Expedient enantioselective synthesis of the Δ4-oxocene cores of (+)-laurencin and (+)-prelaureatin

Article abstract of DOI:10.1021/ol1021965

An expedient enantioselective synthesis of the Δ⁴-oxocene cores present in (+)-laurencin and (+)-prelaureatin was accomplished in eight steps via a novel one-pot regio- and stereoselective ring cyclization- fragmentation-expansion cascade from the tetrahydrofuran precursors which were prepared by stereocontrolled cyclization from vinylsilanes. This process is highlighted by an intramolecular oxo-carbenoid insertion and a β-silyl fragmentation sequence.

Full text of DOI:10.1021/ol1021965

ORGANIC
LETTERS
2010
Vol. 12, No. 21
4712-4715
Expedient Enantioselective Synthesis of
the ∆4-Oxocene Cores of (+)-Laurencin
and (+)-Prelaureatin‡
Jim Li,*,† Judy M. Suh, and Elbert Chin
Department of Medicinal Chemistry, Roche Palo Alto, 3431 HillView AVenue,
Palo Alto, California 94304, United States
jim.li@roche.com
Received June 1, 2010
ABSTRACT
An expedient enantioselective synthesis of the ∆4-oxocene cores present in (+)-laurencin and (+)-prelaureatin was accomplished in eight
steps via a novel one-pot regio- and stereoselective ring cyclization-fragmentation-expansion cascade from the tetrahydrofuran precursors
which were prepared by stereocontrolled cyclization from vinylsilanes. This process is highlighted by an intramolecular oxo-carbenoid insertion
and a ꢀ-silyl fragmentation sequence.
It is well documented that the species of red algae genus
Laurencia produce diverse, unique, halogenated secondary
metabolites, including a distinctive class of marine natural
products with halogenated C15 cyclic ethers in various ring
sizes.1 Laurencin 12 and laurenyne 23 are two well-known
prototypical examples containing cis R,R′-disubstituted eight-
membered cyclic ethers (Figure 1).4 The second structural
subgroup is represented by prelaureatin 35 which is consti-
Figure 1. Laurencin (1), laurenyne (2), and prelaureatin (3).
tuted with a trans R,R′-disubstituted oxocene core.6
These structurally unique Laurencia marine natural prod-
ucts have been attractive targets to the synthetic community
which had led to both development of new strategies for the
construction of medium-size cyclic ethers7,8 and the total
syntheses of laurencin 1, laurenyne 2, prelaureatin 3, and
other structurally related natural products.9,10
‡ Dedicated to Professor K. C. Nicolaou.
† Current correspondence: Calithera Biosciences, South San Francisco,
CA. E-mail: jli@calithera.com
(1) (a) Faulkner, J. D. Nat. Prod. Rep 2002, 19, 1–48, and early reviews
in the same series. (b) Erickson, K. L. In Marine Natural Products: Chemical
and Biological PerspectiVes; Scheuer, P. J., Ed.: Academic Press: New York,
1983; Vol. V, pp 131-256.
(2) (a) Irie, T.; Suzuki, M.; Masamune, T. Tetrahedron Lett. 1965, 1091–
1099. (b) Irie, T.; Suzuki, M.; Masamune, T. Tetrahedron 1968, 24, 4193–
4205. Cameron, A. F.; Cheung, K. K.; Ferguson, G.; Robertson, J. M. Chem.
Commun. 1965, 24, 638. (c) Cameron, A. F.; Cheung, K. K.; Ferguson, G.;
Robertson, J. M. J. Chem. Soc. B: Phys. Org. 1969, 5, 559–564.
(3) Falshaw, C. P.; King, T. J.; Thomson, R. H. Tetrahedron Lett. 1980,
21, 4951–4954.
Our own investigations of these natural products focused
on the construction of the ∆4-oxocene core via a novel one-
(5) Fukuzawa, A.; Takasugi, Y.; Murai, A. Tetrahedron Lett. 1991, 32,
5597–5598
.
(6) (a) Fukuzawa, A.; Kurosawa, E.; Tobetsu, I. Tetrahedron Lett. 1979,
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Thomson, R. H. J. Chem. Soc., Chem. Commun. 1984, 3, 153–155. (c)
Lyakhova, E. G.; Kalinoysky, A. I.; Dmitrenok, A. S.; Kolesnikova, S. A.;
Fedorov, S. N.; Vaskovsky, V. E.; Stonik, V. A. Tetrahedron Lett. 2006,
(4) (a) Fukuzawa, A.; Kurosawa, E.; Irie, T. Tetrahedron Lett. 1972, 1,
3–6. (b) Gonzalez, A. G.; Martin, J. D.; Martin, V. S.; Norte, M.; Perez,
R.; Ruano, J. Z.; Drexler, S. A.; Clardy, J. Tetrahedron 1982, 38, 1009–
1014. (c) Fukuzawa, A.; Aye, M.; Nakamura, M.; Tamura, M.; Murai, A.
Tetrahedron Lett. 1990, 31, 4895–4898.
47, 6549–6552
.
10.1021/ol1021965  2010 American Chemical Society
Published on Web 10/04/2010

pot regio- and stereoselective ring cyclization-fragmentation-
expansion cascade in a stereocontrolled manner. Herein, we
report an expeditious stereoselective synthesis of ∆4-oxocene
demonstrating this new approach for the first time.
Our retrosynthetic approach to (+)-laurencin 1 and (+)-
prelaureatin 3 is illustrated in Scheme 1. Simplification of the
reaction with ethyl diazoacetate. An acid-mediated intramo-
lecular tetrahydrofuran cyclization of vinylsilane 7 would
subsequently lead to aldehyde precursor 6a upon functional
group manipulation. Finally, enantiomerically pure chiral vi-
nylsilane 7 would be readily assembled from commercially
available (R)-glycidyl benzyl ether 8 and alkyne 9 precursor.
The trans R,R′-disubstituted oxocene core in (+)-prelaureatin
3 can be derived in a similar manner from the (2S,3S,5R)-
diastereomer tetrahydrofuran intermediate 6b.
Scheme 1
.
Retrosynthetic Analysis of Laurencin (1) and
Prelaureatin (3)
The synthesis of the requisite tetrahydrofuran intermediates
6a and 6b is outlined in Scheme 2. Enantiomerically pure
Scheme 2
.
Synthesis of Tetrahydrofuran Intermediates 6a and
6b
alkyl side chains and the bromine in laurencin 1 would render
∆4-oxocene 4. We envision that oxocene 4 could be derived
from the key R-diazo-ꢀ-hydroxy ester 5 intermediate via an
intramolecular oxo-carbenoid insertion and followed by a ꢀ-silyl
fragmentation cascade. R-Diazo-ꢀ-hydroxy ester 5 would then
be readily originated from aldehyde intermediate 6a via an Aldol
(7) (a) Kim, H.; Lee, D.; Kim, S.; Kim, D. J. Am. Chem. Soc. 2007,
129, 2269–2274. (b) Sasaki, M.; Hashimoto, A.; Tanaka, K.; Kawahata,
M.; Yamaguchi, K.; Takeda, K. Org. Lett. 2008, 10, 1803–1806. (c) Burton,
J. W.; Anderson, E. A.; O’Sullivan, P. T.; Collins, I.; Davies, J. E.; Bond,
A. D.; Feeder, N.; Holmes, A. B. Org. Biomol. Chem. 2008, 6, 693–702.
(d) Saitoh, T.; Suzuki, T.; Sugimoto, M.; Hagiwara, H.; Hoshi, T.
Tetrahedron Lett. 2003, 44, 3175–3178.
(8) (a) Kim, B.; Lee, M.; Kim, M.-J.; Lee, H.; Kim, S.; Kim, D.; Koh,
M.; Park, S.; Bum, S.-B.; Shin, K.-J. J. Am. Chem. Soc. 2008, 130, 16807–
16811. (b) Burton, J. W.; O’Sullivan, P. T.; Anderson, E. A.; Holmes, A. B.;
Collins, I. Chem. Commun. 2000, 7, 631–632. (c) Clark, J. S.; Freeman,
P.; Cacho, M.; Thomas, A. W. Tetrahedron Lett. 2004, 45, 8639–8642. (d)
Adsool, V. A.; Pansare, S. V. Org. Biomol. Chem. 2008, 6, 2011–2015. (e)
Kadota, I.; Uyehara, H.; Yamamoto, Y. Tetrahedron 2004, 60, 7361–7365.
(f) Clark, J. S.; Freeman, R. P.; Cacho, M.; Thomas, A. W.; Swallow, S.;
Wilson, C. Tetrahedron Lett. 2004, 45, 8639–8642. Kim, H.; Choi, W.-J.;
Jung, J.; Kim, S.; Kim, D. J. Am. Chem. Soc. 2003, 125, 10238–10240. (g)
Crimmins, M. T.; Emmitte, K. A. Synthesis 2000, 6, 899–903. (h) Edwards,
S. D.; Lewis, T.; Taylor, R. K. Tetrahedron Lett. 1999, 40, 4267–4270.
(9) (a) Murai, A.; Murase, H.; Matsue, H.; Masamune, T. Tetrahedron
Lett. 1977, 2507–2510. (b) Overman, L. E.; Thompson, A. S. J. Am. Chem.
Soc. 1988, 110, 2248–2256. (c) Bratz, M.; Bullock, W. H.; Overman, L. E.;
Takemoto, T. J. Am. Chem. Soc. 1995, 117, 5958–5966. (d) Crimmins,
M. T.; Choy, A. L. J. Am. Chem. Soc. 1999, 121, 5653–5660. (e) Burton,
J. W.; Clark, J. S.; Derrer, S.; Stock, T. C.; Bendall, J. G.; Holmes, A. B.
J. Am. Chem. Soc. 1997, 119, 7483–7498. (f) Robinson, R. A.; Clark, J. S.;
Holmes, A. B. J. Am. Chem. Soc. 1993, 115, 10400–10401. (g) Fujiwara,
K.; Yoshimoto, S.; Takizawa, A.; Souma, S.; Mishima, H.; Murai, A.;
Kawai, H.; Suzuki, T. Tetrahedron Lett. 2005, 46, 6819–6822. (h)
Boeckman, R. K.; Zhang, J.; Reeder, M. R. Org. Lett. 2002, 4, 3891–3894.
(10) (a) Crimmins, M. T.; Elie, A. T. J. Am. Chem. Soc. 2000, 122,
5473–5476. (b) Sugimoto, M.; Suzuki, T.; Haiwara, H.; Hoshi, T. Tetra-
hedron Lett. 2007, 48, 1109–1112. (c) Saioh, T.; Suzuki, T.; Sugimoto,
M.; Hagiwara, H.; Hoshi, T. Tetrahedron Lett. 2003, 44, 3175–3178. (d)
Kim, H.; Lee, H.; Lee, D.; Kim, S.; Kim, D. J. Am. Chem. Soc. 2007, 129,
2269–2274.
homopropargyl alcohol 10a was readily obtained in 84% yield
by treating terminal alkyne 9 with 1.0 equiv of n-BuLi at -78
°C, followed by a regioselective epoxide ring opening of
commercially available (R)-glycidyl benzyl ether 8 in the
presence of 1 equiv of BF3·Et2O. Establishing the absolute
stereoconfiguration of the hydroxyl group in 10a at this stage
proved to be pivotal for the success of the later key transforma-
tion. Although the newly generated alcohol 10a could be directly
converted into the desired regioisomers of 7a and 7b, we found
that protecting the hydroxyl group as acetate in 10b would
provide a better yield for the subsequent hydrosilyation step.11
Stereoselective catalytic cis-hydrosilylation (1.2 equiv of Et3SiH,
0.006 equiv of H2PtCl6·H2O) of alkyne 10b smoothly led to a
mixture of trans-vinylsilyl regioisomers 11a and 11b (ca. 2:1
ratio) in nearly quantitative yield.12 Deacetylation of the
resulting mixture of 11a and 11b to the separable regioisomers
7a and 7b (ca. 2:1 ratio, 94% yield) was readily accomplished
with DIBAL-H at -78 °C. Although each pure vinylsilane
Org. Lett., Vol. 12, No. 21, 2010
4713

could separately lead to the desired tetrahydrofurans 12a and
12b, it was more practical to take this mixture of regioisomers
7a and 7b to the cyclization step directly. Under the influence
of a catalytic amount of TsOH (0.05-0.2 equiv) at 40-60 °C,
this mixture of trans-vinylsilanes 7a and 7b was effectively
cyclized to two readily separable tetrahydrofuran diastereomers
12a and 12b (ca. 3.7-8:1 ratio) in 57-69% isolated yield, while
some starting materials were recovered.13 The stereochemical
assignments of 12a and 12b were confirmed by the NOE
experiments. Key tetrahydrofuran intermediate 6a was finally
derived from the corresponding 12a via a two-step sequence.
The TBDPS group in 12a was initially cleaved by the treatment
with TBAF, and the resulting primary alcohol 13 was subse-
quently oxidized to aldehyde 6a with Dess-Martin periodinane
in 96% yield over two steps. Similarly, intermediate 12b was
converted into aldehyde 6b in 94% overall yield.
Scheme 3. Formation of Tetrahydrofurans 12a and 12b
We observed that the product yield and ratio of the two
tetrahydrofurans from this cyclization were governed by the
catalyst loading, reaction temperature, and time.14 Decomposi-
tion of both starting materials (7a and 7b) and products (12a
and 12b) was observed under either prolonged reaction time
or at elevated reaction temperature. However, it was noteworthy
that acid-catalyzed cyclization of vinylsilane 7a was more facile
than 7b under the given reaction conditions (Scheme 3).
Formation of tetrahydrofurans 12a and 12b (ca. 5.3:1 ratio) in
95% yield from the pure vinylsilane 7a was achieved smoothly
under the optimized milder reaction conditions (0.05 equiv of
TsOH at 45 °C for 24 h). In contrast to 7a, the conversion of
vinylsilane 7b to tetrahydrofurans 12a and 12b (ca. 3.7:1 ratio)
required higher temperature (55-60 °C) and catalyst loading
(0.10 equiv of TsOH) over 48 h. The resulting lower yield (76%
yield) from 7b was likely caused by the undesired protodesi-
lylation under the more forceful reaction conditions. The
diastereoselectivity outcomes of the acid-promoted tetrahydro-
furan cyclization could be rationalized by the proposed mech-
anism from Hosomi and co-workers.15 The stereochemical
configurations of both the silyl groups and the side chains at
the C(2) positions in tetrahydrofurans 12a and 12b were
influenced by the chirality of the homoallylic hydroxyl group
we previously installed in 7a, during the stereoselective pro-
tonation step (Scheme 3). Two possible stabilized diastereomeric
ꢀ-silylcarbenium intermediates 14c and 14d were formed upon
TsOH-mediated protonation of vinylsilane 7a. Preferential
protonation from the re-face of the vinylsilane in transition state
14a over the si-face in 14b was due to the absence of steric
clash between the large Et3Si group and the methylene in the
CH2OBn residue displayed in 14b. Subsequently, the more
accessible transition state 14a led to ꢀ-silycarbenium transition
state 14c, and the further intramolecular cyclization provided
tetrahydrofuran 12a as the major product while the less
favorable transition state 14b afforded 12b as the observed
minor product. For the transformation of vinylsilane 7b to 12a
and 12b, an additional 1,2-silyl group migration was required
from ꢀ-silylcarbenium 14e to 14f prior the tetrahydrofuran
cyclization. The stereochemical assignments of 12a and 12b
were confirmed by the NOE studies.16
With aldehydes 6a and 6b in hand, we set the stage for
introducing the R-diazo-ꢀ-hydroxy ester side chain in interme-
diate 5 via the procedure reported by Holmquist and Roskamp17
(Scheme 4). Gratifyingly, treating aldehyde 6a with a slight
excess of ethyl diazoacetate (1.2 equiv) in the presence of a
catalytic amount of anhydrous SnCl2 (0.1 equiv) in CH2Cl2 at
ambient temperature cleanly afforded the anticipated ꢀ-keto
ester 15 (62-70% yield), accompanied with ∆4-oxocene 4 as
a single diastereomer (20-25% yield).18 We were delighted to
confirm the structure of 4 which resembled the desired eight-
(11) (a) Na, Y.; Chang, S. Org. Lett. 2000, 2, 1887–1889. (b) Hasan, I.;
Kishi, Y. Tetrahedron Lett. 1980, 21, 4229–4232.
(12) (a) Tsipis, C. A. J. Organomet. Chem. 1980, 187, 427–446. (b)
Thorimbert, S.; Malacria, M. Tetrahedron Lett. 1996, 47, 8483–8486. (c)
Blumenkopf, T. A.; Overman, L. E. Chem. ReV. 1986, 86, 857–873.
(13) (a) Miura, K.; Hondo, T.; Okajima, S.; Nakagawa, T.; Takahashi,
T.; Hosomi, A. J. Org. Chem. 2002, 67, 6082–6090. (b) Miura, K.; Hondo,
T.; Takahashi, T.; Hosomi, A. Tetrahedron Lett. 2002, 41, 2129–2132. (c)
Andrey, O.; Glanzmann, C.; Landais, Y.; Parra-Rapado, L. Tetrahedron
1997, 53, 2835–2854. (d) Andrey, O.; Ducry, L.; Landais, Y.; Planchenault,
D.; Weber, V. Tetrahedron 1997, 53, 4939–4352. (e) Andrey, O.; Landais,
Y. Tetrahedron Lett. 1993, 34, 8435–8438. (f) Banuls, V.; Escudier, J.-M.;
Zedde, C.; Claparols, B.; Donnadieu, H.; Plaisncie, H. Eur. J. Org. Chem.
2001, 4693–4700.
(15) (a) Miura, K.; Hondo, T.; Takahashi, T.; Hosomi, A. Tetrahedron
Lett. 2000, 41, 2129–2132. (b) Miura, k.; Hondo, T.; Saito, H.; Ito, H.;
Hosomi, A. J. Org. Chem. 1997, 62, 8292–8293.
(16) The result of the 2,3-cis relationship described here is also similar
to the cyclization of 2-silyl-3-alkenols reported by Landais and co-workers
in ref 13e.
(14) We did not fully optimize the stereoselectivity of this cyclization with
the mixture of 7a and 7b since we would prefer to utilize both diastereomers
12a and 12b for the syntheses of cis- and trans-oxocenes, respectively.
(17) Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54, 3258–
3260.
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Org. Lett., Vol. 12, No. 21, 2010

From transition state 18, a ring expansion from the [3,3,0]bi-
cyclooctane-like core can occur, followed by a simultaneous
ꢀ-Et3Si group syn elimination, to give ∆4-oxocene 4 in a
highly regio- and stereoselective manner.
Scheme 4. Synthesis of Oxocene 4 via a Ring
Formation-Fragmentation-Expansion Cascade
Similarly, aldehyde 6b was also smoothly converted into
ꢀ-keto ester 19 (69% yield) and trans R,R′-disubstituted
oxocene 20 (22% yield) (Scheme 5). The trans configuration
Scheme 5. Synthesis of Oxocene 20
membered cyclic ether core in (+)-laurencin 1. It not only
regioselectively introduced the cis-∆4-olefin, the hydroxyl group,
and two alkyl side chains in the correct positions but also
stereoselectively established the desired cis-orientation of the
C(2) and C(8) side chains adjacent to the oxygen atom in the
core. The stereochemical assignments of this eight-membered
cyclic ether core of 4 were confirmed by NOE studies.19
We postulated this ∆4-oxocene 4 was constructed through
a novel stereocontrolled ring cyclization-fragmentation-
expansion process as illustrated in Scheme 4. From the initial
Sn2+-mediated Aldol reaction, the diastereomeric adduct 16
subsequently loses N2 to form the carbene intermediate 17. The
resulting carbene 17 undergoes a known ꢀ-hydride shift to give
the expected ꢀ-keto ester product 15 (pathway a).17,20 In the
second plausible pathway, a tricyclic oxo-ylide transition state
18 is stereoselectively formed via an oxo-carbenoid insertion
by the oxygen atom from the tetrahydrofuran ring in 17.21,22
In this highly organized hydrindane-type transition state 18,
the enforcing proximity of three reacting partners accounts
for the observed stereoselectivity in 4. It is noteworthy that
H(2) adapts a preferable (S)-orientation in 18 that would
avoid the potential steric clash with the Et3Si group sitting
below the furan ring in a highly congested environment.
in 20 resembles the laurenan core structure in (+)-prelaureatin
3, another member in the Laurencia family. NOE experiments
clearly indicated the trans relationship based on the interaction
between H(2) and H(9), yet lacked of any interaction between
H(2) and H(8) as displayed in oxocene 4. The installed chirality
at C(8) from the early stage was able to direct the subsequent
stereochemical outcomes of the C(2) and C(3) positions in both
oxocene transformations. Further manipulation of both R and
R′ side chains in oxocenes 4 and 20 should lead to (+)-laurencin
1 and (+)-prelaureatin 3.
In summary, an expedient enantioselective synthesis of eight-
membered cyclic ethers was achieved in eight steps (ca. 11%
overall yield for 4) from commercially available materials. This
work highlights the unique one-pot ring cyclization-
fragmentation-expansion cascade via a rapid stereocontrolled
oxo-carbenoid insertion and subsequent ꢀ-silyl fragmentation
process from the tetrahydrofuran precursor. Application of this
methodology has led to the construction of both enantiomeri-
cally pure cis R,R′- and trans R,R′-disubstituted ∆4-oxocenes
as precursors with all the requisite elements toward the total
syntheses of marine natural products, (+)-laurencin 1, (+)-
prelaureatin 3, and other members in the Laurencia family. This
work will be reported in due course.
(18) We have found that SnCl2 was the most effective catalyst for this
transformation based on our preliminary studies with the Lewis acid catalysts
reported in ref 17.
(19) The stereochemical assignment of C(3) is based on our studies of an
oxocene 4 analogue, via the ester group reduction (LAH) in 4 and converting
the resulting diol to the diacetate. NMR spectroscopic analysis of this diacetate
compound indicated a 2,3-trans relationship, and its data also were different
from the 2,3-cis diacetate oxocene analogue reported by Crimmins et al. in ref
9d. The 1H NMR coupling constant (J ) 9.4 Hz) between H(2) and H(3) in 4,
as suggested by one reviewer, is also in agreement with an anti-configuration
reported in the studies on related oxocenes by Holmes et al. in ref 9e.
(20) In our prelimiary studies, 15 was also demonstrated to serve as a
precursor to the oxocene. The side chain in compound 15 was first converted
into an R-diazo-ꢀ-keto ester, and the resulting tetrahydrofuran then
underwent the SnCl2-mediated oxo-carbenoid insertion-ring-fragment-
expansion cascade to the ꢀ-keto ester oxocene via a two-step process similar
to the one-pot process described in Schemes 1 and 4.
Acknowledgment. We thank our Roche Palo Alto col-
leagues, Robert Greenhouse, Paul Keitz, Hans Maag, Joseph
Muchowski, and Hanbiao Yang, for their valuable comments
in this manuscript preparation. We thank Yanzhou Liu and Kate
Comstock of the Analytical Group at Roche Palo Alto for NMR
and mass spectroscopic analysis. We also acknowledge Roche
Palo Alto for the summer internship (J.M.S.).
(21) (a) Padwa, A.; Sa, M. M. Tetrahedron Lett. 1997, 38, 5087–5090.
(b) Padwa, A.; Weingarten, M. D. Chem. ReV. 1996, 96, 223–270, and
Supporting Information Available: Experimental pro-
1
cedures, H and 13C NMR spectra of new compounds, and
references cited therein
.
(22) In contrast to our observation here, a carbenoid C-H insertion and
ylide formation of a similar tetrahydrofuran intermediate were reported in
the synthetic studies of neoliacinic acid: (a) Clark, J. S.; Baxter, C. A.;
Dossetter, A. G.; Poigny, S.; Castro, J. L.; Whittingham, W. G. J. Org.
spectral data. This material is available free of charge via
the Internet at http://pubs.acs.org.
Chem. 2008, 73, 1040–1055
.
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