Toward the total synthesis of bryostatin 11: Stereoselective construction of the C13-exocyclic enoate in the C1-C16 fragment

Article abstract of DOI:10.1080/00397911.2010.516462

We have utilized a spiroketal template in an approach to the C1-C16 fragment of bryostatin. The stereoselective construction of an exocyclic enoate at C13 and insertion of a vinyl group on C15 were accomplished by using Peterson-Yamamoto olefination and copper-catalyzed addition of vinyl magnesium bromide, respectively. Copyright

Full text of DOI:10.1080/00397911.2010.516462

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Toward the Total Synthesis of Bryostatin
11: Stereoselective Construction of the
C13-Exocyclic Enoate in the C1–C16
Fragment
Kyoko Nakagawa-Goto a & Michael T. Crimmins a
a Department of Chemistry , University of North Carolina , Chapel
Hill , North Carolina , USA
Published online: 11 Jul 2011.
To cite this article: Kyoko Nakagawa-Goto & Michael T. Crimmins (2011) Toward the Total Synthesis
of Bryostatin 11: Stereoselective Construction of the C13-Exocyclic Enoate in the C1–C16 Fragment,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 41:20, 3032-3038, DOI: 10.1080/00397911.2010.516462
To link to this article: http://dx.doi.org/10.1080/00397911.2010.516462
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Synthetic Communications1, 41: 3032–3038, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.516462
TOWARD THE TOTAL SYNTHESIS OF BRYOSTATIN 11:
STEREOSELECTIVE CONSTRUCTION OF THE
C13-EXOCYCLIC ENOATE IN THE C1–C16 FRAGMENT
Kyoko Nakagawa-Goto and Michael T. Crimmins
Department of Chemistry, University of North Carolina, Chapel Hill, North
Carolina, USA
GRAPHICAL ABSTRACT
Abstract We have utilized a spiroketal template in an approach to the C1–C16 fragment of
bryostatin. The stereoselective construction of an exocyclic enoate at C13 and insertion of a
vinyl group on C15 were accomplished by using Peterson–Yamamoto olefination and
copper-catalyzed addition of vinyl magnesium bromide, respectively.
Keywords Bryostatin 11; spiroketal chemistry; stereoselective exocyclic enoation
INTRODUCTION
The bryostatin family[1] (Fig. 1) of marine macrolides contains well-known
antitumor drug candidates with low toxicity and a unique mode of action against
protein kinase C.[2] Bryostatin 1 (1) is under investigation in human clinical trials
for use alone or in combination with other chemotherapies.[3] Furthermore, 1
improves memory and learning in animal models, indicating a potential for the treat-
ment of neurological disorders such as depression and Alzheimer’s disease.[4]
Because of their structural complexity as well as potent biological activity, the bryos-
tatins are challenging synthetic targets. Four total syntheses of a bryostatin have
been completed until 2010,[5] and many partial preparations have been reported.[6]
Simplified analogs have also been designed and studied for biological activities by
Wender, Keck, and Hale et al.[7] However, the development of an effective synthetic
route is still required for continued and productive biological study, because of
the limited supply of these compounds from natural sources. Our synthetic target,
Received August 14, 2010.
Address correspondence to Kyoko Nakagawa-Goto, Eshelman School of Pharmacy, University of
North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA (present address). E-mail: goto@
email.unc.edu
3032

TOWARD THE TOTAL SYNTHESIS OF BRYOSTATIN 11
3033
Figure 1. Structure of bryostatins.
bryostatin 11 (2), has the simplest structure of the family of structures. Our synthetic
efforts toward 2 began with disconnection of both the C16–C17 olefin and the ester-
linkage to divide the molecule into two fragments, a C1–C16 fragment and a C17–
C25 fragment.
Retrosynthetic analysis of the C1–C16 fragment using our established spiroke-
tal chemistry[8] is shown in Fig. 2. We have previously accomplished a chelation-
controlled stereoselective reductive spiroketal cleavage[9] and a copper-catalyzed
stereoselective addition of a vinyl group to an unsaturated spiroketal.[10] Herein,
we describe an approach to the synthesis of the C1–C16 fragment of bryostatin 11
using a spiroketal as a stereochemical template as well as the stereoselective con-
struction of an exocyclic enoate on C15.
Monoprotection of 2,2-dimethyl-1,3-propanediol (8) using two methods [NaH,
MOMCl or (MeO)3CH, and then diisobutylaluminumhydride (DIBAL)[11]] provided
the mono-MOM ether (Scheme 1). The remaining alcohol was oxidized under Swern
conditions to an aldehyde. Brown’s asymmetric allylation[12] of this aldehyde was
Figure 2. Retrosynthetic analysis of top half fragment.

3034
K. NAKAGAWA-GOTO AND M. T. CRIMMINS
Scheme 1. Reagents and conditions: (a) NaH, MOMCl (78%), or (MeO)3CH, then DIBALH (72%); (b)
(COCl)2, DMSO, then Et3 N; (c) 4-ICr2B-allyl, then 30% H2O2, NaOH; (d) PMBCl, KH, THF (66% from
9); (e) OsO4, NMO, NaIO4 (86%); (f) CH3C(O)CH2CH2OTBDPS (23), LDA, (71%); (g) Me4NHB(OAc)3,
CH3CN=AcOH, ꢀ30 ꢁC, 22 h (98%, anti=syn ¼ 7.8:1); (h) Me2C(OMe)2, pTsOH, THF (96%), then separ-
ation; (i) 70% HOAc (93%); (j) TIPSOTf, 2,6- lutidine (93%); (k) 0.5% cHCl=iPrOH, 70 ꢁC, 6 h (69%. two
recycle yield); (l) (COCl)2, DMSO, then Et3 N (92%); (m) LiHMDS, 2-methylpyrone, ꢀ78 ꢁC, 1 h (41%,
rsm 58%); (n) TESOTf, 2,6-lutidine (98%); (o) DDQ, CH2Cl2=H2O (19:1, v=v), rt, 1 h (94%); (p) 0.2%
TFA=PhH, rt, 3 d, (79%); (q) vinyl MgBr, [(nBu3P)CuI]4, ꢀ45 ꢁC, 0.5 h, (85%); (r) see Table 1; (s) HF ꢂ Py,
Py, Py, THF, rt, 3 d (76%, rsm 20%); (t) (COCl)2, DMSO, then Et3 N (90%); (u) NaClO2, NaH2PO4,
2-methyl-2-butene then BnBr, CsCO3 for a or allyl Br, CaCO3 for b (80%, 2 steps); (v) TASF, DMF,
rt, 1 d (63%, rsm 10%). Rsm, recovered starting material.
followed by protection of the resulting alcohol as the p-methoxybenzyl (PMB) ether
and oxidative cleavage of the terminal olefin to give aldehyde 9. The
chelation-controlled aldol addition between 9 and ketone 22[13] afforded b-hydroxy-
ketone 10 with the required configuration at C5 in 71% yield. Evans–Saksena
reduction[14] of 10 induced a 7.6:1 ratio in favor of anti-diol, which was inseparable
from the syn-diol. In contrast, the reduction of 10 with LiAl(OtBu)3 in the presence
of LiI[13] showed only a low preference for the anti-isomer. The mixture of anti=syn-
C3, C5-diol was protected as the acetonide, which could be separated from the unde-
sired syn-diol. The stereochemical assignments of C3 and C5 were supported by the
13C NMR spectroscopic data of 11, which showed the acetonide carbons at 25.98
and 25.71 ppm.[15] Deprotection of the acetonide with HOAc, followed by reprotec-
tion of the diol hydroxyl groups as triisopropylsilyl (TIPS) ethers, gave the fully pro-
tected C1–C9 linear subunit 12. Careful treatment of 12 with 0.5% HCl in i-PrOH[16]
selectively removed only the MOM ether to give primary alcohol 13 along with
recovered starting material, which was recycled under the same conditions to supply
13 in 69% yield after two cycles. Lithiation of 2-methylpyrone with LiHMDS fol-
lowed by addition of aldehyde 14, obtained by Swern oxidation of 13, produced
15 in 41% yield along with 58% of recovered starting material, which is reusable.
Because protection of the secondary alcohol as the TBS ether produced only the con-
jugated olefin resulting from dehydration, alcohol 15 was protected as the TES ether
to provide 16. Oxidative cleavage of the PMB ether with 2,3-dichloro-5,6-
dicyanobenzoquinone (DDQ) afforded the secondary alcohol, which upon exposure

TOWARD THE TOTAL SYNTHESIS OF BRYOSTATIN 11
3035
Table 1. Steroselective construction of exocyclic olefin on C13 (18 to 19)
Yields (%)
(19a/19bb) Rsm
Entry Reagents
Bases
Additive
Solvents
Conditions
1
2
A
B
LDA
NaH
NaH
—
—
THF
THF
ꢀ78 ꢁC, 1.5 h
ꢀ30 ꢁC to rt, 45 h
ꢀ45 ꢁC to rt, 25 h
ꢀ45 ꢁC to rt, 44 h
rt, 3 h
77 (12:1)
51 (2.3:1)
46 (1.4:1)
57 (5:1)
27 (1.5:1)
12 (4:1)
17 (3.8:1)
28 (4:1)
—
—
39
3
15-Crown-5a PhCH3
29
14
4
tBuOK
LiCl=DBU
Triton B
NaH
—
—
—
THF
CH3CN
THF
5
49
46
6
ꢀ78 ꢁC to rt, 41 h
ꢀ45 ꢁC to rt, 25 h
ꢀ45 ꢁC to rt, 42 h
ꢀ78 ꢁC to ꢀ35 ꢁC, 26 h
ꢀ45 ꢁC to rt, 48 h
ꢀ30 ꢁC, 7 d
7
C
15-Crown-5a PhCH3
77
60
8
tBuOK
NaHMDS
tBuOK
nBuLi
—
—
—
—
—
THF
THF
THF
THF
THF
9
D
E
F
70
21
10
11
12
28 (3.8:1)
—
65d (?)c
72
<20
tBuOK
ꢀ45 ꢁC to rt, 48 h
aNo reaction was observed when performed without crown ether.
bDetermined by 1H NMR spectroscopy.
cThe ratio of compounds was hard to determine because of the complex NMR spectra.
dThe resulting compound was (ꢀ)-trans-2-(a-cumyl)cyclohexanoate instead of methyl ester 19.
to trifluoroacetic acid in benzene resulted in the spiroenone 17 in 79% yield.
Copper-catalyzed addition of vinyl magnesium bromide to the enone gave 18 in
85% yield with excellent stereoselectivity at C15. With the desired spiroketal 18 in
hand, we turned to the stereoselective incorporation of the C13 enoate. Numerous
studies have reported stereoselective construction of the exocyclic olefin for bryosta-
tin synthesis.[17] However, various Horner–Wadsworth–Emmons reagents, including
Figure 3. Stereochemistry of 20.

3036
K. NAKAGAWA-GOTO AND M. T. CRIMMINS
chiral phosphonates, and reaction conditions resulted in poor yield or selectivity of
products as shown in Table 1. Finally, Peterson–Yamamoto olefination[18] effectively
afforded a favorable 11.5:1 mixture of isomers (19a=19b) in 77% yield (entry 1). A
similar selective exocyclic olefination under Peterson–Yamamoto conditions was
reported by Evans.[19] Both studies indicated that the selectivity might be supported
by an axial-alcohol or alkoxy group at the b-position to the cyclic ketone. Subse-
quently, the triethylsilyl (TES) and tert-butyldiphenylsilyl (TBDPS) groups were
cleaved simultaneously by treating 19 with buffered HF ꢂ py in tetrahydrofuran
(THF) solution. The resulting diol was oxidized to a keto-akdehyde 20, which was
converted to the allyl or benzyl ester 21a or 21b, respectively. Treatment of 21a/b
with TASF in dimethylformamide (DMF) generated the desired diol 22. Lewis
acid–promoted chelation-controlled stereoselective reductive cleavage of 22 to give
4 is currently in progress.
The relative stereochemistry of the C13 enoate of 20 was assigned by 1H NMR,
which showed a significant downfield shift of the C14 equatorial proton (1.96 ppm)
resulting from the electronic effect of the carbonyl group of the a,b-unsaturated
ester. The assignment was also supported by a nuclear Overhauser effect spec-
troscopy (NOESY) experiment, in which the nuclear Overhauser effect (nOe) was
observed between the C12 equatorial proton and the olefin proton as shown in Fig. 3.
ACKNOWLEDGMENT
K. Nakagawa-Goto acknowledges support from a research fellowship from Uehara
Memorial Foundation in Japan.
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