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How to cite: Angew. Chem. Int. Ed. 2022, 61, e202117480

Total Synthesis Hot Paper International Edition: doi.org/10.1002/anie.202117480
German Edition: doi.org/10.1002/ange.202117480

Enantioselective Synthesis of ( )-10-Hydroxyacutuminine

Denise C. Grünenfelder, Raul Navarro, Haoxuan Wang, Nicholas J. Fastuca, John R. Butler,
and Sarah E. Reisman*

Abstract: An enantioselective synthesis of ( )-10-

hydroxyacutuminine is reported. Central to our strategy
is a photochemical [2+2] cycloaddition that forges two
of the quaternary stereocenters present in the acutumine
alkaloids. A subsequent retro-aldol/Dieckmann se-
quence furnishes the spirocyclic cyclopentenone. Efforts
to chlorinate the acutumine scaffold at C10 under
heterolytic or radical deoxychlorination conditions led
to the synthesis of an unexpected cyclopropane-contain-
ing pentacycle.

The spirocyclic alkaloid ( )-acutumine (1, Figure 1a) was

first isolated from the Chinese moonseed plant (Sinomenium
acutum),[1] a climbing shrub used in traditional folk medicine
for its analgesic, anti-inflammatory, and anti-rheumatic
properties.[2] After its isolation in 1929, the structure of 1
evaded elucidation for nearly 40 years, until it was finally
solved by single-crystal X-ray diffraction in 1967.[3] In
preliminary studies, ( )-1 was shown to exhibit selective T-
cell cytotoxicity and anti-amnesic activity, the latter which
was investigated in a Morris mouse model[4] and patented in
2003.[5] Since the initial isolation of 1, several additional
acutumine alkaloids have been isolated, including ( )-
dechloroacutumine (2) and ( )-acutuminine (3).[6] These
alkaloids contain densely functionalized [4.3.3]propellane
cores with a spirofused cyclopentenone and vicinal quater- Figure 1. Representative members of the acutumine alkaloids and
retrosynthetic analysis of ( )-acutuminine (3).
nary centers. In addition, 1 and 3 bear a neopentyl chloride,
a rare structural feature for terrestrial natural products. Due
to their complex and unusual structures, there has been
significant interest in the biosynthesis,[7] biological Although we were ultimately interested in preparing
activity,[5, 8] and de novo syntheses of the acutumine ( )-1, we initially targeted ( )-acutuminine (3), anticipating
alkaloids.[9] Two completed syntheses of 1 have been that late-stage oxidation at C1 might enable conversion of 3
disclosed, the first from Castle and co-workers in 2009[9e] to 1. Conceptually, we sought to build the acutumine-type
and the second from Herzon and co-workers in 2013.[9h] In propellane core via an overbred intermediate, cyclobutane
this communication, we report a synthetic approach to the 6, the product of an intramolecular [2+2] cycloaddition
acutumine alkaloids that leverages a [2+2] cycloaddition/ (Figure 1b).[10] Scission of the extraneous C4 C5 bond by a
retro-aldol sequence to build the propellane core and retro-aldol reaction could reveal ketoester 5, which in turn
provides access to ( )-10-hydroxyacutuminine (4). could undergo Dieckmann condensation to give spirocyclo-
pentenone 4. As it was originally planned, this approach
would leverage the intrinsic reactivity of the carbonyl
[*] D. C. Grünenfelder, R. Navarro, H. Wang, N. J. Fastuca, J. R. Butler, functional groups and bring in C2, C4, and C6 at the correct
Prof. S. E. Reisman oxidation level. Epoxide 7 was targeted as the precursor to 6
The Warren and Katharine Schlinger Laboratory of Chemistry and based on preliminary studies,[9g] which revealed that the
Chemical Engineering, Division of Chemistry and Chemical Engi-
dimethoxy enone of 3 must be masked to enable the desired
neering, California Institute of Technology
Pasadena, CA 91125 (USA) [2+2] photocycloaddition. Epoxide 7 was envisioned to arise
E-mail: reisman@caltech.edu from the 1,2-addition of ketofuran 9 to N-sulfinyl imine 8
Homepage: http://reismangroup.caltech.edu followed by pyrrolidine formation and epoxidation.[9g, 11] In

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this plan, a C10 alcohol would be introduced early in the In the forward sense, the synthesis began with the
synthesis to serve as a precursor to the requisite C10 preparation of 15 (Scheme 1). Subjection of sulfinyl imine 8
chloride. Although there was some concern about the to the enolate derived from ketofuran 9 furnished desired
reactivity of the neopentyl alcohol, we hoped to leverage a 1,2-addition product 10 in 90 % yield and excellent diaster-
radical deoxychlorination for this transformation. eomeric ratio (dr). Slow addition of the imine to the pre-
formed enolate via syringe pump enabled the reaction to be
carried out in high yield, giving > 20 g of 10 in a single
reaction. Subsequent reduction[12] and TBS-protection of the
C10 alcohol was followed by N-methylation and ketal
deprotection[13] to give dienone 12, thus setting the stage for
pyrrolidine formation. Stille cross-coupling of 12 with
alkenyl stannane 13 was followed by amine deprotection[14]
and reductive cyclization to form the pyrrolidine. Subse-
quent selective epoxidation of the C7 C8 olefin afforded 7,
a key intermediate well suited for an intramolecular photo-
chemical [2+2] cycloaddition.[9g] Indeed, when a pentane
solution of 7 was subjected to UVA light, it underwent
smooth [2+2] cycloaddition to furnish cyclobutane 15 in
60 % yield. This strategic reaction allowed for the construc-
tion of the vicinal quaternary stereocenters at C11 and C12
in a single step.
With key cyclobutane 15 in hand, we sought to oxidize
the dihydrofuran to the requisite lactone (17, Scheme 2).
Canonical reaction conditions, such as Pd-mediated Wacker
oxidation, failed to give the desired product in good yield,
even when stoichiometric Pd was employed. Surprisingly, it
was found that treatment of 15 with methoxide at room
temperature furnished the corresponding methyl acetal at
C2; when the reaction was carried out at 70 °C, methoxide
addition to the epoxide also occurred, giving enol ether 16.
Subjection of 16 to BF3·Et2O and m-CPBA[15] delivered the
lactone 17 in 71 % yield over two steps. It was crucial to
utilize two equivalents of BF3·Et2O to mask the basic amine,
which is otherwise rapidly oxidized by m-CPBA. Subjection
of lactone 17 to K2CO3 in MeOH resulted in the desired
Scheme 1. Synthesis of cyclobutane 15. retro-aldol fragmentation to furnish ketone 18 in quantita-
tive yield. At this stage, two major challenges remained to
access the carboskeleton of ( )-acutuminine (3): 1) Die-
eckmann cyclization of 18, and 2) oxidation at C8 to the
dimethoxy enone. Unfortunately, the Dieckmann cyclization
of 18 was not successful under a variety of basic conditions.
Likewise, all efforts to oxidize 18 to install the C7 C8
dimethoxy enone failed.[16] It was discovered, however, that
treatment of 18 with tris(dimethylamino)sulfonium
difluorotrimethyl silicate (TASF) resulted in desilylation,
lactone formation, and intramolecular aldol cyclization to
give bridging ketone 19. We hypothesized that under basic
conditions, retro-aldol from 19 could generate the enolate at
C3, which could undergo Dieckmann cyclization to the
desired spirocycle. Unfortunately, we were not successful at
advancing 19 to 20 by this pathway.
We returned to epoxide 15 and discovered that the
methoxide-mediated epoxide opening could be terminated
by addition of H2O2, which directly furnished meth-
oxyepoxide 21 (Scheme 3). Treatment of 21 with BF3·Et2O
in MeOH afforded ketal 22 in 61 % yield over two steps.
Subsequent oxidation to the lactone with m-CPBA was
followed by methoxide-initiated retro-aldol to give ketone
Scheme 2. Successful retro-aldol to Dieckmann precursor 18. 23 in good yield. With C7 and C8 at the correct oxidation

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Scheme 4. Successful spirocycle synthesis.

subjection of α-bromoketone 30 to KOtBu in tamyl alcohol

resulted in Dieckmann condensation. The resulting vinyl-
ogous acid was methylated with K2CO3 and MeI to give 31
Scheme 3. Efforts to access the requisite C7/C8 oxidation pattern and
with excellent regioselectivity; the desired isomer was
spirocyclopentenone. confirmed via nOe.[18] Subsequent Pd-catalyzed debromina-
tion furnished spirocycle 32 in 91 % yield.
From 32, completion of the synthesis required: 1) for-
level, the dimethoxy enone was anticipated to be accessible rmation of the C7/C8 dimethoxy enone, and 2) C10
by methylation of the C8 alcohol followed by elimination of desilylation and chlorination. A survey of Lewis acids found
methanol. Surprisingly, O-methylation of 23 proved chal- that treatment of 32 with excess BCl3 at 40 °C resulted in
lenging. Attempts to O-methylate 22 with KH and MeI elimination of methanol and cleavage of the triethylsilyl
instead afforded C5-methylation.[17] As previously observed group, revealing the vinylogous acid (Scheme 4). Subsequent
(18 to 19) attempts to promote the base-mediated Die- methylation with TMS-diazomethane afforded the desired
ckmann cyclization instead gave bridging ketone 24. vinylogous ester 33 as a separable 3 : 1 mixture with
At this stage, a number of substrates had been found to undesired isomer 34. In addition, 33 % of ketal 32 could be
form the C3 C6 bridging ketone in preference to the desired recovered after this two-step process and recycled. Single-
spirocyclopentenone. We rationalized that bridging ketones crystal X-ray diffraction of 34 corroborated our NMR
such as 19 (Scheme 2) and 24 (Scheme 3) were formed assignments of the vinylogous ester isomers and the absolute
kinetically, and that they populated local minima, thermody- configuration.
namically. However, it was expected that the Dieckmann Silyl ether 33 was desilylated using TASF (Scheme 5),
condensation product (e.g. 20, 25), once obtained, should be affording ( )-10-hydroxyacutuminine (4) in 83 % yield.
thermodynamically favored. We hypothesized that an elec- Unfortunately, chlorination of hindered neopentyl alcohol 4
tron-withdrawing substituent at C3 could lower the pKa at proved challenging. A number of SN1, SN2, and double
that position and shift the equilibrium from 26 towards 27, inversion pathways were investigated, leading either to
allowing us to ultimately drive the reaction to the spirocyclic substrate decomposition or unreacted starting material.[19]
product 28. Since radical reactions are generally less sensitive to steric
To test this hypothesis, we set out to prepare an α- encumbrance, our focus turned to homolytic fragmentation
substituted ketone such as 27 (Scheme 3). Returning to 23, of the C10–oxygen bond in the presence of a chlorine atom
C3 was successfully brominated by a two-step sequence source. Both canonical radical initiators (such as AIBN[20, 21]
involving conversion to bis-silylated bridging enol ether 29 or Et3B/O2)[22] and photoredox-mediated conditions were
followed by treatment with NBS to give 30 (Scheme 4). surveyed.[23] Unfortunately, all reactions were accompanied
Reaction via the silyl enol ether and slow, portion-wise by decomposition, with very little mass recovery. Similarly,
addition of NBS were crucial to avoid undesired oxidation attempts to perform radical deoxygenation at C10 toward
of the pyrrolidine ring. Consistent with our hypothesis,

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Takase and Dr. Julie L. Hofstra for solving the X-ray crystal
structure of 34. We also thank Dr. Nicholas G. W. Cowper,
Dr. Elliot P. Farney, and Dr. Jordan C. Beck for helpful
discussions, and Yujia Tao for the synthesis and character-
ization of ketone 24, as well as assistance in the chlorination
trials of cyclopropane 35. Financial support was provided by
the National Science Foundation (graduate research fellow-
ship to D. C. G., Grant No. DGE-1144469, and CAREER-
1057143, CHE-1800536 to S. E. R.) and is gratefully
acknowledged.

Conflict of Interest
Scheme 5. Synthesis of ( )-10-hydroxyacutuminine (4) and cyclopro-
The authors declare no conflict of interest.
pane 35.

Data Availability Statement

( )-dechloroacutumine (2) were also unfruitful, also result-
ing in decomposition. The data that support the findings of this study are available
Having failed at promoting radical deoxychlorination of in the supplementary material of this article.
4, a strategy involving elimination to form the C9 C10
alkene followed by hydrochlorination was pursued. Based Keywords: Acutumine Alkaloids · Deoxychlorination ·
on prior work by Herzon and King,[9h] it was hypothesized Dieckmann Cyclization · Total Synthesis · [2+2] Cycloaddition
that this strained alkene should be accessible. As further
illustration of the unique reactivity of this propellane system:
when alcohol 4 was subjected to Martin sulfurane
(Scheme 5), cyclopropane 35 was instead formed. Similar
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some decomposition during the Dieckmann cyclization. The Version of record online: February 23, 2022

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