Communication
Total Synthesis of Ritterazine B
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ABSTRACT: The first total synthesis of the cytotoxic alkaloid ritterazine B is reported. The synthesis features a unified approach to
both steroid subunits, employing a titanium-mediated propargylation reaction to achieve divergence from a common precursor.
Other key steps include gold-catalyzed cycloisomerizations that install both spiroketals and late stage C−H oxidation to incorporate
the C7′ alcohol.
itterazine B (1) is a bis-steroidal pyrazine (BSP) natural
Rproduct that was isolated in 1995 from the marine
tunicate Riterella tokioka off of Japan’s Izu Peninsula.1 The
BSPs include some of the most potent anticancer compounds
discovered to date,2 and 1, in particular, has been described as
“among the most potent growth inhibitors ever tested” by the
National Cancer Institute (NCI).3−5 It possesses subnanomo-
lar activity against P388 leukemia cells (0.17 nM IC50)6 and an
average GI50 of 3.2 nM in the NCI-60 cell line screen.5,7 Given
that the BSPs display distinct activity patterns in NCI-60
COMPARE analyses, they are proposed to act by a distinct
mode of action from existing chemotherapies.4,7,8
8 as the starting material was seen as strategic: the C5−C6
alkene would provide a handle for late-stage B-ring oxidation.
This tactic has yet to be utilized in synthetic approaches to the
BSPs,11 which could be why BSPs with C7/C7′ oxidation have
not previously been synthesized.7
In the forward sense, known steroid 9 (prepared in two steps
from 8)13 was treated with excess tert-butyldimethylsilyl triflate
and triethylamine (Et3N) to protect the C3 and C12 alcohols
and form the silyl enol ether at C17 (Scheme 1A). Direct
addition of isopropanol and N-bromosuccinimide to the
reaction mixture afforded α-bromoketone 10 in quantitative
yield in one pot. Elimination of the C16 bromide under basic
conditions gave an inconsequential mixture of isomeric enones
(Δ14,15 and Δ15,16 not shown), which converged to dienol ether
11 on treatment with Et3N and trimethylsilyl triflate. Selective
epoxidation of the C16−C17 alkene with dimethyldioxirane
and subsequent addition of tetrabutylammonium fluoride
(TBAF) provided α-hydroxyketone 12 in 92% yield, which
would serve as our divergent intermediate.
At this stage, we turned our attention to preparing the
distinct spiroketals found in the western and eastern steroids 2
and 3, respectively. To this end, titanium-mediated prop-
argylations based on conditions reported by Sato and co-
workers proved uniquely effective (Scheme 1B).14 Deproto-
nation of the C16 alcohol by treatment of 12 with n-
butyllithium, followed by addition of the organotitanium
species derived from either propargyl bromide 6 or 7 resulted
in 1,2-addition to give alkyne 13 in 54% yield or 14 in 56%
yield. These additions occurred with exclusive β-face selectivity
despite the axial methyl group,15 possibly due to the formation
of an α-disposed cyclic chelate between the C16 and C17
oxygens. While excellent diastereoselectivity was obtained at
Although the BSPs are known to induce apoptosis,3 a lack of
natural material has hampered translational investigations of 1
and related compounds. Landmark studies from Shair and co-
workers implicated BSPs as high-affinity ligands for oxysterol
binding proteins,4 while more recent evidence indicates that
the endoplasmic reticulum-specific heat-shock protein GRP78
may be their efficacious target.9,10 Given these promising
foundational studies, improved synthetic access to 1 is required
to fully evaluate its potential as a chemotherapeutic.2,8 In this
communication, we report the first total synthesis of 1. Our
approach uses a common strategy to prepare both of the
steroid spiroketals from trans-dehydroandrosterone, a com-
mercially available and inexpensive steroid.
In line with prior efforts to the BSPs,5,11 our retrosynthetic
analysis began with scission of the central pyrazine ring,
revealing the “western” and “eastern” steroids 2 and 3,
respectively (Figure 1). To streamline our route development,
we sought to prepare both 2 and 3 from a common starting
material, using the same general tactics for C−C bond
formation and spiroketalization. In this vein, steroids 2 and 3
were simplified to the corresponding alkynes 4 and 5, where
transition metal-catalyzed cycloisomerization12 would be used
to form the respective spiroketals. This retrosynthetic step
shifted the synthetic challenge to the union of differentiated
alkyne fragments with a common steroid core. We envisioned
preparing alkynes 4 and 5 by 1,2-addition of the propargyl-
metal species derived from 6 or 7 to an α-hydroxy ketone
accessible from trans-dehydroandrosterone (8). The choice of
Received: February 4, 2021
Published: March 9, 2021
J. Am. Chem. Soc. 2021, 143, 4187−4192
© 2021 American Chemical Society
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