Prins cyclization of bis(silyl) homoallylic alcohols to form 2,6-cis-tetrahydropyrans containing a geometrically defined exocyclic vinylsilane: Efficient synthesis of ring b of the bryostatins

Article abstract of DOI:10.1002/anie.201201323

Prins Charming: Prins cyclization of a bis(silyl) homoallylic alcohol with an aldehyde shows excellent cis and Zselectivity to form tetrahydropyrans containing a geometrically defined exocyclic vinylsilane. This reaction was used as the key step in the synthesis of ringB of the bryostatins. Copyright

Full text of DOI:10.1002/anie.201201323

Angewandte
Chemie
DOI: 10.1002/anie.201201323
Synthetic Methods
Prins Cyclization of Bis(silyl) Homoallylic Alcohols to Form 2,6-cis-
Tetrahydropyrans Containing a Geometrically Defined Exocyclic
Vinylsilane: Efficient Synthesis of Ring B of the Bryostatins**
Ji Lu, Zhenlei Song,* Yuebao Zhang, Zubao Gan, and Hongze Li
Bryostatins[1] are a class of complex macrolides produced by
a bacterial symbiont of the marine bryozoan Bugula neritina
(Figure 1).[2] Since the first isolation of bryostatin 1 by Pettit
and co-workers in 1982,[3] some 20 members of this family
have been described. The bryostatins have shown remarkable
biological activity against a range of cancers[4] and other
diseases such as Alzheimerꢀs.[5] They have also been used
extensively in clinical trials against these diseases.[1a,6]
Because of their attractive biological activities and
unusual structures, bryostatins have remained popular syn-
thetic targets for three decades.[7] The main challenge
presented by the bryostatins is the construction of the cis-
tetrahydropyran rings B and C, which contain geometrically
defined exocyclic methyl enoates. It is noteworthy that
a similar ring skeleton can be found in the structure of (À)-
exiguolide (Figure 1),[8] which is thought to be a structurally
simpler naturally occurring analogue of the bryostatins.[9] In
recent total syntheses of bryostatins, ring B was generally
Scheme 1. Strategies towards the synthesis of ring B of the bryostatins.
a) Strategy used by Evans et. al. (bryostatin 2); Yamamura et al.
(bryostatin 3); Keck et. al. (bryostatin 1); Wender et al. (bryostatin 9);
Krische et al. (bryostatin 7). b) Strategy used by Trost et al. (bryosta-
tin 16). c) This work: Prins cyclization of bis(silyl) homoallylic alcohol
with aldehyde. Cp=cyclopentadienyl, HMDS=hexamethyldisilazide,
NBS=N-bromosuccinimide.
formed by a stepwise strategy, in which the cis-tetrahydropy-
ranone was constructed first with a subsequent asymmetric
Horner–Wadsworth–Emmons reaction using Fujiꢀs chiral
binol phosphonate 2[10] (Scheme 1a). Although the exocyclic
methyl enoate was produced in good yield, the Z/E selectivity
was only in the range of 4:1 to 8:1. In the total synthesis of
bryostatin 16, Trost and Dong constructed ring B using an
approach based on a ruthenium-catalyzed tandem alkyne–
enone coupling/Michael addition (Scheme 1b).[7e,f] While the
cis stereochemistry and Z configuration were established in
one step, the reaction showed only moderate efficiency and
gave 6 in 34% yield (80% based on recovered starting
material).
Figure 1. Structures of bryostatin 1 and (À)-exiguolide.
[*] J. Lu, Prof. Dr. Z.-L. Song, Y.-B. Zhang, Z. Gan, H.-Z. Li
Key laboratory of Drug-Targeting and Drug Delivery System of the
Education Ministry, Department of Medicinal Chemistry
West China School of Pharmacy, Sichuan University
Chengdu, 610041 (China)
E-mail: zhenleisong@scu.edu.cn
Prof. Dr. Z.-L. Song
State Key Laboratory of Biotherapy, West China Hospital
Sichuan University, Chengdu, 610041(China)
Bis(silyl) compounds,[11] a special type of organosilane, are
attractive synthons because of their great potential for
bifunctional reactivity. As part of our continuing efforts to
explore bis(silyl) chemistry,[12] we became intrigued by
a proposal to form ring B of the bryostatins by using the
new strategy shown in Scheme 1c. In this approach, the
bis(silyl) group in 7 plays a bifunctional role: one silyl group
reacts as an allylsilane, which undergoes a Prins cyclization[13]
[**] We are grateful for the financial support from the National Natural
Science Foundation of China (21172150, 21021001), the National
Basic Research Program of China (973 Program, 2010CB833200),
and Sichuan University (Distinguished Young Scientist Program,
2011SCU04A18).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201201323.
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Table 1: Screening of reactions conditions of Prins cyclization.[a]
Table 2: Scope of Prins cyclization of 7a with aldehydes.[a]
Aldehyde
Product
Yield (Z)-8/
[%][b] (E)-8/8’
Entry
Si
Lewis Acid
(equiv)
Yield
[%][c]
(Z)-8a/
[c]
(E)-8a/8a’[d]
1
2
PhCHO
2-thiophene-
aldehyde
(Z)-8b 86
(Z)-8c 80
100:0:0
100:0:0
1
2
3
4
5
Me3Si
Me3Si
Me3Si
Me3Si
Et3Si
BF3·OEt2 (1.5 equiv)
TMSOTf (1.0 equiv)
TMSOTf (1.5 equiv)
TMSOTf (2.0 equiv)
TMSOTf (1.5 equiv)
62
80
82
79
45
76:18:6
84:0:16
94:0:6
89:0:11
55:0:45[e]
3
4
5
6
7
8
9
BnOC4H8CHO
BrC3H6CHO
(Z)-8d 90
(Z)-8e 69
(Z)-8f 88
(Z)-8g 81
(Z)-8h 93
(Z)-8i 88
(Z)-8j 60
100:0:0
98:0:2
[a] Reaction conditions: 7a (0.15 mmol), C6H11CHO (0.30 mmol) in
Et2O (1.5 mL) at À788C for 20 min. [b] The Z configuration and
cis stereochemistry were assigned by NOE experiments on (Z)-8a, and
additionally confirmed by NOE experiments on (Z)-8h, (Z)-8o, and (Z)-
8r. [c] Yields of products after purification by silica gel column
chromatography. [d] Ratios were determined by 1H NMR spectroscopy.
[e] Ratio of (Z)-8aa/(E)-8aa/8a’. Cy=cyclohexyl, Si=silyl group,
TMS=trimethylsilyl, Tf=trifluoromethanesulfonate.
100:0:0
100:0:0
100:0:0
98:0:2
with an aldehyde to form the cis-tetrahydropyran (Z)-8, thus
generating the exocyclic double bond in the Z configura-
tion.[14] The other silyl group reacts as the vinylsilane, which
undergoes bromination and carbonylation with retention of
configuration to give methyl enoate 9. Herein we report
studies of this Prins cyclization and its utility in the synthesis
of ring B of the bryostatins.
The bis(silyl) homoallylic alcohol 7a as a model substrate
was prepared in 58% yield by a zinc-promoted Barbier
reaction[15] of bis(silyl) allyl bromide with butanal. Prins
cyclization of 7a with cyclohexanal was initially performed in
Et2O using BF3·OEt2 as a Lewis acid (Table 1, entry 1). While
the desired cyclization proceeded readily at À208C to give cis-
tetrahydropyrans in a 62% overall yield, the exocyclic
vinylsilane formed with only moderate Z/E selectivity [(Z)-
8a/(E)-8a = 76:18], along with partial desilylation to give
a small amount of 8a’. To our delight, TMSOTf proved
effective at providing a higher yield and exclusive Z selectiv-
ity (entry 2). Moreover, under the optimized reaction con-
ditions using 1.5 equivalents of TMSOTf, desilylation was
minimized to give (Z)-8a and 8a’ in the ratio 94:6 (entry 3).
The bis(silyl) group appeared to be crucial for efficiency, as
the reaction involving a substrate containing a bulkier
bis(triethylsilyl) group suffered from both poor yield and
severe desilylation (entry 5).
The scope of this approach was further tested using 7a. As
summarized in Table 2, the reaction shows wide applicability
to various aldehydes including aryl aldehydes (entries 1 and
2), functionalized alkyl aldehydes (entries 3–6), a,b-unsatu-
rated aldehydes (entries 7–10), and propargyl aldehyde
(entry 11). Although tetrahydropyran was produced as
a single cis diastereomer as expected, we were surprised to
find that the control of the exocyclic alkene geometry appears
to be independent of the R2 group in the aldehydes, with all
reactions giving the Z vinylsilane exclusively. In entry 6, the
aldehyde group underwent Prins cyclization selectively and
the ketone was left untouched. In addition, the reaction is also
100:0:0
10
11
(Z)-8k 75
(Z)-8l 73
100:0:0
100:0:0
(Z)-
65
12 HC(OMe)3
100:0:0
100:0:0
8m
13
(Z)-8n 78
[a] Reaction conditions: 7a (0.10m), aldehyde (2.0 equiv) and TMSOTf
(1.5 equiv) in Et2O at À788C for 20 min. [b] Yields of products after
purification by silica gel column chromatography. [c] The ratios were
1
determined by H NMR spectroscopy. Bn=benzyl.
suitable for trimethyl orthoformate and acetal to give (Z)-8m
and (E)-8n in 65 and 78% yield, respectively.
The Prins cyclization of various bis(silyl) homoallylic
alcohols containing different R1 groups was further tested
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Table 3: Scope of Prins cyclization of bis(silyl) homoallylic alcohols 7
with butanal.[a]
Scheme 2. Model analysis to explain the observed Z selectivity during
Alcohol
Product
Yield (Z)-8/
formation of exocyclic vinylsilane
[%][b] (E)-8/8’[c]
should be energetically more favorable, which would explain
the observed exclusive Z selectivity.
1
2
3
4
7b: R1 =Cy
(Z)-8o 83
100:0:0
100:0:0
98:0:2
93:0:7
The Prins cyclization of 7a with ketal 10 also proceeds
smoothly to generate the desired tetrahedropyran (Z)-8t in
62% yield, along with 12% of the desilylated product 8t’
(Scheme 3). However, the Z/E selectivity in this case is only
1:1. The steric interaction between cyclohexyl and silyl groups
in TS(Z)-8t probably makes it energetically comparable to
TS(E)-8t, which has a steric interaction between H2 and the silyl
groups. Thus the reaction would proceed through both of
these transition states and provide both (Z)-8t and (E)-8t
with poor Z/E selectivity.
7c: R1 =CH2(iPr)
7d: R1 =C3H6OBn
(Z)-8p 83
(Z)-8q 87
(Z)-8r 98
Application of this methodology to the synthesis of ring B
of the bryostatins is shown in Scheme 4. The synthesis began
with the known chiral epoxide 11.[18] Epoxide ring opening by
the Grignard reagent 12 and subsequent bromination[19] gave
the vinyl bromide 13 in an overall 78% yield. The key
precursor 15 was in turn obtained in 88% yield by a [Pd-
(PPh3)4]-catalyzed Kumada coupling[20] of 13 with bis(tri-
methylsilyl) magnesium chloride 14.[11e] Prins cyclization of 15
with aldehdye 16[21] was performed under standard reaction
conditions to generate the desired cis-tetrahydropyran 17 in
92% yield with exclusive Z selectivity. Bromination of the
exocyclic vinylsilane in 17 with NBS then gave 18 in 88%
yield and with retention of the Z configuration.[7f] A final
carbonylation step[7f] led to formation of methyl enoate and
generated 19 as the C9–C19 fragment of the bryostatins in
73% yield.
Herein we have described an interesting Prins cyclization
of bis(silyl) homoallylic alcohols with aldehydes. The reaction
provides a direct entry to diverse cis-tetrahydropyrans con-
taining a geometrically defined exocyclic vinylsilane. Using
this approach as a key step also led to an efficient synthesis of
ring B of the bryostatins, thus demonstrating the attractive
bifunctional activity of the bis(silyl) group. Further applica-
5
(Z)-8s 89
100:0:0
[a] Reaction conditions: 7 (0.10m), aldehyde (2.0 equiv), and TMSOTf
(1.5 equiv) in Et2O at À788C for 20 min. [b] Yields of products after
purification by silica gel column chromatography. [c] The ratios were
1
determined by H NMR spectroscopy.
with butanal (Table 3). Interestingly, although the steric and
electronic properties of the R1 group varied substantially, all
reactions still showed exclusive Z selectivity. Even in the
reactions of 7e and 7 f, in which the R1 substituent is a cation-
stabilizing alkenyl group, no formation of the E isomer was
observed. This result also implies that the competitive 2-
oxonia Cope rearrangement, which is observed to be much
faster than Prins cyclization in typical systems,[16] does not
take place in our reaction.
The results in Table 2 and Table 3 illustrate a remarkable
feature of this reaction, namely that configurational control of
the exocyclic vinylsilane is independent of both the R1 and R2
groups. Thus, the reaction always shows reliable Z selectivity,
with the silyl group falling on the same side as the
incorporated aldehyde. A rationalization of this interesting
stereoselectivity is proposed in Scheme 2. Formation of cis-
tetrahydropyran can be understood by considering the Prins
cyclization to proceeds via a widely recognized chair-like
transition state,[16e,17] in which both R1 and R2 groups lie in the
pseudoequatorial position. Thus the antiperiplanar arrange-
ments in TSZ and TSE, in which another silyl group adopts
a different orientation, can be expected to give (Z)-8 and (E)-
8, respectively. While TSE suffers from a steric interaction
between the silyl group and H2 in the pseudoaxial position,
a similar interaction between the silyl group and H6 in TSZ
appears to be tolerable because H6 points inside. Thus TSZ
Scheme 3. Prins cyclization of 7a with ketal 10. TMSOTf=trimethylsilyl
trifluoromethanesulfonate.
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Received: February 17, 2012
Published online: && &&, &&&&
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[14] To simplify the discussion, the vinylsilane, in which the silyl
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Keywords: cyclizations · heterocycles · natural products ·
silanes · synthetic methods
.
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4
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Synthetic Methods
J. Lu, Z.-L. Song,* Y.-B. Zhang, Z. Gan,
H.-Z. Li
&&&& — &&&&
Prins Cyclization of Bis(silyl) Homoallylic
Alcohols to Form 2,6-cis-Tetrahydropyrans
Containing a Geometrically Defined
Exocyclic Vinylsilane: Efficient Synthesis
of Ring B of the Bryostatins
Prins Charming: Prins cyclization of
a bis(silyl) homoallylic alcohol with an
aldehyde shows excellent cis and Z selec-
tivity to form tetrahydropyrans containing
a geometrically defined exocyclic vinyl-
silane. This reaction was used as the key
step in the synthesis of ring B of the
bryostatins.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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These are not the final page numbers!