11-Step Total Synthesis of (-)-Maoecrystal v

Article abstract of DOI:10.1021/jacs.6b06623

An expedient, practical, and enantioselective route to the highly congested ent-kaurane diterpene maoecrystal V is presented. This route, which has been several years in the making, is loosely modeled after a key pinacol shift in the proposed biosynthesis. Only 11 steps, many of which are strategic in that they build key skeletal bonds and incorporate critical functionalities, are required to access (-)-maoecrystal V. Several unique and unexpected maneuvers are featured in this potentially scalable pathway. Reevaluation of the biological activity calls into question the initial exuberance surrounding this natural product.

Full text of DOI:10.1021/jacs.6b06623

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1
1-Step Total Synthesis of (−)-Maoecrystal V
§
§,†
Artiom Cernijenko, Rune Risgaard, and Phil S. Baran*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
S Supporting Information
*
ABSTRACT: An expedient, practical, and enantioselec-
tive route to the highly congested ent-kaurane diterpene
maoecrystal V is presented. This route, which has been
several years in the making, is loosely modeled after a key
pinacol shift in the proposed biosynthesis. Only 11 steps,
many of which are strategic in that they build key skeletal
bonds and incorporate critical functionalities, are required
to access (−)-maoecrystal V. Several unique and
unexpected maneuvers are featured in this potentially
scalable pathway. Reevaluation of the biological activity
calls into question the initial exuberance surrounding this
natural product.
he combination of striking structural features and exciting
T
bioactivity exhibited by the ent-kaurane diterpene maoe-
1
crystal V (1, Figure 1B) has attracted extensive interest within
2
−4
the organic community since 2004.
As the most structurally
complex member within this family of terpenes, it features a
densely interlocked array of ring systems nestled within adjacent
vicinal quaternary stereocenters (C-9/10, ent-kaurane number-
ing). The [2.2.2] bicyclic portion of the molecule is a clear signal
for the use of the Diels−Alder transform, and thus all successful
4
total syntheses to date have relied on this strategic maneuver
(Figure 1A). In striking contrast, the biosynthetic route to this
system is proposed to arise via an unusual pinacol-type shift of
5
cation 2 (Figure 1B). It was reasoned that a route to 1 loosely
patterned off of this theme might efficiently access the C-9
bridgehead quaternary center of the [2.2.2] bicycle and allow for
a convergent fragment assembly at the C-9/10 juncture. Here, an
11-step enantioselective route to 1 is described based on the
realization of this hypothesis. Using synthetic 1 it was also
revealed that despite the original report, maoecrystal V exhibits
virtually no cytotoxicity in any cancer cell line tested.
The key strategic disconnections made on 1 (Figure 1B)
involved: (1) removal of the unsaturation at C-2/3; (2) masking
of the C-15 ketone as an olefin to avoid epimerization at C-16;
Figure 1. A unique approach to maoecrystal V (1).
(
3) nitrile-assisted delivery of C-7; and (4) extrusion of
The synthesis of 1 commenced (Scheme 1) with a highly
enantioselective conjugate addition of an allyl silane to
cyclohexenone to deliver 7 in 80% isolated yield (99% ee).
Among the many ligands explored, the TADDOL-derived
phosphine-phosphite L1 designed by Schmalz was singularly
formaldehyde from C-10 to furnish 3. Whereas the first and
second tasks were anticipated to be straightforward, the
remaining were not. For example, there was no clear way to
predict the stereoselectivity of cyanide addition (or any other
small nucleophile) to C-8. In addition, the challenge of installing
the hydroxymethyl group onto a ketone such as 3 was even
reported to be insurmountable. A pinacol shift and olefin
isomerization of 4 traces back to two simple ketones (5 and 6).
The simplicity of this approach beckoned to be experimentally
probed despite the clear warning signs present at the outset.
6
successful. The use of CuI·0.75DMS was also critical to
7
minimize dimerization of the Grignard reagent. A profound
3a
solvent effect was also observed with a mixture of PhMe/MeTHF
Received: June 27, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/jacs.6b06623
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Scheme 1. Total Synthesis of (−)-Maoecrystal V (1)
a
Reagents and conditions: (1) CuI·0.75DMS (0.60 mol %), L1 (0.80 mol %), TMSCH C(MgBr)CH (2.5 equiv), PhMe/MeTHF, −78 °C (80%,
2
2
9
9% ee); (2) LiTMP (1.02 equiv), THF, −78 °C; then Davis oxaziridine (1.3 equiv), THF, DMPU, −78 °C; then Ac O (1.2 equiv), −78 to 0 °C
2
(
64%); (3) EtAlCl (2.0 equiv), PhMe, 0 °C (77%); (4) NaH (1.2 equiv), Bu NI (1.0 equiv), Me SO (3.0 equiv), DMF, 23 °C; then aq. LiOH (8.5
2 4 2 4
equiv), 23 °C; (5) Py·SO (3.5 equiv), Et N (8.5 equiv), DMSO, DCM, 0 to 23 °C (81%, 2 steps); (6) i-PrMgCl·LiCl (1.5 equiv), 6 (1.5 equiv),
3
3
PhMe, −78 to 0 °C; then aq. TsOH (6.5 equiv), 0 to 85 °C (45%); (7) NaHMDS (1.3 equiv), LaCl ·2LiCl (1.0 equiv), THF, DMPU, CH O (10
3
2
(g)
equiv), −45 °C (84%, 2:1 dr); (8) TFA (0.50 equiv), HC(OMe) , MeOH, 60 °C; then Zn(OTf) (2.0 equiv), LiBH (8.5 equiv), DCM, 23 °C
3
2
4
(
(
83%, 3:1 dr); (9) TsOH (5.0 mol %), H O (2.0 equiv), THF, 23 °C; then DNBCl (3.5 equiv), DMAP (0.20 equiv), Et N (5.0 equiv), 23 °C
2 3
86%); (10) MsOH (5 × 0.50 equiv), HC(OMe) , MeOH, 65 °C; then ZnI (0.30 equiv), TMSCN (5.0 equiv), 23 °C; then aq. LiOH (12 equiv);
3
2
then aq. HCl (20 equiv), 65 °C (82%); (11) DMDO (2 × 3.0 equiv), acetone, 23 °C; then InI (5.0 mol %), MgI (1.2 equiv), MeCN, 23 °C; then
3
2
DMP (3.0 equiv), 23 °C; then aq. Oxone (10 equiv), Bu NHSO (0.10 equiv), pH = 7.4 buffer, 23 °C (76%); DMS = dimethyl sulfide, MeTHF = 2-
4
4
methyltetrahydrofuran, LiTMP = lithium 2,2,6,6-tetramethylpiperidide, DMPU = N,N′-dimethylpropyleneurea, DMSO = dimethyl sulfoxide, DCM
dichloromethane, TsOH = p-toluenesulfonic acid, NaHMDS = sodium bis(trimethylsilyl)amide, TFA = trifluoroacetic acid, DNBCl = 3,5-
dinitrobenzoyl chloride, MsOH = methanesulfonic acid, DMDO = dimethyldioxirane, DMP = Dess−Martin periodinane.
=
being essential to obtain consistently high yield and
enantioselectivity on 20 g scale.
from poor regioselectivity. Gratifyingly, deprotonation of 7 with9
LiTMP followed by sequential treatment with Davis oxaziridine
The seemingly simple α-acetoxylation of ketone 7 turned out
to be remarkably difficult to execute in a scalable way. Rubottom
oxidation was unsuccessful due to competitive oxidation of
electron-rich allyl silane moiety. Oxidants such as MoOPH,
and Ac O in a mixture of THF/DMPU gave the desired α-
acetoxylated product 8 in 64% yield as an inconsequential
2
mixture of diastereomers (2:1) on a 30 g scale.
10
The ensuing Sakurai reaction initially suffered from extensive
protodesilylation, possibly due to the fact that such a cyclization
is disfavored by Baldwin rules, being analogous to a 5-enolendo-
Pb(OAc)4 and Mn(OAc) gave complex mixtures, while
3
8
Tomkinson’s reagent and similar enamine chemistry suffered
B
DOI: 10.1021/jacs.6b06623
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
11
exo-trig in terms of orbital alignment. However, in an extensive
precedent (freshly prepared Zn(BH ) showed no reactivity and
4
2
evaluation of >50 Lewis acids, EtAlCl was found to be singularly
successful, providing the desired [3.2.1] bicycle 9 in 77% yield. It
the Zn salt must be added before the borohydride). Of the >100
reducing conditions brought to bear on this step, this was the
only one capable of providing the desired diastereomer as the
major product (for a more extensive list, see SI).
2
is worth noting that in addition to the use of EtAlCl , the α-
2
acetoxy group was essential as silyl or benzyl ethers and the free
alcohol all failed to react productively. Methylation with Me SO4
The final carbon atom was appended onto C-8 of 13 in a
relatively straightforward fashion. Thus, rupture of the ketal and
concomitant masking of the primary alcohol with a 3,5-
dinitrobenzoyl (DNB) group delivered 14 in 86% yield (steps
7−9 were all carried out on a gram-scale). It was essential to
transform 13 to 14 without isolation of any intermediates, as the
free alcohol equilibrates to a mixture of hemiketals that are
difficult to manipulate. The DNB group was fortuitously chosen
in order to render intermediates crystalline for stereochemical
assignment but was later realized to be essential (use of a Bz ester
was unsuccessful). Formation of the strained THF ring of 1 could
2
and in situ hydrolysis, followed by Parikh−Doering oxidation
afforded ketone 5 in 81% over 2 steps (>7 g were prepared in a
single pass).
12
With ample quantities of 5 and 6 in hand, the stage was set to
investigate the key 1,2-addition/pinacol rearrangement. Initially,
attempts to add organometallic species generated from protected
versions of 6 (such as ketal or silyl enol ether) resulted in no
observed addition to ketone 5, presumably due to steric
hindrance. Interestingly, it was found that treating unprotected
1
3
6
with i-PrMgCl·LiCl in PhMe resulted in Mg/I exchange and
the obtained Grignard reagent added smoothly to ketone 5 to
be accomplished using a 6:1 ratio of CH(OMe) :MeOH with
3
14
afford 10 (not isolated). Addition of aq. TsOH to the reaction
mixture and heating to 85 °C resulted in gradual pinacol
rearrangement and olefin isomerization to give key intermediate
methanesulfonic acid. The intermediate ketal 15 was directly
exposed to ZnI and TMSCN, smoothly incorporating the C-7
2
carbon which after saponification in the same flask delivered 16,
the complete carbon skeleton of 1.
3
in 45% isolated yield (7 g scale). The remaining mass balance
primarily consisted of an undesired isomer (22% yield) formed
during the pinacol shift (see SI for details).
The synthesis of 1 was completed in a single step from 16 via
the net installation of two oxygen atoms (C-15, C-1), olefin
isomerization (C-1/2 to C-2/3), and tertiary stereogenic center
formation (C-16). The cascade of seven reactions in a single flask
initiated upon exposure to DMDO to generate diepoxide 17 (not
isolated). When subjected to InI and MgI the C-1/2 epoxide is
Not surprisingly, the most challenging step in this synthesis
was the enolate-based installation of the hydroxymethyl group at
C-10 onto 3 to forge the final quaternary center. Aside from
obvious difficulties posed by the steric hindrance of this position,
there were unique chemo- and regioselectivity issues that needed
to be overcome (six possible monohydroxymethylated products
could be formed). In the first instance, there was the hurdle of
engaging the more hindered C-5/10 enolate in the presence of
the more accessible one at C-8/14. Even if that could be
accomplished, it would be extremely difficult to achieve
regioselective hydroxymethylation at the desired C-10 position
versus the less sterically hindered and undesired C-2 position. To
address the chemoselectivity challenge, the C-8 ketone was
initially protected as an ethylene glycol ketal or a cyanohydrin;
these modifications completely shut down the reactivity despite
the multiple conditions evaluated. All ensuing attempts enlisted 3
in the hydroxymethylation event. Roughly 1000 experiments
were conducted changing every conceivable variable from the
base used to deprotonate, the solvent employed, additives, and
the electrophile. Emerging from this exhaustive study was the
3
2
ruptured to the corresponding iodohydrin and a stereospecific
1,2-hydride shift is elicited to install the C-16 stereochemistry.
Subsequent addition of Dess−Martin periodinane oxidized the
C-1 hydroxyl group to produce α-iodoketone 18 that, upon
exposure to aqueous Oxone, oxidized the iodine atom to a
16
putative α-iodoso species which spontaneously eliminated to
deliver enantiopure (−)-1 in 76% isolated yield (verified by X-ray
crystallography, [α]2 = −98.2° (c 1.00, MeOH)). The
3
D
dehydroiodination of 18 could not be accomplished under
basic conditions as the C−I bond appears to adopt an
unfavorable conformation for E2 elimination.
With a robust route to the natural product in hand, it was
screened against 32 different cancer cell lines (including HeLa)
across four different laboratories and showed little to no activity
in any of them, suggesting that the originally exciting findings
17
were either due to a flawed assay or impure 1. The route
described herein was used to prepare >80 mg of (−)-1 to date,
but it could easily be adapted to procure gram quantities had the
biological data been more compelling.
15
remarkable finding that the addition of LaCl ·2LiCl to the
3
extended sodium enolate of 3, followed by quenching with
freshly prepared formaldehyde gas led to the desired adduct 11 in
8
4% yield as a 2:1 diastereomeric mixture favoring 11 (3 g scale).
The primary goal of this study was to demonstrate that the
notorious difficulties surrounding the exotic architecture of 1
could be solved by total synthesis in a practical way. This was
Complete chemoselectivity was achieved because the more
accessible C-8 ketone did not enolize under these conditions
presumably due to (1) increasing angle strain introduced onto
the bicyclic system upon C-8/14 enolate generation and (2)
destabilizing non-bonding interactions between π-systems (see
inset graphic and SI). To the best of our knowledge, this
represents the first use of LaCl ·2LiCl to control the course of an
aldol reaction of an extented enolate and might be of general
utility in similarly challenging contexts.
The next step required the reduction of the more sterically
encumbered C-5 ketone in the presence of the C-8 ketone. Since
reagent-based strategies failed, an internal protection strategy
was devised by selective in situ formation of ketal 12 (TFA,
CH(OMe) ), followed by reduction with LiBH in the presence
2b,3b
eventually
accomplished by employing a strategy not
18
wedded to Diels−Alder type disconnections but rather a
desire to maximize convergency and minimize concession steps
19
(steps 4, 5, and 9). Some of the memorable lessons from this
concise synthesis (73% ideal) include: (1) short access to 5 via a
highly enantioselective conjugate addition and anti-Baldwin
cyclization; (2) convergent coupling of fragments 5 and 6 with
concomitant pinacol shift and olefin isomerization to establish
the [2.2.2] bicycle; (3) the first use of a lanthanide Lewis acid to
control the regio- and stereochemical course of an aldol reaction
3
with an extended enolate; (4) Zn(OTf) -assisted reversal of the
2
stereoselectivity of a bis-neopentyl ketone reduction; (5) an
efficient cascade sequence to install key oxidations and
unsaturation.
3
4
of Zn(OTf) to furnish alcohol 13 in 83%. As with the
hydroxymethylation step, this combination of reagents has no
2
C
DOI: 10.1021/jacs.6b06623
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Total Synthesis of Maoecrystal V. Ph.D. Dissertation, The Scripps
Research Institute, 2011.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b06623.
■
*
S
(
4) For completed total syntheses of maoecrystal V, see: (a) Gong, J.;
Lin, G.; Sun, W.; Li, C.-C.; Yang, Z. J. Am. Chem. Soc. 2010, 132, 16745.
b) Peng, F.; Danishefsky, S. J. J. Am. Chem. Soc. 2012, 134, 18860.
(c) Lu, P.; Gu, Z.; Zakarian, A. J. Am. Chem. Soc. 2013, 135, 14552.
d) Lu, P.; Mailyan, A.; Gu, Z.; Guptill, D. M.; Wang, H.; Davies, H. M.
(
Experimental procedures, analytical data ( H and 13C
NMR, MS) for all new compounds as well as summaries of
unsuccessful approaches (PDF)
Crystallographic data (CIF)
Crystallographic data (CIF)
Crystallographic data (CIF)
Crystallographic data (CIF)
Crystallographic data (CIF)
Crystallographic data (CIF)
Crystallographic data (CIF)
Crystallographic data (CIF)
Crystallographic data (CIF)
Crystallographic data (CIF)
Crystallographic data (CIF)
Crystallographic data (CIF)
Crystallographic data (CIF)
1
(
L.; Zakarian, A. J. Am. Chem. Soc. 2014, 136, 17738. (e) Zheng, C.;
Dubovyk, I.; Lazarski, K. E.; Thomson, R. J. J. Am. Chem. Soc. 2014, 136,
1
7750. (f) Zhang, W.-B.; Shao, W.-B.; Li, F.-Z.; Gong, J.-X.; Yang, Z.
Chem. - Asian J. 2015, 10, 1874.
5) Han, Q.-B.; Cheung, S.; Tai, J.; Qiao, C.-F.; Song, J.-Z.; Tso, T.-F.;
(
Sun, H.-D.; Xu, H.-X. Org. Lett. 2006, 8, 4727.
(6) Robert, T.; Velder, J.; Schmalz, H.-G. Angew. Chem., Int. Ed. 2008,
47, 7718.
(7) Trost, B. M.; Shimizu, M. J. Am. Chem. Soc. 1982, 104, 4299.
(8) Beshara, C. S.; Hall, A.; Jenkins, R. L.; Jones, K. L.; Jones, T. C.;
Killeen, N. M.; Taylor, P. H.; Thomas, S. P.; Tomkinson, N. C. O. Org.
Lett. 2005, 7, 5729.
(
9) Davis, F. A.; Vishwakarma, L. C.; Billmers, J. M.; Finn, J. J. Org.
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(11) Baldwin, J. E.; Lusch, M. J. Tetrahedron 1982, 38, 2939.
12) Enone 6 was made via a modified literature procedure in four
steps, no column chromatography, see SI.
(
(
AUTHOR INFORMATION
Corresponding Author
pbaran@scripps.edu
Present Address
LEO Pharma, Industriparken 55, 2750 Ballerup, Denmark
Author Contributions
These authors contributed equally.
■
*
(13) Ren, H.; Krasovskiy, A.; Knochel, P. Org. Lett. 2004, 6, 4215.
(14) When THF was used as a solvent, the organomagnesium species
generated from 6 reacted with itself upon formation, thus 4−5 equiv of 6
were required to achieve full conversion. In PhMe, this side reaction was
not observed perhaps due to greater aggregation in the non-
coordinating solvent.
†
(15) (a) Krasovskiy, A.; Kopp, F.; Knochel, P. Angew. Chem., Int. Ed.
§
2
006, 45, 497. (b) Hall, L. P.; Gilchrist, J. H.; Collum, D. B. J. Am. Chem.
Notes
Soc. 1991, 113, 9571.
The authors declare no competing financial interest.
(16) Horiuchi, C. A.; Ji, S.-J.; Matsushita, M.; Chai, W. Synthesis 2004,
2
(
, 202.
17) For another recent example of irreproducible biological assays for
ACKNOWLEDGMENTS
Financial support for this work was provided by NIH (GM-
18176) and a graduate fellowship from Bristol-Myers Squibb
■
1
a natural product, see: Villaume, M. T.; Sella, E.; Saul, G.; Borzilleri, R.
M.; Fargnoli, J.; Johnston, K. A.; Zhang, H.; Fereshteh, M. P.; Dhar, M.
T. G.; Baran, P. S. ACS Cent. Sci. 2016, 2, 27.
(to A.C.). We thank Calibr, Stemcentrx, and Sirenas for
(18) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis,
assistance with evaluating the bioactivity of 1, Dr. D.-H. Huang
and Dr. L. Pasternack for NMR spectroscopic assistance, and
Prof. A. L. Rheingold and Dr. C. E. Moore for X-ray
crystallographic analysis.
G. Angew. Chem., Int. Ed. 2002, 41, 1668.
(19) Gaich, T.; Baran, P. S. J. Org. Chem. 2010, 75, 4657.
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DOI: 10.1021/jacs.6b06623
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX