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Synthesis 2016; 48(11): 1700-1710
DOI: 10.1055/s-0035-1561607
special topic
© Georg Thieme Verlag Stuttgart · New York

Asymmetric Iterative Hydration of Polyene Strategy to Cryptocaryols A and B

Thomas J. Hunter
b   MilliporeSigma, 645 Science Drive, Madison, WI 53711, USA
,
Yanping Wang
a   Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA   Email: G.ODoherty@neu.edu
,
Jiamin Zheng
a   Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA   Email: G.ODoherty@neu.edu
,
George A. O’Doherty*
a   Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA   Email: G.ODoherty@neu.edu
› Author Affiliations
Further Information

Publication History

Received: 21 February 2016

Accepted after revision: 11 March 2016

Publication Date:
13 April 2016 (online)

 
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Abstract

The development of two iterative asymmetric hydration approaches to the synthesis of all syn- and syn/anti/syn-1,3,5,7-tetraol motifs is described. These pseudo-symmetric products are synthetic precursors for 1,3-hexol products. The utility of the route to the all syn-1,3,5,7-tetraol diastereoisomer was demonstrated with its use in the synthesis of cryptocaryols A and B, as well as, stereoisomers.


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Key words

asymmetric synthesis - iterative hydration - cryptocaryol A - cryptocaryol B - 1,3-polyols

Cryptocaryols A and B (1 and 2) are two members of a class of 5,6-dihydro-α-pyranone/1,3-polyol natural products that were reported in 2011 by Gustafson (Figure [1]).[1] Using a high-throughput PDCD4 stabilization assay, eight cryptocaryols were found in extracts from the plant Cryptocarya sp. with EC50 ranging from 1.3 to 4.9 μM. Using detailed NMR, HRMS, and CD analyses,[2] [3] the structures for cryptocaryols A and B were tentatively assigned as the purported structures 3 and 4. These initial structures had the correct connectivity but lacked certainty in terms of their absolute and relative stereochemistry. This stereochemical uncertainty was not resolved until the purported and actual structures succumbed to total synthesis by us and others.[4] [5] [6] In addition to elucidating the structure of the cryptocaryols, our successful synthetic efforts provided material for the initial SAR studies of this class of natural products as both stabilizers of PDCD4 and anticancer agents.[7] Thus, both enantiomers of cryptocaryols A (1) and B (2) as well as their diastereomers were prepared and studied.

Our strategy focused on the synthesis of the all syn-tetraol relative configuration of the C-5 to C-15 portion of the cryptocaryols.[8] This approach resulted from the recognition that the complete natural product could be constructed by diastereoselectively appending the C-5/C-15 pyranone and the C-15/C-5 alkyl side chain to a single enantiomer of syn-8. This stereodivergent approach takes advantage of the pseudo-symmetry of syn-8, which allows for its stereoselective elaboration into any of the eight most likely stereoisomers of the cryptocaryols. Herein, we disclose the development of the synthetic chemistry that underpinned this effort. Specifically, this includes the development of a dienoate iterative asymmetric hydration, its elaboration to the asymmetric synthesis of C s- and C 2-symmetric protected tetraol precursors, and finally the use of one of these stereoisomeric polyols for the synthesis, structure elucidation, and medicinal chemistry study of the cryptocaryols (Scheme [1]).

Zoom Image
Figure 1 Cryptocaryol A and B
Zoom Image
Scheme 1 Retrosynthetic analysis of cryptocaryol A and B

Our approach to the 1,3-syn-diol motif builds on the idea that a 3,5-dihydroxy carboxylic ester 12 would result from the iterative alkene hydration of a 2,4-dienoate 9 (Scheme [2]).[9] [10] [11] Key to controlling the sequence and regiocontrol of the first hydration step comes from the recognition that an asymmetric hydration of the distal double bond of a 2,4-dienoate 9 to a 5-hydroxy-1-enoate 11 would result by an asymmetric oxidation and reduction sequence. Finally, the remaining alkene can be diastereoselectively hydrated by the in situ trapping of a hemiacetal using the Evans protocol resulting in the benzylidene protected 3,5-dihydroxy carboxylic ester 12.[12]

Zoom Image
Scheme 2 Asymmetric hydration route to syn-1,3-diol

Our first attempt to execute the initial hydration step began with the Sharpless dihydroxylation of ethyl sorbate (13a) to give 4,5-dihydroxy-1-enoate 14a (71%, 80% ee).[13] [14] We next explored converting the allylic alcohol into ester and carbonate type Pd-π-allyl leaving groups 15a–c (see Table [1] for R).[15] When 15a,b were exposed to our typical π-allyl Pd-hydride reducing conditions [2.5 mol% Pd2(dba)3·CHCl3/6.3 mol% PPh3], a significant amount of reductive elimination occurred along with the benzoate 16a and ethyl carbonate 16b. In contrast, the cyclic carbonate 15c was reduced under the same conditions to give the desired 5-hydroxy-1-enoate 16c without any elimination (70%).[16]

Table 1 Optimization of the Asymmetric Hydration of Dienoatesa

Entry

Compound

R1

R2

Yield (%)

Ratio

1

16a:13a

Bz

Bz

43

4:1

2

16b:13a

CO2Et

CO2Et

47

4:1

3

16c:13a

-(C=O)-

H

70

1:0

a Reaction conditions: a) OsO4 (1 mol%), (DHQ)2PHAL (1.1 mol%), K3FeCN6/MeSO2NH2, 71%; b) BzCl, Et3N, CH2Cl2, 57%; c) ClCO2Et, Et3N, CH2Cl2, 81%; d) (Cl3CO)2CO, pyridine, CH2Cl2, 87%; e) HCO2H/Et3N, Pd2(dba)­3·CHCl3, PPh3, THF, 66 °C.

We next explored the applicability of the protocol on a variety of δ-substituted dienoates 13a–g (Table [2]). When the variously substituted dienoates 13a–g were exposed to the Sharpless dihydroxylation and carbonate forming conditions, carbonates 17a–g were obtained in improved yields and enantiomeric excesses. Similar yields and enantiomeric purities were obtained from the (DHQ)2PHAL or the (DHQD)2PHAL­ ligand system (80–95% ee). Exposing the cyclic carbonates 17a–g to our optimized Pd-reduction conditions [2.5 mol% Pd2(dba)3·CHCl3/6.3 mol% PPh3] gave homoallylic alcohols 18a–g (66–93%) with no loss of enantiomeric excess (80–95% ee). With the demonstrated generality for the first asymmetric hydration set, we next pursued the subsequent hydration/protection step.

Table 2 Scope of Asymmetric Hydration of Polyenea

Entry

Compound

R1

R2

Yield (%) of 14, ee (%)

Yield (%) of 17

Yield (%) of 18

1

a

Et

Me

71, 80

87

70

2

b

Me

Pr

81, 95

94

80

3

c

Et

Ph

79, 95

91

72

Entry

Compound

R1

R2

Yield (%) of ent-14, ee (%)

Yield (%) of ent-17

Yield (%) of ent-18

4

ent-d

Et

CH2OTBS

82, 95

94

88

5

ent-e

Et

(CH2)2OTBS

91, 95

95

87

6

ent-f

Me

(CH2)2OPMB

79, 95

95

93

7

ent-g

Et

CH2OPMB

NA

57

66

a Reaction conditions: a) OsO4 (1 mol%), (DHQ)2PHAL (1.1 mol%), K3FeCN6/MeSO2NH2; a′) OsO4 (1 mol%), (DHQD)2PHAL (1.1 mol%), K3FeCN6/MeSO2NH2; b) (Cl3CO)2CO, pyridine, CH2Cl2; c) HCO2H/Et3N, Pd2(dba)3·CHCl3, PPh3, THF, 66 °C.

b NA: not attempted.

As with the first three steps, we found a broad substrate scope for the Evans acetal forming reaction. Thus, when exposing the δ-hydroxy enoates 18a–g to the Evans procedure (1.1 equiv of benzaldehyde and 0.11 equiv of KOt-Bu, 0 °C, repeat 3 times every 15 min), all but one proceeded smoothly to the desired benzylidene protected 3,5-dihydroxy carboxylic esters 19a–c,e–g. Typical yields for these transformations are in the 60% range. The exception to this was the substrate with the C-6 tert-butyldimethylsiloxy group in Table [3], entry 4. Unfortunately, under the basic conditions, the TBS group migrated to the C-5 alkoxide leaving behind a C-6 alkoxy group, which was ideally poised to intramolecularly add across the enoate to give tetrahydrofuran 20. This issue with silyl-group migration was easily solved by simply switching the TBS group to a base-stable PMB group (19f and 19g).

Table 3 Evans Acetal Formationa

Entry

Compound

R

R′

Yield (%)

1

19a

Me

Et

60

2

19b

Pr

Me

60

3

19c

Ph

Et

52

Entry

Compound

R1

R2

Yield (%)

4

20

CH2OTBS

Et

88

5

ent-19e

CH2CH2OTBS

Et

68

6

ent-19f

CH2CH2OPMB

Me

62

7

ent-19g

CH2OPMB

Et

61

a Reaction conditions: a) PhCHO (1.1 equiv), KOt-Bu (0.11 equiv), 3 times, THF, 0 °C.

Building upon this observation, we decided to use the benzylidene protected 3,5-dihydroxy carboxylic esters with a C-7 OPMB group to build the next 1,3-syn-diol unit (Scheme [3]). To accomplish this, we first needed to append another dienoate functional group onto the carbon chain. This undertaking was most easily accomplished by a DIBALH reduction of the methyl ester in ent- 19f, which cleanly provided aldehyde 21 (93%). A subsequent vinylogous Horner–Wadsworth–Emmons olefination of aldehyde 21 with phosphonate 25 and base gave the desired dienoate 22 (66%).[17] With the E,E-dienoate in place in 22, it can then be elaborated into a second 1,3-syn-diol unit subunit. Simply repeating the four-step iterative hydration sequence of 22 would install the second benzylidine acetal as in ent-syn-8. Thus exposing 22 to the typical Sharpless asymmetric dihydroxylation conditions [OsO4 (1 mol%), (DHQD)2PHAL (1.1 mol%), K3FeCN6, MeSO2NH2], diol 23 was produced as a single diastereomer (71%). Treating diol 23 with triphosgene and base readily converted the diol into a cyclic carbonate, which when exposed to the Pd-reduction conditions [HCO2H/Et3N, 1 mol% Pd2(dba)3·CHCl3/2.5 mol% PPh3] cleanly gave the 5-hydroxy-1-enoate syn-24 (90%). Finally, exposing syn-24 to the Evans acetal formation condition [PhCHO (1.1 equiv), KOt-Bu (0.11 equiv), 3 times, THF, 0 °C) easily converted it into the bis(benzylidene)-protected ester ent-syn-8 in good yield (63%).

Zoom Image
Scheme 3 Iterative oxidation/reduction approach to syn-1,3-polyols. Reagents and conditions: a) DIBALH, CH2Cl2, –78 °C, 93%; b) LiOH·H2O, phosphonate 25, 4 Å molecular sieves, THF, 66%; c) OsO4 (1 mol%), (DHQD)2PHAL (1.1 mol%), K3FeCN6, MeSO2NH2, 71%; d) (Cl3CO)2CO, pyridine, CH2Cl2, 90%; e) Pd2(dba)3·CHCl3 (1 mol%), PPh3 (2.5 mol%), HCO2H/Et3N, THF, 66 °C, 90%; f) PhCHO (1.1 equiv), KOt-Bu (0.11 equiv), 3 times, THF, 0 °C, 63%.

Concerns over the scale-ability and dienoate stability inspired us to pursue an alternative approach for the ste­reoselective installation of the second benzylidene unit (i.e., 22 to syn-8). In this regard, we devised an allylation/cross metathesis strategy (Scheme [4]). This alternative approach began with a one-pot reduction/allylation sequence, which involved an in situ addition of the allyl Grignard reagent directly to the ester 19f/DIBALH reaction mixture.[10] When this reaction was warmed to room temperature and quenched, a 1.2:1 ratio of homoallylic alcohols syn-26 and anti-26 were isolated in good overall yield (91%). Unfortunately, all of our efforts to improve upon this modest selectivity in the allylation reaction were unsuccessful. These efforts included the addition of various chelating Lewis acids (Al, Ti, Zn) in combination with an allyl anion, in an attempt to take advantage of the β-alkoxy group. While these homoallylic alcohols can be separated by silica gel chromatography, the ratio would be improved by an oxidation/reduction reaction sequence. Thus, treatment of a diastereomeric mixture of syn-26 and anti-26 with Dess–Martin periodinane (DMP) reagent gave a clean conversion to the β,γ-unsaturated ketone 27, without any double bond isomerization (90%). Then, treating a THF solution of 27 with L-Selectride at –90 °C provided syn-26 in a 4:1 ratio (89%).

In spite of our desire to try to use a substrate controlled approach to control the stereochemistry in the next benzylidene subunit, a much more practical and simplified procedure resulted when we turned to a reagent control approach in the allylation reaction. This involved turning to the Leighton allylation reagents 29.[18] Thus, this revised procedure to the installation of the second protected diol fragment of 19f began with the same ester to aldehyde reduction with DIBALH (19f to ent-21, 93%) (Scheme [5]). In this alternative approach, exposure of purified aldehyde ent-21 to the (S,S)-Leighton reagent cleanly afforded homoallylic alcohol syn-26 as a single diastereoisomer. A Grubbs II type cross metathesis reaction between syn-26 and ethyl acrylate gave a single alkene isomer, which we previously have shown can be converted into bis(benzylidene)-protected ester syn-8.[19] The stereodivergent aspect of the synthesis can be seen in its ability to just as easily be used for the conversion of 19f into the diastereomeric bis(benzylidene)-protected ester anti-8. This involves the switching of the (S,S)-Leighton reagent to the (R,R)-Leighton reagent in the allylation of ent-21. Thus when ent-21 is treated with the (R,R)-Leighton reagent homoallylic alcohol anti-26 is produced as a single diastereomer. The diastereomeric alcohol anti-26 reacted similarly under the Grubbs II cross-metathesis conditions to give the 5-hydroxy-1-enoate ent-anti-24 (90%). Finally the Evans acetal forming reaction [PhCHO (1.1 equiv), KOt-Bu (0.11 equiv), 3 times, THF, 0 °C, 77%] is used to install the final benzylidene unit in the diastereomeric bis(benzylidene)-protected ester anti-8 (Scheme [5]).

Zoom Image
Scheme 4 Second-generation approach to protected 1,3-syn-polyol. Reagents and conditions: a) DIBALH, CH2Cl2, –78 °C, 1 h, then allyMgCl (2 M THF solution), r.t., 91%; b) DMP, CH2Cl2, 90%; c) L-Selectride, –90 °C, 89%, dr = 4:1; d) ethyl acrylate, Grubbs II cat. (2.5 mol%), CH2Cl2, 99%; e) PhCHO (1.1 equiv), KOt-Bu (0.11 equiv), 3 times, THF, 0 °C, 77%.
Zoom Image
Scheme 5 Synthesis of protected syn- and anti-1,3-polyols. Reagents and conditions: a) DIBALH, CH2Cl2, –78 °C, 93%; b) (S,S)-29, Sc(OTf)3 (2.5 mol%), CH2Cl2, –10 °C, 72%; c) ethyl acrylate, Grubbs II (2.5 mol%), 99%; d) PhCHO (1 equiv), KOt-Bu (0.11 equiv), 3 times, THF, 0 °C, 77%; e) (R,R)-29, Sc(OTf)3 (2.5 mol%), CH2Cl2, –10 °C, 72%; f) ethyl acrylate, Grubbs II cat. (2.5 mol%), 99%; g) PhCHO (1.1 equiv), KOt-Bu (0.11 equiv), 3 times, THF, 0 °C, 77%.

With access to the C s- and C 2-symmetric protected tetraol precursors syn-8 and anti-8, we next looked to install the remaining C-5/C-15 stereochemistry of the cryptocaryols (Scheme [6]). Because we wanted to be able to install both R- and S-stereochemistry at the C-5/C-15, we looked into using a reagent-controlled approach. We found that this was most easily accomplished with the use of the Leighton reagent for the C-5 position and the Noyori hydrogen transfer reaction for the C-15 position.[20] For the Noyori reduction to occur with high stereocontrol, an ynone functionality needed to be introduced, as in 31. This was most easily accomplished by removing the PMB group (DDQ, 92%) and oxidizing the primary alcohol with the Dess–Martin­ reagent (81%) to give 30. An unselective addition of 1-lithiopentadec-1-yne to aldehyde 30 and a subsequent Dess–Martin oxidation was used to give 31 (62%). Exposure of 31 to our typical Noyori reduction conditions [(S,S)-Noyori (5 mol%), Et3N, formic acid, 94%] gave a propargyl alcohol as a single diastereomer, which upon exposure to excess diimide gave secondary alcohol 32 with the desired R-stereochemistry at C-15. The R-stereochemistry at C-5 was installed by reducing the ester to an aldehyde with DIBALH (87%), acylating the C-15 alcohol (Ac2O, 72%) and finally a diastereoselective addition of an allyl anion with the (S,S)-Leighton reagent (75%) resulting in homoallylic alcohol 33. A similar approach was used to convert 32 into 34 with the S-stereochemistry at C-5 [TBSCl, DIBALH, and (R,R)-Leighton; 82%]. However, in this alternative approach the C-15 alcohol was protected as a TBS group.

Zoom Image
Scheme 6 Synthesis of protected tetraol intermediates
Zoom Image
Scheme 7 Synthesis of 1,3-syn-ploly/pyranones

To install the C-5/C-15 with the opposite tetraol stereochemistry (ent-34), all we need to do is apply the same sequences to the opposite ends of the tetraol precursors syn-8 (Scheme [6]). This began with a DIBALH reduction of syn-8 followed by an unselective 1-lithiopentadec-1-yne to resulting aldehyde and a subsequent Dess–Martin oxidation was used to give ynone 35 (62%). Noyori reduction of 35 [(R,R)-Noyori (5 mol%), Et3N, formic acid, 98%] gave a propargyl alcohol as a single diastereomer, which upon exposure to excess diimide gave secondary alcohol 36 with the desired S-stereochemistry at C-15. TBS protection of the secondary alcohol (94%) and DDQ-promoted removal of the PMB group (92%) gave 37. Finally the C-5 R-stereochemistry was installed by oxidation of the primary alcohol and addition of the (S,S)-Leighton reagent (95%).

With all the stereochemistry installed in homoallylic alcohol ent-34, it was readily converted into cryptocaryol A (1), by a three-step procedure. This began with an acrylation of the C-5 alcohol, ring-closing metathesis with the Grubbs I reagent, and aqueous acetic acid deprotection to give 1 (42% over three steps).[21] By replacing the C-15 TBS group with an acetate (TBAF then Ac2O) after the acrylation at C-5, homoallylic alcohol ent-34 could also be converted into cryptocaryol B (2) (28% over five steps). Applying the identical 3- and 5-step sequences to 34 provided ent-cryptocaryol A (ent-1) and ent-cryptocaryol B (ent-2). Both synthetic cryptocaryols A and B, gave identical spectral data as was reported for the natural material.[1] Finally, the homoallylic alcohol 33 was converted into purported cryptocaryol B (4), the initially assigned structure for cryptocaryol B, by a three-step acrylation of the C-5 alcohol, ring-closing metathesis with the Grubbs I reagent and aqueous acetic acid deprotection (35%, over 3 steps) (Scheme [7]).

In conclusion, we have described the full account of our recently completed synthesis of cryptocaryol A (1) and cryptocaryol B (2). The route featured three different approaches to the C s- and C 2-symmetric protected tetraol precursors syn-8 and anti-8, which are key building blocks for the synthesis of many polyacetate type natural products. The utility of this approach was demonstrated in the application of various stereoisomeric analogues of the cryptocaryols, which in turn enabled structure activity relationship studies.

1H and 13C NMR spectra were recorded on a Varian 300, 400, or 500 MHz spectrometer. Chemical shifts were reported relative to internal TMS (δ = 0.00) or CDCl3 (δ = 7.26) or CD3OD (δ = 3.30) for 1H NMR and CDCl3 (δ = 77.2) or CD3OD (δ = 49.05) for 13C NMR. In the case of 19F NMR, trifluoroacetic acid (δ = –76.55) was used as an external reference for Mosher ester analyses. IR spectra were obtained on a FT-IR spectrometer. Optical rotations were measured with a digital polarimeter in the solvent specified. Melting points were determined with a standard melting point apparatus. Flash column chromatography was performed on 60–200 or 230–400 mesh silica gel. Analytical TLC was performed with precoated glass-backed plates and visualized by quenching of fluorescence and by charring after treatment with p-anisaldehyde or KMnO4 stain. Rf values were obtained by elution in the stated solvent ratios. Et2O, THF, CH2Cl2, and Et3N were dried by passing through activated Al2O3 column with argon gas pressure. Commercial reagents were used without purification, unless otherwise noted. Air- and/or moisture-sensitive reactions were carried out under an atmosphere of argon/N2 using oven- or flame-dried glassware and standard syringe/septa techniques.

Complete experimental data for the synthesis of all starting materials, intermediates, and final targeted products (Scheme [7]) are provided in detail in the Supporting Information.


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2-((2R,4R,6R)-6-{2-[(4-Methoxybenzyl)oxy]ethyl}-2-phenyl-1,3-dioxan-4-yl)acetaldehyde (21)

DIBALH (11.5 mL of a 1 M solution in CH2Cl2) was added to a –78 °C solution of the ester ent-19f (3.06 g, 7.64 mmol) in CH2Cl2 (40 mL). After 30 min, acetone was added to quench the reaction and it was stirred for 10 min before warming to r.t. A 20% solution of sodium potassium tartrate (30 mL) was added and the biphasic mixture was stirred until the two layers rapidly separated on cessation of stirring. The aqueous layer was extracted with CH2Cl2 (2 × 20 mL). The combined organic layers were washed with brine, filtered, and concentrated. The crude product was purified by silica gel chromatography to produce benzylidene-protected diol 21 (2.63 g) in 93% yield as a clear oil; Rf = 0.58 (3:2 hexanes–EtOAc); [α]D +37.0 (c 1.0, CH2Cl2).

IR (neat): 3035, 3002, 2858, 2729, 2358, 2060, 1732, 1614, 1586, 1515, 1455, 1345, 1302, 1248, 1176, 1101 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 9.86 (dd, J = 2, 2 Hz, 1 H), 7.44 (m, 2 H), 7.34 (m, 3 H), 7.26 (d, J = 8.5 Hz, 2 H), 6.87 (d, J = 8.5 Hz, 2 H), 5.57 (s, 1 H), 4.47 (d, J = 12 Hz, 1 H), 4.43 (d, J = 12 Hz, 1 H), 4.42 (m, 1 H), 4.09 (dddd, J = 11, 8, 4.5, 2.5 Hz, 1 H), 3.79 (s, 3 H), 3.67 (ddd, J = 9.5, 8.5, 5.5 Hz, 1 H), 3.56 (ddd, J = 9.5, 5.5, 5.5 Hz, 1 H), 2.80 (ddd, J = 17, 7.5, 2 Hz, 1 H), 2.61 (ddd, J = 17, 5, 2 Hz, 1 H), 1.92 (dddd, J = 13.5, 8, 5, 5 Hz, 1 H), 1.84 (m, 1 H), 1.69 (ddd, J = 13, 2.5, 2.5 Hz, 1 H), 1.50 (ddd, J = 12.5, 11, 11 Hz, 1 H).

13C NMR (CDCl3, 125 MHz): δ = 200.4, 159.2, 138.3, 130.5, 129.3, 128.7, 128.2, 128.2, 126.0, 113.8, 100.6, 73.7, 72.7, 71.9, 65.5, 55.3, 49.4, 36.7, 36.0.

HRMS (ESI): m/z calcd for [C22H26O5 + Na + MeOH]+: 425.1940; found: 425.1952.


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Ethyl (2E,4E)-6-((2S,4S,6R)-6-{2-[(4-Methoxybenzyl)oxy]ethyl}-2-phenyl-1,3-dioxan-4-yl)hexa-2,4-dienoate (22)

To phosphonate 25 (469 mg, 2.11 mmol) in THF (8 mL) was added LiOH·H2O­ (81 mg, 1.94 mmol) and 4 Å (1.5 g) molecular sieves. This mixture was heated at reflux for 30 min. before aldehyde 21 (625 mg, 1.69 mmol) dissolved in THF (2 mL) THF was added. This mixture was heated at reflux for 6 h and then filtered through a plug of Celite. The solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography to produce dienoate 22 (523 mg) in 66% yield as a clear oil; Rf = 0.71 (3:2 hexanes–EtOAc); [α]D + 7.8 (c 1.16, CH2Cl2).

IR (neat): 2948, 1714, 1644, 1614, 1586, 1514, 1454, 1367, 1302, 1250, 1173, 1097 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 7.46 (m, 2 H), 7.35 (m, 3 H), 7.26 (d, J = 9 Hz, 2 H), 7.26 (m, 1 H), 6.87 (d, J = 8.7 Hz, 2 H), 6.28 (dd, J = 15.3, 9.6 Hz, 1 H), 6.20 (ddd, J = 15, 6.3, 6.3 Hz, 1 H), 5.82 (d, J = 15.3 Hz, 1 H), 5.51 (s, 1 H), 4.48 (d, J = 11.7 Hz, 1 H), 4.42 (d, J = 11.7 Hz, 1 H), 4.20 (q, J = 7.2 Hz, 2 H), 4.02 (dddd, J = 12, 7.5, 4.5, 2.5 Hz, 1 H), 3.91 (m, 1 H), 3.79 (s, 3 H), 3.66 (ddd, J = 9, 9, 5.1 Hz, 1 H), 3.56 (ddd, J = 9.6, 5.4, 5.4 Hz, 1 H), 2.53 (ddd, J = 14.7, 6.3, 6.3 Hz, 1 H), 2.42 (ddd, J = 14.4, 6.6, 6.6 Hz, 1 H), 1.76–1.98 (m, 2 H), 1.60 (ddd, J = 13.2, 2.4, 2.4, Hz, 1 H), 1.44 (ddd, J = 13.2, 11.1, 11.1 Hz, 1 H), 1.30 (t, J = 7.2 Hz, 3 H).

13C NMR (CDCl3, 75 MHz): δ = 166.9, 159.0, 144.3, 138.8, 138.5, 130.6, 130.4, 129.1, 128.4, 128.0, 125.9, 120.0, 113.6, 100.3, 75.7, 73.5, 72.5, 65.4, 60.1, 55.1, 39.2, 36.5, 35.9, 14.2.

HRMS (ESI): m/z calcd for [C28H34O6 + Na]+: 489.2253; found: 489.2227.


#

Ethyl (4R,5R,E)-4,5-Dihydroxy-6-((2R,4S,6R)-6-{2-[(4-methoxybenzyl)oxy]ethyl}-2-phenyl-1,3-dioxan-4-yl)hex-2-enoate (23)

Into a 25 mL round bottom flask containing dienoate 22 (131 mg, 0.28 mmol) were added t-BuOH (2 mL), H2O (2 mL), K3Fe(CN)6 (277 mg, 0.84 mmol), K2CO3 (116 mg, 0.84 mmol), MeSO2NH2 (27 mg, 0.28 mmol), and (DHQD)2-PHAL (13 mg, 16.8 μmol). The mixture was stirred at r.t. for 15 min and then cooled to 0 °C. To this solution was added OsO4 (3.6 mg, 14 μmol) and the reaction mixture was stirred vigorously at 0 °C overnight. The reaction was quenched with sat. aq Na2SO3 (4 mL) at r.t. EtOAc (5 mL) was added to the reaction mixture, and after separation of the layers, the aqueous phase was further extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with aq 2 N KOH (10 mL) to remove the methanesulfonamide and brine, and then dried (anhyd Na2SO4). After removal of the solvents in vacuo, flash chromatography on silica gel afforded 99 mg (71%) of 23 as a clear oil; Rf = 0.16 (3:2 hexanes–EtOAc); [α]D +18.6 (c 1.2, CH2Cl2).

IR (neat): 3478, 2914, 1713, 1660, 1613, 1586, 1547, 1514, 1463, 1454, 1304, 1100 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 7.41 (m, 2 H), 7.35 (m, 3 H), 7.26 (d, J = 9 Hz, 2 H), 6.96 (dd, J = 15.5, 5 Hz, 1 H), 6.87 (d, J = 9 Hz, 2 H), 6.14 (dd, J = 15.5, 2 Hz, 1 H), 5.56 (s, 1 H), 4.45 (d, J = 11.5 Hz, 1 H), 4.45 (d, J = 11.5 Hz, 1 H), 4.20 (q, J = 7 Hz, 2 H), 4.19 (m, 2 H), 4.07 (dddd, J = 10.5, 7.5, 4, 2 Hz, 1 H), 3.93 (dddd, J = 9.5, 4.5, 2.5, 2.5 Hz, 1 H), 3.79 (s, 3 H), 3.65 (ddd, J = 9, 8, 5 Hz, 1 H), 3.56 (ddd, J = 9.5, 5.5, 5.5 Hz, 1 H), 1.92 (m, 2 H), 1.84 (m, 1 H), 1.77 (ddd, J = 15, 3, 3 Hz, 1 H), 1.62 (m, 1 H), 1.52 (ddd, J = 13, 11, 11 Hz, 1 H), 1.29 (t, J = 7 Hz, 3 H).

13C NMR (CDCl3, 125 MHz): δ = 166.3, 159.2, 146.8, 138.1, 130.5, 129.4, 129.0, 128.4, 126.0, 122.4, 113.8, 100.7, 80.7, 77.1, 73.8, 73.1, 72.7, 65.4, 60.5, 55.3, 38.6, 37.0, 36.0, 14.3.

HRMS (ESI): m/z calcd for [C28H36O8 + Na]+: 523.2308; found: 523.2329.


#

Ethyl (E)-3-{(4R,5R)-5-[((2R,4R,6R)-6-{2-[(4-Methoxybenzyl)oxy]ethyl}-2-phenyl-1,3-dioxan-4-yl)methyl]-2-oxo-1,3-dioxolan-4-yl}acrylate (23a)

Into a 10 mL volumetric flask containing diol 23 (90 mg, 0.18 mmol) and pyridine (57 μL) was placed CH2Cl2 (2 mL). This mixture was cooled to 0 °C and triphosgene (27 mg, 0.09 mmol) dissolved in CH2Cl2­ (1 mL) was added slowly using an addition funnel. The reaction mixture was stirred for 1.5 h and quenched with sat. aq NH4Cl (4 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were washed with sat. aq NaHCO3 (10 mL), brine (10 mL), and dried (anhyd Na2SO4). After removal of the solvents in vacuo, flash chromatography on silica gel afforded 23a as a clear colorless oil (87 g, 92%); Rf = 0.11 (4:1 hexanes–EtOAc); [α]D +39.3 (c 1.7, CH2Cl2).

IR (neat): 2920, 1810, 1716, 1668, 1615, 1586, 1560, 1516, 1456, 1248 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 7.42 (m, 2 H), 7.36 (m, 3 H), 7.27 (d, J = 8.7 Hz, 2 H), 6.88 (d, J = 8.7 Hz, 2 H), 6.83 (dd, J = 15.6, 5.7 Hz, 1 H), 6.14 (dd, J = 15.6, 1.5 Hz, 1 H), 5.51 (s, 1 H), 5.14 (ddd, J = 7.2, 5.7, 1.5 Hz, 1 H), 4.63 (ddd, J = 6.6, 5.1, 5.1 Hz, 1 H), 4.48 (d, J = 11.7 Hz, 1 H), 4.43 (d, J = 11.7 Hz, 1 H), 4.20 (q, J = 7.2 Hz, 2 H), 4.02–4.18 (m, 2 H), 3.80 (s, 3 H), 3.66 (ddd, J = 9.3, 8.1, 5.1 Hz, 1 H), 3.57 (ddd, J = 11.1, 5.4, 5.4 Hz, 1 H), 2.08–2.18 (m, 2 H), 1.80–1.98 (m, 2 H), 1.58 (m, 2 H), 1.29 (t, J = 7.2 Hz, 3 H).

13C NMR (CDCl3, 75 MHz): δ = 164.7, 159.0, 153.5, 139.1, 137.9, 130.3, 129.2, 128.7, 128.1, 125.8, 124.8, 113.6, 100.5, 79.4, 78.0, 73.6, 72.5, 71.9, 65.2, 60.9, 55.1, 37.7, 36.2, 35.8, 14.0.

HRMS (ESI): m/z calcd for [C29H34O9 + Na]+: 549.2101; found: 549.2082.


#

Ethyl (S,E)-5-Hydroxy-6-((2R,4S,6R)-6-{2-[(4-methoxybenzyl)oxy]ethyl}-2-phenyl-1,3-dioxan-4-yl)hex-2-enoate (syn-24)

Into a 10 mL round bottom flask fitted with a condenser and maintained under N2 were placed 23a (80 mg, 0.152 mmol), Pd2(dba)3·CHCl3­ (1.6 mg, 1.5 μmol), PPh3 (1 mg, 3.8 μmol), and THF (1.5 mL). Et3N (63 μL, 0.46 mmol) and formic acid (17 μL, 0.46 mmol) were added and the mixture was allowed to reflux for 3 h. The reaction was cooled to r.t. and quenched with sat. aq NaHCO3 (2 mL). The aqueous layer was extracted with Et2O (3 × 5 mL). The organic layer was washed with brine (5 mL) and dried (anhyd Na2SO4). After removal of the solvents in vacuo, flash chromatography on silica gel afforded syn-24 as a yellow oil (66 mg, 90%); Rf = 0.22 (3:2, hexanes–EtOAc); [α]D +7.7 (c 1.0, CH2Cl2).

IR (neat): 3518, 3035, 2938, 2863, 1886, 1722, 1714, 1658, 1652, 1614, 1586, 1514, 1463, 1454, 1368, 1302, 1248, 1174 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 7.41 (m, 2 H), 7.34 (m, 3 H), 7.26 (d, J = 9 Hz, 2 H), 6.98 (ddd, J = 15.5, 7.5, 7.5 Hz, 1 H), 6.86 (d, J = 8.5 Hz, 2 H), 5.90 (ddd, J = 15.5, 1.5, 1.5 Hz, 1 H), 5.56 (s, 1 H), 4.46 (d, J = 12 Hz, 1 H), 4.42 (d, J = 12 Hz, 1 H), 4.18 (q, J = 7 Hz, 2 H), 4.03–4.15 (m, 3 H), 3.79 (s, 3 H), 3.65 (ddd, J = 9.5, 8.5, 5 Hz, 1 H), 3.55 (ddd, J = 9.5, 5.5, 5.5 Hz, 1 H), 2.39 (m, 2 H), 1.92 (dddd, J = 14, 8.5, 5.5, 5.5 Hz, 1 H), 1.76–1.86 (m, 2 H), 1.68 (ddd, J = 14.5, 2.5, 2.5 Hz, 1 H), 1.60 (ddd, J = 13, 2.5, 2.5 Hz, 1 H), 1.50 (ddd, J = 13, 11, 11 Hz, 1 H), 1.29 (q, J = 7 Hz, 3 H).

13C NMR (CDCl3, 75 MHz): δ = 166.3, 159.2, 145.0, 138.2, 130.5, 129.3, 128.9, 128.3, 126.0, 123.8, 113.8, 100.6, 77.4, 73.8, 72.7, 70.0, 65.5, 60.3, 55.3, 42.1, 40.2, 37.1, 36.0, 14.3.

HRMS (ESI): m/z calcd for [C28H36O7 + Na]+: 507.2359; found: 507.2348.


#

Ethyl 2-{(2R,4R,6R)-6-[((2R,4R,6R)-6-{2-[(4-Methoxybenzyl)oxy]ethyl}-2-phenyl-1,3-dioxan-4-yl)methyl]-2-phenyl-1,3-dioxan-4-yl}acetate (ent-syn-8)

To a solution of alcohol syn-24 (75 mg, 0.155 mmol) in THF (1.5 mL) at 0 °C was added benzaldehyde (15 μL, 0.16 mmol), followed by KOt-Bu (1.7 mg, 0.016 mmol). The solution was stirred for 15 min. The addition of benzaldehyde/KOt-Bu was repeated 3 more times and the reaction was quenched with pH 7 phosphate buffer (1 mL) and diluted with Et2O (3 mL). The layers were separated, and the aqueous layer was extracted with Et2O (3 × 5 mL). The combined organic layers were washed with brine, dried (anhyd Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography to produce (syn,syn,syn)-dibenzylidene ent-syn-8 (58 mg) in 63% yield as a clear oil; Rf = 0.26 (4:1 hexanes–EtOAc); [α]D +18.9 (c 0.9, CH2Cl2).

IR (neat): 2920, 2864, 1732, 1614, 1586, 1514, 1455, 1346, 1303, 1248, 1216, 1112, 1028 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 7.49 (m, 4 H), 7.36 (m, 6 H), 7.27 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 2 H), 5.59 (s, 1 H), 5.54 (s, 1 H), 4.50 (d, J = 11.7 Hz, 1 H), 4.44 (d, J = 11.7 Hz, 1 H), 4.35 (dddd, J = 11.1, 6.6, 6.6, 2.1 Hz, 1 H), 4.18 (q, J = 7.2 Hz, 2 H), 4.02–4.18 (m, 3 H), 3.79 (s, 3 H), 3.69 (ddd, J = 9, 8.1, 5.1 Hz, 1 H), 3.60 (ddd, J = 9.6, 5.7, 5.7 Hz, 1 H), 2.76 (dd, J = 15.6, 7.2 Hz, 1 H), 2.54 (dd, J = 15.6, 6 Hz, 1 H), 2.16 (ddd, J = 15.6, 7.2 Hz, 1 H), 1.64–2.00 (m, 5 H), 1.45–1.62 (m, 2 H), 1.28 (t, J = 7.2 Hz, 3 H).

13C NMR (CDCl3, 75 MHz): δ = 170.6, 160.0, 138.6, 138.2, 130.4, 129.2, 128.5, 128.4, 128.0, 128.0, 125.9, 125.9, 113.6, 100.4, 100.3, 73.6, 73.1, 72.9, 72.9, 72.5, 65.5, 60.5, 55.1, 41.6, 40.9, 36.7, 36.2, 36.0, 14.1.

HRMS (ESI): m/z calcd for [C35H42O8 + Na]+: 613.2777; found: 613.2785.


#

(R)-1-((2S,4R,6S)-6-{2-[(4-Methoxybenzyl)oxy]ethyl}-2-phenyl-1,3-dioxan-4-yl)pent-4-en-2-ol (syn-26) and (S)-1-((2S,4R,6S)-6-{2-[(4-Methoxybenzyl)oxy]ethyl}-2-phenyl-1,3-dioxan-4-yl)pent-4-en-2-ol (anti-26)

To a solution of ester 19f in CH2Cl2 (10 mL) at –78 °C was added DIBALH (3.75 mL, 1.0 M solution in CH2Cl2). This solution was allowed to stir for 1 h when allylmagnesium chloride (2.5 mL, 2 M solution in THF) was added to the flask. The reaction was allowed to warm to r.t. and stirred for 3 h, after which MeOH (1 mL) and a 20% sodium potassium tartrate solution (10 mL) were added. This solution was stirred vigorously until the layers separated rapidly upon cessation of stirring. The aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The organic layers were combined and washed with brine and dried (anhyd Na2SO4). Removal of the solvents in vacuo followed by passage through a short pad of silica gel yielded the alcohol (876 mg, 85%) as a clear oil and a mixture of diastereomers.


#

syn-26

Rf = 0.19 (4:1 hexanes–EtOAc); [α]D 21 –19.2 (c 0.92, CH2Cl2).

IR (neat): 3532, 3071, 2918, 1727, 1641, 1614, 1586, 1515, 1455, 1303, 1247, 1174, 1102 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 7.43 (m, 2 H), 7.33 (m, 3 H), 7.26 (d, J = 8.5 Hz, 2 H), 6.87 (d, J = 8.5 Hz, 2 H), 5.85 (dddd, J = 17.5, 10.5, 7, 7 Hz, 1 H), 5.56 (s, 1 H), 5.13 (m, 2 H), 4.47 (d, J = 11.5 Hz, 1 H), 4.43 (d, J = 11.5 Hz, 1 H), 4.12 (dddd, J = 11.5, 8.5, 3.5, 2.5 Hz, 1 H), 4.06 (dddd, J = 11, 8, 4.5, 2.5 Hz, 1 H), 3.98 (dddd, J = 9, 6, 6, 2.5 Hz, 1 H), 3.79 (s, 3 H), 3.66 (ddd, J = 9.5, 8.5, 5 Hz, 1 H), 3.56 (ddd, J = 9.5, 5.5, 5.5 Hz, 1 H), 2.26 (m, 2 H), 1.92 (dddd, J = 14, 8.5, 5.5, 5.5 Hz, 1 H), 1.84 (m, 1 H), 1.79 (ddd, J = 14.5, 9.5, 9.5 Hz, 1 H), 1.70 (ddd, J = 14.5, 3.5, 2.5 Hz, 1 H), 1.62 (ddd, J = 13, 2.5, 2.5 Hz, 1 H), 1.50 (ddd, J = 13.5, 11.5, 11.5 Hz, 1 H).

13C NMR (CDCl3, 125 MHz): δ = 159.2, 138.3, 134.8, 130.5, 129.3, 128.8, 128.2, 126.0, 117.6, 113.8, 100.6, 77.3, 73.9, 72.7, 70.4, 65.5, 55.3, 42.0, 42.0, 37.2, 36.0.

HRMS (ESI): m/z calcd for [C25H32O5 + Na]+: 435.2147; found: 435.2132.


#

anti-26

Rf = 0.19 (4:1 hexanes–EtOAc); [α]D –25.6 (c 1.0, CH2Cl2).

IR (neat): 3446, 3069, 2917, 2861, 1718, 1700, 1684, 1654, 1637, 1613, 1586, 1514, 1456, 1405, 1100, 1028 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 7.44 (m, 2 H), 7.34 (m, 3 H), 7.26 (d, J = 9 Hz, 2 H), 6.87 (d, J = 9 Hz, 2 H), 5.84 (dddd, J = 17.5, 11, 7.5, 7.5 Hz, 1 H), 5.54 (s, 1 H), 5.15 (m, 2 H), 4.47 (d, J = 11.5 Hz, 1 H), 4.43 (d, J = 11.5 Hz, 1 H), 4.17 (m, 1 H), 4.04 (m, 2 H), 3.79 (s, 3 H), 3.67 (ddd, J = 9, 8.5, 5 Hz, 1 H), 3.57 (ddd, J = 9.5, 5.5, 5.5 Hz, 1 H), 2.30 (m, 2 H), 1.93 (dddd, J = 14, 8.5, 5.5, 5.5 Hz, 1 H), 1.84 (m, 1 H), 1.78 (ddd, J = 15, 8.5, 3 Hz, 1 H), 1.69 (ddd, J = 14.5, 9, 3 Hz, 1 H), 1.55 (m, 2 H).

13C NMR (CDCl3, 125 MHz): δ = 159.2, 138.7, 134.8, 130.6, 129.3, 128.6, 128.2, 126.0, 118.0, 113.8, 100.6, 74.2, 73.9, 72.7, 67.0, 65.6, 55.3, 42.3, 42.1, 36.9, 36.1.

HRMS (ESI): m/z calcd for [C25H32O5 + Na]+: 435.2147; found: 435.2132.


#

1-((2S,4S,6S)-6-{2-[(4-Methoxybenzyl)oxy]ethyl}-2-phenyl-1,3-dioxan-4-yl)pent-4-en-2-one (27)

In a 10 mL round bottom flask was placed the alcohol 26 (90 mg) in CH2Cl2 (2 mL). To this solution was added of Dess–Martin periodinane (140 mg, 0.33 mmol). The reaction was stirred for 1.5 h. Et2O was added to the reaction and the solution was filtered through a pad of silica gel, followed by removal of the solvents under reduced pressure. The crude product was purified by silica gel chromatography to produce 80 mg (89% yield) of ketone 27 as a clear oil; [α]D +22.3 (c 1.0, CH2Cl2).

IR (neat): 2922, 1714, 1644, 1614, 1586, 1515, 1455, 1360, 1347, 1245, 1174, 1098, 1028 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 7.42 (m, 2 H), 7.33 (m, 3 H), 7.26 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 2 H), 5.93 (dddd, J = 17.1, 10.2, 7.2, 7.2 Hz, 1 H), 5.54 (s, 1 H), 5.18 (m, 2 H), 4.47 (d, J = 11.7 Hz, 1 H), 4.43 (d, J = 11.7 Hz, 1 H), 4.34 (m, 1 H), 4.06 (dddd, J = 10.5, 7.5, 4.5, 2.7 Hz, 1 H), 3.79 (s, 3 H), 3.66 (ddd, J = 9, 7.8, 5.4 Hz, 1 H), 3.56 (ddd, J = 9.3, 5.7, 5.7 Hz, 1 H), 3.25 (m, 2 H), 2.90 (dd, J = 16.2, 7.2 Hz, 1 H), 2.57 (dd, J = 16.2, 5.7 Hz, 1 H), 1.84 (m, 2 H), 1.70 (ddd, J = 12.9, 2.4, 2.4 Hz, 1 H), 1.40 (ddd, J = 12.9, 11.1, 11.1 Hz, 1 H).

13C NMR (CDCl3, 75 MHz): δ = 206.2, 159.0, 138.3, 130.3, 130.0, 129.1, 128.4, 128.0, 125.8, 119.0, 113.6, 100.3, 73.5, 72.9, 72.5, 65.4, 55.1, 48.7, 48.0, 36.7, 35.9.

HRMS (ESI): m/z calcd for [C25H30O5 + Na]+: 433.1991; found: 433.1997.


#

(R)-1-((2S,4R,6S)-6-{2-[(4-Methoxybenzyl)oxy]ethyl}-2-phenyl-1,3-dioxan-4-yl)pent-4-en-2-ol (syn-26)

From 27 : To a solution of ketone 27 (55 mg, 0.13 mmol) in THF (1.5 mL) at –90 °C was added a 1.0 M solution of L-selectride in THF (0.26 mL, 0.26 mmol). After stirring for 3 h, a solution of 30% H2O2 and aq 1 M NaOH were added and the reaction was allowed to warm to r.t. and diluted with Et2O. The organic layer was separated, washed with sat. aq Na2S2O3 and brine, dried (anhyd Na2SO4), filtered, and concentrated. The crude material was purified by flash chromatography to provide 48 mg (89%) of alcohol 26 as a mixture (4:1) of diastereomers.

From ent-21: To a stirred solution of ent-21 (2.23 g, 6.02 mmol) in CH2Cl2 (20 mL) at –10 °C was added a solution of (S,S)-Leighton reagent (5.01 g, 9.03 mmol) in CH2Cl2 (10 mL) slowly via syringe, followed by Sc(OTf)3 (74.1 mg, 0.151 mmol) under N2. Then the resulting mixture was transferred to a freezer at –10 °C. After 12 h, the reaction was quenched by adding aq 1 N HCl (20 mL). The formed solid was filtered through a fritted funnel, and the filtrate was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried (anhyd Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (10 to 30% EtOAc in hexanes) on silica gel (50 mL) to afford syn-26 (1.79 g, 72%, dr = 8.7:1.0) as a colorless oil.


#

(S)-1-((2S,4R,6S)-6-{2-[(4-Methoxybenzyl)oxy]ethyl}-2-phenyl-1,3-dioxan-4-yl)pent-4-en-2-ol (anti-26)

To a stirred solution of ent-21 (1.10 g, 3.0 mmol) in CH2Cl2 (10 mL) at –10 °C was added a solution of (R,R)-Leighton reagent (2.50 g, 4.51 mmol) in CH2Cl2 (5 mL) slowly via syringe, followed by Sc(OTf)3 (37 mg, 0.075 mmol) under N2. Then the resulting mixture was transferred to freezer at –10 °C. After 12 h, the reaction was quenched by adding aq 1 N HCl (10 mL). The formed solid was filtered through a fritted funnel, and the filtrate was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with brine, dried (anhyd Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (10 to 30% EtOAc in hexanes) on silica gel (50 mL) to afford anti-26 (1.79 g, 72%, dr = 8:1) as a colorless oil.


#

Ethyl (S,E)-5-Hydroxy-6-((2S,4R,6S)-6-{2-[(4-methoxybenzyl)oxy]ethyl}-2-phenyl-1,3-dioxan-4-yl)hex-2-enoate (ent-anti-24)

To a stirred solution of anti-26 (2.95 g, 7.15 mmol) in CH2Cl2 (10 mL) at r.t. was added ethyl acrylate (30.4 mL, 0.286 mol), followed by the Grubbs second-generation catalyst (146 mg, 0.179 mmol) under N2. The resulting mixture was degassed by two freeze-pump-thaw cycles, then warmed to r.t. and stirred at the same temperature. After 3 h, the mixture was diluted with hexanes (100 mL), and purified by flash chromatography (20 to 50% EtOAc in hexanes) on silica gel (100 mL) to afford anti-29 (3.43 g, 99%) as a colorless oil; Rf = 0.34 (50% EtOAc in hexanes); [α]D 21 –15.6 (c 1.79, CH2Cl2).

IR (neat): 3501, 3037, 2917, 1888, 1715, 1698, 1652, 1614, 1586, 1515, 1456, 1246 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 7.42 (m, 2 H), 7.34 (m, 3 H), 7.26 (d, J = 8.7 Hz, 2 H), 6.98 (ddd, J = 15.6, 7.2, 7.2 Hz, 1 H), 6.86 (d, J = 8.7 Hz, 2 H), 5.91 (ddd, J = 15.6, 1.5, 1.5 Hz, 1 H), 5.52 (s, 1 H), 4.47 (d, J = 11.7 Hz, 1 H), 4.42 (d, J = 11.7 Hz, 1 H), 4.18 (q, J = 7.2 Hz, 2 H), 4.17 (m, 2 H), 4.05 (m, 1 H), 3.78 (s, 3 H), 3.65 (ddd, J = 9.3, 8.1, 5.4 Hz, 1 H), 3.56 (ddd, J = 9.6, 5.4, 5.4 Hz, 1 H), 2.40 (m, 2 H), 1.80–1.98 (m, 2 H), 1.72–1.78 (m, 2 H), 1.55 (m, 2 H), 1.28 (t, J = 7.2 Hz, 3 H).

13C NMR (CDCl3, 75 MHz): δ = 166.1, 159.0, 144.9, 138.4, 130.3, 129.1, 128.5, 128.0, 125.8, 123.7, 113.6, 100.4, 73.9, 73.7, 72.5, 66.7, 65.4, 60.2, 55.1, 41.9, 40.3, 36.5, 35.9, 14.2.

HRMS (ESI): m/z calcd for [C28H36O7 + Na]+: 507.2359; found: 507.2329.


#

Ethyl 2-{(2R,4R,6R)-6-[((2S,4S,6S)-6-{2-[(4-Methoxybenzyl)oxy]ethyl}-2-phenyl-1,3-dioxan-4-yl)methyl]-2-phenyl-1,3-dioxan-4-yl}acetate (anti-8)

To a stirred solution of ent-anti-24 (0.75 g, 1.6 mmol) in THF (30 mL) at 0 °C was added benzaldehyde (0.18 mL, 1.75 mmol), followed by KOt-Bu (0.02g, 0.175 mmol) under N2. The resulting mixture was stirred for 15 min. Then the addition of benzaldehyde/KOt-Bu was repeated 3 more times. The mixture was passed through a pad of silica gel, and the silica gel was washed with EtOAc (100 mL). The filtrate was concentrated, and the crude residue was purified by flash chromatography (5 to 40% EtOAc in hexanes) on silica gel to afford anti-8 (0.72 g, 77%) as a colorless oil; Rf = 0.41 (30% EtOAc in hexanes); [α]D 21 –18.0 (c = 1.72, CH2Cl2).

IR (neat): 2918, 2859, 1732, 1512, 1247, 1107, 1010 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.57–7.41 (m, 4 H), 7.43–7.28 (m, 6 H), 7.26 (d, J = 9.0 Hz, 2 H), 6.86 (d, J = 9.0 Hz, 2 H), 5.58 (s, 1 H), 5.53 (s, 1 H), 4.45 (d, J = 11.6 Hz, 1 H), 4.43 (d, J = 11.5 Hz, 2 H), 4.34 (dddd, J = 11.5, 7.0, 7.0, 2.5 Hz, 1 H), 4.17 (q, J = 7.0 Hz, 2 H), 4.13 (m, 3 H), 3.78 (s, 3 H), 3.68 (ddd, J = 8.5, 8.5, 5.0 Hz, 1 H), 3.58 (ddd, J = 9.5, 5.5, 5.5 Hz, 1 H), 2.74 (dd, J = 15.5, 7.0 Hz, 1 H), 2.53 (dd, J = 15.5, 6.0 Hz, 1 H), 2.15 (ddd, J = 14.0, 7.0, 7.0 Hz, 1 H), 1.93 (dddd, J = 14.0, 8.0, 5.0, 5.0 Hz, 1 H), 1.86 (dddd, J = 14.0, 8.0, 5.5, 4.5 Hz, 1 H), 1.81 (ddd, J = 13.0, 2.5, 2.5 Hz, 1 H), 1.76 (ddd, J = 14.0, 6.0, 6.0 Hz, 1 H), 1.68 (ddd, J = 13.0, 2.5, 2.5 Hz, 1 H), 1.55 (ddd, J = 13.0, 11.5, 11.5 Hz, 1 H), 1.51 (ddd, J = 13.0, 11.5, 11.5 Hz, 1 H), 1.27 (t, J = 7.2, 3 H).

13C NMR (100 MHz, CDCl3): δ = 171.0, 159.4, 139.0, 138.6, 130.7, 129.6, 129.0, 128.9, 128.41, 128.38, 126.29, 126.26, 114.0, 100.8, 100.7, 74.0, 73.5, 73.27, 72.20, 72.9, 65.9, 60.9, 55.5, 41.9, 41.2, 37.1, 36.6, 36.4, 14.5.

HRMS (ESI): m/z [M + Na]+ calcd for C35H42O8Na: 613.2777; found: 613.2785.


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Acknowledgment

We are grateful to NIH (GM090259) and NSF (CHE-1213596) for financial support of this research.

Supporting Information

    Supporting information for this article is available online at http://dx.doi.org.accesdistant.sorbonne-universite.fr/10.1055/s-0035-1561607.
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Figure 1 Cryptocaryol A and B
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Scheme 1 Retrosynthetic analysis of cryptocaryol A and B
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Scheme 2 Asymmetric hydration route to syn-1,3-diol
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Scheme 3 Iterative oxidation/reduction approach to syn-1,3-polyols. Reagents and conditions: a) DIBALH, CH2Cl2, –78 °C, 93%; b) LiOH·H2O, phosphonate 25, 4 Å molecular sieves, THF, 66%; c) OsO4 (1 mol%), (DHQD)2PHAL (1.1 mol%), K3FeCN6, MeSO2NH2, 71%; d) (Cl3CO)2CO, pyridine, CH2Cl2, 90%; e) Pd2(dba)3·CHCl3 (1 mol%), PPh3 (2.5 mol%), HCO2H/Et3N, THF, 66 °C, 90%; f) PhCHO (1.1 equiv), KOt-Bu (0.11 equiv), 3 times, THF, 0 °C, 63%.
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Scheme 4 Second-generation approach to protected 1,3-syn-polyol. Reagents and conditions: a) DIBALH, CH2Cl2, –78 °C, 1 h, then allyMgCl (2 M THF solution), r.t., 91%; b) DMP, CH2Cl2, 90%; c) L-Selectride, –90 °C, 89%, dr = 4:1; d) ethyl acrylate, Grubbs II cat. (2.5 mol%), CH2Cl2, 99%; e) PhCHO (1.1 equiv), KOt-Bu (0.11 equiv), 3 times, THF, 0 °C, 77%.
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Scheme 5 Synthesis of protected syn- and anti-1,3-polyols. Reagents and conditions: a) DIBALH, CH2Cl2, –78 °C, 93%; b) (S,S)-29, Sc(OTf)3 (2.5 mol%), CH2Cl2, –10 °C, 72%; c) ethyl acrylate, Grubbs II (2.5 mol%), 99%; d) PhCHO (1 equiv), KOt-Bu (0.11 equiv), 3 times, THF, 0 °C, 77%; e) (R,R)-29, Sc(OTf)3 (2.5 mol%), CH2Cl2, –10 °C, 72%; f) ethyl acrylate, Grubbs II cat. (2.5 mol%), 99%; g) PhCHO (1.1 equiv), KOt-Bu (0.11 equiv), 3 times, THF, 0 °C, 77%.
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Scheme 6 Synthesis of protected tetraol intermediates
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Scheme 7 Synthesis of 1,3-syn-ploly/pyranones