Synthetic studies toward bryostatin 1: preparation of a C1-C16 fragment by pyran annulation

Article abstract of DOI:10.1016/j.tetlet.2006.09.094

An expeditious assembly of a C₁-C₁₆ subunit of bryostatin 1 is described. A pyran annulation reaction was utilized to form the B-ring by reaction of a hydroxy-allylsilane with a fully elaborated A-ring subunit. This annulation proces

Full text of DOI:10.1016/j.tetlet.2006.09.094

Tetrahedron Letters 47 (2006) 8267–8270
Synthetic studies toward bryostatin 1:
preparation of a C1–C16 fragment by pyran annulation
Gary E. Keck,* Dennie S. Welchꢀ and Yam B. Poudel
Department of Chemistry, University of Utah, 315 South 1400 East, RM 2020, Salt Lake City, UT 84112-0850, USA
Received 7 September 2006; accepted 19 September 2006
Available online 10 October 2006
Abstract—An expeditious assembly of a C1–C16 subunit of bryostatin 1 is described. A pyran annulation reaction was utilized to
form the B-ring by reaction of a hydroxy-allylsilane with a fully elaborated A-ring subunit. This annulation process proceeded with
complete diastereoselectivity and in excellent isolated yield despite the presence of potentially sensitive functionality in the A-ring
segment.
Ó 2006 Elsevier Ltd. All rights reserved.
Bryostatin 1, isolated by Petit and co-workers from a
marine bryozoan in 1982,1,2 is of great interest as a
potential chemotherapeutic agent for cancer, with some
80 clinical trials completed or ongoing.3 Although bryo-
statin 1 has shown limited utility as a single agent,
remarkable synergies with established chemotherapy re-
gimes have been documented.4 Recent studies have also
revealed a role for this agent in memory and as a poten-
tial therapeutic for Alzheimer’s disease.5 Although the
exact mode of action of bryostatin with respect to these
biological effects remains unknown, it’s exceptionally
high affinity for protein kinase C (PKC) isozymes is
well-established.6 Structurally, this 20-membered mac-
rolactone with a polyacetate backbone that houses three
pyran rings continues to be a daunting challenge as only
three completed total syntheses7–9 of bryostatin have
been disclosed despite the many ongoing investigations
that are directed toward the total synthesis of this
impressive target.10
An approach to the synthesis of bryostatin 1 is indicated
in Scheme 1. Here, application of our pyran annulation
Me
Me
Me
Me
11
HO
Me
MeO
OAc
Me
H
OAc
MeO2C
OAc
A
B
O
O
O
O
5
TMS
2
TBSO
PMBO
1
16
O
OH
O
O
HO
H
OH
O
Me
Me
O
C
TBDPSO
H
OH
4
TBDPSO
StBu
Me
Me
O
OH
bryostatin 1
O
Me
OH
OBOM
n
-Pr
O
CO2Me
Me
9
Me
3
5
1
O
Me
H
O
H
OTMS
StBu
OR1 OR2 StBu
+
+
TBSO
AcO
Me
RO
O
TBSO
4
SnBu3
7
6
5
R = PMB
1,3-anti to C5 alkoxy
R1 = PMB, R2 = TBDPS
Scheme 1. Retrosynthetic approach to bryostatin 1.
Keywords: Bryostatin; Chelation; Allylation; Stannane.
*
Corresponding author. Tel.: +1 801 581 7055; e-mail: keck@chem.utah.edu
ꢀ Present address: Department of Chemistry, Harvard University, Cambridge, MA 02139, USA.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.094

8268
G. E. Keck et al. / Tetrahedron Letters 47 (2006) 8267–8270
methodology,11 which has found success in our bryosta-
tin analogue program,12 was envisioned to unite a C-
ring b-hydroxy allylsilane such as 3 with an A-ring sub-
unit 2, with concurrent formation of the B-ring (Scheme
1). However, the presence of the lactol methyl ether in 2,
and its disposition b to the aldehyde carbonyl, was re-
garded as a potentially disastrous liability due to the
strong Lewis acidic conditions (TMSOTf) required to
promote the annulation process. We expected that the
A-ring aldehyde 2 would be available from acyclic
precursor 4, which can be seen to possess an anti,anti
relationship of the C3–C5–C7 stereotriad. Thus the C5
stereocenter could potentially be employed to control
the stereoselective introduction of the C3 and the C7 ste-
reocenters in sequential chelation-controlled additions
at both ends of a b-alkoxy dialdehyde such as 6.13,14
The formation of the initial C5 stereocenter with high
stereoselectivity would thus be imperative. It was hoped
that our catalytic asymmetric allylation (CAA)15 reac-
tion would satisfy this requirement. The p-methoxy-
benzyl group was regarded as an ideal protecting
group for the C5 hydroxyl based upon its compatibility
with chelating Lewis acids.
O
O
Me
Me
a
OTBS
b
EtO
EtO
EtO
OTBS
c
I
Me
13
16
15
14
O
OTBS
OTBS
HO
Me
d
Me
Me
Me
17
OTBS
Bu3Sn
Me
Me
7
Scheme 3. Reagents and conditions: (a) LDA, THF, ꢀ78 °C, 30 min;
2-iodo-1-(t-butyldimethylsilanoxy)ethane, ꢀ78 °C to rt, 15 h, 79%; (b)
t-BuOK, THF, 0 °C, 2 h, 93%; (c) DIBAL, CH2Cl2, 0 °C, 2 h, 94%; (d)
n-BuLi, THF, ꢀ78 °C, 45 min; MsCl, ꢀ78 °C, 1.25 h; Bu3SnLi, ꢀ78 °C
to rt, 20 h, 72%.
yield.17 Migration of the olefin to give the thermody-
namically favored a,b-unsaturated ester 16 was effected
by exposure to t-BuOK in THF in 93% yield. Here, it
was found that rigorous exclusion of oxygen during
the isomerization was necessary to prevent autoxidation
of the potassium enolate.18 Full-reduction of the ester
proceeded uneventfully to give the allylic alcohol 17.
The synthesis of the requisite C1–C7 aldehyde fragment
along these lines has been recently disclosed and is sum-
marized in Scheme 2.16 This route affords 12 in 57%
yield over the eight-step sequence.
This set the stage for introduction of the stannyl moiety,
which unexpectedly proved to be rather difficult. Our
initial intention was to convert the alcohol to the corre-
sponding bromide or chloride and effect a displacement
reaction with tributyltinlithium.19 However, attempted
conversion of the alcohol to the corresponding chloride
or bromide yielded compounds that proved unstable
with respect to isolation and purification. It was critical
that pure materials be obtainable here to preclude exten-
sive purification of the desired allylstannane. It was thus
necessary to convert the hydroxyl functionality to a suit-
able leaving group followed by direct exposure, without
workup, to the tin nucleophile. This in turn required
that the reaction used to activate the hydroxyl group
be free of byproducts which could interfere with the
use of tributyltinlithium. The most efficient manner de-
vised to accomplish this proceeded via in situ formation
of the mesylate at ꢀ78 °C (reaction of the alcohol with
1 equiv of n-BuLi followed by the addition of mesyl
chloride) followed by addition of tributyltinlithium
and slow warming of the mixture to room tempera-
ture.18 This afforded allylstannane 7 in 50% overall yield
for the sequence (from ester 13).
In the most critical operation required to prepare the A-
ring intermediate 2, allylstannane 7 was to be employed
to introduce the gem-dimethyl group in a stereoselective
addition reaction with an aldehyde such as 6. We have
found the preparation of such allylstannanes incorpo-
rating the tetrasubstituted olefin structural motif to be
a challenging proposition. Ultimately, we devised a
route to such intermediates via a sequence utilizing the
vinylogous alkylation of ester enolates. (Scheme 3).
Thus, alkylation of the extended lithium enolate of
commercially available ethyl 2,2-dimethylacrylate with
iodide 14 derived from iodo-ethanol proceeded in 79%
H
a, b
c, d
O
OTBDPS
PMBO
OTBDPS
8
9
StBu
5
StBu
OTMS
H
Ti(Cl)2(Oi-Pr)2, PhCH3
PMBO
O
PMBO
OH
11
O
95%, 41:1
10
H
O
e, f, g
Consistent with our previous observations,16 the nucleo-
philic addition of stannane 7 to aldehyde 12 required
the use of a strongly activating Lewis acid with the
ability to chelate, as neither MgBr2ÆOEt2 nor Ti(Cl)2-
(Oi-Pr)2 provided sufficient activation to promote this
reaction (Scheme 4). In the event, precomplexation of
the aldehyde 12 with excess Me2AlCl in toluene at
ꢀ78 °C followed by the addition of stannane 7 afforded
the coupled product 18 in 86% yield and as a single
diastereomer as judged by 1H and 13C NMR
spectroscopy.20
PMBO
StBu
12
TBDPSO
O
Scheme 2. Reagents and conditions: (a) (S)-(ꢀ)-1,10-bi-2-napthol,
˚
Ti(Oi-Pr)4, 4 A MS, CH2Cl2, ꢀ20 °C, 5 days, 90%, 93% ee; (b)
PMBOC(NH)CCl3, CSA, CH2Cl2, rt, 12 h, 76%; (c) TBAF, THF, rt,
12 h, 95%; (d) SO3Æpy, Et(i-Pr)2NH, DMSO, CH2Cl2, ꢀ5 °C, 30 min,
97%; (e) TBDPSCl, imidazole, DMF, rt, 24 h, 92%; (f) OsO4, NMO,
t-BuOH/THF/H2O, rt, 14 h; (g) Pb(OAc)4, PhH, rt, 1 h, 99% (two
steps).

G. E. Keck et al. / Tetrahedron Letters 47 (2006) 8267–8270
8269
Me
Me
Me
H
O
Me
Me
Me
MeO
MeO
11
H
OAc
OAc
Me2AlCl (5.0 equiv)
PMBO
+
TMSOTf, Et2O, -78 °C, 5h;
7
O
O
O
O
PhCH3, -78 °C, 1.5 h, 86%
TBSO
SBut
SnBu3
TMS
single isomer
1
16
O
O
OH
OBn
TBDPSO
85%, single diastereomer
BPSO
OH
O
7
12
TBDPSO
StBu
StBu
22
OBn
Me
Me
2
21
Scheme 6. Formation of the B-ring by pyran annulation.
TBSO
PMBO
StBu
to the action of TMSOTf at ꢀ78 °C yielded the AB bicy-
cle 22 in 85% yield and as a single diastereomer, thus
confirming the viability of 2 as a suitable substrate for
the pyran annulation. The expected stereochemistry of
the newly formed pyran was corroborated by diagnostic
NOE transfers from the C11 proton to the C15 and C9
methoxy protons. Our concerns regarding the potential
Lewis acid lability of the mixed acetal b to the aldehyde
during the pyran annulation were not totally un-
founded, however. It was noted that aldehyde 2 was
quite acid sensitive in that it proved unstable in CDCl3
as NMR solvent unless the CDCl3 was pretreated with
K2CO3. Moreover, it was found that monitoring of
the pyran annulation reaction itself by TLC gave mis-
leading results using aliquots spotted directly from the
reaction mixture, as products other than 22 were ob-
served as the major materials. Only the disappearance
of starting materials could be reliably monitored in this
way. After completion of the reaction and quenching at
low temperature, however, 2 is observed as essentially
the only product. It should be noted that the pyran
annulation reaction was best quenched cold (at
BPSO
O
18
Scheme 4. C7–C8 bond construction and installation of the gem-
dimethyl moiety.
Me Me
Me Me
OH
OAc
a, b
TBSO
PMBO
TBSO
HO
StBu
StBu
19
TBDPSO
18
TBDPSO
c
O
O
Me Me
HO
OAc
O
d,e
TBSO
O
StBu
20
TBDPSO
Me
Me
MeO
H
OAc
9
O
O
5
1
O
2
ꢀ78 °C) initially by addition of Hunigs base followed
¨
TBDPSO
StBu
by the addition of aqueous NaHCO3 solution.
Scheme 5. Reagents and conditions: (a) Ac2O, DMAP, Et3N, CH2Cl2,
rt, 24 h, 94%; (b) DDQ, 2:1 CH2Cl2/pH 7.0 buffer, rt, 2 h, 94%; (c) O3,
CH2CH2, ꢀ78 °C, 5 min; DMS, rt, 12 h, 91%; (d) CSA, MeOH, rt,
1.25 h, 99%; (e) SO3Æpy, Et(i-Pr)2NH, DMSO, CH2Cl2, ꢀ5 °C, 1 h,
88%.
The success of the pyran annulation to form the B-ring
(Scheme 6) with the model allylsilane suggests that A-
ring aldehyde 2 could be joined with a more complex
C-ring b-hydroxy allylsilane, as proposed in our retro-
synthetic analysis (Scheme 1). It worth noting that the
AB bicyclic material 22 was accessed in 26% overall
yield, over a 17-step sequence that began with commer-
cially available 1,3-propanediol. This represents, to the
best of our knowledge, the most expedient route to an
AB bicyclic system of bryostatin 1 reported to date. In
this regard, it should be noted that both Evans and
Yamamura have documented that the exocyclic enoate
at C13 in bryostatin 1 can be introduced in advanced
intermediates (with the entire macrocylic skeleton in
place) using the BINOL based phosophonate reagent
developed by Fuji.21 Thus introduction of the unsatu-
rated ester is anticipated to require two additional steps
of oxidative olefin cleavage and Emmons reaction.
Efforts to extend the strategy and methodology
described herein to the total synthesis of bryostatin 1
and analogues are in progress.
Conversion of this acyclic material to the A-ring of bryo-
statin 1 first required acetylation of the C7 hydroxyl
group, which proceeded uneventfully under standard
conditions to give acetate 19 in 94% yield (Scheme 5).
Subsequent oxidative PMB removal was realized in
94% yield under buffered DDQ conditions. Ozonolysis
with reductive work-up proceeded in 91% yield to give
lactol 20 as the sole product; none of the open-chain
1
keto-alcohol isomer was detected by H NMR of the
crude reaction product. The stereochemistry about the
A-ring was established unambiguously at this stage by
an NOE experiment which revealed interactions between
the C5, C7, and lactol OH protons, thereby confirming
the suspected stereochemical outcome of the key frag-
ment coupling reaction. Deprotection of the TBS ether
with simultaneous formation of the methyl ketal was car-
ried out in a single operation by treatment with acidic
methanol to give the corresponding primary alcohol.
Subsequent Parikh–Doering oxidation then afforded
the desired aldehyde A-ring subunit 2 in 88% yield.
Acknowledgments
Financial support from the National Institutes of
Health (through GM-28961) is gratefully acknowl-
edged. Mr. Robert Giles is acknowledged for helpful
In the critical event, subjection of an ether solution of
aldehyde 2 and the known b-hydroxy allylsilane 2111

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G. E. Keck et al. / Tetrahedron Letters 47 (2006) 8267–8270
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Complete experimental details, characterization data,
1
and copies of H and 13C NMR spectra for compounds
described herein. Supplementary data associated with
this article can be found, in the online version, at
doi:10.1016/j.tetlet.2006.09.094.
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