Total Syntheses of Aromatic Abietane Diterpenoids Utilizing Advances in the Pummerer Rearrangement

Article abstract of DOI:10.1021/acs.orglett.8b02060

The first total syntheses of triptobenzene T, vitexifolin C, 4-epi-triptobenzene L, triptobenzene L, and nepetaefolin F have been accomplished through an enantioselective, common intermediate approach and have enabled the confirmation and/or establishment of the absolute stereochemistry of each natural product synthesized. Application of three new and/or underutilized Pummerer reaction pathways proved critical to the synthetic work. A proline sulfonamide-catalyzed Yamada-Otani reaction was used to access the highly functionalized cyclohexane A ring core, including the C₁₀ all-carbon quaternary stereocenter. Additionally, the importance of the A ring unsaturation for controlling the stereoselectivity during the C₄ alkylation is showcased.

Full text of DOI:10.1021/acs.orglett.8b02060

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Total Syntheses of Aromatic Abietane Diterpenoids Utilizing
Advances in the Pummerer Rearrangement
Xin Li and Rich G. Carter*
Department of Chemistry, Oregon State University, Corvallis, Oregon 97331, United States
S
* Supporting Information
ABSTRACT: The first total syntheses of triptobenzene T, vitexifolin C, 4-
epi-triptobenzene L, triptobenzene L, and nepetaefolin F have been
accomplished through an enantioselective, common intermediate approach
and have enabled the confirmation and/or establishment of the absolute
stereochemistry of each natural product synthesized. Application of three new
and/or underutilized Pummerer reaction pathways proved critical to the
synthetic work. A proline sulfonamide-catalyzed Yamada−Otani reaction was
used to access the highly functionalized cyclohexane A ring core, including the
C
10 all-carbon quaternary stereocenter. Additionally, the importance of the A
ring unsaturation for controlling the stereoselectivity during the C4 alkylation is showcased.
he abietane diterpenoid family of natural products
represents a sizable collection of compounds that possess
Scheme 1. Retrosynthetic Analysis
T
both an interesting tricyclic core and intriguing biological
activity (Figure 1).1,2 Despite this appealing combination of
Figure 1. Abietane-type diterpenoid natural products.
incorporation of more functionality in both the A and B rings. In
turn, this sulfoxide 9 could be readily accessed through our
enantioselective proline sulfonamide-catalyzed Yamada−Otani
reaction4 from the benzylic aldehyde 10 and the enone 11.
Our successful construction of the common intermediate 9
and its utilization in divergent Pummerer cyclization pathways is
showcased in Scheme 2. Starting from aldehyde 10 (two steps
from 4-isopropylacetophenone), proline sulfonamide-catalyzed
Yamada−Otani reaction with known enone 118 using our
improved DMSO conditions8 gave the desired sulfide 13 in high
diastereo- and enantioselectivity. The stereoselectivity of this
process could be further enhanced from a single recrystallization
to >20:1 dr and >99:1 er. Subsequent oxidation using H2O2 with
1,1,1,3,3,3-hexafluoroisopropanol (HFIP)9 smoothly provided
the Pummerer cyclization precursor 9. In accord with our
attributes, significant cross sections of the family have not been
previously synthesized.3 We became intrigued by the possibility
of utilizing our proline sulfonamide-catalyzed Yamada−Otani
chemistry4 to provide rapid access to the core carbon backbone,
including the challenging all-carbon quaternary stereocenter at
C10. Herein, we describe the first total syntheses of five separate
members of this natural product family through the efficient use
of an enantioenriched common intermediate.
Our overarching synthetic approach is outlined in Scheme 1.
The pioneering work using the polyene cyclization5 to access the
abietane diterpenoids6 laid an important foundation for how to
construct these ring systems. While powerful, these approaches
do limit the wealth of functionality that can be built into the
cyclization precursor(s). In contrast, we envisioned exploiting
our recently discovered advances in the Pummerer cyclization7
of a prerequisite sulfoxide 9 to access the tricyclic cyclo-
hexenones 7 or 8. This approach allows for the early and efficient
Received: July 1, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02060
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Synthesis of Key Intermediates via Pummerer
Cyclizations
Scheme 3. Total Synthesis of 3α,7β-Dihydroxyabieta-
8,11,13-triene (ent-Triptobenzene T)
trifluoroacetate ester 20 derivative as an intermediate through
in situ analysis (1H NMR, 19F NMR) of the reaction prior to
NaOH (aq) treatment as well as through HRMS. This reaction
likely proceeds through formation of a benzylic carbocation after
acylation of the sulfoxide by TFAA, which is in turn trapped by
the trifluoroacetate counterion. Compound 1 was in agreement
(1H NMR, 13C NMR, [α]D) with the literature values10,12 for the
ent-triptobenzene T (1). This synthesis enabled the definitive
assignment of the absolute configuration of this natural product
where some confusion previously existed.13
Our next synthetic target was vitexifolin C (Scheme 4).
Starting from tricycle 8, enolization and formylation at C4
generated the desired aldol product in excellent dr (>20:1).
Subsequent silylation with TIPSOTf generated the silyl ether
21. Standard hydrogenation of both alkenes produced the
methodological work,7 Pummerer cyclization under short initial
reaction time (30 min) proceeded through our novel acyl
oxonium ion pathway (compound 16) to yield the eliminated
tricycle 8 in 54% yield. In contrast, the tricyclic sulfide can be
accessed via the vinyl sulfide pathway (compound 15) in high
yield (81%) through extended initial reaction time prior to
addition of the BF3·Et2O.7
Scheme 4. Total Synthesis of Vitexifolin C
With rapid routes established for accessing the prefunction-
alized tricyclic core, our efforts shifted to the synthesis of the
abietane diterpenoid natural products. Our first target was
triptobenzene T10 (1) (Scheme 3). Dimethylation of the
tricyclic enone 7 provided the adduct 17. Selective hydro-
genation of the enone alkene in the presence of the benzylic
sulfide was smoothly accomplished with Pd/C and H2 in
methanol. Subsequent reduction produced the alcohol 18 as a
single observed stereoisomer. Sulfide oxidation using H2O2/
HFIP oxidation9 cleanly provided the sulfoxide 19 as a mixture
of stereoisomers on sulfur. While we had planned to conduct a
traditional Pummerer rearrangement of sulfoxide 19, we were
pleased to find that a nonoxidative-type Pummerer rearrange-
ment11 had, in fact, occurred to provide the ent-triptobenzene T
(1) directly in 2.6:1 dr favoring the desired stereochemistry
(62% isolated yield of the pure diastereomer). To our
knowledge, this is the first example of nonoxidative-type
Pummerer rearrangement that has occurred without neighbor-
ing group participation. We have observed the key bis-
B
DOI: 10.1021/acs.orglett.8b02060
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
saturated ketone 22. Stereoselective addition of MeMgBr to the
C3 ketone provided the desired isomer in 9:1 dr. The selectivity
in this process was likely governed by the steric bulk of the
neighboring and nonchelating CH2OTIPS moiety. Removal of
the silyl ether produced the diol 23. Finally, Grieco−Nishizawa
elimination provided vitexifolin C (2) in good yield and
excellent agreement with the isolation data14 (1H NMR, 13C
NMR, [α]D).
Scheme 6. Total Syntheses of Triptobenzene L and
Nepetaefolin F
We next set out to access C19-oxygenated triptobenzene L and
nepetaefolin F from the same eliminated tricycle 8 (Scheme 5).
Scheme 5. Total Synthesis of 4-epi-Triptobenzene L
alcohol with concomitant removal of the C7 sulfide. Finally,
DIBAL-H reduction of the ester 29 produced triptobenzene L
(4). Selective acylation of 4 completed a protecting-group free
total synthesis nepetaefolin F (5). In both cases, synthetic 4 and
5 were in excellent agreement (1H NMR, 13C NMR, [α]D) with
the literature values19,20 for the isolated natural products.
The unexpected selectivity in the C4 alkylation of compounds
27 and 30 is worthy of further comment (Figure 2). We
hypothesized that further flattening of the A ring (32 and 33)
should maximize the steric hindrance on the top face (due to the
Use of Mander’s reagent cleanly incorporated the methyl ester
moiety as the equatorial isomer 24, likely through an
epimerization process due to the acidity of the C4 methine
proton. We were concerned about the stereoselectivity in the
subsequent alkylation of 24 based on the literature examples of
related structures which showed a strong preference for the β-
epimer of the methyl moiety, particularly for a C1,2-unsaturated
enone ester system.15 Based on work by Mander and
Deslongchamps,16 we hypothesized that removal of the
unsaturation might reduce the preference for the β-epimer in
this transformation. Unfortunately, the alkylation of this
hydrogenated β-ketoester 25 provided the undesired stereo-
chemistry (2.3:1 dr) at C4, in alignment with prior reports on
related scaffolds.16 We attribute this modest stereoselectivity to
the conflicting preferences between stereoelectronic factors of
half-chair alkylations17 and the C10 methyl moiety. Subsequent
conversion further confirmed this assignment as natural product
4-epi-triptobenzene L (3) based on comparison with the
literature values.18
The completion of the total syntheses of both triptobenzene L
and nepetaefolin F is shown in Scheme 6. As noted in Scheme 5,
alkylation of saturated β-ketoester 25 with methyl iodide
provided poor selectivity. Interestingly, alkylation of enone ester
27 using KOtBu and MeI smoothly gave the desired α
stereoselectivity (>20:1 dr) in excellent yield. Similarly,
methylation of the TBS-enol ether 30 (derived from β-ketoester
25) also exclusively provided the desired stereoisomer 31 (eq 1).
These results are in stark contrast to the work by Wenkert and
co-workers on a similar tricyclic system.15 Next, stereoselective
reduction of enone 28 using NiCl2/NaBH4 produced the C3
Figure 2. Possible explanation for stereoselective in alkylations.
C
DOI: 10.1021/acs.orglett.8b02060
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(5) (a) Stork, G.; Burgstahler, A. W. J. Am. Chem. Soc. 1955, 77, 5068−
5077. (b) Eschenmoser, A.; Arigoni, D. Helv. Chim. Acta 2005, 88,
3011−3050. (c) Yoder, R. A.; Johnston, J. N. Chem. Rev. 2005, 105,
4730−4756.
C10 methyl and the C6 methylene moieties) while diminishing
the stereoelectronic factors (half chair product vs chair product)
that guide enolate alkylations in more conformationally flexible
six-membered rings (e.g., substituted cyclohexanones).21 This
strategy should provide synthetic chemists with a valuable
method for accessing high levels of α facial selectivity in related
tricyclic systems.
In summary, the enantioselective total syntheses of multiple
abietane diterpenoids (specifically ent-triptobenzene T, vitex-
ifolin C, 4-epi-triptobenzene L, triptobenzene L, and nepetae-
folin F) have been accomplished using a unified, common
intermediate approach and have enabled the confirmation and/
or establishment of the absolute stereochemistry of each natural
product. In each case, these natural products had not been
previously prepared synthetically. Key to these syntheses was the
discovery of new insights for the Pummerer reactionincluding
the utilization of three separate mechanisms (vinyl sulfide,
acylated oxonium ion and nonoxidative pathways). Additionally,
the importance of A ring unsaturation for the stereoselective
alkylation16b,22 has been unearthed during the syntheses of
triptobenzene L (4) and nepetaefolin F (5). Our highly efficient
approaches open the door for biological evaluation of these
natural products as well as related analogues. Further application
of this work will be reported in due course.
(6) (a) Tada, M.; Nishiiri, S.; Yang, Z.; Imai, Y.; Tajima, S.; Okazaki,
N.; Kitano, Y.; Chiba, K. J. Chem. Soc., Perkin Trans. 1 2000, 2657−
2664. (b) Ishihara, K.; Ishibashi, H.; Yamamoto, H. J. Am. Chem. Soc.
2001, 123, 1505−1506. (c) Surendra, K.; Rajendar, G.; Corey, E. J. J.
Am. Chem. Soc. 2014, 136, 642−645. (d) Fan, L.; Han, C.; Li, X.; Yao, J.;
Wang, Z.; Yao, C.; Chen, W.; Wang, T.; Zhao, J. Angew. Chem., Int. Ed.
2018, 57, 2115−2119. (e) Tao, Z.; Robb, K. A.; Zhao, K.; Denmark, S.
E. J. Am. Chem. Soc. 2018, 140, 3569−3573.
(7) Li, X.; Carter, R. G. Org. Lett. 2018, DOI: 10.1021/
acs.orglett.8b02059.
(8) Goswami, S.; Harada, K.; El Mansy, M. F.; Lingampally, R.; Carter,
R. G. Angew. Chem., Int. Ed. 2018, 57, 9117−9121.
́
́
(9) Ravikumar, K. S.; Zhang, Y.-M.; Begue, J.-P.; Bonnet-Delpon, D.
Eur. J. Org. Chem. 1998, 1998, 2937−2940.
(10) 3α,7β-Dihydroxyabieta-8,11,13-triene (1) has not previously
been assigned a name; however, its structure is consistent with the
triptobenzene family of natural products. Consequently, we have
assigned the name ent-triptobenzene T to compound 1. Tanaka, C. M.
A.; Radke, V. S. C. O.; Silva, C. C. da; Nakamura, C. V.; de Oliveira, P.
L.; Kato, L.; de Oliveira, C. M. A. Quim. Nova 2010, 33, 30−32.
(11) Crucianelli, M.; Bravo, P.; Arnone, A.; Corradi, E.; Meille, S. V.;
Zanda, M. J. Org. Chem. 2000, 65, 2965−2971.
(12) Wang, L.-J.; Xiong, J.; Lau, C.; Pan, L.-L.; Hu, J.-F. J. Asian Nat.
Prod. Res. 2015, 17, 1220−1230.
ASSOCIATED CONTENT
* Supporting Information
■
(13) In the original isolation paper by de Oliveira and co-workers (ref
10) for natural 3α,7β-dihydroxyabieta-8,11,13-triene, the observed
optical rotation is below the level of quantification due to the low (c =
0.011) concentration ([α]D = +17, c = 0.011, MeOH). Subsequently,
Hu and co-workers (ref 12) reported a more concentrated sample of
natural 3α,7β-dihydroxyabieta-8, 11, 13-triene ([α]D = +7.0, c = 0.23,
MeOH). It is critical to note that Hu and co-workers draw the
enantiomeric configuration of the natural product to de Oliveira’s
originally proposed structure. Our synthesized material confirmed Hu’s
assignment of 3α,7β-dihydroxyabieta-8,11,13-triene is correct. Syn-
thetic 1 is consistent with the enantiomer of the natural product ([α]D =
−1.7, c = 0.41, MeOH). We attempted to make a more concentrated
sample of this synthetic material in methanol; however, a c = 0.41
appears to represent a saturated solution of 1. We also collected the
optical rotation of synthetic 1 in an alternate solvent with better
solubility properties ([α]D = −3.8, c = 0.82, CHCl3). Unfortunately,
neither ref 10 nor 12 reported the optical rotations in any solvent other
than MeOH. Furthermore, the absolute stereochemistry of synthetic 1
is independently consistent with both of the other synthesized natural
products in this manuscript and the known stereochemical model for
the Yamada−Otani reaction (ref 4).
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b02060.
Complete experimental details (PDF)
1H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: rich.carter@oregonstate.edu.
ORCID
Rich G. Carter: 0000-0002-9100-1791
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Prof. Claudia Maier (OSU) and Jeff Morre (OSU) are
■
́
(14) Ono, M.; Yanaka, T.; Yamamoto, M.; Ito, Y.; Nohara, T. J. Nat.
Prod. 2002, 65, 537−541.
acknowledged for mass spectra data. The authors are grateful
to Subir Goswami (OSU), Maxson Richards (OSU), and Dr.
Roger Hanselmann (Akebia Therapeutics) for their assistance
and helpful discussions. Financial support has been provided by
the National Science Foundation (CHE-1665246) and Oregon
State University.
(15) Wenkert, E.; Afonso, A.; Bredenberg, J. B. s.; Kaneko, C.; Tahara,
A. J. Am. Chem. Soc. 1964, 86, 2038−2043.
(16) (a) Germain, J.; Deslongchamps, P. J. Org. Chem. 2002, 67,
5269−5278. (b) Hutt, O. E.; Mander, L. N. J. Org. Chem. 2007, 72,
10130−10140.
(17) Caine, D. In Comprehensive Organic Synthesis; Trost, B., Ed.;
Pergamon Press: Oxford, UK, 1991; Vol. 3, p 1.
REFERENCES
■
(18) Lekphrom, R.; Kanokmedhakul, S.; Kanokmedhakul, K. Planta
Med. 2010, 76, 726−728.
(1) (a) Gonzalez, M. A. Eur. J. Med. Chem. 2014, 87, 834−842.
(b) Gonzalez, M. A. Nat. Prod. Rep. 2015, 32, 684−704. (c) Hanson, J.
R. Nat. Prod. Rep. 2013, 30, 1346−1356.
(19) Duan, H.; Takaishi, Y.; Momota, H.; Ohmoto, Y.; Taki, T.; Jia,
Y.; Li, D. J. Nat. Prod. 1999, 62, 1522−1525.
(2) San Feliciano, A.; Gordaliza, M.; Salinero, M. A.; del Corral, J. A.
Planta Med. 1993, 59, 485−490.
(20) Zhang, C. G.; Chou, G. X.; Mao, X. D.; Yang, Q. S.; Zhou, J. L. J.
Nat. Prod. 2017, 80, 1742−1749.
́
(3) Gonzalez, M. A. Tetrahedron 2015, 71, 1883−1908.
(21) (a) House, H. O.; Umen, M. J. J. Org. Chem. 1973, 38, 1000−
1003. (b) Kayser, R. H.; Brault, M.; Pollack, R. M.; Bantia, S.; Sadoff, S.
F. J. Org. Chem. 1983, 48, 4497−4502.
(4) (a) Yang, H.; Carter, R. G. Org. Lett. 2010, 12, 3108−3111.
(b) Yang, H.; Banerjee, S.; Carter, R. G. Org. Biomol. Chem. 2012, 10,
4851−4863. (c) Pierce, M.; Johnston, R. C.; Mahapatra, S.; Yang, H.;
Carter, R. G.; Cheong, P. H.-Y. J. Am. Chem. Soc. 2012, 134, 13624−
13631.
(22) Stork, G.; Schulenberg, J. W. J. Am. Chem. Soc. 1962, 84, 284−
292.
D
DOI: 10.1021/acs.orglett.8b02060
Org. Lett. XXXX, XXX, XXX−XXX