/16
B: 22/6/8
7
8
A: 32/9/13
B: 6/7/11
Figure 5. Mechanistic rationale for the regioselective CÀH oxidation.
A: 20/11/7
B: 21/9/11
destabilizes the type B radical, thereby leading to exclusive for-
mation of enone 20 (entry 1, Table 1). Such inductive effect,
however, is markedly attenuated in the homologated substrate
15e (R=CH2CH2CO2Me, Figure 5c), resulting in the selective
formation of transposed enone 20e (entry 6, Table 1) via the
more substituted (hence, more stable) tertiary allylic radical B.
While cyclopentene 15d (R=CO2Me, Figure 5c) also gives the
transposed enone 20d (entry 5, Table 1), it represents a differ-
ent scenario, in which the tertiary allylic radical B is further sta-
bilized through extended conjugation with the ester moiety
(Figure 5c). Regioselectivities for other substrates in Table 1
could be likewise explained. Switching the catalyst from
[Rh2(cap)4] to Mn(OAc)3 gives the same trend in selectivity,
albeit in most cases with a decrease in yield (conditions B,
Table 1). Interestingly and as shown in Table 1 (entries 7–9),
bis-oxidation was observed in some cases leading to conjugat-
ed diketones 20 f’–20h’ as minor products.
9
A: 43/10
B: 34/11
10
11
A: 64
B: 27
[a] Reactions were carried out on 1.0 mmol scale at 258C. Conditions A:
[Rh2(cap)4] (0.005 equiv), tBuOOH (5.0 equiv), K2CO3 (0.5 equiv), CH2Cl2,
1.5 h; then [Rh2(cap)4] (0.005 equiv), tBuOOH (5.0 equiv), 1.5 h. Conditions
B: Mn(OAc)3 (0.25 equiv), tBuOOH (4.0 equiv), 3 Š MS, EtOAc, 24 h.
[b] Yields refer to chromatographically isolated and spectroscopically
pure products. In cases where multiple products were generated, yields
were shown in the same order as the listed structures.
C
tBuOO (or its Rh-bound counterpart) at the more sterically ac-
Returning to the synthesis of the targeted enone 13
(Scheme 1a), Luche reduction (NaBH4, CeCl3·7H2O)[28] of enone
20 afforded hydroxyl ester 21 (95%, ca. 10:1 d.r., inconsequen-
tial), whose partial reduction with DIBAL-H gave the corre-
sponding hydroxyl aldehyde (not shown), thus setting the
stage for the Wittig olefination. In the event, treatment of 2.5
equivalents of w-(para-methoxybenzyloxy)pentyltriphenylphos-
phonium iodide [IPh3P(CH2)5-OPMB, 26; synthesized in one
step from iodide 25,[29] Scheme 1b], with NaHMDS at 08C, fol-
lowed by addition of the above hydroxyl aldehyde at À788C
and reaction at 258C for 12 h, furnished the desired (Z)-olefin
22 in high yield (75% from 21) and selectivity [(Z):(E)ꢀ10:1 as
cessible site furnishes peroxide C. Elimination of tBuOH from
the latter then affords the observed transposed enone product
D (Figure 5b).
Alternatively, formation of the isomeric radical B’ could
occur by removal of the secondary allylic hydrogen. Subse-
quent CÀO bond formation and elimination would give rise to
enone D’ via the intermediacy of peroxide C’ (Figure 5b). The
ratio of the final products D and D’ depends on the relative
stability of radicals B and B’, which in turn is determined by
the nature of the R group.[27] In substrate 15 (R=CH2CO2Me,
Figure 5c), the electron-withdrawing ester moiety inductively
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judged by NMR spectroscopic analysis]. Finally, the coveted
enone fragment 13 was obtained after PCC oxidation of allylic
alcohol 22 (93%).[17d,e] An alternative synthesis of 22 from 21
involved initial silylation of the latter (TBSCl, 92%), followed by
DIBAL-H reduction and Wittig olefination (92% for the two
steps), and a final desilylation (TBAF, 91%). Despite its greater
step count, this four-step sequence provided alcohol 22 in
slightly higher overall yield (77% vs. 75%), and required less
phosphonium salt 26 for the olefination step (1.5 equiv vs.
2.5 equiv).
After much experimentation, it was eventually found that the
projected transformation could be accomplished by mixing
hex-3-ynal [17, freshly prepared by DMP-oxidation of 3-hexyn-
1-ol (33),[31] Scheme 2c] with TMS-protected acetal 34[32] and
the (R)-NOBIN catalyst developed by Carreira and co-work-
ers.[33] The crude silyl aldolate was then treated with TBAF to
afford homopropargylic alcohol 35 in 72% yield and 95% ee
(determined by 19F NMR analysis of its Mosher ester derivative).
A full Mosher ester analysis[34] of alcohol 35 revealed the abso-
lute configuration of its chiral center to be (S) (as drawn in
Scheme 2c; see Supporting Information for details). Protection
of the newly generated alcohol in 35 (TBSCl) followed by par-
tial reduction of the alkyne (H2, Lindlar cat., quinoline) provid-
ed (Z)-alkene 36 as the only geometrical isomer (87% over the
two steps). The benzyl ester moiety was then reduced with
DIBAL-H to give the desired b-siloxyaldehyde 14 (89%).
The final stages of the synthesis of D12-PGJ3 (1) are summar-
ized in Scheme 3. Thus, regioselective deprotonation of cyclo-
pentenone 13 (1.0 equiv) at the C12 position was achieved
with LDA at À788C (Scheme 3a). Addition of the aldehyde
fragment 14 (1.2 equiv) to the so generated enolate at À788C
followed by stirring for 30 min at the same temperature fur-
nished the desired product 37 (79%) as an inconsequential
Construction of the b-siloxyaldehyde fragment 14 (Figure 4)
required an asymmetric Mukaiyama aldol reaction between
a b,g-unsaturated aldehyde (e.g., 17, Figure 4) and a suitable
two-carbon unit. However, the inherent lability of the b,g-unsa-
turated aldehyde system as well as its propensity to undergo
isomerization cast doubt on the feasibility of this transforma-
tion. Indeed, Shao and Huang reported that treatment of silyl
ketene acetal 27 in the presence of boron catalyst 29 fur-
nished only the allenyl alcohol 30 (together with its silylated
derivative) (Scheme 2a).[30] Moreover, our initial attempts to
achieve the desired Mukaiyama aldol using (Z)-hex-3-enal (32)
proved fruitless due to extensive decomposition (Scheme 2b).
Scheme 3. Coupling of fragments 13 and 14 and completion of the synthe-
sis of D12-PGJ3 (1). Reagents and conditions: a) LDA (2.0 equiv), 13
(1.0 equiv), THF, À788C, 20 min; then 14 (1.2 equiv), À788C, 30 min, 79%;
b) MsCl (5.0 equiv), Et3N (10 equiv), CH2Cl2, 08C, 5 min; c) Al2O3 (21 equiv),
CH2Cl2, 258C, 8 h, 62% for the two steps; d) DDQ (1.5 equiv), CH2Cl2/H2O
(16:1), 08C, 45 min, 87%; e) PCC (2.0 equiv), CH2Cl2, 258C, 2 h; f) NaClO2
(1.5 equiv), NaH2PO4 (1.5 equiv), 2-methyl-2-butene (10 equiv), tBuOH/H2O
(4:3), 258C, 30 min, 86% for the three steps; g) HF (50% aq., 50 equiv),
MeCN, 08C, 45 min, 92%; h) anhydrous Al2O3 (30 equiv), CH2Cl2, 258C, 1 h,
53%. DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone; LDA=lithium diiso-
propylamide; Ms=methanesulfonyl.
Scheme 2. Synthesis of aldehyde fragment 14. a) DMP (1.3 equiv), CH2Cl2, 0
to 258C, 1.5 h, 95% crude; b) BnO(TMSO)C=CH2 (34, 2.0 equiv), (R)-NOBIN
catalyst (0.05 equiv), Et2O, À78 to À158C, 4 h; then aq. work-up; then TBAF
(4.0 equiv), THF, 30 min, 72%, 95% ee; c) TBSCl (2.0 equiv), imid. (3.0 equiv),
CH2Cl2, 258C, 3 h; d) Pd (5% on CaCO3/Pb, Lindlar cat., 0.1 equiv), quinoline
(1.0 equiv), H2, EtOAc, 258C, 30 min, 87% for the two steps; e) DIBAL-H
(1.3 equiv), CH2Cl2, À78 to À258C, 1 h, 89%. DMP=Dess–Martin periodi-
nane; NOBIN=2-amino-2’-hydroxy-1,1’-binaphthyl; TMS=trimethylsilyl.
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pair of C13 epimers (ca. 3:1 d.r.).[17d,e] Brief exposure of the
aldol product 37 (mixture of epimers) to a mixture of MsCl and
Et3N gave the corresponding mesylate (38, ca. 3:1 d.r.), which,
even in the presence of excess Et3N, did not undergo b-elimi-
nation in the reaction medium. The latter transformation re-
quired the action of commercial neutral Al2O3 (Brockmann I,
50–200 mm, used as received) and led to the pivotal cross-con-
jugated dienone system (see 39, Scheme 3a, 62% for the two
steps), while leaving the C15-OTBS group intact.[17d,e] Two as-
pects of this elimination reaction deserve further comment.
First, both diastereomers of mesylate 38 selectively produced
the desired, and most likely the more thermodynamically
stable (E)-D12-isomer,[35] although there was a notable differ-
ence in the rate of elimination. Second, due to its hygroscopic
nature, commercial Al2O3 is likely to contain a small amount of
moisture. This factor turned out to be essential for the success
of this reaction as anhydrous Al2O3 (obtained by heating the
commercial reagent at 4008C under vacuum for 5 min prior to
the reaction) gave only the double elimination product 42 in
53% yield, as shown in Scheme 3b.
velopment of multiple synthetic routes toward D12-PGJ3 (1)
would allow more facile modification of the parent structure,
we set out to develop alternative strategies toward the two
key fragments 13 and 14. Below, we describe our second- and
third-generation syntheses of b-siloxyaldehyde fragment 14
featuring conceptually different means to construct the C15
hydroxyl-bearing stereocenter.
The second-generation retrosynthetic analysis of aldehyde
14 stemmed from its discernible structural relationship with al-
cohol 43 (Figure 6), a known compound that could be pre-
pared in enantioenriched form by a catalytic asymmetric Keck
allylation between aldehyde 44 and allyl tri-n-butylstannane
(45).[38] Conversion of 43 to 14 was anticipated to be straight-
forward through successive functional group manipulations at
both ends of the starting material (43). Thus, in the forward
sense (Scheme 4), exposure of aldehyde 44 and stannane 45
to catalytic amounts of Ti(OiPr)4 and (S)-BINOL in the presence
of oven-dried (1008C) 4 Š molecular sieves (4 Š MS) afforded
homoallylic alcohol 43 in 87% yield and >95% ee.[38,39] It has
been suggested by Kurosu and Lorca that 4 Š MS actually
serve as a controllable water source in Ti(OiPr)4/BINOL-cata-
lyzed Keck allylation reactions.[39] In line with this notion, we
found in our case that repetitive heating of the molecular
sieves with a propane flame under high vacuum led to signifi-
cantly decreased substrate conversion. When the oven-dried
At this stage, the PMB protecting group in dienone 39
(Scheme 3a), which had served well in its role to cap the C1
hydroxyl group, was cleaved with DDQ (87%). The resulting
primary alcohol 40 was converted to the corresponding car-
boxylic acid 41 through a two-step oxidation process [PCC;
then NaClO2 (Pinnick oxidation),[36] 86%].[17d,e] The final desilyla-
tion was then accomplished with 50% aqueous HF in MeCN,
furnishing D12-PGJ3 (1) in 92% yield after careful purification.
The UV, HPLC, and mass spectrum were in agreement with
those of the biosynthetically generated D12-PGJ3 (1) by the
Prabhu–Paulson team.[3a,16] Furthermore, we were able to
1
obtain a H NMR spectrum of a minute amount of a sample of
D12-PGJ3 (1) from these investigators, comparison of which
with that of synthetic D12-PGJ3 (1) revealed the identity of the
two samples (see Supporting Information of reference [16]).
Next, a stability test for D12-PGJ3 (1) was carried out and, inter-
estingly, the natural D12-PGJ3 (1) was stable when stored neat
at 258C with only small amounts of degradation products ob-
Figure 6. Second-generation retrosynthetic analysis of aldehyde fragment
14. TBDPS=tert-butyldiphenylsilyl.
1
served after one week (as judged by H and 13C NMR spectro-
scopic analysis). When dissolved in unneutralized CDCl3, how-
ever, D12-PGJ3 (1) gave notable decomposition after a few
days, likely owing to the residual acid present in the NMR sol-
vent.
Improved syntheses of b-siloxyaldehyde fragment 14
Our first-generation synthesis of D12-PGJ3 (1) rendered this
scarce biomolecule readily available for biological investiga-
tions and provided confirmation of its structural assignment.
However, the developed route was not without drawbacks. For
example, the synthesis of b-siloxyaldehyde fragment 14 re-
quired careful handling of the labile b,g-unsaturated aldehyde
17, prior synthesis of the (R)-NOBIN catalyst (four steps from
rather expensive commercially available reagents[33,37]), and the
potentially pyrophoric palladium catalyst for hydrogenation, all
of which hampered its application on gram-scale synthesis. To
overcome these limitations, and with the expectation that de-
Scheme 4. Second-generation synthesis of aldehyde fragment 14 via asym-
metric Keck allylation. Reagents and conditions: a) Ti(OiPr)4 (0.025 equiv), (S)-
BINOL (0.05 equiv), 4 Š MS, toluene, 258C, 2.5 h; then 44 (1.0 equiv),
CH2 =CHCH2Sn(nBu)3 (45, 1.5 equiv), À78 to À208C, 5 d, 87%; b) TBAF
(2.0 equiv), THF, 258C, 2 h, 83%; c) TBSCl (2.5 equiv), imid. (5.0 equiv), CH2Cl2,
258C, 15 h, 87%; d) O3, NaHCO3, CH2Cl2, À788C; then PPh3 (2.0 equiv), 258C,
3 h, 97%; e) BrPh3P(CH2)2Me (2.0 equiv), NaHMDS (2.0 equiv), THF, À78 to
258C, 2 h, 87%; f) py·HBr3 (0.1 equiv), MeOH, À108C, 1.25 h, 63%; g) DMP
(1.3 equiv), CH2Cl2, 0 to 258C, 2 h, 99%. BINOL=1,1’-binaphthol; py=pyri-
dine.
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4 Š MS were used directly, consistent yields and enantioselec-
tivities could be obtained on gram-scale.
the b-siloxyaldehyde fragment 14 was then completed upon
PMB-deprotection of the olefin (DDQ, 90%) and subsequent
oxidation of the resulting primary alcohol (50, DMP, 99%).
The above second- and third-generation approaches to alde-
hyde 14 greatly improved the scalability of this key building
block by avoiding the use of sensitive intermediates or expen-
sive catalyst precursors. As a demonstration of the efficiency of
our synthesis, we note that 25 grams of alcohol 50 (Scheme 5,
the direct precursor of aldehyde 14) could be prepared in
a single batch from commercially available l-aspartic acid (52)
following this third-generation synthetic route (Scheme 5).
Deprotection of the TBDPS group in 43 (TBAF, 83%,
Scheme 4) and protection of the resulting diol (TBSCl, imid.,
87%) afforded bis-TBS ether 46, whose ozonolysis (O3; PPh3,
97%)[40] and Wittig olefination [BrPh3P(CH2)2-Me, NaHMDS,
87%] gave (Z)-alkene 49 as the major geometrical isomer
[(Z):(E) ca. 8:1]. Selective desilylation of 49 was carried out with
catalytic amounts of py·HBr3 in MeOH.[41] Although the yield of
primary alcohol 50 was moderate (63%) and attempts to im-
prove the selectivity by using a bulkier alcohol nucleophile
(e.g., iPrOH)[42] were unsuccessful, the over-desilylated diol by-
product (not shown) could be recycled by converting it back
to bis-TBS ether 49. Finally, oxidation of alcohol 50 with DMP
provided the b-siloxyaldehyde fragment 14 in excellent yield
(99%).
Improved syntheses of cyclopentenone fragment 13
Concurrent with the above efforts, we were also searching for
alternative syntheses of the cyclopentenone fragment 13
(Figure 4), with the ultimate goal of devising a short, enantio-
selective and readily scalable synthesis of this 4-alkyl-substitut-
ed 2-cyclopentenone, a commonly found structural motif in
natural and designed molecules of biological and medical im-
portance.[13,45–47] Furthermore, such molecules often serve as
building blocks or intermediates in the construction of target
molecules.[48,49] Not surprisingly, enantioselective synthesis of 4-
substituted 2-cyclopentenones has been the subject of numer-
ous studies, with notable successes achieved through enzy-
matic resolution,[50] Pauson–Khand reaction,[51] Nazarov cycliza-
tion,[52] and asymmetric Tsuji–Trost allylation as utilized in our
original synthesis of this fragment (see Scheme 1).
One shortcoming of the above strategy was the use of the
toxic stannane reagent 45 (Scheme 4). To circumvent this prob-
lem, we turned our focus to a chiral-pool-based strategy. Spe-
cifically, we postulated that the known terminal epoxide 51,[43]
available in three steps from l-aspartic acid (52), could serve as
a suitable precursor to aldehyde 14 as shown in retrosynthetic
format in Figure 7. Scheme 5 summarizes the preparation of al-
dehyde fragment 14 starting from l-aspartic acid (52).
BF3·Et2O-mediated epoxide opening of 51 with the lithium ace-
tylide derived from 1-butyne and n-butyllithium provided, after
silylation of the newly generated homopropargylic alcohol 53,
internal alkyne 54 (80% over the two steps). Hydrogenation of
the latter with Lindlar catalyst gave small amounts of the un-
desired (E)-isomer [(Z):(E) ca. 20:1]. On the other hand, P-2
nickel boride, generated from Ni(OAc)2·4H2O, NaBH4 and 1,2-
ethylenediamine,[44] gave the desired (Z)-alkene in high yield
(93%) and higher (Z):(E) selectivity (ca. 30:1). The synthesis of
The basic concept of our second-generation strategy toward
cyclopentenone fragment 13, or more specifically to its viable
precursor 21 is shown retrosynthetically in Figure 8. Thus, it
was envisioned that 21 could be formed from bridged lactone
57 whose origin was traced to bicyclic ketone 56 via a Baeyer–
Villiger reaction. The inspiration and confidence in this plan
came from Corey’s landmark synthesis of PGF2a (61, Figure 8b),
in which substituted bicyclic ketone 59 was converted to lac-
tone 60 with m-CPBA in high yield, and thence to PGF2a as in-
dicated in Figure 8b.[53] This seemingly straightforward route
(Figure 8a) suffered in reality from a severe flaw (vide infra),
which was, interestingly but perhaps fortunately in retrospect,
overlooked before attempting its laboratory execu-
tion.
Figure 7. Third-generation retrosynthetic analysis of aldehyde fragment 14.
Bicyclic ketone 56 was prepared following a modi-
fied literature procedure as shown in Scheme 6a.[54]
Thus, enantioselective hydrosilylation of norborna-
diene (62) with HSiCl3 in the presence of catalytic
amounts of [(h3-C3H5)PdCl]2 and (S)-MOP afforded
a crude silane 62a, which was subjected to a sequen-
tial Tamao–Fleming reaction (KF, H2O2, 50% from 62)
and Swern oxidation [(COCl)2, DMSO, 90%] to give
ketone 56 in enantioenriched form.[54,55] We note that
the hydrosilylation step was amenable to large-scale
Scheme 5. Third-generation synthesis of aldehyde fragment 14 from l-aspartic acid (55).
Reagents and conditions: a) 1-butyne (2.0 equiv), nBuLi (1.5 equiv); then 51 (1.0 equiv),
BF3·Et2O (1.4 equiv), THF, À788C, 2 h, 85%; b) TBSCl (1.5 equiv), imid. (3.0 equiv), CH2Cl2, 0
to 258C, 4 h, 94%; c) Ni(OAc)2·4H2O (0.16 equiv), NaBH4 (0.38 equiv), 1,2-ethylenediamine
(1.8 equiv), H2, EtOH, 258C, 6 h, 93%; d) DDQ (1.5 equiv), CH2Cl2/pH 7 buffer (20:1), 08C,
12 h, 90%; e) DMP (1.5 equiv), CH2Cl2, 0 to 258C, 2 h, 99%.
reactions due to the exceedingly low catalyst loading
(0.05 mol%) and solvent-free conditions. Exposure of
ketone 56 to several standard Baeyer–Villiger oxida-
tion conditions (e.g., m-CPBA, H2O2/NaOH) resulted in
the predominant formation of rearranged lactone 58,
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to 58 under both acidic and basic reaction conditions, owing
to its inherent strain and the allylic nature of the carboxylate
functionality.[56] This behavior largely explains the obscurity of
lactone 57 as a useful chiral synthon, despite its initial identifi-
cation as early as 1958.[56a]
Although dismayed by this finding, we were tempted by the
conciseness of the proposed synthesis of fragment 13
(Figure 8) and decided to address this problem. However, none
of the common tactics, including buffering the acidic condi-
tions (e.g., m-CPBA/NaHCO3), reducing the strength of base
(e.g., H2O2 with NaHCO3 or Na2HPO4 instead of NaOH) or
changing of peroxide reagent (e.g., tBuOOH) proved effective.
Eventually, we were delighted to discover that Ph3COOLi (gen-
erated in situ from Ph3COOH and nBuLi at À788C,
Scheme 6a)[57] was exceptionally effective, furnishing the de-
sired lactone 57 with complete substrate conversion and mini-
mal isomerization (as judged by TLC monitoring of the reac-
tion mixture). While attempts to isolate this coveted intermedi-
ate (i.e., 57) failed, direct addition of NaOMe (as MeOH solu-
tion) to the reaction mixture followed by warming to 08C pro-
vided the ring-opened methyl ester 21 in 82% yield. Following
our previously developed sequence (see Scheme 1), reduction
of ester 21 to the corresponding aldehyde (63) (DIBAL-H, 95%)
followed by Wittig olefination [IPh3P(CH2)5OPMB, NaHMDS] and
oxidation (PCC, 73% for the two steps) completed the synthe-
sis of enone 13 in six total steps (cf. nine steps for the original
route, Scheme 1). Interestingly, attempted direct reduction of
the crude lactone 57 to aldehyde 63 with several Al-based re-
agents (e.g., DIBAL-H, Red-Al, iBu2AlH·KOtBu[58]) invariably led
to a mixture of 63 and diol 67,[59] even with only one equiva-
lent of the reducing agent (see Scheme 6b). We hypothesize
that the strained nature of the expected “tetrahedral inter-
mediate” (64, Scheme 6b) caused it to break down to alde-
hyde 65 even at the low temperature of the reaction. The
latter was then further reduced under the reaction conditions
to afford diol 67 after aqueous work-up. In accord with this hy-
Figure 8. Second-generation retrosynthetic analysis of cyclopentenone frag-
ment 13.
1
pothesis, the H NMR spectrum of aldehyde 63 showed no de-
tectable signals of the corresponding bridged hemiacetal 68
(the speculative hydrolysis product of intermediate 64,
Scheme 6b), indicating the predominant existence of the
open-chain tautomer of this species.
Aiming for further improvement, and in search of an alterna-
tive mode of attachment of the top side-chain, and in order to
further shorten the synthetic route toward cyclopentenone
fragment 13, we opted for the Stork–Danheiser enone synthe-
sis[60] (Figure 9), with the hope that a suitable chiral auxiliary
Scheme 6. Second-generation synthesis of cyclopentenone fragment 13 via
Baeyer–Villiger oxidation. Reagents and conditions: a) HSiCl3 (0.99 equiv),
[(h3-C3H5)PdCl]2 (0.0005 equiv), (S)-MOP (0.002 equiv), neat, À10 to 08C, 24 h;
then KF (6.0 equiv), KHCO3 (9.0 equiv), H2O2 (35% aq., 6.2 equiv), THF/MeOH
(1:1), 258C, 12 h, 50%; b) (COCl)2 (1.3 equiv), DMSO (1.4 equiv), CH2Cl2,
À788C, 30 min; then Et3N (2.8 equiv), À78 to 258C, 2 h, 90%; c) Ph3COOH
(1.3 equiv), nBuLi (1.2 equiv), À788C, 6 h; then NaOMe (2.0 equiv), 08C, 4 h,
82%; d) DIBAL-H (2.2 equiv), CH2Cl2, À788C, 45 min, 95%;
e) IPh3P(CH2)5OPMB (26, 2.5 equiv), NaHMDS (3.0 equiv), THF, À78 to 258C,
18 h; f) PCC (2.0 equiv), CH2Cl2, 258C, 3 h, 73% for the two steps. DMSO=di-
methyl sulfoxide; MOP=2-(diphenylphosphino)-2’-methoxy-1,1’-binaphthol.
along with small amounts of the desired product 57
(Scheme 6a) and the corresponding ring-opened hydroxyl car-
boxylic acids (not shown). Literature survey revealed numerous
reports on the notorious proclivity of lactone 57 to isomerize
Figure 9. Third-generation retrosynthetic analysis of cyclopentenone frag-
ment 13.
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(e.g., l-menthol) incorporated into the vinylogous ester 69
would exert a degree of stereoinduction on the enolate alkyla-
tion at C8 (PGJ numbering) with allylic bromide 70. Should the
diastereoselectivity be moderate, the two diastereomeric alky-
lation products were expected to be separable by chromatog-
raphy, and the undesired diastereomer potentially could be
isomerized under basic conditions. If successful, this route
toward enone 13 would only include three steps from com-
mercially available 1,3-cyclopentanedione (71), namely auxiliary
incorporation, diastereoselective alkylation, and vinylogous
ester reduction (see Figure 9).
DMI (as an eco-friendly surrogate for HMPA), followed by addi-
tion of allylic bromide 73 furnished a mixture of C8-epimers
75 and 76, with the major product being the desired diaste-
reomer 76 (75:76 ca. 1:2.2, Scheme 7b). As expected, the two
diastereomers could be readily separated by flash column
chromatography, and the undesired isomer 75 could be par-
tially epimerized by exposure to KOtBu/tBuOH[62a] (75:76 ca.
1:1). This sequence was successfully carried out on a relatively
large scale providing over ten grams of vinylogous ester 76
(69% combined yield from 74). The menthol auxiliary was then
reductively cleaved from 76 with DIBAL-H to afford enone 13
(76%) via the intermediacy of aluminum complex 77
(Scheme 7b). It should be noted that among the several chiral
substrates we screened [i.e., those derived from (À)-menthol
(74), (À)-8-phenylmenthol (74a), (+)-fenchol (74b), (+)-bor-
neol (74c) and (+)-isopinocampheol (74d), see Table 2], (À)-8-
phenylmenthol and (+)-fenchol (entries 2 and 3, Table 2, re-
spectively) gave comparable results. However, (À)-menthol
was preferred due to its lower cost.
Execution of this plan began with the preparation of allylic
bromide 70 as outlined in Scheme 7a. Thus, (Z)-selective par-
tial hydrogenation of the internal alkyne in 72[61] proceeded
smoothly with 1,2-ethylenediamine-modified nickel boride[44]
and H2 (1 atm) in the absence of light to generate allylic alco-
hol 73 (92%), which was then converted to the desired allylic
bromide 70 (CBr4, PPh3, 88%). On the other hand, installation
of the l-(À)-menthol auxiliary, which had been successfully ap-
plied in related transformations,[62] was achieved by acid-cata-
lyzed formation of vinylogous ester 74[62b] (Scheme 7b), setting
the stage for the diastereoselective alkylation. In the event, re-
gioselective deprotonation of 74 with LDA in the presence of
Table 2. Optimization of diastereoselective alkylation of cyclopentenone-
s.[a]
Entry
1
Substrate
Yield [%][b]
d.r.
79
69:31[c]
2
3
79
87
69:31[c]
65:35[c]
4
5
50
57
54:46[c]
59:41[c]
[a] Reactions were carried out on 1.0 mmol scale at 258C. Reagents and
conditions: LDA (1.15 equiv), DMI (1.2 equiv), THF, À788C; then 70
(1.3 equiv), À408C, 8 h. [b] Yields refer to chromatographically isolated
and spectroscopically pure products. [c] relative stereochemistry d.r.
Scheme 7. Third-generation synthesis of cyclopentenone fragment 13 via
diastereoselective alkylation. Reagents and conditions: a) Ni(OAc)2·4H2O
(0.16 equiv), NaBH4 (0.38 equiv), 1,2-ethylenediamine (1.8 equiv), H2, EtOH,
258C, 6 h, 92%; b) CBr4 (1.6 equiv), PPh3 (1.6 equiv), MeCN, À108C, 30 min,
88%; c) p-TSA·H2O (0.1 equiv), L-(À)-menthol (1.2 equiv), C6H6, 808C, 8 h,
81%; d) LDA (1.10 equiv), DMI (1.2 equiv), THF, À788C, 45 min; then 70
(1.2 equiv), À408C, 8 h (75:76 ca. 1:2.2); then chromatographic separation;
e) KOtBu (0.5 equiv), tBuOH (0.6 equiv), THF, 08C, 2 h (75:76 ca. 1:1); then
chromatographic separation, 69% combined yield of 76 for the two steps;
f) DIBAL-H (1.5 equiv), Et2O, 08C, 30 min, 76%. p-TSA=para-toluenesulfonic
acid.
Streamlined synthesis of D12-PGJ3 (1)
With the syntheses of both key fragments 13 and 14 opti-
mized, their union and subsequent conversion to D12-PGJ3 (1)
could follow the previously developed sequence (see
Scheme 3a). However, careful inspection of the final stage of
the original synthesis revealed further room for improvement.
Specifically, the PMB-protected C1 primary alcohol 39 (see
Scheme 3a) was transformed to the natural product (i.e., 1)
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through four steps, namely PMB-deprotection, oxidation to the
aldehyde, subsequent oxidation to the carboxylic acid, and
eventual TBS-removal with aqueous HF. We reasoned that if
the C1 tert-butyl ester counterpart of 39 (i.e., 86, Scheme 8b)
could be prepared, subjection of this intermediate to the
action of suitable acidic conditions should cleave both the TBS
group and the tert-butyl ester, thereby shortening the entire
synthesis by three steps.
asymmetric alkynylation conditions,[65] this protocol for hydrox-
ymethylation of terminal alkynes avoids the use of nBuLi, pro-
ceeding instead via the corresponding alkynylzinc triflate. Par-
tial hydrogenation of the alkyne moiety in 80 [H2, Ni(OAc)2
·4H2O, NaBH4, 1,2-ethylenediamine, 89%][44] and conversion of
the resulting primary alcohol 81 to allylic bromide 78 (CBr4,
PPh3, 90%) followed previously developed conditions as de-
scribed in Scheme 7a for the preparation of its C1-OPMB coun-
terpart (i.e., 70).
As outlined in Scheme 8b, alkylation of vinylogous ester 74
(prepared according to Scheme 7b) with allylic bromide 78
gave a mixture of separable diastereomers 82 and 83 (82:83
ca. 1:2). The minor, undesired diastereomer 82 was subjected
to KOtBu/tBuOH epimerization to obtain an equal mixture of
82 and 83, thereby providing 83 in 62% combined yield from
74. Reduction of vinylogous ester 83 with DIBAL-H at 08C was
initially troublesome due to concomitant reduction of the tert-
butyl ester moiety. However, good yield of enone 84 (74%)
was restored by lowering the reaction temperature to À408C.
Switching the reducing agent to LiAlH4 further improved the
yield of this reduction to 83%. This optimized sequence al-
lowed the preparation of enone 84 on gram scale, setting the
stage for its union with the aldehyde fragment 14.
To implement this strategy, we began by targeting allylic
bromide 78 (Scheme 8a) bearing a tert-butyl ester group at
C1. Starting from the readily available terminal alkyne 79[63]
(Scheme 8a), the synthesis of propargylic alcohol 80 was ac-
complished by using the conditions developed by Hale et al.
[Zn(OTf)2, TMEDA, (CH2O)n, 80%].[64] Adapted from Carreira’s
As it turned out, the presence of the ester moiety in 84 de-
manded a reevaluation of the aldol reaction, as the originally
employed conditions (addition of enone 84 to LDA, followed
by addition of aldehyde 14) provided a significant amount of
bis-aldol product as a result of deprotonation at the a-posi-
tions of both the ketone and the ester moieties, respectively.
On the other hand, when LDA was added dropwise to a solu-
tion of 84 at À788C, the resulting enolate was trapped by the
remaining enone itself before the addition of aldehyde 14. We
reasoned that such enone dimerization process could be inhib-
ited by addition of LDA to a pre-mixed solution of 84 and 14
at À788C. In practice, this protocol successfully delivered the
coveted aldol product 85 with markedly improved efficiency,
despite the potential competing deprotonation of the a-H of
the aldehyde (14). This remarkable chemoselectivity (selective
enolate generation from a ketone in the presence of an alde-
hyde) may be attributed in part to the bulky b-siloxy group of
the aldehyde fragment, which blocked access of LDA to the a-
H. Proceeding with the streamlined synthesis, it was discov-
ered that the original, two-step protocol for elimination (MsCl,
Et3N; Al2O3) could now be accomplished in one step by treat-
ing aldol product 85 with MsCl in the presence of excess
DMAP, providing the cross-conjugated dienone 86 in 43%
yield (49% based on recovered enone 84). Finally, we were
pleased to find that both the tert-butyl and the TBS groups
were readily cleaved under the influence of 48% aqueous HBF4
(92%), thus completing the total synthesis of D12-PGJ3 (1) in six
steps from commercially available 1,3-cyclopentanedione (74)
(cf. 16 steps for the first-generation synthesis).
Scheme 8. Streamlined synthesis of D12-PGJ3 (1). Reagents and conditions:
a) Zn(OTf)2 (1.9 equiv), TMEDA (2.0 equiv), Et3N (2.0 equiv), (CH2O)n
(5.0 equiv), toluene, 258C, 48 h, 80%; b) Ni(OAc)2·4H2O (0.16 equiv), NaBH4
(0.38 equiv), 1,2-ethylenediamine (1.8 equiv), H2, EtOH, 258C, 8 h, 89%,
(Z):(E)=50:1; c) CBr4 (1.5 equiv), PPh3 (1.5 equiv), MeCN, 08C, 30 min, 90%;
d) LDA (1.10 equiv), THF, À788C; then 74 (1.0 equiv), À788C, 45 min; then
78 (1.2 equiv), DMI (1.2 equiv), À78 to 08C, 6 h (82:83 ca. 1:2); then chroma-
tographic separation; e) KOtBu (0.5 equiv), tBuOH (0.6 equiv), THF, 08C,
45 min (82:83 ca. 1:1); then chromatographic separation, 62% combined
yield of 83 for the two steps; f) DIBAL-H (2.0 equiv), Et2O, À408C, 1 h, 74%;
or LiAlH4 (0.6 equiv), THF, À408C, 1 h, 83%; g) 84 (1.0 equiv), 14 (1.3 equiv),
premixing, THF, À788C; then LDA [2.0 equiv (dropwise over 1 h)], À788C;
then À788C, 30 min; h) MsCl (3.0 equiv), DMAP (15 equiv), CH2Cl2, À10 to
258C, 12 h, 43% for the two steps (49% based on recovered 84); i) HBF4
(48% aq., 25 equiv), solvent, 08C, 30 min, 92%. TMEDA=N,N,N’,N’-tetrame-
thylethylenediamine.
Conclusion
The total synthesis of D12-PGJ3 (1) was accomplished through
a number of different synthetic routes that evolved from our
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original strategy of 16 steps to a streamlined process consist-
ing of only six steps from commercially available starting mate-
rials. Highlights of the described work include a catalytic asym-
metric Tsuji–Trost coupling reaction, a catalytic asymmetric Mu-
kaiyama aldol reaction, a Rh-catalyzed CÀH functionalization,
preparation and utilization of the chiral version of a bicyclic
lactone building block for the synthesis of substituted cyclo-
pentenones, and a diastereoselective alkylation of cyclopente-
nones carrying chiral menthol-type auxiliaries. The developed
synthetic routes are suited for the synthesis of a wide range of
analogues of D12-PGJ3 (1) and related compounds, as well as
large scale preparation of D12-PGJ3. Applications of these syn-
thetic strategies and technologies to the synthesis of designed
analogues of this class of compounds as potential anticancer
agents are described in reference [66].
Experimental Section
For full experimental procedures and physical properties of com-
pounds see Supporting Information (S1–S127).
Acknowledgements
[19] O. Jacquet, T. Bergholz, C. Magnier-Bouvier, M. Mellah, R. Guillot, J.-C.
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We thank Drs. Lawrence B. Alemany and Quinn Kleerekoper for
NMR-spectroscopic assistance and Drs. Christopher L. Penning-
ton and Ian Riddington (University of Texas at Austin) for mass-
spectrometric assistance. This work was supported by the Na-
tional Institutes of Health (USA) (grant AI055475), the Cancer
Prevention & Research Institute of Texas (CPRIT) (USA), and The
Welch Foundation (USA) (grant C-1819).
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Keywords: antitumor agent · asymmetric catalysis · chiral
auxiliary · prostaglandin · total synthesis
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Received: March 28, 2016
Published online on May 17, 2016
Chem. Eur. J. 2016, 22, 8559 – 8570
www.chemeurj.org
8570
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim